Transient Ischemic Attack
and Stroke
Transient Ischemic Attack and Stroke
Diagnosis, Investigation and Management
Sarah T. Pendlebury
Matthew F. Giles
Peter M. Rothwell
Cambridge University Press
The Edinburgh Building, Cambridge CB2 8RU, UK
First published in print format
ISBN-13 978-0-521-73512-4 ISBN-13 978-0-511-53338-9
© S. Pendlebury, M. Giles and P. Rothwell 2009
Every effort has been made in preparing this publication to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved.
Nevertheless, the authors, editors and publishers can make no warranties that the information contained
herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential
damages resulting from the use of material contained in this publication. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.
2009
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Contents
Foreword vii
Section 1 –Epidemiology, risk factors, pathophysiology and causes of transient ischemic attacks and stroke
1 Epidemiology 1 2 Risk factors 16 3 Genetics 30
4 Anatomy and physiology 38 5 Pathophysiology of acute cerebral
ischemia 49
6 Causes of transient ischemic attack and ischemic stroke 55 7 Causes of spontaneous intracranial
hemorrhage 91
Section 2 –Clinical features, diagnosis and investigation
8 Clinical features and differential diagnosis of a transient ischemic attack 101
9 The clinical features and differential diagnosis of acute stroke 113 10 Brain imaging in transient ischemic
attack and minor stroke 132 11 Brain imaging in major acute
stroke 145
12 Vascular imaging in transient ischemic attack and stroke 159 13 Non-radiological investigations
for transient ischemic attack and stroke 173
Section 3 –Prognosis of transient ischemic attack and stroke
14 Methods of determining prognosis 179
15 Short-term prognosis after transient ischemic attack and minor stroke 195
16 Short-term prognosis after major stroke 207
17 Long-term prognosis after transient ischemic attack and stroke 213
Section 4 –Treatment of transient ischemic attack and stroke
18 Methods of assessing treatments 223
19 Acute treatment of transient ischemic attack and minor stroke 239
20 Acute treatment of major stroke:
general principles 250
21 Specific treatments for major acute ischemic stroke 257
v
22 Specific treatment of acute intracerebral hemorrhage 267 23 Recovery and rehabilitation
after stroke 274
Section 5 –Secondary prevention
24 Medical therapies 285 25 Carotid endarterectomy 290 26 Carotid stenting and other
interventions 304
27 Selection of patients for carotid intervention 312
28 Intervention for asymptomatic carotid stenosis 331
Section 6 –Miscellaneous disorders
29 Cerebral venous thrombosis 341 30 Spontaneous subarachnoid
hemorrhage 348
31 Vascular cognitive impairment:
definitions and clinical diagnosis 362
32 Vascular cognitive impairment:
investigation and treatment 372
Index 380
The color plates appear between pages 216 and 217.
Foreword
The provenance of this book on stroke goes back to the 1990s when Peter Rothwell joined our stroke research group in Edinburgh. It moves to Oxford where he married and works with Sarah Pendlebury, who is a geriatrician, and continues with Matthew Giles– the third author– who was a research fellow on Peter's Oxford Vascular Study (OXVASC), which he based on the earlier Oxfordshire Community Stroke Project (OCSP) which I ran in the 1980s. A 30 year cycle. During that time, the management of stroke has changed completely.
We have sharpened up, we are faster, and governments, certainly in the UK, now make stroke one of their top priorities. We have stroke units staffed by stroke specialists. All people with strokes coming to hospital get CT scanned, more and more have MR scanning– not some time in the next few weeks, but within hours. Thirty years ago, we didn't know that aspirin was an effective drug for stroke secondary prevention, statins were somewhere over the horizon, blood pressure lowering long term after stroke was controversial, carotid surgery was out of control, vascular dementia was a minority interest, and there were no coils to occlude intracranial aneurysms. Everything has changed, and it is all somewhere in this book. Indeed, the authors’ practice-based research has been responsible for a lot of these changes. Well perhaps not quite everything has changed; some things are much the same. Clinical skills are still needed, and clinical common sense, which is embedded in what we would now call clinical epidemiology, a rather special interest of the authors which should be obvious even to the casual reader. It is impossible to imagine what stroke medicine will look like in another 30 years, but in the meantime this is what it looks like now.
Professor Charles Warlow
vii
Section 1 Chapter
1 Epidemiology, risk factors,
pathophysiology and causes of
transient ischemic attacks and stroke Epidemiology
In order to understand the clinical management of transient ischemic attacks (TIAs) and stroke, to plan clinical services or to design randomized controlled trials, and to measure the overall impact of treatments, it is important to understand the epidemiology of stroke.
