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Oxford Textbook of Stroke and Cerebrovascular Disease
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1 Oxford Textbook of Stroke and Cerebrovascular Disease Edited by Bo Norrving Professor in Neurology Department of Clinical Sciences Section of Neurology Lund University Lund, Sweden Series Editor Christopher Kennard
3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University press in the UK and in certain other countries © Oxford University Press 2014 The moral rights of the authors have been asserted First Edition published in 2014 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2013952006 ISBN 978–0–19–964120–8 Printed in China by C&C Offset Printing Co. Ltd Oxford University press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breast-feeding
Stroke has always been a worldwide problem, but only now is it being recognized as a global, treatable, and preventable condition, largely through scientific advances and the work of stroke leaders such as the contributors to this volume. Knowledge accrues in pieces but is understood in patterns. The internet has made information available in unprecedented quanti- ties, but of uneven value. Bits and bytes of information are but a few clicks away. However, these pieces have to be put in patterns, in context, and we need to recognize the fact that we still know much less than we need to know, hence the need for a comprehensive, credible, and accessible book. Bo Norrving and his international cast of authors offer such a volume. In addition to the usual chapters on anatomy, pathophysi- ology, diagnosis, treatment, and rehabilitation, there are chapters on the increasingly recognized areas of silent infarcts and micro- bleeds, vascular cognitive impairment and dementia, and the long-term management of stroke. As a former President of the World Stroke Organization, the editor has led efforts to put stroke at the forefront of global health policy by working with the World Health Organization and the United Nations. This enlarged vision of stroke is reflected in a chapter on primary stroke prevention and one on healthcare services, topics that do not usually feature in books on stroke. May this book enjoy the broad readership that it deserves. Vladimir Hachinski, CM, MD, FRCPC, DSc, Dr. honoris causa X5 President, World Federation of Neurology Foreword
Stroke is huge by any measure: often cited data from the Global Burden of Disease project are that there are 6 million deaths due to stroke per year worldwide, 15 million cases of stroke per year, and 30 million persons who have survived a stroke. Other stroke measures are one new stroke every other second, every sixth sec- ond stroke kills someone, and one in six will have a stroke during their lifetime. Such numbers have different meanings to differ- ent stakeholders. For the patient who has developed a stroke, and for the carers, such data are of little interest (more than possibly telling that ‘you are in good company, welcome to the club’)— my own stroke is more than enough for me. For health person- nel the figures are more alarming: how can we take good care of so many patients, do we have the beds at the stroke unit (and is there a stroke unit at all?), are there rehabilitation and follow-up resources available? Who can do the job, who have the right edu- cation and competence? For health administrators, healthcare planners, and politicians the numbers should be alarming: what are the precise numbers in my country or region? What is the trend? What can be done (and what can I do) to help and to pre- vent stroke? And, will the numbers affect the financial situation in my community? Fortunately the stroke scene is changing—the Cinderella tale being a good analogy of what has happened. Only a few decades ago (when I started in neurology as my first summer job) stroke had the lowest priority at the emergency department because there was no hurry and nothing could be done acutely. Stroke units were unheard of—at my local hospital there was even a hospital agreement by which patients who were impossible to rehabilitate (definition: age 65 years and above) were outsourced to various other departments (dermatology, renal disease, oncol- ogy . . . ) so that the burden of stroke to the hospital could be shared. Patients used to stay in bed for 1–2 weeks before any mobilization took place. Heparin treatment was widely used to prevent or treat progressing stroke whereas antiplatelets and statins were unknown at that time. Carotid surgery was per- formed by thoracic surgeons with rates of serious complication well above 10%. Any ultra-early therapy was regarded as doomed to fail since science told us that brain cells could not survive more than 5–10 minutes of ischaemia. Looking back, I have some diffi- culties understanding why stroke nevertheless caught my interest and attracted me. Readers of this preface need not be told in detail what has hap- pened during the last few decades: the introduction of acute neuroimaging and other diagnostic tools, the demonstration of acute thrombolytic therapy as one of medicine’s best buys, the glory of organized stroke care (including early mobilization), the development of secondary prevention strategies that have changed the prognosis after stroke drastically, and the demonstration that rehabilitation works—just to mention a few of the groundbreaking changes that have taken place. There has also been an avalanche of knowledge of mechanisms, causes, unusual features, stroke subtypes, and genetics. Advances in science have had a profound impact on clinical practice in stroke. Another major change is a focus on stroke prevention through joint actions with other non-communicable diseases (NCDs) that share similar risk factors. Stroke is not acting alone in this movement, but is part of the NCD cluster that has rightfully received high governmental attention during the last few years. Stroke shares many risk factors with heart disease, peripheral vascular disease, cancer, dementia, and pulmonary disease—just to mention a few members of the NCD family. The World Stroke Organization emphasizes three pillars in the Global Agenda for Stroke: prevention, acute care, and long-term management. The latter component has been particularly neglected and warrants much more attention in the future. Few areas in medi- cine have such broad outreach, involve so many sectors of health- care, and have such a profound influence on public health as stroke. For this book I have had the privilege of working together with many of today’s most outstanding stroke scientists. I am grateful to all of you for sharing your deep knowledge, and for making your- selves available for the task. I take this opportunity to thank you all most warmly for your contributions to this volume. I also thank the very large number of people in the scientific stroke community, within the World Stroke Organization and regional stroke organiza- tions, who have provided me with inspiration for the present work. I would also like to thank the staff at Oxford University Press for expert help and support in making this book available. My thanks go to Peter Stevenson who set me the task initially, to Eloise Moir-Ford for keeping track of all manuscript versions and chapter status, to Papitha Ramesh and Nic Williams for copy editing, and to the many other people at Oxford University Press who have been involved with this book. It has been a pleasure working with you. Preface
preface viii Finally, my thanks to my wife Lena and my three children (David, Marcus, and Maria) for having been (quite) tolerant of the intru- sion of my out-of-usual-business-hours’ work into family pleasures and duties. It is my hope that the book will be read, will be disseminated broadly, and will finally lead to benefits for patients and carers. Only at the latter stage has a textbook like this one served its ulti- mate purpose. Bo Norrving Lund, Sweden October 2013
List of Abbreviations xi List of Contributors xiii 1 Epidemiology of stroke 1 Valery Feigin and Rita Krishnamurthi 2 Risk factors 9 Arne Lindgren 3 Arteries and veins of the brain: anatomical organization 19 Laurent Tatu, Fabrice Vuillier, and Thierry Moulin 4 Pathophysiology of transient ischaemic attack and ischaemic stroke 35 Jong S. Kim 5 Pathophysiology of non-traumatic intracerebral haemorrhage 51 Constanza Rossi and Charlotte Cordonnier 6 Spontaneous intracranial subarachnoid haemorrhage: epidemiology, causes, diagnosis, and complications 61 Laurent Thines and Charlotte Cordonnier 7 Clinical features of transient ischaemic attacks 79 David Calvet and Jean-Louis Mas 8 Clinical features of acute stroke 85 José M. Ferro and Ana Catarina Fonseca 9 Diagnosing transient ischaemic attack and stroke 94 Bruce Campbell and Stephen Davis 10 Management of stroke: general principles 106 Mehmet Akif Topcuoğlu and Hakan Ay 11 Acute phase therapy in ischaemic stroke 124 Krassen Nedeltchev and Heinrich P. Mattle 12 Acute management and treatment of intracerebral haemorrhage 130 Marek Sykora, Jennifer Diedler, and Thorsten Steiner 13 Acute treatment in subarachnoid haemorrhage 139 Katja E. Wartenberg 14 Less common causes of stroke: diagnosis and management 153 Turgut Tatlisumak, Jukka Putaala, and Stephanie Debette 15 Secondary prevention of stroke 163 Thalia S. Field and Oscar R. Benavente 16 Prognosis after stroke 185 Vincent Thijs 17 Silent cerebral infarcts and microbleeds 194 Bo Norrving 18 Complications after stroke 203 Hanne Christensen, Elsebeth Glipstrup, Nis Høst, Jens Nørbæk, and Susanne Zielke 19 Vascular cognitive impairment and dementia 215 Didier Leys, Kei Murao, and Florence Pasquier 20 Brain repair after stroke 225 Steven C. Cramer 21 Rehabilitation after stroke 234 Katharina Stibrant Sunnerhagen 22 The long-term management of stroke 243 Reza Bavarsad Shahripour and Geoffrey A. Donnan 23 Primary prevention of stroke 255 Anna M. Cervantes-Arslanian and Sudha Seshadri 24 Organized stroke care: Germany and Canada 270 Silke Wiedmann, Peter U. Heuschmann, and Michael D. Hill Index 279 Contents
ACA anterior cerebral artery ACE angiotensin-converting enzyme AChA anterior choroidal artery ACoA anterior communicating artery ADL activities of daily living ADL Alzheimer disease AF atrial fibrillation AHA American Heart Association AICA anterior inferior cerebellar artery ARB angiotensin receptor blocker ARER absolute risk reduction ASA American Stroke Association AUC area under the curve AVM arteriovenous malformation BI Barthel Index CAA cerebral amyloid angiopathy CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy CARASIL cerebral autosomal recessive arteriopathy with subcortical infarcts and leucoencephalopathy CAS carotid angioplasty and stenting CBV cerebral blood volume CEA carotid endarterectomy CEAD cervical artery dissection CEAD carotid endarterectomy CHS Cardiovascular Health Study CMB cerebral microbleed CNS central nervous system CSF cerebrospinal fluid CT computed tomography CTV computed tomography venography CVD cerebrovascular disease CVT cerebral venous thrombosis DALY disability-adjusted life year DAVF dural arteriovenous fistula DCI delayed cerebral ischaemia DNR do not resuscitate DOAC direct oral anticoagulant DSA digital subtraction angiography DVT deep vein thrombosis DWI diffusion-weighted imaging ECG electrocardiogram eGFR estimated glomerular filtration rate ESO European Stroke Organisation EVD extraventricular drain FDA Food and Drug Administration FFP fresh frozen plasma FHS Framingham Heart Study FLAIR fluid attenuated inversion recovery GABA gamma-aminobutyric acid GOS Glasgow Outcome Scale GOS Glasgow Outcome Scale GRE gradient echo HANAC hereditary angiopathy with nephropathy, aneurysm, and muscle cramps HDL high-density lipoprotein HERNS hereditary endotheliopathy with retinopathy, nephropathy, and stroke HR hazard ratio IA intra-arterial IAT intra-arterial thrombolysis ICH intracerebral haemorrhage IDR incidence density ratio IHD ischaemic heart disease INR international normalized ratio IST International Stroke Trial ITT intention-to-treat LDL low-density lipoprotein LP lumbar puncture LUTS lower urinary tract symptoms MAP mean arterial pressure MCA middle cerebral artery MET S metabolic syndrome MMSE Mini Mental State Examination MoCA Montreal Cognitive Assessment MRI magnetic resonance imaging mRS modified Rankin Scale MRV magnetic resonance venography List of Abbreviations
list of abbreviations xii MTT mean transit time NCD non-communicable disease NG nasogastric NHS Nurses’ Health Study NICC neurocritical care unit NIHSS National Institutes of Health Stroke Scale NINDS National Institute of Neurological Disorders and Stroke NMDA N-methyl-D-aspartate NOAC novel oral anticoagulant NVAF non-valvular atrial fibrillation OCSP Oxfordshire Community Stroke Project OHS Oxford Handicap Score PAR population attributable risk PbtO2 partial pressure of cerebral tissue oxygen PCA posterior cerebral artery PCC prothrombin complex concentrate PChA posterior choroidal arteries PE pulmonary embolus PEG percutaneous endoscopic gastrostomy PET positron emission tomography PFO patent foramen ovale PHS Physicians’ Health Study PICA posterior inferior cerebellar artery PoCA posterior communicating artery PRN pro re nata (as needed) PSD post-stroke dementia RCVS reversible cerebral vasoconstriction syndrome RR relative risk RRR relative risk reduction rtPA recombinant tissue plasminogen activator SAH subarachnoid haemorrhage SCA superior cerebellar artery SCD sickle cell disease SCI silent cerebral infarct SCM silent cerebral microbleed SDB sleep-disordered breathing SD standard deviation SES socioeconomic status SIADH syndrome of inappropriate secretion of antidiuretic hormone SITCH Surgical Trial in Intracerebral Haemorrhage SLE systemic lupus erythematosus SNP single-nucleotide polymorphism SWI susceptibility-weighted imaging TBI traumatic brain injury TCS Takotsubo cardiomyopathy syndrome Tmax time to maximum TOAST Trial of Org 10172 in Acute Stroke Treatment TOF time-of-flight tPA tissue plasminogen activator TTP time to peak UK United Kingdom US United States VaD vascular dementia VCI vascular cognitive impairment WFNS World Federation of Neurological Surgeons Scale WHO World Health Organization WHS Women’s Health Study WML white matter lesion
Hakan Ay Stroke Service, Department of Neurology, A.A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Oscar R. Benavente Stroke and Cerebrovascular Health, Vancouver Stroke Program, Brain Research Center, Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada David Calvet Paris Descartes University, Centre de Psychiatrie et Neurosciences INSERM UMR 894, and Department of Neurology, Centre Hospitalier Sainte-Anne, Paris Bruce Campbell Department of Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia Anna M. Cervantes-Arslanian Boston University Department of Neurology, Boston, MA, USA Hanne Christensen Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark Charlotte Cordonnier Department of Neurology and Stroke Unit, Université Lille Nord de France, Lille, France Steven C. Cramer Departments of Neurology and Anatomy & Neurobiology, University of California, Irvine, Irvine, CA, USA Stephen Davis President, World Stroke Organization; Director, Neuroscience and Continuing Care Service; Director, Melbourne Brain Centre at RMH; Director of Neurology, The Royal Melbourne Hospital, Melbourne, Australia Stephanie Debette Université de Versailles Saint-Quentin-en-Yvelines, France; and Inserm U740, Université Paris, Paris, France; and Department of Neurology, Lariboisière University Hospital, DHU Neurovasc Sorbonne Paris-Cité, Paris, France; and Department of Neurology, Boston University School of Medicine, The Framingham Heart Study, Boston, MA, USA Jennifer Diedler Department of Neurology, University of Heidelberg, Heidelberg, Germany Geoffrey A. Donnan Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia Valery Feigin National Institute for Stroke and Applied Neurosciences, Faculty of Health & Environmental Sciences AUT University, Auckland, New Zealand José M. Ferro Department of Neurosciences, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal Thalia S. Field Vancouver Stroke Program, Brain Research Center, Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada Ana Catarina Fonseca Department of Neurology, Hospital de Santa Maria, Lisboa, Portugal Elsebeth Glipstrup Mental Health Services, Bispebjerg Hospital, Copenhagen, Denmark Nis Høst Department of Cardiology, Bispebjerg Hospital, Copenhagen, Denmark Peter U. Heuschmann Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany Michael D. Hill Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada Jong S. Kim University of Ulsan, College of Medicine, Seoul, South Korea; and Stroke Center, Asan Medical Center, Seoul, South Korea Rita Krishnamurthi National Institute for Stroke and Applied Neurosciences, Faculty of Health & Environmental Sciences, AUT University, Auckland, New Zealand Didier Leys Université Lille Nord de France, Lille, France Arne Lindgren Department of Neurology Lund, Skåne University Hospital, Lund, Sweden Jean-Louis Mas Paris Descartes University, Centre de Psychiatrie et Neurosciences INSERM UMR 894 and Department of Neurology, Centre Hospitalier Sainte-Anne, Paris, France Heinrich P. Mattle Department of Neurology, Inselspital, Bern, Switzerland Thierry Moulin Service de Neurologie 2,Centre Hospitalier Universitaire, Université de Franche-Comté, Besançon, France List of Contributors
list of contributors xiv Kei Murao Université Lille Nord de France, Lille, France Krassen Nedeltchev Triemli Hospital, Zurich, Switzerland Jens Nørbæk Mental Health Services, Bispebjerg Hospital, Copenhagen, Denmark Bo Norrving Department of Clinical Sciences, Section of Neurology, Lund University, Lund, Sweden Florence Pasquier Université Lille Nord de France, Lille, France Jukka Putaala Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland Constanza Rossi Department of Neurology and Stroke Unit, University of Lille Nord de France, Lille, France Sudha Seshadri Boston University Department of Neurology, Boston, MA, USA Reza Bavarsad Shahripour Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia Thorsten Steiner Department of Neurology, University of Heidelberg, Heidelberg, Germany; and Department of Neurology, Klinikum Frankfurt Höchst, Frankfurt, Germany Katharina Stibrant Sunnerhagen Department of Clinical Neurosciences, University of Gothenburg, Institute of Neuroscience and Physiology, Sweden Marek Sykora Department of Neurology, University of Heidelberg, Heidelberg, Germany; and Department of Neurology, Comenius University, Bratislava, Slovakia Laurent Tatu Laboratoire d’Anatomie, UFR Sciences médicales et pharmaceutiques, Université de Franche-Comté, Besançon, France; and Service d’Explorations et pathologies neuro-musculaires, Centre Hospitalier Universitaire, Université de Franche-Comté, Besançon, France Turgut Tatlisumak Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland Vincent Thijs Department of Neurology, University Hospitals Leuven, Leuven, Belgium Laurent Thines Division of Neurosurgery, Department of Neurosciences and Locomotive System, Lille University Hospital, Lille, France Mehmet Akif Topcuoğlu Hacettepe University Hospitals, Department of Neurology, Ankara, Turkey Fabrice Vuillier Laboratoire d’Anatomie, UFR Sciences médicales et pharmaceutiques, Université de Franche-Comté, Besançon, France; and Service de Neurologie 2, Centre Hospitalier Universitaire, Université de Franche-Comté, Besançon, France Silke Wiedmann Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany Katja E. Wartenberg Neurocritical Care Unit, Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany Susanne Zielke Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark
Introduction Stroke is the second most common cause of death worldwide and a frequent cause of adult disability in developed countries (1, 2). Stroke burden on families and society is projected to rise from approximately 38 million disability-adjusted life years (DALYs) lost globally in 1990 to 61 million DALYs in 2020 (3) due to population ageing. Stroke also has a large physical, psychological, and finan- cial impact on patients/families, the healthcare system, and society (4, 5). Lifetime costs per stroke patient range from US$59,800 to US$230,000 (5). The majority (about 75%) of cases of stroke occur in people over the age of 65 years (6, 7), and about one-third of patients die of stroke within a year of onset (8, 9). Over half of survi- vors remain dependent on others for everyday activities, often with significant adverse effects on caregivers (10). Many factors increase the risk of stroke, and these are generally divided into two catego- ries: modifiable and non-modifiable risk factors. Age, gender, and ethnicity are non-modifiable risk factors for stroke. Modifiable or potentially modifiable risk factors include a number of physiologi- cal and environmental factors and include hypertension, elevated total cholesterol, smoking, physical inactivity, alcohol consump- tion, and atrial fibrillation (11). Stroke mortality data are available from more than 24 countries (12, 13) showing that, in general, rates have declined for several decades. In some countries, stroke mortality has declined since the early 1950s, but the rate of this decline has recently slowed (14–17). While large national or international stroke mortality data may be used for determining overall burden of fatal strokes and trends in stroke mortality, stroke mortality data are often not accurate (diagnosis classification bias) and have limited value for healthcare planning and organization. The role of changes in inci- dence and improved survival to downward trend in stroke mor- tality are not adequately quantified, chiefly due to difficulties in measuring stroke incidence accurately (18, 19); however the results from the World Health Organization (WHO) Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) pro- ject suggested that both declining and increasing stroke mortality were principally attributable to changes in case fatality rather than changes in incidence (20). Importance of population-based studies Epidemiological studies form the basis of much of the medi- cal research and current knowledge in stroke to inform health professionals about best strategies for stroke care organization, prevention, and management. The gaps in knowledge in stroke pre- vention and management are continually filled by randomized con- trol trials, case–control, and cohort studies (see Table 1.1). Some of the most informative studies on stroke burden and optimal health- care organization have arisen from population-based stroke inci- dence and outcome studies. It is important that stroke is seen and studied in a population context, as a large proportion of the bur- den of care for stroke is borne outside the hospital sector (11–13). Further, changes in referral patterns can distort longitudinal trends derived from hospitalized cases. Assessing the need for prevention strategies and services is best achieved via population-based stroke registers to determine incidence and outcome (13). Data on population trends in stroke incidence reflect the success/ failure of prevention strategies, while trends in case fatality and outcome reflect changes in stroke management. Both are needed to plan stroke services given high healthcare costs and limited resources. Accurate and representative population-based data are also crucial to: (i) determine the true incidence, causes and out- come of stroke; (ii) implement evidence-based healthcare planning, across the care spectrum; (iii) evaluate the need for and impact of preventative/management strategies; (iv) address persistent uncer- tainty about what key factors (socioeconomic and health service) impact stroke recovery; (v) examine the natural course of recovery, in particular for cognitive and behavioural outcomes; (vi) provide information on access and satisfaction with stroke services; and (vii) identify service gaps/unmet needs to ensuring evidence-based policy, resource allocation, prevention planning, management ser- vices, and evaluation of service performance. Assessing the need for prevention strategies and services is most sensitively achieved with the use of population-based registers to determine the incidence and outcome of stroke. However, study- ing stroke in a population-based fashion is particularly challenging (19), so that such epidemiological studies are relatively rare com- pared with studies using mortality data, hospital-based stroke reg- isters, or incidence studies in younger age groups only. In 1987, Malmgren et al. (23) published a list of 12 criteria related to definitions, methods, and mode of data presentation, by which the quality of population-based studies of stroke could be judged. These criteria have been updated by Sudlow et al. (19) in 1997 and most recently by Feigin et al. (Table 1.2) (24, 25). However, these criteria are so demanding in practice that even the stroke component of the WHO MONICA project is generally regarded as having failed to meet them (18). Even among many reg- isters that are population based, many were limited to people under the age of 75 years, yet only half of all strokes occur in these age groups. Although ‘ideal’ stroke incidence studies based on both core Epidemiology of stroke Valery Feigin and Rita Krishnamurthi CHAPTER 1
