Warlow’s Stroke To Strong and Angela: for your unwavering support; and to Tim, Gem, Tess, and Stella: for being behind everything I do. Fan Z. Caprio

To Prof. Charles Warlow who inspired me and many others to become a stroke trialist and to my wife, Vidula Verma, who has tolerated being married to one. Christopher Chen

To my late father, Harold L. Gorelick, for his innovative spirit, common sense, life accomplishments, and love of family. Philip B. Gorelick

To the patients, teachers and colleagues who taught me everything I know; and to Lindsay, Calum and Magnus, for their support and forebearance. Malcolm Macleod

To Prof. Charles Warlow, who is not only a great neurologist, but also a great sailor. Heinrich Mattle Warlow’s Stroke Practical Management

Fourth Edition

Edited by Graeme J. Hankey MBBS, MD, FRACP, FRCPE, FAHA, FESO, FAAHMS Professor of Neurology, Medical School, The University of Western Australia, Perth, Australia Consultant Neurologist, Sir Charles Gairdner Hospital, Perth, Western Australia Malcolm Macleod BSc(Hons), MBChB, PhD, FRCP Professor of Neurology and Translational Neurosciences at the University of Edinburgh, and Honorary Consultant Neurologist and Head of Neurology, NHS Forth Valley, UK Philip B. Gorelick MD, MPH, FACP, FAHA, FAAN, FANA Professor Translational Science and Molecular Medicine at Michigan State University, Grand Rapids, MI, USA Adjunct Professor, Davee Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, USA International Fellow, Population Health Research Institute affiliated with McMaster University Faculty of Health Sciences and Hamilton Health Sciences, Hamilton, ON, Canada Professor Emeritus, Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago, IL, USA Christopher Chen BA, BMBCh, FRCP Director, Memory Aging & Cognition Centre, National University Health System, Singapore Associate Professor, Department of Pharmacology, National University of Singapore, Singapore Senior Consultant Neurologist, Department of Psychological Medicine, National University Hospital, Singapore Fan Z. Caprio MD Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Heinrich Mattle MD, FRCPE, FAHA, FESO Professor, Senior Consultant, Department of Neurology, University of Bern, Bern, Switzerland This edition first published 2019 © 2019 by John Wiley & Sons Ltd

Edition History 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 (3e, 2007)

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Library of Congress Cataloging‐in‐Publication Data Names: Hankey, Graeme J., editor. Title: Warlow’s stroke : practical management / edited by Graeme Hankey, Malcolm Macleod, Philip Gorelick, Christopher Chen, Fan Caprio, Heinrich Mattle. Other titles: Stroke (Warlow) | Stroke Description: Fourth edition. | Hoboken, NJ : Wiley-Blackwell, 2019. | Preceded by Stroke / C. Warlow … [et al.]. 3rd ed. c2008. | Includes bibliographical references and index. | Identifiers: LCCN 2018039802 (print) | LCCN 2018040801 (ebook) | ISBN 9781118492420 (Adobe PDF) | ISBN 9781118492413 (ePub) | ISBN 9781118492222 (hardcover) Subjects: | MESH: Stroke–therapy | Intracranial Hemorrhages–therapy | Ischemic Attack, Transient–therapy Classification: LCC RC388.5 (ebook) | LCC RC388.5 (print) | NLM WL 356 | DDC 616.8/1–dc23 LC record available at https://lccn.loc.gov/2018039802 Cover images: MR images of a 66-year-old woman with an acute stroke because of a proximal middle cerebral artery occlusion on the right, visible on the MR angiogram (right). The diffusion-weighted image (left) shows the core of the infarct and the perfusion-weighted image (center) shows the perfusion deficit. The perfusion deficit is much larger than the core of the infarct and demonstrates a large volume of brain tissue that was salvaged with successful reperfusion. Images courtesy of Professor Jan Gralla, Department of Diagnostic and Interventional Neuroradiology, University of Bern, Inselspital, Bern, Switzerland. Cover design by Wiley

Set in 10/12 pt Warnock by SPi Global, Pondicherry, India

10 9 8 7 6 5 4 3 2 1 v

Contents

Contributors vii Acknowledgments xi Abbreviations xiii

1 Introduction 1

2 Development of knowledge about cerebrovascular disease 7 Jan van Gijn

3 Is it a vascular event and where is the lesion? 37 Simon Jung and Heinrich P. Mattle

4 Which arterial territory is involved? 129 John C.M. Brust

5 What is the role of imaging in acute stroke? 171

5A Neuroimaging 172 Marwan El‐Koussy

5B Ultrasound of the extra‐ and intracranial arteries 224 Georgios Tsivgoulis and Apostolos Safouris

5C Cardioembolic stroke 241 Issam Mikati and Zeina Ibrahim

6 What caused this transient or persisting ischemic event? 267 Fernando D. Testai

7 Unusual causes of ischemic stroke and transient ischemic attack 345 Fan Z. Caprio and Chen Lin

8 What caused this intracerebral hemorrhage? 399 Farid Radmanesh and Jonathan Rosand

9 What caused this subarachnoid hemorrhage? 437 Matthew B. Maas and Andrew M. Naidech

10 A practical approach to the management of stroke and transient ischemic attack 455 H. Bart van der Worp and Martin Dennis

11 What are this patient’s problems? A problem‐based approach to the general management of stroke 481 Yannie Soo, Howan Leung, and Lawrence Ka Sing Wong vi Contents

12 Have the patient’s cognitive abilities been affected? 579 Leonardo Pantoni

13 Specific treatment of acute ischemic stroke 587 Eivind Berge and Peter Sandercock

14 Specific treatment of intracerebral hemorrhage 657 Shoichiro Sato and Craig S. Anderson

15 Specific treatment of aneurysmal subarachnoid hemorrhage 679 Gregory Arnone and Sepideh Amin‐Hanjani

16 Specific interventions to prevent intracranial hemorrhage 723 Preston W. Douglas, Clio A. Rubińos, and Sean Ruland

17 Preventing recurrent stroke and other serious vascular events 745 Cathra Halabi, Rene Colorado, and Karl Meisel

18 Rehabilitation after stroke: evidence, practice, and new directions 867 Coralie English, Audrey Bowen, Debbie Hébert, and Julie Bernhardt

19 The organization of stroke services 879 Peter Langhorne, Jeyaraj Durai Pandian, and Cynthia Felix

20 Reducing the impact of stroke and improving public health 933 Graeme J. Hankey and Philip B. Gorelick

Index 953

Color plate section is found facing page 304 vii

Contributors

Sepideh Amin‐Hanjani, MD, FAANS, FACS, FAHA Fan Z. Caprio, MD Professor and Residency Program Director Assistant Professor of Neurology Co‐Director, Neurovascular Surgery Division of Stroke and Neurocritical Care Department of Neurosurgery, Ken and Ruth Davee Department of Neurology University of Illinois at Chicago Northwestern University Feinberg School of Medicine Chicago, IL, USA Chicago, IL, USA