Definitions of transient ischemic attack and stroke
A stroke is defined as rapidly developing clinical symptoms and/or signs of focal, and at times global (applied to patients in deep coma and to those with subarachnoid hemor- rhage), loss of brain function, with symptoms lasting more than 24-hours or leading to death, with no apparent cause other than that of vascular origin (Hatano1976). Conven- tionally, a TIA is distinguished from stroke on the basis of an arbitrary 24-hour cut-off for resolution of symptomsBox 1.1.Hence a TIA is defined as an acute loss of focal brain or monocular function with symptoms lasting less than 24-hours and which is thought to be caused by inadequate cerebral or ocular blood supply as a result of arterial thrombosis, low flow or embolism associated with arterial, cardiac or hematological disease (Hatano1976).
Since the early part of the twentieth century, a variety of definitions of TIA have been used (Table 1.1). However, the definition given in Box 1.1 has recently been challenged since the 24-hour time limit is arbitrary, rather than being based on clinical, imaging or pathological criteria. The 24-hour cut-off does not reflect the fact that the majority of TIAs last for less than 60 minutes, nor does it indicate a lack of infarction on brain imaging.
Some TIAs are associated with radiological evidence of cerebral infarction, but there is poor correlation between clinical and imaging findings (Table 1.2). An alternative, but contro- versial (Eastonet al.2004), definition for TIA has been proposed as comprising a transient episode of neurological dysfunction caused by focal brain or retinal ischemia without evidence of acute infarction on brain imaging (Albers et al. 2002). The proposed new definition for TIA has the problem that brain imaging does not correlate particularly well with pathological infarction: brain imaging may be normal in clinically definite stroke,
Box 1.1. Definitions of transient ischemic attack and stroke as used in this book
Transient ischemic attack. An acute loss of focal brain or monocular function with symptoms lasting less than 24-hours and which is thought to be caused by inadequate cerebral or ocular blood supply as a result of arterial thrombosis, low flow or embolism associated with arterial, cardiac or hematological disease (Hatano1976).
Stroke. Rapidly developing clinical symptoms and/or signs of focal, and at times global (applied to patients in deep coma and to those with subarachnoid hemorrhage), loss of brain function, with symptoms lasting more than 24-hours or leading to death, with no apparent cause other than that of vascular origin (Hatano1976).
1
silent infarction may occur and imaging sensitivity is highly dependent on both imaging method and area of the brain being examined. Moreover, there is uncertainty regarding the pathological correlates of imaging changes such as diffusion-weighted magnetic resonance imaging (DWI) hyperintensity (Chs. 10and 11) and leukoaraiosis, and, as imaging tech- nology advances, what is defined as TIA will change. The definition of TIA used throughout this book is, therefore, the conventional one based on symptoms or signs lasting less than 24-hours.
Anything that causes a TIA may, if more severe or prolonged, cause a stroke (Sempere et al.1998). There are many non-vascular conditions that may cause symptoms suggestive of TIA or stroke, and these are referred to in this book as“TIA mimics” or “stroke mimics.”
The separation of TIA from stroke on the basis of a 24-hour time limit is useful since the differential diagnosis of the two syndromes is different to some extent (i.e. the spectrum of TIA mimics differs from that of stroke mimics).
Given the common mechanisms underlying TIA and stroke, the investigation of patients with these syndromes is similar. However, in TIA and minor stroke, the emphasis is on rapid identification and treatment of the underlying cause in order to prevent a recurrent and possibly more severe event, whereas in severe stroke, the initial emphasis of investigation is on targeting treatment to minimize subsequent deficit. Therefore, in this book, we have considered TIA and minor stroke separately from severe stroke to reflect the difference in clinical approach to minor versus more severe cerebrovascular events.
There is no accepted definition for what constitutes “minor” stroke. This distinction between minor and major stroke is sometimes based on an a score on the National
Table 1.1. History of the definition of transient ischemic attack
Year Description
1914 Hunt (1914) Characterized“the role of the carotid arteries in the causation of vascular lesions of the brain” and described“attacks of threatened hemiplegia and cerebral intermittent claudication”
1954; CM Fisher at the First and Second Conferences on Cerebral Vascular Diseases, Princeton, USA
Described“transient ischemic attacks . . . which may last from a few seconds up to several hours, the most common duration being a few seconds up to 5 or 10 minutes”
1961; CM Fisher at the Third Conference on Cerebral Vascular Diseases
TIA described as“the occurrence of single or multiple episodes of cerebral dysfunction lasting no longer than one hour and clearing without significant residuum” 1964 Acheson and Hutchinson (1964) Series of patients with“transient cerebral ischemia”
defined as“duration of attack less than an hour”
1964 Marshall (1964) Series of 180 patients with TIAs defined as“of less than 24-hours duration”
1975 Advisory Council for National Institute of Neurological and Communicative Disorders and Stroke (1975)
TIA defined as lasting“no longer than a day (24-hours)”, although typically lasting from 2 to 15 minutes
1976 World Health Organization bulletin (Hatano 1976)
TIA defined as lasting less than 24-hours
2002 For the TIA Working Group (Albers et al.2002) TIA definition proposed based on absence of infarction on brain scanning and a 1 hour time window Note:
TIA, transient ischemic attack.
