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9.3 Cerebrovascular disease

9.3 Cerebrovascular disease
Oxford Textbook of Public Health

9.3
Cerebrovascular disease

Heizo Tanaka, Hiroyasu Iso, Tetsuji Yokoyama, Nobuo Yoshiike, and Yoshihiro Kokubo

Death rates

Crude death rates

Age-adjusted death rates
Incidence

Definition and classification of stroke

Case ascertainment and verification of diagnosis

Incidence rates
Prognosis of stroke
Pathology, aetiology, and traditional risk factors for stroke subtypes

Subarachnoid haemorrhage

Intracerebral haemorrhage

Embolic infarction

Large-artery occlusive infarction

Lacunar infarction

Cultural differences in distribution of stroke subtypes
New risk factors

Homocysteine

Diabetes mellitus

Carotid ultrasonography

Fibrinogen

Plasminogen activator inhibitor-1 and tissue plasminogen activator
Genetic factors

Angiotensin-converting enzyme gene

Apolipoprotein E gene

Methylenetetrahydrofolate reductase gene

Fibrinogen gene
Lifestyle

Diet

Physical activity

Alcohol

Smoking
Strategies for prevention of stroke

Community intervention for stroke prevention

Strategies and organization for hypertension control programme
Summary
Appendices
Chapter References

Cerebrovascular disease ranks third or higher as a cause of death in industrialized countries. It is also a major contributor to disability. For example, in 1995 the Japanese Ministry of Health and Welfare reported that, in Japan, 32.7 per cent of 284 000 elderly people with severe disability were paralysed as the result of a stroke (Ministry of Health and Welfare 1997).
The documentation of functional gain is insufficient, and increased consideration must be given to quality of life for people with low activities of daily living after the attack. In addition, there are some forms of cerebrovascular disease that include progressive dementia.
According to predictions based on secular trends for the leading causes of death over the past 50 to 100 years in the United States and West European countries, stroke will emerge as a more frequent cause of death than ischaemic heart disease in developing countries after infectious and malnutritional diseases are overcome.
Thus stroke continues to be a major cause of death as well as physical and mental disability, and valid information about its epidemiology and prevention is needed in developed and developing countries alike.
Death rates
In this section we present the pattern of mortality from cerebrovascular disease for males and females by country/area over the last 45 years (WHO 1994, 1996, 1998). During this period, the International Statistical Classification of Diseases, Injuries and Cause of Death (ICD) has been revised five times. As shown in Table 1, the sixth and seventh revisions for 1948 to 1968 (ICD-6 and ICD-7) classified cerebrovascular disease into four categories. Substantial changes were made in the eighth and ninth revisions (ICD-8 and ICD-9). Cerebral embolism and thrombosis (code 332 in ICD-6 and ICD-7) were divided into codes 432, 433, and 434 in ICD-8 and codes 433 and 434 in ICD-9. Transient cerebral ischaemia, code 435 in ICD-8 and ICD-9, replaced spasm of cerebral arteries, code 333 in ICD-6 and ICD-7. Major changes were made in ICD-9 and the current tenth revision (ICD-10). These changes may affect the apparent secular trend in the death rate from cerebrovascular disease in some countries. In fact, there was a remarkable increase in the rate in Japan 1995 (when ICD-10 was introduced) which was entirely due to changes in coding. Thereafter, it tended to decrease as previously (Ministry of Health and Welfare 1999).

Table 1 Cerebrovascular disease codes according to the sixth, seventh, eighth, ninth, and tenth revisions of International Statistical Classification of Diseases, Injuries and Cause of Death

According to the Framingham Study (Corwin et al. 1982), 40 per cent of 280 decedents with verified stroke had no mention of stroke on the death certificate and 21 per cent of certificates listing stroke were false positives. There was little change in this pattern of error during the 30 years of the study from 1950 to 1980.
Since computed tomography (CT) came into widespread use around 1975, the validity of the diagnosis of stroke has rapidly improved in some countries. Before the development of CT, however, the antemortem diagnosis of stroke rested primarily on clinical diagnosis, consisting of history taking and physical examination, rather than on laboratory measurements. If deaths from cerebrovascular disease are considered as a single entity, as was done in this section, the clinical diagnosis appears to be reliable but its accuracy for differentiating the subtypes of stroke is more or less open to question (Tanaka et al. 1982).
Crude death rates
Crude death rates must not be cited to make international comparisons or to assess changes with time in a certain population. However, the rates do provide the absolute magnitude of deaths attributed to cerebrovascular disease in a population.
Table 2 shows crude death rates per 100 000 population from cerebrovascular disease in 33 countries/areas for the most recent year in which they were tabulated (WHO 1996, 1998). The rates ranged from 24.1 per 100 000 (Mexico) to 284.3 (Bulgaria) for males and from 27.3 per 100 000 (Mexico) to 347.2 (Russia) for females. Using the reported average rates of 103.3 for males and 130.0 for females, as well as the 1995 world population size estimated by the United Nations (5687 million), the number of people killed annually by cerebrovascular disease can be estimated at 6.6 million.

Table 2 Crude death rates from cerebrovascular disease in selected countries/areas (most recent year)

Age-adjusted death rates
Figure 1 and Figure 2 show secular trends in age-adjusted death rates from cerebrovascular disease for males in selected countries during the period from 1950 to 1995 (WHO 1994, 1996, 1998). (Since the data for females are similar to those for males, they are not presented here.) As shown in Fig. 1, the age-adjusted rates from cerebrovascular disease tended to decrease for this period in the United States and Western Europe, excluding Spain where a slight increasing trend was observed from 1950 to 1979.

Fig. 1 Secular trends in age-adjusted death rate from cerebrovascular disease in selected countries (United States, West European Countries), males (WHO 1994, 1996, 1998).

Fig. 2 Secular trends in age-adjusted death rate from cerebrovascular disease in selected countries/areas (Argentina, Japan, Mauritius, East Europe), males (WHO 1994, 1996, 1998).

Figure 2 illustrates the trends in Argentina, Mauritius, Japan, and some East European countries. Although the Japanese rate was the highest in the world and increased from 1950 to 1964, it tended to decrease after 1965, reaching the level of West European countries in recent years. This declining trend appears to have been accelerated by nationwide community-based control of hypertension and lifestyle modernization associated with a background of high economic growth (Tanaka et al. 1982, 1992).
In East European countries, however, the rates tended to increase for the period 1955 to 1984 and to decrease slightly after 1985. Romania, Bulgaria, and Poland showed increasing trends even in the 1990s.
Incidence
Definition and classification of stroke
In incidence studies, stroke is defined as the occurrence of rapidly developing clinical signs of focal or global disturbances of cerebral function which last for more than 24 h or result in death for which there is no apparent cause other than a vascular accident (WHO 1971, 1972, 1973). Transient episodes of cerebral ischaemia are excluded by this definition. An attempt is made to diagnose the anatomical subtype of stroke (subarachnoid haemorrhage, intracerebral haemorrhage, cerebral infarction, and undetermined type) on the basis of clinical symptoms and signs. If CT or magnetic resonance imaging (MRI) findings are available in the population under study, they play a decisive role in the diagnosis of stroke subtypes (see below).
Case ascertainment and verification of diagnosis
The setting up of stroke registries is the most appropriate method of data acquisition on morbidity (WHO 1971, 1972, 1973). Any doctor who is called in to see a stroke patient should notify the registry. The sources of notification may be general practitioners, ambulance personnel, the ‘telephone alarm service’, hospital reception staff, the police, field nurses, medico-legal authorities, and so on according to local circumstances. The patients should also be referred by lay personnel in charge of health services in the area. In general, death certificates, social insurance records, and general practitioner records are also reviewed periodically. Mass screening examinations or a prevalence study of the total population are the only means of detecting patients who survived stroke but who were not recorded in the documents as described above.
All patient information is considered by the registry physicians or neurologists to determine whether the patient meets the criteria as a stroke case; such information includes early stages of the attack, clinical state at time of maximal impairment, and clinical and laboratory findings at the first medical treatment, in particular, CT, MRI, and angiographic findings, if performed.
Incidence rates
Although data about the incidence of stroke are now available from many more sources than previously, it is still difficult to compare studies. The methods of ascertainment, definition, and classification of stroke and the size of the population differ from one study to another. Some data are based on community-wide surveys, while others are based on hospital surveys. Even population-based studies do not always cover the entire adult population aged 30 or 35 years and older. Not all the studies deal with the first stroke alone and repeated episodes are often included in the incidence. There are not many reports about the incidence by age, sex, and subtype of stroke. Furthermore, age-specific incidences are shown for the decades 35 to 44 years, 45 to 54 years, etc. in some reports, but for the decades 30 to 39 years, 40 to 49 years, etc. in others. Therefore only available community-based studies on stroke that were performed under conditions comparable with those mentioned in the previous section are reviewed and summarized here.
Table 3, Table 4, Table 5 and Table 6 present an international comparison of stroke incidence by subtype (Eisenberg et al. 1964; Katsuki et al. 1964; Parrish et al. 1966; Eckstrom et al. 1969; Alter et al. 1970; Whisnant et al. 1971; Matsumoto et al. 1973; Melamed et al. 1973; Abu-Zeid et al. 1975a,b; Kojima 1976; Zupping and Roose 1976; Tanaka et al. 1981a; Broderick et al. 1989; Wender et al. 1990; Hu et al. 1992; Jerntorp and Berglund 1992; Lindenstrom et al. 1992; Tuomilehto et al. 1992; Bonita et al. 1993; Czlonkowska et al. 1994; Thorvaldsen et al. 1995; Truelsen et al. 1998c; Vemmos et al. 1999). In Table 3 and Table 5, group A is based on the age-specific incidences for the decades 30 to 39 years, 40 to 49 years, etc. (Appendix 1) and group B in Table 4 and Table 6 is based on those for the decades 35 to 44 years, 45 to 54 years, etc. (Appendix 2). The World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease (WHO MONICA) Project populations are also included in group B. This project started in the first half of the 1980s to register continuously the occurrence of myocardial infarction and stroke in many populations using a common protocol (Tunstall-Pedoe et al. 1988). The incidence rates may be fairly comparable among these MONICA populations.