oxford textbook of stroke and cerebrovascular disease 2 and supplementary criteria (24, 25) are the most valuable source of information for developing evidence-based strategies for stroke pre- vention and health services, to address the problem of accurate and comparable stroke incidence studies in less affluent countries with limited resources where most strokes occur, a WHO stepwise stroke surveillance approach (26) can be recommended (Figure 1.1). An alternative approach for studying stroke incidence and preva- lence in countries with very limited resources could include a com- bination of a stroke prevalence survey (e.g. door-to-door study) with a study of death certificates (verbal autopsy procedures) in the same community (Figure 1.2), as recently recommended by Feigin (27). Stroke burden in high-income countries Historically, information on stroke incidence, prevalence, early case-fatality came predominantly from studies in high-income countries. In addition, long-term trends in stroke incidence in different populations are not well characterized, largely due to difficulties of population-based stroke surveillance (19, 28, 29). However recent studies in mid- to low-income countries have allowed comparisons in stroke burden and current trends. A recent systematic review of worldwide stroke incidence and early case-fatality (29) found that over the last four decades (1970–2008) there was a statistically significant 42% decrease in stroke incidence rates (1.1% annual reduction) in high-income countries (Figure 1.3A), with the more pronounced reduction in people younger than 75 years and in people with ischaemic stroke. This decrease may be attributable to the effective implementation of preventative measures and management of risk factors in these populations. However, in low- to middle-income countries stroke incidence rates for the same time period have increased by over 100% and currently exceed those in high-income countries. It was also shown that the risk of stroke is increasing with the age of the population in developed countries (Figure 1.4) (30). The reasons for this dif- ference are unclear, but are a matter of great importance for two main reasons: (i) stroke is a leading cause of disability in adults and (ii) the elderly (the most stroke-prone age group) constitute the fastest-growing segment of the population. Currently (2000–2008), proportional frequency of ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage Table 1.1 Common epidemiological terms Term Definition Comments Incidence The number of new cases of a disease that occur over a specified period of time The incidence rate is a measure of morbidity (illness) and can be looked at in any population group such as males, persons exposed to a particular chemical toxin, etc. Attack rate A measure of how fast a disease is occurring in a population Attack rates tell us how many new cases of a disease occur over a specific period of time Prevalence The proportion of the population affected by a disease at that time Prevalence is calculated by dividing the number of people who have the disease by the number of people in the community. It provides a snapshot of who has the disease at that point in time and does not take into account the duration of the disease Mortality A measure of the proportion of deaths over a specific time period in a given population Mortality is measured in the entire population at risk from dying from the disease, including both those who have and do not have the disease Case-fatality A measure of the proportion of deaths over a specific period of time in individuals with a specified disease Case-fatality is a measure of the severity of that disease. In contrast to mortality, case-fatality is limited to those who already have the disease Population attributable risk (PAR) A measure of the proportion of disease incidence in a total population that can be attributed to a specific exposure The PAR tells us the extent to which the elimination of a particular exposure would reduce the incidence rate of a particular disease in the whole population Disability-adjusted life year (DALY) Years of life lost to premature death and years lived with a disability of a specified severity and duration DALYs are a means of expressing the overall burden of a disease. Each DALY is 1 lost year of healthy life Randomized clinical trial (RCT) A type of study design used to evaluate a particular intervention usually for the treatment or prevention of a disease. The subjects are randomly allocated to either the treatment (e.g. the test drug) or control (e.g. no treatment) group An RCT can be used to study the effectives of a new drug to treat a condition compared to another drug or no treatment at all. In a ‘double-blind’ RCT both the subjects in the study and the researcher measuring the outcome are unaware of the allocation of the treatment groups, thus reducing bias Cohort studies A population with an exposure and a population without the exposure are followed to compare an outcome of interest between the groups Typically, the study population must be followed up for a long period of time for the outcome of interest to develop. A well-known example is the Framingham study (21) Case–control studies A study design aimed to examine the possible relation of an exposure to a certain disease. A group with the disease (cases) is compared with a group without the disease (controls) If there is an association of an exposure with a disease, there should be a higher prevalence of the exposure in the cases than in the controls Adapted from Gordis (22).
CHAPTER 1 epidemiology of stroke 3 Table 1.2 Gold standards for an ‘ideal’ stroke incidence study Domains Core criteria Supplementary criteria Standard definitions • World Health Organization definition of stroke • At least 80% CT/MRI verification of the diagnosis of ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhagea • First-ever-in-a-lifetime stroke • Classification of ischaemic stroke into subtypes (e.g. large artery disease, cardioembolic, small artery disease, other)a • Recurrent strokea Standard methods • Complete, population-based case ascertainment, based on multiple overlapping sources of information (hospitals, outpatient clinics, general practitioners, death certificates)b • Prospective study design • Large, well-defined and stable population, allowing at least 100,000 person-years of observationb • Follow-up of patients’ vital status for at least 1 montha • Reliable method for estimating denominator (not more than 5 years old census data)b • Ascertainment of patients with TIA, recurrent strokes and those referred for brain, carotid or cerebral vascular imaginga • ‘Hot pursuit’ of cases • Direct assessment of under-ascertainmenta by regular checking of general practitioners’ databases and hospital admissions for acute vascular problems and cerebrovascular imaging studies and/or interventions Standard data presentation • Complete calendar years of data; not more than 5 years of data averaged togetherb • Men and women presented separately • Mid-decade age bands (e.g. 55–64 years) used in publications, including oldest age group (≥85 years)b • 95% confidence interval around rates • Unpublished 5-year age bands available for comparison with other studies a New criteria. b Updated, modified from Sudlow and Warlow (19). Reprinted from Feigin and Carter (25) with permission. Step 1 Step 2 Step 3 Community events Module 6 Hospital events & vital status Module 1 + Disability Module 2 + Subtype Module 3 Autopsy Module 5 Population- based Hospital- based Population coverage Non-fatal events in community Fatal events in community Events in hospital Comprehensive Expanded Standard Cause of death (death certifi- cate or verbal autopsy) Module 4 in high-income countries were estimated as 82%, 11%, and 3%, respectively (29). Early (1-month) case fatality in high-income countries has decreased over the last four decades from 35.9% to 19.8%, potentially due to improved management of acute strokes, and possibly a shift towards less severe strokes. Overall, case-fatality within 1 month of stroke onset in high-income countries is cur- rently about 23% and is higher for intracerebral haemorrhage (42%) and subarachnoid haemorrhage (32%) than for ischaemic stroke (16%) (30). A recent systematic review of population-based stroke incidence and prevalence studies showed the age-standardized prevalence of stroke in people aged 65 years and older ranges worldwide from 46–72 per 1000 population (Figure 1.5) (30). Stroke makes a signif- icant contribution to disability burden in low- and middle-income Fig. 1.1 STEP-wise approach to stroke surveillance. (Adapted from Truelsen et al. (24) with permission.)
oxford textbook of stroke and cerebrovascular disease 4 countries (31), and the recent 2010 Global Burden of Disease Project ranked stroke as the fifth highest cause of DALYs worldwide in 2010 (an increase of 19% from 1990) (32). In terms of global variation, stroke burden was shown to be higher in China, Africa, and South America, and lower national income was associated with higher relative mortality and burden of stroke (33). Stroke burden in low- to middle-income countries One of the major challenges in stroke epidemiology is the lack of good-quality epidemiological studies in developing countries (34). According to WHO estimates, death from stroke in devel- oping (low- and middle-income) countries in 2001 accounted for 85.5% of stroke deaths worldwide (35), and the number of DALYs, which comprises years of life lost and years lived with disability (35), in these countries was almost seven times that in developed (high-income) countries (4, 27). Recent meta-analysis of population-based stroke incidence stud- ies (29) showed that unlike high-income countries, the incidence of stroke in low- to middle-income countries has increased by 100% over the last four decades (1970–2008) (Figure 1.3B). Stroke incidence rates in low- to middle-income countries increased with increasing age in a similar manner to high-income countries (Figure 1.6). Although ischaemic stroke is the dominating stroke pathologi- cal type all over the world, the proportional frequency of intrac- erebral haemorrhage in low- to middle-income countries tends to be noticeably greater than that in high-income countries (Figure 1.7) (29). There is evidence from recent studies that the risk factors for stroke in middle- to low-income countries are similar to that in high-income countries, including high blood pressure, smoking, and obesity, although the relative significance of stroke risk fac- tors in high- and low- to middle-income countries may be dif- ferent (see Chapter 2). The increase in stroke incidence in low- to middle-income counties may be attributed to the poor manage- ment of these risk factors. While early case fatality is similar to that of high-income countries, the decrease in early case fatality is not as high as that in high-income countries. Gender and ethnic differences in stroke burden There are notable gender and ethnic differences in stroke incidence and outcomes both in high- and mid- to low-income countries. Both socioeconomic and ethnic differences in the risk of stroke have been seen in many countries (36–39). For example, higher risks have been observed among Maori and Pacific people in New Zealand (40, 41), and in the black populations in the United States (36) and United Kingdom (37), compared to the white popula- tion. Higher stroke attack rates in lower socioeconomic groups are probably related to several factors. As a general rule, lower socio- economic groups are more frequently exposed to risk factors for cardiovascular disease, including hypertension, smoking, diabetes, and excessive consumption of alcohol (42). In addition, it has been suggested that lower socioeconomic groups have less access to, or make less effective use of, services that are important to the man- agement of these risk factors, such as early detection and control of hypertension (43). Similarly, many of the ethnic differences in stroke risk have been attributed to differences in socioeconomic circumstances and exposure to risk factors (43). However, studies of cardiovascular disease have found that not all of the differences in attack rates among ethnic groups can be explained by differences Study population (about 25,000–30,000) Prevalence study (door-to-door survey) Questionnaire to identify subjects with possible stroke over the past 3 years Clinical examination of screened positive subjects Stroke is not confirmed Stroke is not confirmed Stroke confirmed First-ever stroke First-ever stroke Incident stroke cases Stroke confirmed Verbal autopsy procedure Stroke suspected (stroke mentioned in death certificate) Study of death certificates over the past 3 years Stroke not suspected Fig. 1.2 An alternative approach for studying stroke epidemiology in resource-poor countries. (Reprinted from Feigin (25) with permission.)
CHAPTER 1 epidemiology of stroke 5 0 50 100 150 200 250 300 350 400 (a) (b) 1970-1979 1980-1989 1990-1999 2000-2008 Rochester, MN Tartu, Estonia Copenhagen, Denmark Dublin, Ireland North Karelia, Finland Saku, Japan Frederiksberg, Denmark Espoo-Kauniainen, Finland Soderham, Sweden Shibata, Japan Tilburg, Netherlands Oyabe, Japan2 Auckland, NZ Turku, Finland (1982) Dijon, France Ubmbia, Italy Malmo, Sweden Valley d'Aosta, Italy Perth, Australia Belluno, Italy Greater Cincinnati, USA Arcadia, Greece L'Aquila, Italy East Lancashire, UK Inherred, Norway Erlangen, Germany South London, UK Vibo Valentia, Italy Melbourne, Australia Scottish Borders region, UK Porto, Portugal Porto, Portugal2 Orebro, Sweden Barbados Lund-Orup, Sweden Oxfordshire, UK 0 50 100 150 200 250 1970-1979 1980-1989 1990-1999 2000-2008 Ibadan, Nigeria Ulan Bator, Mongolia Rohtak, India Colombo, Sri Lanka Novosibirsk, Russia Krasnoyarsk, Russia Martinique, French WestIndies Uzhgorod, West Ukraine Tbilisi, Georgia iquque, Chile Matao, Brazil Mumbai, India Fig. 1.3 (a) Age-adjusted annual incidence of stroke in high income countries per 100,000/year*. (b) Age-adjusted annual incidence of stroke in low to middle income countries 100,000/year*. (Reprinted from Feigin et al. (13) with permission.) in conventional cardiovascular risk factors, suggesting genetic and other factors are important (44). Thus, there remains considerable uncertainty regarding the relative importance of stroke risk factor management and control and other factors in the aetiology of these inequalities. There is also some evidence suggesting ethnic differences in stroke outcomes. In a recent prospective population-based study of 1127 patients with acute stroke in Auckland, New Zealand the risk of dependency, as measured by Frenchay Activities, at 6 months post-stroke was higher in non-Europeans (Asian and Pacific
oxford textbook of stroke and cerebrovascular disease 6 Four regions of the U SA Auckland, N Z Taiwan, China North Yorkshire, U K Rotterdam , N L L’Aquila, Italy Newcastle U K Men Women Both 0 10 20 30 40 50 Cases per 1000 per year 60 70 80 90 100 Fig. 1.5 Age-standardized prevalence of stroke per 1000 population in selected studies of people aged 65+ years. (Reprinted from Feigin et al. (26) with permission.) 0 <45 45–54 55–64 Rohtak, India (1971–74) Ibadan, Nigeria (1971–74) Colombo, Sri Lanka (1971–74) Martinique, French West Indies (1998–99) Iquique, Chile (2000-02) Years 65–74 75+ 2 4 6 8 10 Rate per 1000 per year 12 14 16 Fig. 1.6 Age-specific annual incidence of first-ever-in-lifetime stroke per 1000 population in selected developing countries. (Reprinted from Feigin (26) with permission.) 0.00 <45 45–54 55–64 Age (years) 65–74 75–84 85+ 5.00 10.00 15.00 20.00 25.00 Cases per 1000 per year 30.00 35.00 40.00 45.00 Melbourne, Australia Frederiksberg, Denmark L’Aqulia, Italy Uzhgorod, Ukraine Innherred, Norway Arcadia, Greece Oyabe, Japan South London, UK Perth, Australia French West Indies Novosibirsk, Russia Auckland, NZ Belluno, Italy Erlangen, Germany Espo-Kauniainen, Finland Fig.1.4 Age-specific stroke incidence rates in selected, primarily high income countries per 1000-person-years. (Reprinted from Feigin et al. (13) with permission.) people) compared to Europeans (after adjustment for casemix vari- ables) (45). Measures of handicap and quality of life were also worse in non-Europeans. Some ethnic differences particularly in stroke outcomes may be attributable to socioeconomic status and acces- sibility to healthcare, and/or to a higher prevalence of risk factors in some ethnic groups. Additionally, there are gender differences in stroke. The lifetime risk of stroke in women (one in five) is greater than in men (one in six) (46). This higher risk is primarily due to the greater life expec- tancy of women. Worldwide evidence of better outcomes in male stroke survivors is accumulating (47–51), yet reasons for these gen- der differences in stroke outcomes are also unclear. Recent research shows poorer functional outcomes and quality of life post stroke in women are not due to differences in age, pre-stroke function, and comorbidities (47). As women often have their stroke later in relation to men they are also usually the most important fam- ily caregivers (52). Their state of health can affect the health and well-being of other family members and demands placed upon
CHAPTER 1 epidemiology of stroke 7 them in providing care to men and others within their social net- work can also increase their risk of stroke (52, 53). A study of stroke incidence in women showed that two-thirds of women with stroke were not partnered compared with one-third of men (52). Due to their greater life expectancy, more elderly women are likely to be living alone, thus there is a greater risk of the need for institution- alized care after stroke. More intensive treatment/rehabilitation may be needed to improve outcomes for women, along with fur- ther research to explore underlying biological mechanism of gen- der differences in outcome (51). Accurate population-based data on gender and ethnic differences in stroke burden and service use will facilitate implementation of evidence-based recommendations to bridge gaps in health services and increase uptake of lifestyle changes in ethnic and sex groups (39). Suggested public health strategies to reduce the global stroke burden The global stroke burden, particularly in low- to middle-income coun- tries is likely to reach epidemic proportions if current trends continue. In developing countries, there has been a shift towards urbanization drivenbysocialandeconomicchanges.Thishasledtochangestowards poorer diet and lifestyle choices thus increasing the prevalence of risk factors, including smoking. With increasing life expectancy leading to older populations, the burden of stroke will become a major cause for concern unless urgent action is taken to implement population-based prevention at local government and international levels. For stroke prevention programmes to be effective, they should be designed with an understanding of the independent relative risk, prevalence, independent population attributable risk, and adapta- tion of proven measures to modify or control the specific risk factor (54, 55). Public health strategies to reduce global stroke burden include increasing public stroke awareness, increasing awareness of stroke risk factors, and the importance and effectiveness of pre- vention. Additionally, local and national government bodies need to take responsibility to improve lifestyle factors, for example, by making fresh fruits and vegetables more affordable. Ways to reduce tobacco use and reduce dietary salt intake must be explored and implemented to reduce stroke risk. There is sufficient evidence for effective strategies for stroke prevention (see Chapter 22); the chal- lenge now is to apply this knowledge effectively to reduce the bur- den of stroke globally. References 1. Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and mortality: estimates from monitoring, surveillance, and modelling. Lancet Neurol. 2009;8(4):345–354. 2. Rothwell PM. The high cost of not funding stroke research: a comparison with heart disease and cancer. Lancet. 2001;357(9268): 1612–1616. 3. Mackay J, Mensah GA. The Atlas of Heart Disease and Stroke. Geneva: World Health Organization; 2004. 4. Strong K, Mathers C, Bonita R. Preventing stroke: saving lives around the world. Lancet Neurology. 2007 Feb;6(2):182–187. 5. Caro JJ, Huybrechts KF, Duchesne I. Management patterns and costs of acute ischemic stroke: an international study. Stroke. 2000 Mar;31(3):582–590. 6. Bonita R, Anderson CS, Broad JB, Jamrozik KD, Stewart-Wynne EG, Anderson NE. Stroke incidence and case fatality in Australasia. A comparison of the Auckland and Perth population-based stroke registers. Stroke. 1994 Mar;25(3):552–557. 7. Bonita R, Broad JB, Beaglehole R. Changes in stroke incidence and case-fatality in Auckland, New Zealand, 1981-91. Lancet. 1993;342(8885):1470–1473. D ijon, France (1987) Perth, Australia (1989) Um bria, Italy (1988) O xfordshire, U K (1984) Aosta, Italy (1989) Frederiksberg, D enm ark (1989) Soderham n, Sweden (1990) M elbourne, Australia (1996) Perth, Australia (1995) South London, U K (1995) Erlangen, G erm any (1994) Arcadia, Greece (1993) Belluno, Italy (1992) L’aquila, Italy (1994) Inherred, N orway (1994) M artinique, French W est Indies (1998) O xfordshire, U K (2002) Iquique, Chile (2002) Rochester, U SA (1988) 100 Undetermined pathological type of stroke Subarachnoid haemorrhage Intracerebral haemorrhage Cerebral infarction 90 80 70 60 50 40 Percentage 30 20 10 0 Fig. 1.7 Proportional frequency of stroke subtypes in selected populations. CI: cerebral infarction; ICH: intracerebral haemorrhage; SAH: subarachnoid haemorrhage; UND: undetermined pathological type of stroke. (Modified from Feigin (13) with permission.)