Craig S. Anderson, MD, PhD, FRACP Rene Colorado, MD, PhD Neurological and Mental Health Division, The George Medical Director, Stroke Center, Salinas Valley Institute for Global Health Australia Sydney, Australia Memorial Healthcare System The George Institute for Global Health China, Peking Salinas, CA, USA University Health Sciences Center Beijing, P.R. China Adjunct Instructor, Department of Neurology Division of Medicine, University of New South Wales University of California, San Francisco Sydney, Australia San Francisco, CA, USA Neurology Department, Royal Prince Alfred Hospital Sydney, Australia Martin Dennis, MD, MB, BS, MRCP, FRCPE, FESO Gregory Arnone, MD Chair of Stroke Medicine, Centre for Clinical Brain Neurosurgery Resident, Sciences, Stroke Research Group, University of Department of Neurosurgery Edinburgh, Edinburgh, UK University of Illinois at Chicago Chicago, IL, USA Preston W. Douglas, MD Department of Neurology, Loyola University Eivind Berge, MD, PhD, RCPE, FESO Chicago‐Stritch School of Medicine, Maywood, Senior consultant, Department of Internal Medicine, IL, USA Oslo University Hospital, Oslo, Norway Professor, Institute of Clinical Medicine, Marwan El‐Koussy, MD University of Tromsø, Tromsø, Norway Neuroradiology Consultant, Staff Member Institute for Diagnostic and Interventional Julie Bernhardt, PhD Neuroradiology Professor, The Florey Institute of Neuroscience and University Hospital Bern (Inselspital) Mental Health, University of Melbourne, Melbourne, Bern, Switzerland Australia

Audrey Bowen, MSc, PhD, AFBPsS, CPsychol Coralie English, PhD Division of Neuroscience and Experimental Psychology, Associate Professor Physiotherapy, School of Health School of Biological Sciences, University of Manchester Sciences, University of Newcastle, Callaghan, NSW, MAHSC, UK Australia

John C.M. Brust, MD Cynthia Felix, MD, PGDGM Professor of Neurology Head of Geriatric Medicine Columbia University College of Physicians & Surgeons Welcare Hospital New York, NY, USA Kochi, Kerala, India viii Contributors

Philip B. Gorelick, MD, MPH, FACP, FAHA, FAAN, FANA Howan Leung, MD Professor Translational Science and Molecular Division of Neurology, Department of Medicine and Medicine at Michigan State University, Grand Rapids, Therapeutics MI, USA Prince of Wales Hospital Adjunct Professor, Davee Department of Neurology, The Chinese University of Hong Kong Northwestern Feinberg School of Medicine, Chicago, Hong Kong IL, USA International Fellow, Population Health Research Chen Lin, MD Institute affiliated with McMaster University Faculty Vascular Neurology Fellow and NIH StrokeNet of Health Sciences and Hamilton Health Sciences, Research Fellow Hamilton, ON, Canada Division of Stroke and Neurocritical Care, Ken and Professor Emeritus, Department of Neurology Ruth Davee Department of Neurology, and Rehabilitation, University of Illinois College of Northwestern University Feinberg School of Medicine Medicine, Chicago, IL, USA Chicago, IL, USA

Cathra Halabi, MD Matthew B. Maas, MD, MS Assistant Clinical Professor of Neurology Department of Neurology Director, Neurorecovery Clinic Northwestern University Division of Neurovascular, Department of Neurology Chicago, IL, USA University of California, San Francisco Heinrich P. Mattle, MD San Francisco, CA, USA Professor Graeme J. Hankey, MBBS, MD, FRACP, FRCP, FRCPE, FAHA, Department of Neurology FESO, FAAHMS University Hospital of Bern, Inselspital Bern, Switzerland Professor of Neurology, Medical School, The University of Western Australia, Perth, Australia Karl Meisel, MD, MA Consultant Neurologist, Sir Charles Gairdner Hospital, Assistant Professor of Neurology Perth, Western Australia Director, Outpatient Stroke Clinic Division of Neurovascular, Department of Neurology Debbie Hébert, BSc (OT), MSc (Kin), OT Reg. (Ont) University of California, San Francisco Associate Professor, Department of Occupational San Francisco, CA, USA Science and Occupational Therapy, University of Toronto, ON, Canada Issam Mikati, MD, FASE, FACC Practice Lead (Occupational Therapy) and Clinic Lead Associate Director, Northwestern Memorial Hospital for the Rocket Family Upper Extremity Clinic, Toronto Echocardiography Lab Rehabilitation Institute, Toronto, ON, Canada Professor of Medicine and Radiology: Division of Cardiology, Department of Internal Medicine and Zeina Ibrahim Radiology, Feinberg School of Medicine Advanced Imaging Cardiologist Chicago, IL, USA Department of Medicine, Division of Cardiology Mount Sinai Hospital Andrew M. Naidech, MD, MSPH Chicago, IL, USA Department of Neurology Northwestern University Simon Jung, MD Chicago, IL, USA Associate Professor Department of Neurology Jeyaraj Durai Pandian, MD, DM, FRACP, FRCP, FESO University Hospital of Bern, Inselspital Professor and Head, Department of Neurology, Bern, Switzerland Christian Medical College Ludhiana, Punjab, India Peter Langhorne, MBChB, PhD, FRCP Professor of Stroke Care Leonardo Pantoni, MD, PhD Institute of Cardiovascular and Medical Sciences, “Luigi Sacco” Department of Biomedical and Clinical University of Glasgow, UK Sciences, University of Milan, Milano, Italy Contributors ix

Farid Radmanesh Yannie Soo, MBChB MRCP(Lond), FHKCP, FHKAM(Medicine) Division of Neurocritical Care and Emergency Neurology Division of Neurology, Department of Medicine and Center for Genomic Medicine Therapeutics, Prince of Wales Hospital Massachusetts General Hospital, Boston, MA, USA The Chinese University of Hong Kong, Hong Kong

Jonathan Rosand Fernando D. Testai, MD, PhD, FAHA Henry and Allison McCance Center for Brain Health Associate Professor of Neurology Division of Neurocritical Care and Emergency Neurology Vascular Neurology Section Head Center for Genomic Medicine Department of Neurology and Rehabilitation Massachusetts General Hospital, Boston, MA, USA University of Illinois at Chicago Medical Center Program in Medical and Population Genetics Chicago, IL, USA Broad Institute, Cambridge, MA, USA Georgios Tsivgoulis, MD Clio A. Rubińos, MD Second Department of Neurology, National & Department of Neurology, Loyola University Kapodistrian University of Athens, School of Chicago‐Stritch School of Medicine, Maywood, Medicine, “Attikon” University Hospital, Athens, Greece IL, USA Department of Neurology, University of Tennessee HealthScience Center, Memphis, TN, USA Sean Ruland, DO Professor H. Bart van der Worp, MD, PhD Medical Director Neuroscience Intensive Care Unit Department of Neurology and Neurosurgery, Quality Medical Director, Neuroscience Service Line Brain Center Rudolf Magnus, University Medical Department of Neurology Center Utrecht, The Netherlands Loyola University Chicago‐Stritch School of Medicine Maywood, IL, USA Jan van Gijn, FRCP, FRCP(Edin) Emeritus Professor of Neurology Apostolos Safouris, MD University of Utrecht, The Netherlands Second Department of Neurology, National & Kapodistrian University of Athens, School of Medicine, Lawrence Ka Sing Wong, MBBS, MHA, MD, MRCP, “Attikon” University Hospital, Athens, Greece FRCP(Lond), FHKAM(Medicine) Stroke Unit, Metropolitan Hospital, Pireaus, Greece Division of Neurology, Department of Medicine and Therapeutics Peter Sandercock, DM Prince of Wales Hospital Emeritus Professor of Medical Neurology, Centre The Chinese University of Hong Kong for Clinical Brain Sciences, University of Edinburgh, Hong Kong Edinburgh, UK

Shoichiro Sato, MD, PhD Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center Osaka, Japan Neurological and Mental Health Division, The George Institute for Global Health Australia, Sydney, Australia

xi

Acknowledgments

We are grateful to the authors for their work updating, inspired and taught us; and our students who keep asking revising, and providing new chapters. questions. We thank the team at Wiley Blackwell for their contri- This textbook is the legacy of Charles Warlow, Jan Van bution to this project, and Gill Whitley for her dedicated Gijn, Peter Sandercock, John Bamford, Martin Dennis, assistance. Graeme Hankey, Joanna Wardlaw, Peter Langhorne, We also thank our families for their understanding Cathie Sudlow, Gabriel Rinkel, and Peter Rothwell who and support; our patients, colleagues and mentors who coauthored its earlier editions.

xiii

­Abbreviations

We don’t care much for abbreviations. They are not liter- However, we will avoid them as far as we can in tables, ate (Oliver Twist was not abbreviated to OT each time figures and the practice points. We will try to define any Dickens mentioned his name!), they don’t look good on abbreviations the first time they are used in each chapter, the printed page, and they make things more difficult to or even in each section if they are not very familiar. But, read and understand, particularly for non‐experts. But if we fail to be comprehensible, then here is a rather long they do save space and so we have to use them a bit. list to refer to.