Table 3 Crude stroke incidence rates per 1000 populationa in selected communities (group A)

Table 4 Crude stroke incidence rates per 1000 populationa in selected communities (group B)

Table 5 International comparison of incidence of stroke by subtype per 1000 population (group A)

Table 6 International comparison of incidence of stroke by subtype per 1000 population (group B)

We estimated the average stroke incidence in the age group 30 years and over using the data reported from several populations (group A, Table 3). The average incidences were as follows: all strokes, 3.57 per 1000 for males and 2.94 per 1000 for females; intracerebral haemorrhage, 1.78 per 1000 for males and 1.12 per 1000 for females; cerebral infarction, 2.44 per 1000 for males and 2.15 per 1000 for females. In group B (Table 4), the average incidence of all strokes in the age group 35 years and over was 4.55 per 1000 for males and 3.36 per 1000 for females. There are few data about subtypes for this group.
The sex- and age-adjusted incidence was computed according to the world ‘new’ standard population (WHO 1994). The sex- and age-adjusted incidence for people in the age group 30 to 59 years (group A, Table 5) or 35 to 64 years (group B, Table 6) was also computed, because stroke is the most serious health problem in those middle-aged people.
Since mortality rates have declined in some countries (Fig 1 and Fig 2) and a decreasing trend in the incidence of stroke has been observed in some communities, the observation period during which the age-adjusted incidences were compared among studies (Tanaka et al. 1981b) should be taken into account. In group A (Table 5), both males and females in Akita, Japan (1964–1969), had the highest age-adjusted incidence of intracerebral haemorrhage, cerebral infarction, and all strokes, although there has been a marked decreasing trend in the rates in the population recently (Shimamoto et al. 1989).
For males of group B (Table 6), the age-adjusted incidence of all stroke was much higher in non-white people living in Missouri (1964–1965), than in any other population of males. Males aged 35 to 64 years in Fargo–Moorhead (1965–1966), Copenhagen (1976–1988), Shibata (1976–1978), North Karelia (1985–1987), Kuopio (1985–1987), Kaunas (1985–1987), and Novosibirsk (1985–1987) showed a relatively high incidence (more than 2 per 1000). The age-adjusted incidence of intracerebral haemorrhage for males in the age group of 35 to 64 years was higher in Shibata (1976–1978) than in other areas, and that of cerebral infarction was higher in Rochester (1955–1969).
For females aged 35 to 64 years in group B (Table 6), the age-adjusted incidence of all strokes ranged from 0.45 (Rhein–Neckar region, 1985–1987) to 2.32 (non-white, Missouri, 1964–1965). A relatively high incidence (more than 1 per 1000) was observed in Jerusalem (1960–1967), Beijing (1985–1987), Kaunas (1985–1987), Middlesex (1964–1965), Fargo–Moorhead (1965–1966), Taiwan (1986–199), Kuopio (1985–1987), Novosibirsk (1985–1987), and Mid-Missouri (non-white) (1964–1965) in that order. The incidences of intracerebral haemorrhage in Middlesex (0.49 per 1000 in 1957–1958) and of cerebral infarction in Rochester (0.58 per 1000 in 1955–1969) were the highest among the selected studies.
A relatively high incidence of stroke was observed in the 1940s and 1950s in the United States, which has been one of the countries with the lowest mortality from stroke in the world for the past 50 years and has shown declining trends in the incidence of stroke. This high rate corresponds to the rate for Japan in the 1960s and to the rates for Taiwan, Finland, and Poland in the 1980s. In Rochester, a gradual decrease in the incidence of all strokes very long term has been reported (Table 6).
Prognosis of stroke
The accuracy of long-term prognosis after the onset of stroke in a population depends on the completeness of case ascertainment rather than on follow-up. Some patients may die at home immediately after the attack or during transportation by ambulance. There is a possibility that they would be missed from the denominator for the survival rate. Therefore there have been relatively few community-based studies of stroke prognosis. Table 7 shows the cumulative risk of death (1 – survival rate) (Sacco et al. 1982; Dyken 1983; Scmidt et al. 1988; Kojima et al. 1990; Chen et al. 1992; Tanaka et al. 1992; Dennis et al. 1993; Hong et al. 1994; Bonita et al. 1995; Lauria et al. 1995; Truelsen et al. 1998a), although it is not comparable between studies because of the difference in age composition. Within a study district, risk of death after cerebral infarction appears to be lower than that after cerebral or subarachnoid haemorrhage. A Japanese epidemiological research group sponsored by the National Cardiovascular Center registered all the first-ever stroke patients and followed them prospectively for up to 10 years in five populations in the Osaka, Hiroshima, and Niigata Prefectures (Tanaka et al. 1992). As seen in Fig. 3 (survival rates within 5 years), the sex- and age-adjusted vital prognosis of intracerebral haemorrhage and infarction improved between the periods 1965–1974 and 1985–1990. The major contributor to the increase in the survival rates appeared to be the decline in the number of patients with severe stroke as well as improved medical care.

Table 7 Vital prognosis after the onset of first-ever stroke

Fig. 3 Sex- and age-adjusted survival curves within 5 years after first-ever stroke determined by the Cox Proportional Hazard Model for five populations in Japan.