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Stewart JA, Dundas R, Howard RS, Rudd AG, Wolfe CD. Ethnic differences in incidence of stroke: prospective study with stroke register. BMJ. 1999;318(7189):967–971. 38. van Rossum CT, van de MH, Breteler MM, Grobbee DE, Mackenbach JP. Socioeconomic differences in stroke among Dutch elderly women: the Rotterdam Study. Stroke. 1999 02;30(2):357–362. 39. Feigin VL, Rodgers A. Ethnic disparities in risk factors for stroke: what are the implications? Stroke. 2004;35(7):1568–1569. 40. Bonita R, Broad JB, Beaglehole R. Ethnic variations in stroke incidence and case fatality: the Auckland Stroke study. Stroke. 1997;28:758–761. 41. Feigin V, Carter K, Hackett M, Barber PA, McNaughton H, Dyall L, et al. Ethnic disparities in incidence of stroke subtypes: Auckland Regional Community Stroke Study, 2002–2003. Lancet Neurol. 2006;5(2):130–139. 42. Kaplan GA, Keil JE. Socioeconomic factors and cardiovascular disease: a review of the literature. Circulation. 1993 Oct;88(4:Pt 1):1973–1998. 43. Casper M, Wing S, Strogatz D, Davis CE, Tyroler HA. Antihypertensive treatment and US trends in stroke mortality, 1962 to 1980. Am J Public Health. 1992 Dec;82(12):1600–1606. 44. Anand SS, Yusuf S, Vuksan V, Devanesen S, Teo KK, Montague PA, et al. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet. 2000;356(9226):279–284. 45. Rose SB, Lawton BA, Elley CR, Dowell AC, Fenton AJ. The ‘Women’s Lifestyle Study’, 2-year randomized controlled trial of physical activity counselling in primary health care: rationale and study design. BMC Public Health. 2007;7:166. 46. Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB, et al. The lifetime risk of stroke: estimates from the Framingham Study. Stroke. 2006;37(2):345–350. 47. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, et al. 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Introduction It is of great importance to identify the risk factors for stroke and to what extent these different risk factors contribute to the general as well as the individual risk burden for stroke. The term risk factor has been used since the 1960s (1). A risk factor has been defined as a factor (trait) associated with a pathological medical condition. However, such an association is not sufficient to establish a factor to be a risk factor. A specific trait may be seen in individuals after disease onset but its occurrence does not prove that this caused the disease. For example, if hypertension is often seen in stroke patients, does this necessarily mean that hypertension is the cause of stroke, or could possibly hypertension be the result of the stroke instead? Because of this, prospective cohort studies are often needed to identify risk factors. If a factor observed before stroke onset can be related to stroke occurring later in life, this indicates that this factor may indeed be a risk factor. However, some factors may be analysed also after stroke onset without this caveat, especially factors that are not influenced by the disease onset, e.g. gender and variations in the human genome. An additional proof that a trait is actually a risk fac- tor for stroke is if treatment of the trait leads to a reduced incidence of stroke. The amount of influence a specific risk factor has on risk is often measured as relative risk, odds ratio (OR), hazard ratio, and population attributable risk (PAR) (Table 2.1). PAR is the portion of risk for a disease caused by a specific factor. The numerical value of the PAR indicates how much of the disease that would be avoided if the risk factor could be completely elimi- nated. Therefore it is related to absolute risk for a specific factor. Interestingly, even though ischaemic heart disease (IHD), stroke, and peripheral artery disease are all arterial diseases, the impor- tance of risk factors influencing these conditions seem to vary. Thus hypertension is most important for stroke whereas lipid alterations seem to be more important for myocardial infarction (Figure 2.1) (4). Risk factors for ischaemic arterial cerebrovascular disease Non-modifiable factors Birth weight Low birth weight is reported to be associated with increased stroke risk in adult life (5). Even after adjustment for childhood socioeco- nomic factors the risk of vascular disease in adulthood may remain (6). A relation between low birth weight and higher blood pres- sure (BP) in adults has been observed (7). The relation between low birth weight and stroke may be more pronounced for haemorrhagic stroke (8). It could be suggested that the birth weight is, from a pop- ulation perspective, a modifiable risk factor if taking the nutritional situation of the mother during pregnancy into account. Gender Male gender increases the risk for ischaemic stroke (9, 10). The risk of stroke for men is about 1.3 times as high as for women at a given age except in the highest ages (Figure 2.2). However, this gender difference is less evident when taking the number of risk factors in each individual into account (11). Early menopause has been asso- ciated with increased stroke risk (12) and after menopause several vascular risk factors become more prevalent in women (10). The difference in risk between the genders seems to disappear in high age over 80–85 years of age (9). The gender risk is different for suba- rachnoid haemorrhage where the risk is higher for women (13). Age Stroke incidence increases markedly with age (Figure 2.2) (9, 14, 15). This steep increase in stroke incidence by age is observed in both men and women. In the OXVASC study, the rate of stroke increased from 1.76 per 1000 individuals per year for individu- als aged 55–64 years to 16.47 for those aged 85 or more (14). The increased incidence with age is seen for ischaemic stroke (16) as Risk factors Arne Lindgren CHAPTER 2 Table 2.1 Different terms used for describing influence of risk. For details, see (2, 3) Term Definition Absolute risk Risk in absolute number, e.g. if the risk is 1/100 for stroke if the person has a trait and 1/200 if the person does not have the trait Relative risk Relative comparison between two situations, e.g. if the risk is 1/100 for the person with the trait and 1/200 for the person without the train—then the relative risk is 2 Odds ratio Used in, e.g. retrospective case–control studies to estimate relative risk. Calculated as the odds of having a disease if having the trait divided by the odds of not having the disease if having the trait Hazard ratio Used for comparing survival in two different groups during a specific studied time period. The observed number divided by expected number in group 1 is compared (divided) by the observed number divided by expected number in group 2 Population attributable risk Proportion of risk for a disease caused by a specific factor. Indicates how much of the disease that could be avoided if the risk factor was not present
oxford textbook of stroke and cerebrovascular disease 10 well as for intracerebral haemorrhage (ICH) (17) and also to some extent for subarachnoid haemorrhage (18). The risk of stroke more than doubles with each decade of increased age after 55 years of age at least up to age 84 (16, 19, 20). Also after age 84, the stroke risk continues to increase (19). Ethnicity There are considerable variations in stroke incidence between dif- ferent ethnic groups. People of African origin have a higher risk of all stroke types compared with Caucasians. This risk is at least 1.2 times higher and even higher for ICH (21). It is possible that this can in part be explained by poorer management of treatable risk factors. The proportion of ICH is higher (about 28%) among Chinese than among Caucasians (22). This increased proportion may remain also after emigration to Western countries; in one study 24% of reported strokes were of haemorrhagic type (23). It has also been reported that in ischaemic stroke, the prevalence of intracranial artery stenosis is more frequent in East Asians (24, 25) and African Americans (26) than in Caucasians. Familiar/genetic causes (specific or polygenetic) Even after accounting for all established risk factors there seems to be an increased risk of stroke among some families. This and other observations have led to the conclusion that some inherited factors may contribute to the risk of stroke. The heritability of ischaemic stroke when using genome-wide association study data has been calculated as 37.9% overall, ranging from 40.3% for large ves- sel disease to 32.6% for cardioembolic and 16.1% for small vessel disease (27). Several rare stroke syndromes have been associated with mono- genetic variations, e.g. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy; NOTCH3 gene) (28), CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leucoencephalopathy; HTRA gene), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; mitochondrial disease), HERNS (hereditary endotheliopathy with retinopathy, nephropa- thy, and stroke; TREX1 gene), homocystinuria, Fabry disease (alpha galactosidase gene), Ehlers–Danlos syndrome type IV, Marfan syndrome, pseudoxanthoma elasticum, HANAC (heredi- tary angiopathy, nephropathy, aneurysm, and muscle cramps syn- drome; COL4A1 mutation), and other syndromes (29). Typically these syndromes include stroke or stroke-like episodes as only one of several different clinical manifestations of the syndrome in ques- tion. It should be emphasized that in some cases stroke is the pre- senting symptom before other symptoms that indicate the specific syndrome are seen. For details, please see Chapter 14. Sickle cell disease (SCD) increases the risk of stroke in childhood with a prevalence of cerebral infarct of 11% at the age of 20 years (30). SCD children with increased transcranial Doppler ultrasound veloci- ties of the middle cerebral arteries have a particularly high risk. At ages 20–30 years these patients also have a risk of cerebral haemor- rhage (30). Cerebral infarcts have also been reported in other related genetic haemoglobin variations though at a lower rate compared with SCD (30). Additional details on SCD are provided in Chapter 14. The common stroke phenotypes have been more difficult to relate to specific genetic variations. However, there are now reports emerging that certain common genotypes, especially single-nucleotide polymorphism (SNP) variations, are associated with increased risk of intermediate phenotypes that subsequently increase the risk of stroke. Such intermediate phenotypes that may be genetically influenced include hypertension, diabetes mellitus, and heart disease. One example is atrial fibrillation (AF) that has been shown to be related to genetic variations and specific types of ischaemic stroke. AF has in genome-wide association studies been related to SNPs in the PITX gene, the ZHFX3 gene, and the KCNN3 gene (31). There are also reports of genetic variations that seem to be more directly related to common subtypes of ischaemic stroke. Typically these reports have included large international collaborations such as the International Stroke Genetics Consortium. SNP variations in the chromosome 9p21 region have been related to ischaemic stroke (32), and these associations seem more evident for the large vessel type of stroke (33). Recently, a new SNP in HDAC9 on chro- mosome 7p21.1 was associated with large vessel ischaemic stroke (34). Very recently another study reported a locus on chromosome 6p21.1 related to the ischaemic stroke subtype large artery athero- sclerosis (35). The Metastroke collaboration was able to confirm several of these findings (36). Also for ICH there have been reports on genetic associations. The APOE ε2 and ε4 alleles are mostly related to lobar ICH and likely amyloid angiopathy whereas ε4 is also, although not with the same high degree of significance, related to deep ICH (37). Hypertension Myocardial infarction Stroke 0 10 20 30 Per cent PAR 40 50 60 Smoking Main modifiable risk factors Diabetes ApoB/ApoA1 ratio Fig. 2.1 Degree of influence of some risk factors for stroke and myocardial infarction. (Endres M, Heuschmann PU, Laufs U, Hakim AM. Primary prevention of stroke: Blood pressure, lipids, and heart failure. Eur Heart J. 2011;32:545–552) 55–59 0 5 10 15 10-Year probability of stroke/100 20 25 Men Women 60–64 65–69 Age, years 70–74 75–79 80–84 Fig. 2.2 Average 10-year probability of stroke according to age in men and women per 100 (%). (Wolf PA, Belanger AJ, D’Agostino RB. Quantifying stroke risk factors and potentials for risk reduction. Cerebrovasc Dis. 1993;3(Suppl 1):7–14.)
CHAPTER 2 risk factors 11 Other diseases and measurable traits Hypertension Hypertension is the most important treatable risk factor for stroke (4). History of hypertension increases the OR to 2.6 for stroke and has a PAR of 35% (38). The individual relative risk for stroke in hypertensives may be higher—up to 8 in a group of individuals with a mean age of 47 years to develop a stroke during a 10-year follow-up period (39). Hypertension is commonly detected among stroke patients under 55 years of age (40, 41). Hypertension remains to be a stroke risk factor in the elderly and also at ages over 60 is it useful to treat hypertension to prevent stroke (42). At even higher ages the importance of hypertension as a stroke risk factor is some- what more difficult to assess because the prevalence of hypertension is so high in these age groups (43). However, hypertension treat- ment seems to reduce stroke risk also in the very elderly, indicating that it is also important to control BP among these individuals (44). Both systolic (Figure 2.3) (45) and diastolic (46) BP is of impor- tance for stroke risk. Not only hypertension but also BP within the normal range may be a risk factor for stroke. There is no thresh- old for BP—also rather normal BP levels carry an increased risk of stroke (47) and a considerable proportion of strokes occur among people with high–normal BP or ‘mild’ hypertension (45). A systolic BP increase of 20 mmHg or a diastolic BP increase of 10 mmHg more than doubles the risk of stroke death (47). Not only may the BP measured at a certain time be related to stroke risk, it has been suggested that BP variability and episodic hypertension may increase the stroke risk (48). This may have impli- cations for how BP will be measured and evaluated in the future and also influence which antihypertensive drugs are preferred. Stroke/transient ischaemic attack A previous stroke is a powerful risk factor of a new stroke. The risk of a new stroke varies considerably depending on the patho- genetic mechanism of the first stroke and on the simultaneous presence of other risk factors. A risk of about 9% during an aver- age follow-up of 2.5 years, i.e. about 3.6% per year, was reported in the PROFESS trial which included patients with a mean age of 66 years (49). Also, transient ischaemic attack (TIA) indicates an increased the risk for a subsequent stroke both in the short term and long term. In one study, the risk of stroke within 90 days of a TIA was on average 10.5% but depended on the characteristics of the TIA with higher risk among those with a TIA with weakness or speech impairment, diabetes mellitus, age over 60 years, or longer TIA duration (50). Silent cerebral infarcts/white matter disease Presence of silent cerebral infarcts increases the stroke risk by at least two to three times independently of other vascular risk fac- tors (51, 52). Both periventricular and subcortical white matter hyperintensities also increase the risk of subsequent stroke, inde- pendently of the presence of silent brain infarcts (52). Atrial fibrillation AF is a powerful risk factor for stroke. The abnormal contractions of the atrium of the heart lead to non-laminar blood flow in the left atrium. The blood flow in the left atrial appendage also becomes disturbed and the general opinion is that the blood clots in AF usu- ally develop in the left atrial appendage. Fragments of or the whole clot then detach from the left atrial appendage and embolize to the cerebral arteries or other parts of the arterial system. The risk for stroke depends on whether other factors are present simultaneously with the AF. The often used CHADS2 score (one point for each of: congestive heart failure, hypertension, age >75, diabetes; and 2 points for stroke or TIA) is a useful method to estimate stroke risk in patients with AF. With none of the factors mentioned in CHADS2, the yearly risk of stroke in patients is on average 1.9%, with one factor present the risk is about 2.8%, and with all factors present the yearly risk is on average 18.2% (53, 54). The more recently developed CHA2DS2-VASc may be even more precise in determining stroke risk in AF patients (Table 2.2). Other cardiac conditions including patent foramen ovale There are many heart conditions that have been suggested to be associated with increased stroke risk (see Table 2.3). Some of these conditions are well established, e.g. AF (see ‘Atrial fibrillation’ sec- tion above), mitral valve stenosis, acute anterior transmural myo- cardial infarct, atrial myxoma, mechanical heart valve prosthesis in the mitral or aortal position, whereas other are considered more equivocal regarding stroke risk. The latter include patent foramen ovale (PFO), atrial septal aneurysm, mitral annulus calcifications, and others (55). A PFO is a remaining connection between the right and left atrium of the heart. If the connection is larger and not having over- lapping structures functioning as a valve the condition is instead an atrial septal defect. In both cases there is a theoretical possibil- ity that a venous thrombus travelling as an embolus in the venous system to the heart may pass directly from the right atrium on the venous side of the heart directly to the left atrium on the arterial side of the heart and then continue to travel out into the arterial system. Another possibility that has been proposed is that a throm- bus may form in situ in the channel that often constitutes the PFO and then detach as an embolus. The relation between PFO and the risk of ischaemic stroke has been debated. PFO is often present in the general population at a rate of about 20–25%. Therefore there is a possibility that the PFO is just a coincident finding in the stroke patient. However, some reports have indicated that among young patients with cryptogenic ischaemic stroke, PFO may be seen more 100 0 5 10 15 0 3 11 17 18 16 11 8 8 8 20 25 120 140 Systolic blood pressure (mmHg) 160 180 200 0 10 20 Stroke mortality/1000 person-years Population distribution (%) 30 40 50 Fig. 2.3 Influence of systolic BP on stroke mortality. (Marmot MG, Poulter NR. Primary prevention of stroke. Lancet. 1992;339:344–347.)