Institutes of Health Stroke Scale (NIHSS) at assessment of 3 (Wityk et al.1994) or a score of 2 on the modified Rankin Scale (mRS) at 1 month. Such distinctions are problematic because the NIHSS score will vary with time after the stroke and the mRS at 1 month may increase if a minor stroke is followed by a major stroke. We take the pragmatic view that minor stroke includes those strokes mild enough for patients to be seen in an emergency outpatient setting or to be sent home after initial assessment and treatment in hospital.
Approximately 85% of all first-ever strokes are ischemic; 10% are caused by primary intracerebral hemorrhage and approximately 5% are from subarachnoid hemorrhage (Rothwellet al.2004). Within ischemic stroke, 25% are caused by large artery disease, 25%
by small vessel disease, 20% by cardiac embolism, 5% by other rarer causes, and the remaining 25% are of undetermined etiology. Ischemic stroke may also be classified by anatomical location using simple clinical features as total anterior circulation stroke, partial anterior circulation stroke, lacunar stroke and posterior circulation stroke. This is of some help in identifying the likely underlying pathology and gives information as to prognosis (Ch. 9).
The burden of transient ischemic attack and stroke
Each year there are about one million strokes in the European Union (Sudlow and Warlow 1997), making it by far the most common neurological disorder (MacDonaldet al.2000) (Table 1.3). Approximately 25% of men and 20% of women can expect to suffer a stroke if they live to be 85 years old (Bonita1992) and stroke is the second most common cause of death worldwide (Murray and Lopez1996). However, mortality data underestimate the true burden of stroke since, in contrast to coronary heart disease and cancer, the major burden
Table 1.2. Advantages and disadvantages of conventional and imaging-based definitions of transient ischemic attack
Definition Advantages Disadvantages
Conventional definition
Diagnosis can be made at assessment (provided that symptoms have resolved) either prior to imaging or in centers where imaging is unavailable
Diagnosis based on an arbitrary cut-point of no physiological or prognostic significance
Comparisons with previous studies using conventional definition possible
Diagnosis based on patient recall, which may vary with time
Diagnosis cannot be made with certainty within 24-hours in a patient with resolving (but persistent) symptoms
Imaging- based definition
Based on pathophysiological endpoint and emphasizes prognostic importance of cerebral infarction
Diagnosis based on interpretation of imaging, which is likely to vary between individuals and centers; also, sensitivity of imaging techniques is likely to increase with time with developments in computed tomography and magnetic resonance technology
Majority of transient ischemic attacks last less than 60 minutes
Pathophysiological significance of changes on new imaging techniques not fully understood
Encourages use of neurodiagnostic investigations
Classification of events lasting>1 hour without infarction unclear
Consistent with the distinction between unstable angina and myocardial infarction
Diagnosis cannot be made in centers where no imaging is available
Chapter 1: Epidemiology
3
of stroke is chronic disability rather than death (Wolfe 2000). Brain diseases, of which stroke forms a large proportion, cause 23% of healthy years lost and around 50% of years of life lived with disability in Europe (Olesen and Leonardi2003).
Approximately a third of stroke survivors are functionally dependent at one year and stroke is the commonest cause of neurological disability in the developed world (Murray and Lopez1996; MacDonaldet al.2000). Stroke also causes secondary medical problems, including dementia, depression, epilepsy, falls and fractures. In the UK, the costs of stroke are estimated to be nearly twice those of coronary heart disease (British Heart Foundation Statistics Database1998; Rothwell2001), accounting for about 6% of total National Health Service (NHS) and Social Services expenditure (Rothwell2001). As the population ages over the coming two decades, the total stroke rate will probably increase unless there are substantial decreases in age- and sex-specific incidence (Rothwell et al. 2004a). Stroke deaths are projected to increase from 4.5 million worldwide in 1990 to 7.7 million in 2020, when stroke will account for 6.2% of the total burden of illness (Bonita1992; Sudlow and Warlow1997; Menkenet al.2000).
Additionally, TIAs are also common, and it is estimated that 54 000 TIAs occur each year in England (Giles and Rothwell2007). By definition, TIA causes transient symptoms only and, therefore, has no long-term sequelae per se. However, the importance of TIA lies in the high early risk of stroke and the longer-term risk of other vascular disease. Indeed, it has been estimated that approximately 20% of strokes are preceded by TIA (Rothwell and Warlow2005).