The case-fatality rate is not a satisfactory measure of survival for stroke, a chronic disease, but it may be useful until the survival data are accumulated. According to the Lehigh Valley Recurrent Stroke Study, 9.2 per cent of the 30-day stroke survivors (n = 662) were dead at 6 months and the case-fatality rates were 13.1, 21.3, 26.8, and 28.0 per cent at 1, 2, 3, and 4 years respectively (Lai et al. 1995). The case-fatality rate was 29.0 per cent (108 of 373) at 12 months in Glasgow, United Kingdom (Muir et al. 1996). Prognosis in severe stroke patients who required mechanical ventilation in neurological critical care units was analysed in Heidelberg, Germany, and the 1-year case fatality was reported to be 66.9 per cent (83 of 124) (Steiner et al. 1997). Conversely, some studies reported that the case-fatality rate had declined recently. A study from Sweden reported that the decline in stroke fatality rates during the period from 1971 to 1987 appeared to be related to decreases in blood pressure levels and smoking habits (Harmsen et al. 1992). According to the Minnesota Heart Study, age- and sex-adjusted case fatality of hospital admitted patients in the United States improved significantly from 1970 to 1985; the odds ratio of death within 28 days in 1985 versus 1970 was 0.55 and that within 5 years was 0.72. Improved medical care and decreased severity of stroke probably contributed to the gain in survival (McGovern et al. 1993).
In the United States in the Lehigh Valley Recurrent Stroke Study (Lai et al. 1994), a 13 per cent stroke recurrence rate over an average of 24 months and a 19 per cent rate by the fourth year were observed. Control of hypertension and atrial fibrillation reduced the risk of stroke recurrence after a cerebral infarction. A rate of 14 per cent was observed for 24 months by Hier et al. (1991). In Rochester, Minnesota, the recurrence rate was 10 per cent in the first year and 20 per cent by the fifth year (Whisnant et al. 1971; Matsumoto et al. 1973). The recurrence rate after 1 month was 1.9 per cent of 474 cases in Belluno, Italy (Lauria et al. 1995).
Pathology, aetiology, and traditional risk factors for stroke subtypes
Stroke is a complex of subtypes, and includes subarachnoid haemorrhage, intracerebral haemorrhage, embolic infarction, and thrombotic infarction consisting of large-artery occlusive infarction and lacunar infarction. These subtypes may have different pathologies, aetiologies, and risk factors, some of which are similar to those in ischaemic heart disease but some of which are not. The wide use of CT or the recent use of MRI in some developed countries enables reliable diagnosis of stroke subtypes in clinical settings, and the data can be used for epidemiological studies (Walker et al. 1981; Foulkes et al. 1988; Sankai et al. 1991; C.S. Anderson et al. 1993; Iso et al. 2000).
Subarachnoid haemorrhage
Subarachnoid haemorrhage is defined as haemorrhage in the subarachnoid space, usually caused by the rupture of a saccular aneurysm of large to medium-sized cerebral arteries (diameter, 1–5 mm) or, less commonly, by arteriovenous malformation and other causes. Haemorrhages occurring in the intraparenchymal regions, but demonstrated to be due to aneurysm or arteriovenous malformation, are usually regarded as subarachnoid haemorrhage. Saccular aneurysm is the result of the loss of medial smooth muscle cells along with few proliferations in the intima and a weak adventitia. In addition to hypertension, animal studies indicate that spasms in cerebral arteries may increase haemodynamic stress in vulnerable sites for the development and rupture of saccular aneurysms. Hypertension, smoking, and heavy drinking increase the risk of subarachnoid haemorrhage. The contribution of dyslipidaemia (high or low total cholesterol) and diabetes is minimal in contrast to ischaemic heart disease.
Intracerebral haemorrhage
Intracerebral haemorrhage is defined as haemorrhage in the intraparenchymal regions of the brain not due to aneurysm or arteriovenous malformation. This stroke subtype is usually caused by the rupture of microaneurysms resulting from arterionecrosis (fibrinoid necrosis or lipohyalinosis) of small intracerebral penetrating arterioles (diameter, 100 to 200 µm) of the basal ganglia, thalamus, and brainstem regions. Penetrating arteries are more vulnerable to arterionecrosis through hypertension than small arteries in subcortical regions because they have larger lumens relative to their wall thickness, sustain higher wall stress from blood pressure, and are liable to injury of cell membranes.
The contribution of hypertension to intracerebral haemorrhage is strongest among the stroke subtypes. This means that acute and severe hypertension is likely to cause intracerebral haemorrhage in middle-aged adults, in contrast with ischaemic heart disease, for which low levels of serum total cholesterol are associated with an increased risk of intracerebral haemorrhage (Komachi et al. 1977; Kagan et al. 1980; Tanaka et al. 1982; Iso et al. 1989). The increased risk of haemorrhagic stroke with decreased cholesterol concentration was also suggested from recent meta-analysis for 13 cohorts from the People’s Republic of China and five from Japan (Eastern Stroke and Coronary Heart Disease Collaborative Research Group 1998). This inverse association may in part be due to the association of low saturated fat and animal protein with the risk of intracerebral haemorrhage (Iso et al. 2001).
Considerable evidence suggests that very low serum cholesterol levels accelerate angionecrosis of intracerebral penetrating arteries particularly in the presence of hypertension (Kagan et al. 1980; Tanaka et al. 1982; Iso et al. 1989). In hypertensive rats, a diet-induced increase in serum cholesterol from very low to moderate levels was associated with a reduction in arterionecrosis and strokes. Hypertensive patients with ischaemic cerebral infarction and extracerebral atherosclerosis had higher serum cholesterol levels and less arterionecrosis than hypertensive patients without cerebral infarction. In addition, neonatal rat cardiomyocytes depleted of cholesterol were more prone to anoxia because cholesterol depletion increases permeability and ion fluxes across the membranes of a cardiomyocite, which may lead to cell death. In addition to a possible direct effect on vascular walls, low serum cholesterol levels may prevent atherosclerosis in carotid arteries and large to medium-sized cerebral arteries, which in turn exposes the distal penetrating arteries to higher wall stress and may enhance arterionecrosis in the presence of hypertension.
Heavy drinking also increases the risk of intracerebral haemorrhage due to increased blood pressure levels and reduced platelet aggregation, as it does that of subarachnoid haemorrhage. High serum total cholesterol or glucose intolerance does not affect the risk of intracerebral haemorrhage. The effect of smoking is also minimal.
Embolic infarction
Embolic infarction is regarded as cerebral infarction caused by emboli from extracranial regions. Sources of emboli include ulcerating atherosclerotic plaques in the carotid artery, mural thrombi associated with myocardial infarction (a consequence of surgery for coronary heart disease), atrial fibrillation, valvular heart disease, bacterial endocarditis, and other sources. Some of these sources (carotid plaque and mural thrombosis associated with myocardial infarction and a consequence of surgery for heart disease) are associated with atherosclerosis in origin, and therefore have similar risk factors to those in ischaemic heart disease, but the others are not. This means that risk factors for embolic infarction depend on the sources of emboli.
A close and strong relationship between atrial fibrillation and the subsequent incidence of cerebral infarction (relative risk, 2.6–4.5) was reported by several American and European studies (Wolf et al. 1978, 1991; Kannel et al. 1982; Benjamin et al. 1994). Although this association was identified by some Japanese prospective studies (Tanaka et al. 1985; Kitamura et al. 1991), the aetiology of atrial fibrillation may differ between the Japanese and Caucasians. According to the Framingham Study (Benjamin et al. 1994), most people with atrial fibrillation had suffered from valvular or ischaemic heart disease. In Japanese studies (Tanaka et al. 1985; Kitamura et al. 1991), however, less than 5 per cent of the subjects with atrial fibrillation at entry had a previous history of valvular disease and the rest (elderly people) had had mild to moderate hypertension for more than 20 years without any heart or atherosclerotic disease. Thus they concluded that atrial fibrillation was mainly due to long-term hypertension, not atherosclerosis.
Large-artery occlusive infarction
Large-artery occlusive infarction is defined as infarction involving the cortical artery regions in the cerebrum and cerebellum (cortex and subcortical areas), presumably caused by in situ thrombosis of large or medium-sized cerebral arteries (diameter 1 to 5 mm). This diagnosis is made even when accompanied by infarction of the internal capsule, corona radiata, or basal ganglia on the same side because the occlusion of medium-sized arteries before the branches of small penetrating arteries also cause lacunar infarction. Pathology for this stroke subtype is similar to that for ischaemic heart disease, that is, atherosclerosis in medium-sized arteries, which is characterized by proliferation of intima and medial smooth muscle cells with depositions of lipids and fibrin.
Major risk factors for ischaemic heart disease (high total low-density lipoprotein-cholesterol levels, low high-density lipoprotein-cholesterol levels, glucose intolerance, smoking, hypertension) also increase the risk of this stroke subtype. However, it is not known whether the aetiology is identical between this stroke subtype and ischaemic heart disease.
Lacunar infarction
Lacunar infarction has been defined as one or multiple infarctions involving focal, small, and deep areas such as the internal capsule, corona radiata, basal ganglia, and brainstem, without involvement of the cortex, that are caused by occlusion of small penetrating arteries.
This stroke subtype results from the occlusion of small penetrating arterioles (diameter, 100–200 µm), mostly by arteriosclerosis and sometimes by atherosclerotic plaques in large cerebral arteries in the origin of penetrating arteries. Unlike atherosclerosis, this small-vessel pathology is characterized by the loss of medial smooth muscle cells and degenerative changes of intima with fibrin deposition. During the ‘healing process’ for these degenerative changes, macrophages infiltrate the intima filled with fat or hemosiderin, and fibroblastic connective tissue replaces fibrinoid material, which causes occlusion of the vascular lumen.
Thus, compared with intracerebral haemorrhage, moderate hypertension with a longer duration, as usually indicated by hypertensive end-organ effects in the electrocardiograms and fundscopic findings, is likely to cause lacunar infarction in the elderly. In addition to hypertension, glucose intolerance also increases the risk of this type of stroke as a microvascular disorder in diabetes, whereas the contribution of dyslipidaemia and smoking is small.
Cultural differences in distribution of stroke subtypes
The distribution of stroke subtypes may differ between Western and Asian countries (Mohr et al. 1978; Walker et al. 1981; Foulkes et al. 1988; Sankai et al. 1991; C.S. Anderson et al. 1993; Iso et al. 2000). As shown in Fig. 4, large-artery occlusive infarction is most common in Western countries, while intracerebral haemorrhage and lacunar infarction is most common in Japan. No large regional difference exists in the proportion of subarachnoid haemorrhage or embolic infarction. However, embolic origins may be mostly atherogenic in Western countries, but not in Japan. Risk factors for total stroke, therefore, depend on the distribution of stroke subtypes.