oxford textbook of stroke and cerebrovascular disease 12 often than in the general population (56). It has also been discussed that the size of the PFO and a concomitant atrial septal aneurysm (defined as hypermobile part of the septum between the right and left atrium) may increase the risk of stroke (57). Lipid changes Serum lipid levels do not play such an important risk factor role for ischaemic stroke as for IHD (20, 58). Even so, increased choles- terol levels are related to ischaemic stroke risk, although this may differ between different pathogenetic subtypes of ischaemic stroke (58). Cholesterol levels are associated with carotid artery athero- sclerosis (59) and it is therefore likely that cerebral infarcts caused by large vessel disease are more clearly related to increased choles- terol levels. Conversely, reports indicate that low cholesterol levels may increase the risk of ICH (60, 61) and observations have related intense lowering of cholesterol levels in stroke patients to a slightly increased risk of ICH (62). The situation regarding triglyceride lev- els and risk of stroke is unclear (20). Coagulation disorders Antiphospholipid antibodies including anticardiolipin antibod- ies and lupus anticoagulant have been associated with ischaemic stroke. Even though the situation is complex with different assays and cut-off levels used, there is probably an increased stroke risk for patients with high levels of these antibodies (63). Several other coagulation disorders are associated with increased risk of venous thrombosis, but it is much less clear how these affect the arterial situation (63). It is possible that in some situations a coagulation disorder causing a venous thrombosis may give rise to paradoxical embolism through a PFO. Homocysteine Increasedhomocysteinelevelshavebeenobservedinstrokepatients (64). Even so, the importance of increased homocysteine levels for stroke risk has been debated. Two reasons for this are: (i) that the situation is complicated by the relation between homocysteine levels and other vascular risk factors, e.g. age and decreased renal function, both of which in their turn influence stroke risk; and (ii) that studies have been unable to clearly demonstrate that homo- cysteine lowering therapy decreases stroke risk (65). Diabetes mellitus Diabetes mellitus has a deteriorating effect on arterial blood ves- sels and is a risk factor for ischaemic stroke. The relative risk of ischaemic stroke for diabetic individuals has been estimated to be between 1.3 and 6 (20, 66). Diabetes also increases the risk of stroke recurrence (66). Lacunar infarcts may be more common in diabetic patients (67) although this has not always been reported (68). The effect of diabetes may in part be mediated by other risk factors such as hypertension and lipid alterations and it is also possible that these and other risk factors such as smoking potentiate each other. Migraine The relation between migraine and stroke is complex (69). Migraine and ischaemic stroke often occur in the same patients. Migraine-like symptoms may indicate another underlying disease that may cause a stroke, e.g. arteriovenous malformation, arterial dissection, CADASIL, MELAS, encephalitis, or even atherosclerosis. It is also of interest that migraine has been related to increased prevalence of white matter hyperintensities on magnetic resonance imaging. However, also in patients without migraine caused by another dis- ease, there seems to be an increased risk of stroke, and the risk is higher for patients with migraine with aura compared with patients with migraine without aura. The risk of stroke in migraineurs may be higher in women than in men (70). The increased risk among individuals with migraine with aura has been reported to represent a relative risk of 2.27 (71). However, the individual risk in younger patients who report migraine with aura, e.g. under 45 years of age, is still low due to the low overall stroke incidence in younger ages. Migraine as a risk factor for stroke seems to interact with other risk factors such as smoking and use of oral contraceptives. The cerebral infarct supposed to be caused by migraine with aura has symptoms similar to those experienced in the aura phase. It has been sug- gested that a pronounced cortical spreading depression may cause local ischaemia so profound that an infarct develops. Other the- ories have included that the increased prevalence of PFO among Table 2.2 CHA2DS2VASc score and risk of stroke in patients with AF. Risk factor-based approach expressed as a point based scoring system, with the acronym CHA2DS2–VASc (Note: maximum score is 9 since age may contribute 0, 1, or 2 points) Risk factor Score Congestive heart failure/LV dysfunction 1 Hypertension 1 Age ≥ 75 2 Diabetes mellitus 1 Stroke/TIA/thrombo-embolism 2 Vascular diseasea 1 Age 65–74 1 Sex category (i.e. female sex) 1 Maximum score 9 Adjusted stroke rate according to CHA2DS2– VASc score CHA2DS2 –VASc score Patients (n = 7329) Adjusted stroke rate (%/year)b 0 1 0% 1 422 1.3% 2 1230 2.2% 3 1730 3.2% 4 1718 4.0% 5 1159 6.7% 6 679 9.8% 7 294 9.6% 8 82 6.7% 9 14 15.2% a. Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates. b. Based on Lip et al. Stroke. 2010;41:2731–2738. LV = left ventricular. Reproduced from Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: The task force for the management of atrial fibrillation of the European Society of Cardiology. Eur Heart J. 2010;31:2369–2429, with permission.
CHAPTER 2 risk factors 13 patients with migraine with aura is a possible mechanism for the increased risk of stroke in these patients. However, this has been questioned and it is possible that this is only an epiphenomen, i.e. that migraine with aura and PFO coexist in the same patients with- out any additional combined mutual influence on stroke risk. For a detailed, up-to date overview about migraine and stroke, please see reference (69). Infection Inflammation measured as, e.g. C-reactive protein or fibrinogen levels, seem to increase the risk of stroke (72). Acute or chronic infections that precede stroke onset and cause an increased stroke risk may at least in part be mediated by inflammation (73). Chronic infections suggested to be related to stroke include agents such as Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus, her- pes simplex virus (HSV)-1, and HSV-2 even though the effect is perhaps more mediated by a ‘total burden’ of infections rather than a single agent (72). Periodontitis has also been related to stroke risk (74).ItseemsclearthatChagasdiseasecausesincreasedriskofstroke (75). Acute infection, e.g. respiratory or urinary tract infection, may precede stroke onset and indicate increased stroke risk (73). Obstructive sleep apnoea Even though obstructive sleep apnoea (OSA) may increase BP and be related to obesity, there seems to be an independent stroke risk related to OSA per se (76). Suggested possible mechanisms include hypercoagubility, atherosclerosis, decreased cerebral blood flow, and paradoxical embolization (76). Interestingly, wake-up stroke has recently been linked to OSA (77). Renal disease Renal dysfunction increases the risk of stroke in individuals with known atherothrombotic disease (78). Microalbuminuria has been independently associated with stroke risk (79). Arterial diseases Carotid artery stenosis or occlusion is a well-known risk factor for stroke. There is a risk in individuals with asymptomatic carotid artery stenosis (80, 81) but the risk is considerably higher in patients with a symptomatic high-degree stenosis (81–83). Aortic plaques are independent risk factors for stroke and severe aortic arch plaques have been reported to confer a risk of cerebral infarct of 10% or more in 1 year (84). Patients with asymptomatic or symptomatic peripheral arterial disease have an increased risk of stroke (85, 86). In addition, carotid artery disease is more fre- quently seen in patients with peripheral artery disease (85). Several diseases with microangiopathy of the brain (87, 88) and sometimes simultaneous vascular involvement of other organs (some with, some without clinical symptoms from other organs than the brain) are related to stroke risk, e.g. CADASIL (28, 89), CARASIL (90), HERNS (91), HANAC (92), HSA (hereditary sys- temic angiopathy) (93), Fabry disease (94), polyarteritis nodosa (95), and other syndromes. Other diseases Several factors that are more uncommon in the general population are also related to stroke risk. These factors include inflammatory disease, e.g. inflammatory bowel disease, haematological disorders, cancer, and different medical or surgical procedures. Please see separate chapters in this book regarding these conditions. Lifestyle risk factors Several lifestyle risk factors have been related to stroke risk. A com- prehensive review on this topic with both tables of relative risk and information on PAR has been given by Chiuve et al. (96). The Royal College of Physicians has provided tables of evidence that include aspects on life style factors (<http://www.rcplondon.ac.uk/ sites/default/files/documents/stroke_evidence_tables_2008.pdf>, accessed 29 Oct 2013). It is of special interest that some factors have been reported as acute triggers of stroke onset (97). The following sections give a more detailed description of lifestyle and stroke risk. Smoking Cigarette smoking approximately doubles the risk for ischaemic stroke (38, 98–100). The situation for ICH is less clear but here smok- ing may also indicate an increased risk (96). There is an even more pronounced relation between cigarette smoking and risk for suba- rachnoid haemorrhage (101). Also, passive smoking carries a risk for stroke (98). Smoking potentiates the effect of other risk factors (20). Cigarette smoking is associated with an increased risk of atheroscle- rosis as well as with the risk of thrombus formation. Individuals who stop smoking reduce their risk of stroke (96, 100) by up to 50% (100). Alcohol Excessive alcohol consumption increases the risk of stroke. Moreover, individuals who do not use any alcohol may have a slightly increased risk (96), and a J-shaped curve for stroke risk regarding alcohol consumption has been suggested (20). It is pos- sible that temporary heavy alcohol consumption increases the risk of immediate stroke (97). Drug abuse Drug abuse can cause stroke due to several pathogenetic mecha- nisms.Intravenousinjectionofadrugmaybeaccompaniedbyother agents such as air or talcum powder with subsequent embolization. Table 2.3 Cardiac changes with possible relation to thromboembolic risk Major potential sources Minor potential sources Atrial fibrillation Patent foramen ovale Recent (<3 months) myocardial infarct Atrial septal aneurysm Thrombus left atrium or ventricle Mitral valve prolapse Dilating cardiomyopathy (EF ≤35 %) Severe mitral annulus calcification Mitral stenosis Calcific aortic stenosis Myxoma Spontaneous echo contrast in left atrium on echocardiography Mechanical prosthetic valve Other (e.g. hypokinetic left ventricular segment, bioprosthetic valve, mitral valve strands) Infective endocarditis Marantic endocarditis Protruding aortic plaque Major potential source: causal relation probable. Minor potential source: sometimes over represented in stroke studies but no certain causal relation. EF = ejection fraction. Modified from reference (55).
oxford textbook of stroke and cerebrovascular disease 14 Drugs or other agents administered simultaneously may cause vas- culitis due to toxic or hypersensitivity reaction. Infectious agents may be injected due to non-sterile conditions and cause, e.g. infec- tive endocarditis with subsequent cerebral embolization. The use of drugs may also unmask other pre-existing lesions such as arte- rial aneurysms, arteriovenous malformations, and tumours. Drugs increasing sympathetic activity such as amphetamine can cause acute BP elevation with subsequent ICH (102). Cocaine is a potent vasoconstrictor agent. Cocaine abuse has been related to both cer- ebral infarct and ICH (102). There are case reports of stroke related to cannabis use but a clear causative risk still remains unsettled (103). It should be mentioned that sympathomimetics and other vasoactive drugs including cannabis, cocaine, and amphetamine— as well as conventional medications with vasoactive effects—have also been associated with the reversible cerebral vasoconstriction syndrome (104). Obesity A body mass index (BMI) of 25 kg/m2 or more in men and 30 kg/ m2 or more in women increases the risk of ischaemic stroke, whereas the risk for ICH does not necessarily increase by BMI increase (96). As an example, a BMI of 30.0–31.9 kg/m2 in women and of 25.0–29.9 kg/m2 in men carry a relative risk of 1.44 and 1.43 for ischaemic stroke, respectively. Waist:hip ratio has also been related to increased stroke risk, even after adjustment for BMI (105). Physical activity Physical activity decreases the risk of stroke compared with no physical activity (106). Daily exercise of at least 30 minutes decreases the relative risk of stroke to between 0.69 and 0.74 (96). Physical activity of at least 30 minutes three to five times per week has been recommended (107). Diet There are many components in diet and it is unclear how these influence stroke risk. Excessive salt intake is related to higher BP (108). Several diets have been related to lower stroke risk. The Alternate Healthy Eating Index (AHEI)-based diet score is based on intake of trans fat, ratio of polyunsaturated to saturated fat, ratio of chicken and fish to red meat, fruits, vegetables, soy, nuts, cereal fibre, and multivitamin use and has been related to lower risk of stroke in women (96). Fruit and vegetables may have a pro- tective effect against both ischaemic and haemorrhagic stroke: one meta-analysis reported that individuals eating three to five servings per day had a relative risk of stroke of 0.89 compared with those consuming less fruit and vegetables (109). Fish consumption may also decrease the risk of stroke (110). Hormone therapy (especially oral contraceptives and hormone replacement therapy) Oral contraceptive use may confer a slightly elevated risk of ischae- mic stroke (111). The results have been debated and questions such as influence on stroke risk by oestrogen dose are not clearly under- stood (20). However, it seems that oral contraceptive use increases the ischaemic stroke risk in females with simultaneous other stroke risk factors such as smoking, hypertension, diabetes mellitus, older age, and hypercholesterolemia (20, 112). The situation regarding risk of ICH is less clear. Hormone replacement therapy has been related to increased risk of stroke with a relative risk of 1.29 (113). It is possible that transdermal oestrogen hormone replacement therapy carries a lower risk of stroke compared to oral oestrogens and further stud- ies are ongoing (10). Other drugs with hormone-like actions such as tamoxifen have also been reported to increase stroke risk (114). One review linked tamoxifen to thromboembolic events but not significantly to stroke risk(115).Thestrokeriskmaybelimitedtotheactivetamoxifentreat- ment period and then decrease in the post-treatment period (116). Stress Self-perceived psychological stress has been associated with increased stroke risk (117) and individuals experiencing major life events have a dose–response relationship with stroke risk (118). These studies mostly refer to an increased risk in the longer per- spective, but it is possible that psychological stress may be a trigger for stroke onset (97). Both negative emotions and anger seem to be more common during the last 2 hours before stroke onset than during the preceding day or year (119). Socioeconomic factors Both comparisons within countries and between countries indicate that low socioeconomic status is associated with increased stroke risk (120). In addition, the deficit after stroke tends to be more severe as well as the mortality ratio in stroke patients with lower socioeconomic status. Even though lower socioeconomic status is related to higher frequency of other stroke risk factors such as hypertension and physical activity, this may not be the only expla- nation why these individuals have an increased risk. The impact of socioeconomic status may vary by age, e.g. in one study there was a clearer association for men 40–59 years old compared to older men (121). Interaction between different risk factors Many individuals have more than one stroke risk factor and it is then difficult to assess how important each risk factor is. This important area is complex and it is often difficult to use different suggested score systems to evaluate how much different risk fac- tors potentiate each other (see Chapter 23 regarding these issues). When considering secondary prevention it is also very important to consider the interaction between different risk factors. Risk factors for intracerebral haemorrhage Some risk factors for ICH have been discussed previously in this chapter. Hypertension and higher age are risk factors for ICH (17, 60, 123). Other risk factors include African American rather than Caucasian ethnicity and lower cholesterol or low-density lipoprotein-cholesterol levels (21, 60, 61). Frequent alcohol use and diabetes mellitus have been related to ICH (123, 124). Results regard- ing the influence of triglyceride levels have been equivocal (60, 123). Genetic factors and cerebral amyloid angiopathy are also of impor- tance (see earlier in this chapter). The risk factors for ICH seem to have varying impact depending on whether the ICH is lobar or deep (124). The risk of ICH increases in patients using antiplatelet or anti- coagulant medications. Cerebral microbleeds are more often seen in ICH patients than in ischaemic stroke/TIA patients (125). Please see Chapter 5 regarding further discussion on risk factors for ICH. Risk factors for subarachnoid haemorrhage Risk factors for subarachnoid haemorrhage are somewhat different than for ischaemic stroke. However, smoking and hypertension are
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf
Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf

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Oxford textbook of stroke and cerebrovascular disease ( PDFDrive ).pdf

  • 1.
  • 2.
  • 3. Oxford Textbook of Stroke and Cerebrovascular Disease
  • 4. Oxford Textbooks in Clinical Neurology Oxford Textbook of Epilepsy and Epileptic Seizures, edited by Simon Shorvon, Renzo Guerrini, Mark Cook, and Samden Lhatoo Oxford Textbook of Vertigo and Imbalance, edited by Adolfo Bronstein Oxford Textbook of Movement Disorders, edited by David Burn Oxford Textbook of Neuromuscular Disorders, edited by David Hilton-Jones and Martin Turner (forthcoming) Oxford Textbook of Neuroimaging, edited by Massimo Filippi (forthcoming) Oxford Textbook of Neurorehabilitation, edited by Volker Dietz and Nick Ward (forthcoming) Oxford Textbook of Neuro-oncology, edited by Tracy Batchelor, Ryo Nishikawa, Nancy Tarbell, and Michael Weller (forthcoming) Oxford Textbook of Cognitive Neurology and Dementia, edited by Masud Husain and Jonathan Schott (forthcoming) Oxford Textbook of Headache Syndromes, edited by Michel Ferrari, Joost Haan, Andrew Charles, David Dodick, and Fumihiko Sakai (forthcoming) Oxford Textbook of Clinical Neurophysiology, edited by Kerry Mills (forthcoming)
  • 5. 1 Oxford Textbook of Stroke and Cerebrovascular Disease Edited by Bo Norrving Professor in Neurology Department of Clinical Sciences Section of Neurology Lund University Lund, Sweden Series Editor Christopher Kennard
  • 6. 3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University press in the UK and in certain other countries © Oxford University Press 2014 The moral rights of the authors have been asserted First Edition published in 2014 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2013952006 ISBN 978–0–19–964120–8 Printed in China by C&C Offset Printing Co. Ltd Oxford University press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breast-feeding
  • 7. Stroke has always been a worldwide problem, but only now is it being recognized as a global, treatable, and preventable condition, largely through scientific advances and the work of stroke leaders such as the contributors to this volume. Knowledge accrues in pieces but is understood in patterns. The internet has made information available in unprecedented quanti- ties, but of uneven value. Bits and bytes of information are but a few clicks away. However, these pieces have to be put in patterns, in context, and we need to recognize the fact that we still know much less than we need to know, hence the need for a comprehensive, credible, and accessible book. Bo Norrving and his international cast of authors offer such a volume. In addition to the usual chapters on anatomy, pathophysi- ology, diagnosis, treatment, and rehabilitation, there are chapters on the increasingly recognized areas of silent infarcts and micro- bleeds, vascular cognitive impairment and dementia, and the long-term management of stroke. As a former President of the World Stroke Organization, the editor has led efforts to put stroke at the forefront of global health policy by working with the World Health Organization and the United Nations. This enlarged vision of stroke is reflected in a chapter on primary stroke prevention and one on healthcare services, topics that do not usually feature in books on stroke. May this book enjoy the broad readership that it deserves. Vladimir Hachinski, CM, MD, FRCPC, DSc, Dr. honoris causa X5 President, World Federation of Neurology Foreword
  • 8.