Table 1.3. Comparative incidence and prevalence rates of common neurological conditions measured in a population-based study of approximately 100 000 people registered with 13 general practices in London, UK, and conducted between 1995 and 1996
Condition Incidence rate (95% CI)a Prevalence rate (95% CI)a First TIA or strokeb 2.05 (1.83–2.30)
Second TIA or strokeb 0.42 (0.33–0.55)
Intracranial hemorrhage 0.10 (0.05–0.17) 0.5 (0.2–0.8)
Any stroke 9 (8–11)
Epilepsyc 0.46 (0.36–0.60) 4 (4–5)
First seizure 0.11 (0.07–0.18)
Primary CNS tumor 0.10 (0.05–0.18)
Parkinson's disease 0.09 (0.12–0.27) 2 (1–3)
Shingles 1.40 (1.04–1.84)
Bacterial infection of CNS 0.07 (0.04–0.13) 1 (0.8–2.0)
Multiple sclerosis 0.07 (0.04–0.11) 2 (2–3)
Myaesthenia gravis 0.03 (0.008–0.070)
Guillame–Barré 0.03 (0.01–0.06)
Motor neurone disease 0.02 (0.003–0.050) 0.1 (0.01–0.30)
Notes:
CI, confidence interval; TIA, transient ischemic attack.
aAge- and sex-adjusted rates per 1000 population.
bIncludes ischemic and hemorrhagic stroke.
cTwo or more unprovoked seizures.
Source: From MacDonald et al. (2000).
Understanding of the epidemiology of stroke has lagged behind that of coronary heart disease because of a lack of research funding for stroke (Rothwell2001; Pendleburyet al.2004;
Pendlebury 2007) and because stroke is a much more heterogeneous disorder. Separate assessment of the different stroke subtypes should ideally be made in epidemiological studies of stroke. Stroke subtype identification was often not possible in early studies because of a lack of brain and vascular imaging and it remains problematic today because of the frequent difficulty in ascribing a cause for a given stroke even when imaging is available. The epidemiology of TIA is more challenging even than stroke since patients with TIAs are more heterogeneous and present to a variety of different clinical services, if they present to medical attention at all. Furthermore, reliable diagnosis of TIA requires early and expert clinical assessment (there is no diagnostic test for TIA), making epidemiological studies labor intensive and costly.
Mortality
Stroke mortality rises rapidly with age (Rothwellet al.2005). The increase in mortality in the elderly is mainly a result of the steep rise in the incidence of stroke with age, but also, to a lesser extent, reflects the increase in case fatality in older patients. In other words, older people are more likely to have a stroke (incidence) and, if they do have one, it is more likely to be fatal (case fatality).
The age-standardized death rate attributed to stroke varies six-fold between developed countries while very little is known about the developing world (Inzitariet al.1995; Connor et al.2007). Particularly high reported rates of stroke occur in eastern Europe and Japan, and particularly low rates in certain parts of North America and some western European countries (Feiginet al.2003). The reasons for these differences are unclear but one possibility is that the stroke subtypes more likely to be fatal, particularly intracranial hemorrhage or cardioembolic stroke, are more frequent in countries with high stroke mortality.
Incidence, prevalence and time trends
The incidence of new cases of first-ever TIA or stroke can only be reliably assessed in prospective population-based studies (Sudlow and Warlow 1996; Feigin et al. 2003;
Rothwell et al. 2004) since hospital-based studies are subject to referral bias (Table 1.4).
One of the most comprehensive population-based studies of stroke and TIA incidence is the Oxford Vascular Study, OXVASC, which has near-complete case ascertainment of all patients, irrespective of age, in a population of 91 000 defined by registration with nine general practices in Oxfordshire, UK (Coull et al. 2004). This is in contrast to previous studies, such as the MONICA project and the Framingham study, which had an age cut-off at 65 or 75 years or relied on voluntary participation.
The OXVASC study showed that the annual incidence of stroke in the UK in the first few years of this century, including subarachnoid hemorrhage, was 2.3/1000 and the incidence of TIA was 0.5/1000 (Rothwell et al. 2005), with about a quarter of events occurring in those under the age of 65 and about a half in those above the age of 75 (Fig. 1.1). The incidence of cerebrovascular events in OXVASC was similar to that of acute coronary vascular events in the same population during the same period (Fig. 1.2), with a similar age distribution (Rothwellet al. 2005). Incidence rates, however, measure first- ever-in-a-lifetime definite events only and exclude possible, recurrent and suspected events, so do not represent the true burden of a condition. This is especially true for TIA, where a significant proportion of cases referred to a TIA service have alternative, non-vascular
Chapter 1: Epidemiology
5
conditions. Thus consequently, although the annual incidence of definite, first-ever-in-a-lifetime TIA in OXVASC was 0.5/1000, the rate of definite or possible, incident or recurrent TIA was 1.1/1000, and the rate of all referrals to a TIA clinic including all TIAs, suspected events with non-vascular causes and minor strokes was 3.0/1000 (Giles and Rothwell2007) (Table 1.5).