Fig. 4 The proportions of stroke subtypes among Japanese and Caucasians. EI, embolic infarction; ICH, intracerebral haemorrhage; LAC, lacunar infarction; LAO, large artery occlusive infarction; SAH, subarachnoid haemorrhage; US, unclassified stroke.

New risk factors
In the United States, the roughly estimated population-attributable risks for stroke due to hypertension, cigarette smoking, atrial fibrillation, and heavy alcohol drinking are 49.3 per cent, 12.3 per cent, 9.4 per cent, and 4.7 per cent respectively (Gorelick 1994), implying that approximately three-quarters of stroke occurrences can be explained by these traditional risk factors, while the risk factors for one-quarter of those remain to be resolved. Several new risk factors that have been revealed by recent epidemiological studies may explain considerable parts of them. We briefly refer to these new risk factors in this section.
Homocysteine
We searched the English-language medical literature to find epidemiological studies concerning plasma/serum levels of homocysteine and stroke, and include the papers published during the period 1984 to 1999 in Table 8. Only two of 15 case–control studies reported that homocysteine was not associated with risk of cerebral infarction. Among five nested case–control studies, however, only two studies reported an increased risk of cerebral infarction. All of the three cohort studies observed the positive association.

Table 8 Homocysteine and risk of cerebral infarction

Beresford and Boushey (1997) reviewed 10 studies, which provided odds ratios or sufficient data to calculate odds ratios of the effect of elevated homocysteine on stroke risk. The summary estimates of the odds ratio of stroke and elevated homocysteine concentration was 2.0 (95 per cent confidence intervals, 1.7–2.4). They also calculated a summary odds ratio based on a change of 5 µmol/l in total homocysteine levels using the seven studies that measured fasting or basal levels of total homocysteine. The combined odds ratio was 1.8 (95 per cent confidence intervals, 1.6–2.0). Biologically plausible mechanisms by which homocysteine might alter the risk of developing atherosclerotic disease include endothelial cell desquamation, oxidation of low-density lipoprotein, monocyte adhesion to the vessel wall, and its direct toxicity to the endothelium. The association of elevated levels of homocysteine with some types of stroke, probably cerebral thrombosis in cortical artery regions, appears to be of the same order as that of other traditional risk factors for stroke, and to be causal.
Diabetes mellitus
Diabetes mellitus has recently become one of the most common diseases in Western countries and Japan. Diabetes mellitus may increase the risk of thromboembolic stroke through multiple and potentially synergistic mechanisms (Wolfe et al. 1991), because of acceleration of large-artery atherosclerosis via glycosylation-induced injury, adverse effects on both low-density lipoprotein and high-density lipoprotein cholesterol levels, and plaque formation due to hyperinsulinaemia (Karem 1996).
Patients with diabetes mellitus were found to have excessive risk for cerebral infarction, while the risk of subarachnoid haemorrhage and intracerebral haemorrhage seemed to be unelevated (Abbott et al. 1987; Jamrozik et al. 1994). The Framingham Study (Wolfe et al. 1991) and the American National Health and Nutrition Examination Survey (Kittner et al. 1990) showed increased risk of stroke in diabetic patients, while the Rancho Bernardo Study (Barrett-Connor and Khaw 1988) reported a small increased risk of stroke only for women with diabetes mellitus. A Finish prospective study (Tuomilehto et al. 1996) demonstrated that diabetes mellitus was the strongest risk factor for stroke in a multivariate analysis. A population-based stroke study in Sweden (6370 stroke events) found that the risk of stroke was 4.1 times higher in diabetic men and 5.8 times higher in diabetic women than in non-diabetic subjects (Stegmayr and Asplund 1995). The Honolulu Heart Study (Abbott et al. 1987) observed an increased risk of thrombotic stroke but no increased risk of haemorrhagic stroke for diabetes mellitus among Japanese-American men. The Framingham Study (Kannel and McGee 1979) also showed that the incidence of atherothrombotic stroke (45–74 years) was higher in diabetic than in non-diabetic subjects. A recent case–control study in young adults (15–55 years) reported that the risk of cerebral infarction was 11.6 times higher in diabetic than in non-diabetic subjects (You et al. 1997). In conclusion, glucose intolerance or diabetes mellitus appears to be a risk factor for cerebral infarction.
Carotid ultrasonography
Carotid ultrasonography has been used for measuring the intima and media thickness of carotid arteries. The Rotterdam follow-up study showed that an increased common carotid intima and media thickness of carotid arteries was associated with subsequent stroke events (Bots et al. 1997, 1999a). The Cardiovascular Health Study reported that intima and media thickness of the common and internal carotid arteries was strongly associated with the risk of stroke in asymptomatic older adults (O’Leary et al. 1999) In conclusion, increases in intima and media thickness of carotid arteries are directly associated with an increased risk of cerebral infarction, although the relative risk is small. Carotid ultrasonography is difficult to operate and expensive, and it takes a long time (15–30 min) to measure the intima and media thickness of carotid arteries. The standardization of measurement conditions and procedures is essential to reduce measurement error and bias.
Fibrinogen
Plasma fibrinogen is a major determinant of platelet aggregation and blood viscosity. Higher plasma fibrinogen levels are strongly correlated with the development of cerebral infarction as shown in Table 9. All six case–control studies showed plasma fibrinogen was positively associated with the risk of cerebral infarction (Sharma et al. 1978; Mistry et al. 1990; Qizilbash et al. 1991; Resch et al. 1992; Beamer et al. 1993; Belch et al. 1998). Among three cohort studies (Wilhelmsen et al. 1984; Welin et al. 1987; Smith et al. 1997), only one study reported that plasma fibrinogen was not associated with stroke in women. One cross-sectional study reported that plasma fibrinogen was associated with history of stroke subjects (Lee et al. 1993). There are several mechanisms whereby fibrinogen could promote atherothrombolism: thrombi formation through hypercoagulable state, acceleration of atherosclerosis, and reduction of blood flow due to high blood or plasma viscosity (Qizilbash et al. 1991). In conclusion, plasma fibrinogen is a probable risk factor for cerebral infarction.