  • 9. Stroke is huge by any measure: often cited data from the Global Burden of Disease project are that there are 6 million deaths due to stroke per year worldwide, 15 million cases of stroke per year, and 30 million persons who have survived a stroke. Other stroke measures are one new stroke every other second, every sixth sec- ond stroke kills someone, and one in six will have a stroke during their lifetime. Such numbers have different meanings to differ- ent stakeholders. For the patient who has developed a stroke, and for the carers, such data are of little interest (more than possibly telling that ‘you are in good company, welcome to the club’)— my own stroke is more than enough for me. For health person- nel the figures are more alarming: how can we take good care of so many patients, do we have the beds at the stroke unit (and is there a stroke unit at all?), are there rehabilitation and follow-up resources available? Who can do the job, who have the right edu- cation and competence? For health administrators, healthcare planners, and politicians the numbers should be alarming: what are the precise numbers in my country or region? What is the trend? What can be done (and what can I do) to help and to pre- vent stroke? And, will the numbers affect the financial situation in my community? Fortunately the stroke scene is changing—the Cinderella tale being a good analogy of what has happened. Only a few decades ago (when I started in neurology as my first summer job) stroke had the lowest priority at the emergency department because there was no hurry and nothing could be done acutely. Stroke units were unheard of—at my local hospital there was even a hospital agreement by which patients who were impossible to rehabilitate (definition: age 65 years and above) were outsourced to various other departments (dermatology, renal disease, oncol- ogy . . . ) so that the burden of stroke to the hospital could be shared. Patients used to stay in bed for 1–2 weeks before any mobilization took place. Heparin treatment was widely used to prevent or treat progressing stroke whereas antiplatelets and statins were unknown at that time. Carotid surgery was per- formed by thoracic surgeons with rates of serious complication well above 10%. Any ultra-early therapy was regarded as doomed to fail since science told us that brain cells could not survive more than 5–10 minutes of ischaemia. Looking back, I have some diffi- culties understanding why stroke nevertheless caught my interest and attracted me. Readers of this preface need not be told in detail what has hap- pened during the last few decades: the introduction of acute neuroimaging and other diagnostic tools, the demonstration of acute thrombolytic therapy as one of medicine’s best buys, the glory of organized stroke care (including early mobilization), the development of secondary prevention strategies that have changed the prognosis after stroke drastically, and the demonstration that rehabilitation works—just to mention a few of the groundbreaking changes that have taken place. There has also been an avalanche of knowledge of mechanisms, causes, unusual features, stroke subtypes, and genetics. Advances in science have had a profound impact on clinical practice in stroke. Another major change is a focus on stroke prevention through joint actions with other non-communicable diseases (NCDs) that share similar risk factors. Stroke is not acting alone in this movement, but is part of the NCD cluster that has rightfully received high governmental attention during the last few years. Stroke shares many risk factors with heart disease, peripheral vascular disease, cancer, dementia, and pulmonary disease—just to mention a few members of the NCD family. The World Stroke Organization emphasizes three pillars in the Global Agenda for Stroke: prevention, acute care, and long-term management. The latter component has been particularly neglected and warrants much more attention in the future. Few areas in medi- cine have such broad outreach, involve so many sectors of health- care, and have such a profound influence on public health as stroke. For this book I have had the privilege of working together with many of today’s most outstanding stroke scientists. I am grateful to all of you for sharing your deep knowledge, and for making your- selves available for the task. I take this opportunity to thank you all most warmly for your contributions to this volume. I also thank the very large number of people in the scientific stroke community, within the World Stroke Organization and regional stroke organiza- tions, who have provided me with inspiration for the present work. I would also like to thank the staff at Oxford University Press for expert help and support in making this book available. My thanks go to Peter Stevenson who set me the task initially, to Eloise Moir-Ford for keeping track of all manuscript versions and chapter status, to Papitha Ramesh and Nic Williams for copy editing, and to the many other people at Oxford University Press who have been involved with this book. It has been a pleasure working with you. Preface
  • 10. preface viii Finally, my thanks to my wife Lena and my three children (David, Marcus, and Maria) for having been (quite) tolerant of the intru- sion of my out-of-usual-business-hours’ work into family pleasures and duties. It is my hope that the book will be read, will be disseminated broadly, and will finally lead to benefits for patients and carers. Only at the latter stage has a textbook like this one served its ulti- mate purpose. Bo Norrving Lund, Sweden October 2013
  • 11. List of Abbreviations xi List of Contributors xiii 1 Epidemiology of stroke 1 Valery Feigin and Rita Krishnamurthi 2 Risk factors 9 Arne Lindgren 3 Arteries and veins of the brain: anatomical organization 19 Laurent Tatu, Fabrice Vuillier, and Thierry Moulin 4 Pathophysiology of transient ischaemic attack and ischaemic stroke 35 Jong S. Kim 5 Pathophysiology of non-traumatic intracerebral haemorrhage 51 Constanza Rossi and Charlotte Cordonnier 6 Spontaneous intracranial subarachnoid haemorrhage: epidemiology, causes, diagnosis, and complications 61 Laurent Thines and Charlotte Cordonnier 7 Clinical features of transient ischaemic attacks 79 David Calvet and Jean-Louis Mas 8 Clinical features of acute stroke 85 José M. Ferro and Ana Catarina Fonseca 9 Diagnosing transient ischaemic attack and stroke 94 Bruce Campbell and Stephen Davis 10 Management of stroke: general principles 106 Mehmet Akif Topcuoğlu and Hakan Ay 11 Acute phase therapy in ischaemic stroke 124 Krassen Nedeltchev and Heinrich P. Mattle 12 Acute management and treatment of intracerebral haemorrhage 130 Marek Sykora, Jennifer Diedler, and Thorsten Steiner 13 Acute treatment in subarachnoid haemorrhage 139 Katja E. Wartenberg 14 Less common causes of stroke: diagnosis and management 153 Turgut Tatlisumak, Jukka Putaala, and Stephanie Debette 15 Secondary prevention of stroke 163 Thalia S. Field and Oscar R. Benavente 16 Prognosis after stroke 185 Vincent Thijs 17 Silent cerebral infarcts and microbleeds 194 Bo Norrving 18 Complications after stroke 203 Hanne Christensen, Elsebeth Glipstrup, Nis Høst, Jens Nørbæk, and Susanne Zielke 19 Vascular cognitive impairment and dementia 215 Didier Leys, Kei Murao, and Florence Pasquier 20 Brain repair after stroke 225 Steven C. Cramer 21 Rehabilitation after stroke 234 Katharina Stibrant Sunnerhagen 22 The long-term management of stroke 243 Reza Bavarsad Shahripour and Geoffrey A. Donnan 23 Primary prevention of stroke 255 Anna M. Cervantes-Arslanian and Sudha Seshadri 24 Organized stroke care: Germany and Canada 270 Silke Wiedmann, Peter U. Heuschmann, and Michael D. Hill Index 279 Contents
  • 12.
  • 13. ACA anterior cerebral artery ACE angiotensin-converting enzyme AChA anterior choroidal artery ACoA anterior communicating artery ADL activities of daily living ADL Alzheimer disease AF atrial fibrillation AHA American Heart Association AICA anterior inferior cerebellar artery ARB angiotensin receptor blocker ARER absolute risk reduction ASA American Stroke Association AUC area under the curve AVM arteriovenous malformation BI Barthel Index CAA cerebral amyloid angiopathy CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy CARASIL cerebral autosomal recessive arteriopathy with subcortical infarcts and leucoencephalopathy CAS carotid angioplasty and stenting CBV cerebral blood volume CEA carotid endarterectomy CEAD cervical artery dissection CEAD carotid endarterectomy CHS Cardiovascular Health Study CMB cerebral microbleed CNS central nervous system CSF cerebrospinal fluid CT computed tomography CTV computed tomography venography CVD cerebrovascular disease CVT cerebral venous thrombosis DALY disability-adjusted life year DAVF dural arteriovenous fistula DCI delayed cerebral ischaemia DNR do not resuscitate DOAC direct oral anticoagulant DSA digital subtraction angiography DVT deep vein thrombosis DWI diffusion-weighted imaging ECG electrocardiogram eGFR estimated glomerular filtration rate ESO European Stroke Organisation EVD extraventricular drain FDA Food and Drug Administration FFP fresh frozen plasma FHS Framingham Heart Study FLAIR fluid attenuated inversion recovery GABA gamma-aminobutyric acid GOS Glasgow Outcome Scale GOS Glasgow Outcome Scale GRE gradient echo HANAC hereditary angiopathy with nephropathy, aneurysm, and muscle cramps HDL high-density lipoprotein HERNS hereditary endotheliopathy with retinopathy, nephropathy, and stroke HR hazard ratio IA intra-arterial IAT intra-arterial thrombolysis ICH intracerebral haemorrhage IDR incidence density ratio IHD ischaemic heart disease INR international normalized ratio IST International Stroke Trial ITT intention-to-treat LDL low-density lipoprotein LP lumbar puncture LUTS lower urinary tract symptoms MAP mean arterial pressure MCA middle cerebral artery MET S metabolic syndrome MMSE Mini Mental State Examination MoCA Montreal Cognitive Assessment MRI magnetic resonance imaging mRS modified Rankin Scale MRV magnetic resonance venography List of Abbreviations
  • 14. list of abbreviations xii MTT mean transit time NCD non-communicable disease NG nasogastric NHS Nurses’ Health Study NICC neurocritical care unit NIHSS National Institutes of Health Stroke Scale NINDS National Institute of Neurological Disorders and Stroke NMDA N-methyl-D-aspartate NOAC novel oral anticoagulant NVAF non-valvular atrial fibrillation OCSP Oxfordshire Community Stroke Project OHS Oxford Handicap Score PAR population attributable risk PbtO2 partial pressure of cerebral tissue oxygen PCA posterior cerebral artery PCC prothrombin complex concentrate PChA posterior choroidal arteries PE pulmonary embolus PEG percutaneous endoscopic gastrostomy PET positron emission tomography PFO patent foramen ovale PHS Physicians’ Health Study PICA posterior inferior cerebellar artery PoCA posterior communicating artery PRN pro re nata (as needed) PSD post-stroke dementia RCVS reversible cerebral vasoconstriction syndrome RR relative risk RRR relative risk reduction rtPA recombinant tissue plasminogen activator SAH subarachnoid haemorrhage SCA superior cerebellar artery SCD sickle cell disease SCI silent cerebral infarct SCM silent cerebral microbleed SDB sleep-disordered breathing SD standard deviation SES socioeconomic status SIADH syndrome of inappropriate secretion of antidiuretic hormone SITCH Surgical Trial in Intracerebral Haemorrhage SLE systemic lupus erythematosus SNP single-nucleotide polymorphism SWI susceptibility-weighted imaging TBI traumatic brain injury TCS Takotsubo cardiomyopathy syndrome Tmax time to maximum TOAST Trial of Org 10172 in Acute Stroke Treatment TOF time-of-flight tPA tissue plasminogen activator TTP time to peak UK United Kingdom US United States VaD vascular dementia VCI vascular cognitive impairment WFNS World Federation of Neurological Surgeons Scale WHO World Health Organization WHS Women’s Health Study WML white matter lesion
  • 15. Hakan Ay Stroke Service, Department of Neurology, A.A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Oscar R. Benavente Stroke and Cerebrovascular Health, Vancouver Stroke Program, Brain Research Center, Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada David Calvet Paris Descartes University, Centre de Psychiatrie et Neurosciences INSERM UMR 894, and Department of Neurology, Centre Hospitalier Sainte-Anne, Paris Bruce Campbell Department of Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia Anna M. Cervantes-Arslanian Boston University Department of Neurology, Boston, MA, USA Hanne Christensen Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark Charlotte Cordonnier Department of Neurology and Stroke Unit, Université Lille Nord de France, Lille, France Steven C. Cramer Departments of Neurology and Anatomy & Neurobiology, University of California, Irvine, Irvine, CA, USA Stephen Davis President, World Stroke Organization; Director, Neuroscience and Continuing Care Service; Director, Melbourne Brain Centre at RMH; Director of Neurology, The Royal Melbourne Hospital, Melbourne, Australia Stephanie Debette Université de Versailles Saint-Quentin-en-Yvelines, France; and Inserm U740, Université Paris, Paris, France; and Department of Neurology, Lariboisière University Hospital, DHU Neurovasc Sorbonne Paris-Cité, Paris, France; and Department of Neurology, Boston University School of Medicine, The Framingham Heart Study, Boston, MA, USA Jennifer Diedler Department of Neurology, University of Heidelberg, Heidelberg, Germany Geoffrey A. Donnan Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia Valery Feigin National Institute for Stroke and Applied Neurosciences, Faculty of Health & Environmental Sciences AUT University, Auckland, New Zealand José M. Ferro Department of Neurosciences, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal Thalia S. Field Vancouver Stroke Program, Brain Research Center, Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada Ana Catarina Fonseca Department of Neurology, Hospital de Santa Maria, Lisboa, Portugal Elsebeth Glipstrup Mental Health Services, Bispebjerg Hospital, Copenhagen, Denmark Nis Høst Department of Cardiology, Bispebjerg Hospital, Copenhagen, Denmark Peter U. Heuschmann Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany Michael D. Hill Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada Jong S. Kim University of Ulsan, College of Medicine, Seoul, South Korea; and Stroke Center, Asan Medical Center, Seoul, South Korea Rita Krishnamurthi National Institute for Stroke and Applied Neurosciences, Faculty of Health & Environmental Sciences, AUT University, Auckland, New Zealand Didier Leys Université Lille Nord de France, Lille, France Arne Lindgren Department of Neurology Lund, Skåne University Hospital, Lund, Sweden Jean-Louis Mas Paris Descartes University, Centre de Psychiatrie et Neurosciences INSERM UMR 894 and Department of Neurology, Centre Hospitalier Sainte-Anne, Paris, France Heinrich P. Mattle Department of Neurology, Inselspital, Bern, Switzerland Thierry Moulin Service de Neurologie 2,Centre Hospitalier Universitaire, Université de Franche-Comté, Besançon, France List of Contributors
  • 16. list of contributors xiv Kei Murao Université Lille Nord de France, Lille, France Krassen Nedeltchev Triemli Hospital, Zurich, Switzerland Jens Nørbæk Mental Health Services, Bispebjerg Hospital, Copenhagen, Denmark Bo Norrving Department of Clinical Sciences, Section of Neurology, Lund University, Lund, Sweden Florence Pasquier Université Lille Nord de France, Lille, France Jukka Putaala Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland Constanza Rossi Department of Neurology and Stroke Unit, University of Lille Nord de France, Lille, France Sudha Seshadri Boston University Department of Neurology, Boston, MA, USA Reza Bavarsad Shahripour Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia Thorsten Steiner Department of Neurology, University of Heidelberg, Heidelberg, Germany; and Department of Neurology, Klinikum Frankfurt Höchst, Frankfurt, Germany Katharina Stibrant Sunnerhagen Department of Clinical Neurosciences, University of Gothenburg, Institute of Neuroscience and Physiology, Sweden Marek Sykora Department of Neurology, University of Heidelberg, Heidelberg, Germany; and Department of Neurology, Comenius University, Bratislava, Slovakia Laurent Tatu Laboratoire d’Anatomie, UFR Sciences médicales et pharmaceutiques, Université de Franche-Comté, Besançon, France; and Service d’Explorations et pathologies neuro-musculaires, Centre Hospitalier Universitaire, Université de Franche-Comté, Besançon, France Turgut Tatlisumak Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland Vincent Thijs Department of Neurology, University Hospitals Leuven, Leuven, Belgium Laurent Thines Division of Neurosurgery, Department of Neurosciences and Locomotive System, Lille University Hospital, Lille, France Mehmet Akif Topcuoğlu Hacettepe University Hospitals, Department of Neurology, Ankara, Turkey Fabrice Vuillier Laboratoire d’Anatomie, UFR Sciences médicales et pharmaceutiques, Université de Franche-Comté, Besançon, France; and Service de Neurologie 2, Centre Hospitalier Universitaire, Université de Franche-Comté, Besançon, France Silke Wiedmann Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany Katja E. Wartenberg Neurocritical Care Unit, Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany Susanne Zielke Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark
  • 17. Introduction Stroke is the second most common cause of death worldwide and a frequent cause of adult disability in developed countries (1, 2). Stroke burden on families and society is projected to rise from approximately 38 million disability-adjusted life years (DALYs) lost globally in 1990 to 61 million DALYs in 2020 (3) due to population ageing. Stroke also has a large physical, psychological, and finan- cial impact on patients/families, the healthcare system, and society (4, 5). Lifetime costs per stroke patient range from US$59,800 to US$230,000 (5). The majority (about 75%) of cases of stroke occur in people over the age of 65 years (6, 7), and about one-third of patients die of stroke within a year of onset (8, 9). Over half of survi- vors remain dependent on others for everyday activities, often with significant adverse effects on caregivers (10). Many factors increase the risk of stroke, and these are generally divided into two catego- ries: modifiable and non-modifiable risk factors. Age, gender, and ethnicity are non-modifiable risk factors for stroke. Modifiable or potentially modifiable risk factors include a number of physiologi- cal and environmental factors and include hypertension, elevated total cholesterol, smoking, physical inactivity, alcohol consump- tion, and atrial fibrillation (11). Stroke mortality data are available from more than 24 countries (12, 13) showing that, in general, rates have declined for several decades. In some countries, stroke mortality has declined since the early 1950s, but the rate of this decline has recently slowed (14–17). While large national or international stroke mortality data may be used for determining overall burden of fatal strokes and trends in stroke mortality, stroke mortality data are often not accurate (diagnosis classification bias) and have limited value for healthcare planning and organization. The role of changes in inci- dence and improved survival to downward trend in stroke mor- tality are not adequately quantified, chiefly due to difficulties in measuring stroke incidence accurately (18, 19); however the results from the World Health Organization (WHO) Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) pro- ject suggested that both declining and increasing stroke mortality were principally attributable to changes in case fatality rather than changes in incidence (20). Importance of population-based studies Epidemiological studies form the basis of much of the medi- cal research and current knowledge in stroke to inform health professionals about best strategies for stroke care organization, prevention, and management. The gaps in knowledge in stroke pre- vention and management are continually filled by randomized con- trol trials, case–control, and cohort studies (see Table 1.1). Some of the most informative studies on stroke burden and optimal health- care organization have arisen from population-based stroke inci- dence and outcome studies. It is important that stroke is seen and studied in a population context, as a large proportion of the bur- den of care for stroke is borne outside the hospital sector (11–13). Further, changes in referral patterns can distort longitudinal trends derived from hospitalized cases. Assessing the need for prevention strategies and services is best achieved via population-based stroke registers to determine incidence and outcome (13). Data on population trends in stroke incidence reflect the success/ failure of prevention strategies, while trends in case fatality and outcome reflect changes in stroke management. Both are needed to plan stroke services given high healthcare costs and limited resources. Accurate and representative population-based data are also crucial to: (i) determine the true incidence, causes and out- come of stroke; (ii) implement evidence-based healthcare planning, across the care spectrum; (iii) evaluate the need for and impact of preventative/management strategies; (iv) address persistent uncer- tainty about what key factors (socioeconomic and health service) impact stroke recovery; (v) examine the natural course of recovery, in particular for cognitive and behavioural outcomes; (vi) provide information on access and satisfaction with stroke services; and (vii) identify service gaps/unmet needs to ensuring evidence-based policy, resource allocation, prevention planning, management ser- vices, and evaluation of service performance. Assessing the need for prevention strategies and services is most sensitively achieved with the use of population-based registers to determine the incidence and outcome of stroke. However, study- ing stroke in a population-based fashion is particularly challenging (19), so that such epidemiological studies are relatively rare com- pared with studies using mortality data, hospital-based stroke reg- isters, or incidence studies in younger age groups only. In 1987, Malmgren et al. (23) published a list of 12 criteria related to definitions, methods, and mode of data presentation, by which the quality of population-based studies of stroke could be judged. These criteria have been updated by Sudlow et al. (19) in 1997 and most recently by Feigin et al. (Table 1.2) (24, 25). However, these criteria are so demanding in practice that even the stroke component of the WHO MONICA project is generally regarded as having failed to meet them (18). Even among many reg- isters that are population based, many were limited to people under the age of 75 years, yet only half of all strokes occur in these age groups. Although ‘ideal’ stroke incidence studies based on both core Epidemiology of stroke Valery Feigin and Rita Krishnamurthi CHAPTER 1