ACA Anterior cerebral artery BIH Benign intracranial hypertension ACE Angiotensin‐converting enzyme BMI Body mass index AChA Anterior choroidal artery BOLD Blood oxygenation level‐dependent ACoA Anterior communicating artery BP Blood pressure ACS Acute coronary syndrome C Celsius ACST Asymptomatic Carotid Surgery Trial CAA Cerebral amyloid angiopathy ADC Apparent diffusion coefficient CADASIL Cerebral autosomal dominant ADH Antidiuretic hormone arteriopathy with subcortical infarcts and ADL Activities of daily living leukoencephalopathy ADP Adenosine diphosphate CARASAL Cathepsin A related arteriopathy with ADPKD Autosomal dominant polycystic kidney disease strokes and leukoencephalopathy AF Atrial fibrillation CARASIL Cerebral autosomal recessive arteriopathy AFx Amaurosis fugax with subcortical infarcts and AH Ataxic hemiparesis leukoencephalopathy AICA Anterior inferior cerebellar artery CAST Chinese Acute Stroke Trial AIDS Acquired immune deficiency syndrome CAVATAS Carotid and Vertebral Artery AION Anterior ischemic optic neuropathy Transluminal Angioplasty Study AMI Acute myocardial infarction CBF Cerebral blood flow ANCA Antineutrophil cytoplasmic antibody CBFV Cerebral blood flow velocity ANF Antinuclear factor CBV Cerebral blood volume APS Antiphospholipid syndrome CCA Common carotid artery APT Antiplatelet Trialists’ Collaboration CDU Carotid duplex APTT Activated partial thromboplastin time CEA Carotid endarterectomy ARAS Ascending reticular activating system CE‐MRA Contrast‐enhanced MR angiography ARB Angiotensin II receptor (AT1) blockers CHD Coronary heart disease ARD Absolute risk difference CI Confidence interval ASA Atrial septal aneurysm CJD Creutzfeldt–Jakob disease ASD Atrial septal defect CK Creatine kinase ATIII Antithrombin III CMB Cerebral microbleed ATP Adenosine triphosphate CMRO2 Cerebral metabolic rate of oxygen ATT Antithrombotic Trialists’ Collaboration CMRglu Cerebral metabolic rate of glucose AVF Arteriovenous fistula CNS Central nervous system AVM Arteriovenous malformation COX 2 Cyclo‐oxygenase 2 inhibitors BA Basilar artery CPP Cerebral perfusion pressure BAD Branch atheromatous plaque disease CPSP Central post‐stroke pain xiv ­Abbreviations

CSF Cerebrospinal fluid IAA Internal auditory artery CT Computed tomography IAA Intra‐arterial angiography CTA Computed tomography angiography IAT Intra‐arterial treatment CTP Cerebral perfusion imaging with CT IC Infarct core CTP Computed tomography perfusion ICA Internal carotid artery CVR Cerebrovascular resistance ICH Intracerebral hemorrhage CVST Cerebral venous sinus thrombosis ICIDH International Classification of Impairments, DALY Disability‐adjusted life year Disabilities and Handicaps DAVF Dural arteriovenous fistula ICP Intracranial pressure DBP Diastolic blood pressure ICVT Intracranial venous thrombosis DCHS Dysarthria clumsy‐hand syndrome IADSA Intra‐arterial digital subtraction DIC Disseminated intravascular coagulation angiography DNA Deoxyribose nucleic acid INR International normalized ratio DOAC Direct oral anticoagulants IST International Stroke Trial DPM Diffusion‐perfusion mismatch IVDSA Intravenous digital subtraction angiography DSA Digital subtraction angiography IVIG Intravenous immunoglobulins DSC Dynamic susceptibility contrast IVIM Intravoxel incoherent motion DSM Diagnostic and statistical manual of mental IVM Intracranial vascular malformation disorders kPa Kilopascals DVT Deep venous thrombosis (in the legs or L Litre pelvis) LAA Left atrial appendage DWI Diffusion‐weighted (MR) imaging LACI Lacunar infarction EACA Epsilon‐aminocaproic acid LACS Lacunar syndrome EADL Extended activities of daily living LGN Lateral geniculate nucleus EAFT European Atrial Fibrillation Trial LP Lumbar puncture ECA External carotid artery LSA Lenticulostriate artery ECASS European Cooperative Acute Stroke Study M Molar ECG Electrocardiogram MAC Mitral annular calcification EC‐IC Extracranial–intracranial MAOI Monoamine oxidase inhibitor ECST European Carotid Surgery Trial MAST‐I Multicentre Acute Stroke Trial – Italy EEG Electroencephalogram MCA Middle cerebral artery EMG Electromyography MCTT Mean cerebral transit time ESR Erythrocyte sedimentation rate MELAS Mitochondrial encephalopathy, lactic FAST Face‐Arm‐Speech Test acidosis, and stroke‐like episodes FAT‐SAT Fat saturation sequences MES Microembolic signals FDA Food and Drug Administration MFV Mean flow velocities FIM Functional Independence Measure MI Myocardial infarction FLAIR Fluid attenuated inversion recovery MLF Medial longitudinal fasciculus FMD Fibromuscular dysplasia MLP Mitral leaflet prolapse fMRI Functional magnetic resonance imaging MMSE Mini mental state examination FMZ Flumazenil MND Motor neuron disease GCS Glasgow Coma Scale MR Magnetic resonance GEF Glucose extraction fraction MRA Magnetic resonance angiography GKI Glucose, potassium and insulin MRC Medical Research Council GRE Gradient‐recalled echo MRI Magnetic resonance imaging HACP Homolateral ataxia and crural paresis MRS Magnetic resonance spectroscopy Hg Mercury MRV Magnetic resonance venogram HI Hemorrhagic infarction MTT Mean transit time HIT Heparin‐induced thrombocytopenia NAA N‐acetyl aspartate HITS High intensity transient signals NASCET North American Symptomatic Carotid HIV Human immunodeficiency virus Endarterectomy Trial HMPAO Hexamethylpropyleneamine oxime NCCT Noncontrast CT HTI Hemorrhagic transformation of an infarct NELH National Electronic Library for Health HU Hounsfield units NG Nasogastric ­Abbreviations xv