Table 9 Fibrinogen and risk of cerebral infarction

Plasminogen activator inhibitor-1 and tissue plasminogen activator
The fibrinolytic factors plasminogen activator inhibitor-1 and tissue plasminogen activator mass concentration were shown to be independent predictors for atherothrombotic events (Hamsten 1993; Meade et al. 1993; Lijnen and Collen 1996). While few studies on the relationship between the fibrinolytic variables and stroke were reported, high levels of both tissue plasminogen activator and plasminogen activator inhibitor-1 were observed in patients with a history of stroke (Margaglione et al. 1994; Lindgren et al. 1996; Carter et al. 1998; Kristensen et al. 1998; Macko et al. 1999), and high levels of tissue plasminogen activator predicted an increased risk of stroke in two prospective studies (Ridker et al. 1994; Smith et al. 1997). A prospective study showed that tissue plasminogen activator/plasminogen activator inhibitor-1 complex, a novel fibrinolytic marker, was independently associated with the risk of stroke, especially haemorrhagic stroke (Johansson et al. 2000). This finding supports the hypothesis that disturbances in fibrinolysis precede stroke attacks. In conclusion, the association of plasminogen activator inhibitor-1 and tissue plasminogen activator with stroke will be a subject worthy to be tested further by cohort or case–control studies.
Genetic factors
If candidate genetic polymorphisms for stroke can be identified, screening for the presence of these alleles may identify a substantial proportion of high-risk individuals. Appropriate monitoring of these individuals, in conjunction with targeted intervention, could then delay or avert the onset of stroke. In this section, we summarize several studies on the relationship between some genetic polymorphisms and stroke. However, the findings of the studies have been contradictory.
Angiotensin-converting enzyme gene
Angiotensin-converting enzyme is the rate-limiting enzyme of the renin–angiotensin system and is known to be involved in vascular remodelling (Morishita et al. 1994) and atherosclerosis (Pitt 1994). The angiotensin-converting enzyme gene is located on chromosome 17q23 and consists of 26 exons and 25 introns; insertion (I) and deletion (D) polymorphisms of 287 base pairs are identified in intron 16. The angiotensin-converting enzyme D allele was reported to be associated with elevated plasma angiotensin-converting enzyme levels and angiotensin-converting enzyme activity in a codominant pattern (Rigat et al. 1990). As shown in Table 10, the angiotensin-converting enzyme DD genotype or D allele was found to be associated with cerebrovascular disease in some studies (Markus et al. 1995; Margaglione et al. 1996; Nakata et al. 1997). However, no association was found between angiotensin-converting enzyme DD genotype and cerebral infarction in other studies (Sharma et al. 1994; Ueda et al. 1995; Catto et al. 1996). Maeda et al. (1996) reported that parental history of stroke was associated with angiotensin-converting enzyme DD genotype. Kario et al. (1996) observed that hypertensive patients with angiotensin-converting enzyme D allele appeared to develop cerebral infarction. A meta-analysis concluded that angiotensin-converting enzyme D allele was a modest but independent risk factor for cerebral infarction (Sharma 1998). Conversely, recent cross-sectional and nested case–control studies showed that there was no association between cerebrovascular disease and angiotensin-converting enzyme genotypes (Agerholm-Larsen et al. 1997; Zee et al. 1999).

Table 10 Angiotensin-converting enzyme gene and stroke

Apolipoprotein E gene
The apolipoprotein E e2 allele is associated with lower, and the e4 allele with higher serum total and low-density lipoprotein cholesterol levels as compared with the e3 (Sing and Davignon 1985). As shown in Table 11, the apolipoprotein E e2 allele was found to be associated with cerebral infarction (Couderc et al. 1993), whereas the e4 allele was found to be associated with cerebral infarction (Margaglione et al. 1998; Pedro-Botet et al. 1992; Peng et al. 1999) and with large-vessel thrombotic stroke (Kessler et al. 1997). On the contrary, apolipoprotein E gene polymorphism was shown to be unrelated to either cerebral infarction or haemorrhage in the Japanese population (Nakata et al. 1997). A cohort study reported the protective effect of the e2 allele in an older population (Ferrucci et al. 1997), but that apolipoprotein E gene could not be identified as a risk factor for stroke in other populations (Kuusisto et al. 1995; Basun et al. 1996; Hachinski et al. 1996).

Table 11 Apolipoprotein E alleles and stroke

Kokubo et al. (2000) showed a positive relationship between apolipoprotein E e2 and the risks of cerebral atherothrombosis and cardioembolism, and intracerebral haemorrhage, and more prominent effect of apolipoprotein E e2 on the risks in the elderly group than in the middle-aged group. Meanwhile, a positive association of e4 and the risk of atherothrombotic stroke was shown in the middle-aged group but not in the elderly. Such age-dependent changes in the association of e2 or e4 with stroke was also suggested in other studies. Positive associations between e4 and stroke were detected only in subjects less than 70 years (Pedro-Botet et al. 1992; Kessler et al. 1997; Margaglione et al. 1998; Peng et al. 1999). On the contrary, a positive association between e2 and stroke was found in subjects aged 70 years and over (Couderc et al. 1993).
Methylenetetrahydrofolate reductase gene
Elevated levels of plasma/serum homocysteine are probably associated with the risk of carotid artery stenosis and stroke. A common mutation in methylenetetrahydrofolate reductase (MTHFR) which is a homocysteine metabolic pathway enzyme was associated with increased homocysteine levels and, thus, an increased risk for cardiovascular disease. Several studies in Western populations demonstrated that the prevalence of homozygous C677T mutation was not significantly higher in controls than in patients with cerebrovascular diseases (Table 12) (Markus et al. 1997; Kostulas et al. 1998; Salooja et al. 1998; Gaustadnes et al. 1999; Harmon et al. 1999; Press et al. 1999; Lalouschek et al. 1999a,b). However, one study in a Japanese population showed that the V allele was associated with cerebral infarction (Morita et al. 1998).

Table 12 Methylenetetrahydrofolate reductase (MTHFR) and b-fibrinogen genes, and stroke (case–control study)

Fibrinogen gene
High levels of plasma fibrinogen lead to an increased risk of cerebrovascular disease (Wilhelmsen et al. 1984; Kannel et al. 1987) and peripheral artery disease (Lowe et al. 1993). Fibrinogen consists of a glycoprotein comprising pairs of three non-identical polypeptides: Aa, Bb, and g chains (Doolittle 1983; Henschen et al. 1983). The synthesis of the Bb chain is considered to be a rate-limiting step in the secretion of fibrinogen from hepatocytes (Yu et al. 1984). The 5′ region of the b gene contains binding sites for several trans-acting factors, which largely control the expression of the gene (G.M. Anderson et al. 1993). Carter et al. (1997) reported that fibrinogen Bb448 1/1 genotype was associated with cerebral infarction in females but not in males (Table 12). Fibrinogen 455G/A A allele was found to be an independent risk factor for cerebral infarction in a Japanse population (Nishiuma et al. 1998), whereas no association was observed in a Western population (Kessler et al. 1997).
Lifestyle
Diet
Table 13 summarizes the epidemiological studies which reported associations of dietary intake with stroke. Among them, an inverse relation between fat intake and stroke is noteworthy, because it may imply an aetiological difference between stroke and coronary heart disease.