  • 18. oxford textbook of stroke and cerebrovascular disease 2 and supplementary criteria (24, 25) are the most valuable source of information for developing evidence-based strategies for stroke pre- vention and health services, to address the problem of accurate and comparable stroke incidence studies in less affluent countries with limited resources where most strokes occur, a WHO stepwise stroke surveillance approach (26) can be recommended (Figure 1.1). An alternative approach for studying stroke incidence and preva- lence in countries with very limited resources could include a com- bination of a stroke prevalence survey (e.g. door-to-door study) with a study of death certificates (verbal autopsy procedures) in the same community (Figure 1.2), as recently recommended by Feigin (27). Stroke burden in high-income countries Historically, information on stroke incidence, prevalence, early case-fatality came predominantly from studies in high-income countries. In addition, long-term trends in stroke incidence in different populations are not well characterized, largely due to difficulties of population-based stroke surveillance (19, 28, 29). However recent studies in mid- to low-income countries have allowed comparisons in stroke burden and current trends. A recent systematic review of worldwide stroke incidence and early case-fatality (29) found that over the last four decades (1970–2008) there was a statistically significant 42% decrease in stroke incidence rates (1.1% annual reduction) in high-income countries (Figure 1.3A), with the more pronounced reduction in people younger than 75 years and in people with ischaemic stroke. This decrease may be attributable to the effective implementation of preventative measures and management of risk factors in these populations. However, in low- to middle-income countries stroke incidence rates for the same time period have increased by over 100% and currently exceed those in high-income countries. It was also shown that the risk of stroke is increasing with the age of the population in developed countries (Figure 1.4) (30). The reasons for this dif- ference are unclear, but are a matter of great importance for two main reasons: (i) stroke is a leading cause of disability in adults and (ii) the elderly (the most stroke-prone age group) constitute the fastest-growing segment of the population. Currently (2000–2008), proportional frequency of ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage Table 1.1 Common epidemiological terms Term Definition Comments Incidence The number of new cases of a disease that occur over a specified period of time The incidence rate is a measure of morbidity (illness) and can be looked at in any population group such as males, persons exposed to a particular chemical toxin, etc. Attack rate A measure of how fast a disease is occurring in a population Attack rates tell us how many new cases of a disease occur over a specific period of time Prevalence The proportion of the population affected by a disease at that time Prevalence is calculated by dividing the number of people who have the disease by the number of people in the community. It provides a snapshot of who has the disease at that point in time and does not take into account the duration of the disease Mortality A measure of the proportion of deaths over a specific time period in a given population Mortality is measured in the entire population at risk from dying from the disease, including both those who have and do not have the disease Case-fatality A measure of the proportion of deaths over a specific period of time in individuals with a specified disease Case-fatality is a measure of the severity of that disease. In contrast to mortality, case-fatality is limited to those who already have the disease Population attributable risk (PAR) A measure of the proportion of disease incidence in a total population that can be attributed to a specific exposure The PAR tells us the extent to which the elimination of a particular exposure would reduce the incidence rate of a particular disease in the whole population Disability-adjusted life year (DALY) Years of life lost to premature death and years lived with a disability of a specified severity and duration DALYs are a means of expressing the overall burden of a disease. Each DALY is 1 lost year of healthy life Randomized clinical trial (RCT) A type of study design used to evaluate a particular intervention usually for the treatment or prevention of a disease. The subjects are randomly allocated to either the treatment (e.g. the test drug) or control (e.g. no treatment) group An RCT can be used to study the effectives of a new drug to treat a condition compared to another drug or no treatment at all. In a ‘double-blind’ RCT both the subjects in the study and the researcher measuring the outcome are unaware of the allocation of the treatment groups, thus reducing bias Cohort studies A population with an exposure and a population without the exposure are followed to compare an outcome of interest between the groups Typically, the study population must be followed up for a long period of time for the outcome of interest to develop. A well-known example is the Framingham study (21) Case–control studies A study design aimed to examine the possible relation of an exposure to a certain disease. A group with the disease (cases) is compared with a group without the disease (controls) If there is an association of an exposure with a disease, there should be a higher prevalence of the exposure in the cases than in the controls Adapted from Gordis (22).
  • 19. CHAPTER 1 epidemiology of stroke 3 Table 1.2 Gold standards for an ‘ideal’ stroke incidence study Domains Core criteria Supplementary criteria Standard definitions • World Health Organization definition of stroke • At least 80% CT/MRI verification of the diagnosis of ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhagea • First-ever-in-a-lifetime stroke • Classification of ischaemic stroke into subtypes (e.g. large artery disease, cardioembolic, small artery disease, other)a • Recurrent strokea Standard methods • Complete, population-based case ascertainment, based on multiple overlapping sources of information (hospitals, outpatient clinics, general practitioners, death certificates)b • Prospective study design • Large, well-defined and stable population, allowing at least 100,000 person-years of observationb • Follow-up of patients’ vital status for at least 1 montha • Reliable method for estimating denominator (not more than 5 years old census data)b • Ascertainment of patients with TIA, recurrent strokes and those referred for brain, carotid or cerebral vascular imaginga • ‘Hot pursuit’ of cases • Direct assessment of under-ascertainmenta by regular checking of general practitioners’ databases and hospital admissions for acute vascular problems and cerebrovascular imaging studies and/or interventions Standard data presentation • Complete calendar years of data; not more than 5 years of data averaged togetherb • Men and women presented separately • Mid-decade age bands (e.g. 55–64 years) used in publications, including oldest age group (≥85 years)b • 95% confidence interval around rates • Unpublished 5-year age bands available for comparison with other studies a New criteria. b Updated, modified from Sudlow and Warlow (19). Reprinted from Feigin and Carter (25) with permission. Step 1 Step 2 Step 3 Community events Module 6 Hospital events & vital status Module 1 + Disability Module 2 + Subtype Module 3 Autopsy Module 5 Population- based Hospital- based Population coverage Non-fatal events in community Fatal events in community Events in hospital Comprehensive Expanded Standard Cause of death (death certifi- cate or verbal autopsy) Module 4 in high-income countries were estimated as 82%, 11%, and 3%, respectively (29). Early (1-month) case fatality in high-income countries has decreased over the last four decades from 35.9% to 19.8%, potentially due to improved management of acute strokes, and possibly a shift towards less severe strokes. Overall, case-fatality within 1 month of stroke onset in high-income countries is cur- rently about 23% and is higher for intracerebral haemorrhage (42%) and subarachnoid haemorrhage (32%) than for ischaemic stroke (16%) (30). A recent systematic review of population-based stroke incidence and prevalence studies showed the age-standardized prevalence of stroke in people aged 65 years and older ranges worldwide from 46–72 per 1000 population (Figure 1.5) (30). Stroke makes a signif- icant contribution to disability burden in low- and middle-income Fig. 1.1 STEP-wise approach to stroke surveillance. (Adapted from Truelsen et al. (24) with permission.)
  • 20. oxford textbook of stroke and cerebrovascular disease 4 countries (31), and the recent 2010 Global Burden of Disease Project ranked stroke as the fifth highest cause of DALYs worldwide in 2010 (an increase of 19% from 1990) (32). In terms of global variation, stroke burden was shown to be higher in China, Africa, and South America, and lower national income was associated with higher relative mortality and burden of stroke (33). Stroke burden in low- to middle-income countries One of the major challenges in stroke epidemiology is the lack of good-quality epidemiological studies in developing countries (34). According to WHO estimates, death from stroke in devel- oping (low- and middle-income) countries in 2001 accounted for 85.5% of stroke deaths worldwide (35), and the number of DALYs, which comprises years of life lost and years lived with disability (35), in these countries was almost seven times that in developed (high-income) countries (4, 27). Recent meta-analysis of population-based stroke incidence stud- ies (29) showed that unlike high-income countries, the incidence of stroke in low- to middle-income countries has increased by 100% over the last four decades (1970–2008) (Figure 1.3B). Stroke incidence rates in low- to middle-income countries increased with increasing age in a similar manner to high-income countries (Figure 1.6). Although ischaemic stroke is the dominating stroke pathologi- cal type all over the world, the proportional frequency of intrac- erebral haemorrhage in low- to middle-income countries tends to be noticeably greater than that in high-income countries (Figure 1.7) (29). There is evidence from recent studies that the risk factors for stroke in middle- to low-income countries are similar to that in high-income countries, including high blood pressure, smoking, and obesity, although the relative significance of stroke risk fac- tors in high- and low- to middle-income countries may be dif- ferent (see Chapter 2). The increase in stroke incidence in low- to middle-income counties may be attributed to the poor manage- ment of these risk factors. While early case fatality is similar to that of high-income countries, the decrease in early case fatality is not as high as that in high-income countries. Gender and ethnic differences in stroke burden There are notable gender and ethnic differences in stroke incidence and outcomes both in high- and mid- to low-income countries. Both socioeconomic and ethnic differences in the risk of stroke have been seen in many countries (36–39). For example, higher risks have been observed among Maori and Pacific people in New Zealand (40, 41), and in the black populations in the United States (36) and United Kingdom (37), compared to the white popula- tion. Higher stroke attack rates in lower socioeconomic groups are probably related to several factors. As a general rule, lower socio- economic groups are more frequently exposed to risk factors for cardiovascular disease, including hypertension, smoking, diabetes, and excessive consumption of alcohol (42). In addition, it has been suggested that lower socioeconomic groups have less access to, or make less effective use of, services that are important to the man- agement of these risk factors, such as early detection and control of hypertension (43). Similarly, many of the ethnic differences in stroke risk have been attributed to differences in socioeconomic circumstances and exposure to risk factors (43). However, studies of cardiovascular disease have found that not all of the differences in attack rates among ethnic groups can be explained by differences Study population (about 25,000–30,000) Prevalence study (door-to-door survey) Questionnaire to identify subjects with possible stroke over the past 3 years Clinical examination of screened positive subjects Stroke is not confirmed Stroke is not confirmed Stroke confirmed First-ever stroke First-ever stroke Incident stroke cases Stroke confirmed Verbal autopsy procedure Stroke suspected (stroke mentioned in death certificate) Study of death certificates over the past 3 years Stroke not suspected Fig. 1.2 An alternative approach for studying stroke epidemiology in resource-poor countries. (Reprinted from Feigin (25) with permission.)
  • 21. CHAPTER 1 epidemiology of stroke 5 0 50 100 150 200 250 300 350 400 (a) (b) 1970-1979 1980-1989 1990-1999 2000-2008 Rochester, MN Tartu, Estonia Copenhagen, Denmark Dublin, Ireland North Karelia, Finland Saku, Japan Frederiksberg, Denmark Espoo-Kauniainen, Finland Soderham, Sweden Shibata, Japan Tilburg, Netherlands Oyabe, Japan2 Auckland, NZ Turku, Finland (1982) Dijon, France Ubmbia, Italy Malmo, Sweden Valley d'Aosta, Italy Perth, Australia Belluno, Italy Greater Cincinnati, USA Arcadia, Greece L'Aquila, Italy East Lancashire, UK Inherred, Norway Erlangen, Germany South London, UK Vibo Valentia, Italy Melbourne, Australia Scottish Borders region, UK Porto, Portugal Porto, Portugal2 Orebro, Sweden Barbados Lund-Orup, Sweden Oxfordshire, UK 0 50 100 150 200 250 1970-1979 1980-1989 1990-1999 2000-2008 Ibadan, Nigeria Ulan Bator, Mongolia Rohtak, India Colombo, Sri Lanka Novosibirsk, Russia Krasnoyarsk, Russia Martinique, French WestIndies Uzhgorod, West Ukraine Tbilisi, Georgia iquque, Chile Matao, Brazil Mumbai, India Fig. 1.3 (a) Age-adjusted annual incidence of stroke in high income countries per 100,000/year*. (b) Age-adjusted annual incidence of stroke in low to middle income countries 100,000/year*. (Reprinted from Feigin et al. (13) with permission.) in conventional cardiovascular risk factors, suggesting genetic and other factors are important (44). Thus, there remains considerable uncertainty regarding the relative importance of stroke risk factor management and control and other factors in the aetiology of these inequalities. There is also some evidence suggesting ethnic differences in stroke outcomes. In a recent prospective population-based study of 1127 patients with acute stroke in Auckland, New Zealand the risk of dependency, as measured by Frenchay Activities, at 6 months post-stroke was higher in non-Europeans (Asian and Pacific
  • 22. oxford textbook of stroke and cerebrovascular disease 6 Four regions of the U SA Auckland, N Z Taiwan, China North Yorkshire, U K Rotterdam , N L L’Aquila, Italy Newcastle U K Men Women Both 0 10 20 30 40 50 Cases per 1000 per year 60 70 80 90 100 Fig. 1.5 Age-standardized prevalence of stroke per 1000 population in selected studies of people aged 65+ years. (Reprinted from Feigin et al. (26) with permission.) 0 <45 45–54 55–64 Rohtak, India (1971–74) Ibadan, Nigeria (1971–74) Colombo, Sri Lanka (1971–74) Martinique, French West Indies (1998–99) Iquique, Chile (2000-02) Years 65–74 75+ 2 4 6 8 10 Rate per 1000 per year 12 14 16 Fig. 1.6 Age-specific annual incidence of first-ever-in-lifetime stroke per 1000 population in selected developing countries. (Reprinted from Feigin (26) with permission.) 0.00 <45 45–54 55–64 Age (years) 65–74 75–84 85+ 5.00 10.00 15.00 20.00 25.00 Cases per 1000 per year 30.00 35.00 40.00 45.00 Melbourne, Australia Frederiksberg, Denmark L’Aqulia, Italy Uzhgorod, Ukraine Innherred, Norway Arcadia, Greece Oyabe, Japan South London, UK Perth, Australia French West Indies Novosibirsk, Russia Auckland, NZ Belluno, Italy Erlangen, Germany Espo-Kauniainen, Finland Fig.1.4 Age-specific stroke incidence rates in selected, primarily high income countries per 1000-person-years. (Reprinted from Feigin et al. (13) with permission.) people) compared to Europeans (after adjustment for casemix vari- ables) (45). Measures of handicap and quality of life were also worse in non-Europeans. Some ethnic differences particularly in stroke outcomes may be attributable to socioeconomic status and acces- sibility to healthcare, and/or to a higher prevalence of risk factors in some ethnic groups. Additionally, there are gender differences in stroke. The lifetime risk of stroke in women (one in five) is greater than in men (one in six) (46). This higher risk is primarily due to the greater life expec- tancy of women. Worldwide evidence of better outcomes in male stroke survivors is accumulating (47–51), yet reasons for these gen- der differences in stroke outcomes are also unclear. Recent research shows poorer functional outcomes and quality of life post stroke in women are not due to differences in age, pre-stroke function, and comorbidities (47). As women often have their stroke later in relation to men they are also usually the most important fam- ily caregivers (52). Their state of health can affect the health and well-being of other family members and demands placed upon
  • 23. CHAPTER 1 epidemiology of stroke 7 them in providing care to men and others within their social net- work can also increase their risk of stroke (52, 53). A study of stroke incidence in women showed that two-thirds of women with stroke were not partnered compared with one-third of men (52). Due to their greater life expectancy, more elderly women are likely to be living alone, thus there is a greater risk of the need for institution- alized care after stroke. More intensive treatment/rehabilitation may be needed to improve outcomes for women, along with fur- ther research to explore underlying biological mechanism of gen- der differences in outcome (51). Accurate population-based data on gender and ethnic differences in stroke burden and service use will facilitate implementation of evidence-based recommendations to bridge gaps in health services and increase uptake of lifestyle changes in ethnic and sex groups (39). Suggested public health strategies to reduce the global stroke burden The global stroke burden, particularly in low- to middle-income coun- tries is likely to reach epidemic proportions if current trends continue. In developing countries, there has been a shift towards urbanization drivenbysocialandeconomicchanges.Thishasledtochangestowards poorer diet and lifestyle choices thus increasing the prevalence of risk factors, including smoking. With increasing life expectancy leading to older populations, the burden of stroke will become a major cause for concern unless urgent action is taken to implement population-based prevention at local government and international levels. For stroke prevention programmes to be effective, they should be designed with an understanding of the independent relative risk, prevalence, independent population attributable risk, and adapta- tion of proven measures to modify or control the specific risk factor (54, 55). Public health strategies to reduce global stroke burden include increasing public stroke awareness, increasing awareness of stroke risk factors, and the importance and effectiveness of pre- vention. Additionally, local and national government bodies need to take responsibility to improve lifestyle factors, for example, by making fresh fruits and vegetables more affordable. Ways to reduce tobacco use and reduce dietary salt intake must be explored and implemented to reduce stroke risk. There is sufficient evidence for effective strategies for stroke prevention (see Chapter 22); the chal- lenge now is to apply this knowledge effectively to reduce the bur- den of stroke globally. References 1. Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and mortality: estimates from monitoring, surveillance, and modelling. Lancet Neurol. 2009;8(4):345–354. 2. Rothwell PM. The high cost of not funding stroke research: a comparison with heart disease and cancer. Lancet. 2001;357(9268): 1612–1616. 3. Mackay J, Mensah GA. The Atlas of Heart Disease and Stroke. Geneva: World Health Organization; 2004. 4. Strong K, Mathers C, Bonita R. Preventing stroke: saving lives around the world. Lancet Neurology. 2007 Feb;6(2):182–187. 5. Caro JJ, Huybrechts KF, Duchesne I. Management patterns and costs of acute ischemic stroke: an international study. Stroke. 2000 Mar;31(3):582–590. 6. Bonita R, Anderson CS, Broad JB, Jamrozik KD, Stewart-Wynne EG, Anderson NE. Stroke incidence and case fatality in Australasia. A comparison of the Auckland and Perth population-based stroke registers. Stroke. 1994 Mar;25(3):552–557. 7. Bonita R, Broad JB, Beaglehole R. Changes in stroke incidence and case-fatality in Auckland, New Zealand, 1981-91. Lancet. 1993;342(8885):1470–1473. D ijon, France (1987) Perth, Australia (1989) Um bria, Italy (1988) O xfordshire, U K (1984) Aosta, Italy (1989) Frederiksberg, D enm ark (1989) Soderham n, Sweden (1990) M elbourne, Australia (1996) Perth, Australia (1995) South London, U K (1995) Erlangen, G erm any (1994) Arcadia, Greece (1993) Belluno, Italy (1992) L’aquila, Italy (1994) Inherred, N orway (1994) M artinique, French W est Indies (1998) O xfordshire, U K (2002) Iquique, Chile (2002) Rochester, U SA (1988) 100 Undetermined pathological type of stroke Subarachnoid haemorrhage Intracerebral haemorrhage Cerebral infarction 90 80 70 60 50 40 Percentage 30 20 10 0 Fig. 1.7 Proportional frequency of stroke subtypes in selected populations. CI: cerebral infarction; ICH: intracerebral haemorrhage; SAH: subarachnoid haemorrhage; UND: undetermined pathological type of stroke. (Modified from Feigin (13) with permission.)