NIHSS National Institutes of Health Stroke Score RR Relative risk NINDS National Institute of Neurological Disorders RRR Relative risk reduction and Stroke rtPA Recombinant tissue plasminogen activator NIRS Near infrared spectroscopy SADS Schedule for affective disorders and NNT Number‐needed‐to‐treat schizophrenia NO Nitric oxide SAH Subarachnoid hemorrhage NSAID Nonsteroidal anti‐inflammatory drug SBP Systolic blood pressure OA Ophthalmic artery SCA Superior cerebellar artery OCSP Oxfordshire Community Stroke Project SD Standard deviation OCP Oral contraceptive SDH Subdural hematoma OEF Oxygen extraction fraction SEPIVAC Studio epidemiologico sulla incidenza OHS Oxford Handicap Scale delle vasculopatie acute cerebrali OR Odds ratio SF36 Short form 36 PACI Partial anterior circulation infarction SIADH Syndrome of inappropriate secretion of PaCO2 Arterial partial pressure of carbon dioxide antidiuretic hormone PaO2 Arterial partial pressure of oxygen SK Streptokinase PACS Partial anterior circulation syndrome SLE Systemic lupus erythematosus PCA Posterior cerebral artery SMS Sensorimotor stroke PCC Prothrombin complex concentrate SPAF Stroke prevention in atrial fibrillation (trial) PChA Posterior choroidal artery SPECT Single‐photon emission computed PCoA Posterior communicating artery tomography PCV Packed cell volume STA Superior temporal artery PD Proton density SVD Small‐vessel disease PE Pulmonary embolism SWI Susceptibility‐weighted imaging PEG Percutaneous endoscopic gastrostomy TACI Total anterior circulation infarction PET Positron emission tomography TACS Total anterior circulation syndrome PFE Papillary fibroelastomas TCCD Transcranial color‐coded duplex PFO Patent foramen ovale sonography PH Parenchymatous hematoma TCD Transcranial Doppler PICA Posterior inferior cerebellar artery TEA Tranexamic acid PMS Pure motor stroke TEE Transesophageal echocardiography PNH Paroxysmal nocturnal hemoglobinuria TENS Transcutaneous electrical nerve POCI Posterior circulation infarction stimulation POCS Posterior circulation syndrome TGA Transient global amnesia PRES Posterior reversible encephalopathy syndrome TIA Transient ischemic attack PSE Present state examination TIBI Thrombolysis in brain ischemia PSS Pure sensory stroke Tmax Time to maximum PT Prothrombin time TMB Transient monocular blindness PTA Percutaneous transluminal angioplasty tPA Tissue plasminogen activator PVD Peripheral vascular disease TOAST Trial of ORG 10172 in Acute Stroke PWI Perfusion weighted (MR) imaging Therapy QALYs Quality‐adjusted life years TOF‐MRA Time‐of‐flight MRA QSM Quantitative susceptibility mapping TTE Transthoracic echocardiography RAH Recurrent artery of Heubner TTP Thrombotic thrombocytopenic purpura RCT Randomized controlled trial TTP Time to peak RCVS Reversible cerebral vasoconstriction US Ultrasound syndrome VA Vertebral artery RIND Reversible ischemic neurological deficit VB Vertebrobasilar RLS Right‐to‐left shunt VMR Vasomotor reactivity RNA Ribonucleic acid WHO World Health Organization ROR Relative odds reduction WFNS World Federation of Neurological Surgeons

1

1

Introduction

CHAPTER MENU

1.1 Introduction to the first edition, 1 1.2 Introduction to the second edition, 3 1.3 Introduction to the third edition, 4 1.4 Introduction to the fourth edition, 5

1.1 Introduction to the first edition ­problems – so they are used when they are needed, and not discussed in isolation. For example, to prevent strokes 1.1.1 Aims and scope of the book one needs to know how frequent they are (­epidemiology), what types of stroke there are (pathology),­ what causes We, the authors of this book, regard ourselves as them (aetiology) and what evidence there is to support ­practising – and practical – doctors who look after therapeutic intervention (randomized­ controlled trials). stroke patients in very routine day‐to‐day practice. The Clinicians mostly operate on a need‐to‐know basis, and book is for people like us: neurologists, geriatricians, so when a problem arises they need the information to stroke physicians, radiologists and general internal solve it at that moment, from inside their head, from a physicians. But it is not just for doctors. It is also for colleague – and we hope from a book like this. nurses, therapists, managers and anyone else who wants practical guidance about all and any of the prob- 1.1.2 General principles lems to do with stroke – from aetiology to organization of services, from prevention to occupational therapy, To solve a problem one obviously needs relevant infor- and from any facet of cure to any facet of care. In other mation. Clinicians, and others, should not be making words, it is for anyone who has to deal with stroke decisions based on whim, dogma or the last case, in clinical practice. It is not a book for armchair although most do, at least some of the time – ourselves ­theoreticians, who usually have no sense of proportion included. It is better to search out the reliable informa- as well as difficulty in seeing the wood from the trees. tion based on some reasonable criterion for what is Or, maybe, it is particularly for them so that they can meant by reliable, get it into a sensible order, review be led back into the real world. it and make a summary that can be used at the bedside. The book takes what is known as a problem‐orientated If one does not have the time to do this – and who does approach. The problems posed by stroke patients are dis- for every problem? – then one has to search out someone cussed in the sort of order that they are likely to present else’s systematic review. Or find the answer in this book. themselves. Is it a stroke? What sort of stroke is it? What Good clinicians have always done all this intuitively, caused it? What can be done about it? How can the although recently the process has been blessed with patient and carer be supported in the short term and the title of ‘evidence‐based medicine’, and now even long term? How can any recurrence be prevented? How ‘­evidence‐based patient‐focused medicine’! In this book can stroke services be better organized? Unlike tradi- we have used the evidence‐based approach, at least tional textbooks, which linger on dusty shelves, there are where it is possible to do so. Therefore, where a system- no ‘‐ology’ chapters. Aetiology, epidemiology, pathology atic review of a risk factor or a treatment is available we and the rest represent just the tools to solve the have cited it, and not just emphasized single studies done

Warlow’s Stroke: Practical Management, Fourth Edition. Edited by Graeme J. Hankey, Malcolm Macleod, Philip B. Gorelick, Christopher Chen, Fan Z. Caprio and Heinrich Mattle. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. 2 1 Introduction