Table 13 Inverse association of dietary intake with risk of stroke

Seven cohort studies on dietary fat and stroke have been reported (Reed 1990; Klag and Whelton 1993; Bronner et al. 1995; Gillman et al. 1997; Seino et al. 1997; Sherwin and Price 1997; Iso et al. 2001). Gillman et al. (1997) reported the risk of cerebral infarction was inversely related to intakes of fat, saturated fat, and monounsaturated fat that were assessed by the 24-h recall method. Seino et al. (1997), who estimated dietary intake of fat by a semi-quantitative food frequency questionnaire, observed the same results as Gillman and his colleagues, but the inverse association did not reach statistical significance. Iso et al. (2001) reported an association of a low intake of saturated fat and animal protein with the risk of intracerebral haemorrhage. Four other studies found no relationship between fat or fish oil and stroke.
According to Japanese studies (Tanaka et al. 1992; Konishi et al. 1993), the Japanese used to have only steamed rice, miso (soybean paste) soup, and salted vegetables every meal during the national privation period before 1950, i.e. high carbohydrate and salt, and extremely low fat and animal protein. The average serum cholesterol was less than 160 mg/dl in males aged 40 to 64 years. The subjects with high blood pressure and low serum cholesterol had a very high risk of stroke, particularly intracerebral haemorrhage and cerebral infarction in penetrating artery regions. Thus, a diet-stroke hypothesis was proposed in Japan: low intake of lipids and low levels of serum cholesterol result in the development of stroke. Epidemiological studies are expected to test the hypothesis.
Although it is well established that diet affects coronary heart disease and its risk factors, data about diet and stroke, particularly the subtypes, are insufficient. Nutritional factors that have cardioprotective effects can be applied to prevention against cerebral thrombosis in cortical artery regions, but not intracerebral haemorrhage and cerebral infarction in perforating artery regions. Additional epidemiological studies on diet and subtypes of stroke should be carried out.
Physical activity
A beneficial effect of increasing physical activity on prevention of stroke remains controversial. The Surgeon General’s Report on Physical Activity and Health in 1996 concluded that ‘the existing data do not unequivocally support an association between physical activity and risk of stroke’ (US Department of Health and Human Services 1996). Although several studies have reported an inverse relationship of leisure-time (Wannamethee and Shaper 1992; Haheim et al. 1993; Lindenstrom et al. 1993a; Shinton and Sagar 1993; Gillum et al. 1996; Sacco et al. 1998; Agnarsson et al. 1999) or on-the-job (Abbott et al. 1994; Kiely et al. 1994; Nakayama et al. 1997; Evenson et al. 1999) physical activity to risk of stroke or a U-shaped relationship (Lee and Paffenbarger 1998), others have shown no association between physical activity and stroke (Folsom et al. 1990; Harmsen et al. 1990; Lindsted et al. 1991; Ellekjaer et al. 1992; Kiely et al. 1994; Nakayama et al. 1997; Lee et al. 1999; Evenson et al. 1999), including several cohort studies (Gillum et al. 1996; Nakayama et al. 1997; Lee and Paffenbarger 1998; Agnarsson et al. 1999; Evenson et al. 1999; Lee et al. 1999) which were published after the Surgeon General’s Report (US Department of Health and Human Services 1996). The reasons for the inconsistent findings may be due to combining different subtypes of stroke, measurement errors of physical activity (Paffenbarger et al. 1993), insufficient statistical power to detect the association, and potential confounding factors. The inconsistency may reflect only a weak association between physical activity and stroke (Evenson et al. 1999).
A recent large-scale cohort study of 14 575 middle-aged adults in the United States (Evenson et al. 1999) identified a weak association of on-the-job physical activity with a reduced incidence of cerebral infarction. However, the United States Physician’s Health Study with 533 fatal and non-fatal strokes among 21 823 male physicians (Lee et al. 1999) reported that significant associations between frequency of exercise and ischaemic and haemorrhagic strokes disappeared after adjustment for several confounding variables, concluding that the observed inverse association of physical activity with stroke is mediated through beneficial effects on body weight, blood pressure, serum cholesterol, and glucose tolerance.
Alcohol
Although there have been numerous studies investigating the effect of alcohol consumption on the occurrence of stroke, the relationship between alcohol and stroke seems less clear compared to the J-shaped relationship between alcohol consumption and coronary heart disease. Several case–control (Monforte et al. 1990; Gill et al. 1991; Ben-Shlomo et al. 1992; Palomaki and Kaste 1993; Rodgers et al. 1993; Beghi et al. 1995; Hillbom et al. 1995; You et al. 1997) and cohort (Iso et al. 1995; Kiyohara et al. 1995; Wannamethee and Shaper 1996; Ross et al. 1997; Yuan et al. 1997; Truelsen et al. 1998b; Hart et al. 1999) studies indicated an association of haemorrhagic stroke with habitual or recent heavy drinking of alcoholic beverages. This association was considered to be mediated through acute and chronic effects of alcohol on blood pressure (Wannamethee and Shaper 1996). The protective effect of light to moderate drinking on stroke has not been clearly established (Wannamethee and Shaper 1998) with divergent results from various populations (Gill et al. 1991; Lindenstrom et al. 1993b; Palomaki and Kaste 1993; Rodgers et al. 1993; Jamrozik et al. 1994; Gronbaek et al. 1995; Hansagi et al. 1995; Iso et al. 1995; Kiyohara et al. 1995; Rodriguez et al. 1998; Caicoya et al. 1999; Sacco et al. 1999). This might be partly due to failure to separate ischaemic and haemorrhagic stroke, the use of non-drinkers (including both life-long abstainers and ex-drinkers) as a comparison group (Wannamethee and Shaper 1996, 1998), the possible difference in biological effect amongst beer, wine, and spirits (Truelsen et al. 1998b), or the possible influence of day-to-day patterns of alcohol consumption (Wannamethee and Shaper 1996). Recent studies, taking into account some of the above-mentioned factors that might distort the study results, found that light to moderate consumption of wine was more strongly associated with lower risk of cerebral infarction (Truelsen et al. 1998b; Sacco et al. 1999) than that of beer and spirits, and that light to moderate alcohol consumption approximately up to 30 g/day was protective against cerebral infarction (Sacco et al. 1999; Caicoya et al. 1999) or was not beneficial for stroke risk compared with occasional drinking (Wannamethee and Shaper 1996).
As for subarachnoid haemorrhage, a meta-analysis of nine cohort studies and 11 case–control studies concluded that drinking 150 g or more alcohol per week was associated with an increased risk of subarachnoid haemorrhage with a combined odds ratio being 1.5 for case–control studies and a combined relative risk being 4.7 for cohort studies (Teunissen et al. 1996).
Smoking
Cigarette smoking is considered to be an established risk factor for stroke (Aldoori and Rahman 1998). A number of case–control studies (Bonita et al. 1986; Gill et al. 1989; You et al. 1993; Howard et al. 1998), cohort studies (Abbott et al. 1986; Wolf et al. 1988; Harmsen et al. 1990; Lindenstrom et al. 1993b; Robbins et al. 1994; Wannamethee et al. 1995; Haheim et al. 1996), and a meta-analysis of 32 separate studies (Shinton and Beevers 1989) have indicated a significantly higher risk in current smokers than in non-smokers for cerebral infarction and subarachnoid haemorrhage (Bonita et al. 1986; Longstreth et al. 1992; Juvela et al. 1993; Teunissen et al. 1996). A population-based case–control study in New Zealand found an increased risk of stroke associated with exposure to environmental tobacco smoke among non-smokers and long-term ex-smokers (Bonita et al. 1999). A more notable issue regarding an association between smoking and stroke in the public health field might be a potential effect of smoking cessation to reduce the risk of stroke (Abbott et al. 1986; Wannamethee et al. 1995; Aldoori and Rahman 1998). The Framingham Heart Study clearly showed that smoking cessation reduced the relative risk of stroke to the level of a non-smoker within 5 years after quitting (Wolf et al. 1988). A cohort study investigating the effect of stopping smoking in detail (Wannamethee et al. 1995) revealed that light smokers (less than 20 cigarettes/day) could revert to the risk level of never smokers, while heavy smokers would retain a more than two-fold risk compared with never smokers even 5 years after quitting, and that the benefit of stopping smoking was greater in hypertensive than in normotensive middle-aged men.
Several studies showed a potential synergistic effect of smoking and oral contraceptive use (Oleckno 1988; Higa and Davanipoor 1991), alcohol consumption (Oleckno 1988), hypertension (Bonita 1986; Bonita et al. 1986; Higa and Davanipoor 1991; Haheim et al. 1996), and antihypertensive drug use specifically b-blockers (Medical Research Council Working Party 1988; Higa and Davinpoor 1991). Pharmacological treatment of hypertension in smokers with mild hypertension would be less beneficial for reducing the risk of stroke than that in non-smokers with mild hypertension (Medical Research Council Working Party 1988). These findings suggest that all smokers, especially those with hypertension, should be advised that it is not too late to stop smoking for reducing risk of stroke, no matter how long they have been smoking (Gill et al. 1991).
Strategies for prevention of stroke
Although the natural history of stroke and stroke subtypes is complex, hypertension is the strongest and most consistent risk factor for stroke as well as a major determinant for stroke prognosis. Therefore, the prevention and control of hypertension is a central strategy for primary, secondary, and tertiary prevention of stroke. Dyslipidaemia, glucose intolerance, and smoking have been less consistent risk factors for total stroke, or have been limited to certain stroke subtypes, and thus the control and prevention of these risk factors is of less importance in the prevention of stroke compared with the prevention of ischaemic heart disease.
Strategies for prevention of stroke are categorized as four modalities: primordial, primary, secondary, and tertiary prevention. Primordial prevention, the early phase of primary prevention, attempts to retard the development of hypertension in the early stage of life including childhood, adolescence, and young adults. Modification of lifestyles including diet (reduced intake of sodium and increased intake of potassium), physical activity (increased physical activity for the control and prevention of overweight), and drinking (reduction of excessive alcohol intake) are major health education activities for primary prevention.
Primary prevention, in a usual form, is the early detection of hypertension through systematic blood pressure screenings and the control of hypertension by either pharmacological or non-pharmacological treatments. Various antihypertensive drugs are available and have been demonstrated as effective for reduction of blood pressure levels in hypertensives. Non-pharmacological treatments such as reduction of sodium intake and alcohol intake, increased potassium intake, increased physical activity, and control of overweight are also effective for reduction of blood pressure levels, and reduce medication requirement for hypertensives.
Secondary prevention is the identification of transient ischaemic attacks to prevent the development of completed stroke. Antithrombotic treatment has been demonstrated to be effective to prevent complete stroke among patients with a history of transient ischaemic attack. However, systematic identification of transient ischaemic attacks is a difficult task in communities. Application of antithrombotic treatment within 12 h of the onset of ischaemic stroke is one of the promising treatments to prevent the complete stroke. If ambulance systems develop to support early antithrombotic treatment, this strategy could be a practical method for secondary prevention.
Tertiary prevention is the rehabilitation for stroke patients to prevent or reduce their disabilities and social handicaps. Tertiary prevention also includes medial and social care for disabled stroke patients to improve or maintain quality of life for themselves and their families. Early physical treatment followed by occupational therapy, verbal therapy, and social support is particularly important to improve prognosis in their activities of daily livings and quality of life for a considerable proportion of stroke patients.
Japan suffers higher mortality from stroke and lower mortality from coronary heart disease than Western countries. To ameliorate the epidemic of stroke, a community-based programme for primordial and primary prevention of stroke was launched in several communities in the 1960s. A recent study in two Japanese communities with different intervention intensity provided evidence on the effect of community hypertension control for stroke prevention (Iso et al. 1998).
Community intervention for stroke prevention
There were two agricultural communities (approximately 3000 men and women aged 30 and over in one community and 1500 in the other community with similar age and sex distributions and stable populations over time) in northeastern Japan, 36 miles apart, where mortality from stroke was double that of all Japan. Efforts to control hypertension by systematic blood pressure screening and health education had been widespread in both communities since 1963. However, the fortuitous lack of interest of the government of one community, which started to charge participants for blood pressure screening after 1969, and the retirement of the public health nurse in 1973, caused a difference in penetration of hypertension control efforts. This circumstance permitted the observation of the long-term effect on blood pressure and its clinical sequelae at two levels of intensity of an intervention programme. Furthermore, the full intervention community received continuous government support, systematic education classes for detected hypertensives, and a home broadcasting system for verbal health announcements via a speaker attached to the telephone. The minimal intervention community had no systematic classes or mass-media education.
Approximately 80 per cent of men and 90 per cent of women aged 40 to 69 were screened in both communities in the 1960s. After services were reduced in the reference community, screening rates of general population and hypertensives declined, more in men (to 50 per cent) than in women (to 60 per cent), whereas the full intervention community kept high screening rates. There was a larger decline in stroke incidence for men aged 30 and over in the intervention community (42 per cent in 1970–1975, 53 per cent in 1976–1981, and 75 per cent in 1982–1987) than in the minimal intervention community (5 per cent increase, 20 per cent decrease, and 29 per cent decrease respectively); in women, the decline in stroke incidence was approximately 45 per cent, 50 per cent and 65 per cent respectively in both communities (Fig. 5). Changes in stroke prevalence paralleled those in stroke incidence. Trends in blood pressure levels tended to explain the differential stroke rates in men. The lack of difference in change in stroke rates among women may be because women are more health conscious than men and are more likely to respond to a relatively low programme intensity since the decline in participation in the minimal intervention community in blood pressure screening was not as large in women as men.