Stroke prevalence is the total number of people with stroke in a population at a given time and is usually measured by cross-sectional surveys (Box 1.2). It is a function of stroke incidence and survival and, therefore, varies over time and between populations with differing age and sex structures. In the UK, stroke prevalence is approximately 5/1000 population and in 65 to 74 year olds is approximately 50/1000 in men and 25/1000 in
Table 1.4. Population- and hospital-based incidence studies Study
type
Description Advantages Disadvantages
Population based
Multiple overlapping, prospective methods of case ascertainment used to identify all individuals with condition of interest from a predefined population; includes searches of both primary and secondary care and databases of diagnostic tests and death certification/mortality statistics
More accurate measurement of incidence through minimizing referral bias;
individuals who are not managed in hospital are included, particularly elderly, those with mild condition and fatal events occurring outside hospital
Time consuming and resource intensive
Results of studies conducted in different populations and over different time periods can be directly compared (after statistical adjustment for age and sex)
Patients with the condition but who do not seek medical attention or who are misdiagnosed in primary care not included
Representative of the requirements of an entire population
Mortality statistics are not collected reliably
Hospital based
Methods of case
ascertainment used to identify all cases that are referred, admitted, managed or discharged from hospital setting from a predefined population
Less time consuming and less resource intensive
Prone to referral bias;
outpatient attendance variably included and events managed only in the community not included
Typically, hospital-based databases only searched.
Representative of the requirements for hospital services
Liable to inaccuracies of diagnostic coding
Patients transferred between departments or hospitals either not identified or double counted
Referral rates to hospital vary geographically and over time; comparison between studies, therefore, less reliable
women (Wylleret al.1994; Geddeset al.1996; Botset al.1996). Measuring TIA prevalence is methodologically more challenging because it is difficult to confirm, without direct patient assessment, whether transient neurological symptoms reported in a population survey are of vascular origin. Accurate data are, therefore, lacking, but a large telephone survey of randomly selected households in the USA reported a prevalence of physician- diagnosed TIA of 23/1000 while a further 32/1000 recalled symptoms consistent with TIA that had not been reported to medical attention (Johnstonet al.2003).
A reduction in stroke and TIA incidence since the late 1980s would be expected, given that randomized trials have shown several interventions to be effective in the primary and secondary prevention of stroke. Indeed, it has been estimated that full implementation of currently available preventive strategies could reduce stroke incidence by as much as 50–80% (Murray et al.2003; Wald and Law2003). Stroke mortality rates certainly declined from the 1950s to the 1980s in North America and western Europe (Bonita et al. 1990;
Thom 1993), but this decline has since levelled off. Although apparent trends in stroke mortality are very difficult to interpret because of changes over time in death certification practices and case-fatality, stroke incidence also appeared to decline in the 1960s and 1970s in the USA, Asia and Europe (McGowernet al.1992; Kodama1993; Tunstall-Pedoeet al.
1994; Numminen et al. 1996). However, the majority of subsequent studies during the 1980s and 1990s, when effective preventive treatments had become more widely available, have shown either no change (Wolf et al. 1992; Bonitaet al. 1993; Stegmayr et al.1994) or, more commonly, an increase in age- and sex-adjusted incidence (Johanssonet al.2000;
Medinet al.2004).
Rates per 1000 population per year
Hemorr hagic stroke
Subarachnoid hemorrhage Ischemic stroke
Transient ischemic attack
Age (y ears) Age (years)
0 0. 5 1 1. 5 2 2. 5
< 35 35–44 45 –54 55–64 65–74 75–84 ≥85
0 5 10 15 20 25 30
< 35 35–44 45–54 55–64 65–74 75–84 ≥ 85
0 0. 1 0. 2 0. 3 0. 4 0. 5
< 35 35–44 45–54 55–64 65–74 75–84 ≥ 85
0 5 10 15
< 35 35–44 45–54 55–64 65–74 75–84 ≥85
Fig. 1.1. Age-specific rates of all events for different types of acute cerebrovascular event in men (diamonds) and women (open squares) in Oxfordshire from 2002 to 2005 (Rothwell et al.2005).
Chapter 1: Epidemiology
7
010
20
30
40 0
10
20
30
40
Ra te s pe r 1000 p op ula tio n pe r y ea r
Women
All events Incident events Age (years)
<35≥8575–8465–7455–6445–5435–44<35≥8575–8465–7455–6445–5435–44
010
20
30
40 0
10
20
30
40
Men <35≥8575–8465–7455–6445–5435–44<35≥8575–8465–7455–6445–5435–44 Fig.1.2.Age-specificratesofalleventsandofincidenteventsforstroke(i.e.notincludingtransientischemicattack;closedcircles),myocardialinfarctionandsudde cardiacdeathcombined(i.e.notincludingunstableangina;opencircles),andacuteperipheralvascularevents(triangles)inmenandwomeninOxfordshirefrom 2002to2005(Rothwelletal.2005).