by us or our friends and with results to suit our preju- authors before we got back together for a general dices. But so often there is no good evidence or even any ­discussion – again over a few drinks, but on this occasion evidence at all available, and certainly no systematic at the Stockholm stroke conference in 1994. Momentum reviews. What to do then? Certainly not what most doc- restored, we went home to improve what we had written, tors are trained to do: ‘Never be wrong, and if you are, and the second draft was sent round to everyone for never admit it!’ If we do not know something, we will say comments in an attempt to improve the clarity, remove so. But, like other clinicians, we may have to make deci- duplication, fill in gaps and expunge as much remaining sions even when we do not know what to do, and when neurodogma, neurofantasy and neuroastrology as possi- nobody else does either. One cannot always adopt the ble. Our final discussion was held at the Bordeaux stroke policy of ‘if you don’t know what to do, don’t do it’. meeting in 1995, and the drinks that time were more in Throughout the book we will try to indicate where there relief and celebration that the end was in sight. Home we is no evidence, or feeble evidence, and describe what we all went to update the manuscript and make final do and will continue to do until better evidence becomes improvements before handing over the whole lot to the available; after all, it is these murky areas of practice that publisher in January 1996. need to be flagged up as requiring further research. This process may well have taken longer than a con- Moreover, in clinical practice, all of us ask respected col- ventional multi‐author book in which all the sections are leagues for advice, not because they may know some- written in isolation. But it was surely more fun, and thing that we do not but because we want to know what hopefully the result will provide a uniform and coherent they would do in a difficult situation. 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 1.1.4 Using the book We were all taught to look at the ‘methods’ section of a scientific paper before anything else. If the methods are This is not a stroke encyclopaedia. Many very much no good, then there is no point in wasting time and read- more comprehensive books and monographs are availa- ing further. In passing, we do regard it as most peculiar ble now, or soon will be. Nor is this really a book to be that some medical journals still print the methods sec- read from cover to cover. Rather, it is a book that we tion in smaller letters than the rest of the paper. Therefore, would like to be used on stroke units and in clinics to before anyone reads further, perhaps we should describe help illuminate stroke management at various different the methods we have adopted. stages, both at the level of the individual patient and for It is now impossible for any single person to write a patients in general. So we would like it to be kept handy comprehensive book about stroke that has the feel of and referred to when a problem crops up: how should having been written by someone with hands‐on experi- swallowing difficulties be identified and managed? ence of the whole subject. The range of problems is far Should an angiogram be done? Is raised plasma fibrino- too wide. Therefore, the sort of stroke book that we as gen a cause of stroke? How many beds should a stroke practitioners want – and we hope others do too – has to unit have? And so on. If a question is not addressed at all, be written by a group of people. Rather than putting then we would like to know about it so that it can be dealt together a huge multi‐author book, we thought it would with in the next edition, if there is to be one, which will be better and more informative, for ourselves as well as clearly depend on sales, the publisher, and enough con- readers, to write a book together that would take a par- genial European stroke conferences to keep us going. ticular approach (evidence‐based, if you will) and end up It should be fairly easy to find one’s way around the with a coherent message. After all, we have all worked book from the chapter headings and the contents list at together over many years, our views on stroke are more the beginning of each chapter. If that fails, then the index convergent than divergent, and so it should not be too will do instead. We have used a lot of cross‐referencing terribly difficult to write a book together. to guide the reader from any starting point and so avoid Like many things in medicine, and in life, this book constant reference to the index. started over a few drinks to provide the initial momen- As mentioned earlier, we have tried to be as selective as tum to get going, on the occasion of a stroke conference possible with the referencing. On the one hand, we want in Geneva in 1993. At that time, we decided that the to allow readers access to the relevant literature, but on book was to be comprehensive (but not to the extent of the other hand we do not want the text to be overwhelmed citing every known reference), that all areas of stroke by references – particularly by references to unsound must be covered, and who was going to start writing work. To be selective, we have tried to cite recent which section. A few months later, the first drafts were ­evidence‐based systematic reviews and classic papers then commented on in writing and in detail by all the describing important work. Other references can probably­ 1.2 Introduction to the second edition 3 mostly be found by those who want to dig deeper in the e‐mails the whole attachment back to the first author, reference lists of the references we have cited. copying to other authors for comments perhaps, and so Finally, we have liberally scattered what some would call on until it is perfect. Of course, we still do not all agree practice points and other maxims throughout the book. about absolutely everything all of the time. After all, we These we are all prepared to sign up to, at least in early want readers to have a feel for the rough and ragged 1996. Of course, as more evidence becomes available, growing edge of stroke research, where there is bound to some of these practice points will become out of date. be disagreement. If we all knew what to do for stroke patients there would be no need for randomized con- 1.1.5 Why a stroke book now? trolled trials to help us do better – an unrealistic scenario if ever there was one. So where there is uncertainty, and Stroke has been somewhat of a Cinderella area of medi- where we disagree, we have tried to make that plain. But, cine, at least with respect to the other two of the three on the whole, we are all still prepared to sign up to the most common fatal disorders in the developed practice points. world – coronary heart disease and cancer. But times are In this second edition, we have been able to correct the gradually changing, particularly in the last decade when surprising number of minor typographical errors and stroke has been moving up the political agenda, when hope not to have introduced any more, get all the X‐rays research has been expanding perhaps in the slipstream of the right way up, improve on some of the figures, remove coronary heart disease research, when treatments to some duplication, reorder a few sections, put in some prevent, if not treat, stroke have become available and more subheadings to guide the readers, make the section when the pharmaceutical industry has taken more on acute ischaemic stroke more directive, improve the notice. It seems that there is so much information about index, and generally tidy the whole thing up. It should stroke that many practitioners are beginning to be over- now be easier to keep track of intracranial venous throm- whelmed. Therefore, now is a good time to try to capture bosis and, in response to criticism, we have extended the all this information, digest it and then write down a prac- section on leukoaraiosis, even though it is not strictly tical approach to stroke management based on the best either a cause or a consequence of stroke. We have also available evidence and research. This is our excuse for introduced citations to what we have called ‘floating putting together what we know and what we do not references’ – in other words, published work that is con- know, what we do and why we do it. stantly being changed and updated as new information becomes available. An obvious example is the Cochrane Library, which is updated every 3 months and available 1.2 Introduction to the second edition on CD‐ROM and through the Internet. There are no page numbers, and the year of publication is always the Whether we enjoyed our annual ‘stroke book’ dinners at present one. We have therefore cited such ‘floating refer- the European stroke conferences too much to abandon ences’ as being in the present year, 2000. But we know them, or whether we thought there really was a lot of that this book will not be read much until the year 2001 updating to do, we found ourselves working on this sec- and subsequent years, when readers will have to look at ond edition four short years after the first. It has cer- the contemporary Cochrane Library, not the one pub- tainly helped to have been so much encouraged by the lished in 2000. The same applies to the new British many people who seemed to like the book, and find it Medical Journal series called ‘Clinical Evidence’ which is useful. We have kept to the same format, authors, and being updated every 6 months, and to any websites that principles outlined above in the introduction to the first may be updated at varying intervals and are still very edition. The first step was for all of us to read the whole much worth directing readers towards. book again and collect together any new comments and Rather to our surprise, there is a lot of new information criticisms for each of the other authors. We then rewrote to get across on stroke. Compared with 4 years ago, the our respective sections and circulated them to all the concept of organized stroke services staffed by experts in other authors for their further comments (and they were stroke care has taken root and has allowed the increas- not shy in giving them). We prepared our final words in ingly rapid assessment of patients with ‘brain attacks’. It early 2000. is no longer good enough to sit around waiting 24 h or A huge technical advance since writing the first edition more to see if a patient is going to have a transient ischae- has been the widespread availability of e‐mail and the mic attack or a stroke, and then another 24 h for a com- use of the Internet. Even more than before, we have gen- puted tomography brain scan to exclude intracerebral uinely been able to write material together; one author haemorrhage. These days we have to assess and scan does a first draft, sends it as an attachment across stroke patients as soon as they arrive in hospital, perhaps the world in seconds, the other author appends ideas and give thrombolysis to a few, and enter many more into 4 1 Introduction