Fig. 5 Sex-specific age-adjusted stroke incidence in the full intervention community (•) and the minimal intervention community (m) for men and women aged 30 years. Difference from the minimal intervention community: †p < 0.01, ‡p < 0.001. (Source: Iso et al. 1998.)

Delivery of hypertension control services through intensive, free, community-based screening supplemented by community-based health education and broad citizen support was apparently effective in prevention of stroke.
Strategies and organization for hypertension control programme
Realistic strategies and organization for the hypertension control programme in the above study should be mentioned. These activities are similar to those in prevention programmes for ischaemic heart disease in Europe and the United States in terms of multiple strategies and involvement of existing organizations (Tuomilehto et al. 1980; Farquhar et al. 1990; Luepker et al. 1996), but are different in terms of practical approaches and existing resources related to different cultures and environments.
In the full intervention community, the basic strategies for hypertension control included the following:

systematic blood pressure screening for detection of hypertensives

referral of high-risk individuals to either of two local clinics when antihypertensive medication was required based on the presence of high blood pressure or end-organ effects in the retinal arterioles or electrocardiogram

health education for hypertensives at blood pressure screening sites, at adult classes, and via nurse home visits;

training of volunteers to give health education for dietary improvement

community-wide media-disseminated education to encourage people to participate in blood pressure screening and to reduce salt intake.
The network and organization for the stroke prevention programme included a local government office, a prefectural health centre, two local clinics, research institutes, and task forces, which held regular meetings to discuss the implementation of the programme. Task forces consisted of public health nurses, midwives, community leaders, and their coworkers from each district of the community. Repeated systematic blood pressure screenings for detection, referral, and follow-up of hypertensives were free of charge. Community leaders and their coworkers, appointed by local government, played a role in recruiting residents by distributing recruitment letters and by oral communication. They also assisted with the arrangement, reception, and guidance of blood pressure screenings at community centres and schools. A team of three nurses and four midwives was established to implement adult classes and home visits systematically. Hypertensives newly detected in the later screenings were also invited to adult classes. Classes dealt with blood pressure measurement, counselling on blood pressure management, how to control hypertension for the prevention of stroke, and how to reduce salt intake, including taste tests of low-salt soy bean soup and pickles. Education was focused primarily on reduction of salt intake because the average sodium intake was 20 g/day in the 1960s. High sodium intake came from a traditional Japanese diet, that is, a high intake of rice, salty soybean soup, salt-preserved pickles, and salt-preserved fish, whereas intake of meat, eggs, and dairy foods was extremely low. Reduction of excessive alcohol intake to about five drinks or less per day was also emphasized. The recommendation was made that farmers rest adequately because farm work was extremely hard, but emphasized weight control on a community-wide basis because the prevalence of obesity was very low and most hypertensive people were not obese in the 1960s. One to two times annually, a team of public health nurses and midwives visited hypertensives who did not attend adult classes, to confirm that a referral had occurred and to offer health education.
Volunteers for diet improvements were trained through annual classes, enhancing knowledge of stroke and practical ways of modifying diet and lifestyle for stroke prevention. These training sessions were instructed by trained nurses, nutritionists, and physicians. The volunteers offered health education to people at blood pressure screenings and at regular public meetings held at local public centres, four or five times a year.
Media dissemination was accomplished by a municipal announcement system transmitted via a speaker attached to each household telephone. This announcement system was used primarily in emergencies, such as fire and earthquake, but also to broadcast health education messages. Individuals could turn the speaker off. The announcement system was used to recruit participants to blood pressure screenings and adult classes a week before and during the events. In addition to this campaign, a regular programme on cardiovascular health was aired for three minutes at 06.30, 12.30, and 18.30 every Thursday. Topics, which were revised monthly, were reduction of salt intake, the importance of balanced diet, proper rest, etc.
Summary
Cerebrovascular disease ranks third or higher as a cause of death in industrialized countries. The age-adjusted death rates from cerebrovascular disease tended to decrease in the United States and Western Europe during the period from 1950 to 1995. Although the Japanese rate was the highest in the world and increased from 1950 to 1964, it tended to decrease after 1965, reaching the level of West European countries in recent years. The estimated international average incidence of all strokes in the age group 30 years and over was 3.57 per 1000 for males and 2.94 per 1000 for females: 1.78 and 1.12 for intracerebral haemorrhage and 2.44 and 2.15 for cerebral infarction. The sex- and age-adjusted vital prognosis of intracerebral haemorrhage and infarction has improved during these three decades because of the decline in the number of patients with severe stroke, improvement of medical care, and a decrease in blood pressure levels. Stroke is a complex of subtypes: subarachnoid haemorrhage, intracerebral haemorrhage, embolic infarction, and thrombotic infarction consisting of large-artery occlusive infarction and lacunar infarction. These subtypes may have different pathologies, aetiologies, and risk factors. Hypertension, smoking, and heavy drinking increase the risk of subarachnoid haemorrhage. The contribution of hypertension to intracerebral haemorrhage is strongest among the stroke subtypes. In addition, low levels of serum total cholesterol and heavy drinking are associated with an increased risk of intracerebral haemorrhage. The risk factors for embolic infarction depend on the proportion of sources of emboli, especially atrial fibrillation. Major risk factors for ischaemic heart disease (high total or low-density lipoprotein-cholesterol levels, low high-density lipoprotein-cholesterol levels, glucose intolerance, smoking, and hypertension) also increase the risk of large-artery occlusive infarction, although it is not known whether the aetiology is identical between infarction and ischaemic heart disease. Moderate hypertension with a longer duration, fundoscopic abnormalities, and glucose intolerance are likely to cause lacunar infarction, whereas the contribution of dyslipidaemia or smoking is small. Approximately three-quarters of stroke occurrences can be explained by traditional risk factors such as hypertension, cigarette smoking, heavy drinking, and atrial fibrillation, while the rest remain to be resolved. Several new risk factors that have been revealed by recent epidemiological studies may explain considerable parts of this latter group. For example, elevated homocysteine or fibrinogen levels and increased carotid intima and media thickness increase the risk of cerebral infarction. Meanwhile, several studies have reported the relationships between stroke and genetic polymorphisms: angiotensin-converting enzyme insertion/deletion, apolipoprotein E gene, MTHFR gene, and fibrinogen gene polymorphisms. The early phase of primary prevention of stroke attempts to stop the development of hypertension in the early stages of life. Modification of lifestyles in diet (reduced intake of sodium), physical activity (increased activity for the control and prevention of overweight), and drinking (reduction of excessive alcohol intake) are major health educational activities for primary prevention. They have been shown to decrease stroke in community intervention trials.
Appendices
Appendix 1 Age-specific stroke incidence rates per 1000 population in selected communities (group A)