The most recent studies of time trends in stroke incidence do suggest that age-specific incidence is now falling (Sartiet al.2003; Rothwellet al.2004; Andersonet al.2005; Hardie et al. 2005). Between the periods 1981–1984 and 2002–2004, a 40% reduction in the incidence of fatal and disabling stroke was found in Oxfordshire, UK (Rothwell et al.
2004), although this reduction was less marked in the oldest old (Fig. 1.3). High-quality population-based studies of time trends in TIA and minor stroke are lacking. However, moderate rises in TIA incidence were reported in Oxfordshire, UK, between the periods
Table 1.5. Incidence rates of transient ischemic attack and stroke according to stringency of definition applied and previous cerebrovascular disease measured in OXVASC (2002–2005)
Category of event Incidence rate (95% CI)a
TIA, incident only
Definite 0.47 (0.39–0.56)
Definite and probableb 0.59 (0.5–0.68)
TIA, incident and recurrent
Definite 0.82 (0.72–0.94)
Definite and probableb 0.95 (0.84–1.07)
All definite, probable and suspected TIA (including all referrals to a TIA service with an eventual non-neurovascular diagnosis)
2.06 (1.89–2.23)
Stroke,cincident only
Definite and probable 1.39 (1.25–1.54)
Stroke,cincident and recurrent
Definite and probable 1.85 (1.70–2.02)
All definite, probable and suspected (including all referrals to hospital of suspected stroke with an eventual non-neurovascular diagnosis)
2.29 (1.89–2.23) Notes:
CI, confidence interval; TIA, transient ischemic attack.
aunadjusted rate per 1000 population.
bProbable TIA defined as any transient symptoms lasting less than 24-hours of likely (but not certain) vascular etiology that was felt to justify secondary prevention treatment.
cStroke includes ischemic and primary intracerebral hemorrhage but not subarachnoid hemorrhage.
Source: From Giles and Rothwell (2007).
Box 1.2. Definitions of incidence and prevalence
Incidence rate. The number of new cases of a condition per unit time per unit of population at risk. Usually expressed as the number of new cases per 1000 or 100 000 population at risk per year.
Adjusted/standardized incidence rates. Overall incidence rates depend critically on the age and sex structure of the population studied. For example, a relatively old population may have a higher mortality rate than a younger population even if, age for age, the rates are similar. Incidence rates from different populations are, therefore, often compared following adjustment or standardization by applying age- and sex-specific rates to a “standard”
population.
Prevalence rate. The total number of cases of a condition per unit of population at risk at a given time. Usually expressed as a percentage or the total number of cases per 1000 or 100 000 population at risk.
Chapter 1: Epidemiology
9
1981–1984 and 2002–2004 (Fig. 1.3) (Rothwell et al. 2004) and in Novosibirsk, Russia, between the periods 1987–1988 and 1996–1997 (Feigin et al. 2000) but no significant change in TIA incidence was found in Dijon, France, between 1985 and 1994. It is difficult to find a single explanation for the decline in incidence of major stroke in recent years and a contemporaneous stabilization or increase in the rates of TIA. The former may be related to a decline in the prevalence of causative risk factors or to treatment of risk factors such as hypertension and elevated cholesterol, while the latter is likely to reflect changes in public health awareness and behavior, with people now being more likely to seek medical attention for transient neurological symptoms.
Racial and social factors
There are racial and social differences in susceptibility to stroke and TIA (Forouhi and Satter2006) and in the incidence of the various stroke subtypes (Fig. 1.4). Some of these racial differences are partly caused by differences in risk factor prevalence: hypertension (a)
(b) 0 2 4 6
8
10
< 55 55–64 65–74 75–8 4 85+
Age (y ears)
0 4
8
12 16 20
< 55 65–74 75–8 4 8 5+
Age (years)
Incidence rate per 1000Incidence rate per 1000
55–64
Fig. 1.3. The age- specific incidence of transient ischemic attack (a) and major disabling stroke (b) in Oxfordshire in 1981–1984 (the Oxford Community Stroke Project [OCSP], - - -) and 2002–2004 (the Oxford Vascular Study [OXVASC]—) (Rothwell et al.2004).
and diabetes mellitus are more common in blacks and coronary heart disease is more common in whites, for example (Sacco 2001). Other differences are not properly under- stood, such as the much higher proportion of stroke caused by intracerebral hemorrhage in Southeast Asia and the Far East than in Western countries (Sudlow and Warlow 1996;
Feiginet al.2003).