clinical trials, start aspirin in ischaemic stroke, and get authorities and others keen to track and measure our the multidisciplinary team involved – and all of this well every move. And maybe there is less imperative to write within 24 h of symptom onset. Through the Cochrane books like this which are out of date in at least some ways Library, which was in its infancy when the first edition even before they are published. But then searching the was published, there is now easy, regularly updated Internet for ‘stroke’ does not come up with a coherent ­electronic access to systematic reviews of most of the account of the whole subject of managing stroke patients acute interventions and secondary prevention strategies using the best available evidence, which is what this book for stroke, although the evidence base for rehabilitation is all about. So, with the help and encouragement of techniques is lagging behind. Catheter angiography is Blackwell Publishing, here is the third edition of ‘the giving way to non‐invasive imaging. Magnetic resonance book’ at last. techniques are racing ahead of the evidence as to how We have written the book as before with most of the they should be used in routine clinical practice. For bet- authors commenting on most of the chapters before all ter or worse, coiling cerebral aneurysms is replacing clip- the chapters were finally written in the form you can read ping. The pharmaceutical industry is still tenaciously them in now. Again, you will have to guess who wrote hanging on to the hope of ‘neuroprotection’ in acute what because we can all lay claim to most of the book in ischaemic stroke, despite numerous disappointments. some sense or another. There has been a slight change in Hyperhomocysteinaemia and infections are the pres- the arrangement of the chapters, but loyal readers of the ently fashionable risk factors for ischaemic stroke, and earlier editions will not find this too upsetting – they will they may or may not stand the test of time. So, in this still find what they want in more or less its familiar place, second edition, we have tried to capture all these and as ever we hope the index has been improved. advances – and retreats – and set them in the context of The practice points we all sign up to and our day‐to‐day an up‐to‐date understanding of the pathophysiology of practice should reflect them. The uncertainties we all stroke and the best available evidence of how to manage share – they will be gradually resolved as more research it. Of course, it is an impossible task, because something is done, and more uncertainties will then be revealed. new is always just around the corner. But then ‘break- The biggest change in this edition is succumbing to the throughs’ in medicine take time to mature – maybe years space saving offered by a numbered reference system, until the evidence becomes unassailable and is gradually and a change in the colour scheme from a pastel green to accepted by front‐line clinicians. And then we can all sit various shades of purple. back doing what we believe to be ‘the right thing’ for a As with the second edition, much has changed few more years until the next ‘breakthrough’ changes our and there has been more updating than we originally view of the world yet again. anticipated – what we know about stroke has moved on. We hope that the ideas and recommendations in this Neuroprotection is even less likely to be an effective book will be sufficient 99% of the time – at least for the treatment for ischaemic stroke than it was in the 1990s, next 4 years, when we will have to see about a third we still argue about thrombolysis, clopidogrel cannot edition. very often be recommended, carotid stenting has still to prove its worth, routine evacuation of intracerebral haemorrhage is definitely not a good idea, and hormone 1.3 Introduction to the third edition replacement therapy far from protecting against vascular disease actually seems to increase the risk. But on the Six years have gone quickly by since the second edition, positive side, much has improved in brain and vessel much has happened in stroke research and practice in imaging, it is now clear how much blood pressure lower- the meantime, and two of the authors are on the edge of ing has to offer in secondary stroke prevention, and cho- retirement – so it is time for this third edition of what we lesterol lowering too. Carotid surgery can now be fondly refer to as ‘the book’. Maybe because the original targeted on the few who really need it, not recommended authors were feeling tired, or increasingly unable to for the greater number who may or may not need it. cover in depth all we wanted to, or perhaps because we Coiling has more or less replaced clipping of intracranial wanted to ensure our succession, we have recruited four aneurysms, an astonishing change in practice brought new and younger authors, all of whom have worked about by a large trial energetically led by an interven- closely with us over many years, and whose help we tional neuroradiologist and neurosurgeon. And it is not acknowledged in the earlier editions – Gabriel Rinkel, just acute stroke that needs urgent attention nowadays, Peter Langhorne, Cathie Sudlow and Peter Rothwell. transient ischaemic attacks must be assessed and But, even with their help, the rewriting has had to ­managed very quickly to minimize the early high risk of ­compete with all the far less interesting things which we stroke. Stroke services continue to improve all over the have to do these days to satisfy managers, regulatory world, stroke has moved up the political agenda as we 1.4 Introduction to the fourth edition 5

have managed to wrench it out of the rubric of ‘cardio- Hankey, Peter Sandercock, John Bamford, and Joanna vascular’ disease which always emphasized the cardiac Wardlaw. The third edition, published in 2007, was boosted rather than the cerebral, and more and more people are by the addition of Gabriel Rinkel, Peter Langhorne, Cathie involved in stroke research, which is now a much more Sudlow, and Peter Rothwell to the writing team. All three crowded and competitive field than it was when some of editions were the product of collaborative training and us started in the 1970s. research in evidence‐based stroke medicine in Oxford, Will there be a fourth edition? We don’t know; this Edinburgh, and Utrecht, inspired and led by Charles and will be in the hands of the remaining authors as Charles Jan. Since the third edition, Charles and Jan have retired Warlow and Jan van Gijn dwindle into retirement of a from stroke medicine and the collaborative group has sort, or at least a life that will not require the relentless retired from writing stroke books. battle to keep up with all the stroke literature, critique Meanwhile, loyal readers and the publisher of the first it, absorb anything that is worthwhile, and then put it three editions have requested that the legacy of “Warlow’s into the context of active clinical practice. No one can Stroke” book continue. Hence, a team of international write well about stroke unless they can connect research stroke experts from around the world has assembled to with their own active clinical practice – we are not, we update the original chapters and add additional chapters hope, armchair theoreticians; we try to practise what dedicated to cognition and rehabilitation. We thank our we preach. coauthors and trust that the transition from the third to the fourth edition is seamless and satisfactory.

1.4 Introduction to the fourth edition Graeme Hankey Malcolm Macleod This edition of Warlow’s Stroke sees a “changing of the Philip Gorelick guard” with a fresh complement of authors. The first two Christopher Chen editions, published in 1996 and 2001, were written by Fan Caprio Charles Warlow, Martin Dennis, Jan van Gijn, Graeme Heinrich Mattle

7

2

Development of knowledge about cerebrovascular disease Jan van Gijn

University of Utrecht, The Netherlands

CHAPTER MENU

2.1 Ideas change slowly, 8 2.2 The anatomy of the brain and its blood supply, 8 2.3 What happens in “apoplexy”?, 11 2.4 Cerebral infarction (ischemic stroke), 13 2.5 Thrombosis and embolism, 15 2.6 Transient ischemic attacks, 17 2.7 Intracerebral hemorrhage, 19 2.8 Subarachnoid hemorrhage, 20 2.9 Treatment and its pitfalls, 24 2.10 Epilogue, 28

“Our knowledge of disorders of the cerebral circulation ischemic stroke, the growth of our understanding and its manifestations is deficient in all aspects” was the has been slower. The ubiquity of the term “cerebral opening sentence of the chapter on cerebrovascular dis- thrombosis” up to the 1970s exemplifies how deficient eases in Oppenheim’s textbook of neurology at the begin- our understanding was even at that time [2]. Embolic ning of the twentieth century [1]. More than 100 years occlusion, now known to result more often from arterial later this still holds true, despite the considerable lesions than from the heart, can be detected in an early advances that have been made. In fact, the main reason phase by noninvasive angiographic techniques or for Oppenheim’s lament, the limitations of pathological inferred by means of perfusion imaging, but so often the anatomy, is to some extent still valid. True, our methods source of the clot is still elusive. Also we have learned to of observation nowadays are no longer confined to the distinguish many causes of cerebral infarction other than dead, as they were then. They have been greatly expanded, atherothrombosis, such as arterial dissection, mitochon- first by angiography, then by brain imaging and measure- drial cytopathies, and moya‐moya syndrome, but the ment of cerebral blood flow and metabolism, and most precise pathogenesis of these conditions is still poorly recently by noninvasive methods of vascular imaging understood. such as ultrasound and magnetic resonance angiogra- So it is with humility, rather than in triumph, that we phy. Yet, our observations are still mostly anatomical, look back on the past. In each era the problems of stroke and after the event. It is only in rare instances that are we have been approached by the best minds, with the best able to reconstruct the dynamics of a stroke. At least in tools available at the time. Of course many ideas in the hemorrhagic stroke, brain computerized tomography past were wrong, and so presumably are many of our (CT) or magnetic resonance imaging (MRI) in the acute own. Even though we are firm believers in evidence‐ phase gives an approximate indication of where a blood based medicine, some – perhaps many or even most – of vessel has ruptured (though not why exactly there and our own notions will not survive the test of time. Our then) and how far the extravasated blood has invaded the knowledge may have vastly increased in the recent past brain parenchyma or the subarachnoid space. With but it is still a mere island in an ocean of ignorance.