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Trends in stroke incidence in Auckland, New Zealand, during 1981 to 2003. Stroke. 2005;36(10):2087–2093. 29. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8(4):355–369. 30. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2(1):43–53. 31. Sousa RM, Ferri CP, Acosta D, Albanese E, Guerra M, Huang Y, et al. Contributionofchronicdiseasestodisabilityinelderlypeopleincountries with low and middle incomes: a 10/66 Dementia Research Group population-based survey. Lancet. 2009 Nov 28;374(9704):1821–1830. 32. Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 Dec;380(9859):2197–223. 33. Kim AS, Johnston SC. Global variation in the relative burden of stroke and ischemic heart disease. Circulation. 2011 Jul;124(3):314–323. 34. Feigin VL. Stroke epidemiology in the developing world. Lancet. 2005;365(9478):2160–2161. 35. Mathers CD, Lopez AD, Murray CJL. The burden of disease and mortality by condition: data, methods, and results for 2001. In Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL (eds) Global Burden of Disease and Risk Factors (pp. 45–240). New York: Oxford University Press; 2006. 36. Sacco RL, Boden-Albala B, Gan R, Chen X, Kargman DE, Shea S, et al. Stroke incidence among white, black, and Hispanic residents of an urban community: the Northern Manhattan Stroke Study. Am J Epidemiol. 1998;147(3):259–268. 37. Stewart JA, Dundas R, Howard RS, Rudd AG, Wolfe CD. Ethnic differences in incidence of stroke: prospective study with stroke register. BMJ. 1999;318(7189):967–971. 38. van Rossum CT, van de MH, Breteler MM, Grobbee DE, Mackenbach JP. Socioeconomic differences in stroke among Dutch elderly women: the Rotterdam Study. Stroke. 1999 02;30(2):357–362. 39. Feigin VL, Rodgers A. Ethnic disparities in risk factors for stroke: what are the implications? Stroke. 2004;35(7):1568–1569. 40. Bonita R, Broad JB, Beaglehole R. Ethnic variations in stroke incidence and case fatality: the Auckland Stroke study. Stroke. 1997;28:758–761. 41. Feigin V, Carter K, Hackett M, Barber PA, McNaughton H, Dyall L, et al. Ethnic disparities in incidence of stroke subtypes: Auckland Regional Community Stroke Study, 2002–2003. Lancet Neurol. 2006;5(2):130–139. 42. Kaplan GA, Keil JE. Socioeconomic factors and cardiovascular disease: a review of the literature. Circulation. 1993 Oct;88(4:Pt 1):1973–1998. 43. Casper M, Wing S, Strogatz D, Davis CE, Tyroler HA. Antihypertensive treatment and US trends in stroke mortality, 1962 to 1980. Am J Public Health. 1992 Dec;82(12):1600–1606. 44. Anand SS, Yusuf S, Vuksan V, Devanesen S, Teo KK, Montague PA, et al. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet. 2000;356(9226):279–284. 45. Rose SB, Lawton BA, Elley CR, Dowell AC, Fenton AJ. The ‘Women’s Lifestyle Study’, 2-year randomized controlled trial of physical activity counselling in primary health care: rationale and study design. BMC Public Health. 2007;7:166. 46. Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB, et al. The lifetime risk of stroke: estimates from the Framingham Study. Stroke. 2006;37(2):345–350. 47. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurology. 2008 Oct;7(10):915–926. 48. Kapral MK, Fang J, Hill MD, Silver F, Richards J, Jaigobin C, et al. Sex differences in stroke care and outcomes: results from the Registry of the Canadian Stroke Network. Stroke. 2005 Apr;36(4):809–814. 49. Appelros P, Stegmayr B, Terent A. Sex differences in stroke epidemiology: a systematic review. Stroke. 2009 Apr;40(4): 1082–1090. 50. Feigin VL. [Climatologic aspect of the epidemiology of acute cerebral circulatory disorders (review)]. Zhurnal Nevropatologii i Psikhiatrii Imeni S S Korsakova. 1984;84(9):1406–1412. 51. The New Zealand Adult Nutrition Survey. Methodology Report for the 2008/09 New Zealand Adult Nutrition Survey. Wellington: University of Otago and Ministry of Health 2011. 52. Dyall L, Carter K, Bonita R, Anderson C, Feigin V, Kerse N, et al. Incidence of stroke in women in Auckland, New Zealand. Ethnic trends over two decades: 1981–2003. N ZMed J. 2006;119(1245):U2309. 53. Kerr AJ, Broad J, Wells S, Riddell T, Jackson R. Should the first priority in cardiovascular risk management be those with prior cardiovascular disease? Heart. 2009 Feb;95(2):125–129. 54. Chen L, Rogers SL, Colagiuri S, Cadilhac DA, Mathew TH, Boyden AN, et al. How do the Australian guidelines for lipid-lowering drugs perform in practice? Cardiovascular disease risk in the AusDiab Study, 1999-2000. Med J Aust. 2008 Sep;189(6):319–322. 55. Whisnant JP. Modeling of risk factors for ischemic stroke. The Willis Lecture. Stroke. 1997 09;28(9):1840–1844.
  • 25. Introduction It is of great importance to identify the risk factors for stroke and to what extent these different risk factors contribute to the general as well as the individual risk burden for stroke. The term risk factor has been used since the 1960s (1). A risk factor has been defined as a factor (trait) associated with a pathological medical condition. However, such an association is not sufficient to establish a factor to be a risk factor. A specific trait may be seen in individuals after disease onset but its occurrence does not prove that this caused the disease. For example, if hypertension is often seen in stroke patients, does this necessarily mean that hypertension is the cause of stroke, or could possibly hypertension be the result of the stroke instead? Because of this, prospective cohort studies are often needed to identify risk factors. If a factor observed before stroke onset can be related to stroke occurring later in life, this indicates that this factor may indeed be a risk factor. However, some factors may be analysed also after stroke onset without this caveat, especially factors that are not influenced by the disease onset, e.g. gender and variations in the human genome. An additional proof that a trait is actually a risk fac- tor for stroke is if treatment of the trait leads to a reduced incidence of stroke. The amount of influence a specific risk factor has on risk is often measured as relative risk, odds ratio (OR), hazard ratio, and population attributable risk (PAR) (Table 2.1). PAR is the portion of risk for a disease caused by a specific factor. The numerical value of the PAR indicates how much of the disease that would be avoided if the risk factor could be completely elimi- nated. Therefore it is related to absolute risk for a specific factor. Interestingly, even though ischaemic heart disease (IHD), stroke, and peripheral artery disease are all arterial diseases, the impor- tance of risk factors influencing these conditions seem to vary. Thus hypertension is most important for stroke whereas lipid alterations seem to be more important for myocardial infarction (Figure 2.1) (4). Risk factors for ischaemic arterial cerebrovascular disease Non-modifiable factors Birth weight Low birth weight is reported to be associated with increased stroke risk in adult life (5). Even after adjustment for childhood socioeco- nomic factors the risk of vascular disease in adulthood may remain (6). A relation between low birth weight and higher blood pres- sure (BP) in adults has been observed (7). The relation between low birth weight and stroke may be more pronounced for haemorrhagic stroke (8). It could be suggested that the birth weight is, from a pop- ulation perspective, a modifiable risk factor if taking the nutritional situation of the mother during pregnancy into account. Gender Male gender increases the risk for ischaemic stroke (9, 10). The risk of stroke for men is about 1.3 times as high as for women at a given age except in the highest ages (Figure 2.2). However, this gender difference is less evident when taking the number of risk factors in each individual into account (11). Early menopause has been asso- ciated with increased stroke risk (12) and after menopause several vascular risk factors become more prevalent in women (10). The difference in risk between the genders seems to disappear in high age over 80–85 years of age (9). The gender risk is different for suba- rachnoid haemorrhage where the risk is higher for women (13). Age Stroke incidence increases markedly with age (Figure 2.2) (9, 14, 15). This steep increase in stroke incidence by age is observed in both men and women. In the OXVASC study, the rate of stroke increased from 1.76 per 1000 individuals per year for individu- als aged 55–64 years to 16.47 for those aged 85 or more (14). The increased incidence with age is seen for ischaemic stroke (16) as Risk factors Arne Lindgren CHAPTER 2 Table 2.1 Different terms used for describing influence of risk. For details, see (2, 3) Term Definition Absolute risk Risk in absolute number, e.g. if the risk is 1/100 for stroke if the person has a trait and 1/200 if the person does not have the trait Relative risk Relative comparison between two situations, e.g. if the risk is 1/100 for the person with the trait and 1/200 for the person without the train—then the relative risk is 2 Odds ratio Used in, e.g. retrospective case–control studies to estimate relative risk. Calculated as the odds of having a disease if having the trait divided by the odds of not having the disease if having the trait Hazard ratio Used for comparing survival in two different groups during a specific studied time period. The observed number divided by expected number in group 1 is compared (divided) by the observed number divided by expected number in group 2 Population attributable risk Proportion of risk for a disease caused by a specific factor. Indicates how much of the disease that could be avoided if the risk factor was not present
  • 26. oxford textbook of stroke and cerebrovascular disease 10 well as for intracerebral haemorrhage (ICH) (17) and also to some extent for subarachnoid haemorrhage (18). The risk of stroke more than doubles with each decade of increased age after 55 years of age at least up to age 84 (16, 19, 20). Also after age 84, the stroke risk continues to increase (19). Ethnicity There are considerable variations in stroke incidence between dif- ferent ethnic groups. People of African origin have a higher risk of all stroke types compared with Caucasians. This risk is at least 1.2 times higher and even higher for ICH (21). It is possible that this can in part be explained by poorer management of treatable risk factors. The proportion of ICH is higher (about 28%) among Chinese than among Caucasians (22). This increased proportion may remain also after emigration to Western countries; in one study 24% of reported strokes were of haemorrhagic type (23). It has also been reported that in ischaemic stroke, the prevalence of intracranial artery stenosis is more frequent in East Asians (24, 25) and African Americans (26) than in Caucasians. Familiar/genetic causes (specific or polygenetic) Even after accounting for all established risk factors there seems to be an increased risk of stroke among some families. This and other observations have led to the conclusion that some inherited factors may contribute to the risk of stroke. The heritability of ischaemic stroke when using genome-wide association study data has been calculated as 37.9% overall, ranging from 40.3% for large ves- sel disease to 32.6% for cardioembolic and 16.1% for small vessel disease (27). Several rare stroke syndromes have been associated with mono- genetic variations, e.g. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy; NOTCH3 gene) (28), CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leucoencephalopathy; HTRA gene), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; mitochondrial disease), HERNS (hereditary endotheliopathy with retinopathy, nephropa- thy, and stroke; TREX1 gene), homocystinuria, Fabry disease (alpha galactosidase gene), Ehlers–Danlos syndrome type IV, Marfan syndrome, pseudoxanthoma elasticum, HANAC (heredi- tary angiopathy, nephropathy, aneurysm, and muscle cramps syn- drome; COL4A1 mutation), and other syndromes (29). Typically these syndromes include stroke or stroke-like episodes as only one of several different clinical manifestations of the syndrome in ques- tion. It should be emphasized that in some cases stroke is the pre- senting symptom before other symptoms that indicate the specific syndrome are seen. For details, please see Chapter 14. Sickle cell disease (SCD) increases the risk of stroke in childhood with a prevalence of cerebral infarct of 11% at the age of 20 years (30). SCD children with increased transcranial Doppler ultrasound veloci- ties of the middle cerebral arteries have a particularly high risk. At ages 20–30 years these patients also have a risk of cerebral haemor- rhage (30). Cerebral infarcts have also been reported in other related genetic haemoglobin variations though at a lower rate compared with SCD (30). Additional details on SCD are provided in Chapter 14. The common stroke phenotypes have been more difficult to relate to specific genetic variations. However, there are now reports emerging that certain common genotypes, especially single-nucleotide polymorphism (SNP) variations, are associated with increased risk of intermediate phenotypes that subsequently increase the risk of stroke. Such intermediate phenotypes that may be genetically influenced include hypertension, diabetes mellitus, and heart disease. One example is atrial fibrillation (AF) that has been shown to be related to genetic variations and specific types of ischaemic stroke. AF has in genome-wide association studies been related to SNPs in the PITX gene, the ZHFX3 gene, and the KCNN3 gene (31). There are also reports of genetic variations that seem to be more directly related to common subtypes of ischaemic stroke. Typically these reports have included large international collaborations such as the International Stroke Genetics Consortium. SNP variations in the chromosome 9p21 region have been related to ischaemic stroke (32), and these associations seem more evident for the large vessel type of stroke (33). Recently, a new SNP in HDAC9 on chro- mosome 7p21.1 was associated with large vessel ischaemic stroke (34). Very recently another study reported a locus on chromosome 6p21.1 related to the ischaemic stroke subtype large artery athero- sclerosis (35). The Metastroke collaboration was able to confirm several of these findings (36). Also for ICH there have been reports on genetic associations. The APOE ε2 and ε4 alleles are mostly related to lobar ICH and likely amyloid angiopathy whereas ε4 is also, although not with the same high degree of significance, related to deep ICH (37). Hypertension Myocardial infarction Stroke 0 10 20 30 Per cent PAR 40 50 60 Smoking Main modifiable risk factors Diabetes ApoB/ApoA1 ratio Fig. 2.1 Degree of influence of some risk factors for stroke and myocardial infarction. (Endres M, Heuschmann PU, Laufs U, Hakim AM. Primary prevention of stroke: Blood pressure, lipids, and heart failure. Eur Heart J. 2011;32:545–552) 55–59 0 5 10 15 10-Year probability of stroke/100 20 25 Men Women 60–64 65–69 Age, years 70–74 75–79 80–84 Fig. 2.2 Average 10-year probability of stroke according to age in men and women per 100 (%). (Wolf PA, Belanger AJ, D’Agostino RB. Quantifying stroke risk factors and potentials for risk reduction. Cerebrovasc Dis. 1993;3(Suppl 1):7–14.)