Black populations. The burden of stroke is higher in blacks than whites for both ischemic, particularly small vessel stroke, and hemorrhagic stroke (Wooet al.1999; Schneider et al.2004; Pandey and Gorelick2005; Whiteet al.2005; Wolfeet al.2006a,b). This pattern may be related in part to a higher prevalence of hypertension and diabetes mellitus (Gillum1999; Sacco2001). Intracranial large artery occlusive vascular disease also appears to be more common in blacks than in whites (Saccoet al.1995;
Wityket al.1996; Lynch and Gorelick2000). In the single relevant study, rates of TIA were found to be higher in blacks than whites (Kleindorferet al.2005).
Maori and Pacific Islands. People in New Zealand have a higher stroke incidence than Europeans, perhaps owing to differences in risk factors and health-related behaviors (Bonitaet al.1997; Feiginet al.2006).
Japanese and Chinese populations. Stroke, particularly primary intracerebral hemorrhage, is more common in Japan and China than in Western countries (Huanget al.1990) and this is accompanied by less extracranial but more intracranial arterial disease (Feldmannet al.1990; Leunget al.1993; Saccoet al.1995; Wityket al.1996).
South Asian populations. People of South Asian origin in the UK have a high prevalence of coronary heart disease and stroke, central obesity (as evidenced by high waist-to-hip ratio), insulin resistance, non-insulin-dependent (type 2) diabetes and hypertension (Cappuccio1997; Kainet al.2002; Bhopalet al.2005). This increase in vascular risk seems to be partly a result of genetic susceptibility, such as high serum lipoprotein A levels, and partly dietary- and lifestyle-induced changes in lipid levels.
Fig. 1.4. The proportions of first-ever-in-a-lifetime strokes caused by ischemic stroke (IS), primary intracerebral hemorrhage (PICH), subarachnoid hemorrhage (SAH) and of undetermined cause (UND) in“ideal” incidence studies.
Numbers indicate the percentage estimates (Sudlow and Warlow1997).
Chapter 1: Epidemiology
11
Deprivation. In the UK, both stroke incidence and poor outcome after stroke are greater in areas of socioeconomic disadvantage (Kaplan and Keil1993; Avendañoet al.
2004). This is partly because poverty is associated with adverse health behaviors and risk factors such as smoking (Hartet al.2000a). There is also evidence that poor maternal and infant health is associated with increased mortality from stroke in later life (Barker1995; Martynet al.1996). However, the adverse effect of socioeconomic deprivation also appears to be cumulative throughout life (Davey Smithet al.1997;
Hartet al.2000b).
Seasonal and diurnal variation
In most studies, both stroke mortality and hospital admission rates are higher in winter than in summer (Douglas et al. 1991; Pan et al. 1995; Feigin and Weibers 1997). This seasonal variation might be explained by the complications of stroke being more likely to occur in the winter (e.g. pneumonia) and cannot simply be assumed to reflect stroke incidence. Where incidence has been measured in the community, there is little seasonal variation, at least in temperate climates, although primary intracerebral hemorrhage is somewhat more likely in the winter months and on cold days (Rothwell et al. 1996;
Jakovljevicet al.1996).
Stroke occurs most frequently in the hour or two after waking in the morning, but whether this applies to all subtypes of stroke is difficult to say because of the relatively small proportion of intracranial hemorrhages in most studies (Kelly-Hayes et al. 1995; Elliott 1998). Subarachnoid hemorrhage is very unlikely to occur during sleep and, in general, is most likely to occur during strenuous activities (Wroeet al.1992). There are no equivalent data for TIA, although provisional results from OXVASC suggest that incidence also shows diurnal variation, and apparent TIA incidence falls slightly at the weekend, possibly because patients are less likely to present to medical attention (Gileset al.2006).
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Chapter 1: Epidemiology
15
2 Risk factors
This chapter outlines the major known risk factors for TIA and stroke. Knowledge of these risk factors is necessary in order to understand the aetiology of TIA and stroke, to predict risk and to develop effective preventive strategies.
There are many more data on risk factors for acute coronary events than for ischemic stroke (Bhatia and Rothwell 2005) because of more intensive investigation in routine clinical practice and because heart disease receives much higher levels of research funding than stroke (Rothwell2001; Pendlebury2007).
The main risk factors for stroke are listed inBox 2.1. There are probably few qualitative differences between risk factors for ischemic stroke and coronary heart disease, but there are quantitative differences. Smoking, raised plasma cholesterol and male sex are stronger risk factors for myocardial infarction, while hypertension is a stronger risk factor for stroke.
The tendency for epidemiologists to lump all types of stroke together might explain some of the quantitative differences between risk factors for stroke and coronary heart disease. For example, it is possible that strokes associated with large artery disease have a more similar risk factor profile to coronary heart disease than cardioembolic stroke. To date, differences in risk factor relationships with the different stroke subtypes are unclear (Schulzet al.2004;
Jackson and Sudlow 2005). The prevalence of various demographic and risk factors for different stroke subtypes are shown inTable 2.1.