Warlow’s Stroke: Practical Management, Fourth Edition. Edited by Graeme J. Hankey, Malcolm Macleod, Philip B. Gorelick, Christopher Chen, Fan Z. Caprio and Heinrich Mattle. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. 8 2 Development of knowledge about cerebrovascular disease

2.1 Ideas change slowly description! It is best to become reconciled to the idea that a slow rate of diffusion of new knowledge is una- The history of medicine, like that of kings and queens in voidable. The problem is one of all times. Franciscus world history, is usually described by a string of dates and Biumi, one of the early pathologists, lamented in 1765: names, by which we leapfrog from one discovery to “Sed difficile est adultis novas opiniones inserere, evel- another. The interval between such identifiable advances lere insitas” [But it is ­difficult to insert new opinions in is measured in centuries when we describe the art of adults and to remove rooted ones] [9]. How slowly new medicine at the beginning of civilization, but in mere ideas were accepted and acted upon, against the back- years where our present times are chronicled. This leads ground of contemporary knowledge, can often be to the impression that we are witnessing a dazzling explo- inferred from textbooks, particularly if written by full‐ sion of knowledge. Yet some qualification of this view is time clinicians rather than by research‐minded neurol- needed. First of all, any generation of mankind takes a ogists. Therefore we shall occasionally quote old myopic view of history in that the importance of recent textbooks to illustrate the development of physicians’ developments is overestimated. The Swedish Academy theories about stroke. of Sciences therefore often waits for years, sometimes A reverse problem is that a new discovery or even a even decades, before awarding Nobel prizes, until scien- new fashion may be interpreted beyond its proper limits tific discoveries have withstood the test of time. When and linger on as a distorted idea for decades. Take the exceptions were made for the prize in medicine, the early discovery of vitamin B1 deficiency as the cause of a tropi- accolades were not always borne out: Wagner‐Jauregg’s cal polyneuropathy almost a century ago; the notion that malaria treatment for neurosyphilis (1927) is no longer a neurological condition, considered untreatable almost regarded as a landmark, while Moniz’s prize (1949) for by definition, could be cured by a simple nutritional sup- prefrontal leucotomy no longer seems justified; but at plement made such an impact on the medical commu- least he also introduced contrast angiography of the nity that even in some industrialized countries vitamin brain, though this procedure is now performed increas- B1 is still widely used as a panacea for almost any neuro- ingly less often for diagnostic purposes. We can only logical symptom. hope that the introduction of X‐ray CT by Hounsfield So broadly speaking there are two kinds of medical (Nobel prize for medicine in 1979) will be judged equally ­history, that of the cutting edge of research and that of momentous by future generations as by ourselves. the medical profession as a whole. The landmarks are Another important caveat if one looks back on pro- easy to identify only with the hindsight of present gress in medicine is that most discoveries gain ground ­knowledge. In reality, new ideas often only gradually only slowly. William Harvey’s theory of the circulation dawned on new generations of medical scientists, instead of the blood, published in 1628 [3], was the subject of of the popular notion of a blinding flash of inspiration acrimonious debate throughout the rest of the seven- occurring in a single individual. For this reason, accounts teenth century. Even if new insights were quickly of the history of stroke are not always identical [10, 11]. accepted by peer scientists, it could still be decades Also many important primary sources are not easy to before these had trickled down to the rank and file of interpret – not only because they were written in Latin medical practitioners. The mention of a certain date for but also because “new observations” have sometimes a discovery may create the false impression that this been identified only by later historians, in retrospect, change in medical thinking occurred almost overnight, while the authors at the time attached no importance to like the introduction of a single European currency. In them [12]. most instances, this was far from the truth. An apt example is the extremely slow rate at which the concept of lacunar infarction became accepted by the medical community, despite its potentially profound implica- 2.2 The anatomy of the brain tions in terms of pathophysiology, treatment, and prog- and its blood supply nosis. The first pathological descriptions date from around 1840 [4, 5], but it took the clinicopathological Even before the time of Hippocrates (460–370 bce), correlations of C. Miller Fisher (see Figure 2.10) in the Greek physicians credited the brain with intelligence 1960s before the neurological community and its text- and thought, though another Greek school of medicine books started to take any notice [6–8]. And it was not attributed mental faculties to the heart. In the first until new techniques for brain imaging in the 1980s century­ ce Aretaeus of Cappadocia observed that provided instantaneous clinicoanatomical correlations brain lesions affected movements of the opposite side that no practicing neurologist could avoid knowing of the body [13]; unilateral convulsions after head about lacunar infarcts – some 150 years after the first wounds on the contralateral side led others to the same 2.2 The anatomy of the brain and its blood supply 9 conclusion [14]. Yet, stroke, or “apoplexy” (Greek for attacked by traditionally minded contemporaries as an “being struck down”), was defined as a general, rather iconoclast of Galenic dogmas. Initially he did not go as than focal, disorder of the brain: sudden cessation of far as attacking Galen’s central physiological tenet that motion and sensation, while breathing and the pulse blood could pass through the septum between the right beat were preserved. Its pathogenesis was explained and left ventricle of the heart, allowing the mixture of according to the humoral theory, which assumed a deli- blood and air and the elimination of “soot.” Instead, he cate balance between the four humors: blood, phlegm, praised the creator for having made the openings so black bile, and yellow bile. Anatomy played almost no small that nobody could detect them, another famous part in these explanations. Apoplexy was therefore example of how the power of theory may mislead even often attributed to accumulation of phlegm or black the most inquisitive minds. Only later, in the 1555 edi- bile in the blood vessels of the brain, obstructing the tion of his De humani corporis fabrica, did he firmly state passage of spirits; these spirits (pneuma in Greek) rep- that the interventricular septum was tightly closed. The resented an ethereal form of energy carried by blood, decisive blow to the humoral theory came in 1628, produced in crude form by the liver (natural spirits) through the description of the circulation by William and subsequently refined by the heart (vital spirits) Harvey (1578–1657) [3]; his theory formed the founda- and even more by the – imaginary – network of blood tion for the recognition of the role of blood vessels in the vessels at the base of the brain (mental spirits) [15]. pathogenesis of stroke. Galenus of Pergamon (131–201), a prolific writer and Thomas Willis (1641–1675) is remembered not so animal experimenter whose views dominated medicine much for having coined the term “neurology,” or for his up to the seventeenth century [16], distinguished iatrochemical theories, a modernized version of humoral “karos” from “apoplexy,” in that respiration was unaf- medicine, or for his part in the successful resuscitation of fected in the former condition [17]. Leading Islamic Ann Green after judicial hanging [25], as he is for his physicians like Avicenna (980–1037) tried to reconcile work on the anatomy of the brain, first published in 1664 Galenic tenets with the Aristotelian view of the heart as [26], especially for his description of the vascular inter- the seat of the mind [18]. In Western Europe, mostly connections at the base of the brain (Figure 2.2) [27]. deprived of Greek learning until the fall of Before him, Fallopius, Casserio, Vesling, and Wepfer had Constantinople in 1453 prompted a revival of ancient all observed at least part of the circle [28–31], in the case Greek culture, these Arabic texts were translated into of Casserio and Vesling even with an illustration [32]. Latin before those of Galen and Hippocrates [19]. All But undisputedly, it was Willis who grasped the func- these theories had no anatomical counterpart; dissec- tional implications of these anastomoses in a passage tion of the human body was precluded by its divine illustrating his proficiency in performing necropsies as connotations. Any illustrations of the human brain that well as postmortem experiments (from a posthumous are known before the sixteenth century are crude and translation) [33]: schematic representations of Galenic theories, rather than attempts at copying the forms of nature. As a con- We have elsewhere shewed, that the Cephalick sequence, many non‐neurological disease conditions Arteries, viz. the Carotides, and the Vertebrals, do with sudden onset must have been misclassified as so communicate with one another, and all of them “apoplexy.” in different places, are so ingraffed one in another In 1543 Andries van Wesele (1514–1564), the great mutually, that if it happen, that many of them Renaissance anatomist who Latinized his name to should be stopped or pressed together at once, yet Andreas Vesalius, produced the first accurate drawings the blood being admitted to the Head, by the pas- of the brain in his famous book De humani corporis fab- sage of one Artery only, either the Carotid or the rica libri septem, with the help of the draughtsman Johan Vertebral, it would presently pass thorow all those Stephaan van Calcar and the printer Oporinus in Basle parts exterior and interior: which indeed we have [20]. It was the same year in which Copernicus published sufficiently proved by an experiment, for that Ink De revolutionibus, proclaiming the sun and not the earth being squirted in the trunk of one Vessel, quickly as the center of the universe [21]. Vesalius largely ignored filled all the sanguiferous passages, and every the blood vessels of the brain, although he retracted an where stained the Brain it self. I once opened the earlier drawing (Figure 2.1) depicting the network of dead Carcase of one wasted away, in which the blood vessels at the base of the brain (rete mirabile) that right Arteries, both the Carotid and the Vertebral, Galen had found in pigs and oxen and that had been within the Skull, were become bony and impervi- extrapolated to the human brain ever since [22, 23]. ous, and did shut forth the blood from that side, Before him, Berengario da Carpi had also denied the notwithstanding the sick person was not troubled existence of the rete [24]. Vesalius was vehemently with the astonishing Disease. 10 2 Development of knowledge about cerebrovascular disease