  • 27. CHAPTER 2 risk factors 11 Other diseases and measurable traits Hypertension Hypertension is the most important treatable risk factor for stroke (4). History of hypertension increases the OR to 2.6 for stroke and has a PAR of 35% (38). The individual relative risk for stroke in hypertensives may be higher—up to 8 in a group of individuals with a mean age of 47 years to develop a stroke during a 10-year follow-up period (39). Hypertension is commonly detected among stroke patients under 55 years of age (40, 41). Hypertension remains to be a stroke risk factor in the elderly and also at ages over 60 is it useful to treat hypertension to prevent stroke (42). At even higher ages the importance of hypertension as a stroke risk factor is some- what more difficult to assess because the prevalence of hypertension is so high in these age groups (43). However, hypertension treat- ment seems to reduce stroke risk also in the very elderly, indicating that it is also important to control BP among these individuals (44). Both systolic (Figure 2.3) (45) and diastolic (46) BP is of impor- tance for stroke risk. Not only hypertension but also BP within the normal range may be a risk factor for stroke. There is no thresh- old for BP—also rather normal BP levels carry an increased risk of stroke (47) and a considerable proportion of strokes occur among people with high–normal BP or ‘mild’ hypertension (45). A systolic BP increase of 20 mmHg or a diastolic BP increase of 10 mmHg more than doubles the risk of stroke death (47). Not only may the BP measured at a certain time be related to stroke risk, it has been suggested that BP variability and episodic hypertension may increase the stroke risk (48). This may have impli- cations for how BP will be measured and evaluated in the future and also influence which antihypertensive drugs are preferred. Stroke/transient ischaemic attack A previous stroke is a powerful risk factor of a new stroke. The risk of a new stroke varies considerably depending on the patho- genetic mechanism of the first stroke and on the simultaneous presence of other risk factors. A risk of about 9% during an aver- age follow-up of 2.5 years, i.e. about 3.6% per year, was reported in the PROFESS trial which included patients with a mean age of 66 years (49). Also, transient ischaemic attack (TIA) indicates an increased the risk for a subsequent stroke both in the short term and long term. In one study, the risk of stroke within 90 days of a TIA was on average 10.5% but depended on the characteristics of the TIA with higher risk among those with a TIA with weakness or speech impairment, diabetes mellitus, age over 60 years, or longer TIA duration (50). Silent cerebral infarcts/white matter disease Presence of silent cerebral infarcts increases the stroke risk by at least two to three times independently of other vascular risk fac- tors (51, 52). Both periventricular and subcortical white matter hyperintensities also increase the risk of subsequent stroke, inde- pendently of the presence of silent brain infarcts (52). Atrial fibrillation AF is a powerful risk factor for stroke. The abnormal contractions of the atrium of the heart lead to non-laminar blood flow in the left atrium. The blood flow in the left atrial appendage also becomes disturbed and the general opinion is that the blood clots in AF usu- ally develop in the left atrial appendage. Fragments of or the whole clot then detach from the left atrial appendage and embolize to the cerebral arteries or other parts of the arterial system. The risk for stroke depends on whether other factors are present simultaneously with the AF. The often used CHADS2 score (one point for each of: congestive heart failure, hypertension, age >75, diabetes; and 2 points for stroke or TIA) is a useful method to estimate stroke risk in patients with AF. With none of the factors mentioned in CHADS2, the yearly risk of stroke in patients is on average 1.9%, with one factor present the risk is about 2.8%, and with all factors present the yearly risk is on average 18.2% (53, 54). The more recently developed CHA2DS2-VASc may be even more precise in determining stroke risk in AF patients (Table 2.2). Other cardiac conditions including patent foramen ovale There are many heart conditions that have been suggested to be associated with increased stroke risk (see Table 2.3). Some of these conditions are well established, e.g. AF (see ‘Atrial fibrillation’ sec- tion above), mitral valve stenosis, acute anterior transmural myo- cardial infarct, atrial myxoma, mechanical heart valve prosthesis in the mitral or aortal position, whereas other are considered more equivocal regarding stroke risk. The latter include patent foramen ovale (PFO), atrial septal aneurysm, mitral annulus calcifications, and others (55). A PFO is a remaining connection between the right and left atrium of the heart. If the connection is larger and not having over- lapping structures functioning as a valve the condition is instead an atrial septal defect. In both cases there is a theoretical possibil- ity that a venous thrombus travelling as an embolus in the venous system to the heart may pass directly from the right atrium on the venous side of the heart directly to the left atrium on the arterial side of the heart and then continue to travel out into the arterial system. Another possibility that has been proposed is that a throm- bus may form in situ in the channel that often constitutes the PFO and then detach as an embolus. The relation between PFO and the risk of ischaemic stroke has been debated. PFO is often present in the general population at a rate of about 20–25%. Therefore there is a possibility that the PFO is just a coincident finding in the stroke patient. However, some reports have indicated that among young patients with cryptogenic ischaemic stroke, PFO may be seen more 100 0 5 10 15 0 3 11 17 18 16 11 8 8 8 20 25 120 140 Systolic blood pressure (mmHg) 160 180 200 0 10 20 Stroke mortality/1000 person-years Population distribution (%) 30 40 50 Fig. 2.3 Influence of systolic BP on stroke mortality. (Marmot MG, Poulter NR. Primary prevention of stroke. Lancet. 1992;339:344–347.)
  • 28. oxford textbook of stroke and cerebrovascular disease 12 often than in the general population (56). It has also been discussed that the size of the PFO and a concomitant atrial septal aneurysm (defined as hypermobile part of the septum between the right and left atrium) may increase the risk of stroke (57). Lipid changes Serum lipid levels do not play such an important risk factor role for ischaemic stroke as for IHD (20, 58). Even so, increased choles- terol levels are related to ischaemic stroke risk, although this may differ between different pathogenetic subtypes of ischaemic stroke (58). Cholesterol levels are associated with carotid artery athero- sclerosis (59) and it is therefore likely that cerebral infarcts caused by large vessel disease are more clearly related to increased choles- terol levels. Conversely, reports indicate that low cholesterol levels may increase the risk of ICH (60, 61) and observations have related intense lowering of cholesterol levels in stroke patients to a slightly increased risk of ICH (62). The situation regarding triglyceride lev- els and risk of stroke is unclear (20). Coagulation disorders Antiphospholipid antibodies including anticardiolipin antibod- ies and lupus anticoagulant have been associated with ischaemic stroke. Even though the situation is complex with different assays and cut-off levels used, there is probably an increased stroke risk for patients with high levels of these antibodies (63). Several other coagulation disorders are associated with increased risk of venous thrombosis, but it is much less clear how these affect the arterial situation (63). It is possible that in some situations a coagulation disorder causing a venous thrombosis may give rise to paradoxical embolism through a PFO. Homocysteine Increasedhomocysteinelevelshavebeenobservedinstrokepatients (64). Even so, the importance of increased homocysteine levels for stroke risk has been debated. Two reasons for this are: (i) that the situation is complicated by the relation between homocysteine levels and other vascular risk factors, e.g. age and decreased renal function, both of which in their turn influence stroke risk; and (ii) that studies have been unable to clearly demonstrate that homo- cysteine lowering therapy decreases stroke risk (65). Diabetes mellitus Diabetes mellitus has a deteriorating effect on arterial blood ves- sels and is a risk factor for ischaemic stroke. The relative risk of ischaemic stroke for diabetic individuals has been estimated to be between 1.3 and 6 (20, 66). Diabetes also increases the risk of stroke recurrence (66). Lacunar infarcts may be more common in diabetic patients (67) although this has not always been reported (68). The effect of diabetes may in part be mediated by other risk factors such as hypertension and lipid alterations and it is also possible that these and other risk factors such as smoking potentiate each other. Migraine The relation between migraine and stroke is complex (69). Migraine and ischaemic stroke often occur in the same patients. Migraine-like symptoms may indicate another underlying disease that may cause a stroke, e.g. arteriovenous malformation, arterial dissection, CADASIL, MELAS, encephalitis, or even atherosclerosis. It is also of interest that migraine has been related to increased prevalence of white matter hyperintensities on magnetic resonance imaging. However, also in patients without migraine caused by another dis- ease, there seems to be an increased risk of stroke, and the risk is higher for patients with migraine with aura compared with patients with migraine without aura. The risk of stroke in migraineurs may be higher in women than in men (70). The increased risk among individuals with migraine with aura has been reported to represent a relative risk of 2.27 (71). However, the individual risk in younger patients who report migraine with aura, e.g. under 45 years of age, is still low due to the low overall stroke incidence in younger ages. Migraine as a risk factor for stroke seems to interact with other risk factors such as smoking and use of oral contraceptives. The cerebral infarct supposed to be caused by migraine with aura has symptoms similar to those experienced in the aura phase. It has been sug- gested that a pronounced cortical spreading depression may cause local ischaemia so profound that an infarct develops. Other the- ories have included that the increased prevalence of PFO among Table 2.2 CHA2DS2VASc score and risk of stroke in patients with AF. Risk factor-based approach expressed as a point based scoring system, with the acronym CHA2DS2–VASc (Note: maximum score is 9 since age may contribute 0, 1, or 2 points) Risk factor Score Congestive heart failure/LV dysfunction 1 Hypertension 1 Age ≥ 75 2 Diabetes mellitus 1 Stroke/TIA/thrombo-embolism 2 Vascular diseasea 1 Age 65–74 1 Sex category (i.e. female sex) 1 Maximum score 9 Adjusted stroke rate according to CHA2DS2– VASc score CHA2DS2 –VASc score Patients (n = 7329) Adjusted stroke rate (%/year)b 0 1 0% 1 422 1.3% 2 1230 2.2% 3 1730 3.2% 4 1718 4.0% 5 1159 6.7% 6 679 9.8% 7 294 9.6% 8 82 6.7% 9 14 15.2% a. Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates. b. Based on Lip et al. Stroke. 2010;41:2731–2738. LV = left ventricular. Reproduced from Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: The task force for the management of atrial fibrillation of the European Society of Cardiology. Eur Heart J. 2010;31:2369–2429, with permission.
  • 29. CHAPTER 2 risk factors 13 patients with migraine with aura is a possible mechanism for the increased risk of stroke in these patients. However, this has been questioned and it is possible that this is only an epiphenomen, i.e. that migraine with aura and PFO coexist in the same patients with- out any additional combined mutual influence on stroke risk. For a detailed, up-to date overview about migraine and stroke, please see reference (69). Infection Inflammation measured as, e.g. C-reactive protein or fibrinogen levels, seem to increase the risk of stroke (72). Acute or chronic infections that precede stroke onset and cause an increased stroke risk may at least in part be mediated by inflammation (73). Chronic infections suggested to be related to stroke include agents such as Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus, her- pes simplex virus (HSV)-1, and HSV-2 even though the effect is perhaps more mediated by a ‘total burden’ of infections rather than a single agent (72). Periodontitis has also been related to stroke risk (74).ItseemsclearthatChagasdiseasecausesincreasedriskofstroke (75). Acute infection, e.g. respiratory or urinary tract infection, may precede stroke onset and indicate increased stroke risk (73). Obstructive sleep apnoea Even though obstructive sleep apnoea (OSA) may increase BP and be related to obesity, there seems to be an independent stroke risk related to OSA per se (76). Suggested possible mechanisms include hypercoagubility, atherosclerosis, decreased cerebral blood flow, and paradoxical embolization (76). Interestingly, wake-up stroke has recently been linked to OSA (77). Renal disease Renal dysfunction increases the risk of stroke in individuals with known atherothrombotic disease (78). Microalbuminuria has been independently associated with stroke risk (79). Arterial diseases Carotid artery stenosis or occlusion is a well-known risk factor for stroke. There is a risk in individuals with asymptomatic carotid artery stenosis (80, 81) but the risk is considerably higher in patients with a symptomatic high-degree stenosis (81–83). Aortic plaques are independent risk factors for stroke and severe aortic arch plaques have been reported to confer a risk of cerebral infarct of 10% or more in 1 year (84). Patients with asymptomatic or symptomatic peripheral arterial disease have an increased risk of stroke (85, 86). In addition, carotid artery disease is more fre- quently seen in patients with peripheral artery disease (85). Several diseases with microangiopathy of the brain (87, 88) and sometimes simultaneous vascular involvement of other organs (some with, some without clinical symptoms from other organs than the brain) are related to stroke risk, e.g. CADASIL (28, 89), CARASIL (90), HERNS (91), HANAC (92), HSA (hereditary sys- temic angiopathy) (93), Fabry disease (94), polyarteritis nodosa (95), and other syndromes. Other diseases Several factors that are more uncommon in the general population are also related to stroke risk. These factors include inflammatory disease, e.g. inflammatory bowel disease, haematological disorders, cancer, and different medical or surgical procedures. Please see separate chapters in this book regarding these conditions. Lifestyle risk factors Several lifestyle risk factors have been related to stroke risk. A com- prehensive review on this topic with both tables of relative risk and information on PAR has been given by Chiuve et al. (96). The Royal College of Physicians has provided tables of evidence that include aspects on life style factors (<http://www.rcplondon.ac.uk/ sites/default/files/documents/stroke_evidence_tables_2008.pdf>, accessed 29 Oct 2013). It is of special interest that some factors have been reported as acute triggers of stroke onset (97). The following sections give a more detailed description of lifestyle and stroke risk. Smoking Cigarette smoking approximately doubles the risk for ischaemic stroke (38, 98–100). The situation for ICH is less clear but here smok- ing may also indicate an increased risk (96). There is an even more pronounced relation between cigarette smoking and risk for suba- rachnoid haemorrhage (101). Also, passive smoking carries a risk for stroke (98). Smoking potentiates the effect of other risk factors (20). Cigarette smoking is associated with an increased risk of atheroscle- rosis as well as with the risk of thrombus formation. Individuals who stop smoking reduce their risk of stroke (96, 100) by up to 50% (100). Alcohol Excessive alcohol consumption increases the risk of stroke. Moreover, individuals who do not use any alcohol may have a slightly increased risk (96), and a J-shaped curve for stroke risk regarding alcohol consumption has been suggested (20). It is pos- sible that temporary heavy alcohol consumption increases the risk of immediate stroke (97). Drug abuse Drug abuse can cause stroke due to several pathogenetic mecha- nisms.Intravenousinjectionofadrugmaybeaccompaniedbyother agents such as air or talcum powder with subsequent embolization. Table 2.3 Cardiac changes with possible relation to thromboembolic risk Major potential sources Minor potential sources Atrial fibrillation Patent foramen ovale Recent (<3 months) myocardial infarct Atrial septal aneurysm Thrombus left atrium or ventricle Mitral valve prolapse Dilating cardiomyopathy (EF ≤35 %) Severe mitral annulus calcification Mitral stenosis Calcific aortic stenosis Myxoma Spontaneous echo contrast in left atrium on echocardiography Mechanical prosthetic valve Other (e.g. hypokinetic left ventricular segment, bioprosthetic valve, mitral valve strands) Infective endocarditis Marantic endocarditis Protruding aortic plaque Major potential source: causal relation probable. Minor potential source: sometimes over represented in stroke studies but no certain causal relation. EF = ejection fraction. Modified from reference (55).
  • 30. oxford textbook of stroke and cerebrovascular disease 14 Drugs or other agents administered simultaneously may cause vas- culitis due to toxic or hypersensitivity reaction. Infectious agents may be injected due to non-sterile conditions and cause, e.g. infec- tive endocarditis with subsequent cerebral embolization. The use of drugs may also unmask other pre-existing lesions such as arte- rial aneurysms, arteriovenous malformations, and tumours. Drugs increasing sympathetic activity such as amphetamine can cause acute BP elevation with subsequent ICH (102). Cocaine is a potent vasoconstrictor agent. Cocaine abuse has been related to both cer- ebral infarct and ICH (102). There are case reports of stroke related to cannabis use but a clear causative risk still remains unsettled (103). It should be mentioned that sympathomimetics and other vasoactive drugs including cannabis, cocaine, and amphetamine— as well as conventional medications with vasoactive effects—have also been associated with the reversible cerebral vasoconstriction syndrome (104). Obesity A body mass index (BMI) of 25 kg/m2 or more in men and 30 kg/ m2 or more in women increases the risk of ischaemic stroke, whereas the risk for ICH does not necessarily increase by BMI increase (96). As an example, a BMI of 30.0–31.9 kg/m2 in women and of 25.0–29.9 kg/m2 in men carry a relative risk of 1.44 and 1.43 for ischaemic stroke, respectively. Waist:hip ratio has also been related to increased stroke risk, even after adjustment for BMI (105). Physical activity Physical activity decreases the risk of stroke compared with no physical activity (106). Daily exercise of at least 30 minutes decreases the relative risk of stroke to between 0.69 and 0.74 (96). Physical activity of at least 30 minutes three to five times per week has been recommended (107). Diet There are many components in diet and it is unclear how these influence stroke risk. Excessive salt intake is related to higher BP (108). Several diets have been related to lower stroke risk. The Alternate Healthy Eating Index (AHEI)-based diet score is based on intake of trans fat, ratio of polyunsaturated to saturated fat, ratio of chicken and fish to red meat, fruits, vegetables, soy, nuts, cereal fibre, and multivitamin use and has been related to lower risk of stroke in women (96). Fruit and vegetables may have a pro- tective effect against both ischaemic and haemorrhagic stroke: one meta-analysis reported that individuals eating three to five servings per day had a relative risk of stroke of 0.89 compared with those consuming less fruit and vegetables (109). Fish consumption may also decrease the risk of stroke (110). Hormone therapy (especially oral contraceptives and hormone replacement therapy) Oral contraceptive use may confer a slightly elevated risk of ischae- mic stroke (111). The results have been debated and questions such as influence on stroke risk by oestrogen dose are not clearly under- stood (20). However, it seems that oral contraceptive use increases the ischaemic stroke risk in females with simultaneous other stroke risk factors such as smoking, hypertension, diabetes mellitus, older age, and hypercholesterolemia (20, 112). The situation regarding risk of ICH is less clear. Hormone replacement therapy has been related to increased risk of stroke with a relative risk of 1.29 (113). It is possible that transdermal oestrogen hormone replacement therapy carries a lower risk of stroke compared to oral oestrogens and further stud- ies are ongoing (10). Other drugs with hormone-like actions such as tamoxifen have also been reported to increase stroke risk (114). One review linked tamoxifen to thromboembolic events but not significantly to stroke risk(115).Thestrokeriskmaybelimitedtotheactivetamoxifentreat- ment period and then decrease in the post-treatment period (116). Stress Self-perceived psychological stress has been associated with increased stroke risk (117) and individuals experiencing major life events have a dose–response relationship with stroke risk (118). These studies mostly refer to an increased risk in the longer per- spective, but it is possible that psychological stress may be a trigger for stroke onset (97). Both negative emotions and anger seem to be more common during the last 2 hours before stroke onset than during the preceding day or year (119). Socioeconomic factors Both comparisons within countries and between countries indicate that low socioeconomic status is associated with increased stroke risk (120). In addition, the deficit after stroke tends to be more severe as well as the mortality ratio in stroke patients with lower socioeconomic status. Even though lower socioeconomic status is related to higher frequency of other stroke risk factors such as hypertension and physical activity, this may not be the only expla- nation why these individuals have an increased risk. The impact of socioeconomic status may vary by age, e.g. in one study there was a clearer association for men 40–59 years old compared to older men (121). Interaction between different risk factors Many individuals have more than one stroke risk factor and it is then difficult to assess how important each risk factor is. This important area is complex and it is often difficult to use different suggested score systems to evaluate how much different risk fac- tors potentiate each other (see Chapter 23 regarding these issues). When considering secondary prevention it is also very important to consider the interaction between different risk factors. Risk factors for intracerebral haemorrhage Some risk factors for ICH have been discussed previously in this chapter. Hypertension and higher age are risk factors for ICH (17, 60, 123). Other risk factors include African American rather than Caucasian ethnicity and lower cholesterol or low-density lipoprotein-cholesterol levels (21, 60, 61). Frequent alcohol use and diabetes mellitus have been related to ICH (123, 124). Results regard- ing the influence of triglyceride levels have been equivocal (60, 123). Genetic factors and cerebral amyloid angiopathy are also of impor- tance (see earlier in this chapter). The risk factors for ICH seem to have varying impact depending on whether the ICH is lobar or deep (124). The risk of ICH increases in patients using antiplatelet or anti- coagulant medications. Cerebral microbleeds are more often seen in ICH patients than in ischaemic stroke/TIA patients (125). Please see Chapter 5 regarding further discussion on risk factors for ICH. Risk factors for subarachnoid haemorrhage Risk factors for subarachnoid haemorrhage are somewhat different than for ischaemic stroke. However, smoking and hypertension are