Non-modifiable risk factors Age
Age is the strongest risk factor for ischemic stroke of all subtypes and for primary intracerebral hemorrhage, but it is less important for subarachnoid hemorrhage (Bamford et al.1990; Rothwellet al. 2005). Overall stroke incidence at age 75–84 is approximately 25 times higher than at age 45–54 (seeFig. 1.2).
Sex and sex hormones
Ischemic stroke is slightly more common in men than in women (seeFig. 1.2) although the male excess is less marked than in coronary heart disease and peripheral arterial disease (Rothwell et al. 2005). This excess of vascular events in men has been attributed to differences in endogenous sex hormones, although there is little direct evidence to support this hypothesis. Exogenous high-dose estrogen given to elderly men with prostatic cancer increases their risk of vascular death (Byar and Corle1988) and use of hormone replace- ment therapy in women after the menopause is associated with an increased risk of acute coronary sydrome, stroke and venous thromboembolism (Farquhar et al. 2005; Gabriel et al. 2005). The equalization of vascular risk in elderly males and females is, therefore, probably not explained by the natural menopause, although bilateral oophorectomy
without estrogen replacement in premenopausal women doubles the risk of vascular events (van der Schouwet al.1996). Oral contraceptives increase the risk of ischemic stroke (the risk is less for hemorrhagic stroke) but the increased risk is small for low-dose estrogen preparations unless there are associated factors such as migraine or cigarette smoking (Changet al.1999; Bousser and Kittner2000; Donaghyet al.2002).
Modifiable risk factors Blood pressure
Increasing blood pressure is strongly associated with subsequent stroke risk (Gil-Nunez and Vivancos-Mora 2005; Goldstein and Hankey 2006). The relationship between usual diastolic blood pressure and stroke is “log–linear” throughout the normal range, with no evidence of a threshold below which the risk becomes stable (Rodgerset al.1996). Stroke mortality rises steeply with increasing systolic blood pressure and this is more marked in the young than in the old (Kearney et al. 2005) (Fig. 2.1). Stroke incidence doubles with each 7.5 mmHg increase in usual diastolic blood pressure in Western populations and with each 5.0 mmHg in Japanese and Chinese populations (MacMahon et al. 1990;
Eastern Stroke and Coronary Heart Disease Collaborative Research Group1998; Lewington et al.2002).
The strength of the association between blood pressure and stroke is attenuated with increasing age, although the absolute risk of stroke in the elderly is far higher than in the young (Lewingtonet al.2002). Nevertheless, hypertension is still a risk factor in the very
Box 2.1. Risk factors for ischemic stroke
Factors associated with an increased risk of vascular disease
Increasing age Raised hematocrit
Male sex Sex hormones
Hypertension Excess alcohol consumption
Cigarette smoking Obesity and dieta
Diabetes mellitus Raised white blood cell count
Blood lipids Recent infectiona
Atrial fibrillation Hyperhomocyst(e)inemia
Social deprivation Snoringa
Family history of stroke Corneal arcusa
Physical inactivity Psychological factorsa
Raised von Willebrand factora Low serum albumina
Increasing plasma fibrinogena Diagonal earlobe creasea Raised factor VII coagulant activitya
Raised tissue plasminogen activator antigena Low blood fibrinolytic activitya
Evidence of pre-existing vascular disease
Transient ischemic attacks Cardiac failure
Cervical arterial bruit and stenosis Left ventricular hypertrophy Myocardial infarction/angina Peripheral vascular disease Note:
aPossible association with stroke.
Chapter 2: Risk factors
17
Table 2.1. Demographics and risk factor prevalence in incident strokes in OXVASC Prevalence (%)
ISa PICHb SAHb
Mean age 74.9 75.3 54.8
Male (%) 48.6 50.0 30.3
Previous acute coronary syndrome 11.5 15.4 3.0
Previous acute peripheral vascular event 2.9 3.8 0.0
History of hypertension 56.3 59.6 24.2
Diabetes mellitus 10.1 0.0 3.0
Hypercholesterolemia 20.1 14.3 6.1
Atrial fibrillation 18.2 15.4 0.0
Current smoker 17.2 15.4 24.2
Notes:
IS, ischemic stroke; PICH, primary intracerebral hemorrhage; SAH, subarachnoid hemorrhage.
aThree year data from 2002–2005.
bFive year data from 2002–2007.
Sources: From Rothwell et al. (2004a) and Lovelock et al. (2007).
256
Age at risk:
80–89 y ears 70–79 y ears 60–69 y ears 50–59 y ears 128
64
32
16
Stroke mortality (floating absolute risk and 95% CI) 8 4
120 140
Usual systolic b lood pressure (mm/Hg)
160 180
2
1
Fig. 2.1. Stroke mortality by usual systolic blood pressure and age showing a steep rise in mortality with rising blood pressure and that the rate of risk increase with change in blood pressure is greater in the young than in the old (from Kearney et al.2005). CI, confidence interval.