Figure 2.1 Plate depicting the blood vessels, from Vesalius’s Tabulae anatomicae sex, of 1538 [22]. 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 [231]. Vesalius retracted the existence of a network in his atlas of 1543.

It seems that the idea of infusing colored liquids into from Christopher Wren (1632–1723) [25]. Wren also made blood vessels, practiced from 1659 onwards and later per- the etchings for Willis’s book (he is now mainly remem- fected by Frederik Ruysch (1638–1731) and in the next bered as the architect of St. Paul’s cathedral and many other century by John Hunter (1728–1793) [34, 35], had come churches built after the great fire of London in 1666). 2.3 What happens in “apoplexy”? 11

Figure 2.2 Illustration of the base of the brain from Willis’s Cerebri anatome (1664) [26], showing the interconnections between the right and left carotid systems, and also between these two and the posterior circulation. Drawing by Christopher Wren.

Figure 2.3 Johann Jakob Wepfer (1620–1695). 2.3 What happens in “apoplexy”? the influx of blood and, on the other, extravasation of Willis’s “astonishing Disease,” apoplexy, had traditionally blood into the substance of the brain or the ventricular been attributed to some ill‐defined obstruction, of the cavities. His interpretation was, however, that blockage pathways for “mental spirits” in the cerebral ventricles of arteries as well as extravasation of blood impeded according the tradition of ancient Greek medicine, or, the transmission of “mental spirits” to the brain [12]. after Harvey’s time, of blood flow. Yet, it should be Accordingly, he regarded apoplexy as a process of global remembered that the notion of an intrinsic “nervous stunning of the brain, while the focal nature of the disease energy” only slowly lost ground. Even the great eight- largely escaped him. The four cases of hemorrhage eenth‐century physician Boerhaave, though clearly rec- Wepfer described were massive, at the base of the brain or ognizing the role of blood vessels and the heart in the deep in the parenchyma. In cases with obvious hemiple- development of apoplexy, invoked obstruction of the gia, incidentally a term dating back to the Byzantine phy- cerebrospinal fluid [36]. That Willis had found “bony” sician Paulus Aegineta (625–690) [38], Wepfer’s advocacy and “impervious” arteries in patients who had died from of postmortem studies, against public opposition but causes other than a brain lesion was probably the reason with the support of the officials in Schaffhausen, must that he was not outspoken on the pathogenesis of apo- have been inspired by his stay in Padua, from 1644 to plexy. His contemporaries, Wepfer (1620–1695) in 1647 [39]. This liberal university town, protected against Schaffhausen, and Bayle (1622–1709) in Toulouse, only conservative influences by the powerful and cosmopoli- tentatively associated apoplexy with “corpora fibrosa” tan republic of Venice [40], can be regarded as the center [31], or with calcification of cerebral arteries [37]. of the renaissance in medicine; there he was taught Johann Jakob Wepfer (Figure 2.3) not only recognized about the circulation of blood, the controversial theory arterial lesions, but he also prompted one of the great proposed in 1628 by William Harvey (who had studied advances in the knowledge about stroke by distinguishing in Padua almost 50 years before). Later in his career between, on the one hand, arterial obstruction preventing Wepfer also observed patients who had recovered from 12 2 Development of knowledge about cerebrovascular disease

Figure 2.4 Atheromatous lesions in the aorta and large arteries of Johann Jakob Wepfer (deceased in 1695). The postmortem study was performed in keeping with Wepfer’s previous wishes. The etching was included in a collection of his observations on diseases of the head, published posthumously [41]. Figure 2.5 Illustration from Mistichelli’s book on apoplexy (1709) in which he shows the decussation of the pyramids and also the outward rotation of the leg on the paralyzed side [42]. ­apoplectic attacks, and noted that those most liable to apoplexy were “the obese, those whose face and hands are livid, and those whose pulse is constantly unequal.” When he did not include even a single illustration; characteristi- Wepfer died in 1695, presumably from heart failure, he cally, the title of the book was “De sedibus et causis had arranged that an autopsy should be performed; this ­morborum …” [About the sites and causes of disease] showed extensive atheroma of the aorta and large arteries [43]. Morgagni firmly divided apoplexy into “sanguineous (Figure 2.4) [41]. apoplexy” and “serous apoplexy” (and a third form which That the paralysis in apoplexy was on the opposite side was neither serous nor sanguineous). A decade later, of the brain lesion was clearly explained by Domenico Portal (1742–1832) rightly emphasized that it was impos- Mistichelli (1675–1715) from Pisa, by his observation of sible to distinguish between these two forms during life the decussation of the pyramids (Figure 2.5) [42]. A land- [44]. However, it would be a mistake to assume that mark in the recognition of the anatomical substrate “serous” (nonhemorrhagic) apoplexy was recognized at of stroke – and of many other diseases – was the work that time as being the result of impaired blood flow, of Giovanni Batista Morgagni (1682–1771), professor of let alone of mechanical obstruction of blood vessels. medicine and subsequently of pathological anatomy in Matthew Baillie even linked the arterial hardening with Padua. In 1761 Morgagni published an impressive series brain hemorrhages and not with the serous apoplexies; of clinicopathological observations collected over a life- in his book he also provided one of the first etchings to time (he was 79 at the time of publication), in which illustrate intracerebral hemorrhage (Figure 2.6) [45]. he firmly put an end to the era of systemic (humoral) Although we quoted seventeenth‐century scientists such theories of disease by an organ‐based approach, though as Bayle and Wepfer in that they associated some