Community
Year
Sex
Age-specific incidence (age group)

30–39
40–49
50–59
60–69
70–79
80+

All strokes
Shibata
1976–78
Male
0.26
1.25
3.30
10.42
15.72
27.63
(Niigata, Japan)

Female
0.13
0.22
1.05
3.78
8.01
20.89

Both sexes
0.20
0.71
2.06
6.72
11.24
23.23

Akita (Japan)
1964–69
Male
0.52
2.25
9.46
18.98
23.03
37.74

Female
0.31
1.00
4.60
14.04
19.51
34.56

Both sexes
0.4a
1.6a
7.0a
16.4a
21.0a
35.7a

Osaka (Japan)
1963–68
Male
0
0.85
1.73
11.29
19.92
40.20

Female
0
0.21
1.11
6.63
11.05
17.11

Both sexes
0a
0.5a
1.4a
8.8a
15.1a
25.0a

Hisayama
1961–63
Both sexes

1.77
6.34
13.74
20.83
28.85
(Fukuoka, Japan)

Tartu
1970–73
Male
0.22
0.97
1.97
5.79
15.20
32.4a
(Former USSR)

Female
0.03
0.35
1.31
3.72
12.68
28.2a

Both sexes
0.13
0.62
1.58
4.45
13.29
29.3a

Manitoba (Canada)
1970–71
Male
0.17
0.65
2.13
5.34
10.41
25.25

Female
0.23
0.38
1.16
3.33
9.72
21.87

Both sexes
0.20
0.51
1.63
4.28
9.23
23.39

Poznan (Poland)
1985
Male
0.25
1.10
3.83
5.53
9.64
10.7a

Female
0.15
0.55
1.48
3.47
7.62
9.5a

Both sexes
0.20
0.82
2.59
4.34
8.38
9.8a

Oahu (Hawaii, USA)
1969–72
Male

1.46
3.70
1.92

(Hawaiian Japanese)
1973–76
Male

1.29
2.50
4.78

1977–80
Male

0.27
2.24
4.77
0.00

1981–84
Male

2.38
4.88
6.91

1985–88
Male

2.37
4.54
8.49

Community
Year
Sex
Age-specific incidence (age group)

30–39
40–49
50–59
60–69
70–79
80+

Cerebral haemorrhage
Shibata
1976–78
Male
0.13
0.42
1.02
2.66
2.84
1.78
(Niigata, Japan)

Female
0.07
0.11
0.49
1.11
1.89
1.43

Both sexes
0.10
0.26
0.73
1.80
2.28
1.55

Akita (Japan)
1964–69
Male
0.30
1.02
4.06
6.25
9.82
10.65

Female
0.11
0.64
1.73
4.94
6.33
21.53

Both sexes
0.20
0.82
2.87
5.56
7.86
17.05

Osaka (Japan)
1963–68
Male
0
0.46
0.80
4.31
8.75
7.50

Female
0
0.11
0.50
2.46
4.35
7.73

Both sexes
0
0.27
0.63
3.31
6.36
7.65

Tartu
1970–73
Both sexes
0.04
0.14
0.33
0.89
1.16
3.5a
(Former USSR)

Manitoba (Canada)
1970–71

Urban area

Male
0.09
0.29
0.36

Female
0.13
0.26
0.64

Both sexes
0.11
0.27
0.51

Rural area

Male
0.12
0.26
0.70

Female
0.26
0.06
0.21

Both sexes
0.18
0.16
0.45

Community
Year
Sex
Age-specific incidence (age group)

30–39
40–49
50–59
60–69
70–79
80+

Cerebral infarction
Shibata
1976–78
Male
0
0.24
1.35
6.25
11.57
22.28
(Niigata, Japan)

Female
0
0
0.21
1.84
4.71
16.62

Both sexes
0
0.11
0.73
3.80
7.58
18.59

Akita (Japan)
1964–69
Male
0
0.60
3.93
9.93
11.00
21.29

Female
0
0.23
1.38
4.88
11.52
8.42

Both sexes
0
0.40
2.63
7.29
11.29
12.95

Osaka (Japan)
1963–68
Male
0
0.20
0.69
5.26
8.26
25.70

Female
0
0
0.50
2.06
6.20
7.06

Both sexes
0
0.09
0.58
3.53
7.14
13.40

Tartu
1970–73
Male
0.11
0.51
1.46
4.40
13.49
26.1a
(Former USSR)

Female
0.03
0.14
0.63
2.70
10.77
26.5a

Both sexes
0.07
0.31
0.98
3.24
11.49
25.4a

Manitoba (Canada)
1970–71

Urban area

Male
0.09
0.35
1.58

Female
0.11
0.26
0.55

Both sexes
0.10
0.31
1.03

Rural area

Male
0
0.26
1.18

Female
0
0
0.56

Both sexes
0
0.13
0.87

Oahu (Hawaii, USA)
1969–72
Male

1.46
3.70
1.92

(Hawaiian Japanese)
1973–76
Male

1.29
2.50
4.78

1977–80
Male

0.27
2.24
4.77
0.00

1981–84
Male

2.38
4.88
6.91

1985–88
Male

2.37
4.54
8.49

Community
Year
Sex
Age-specific incidence (age group)

30–39
40–49
50–59
60–69
70–79
80+

Subarachnoid haemorrhage
Shibata
1976–78
Both sexes
0.07
0.23
0.38
0.56
0.00
0.00
(Niigata, Japan)

Tartu
1970–73
Both sexes
0.02
0.18
0.27
0.30
0.66
0.5a
(Former USSR)

Poznan (Poland)
1985
Male
0.06
0.05
0.21
0.21
0.39
0a

Female
0.04
0.14
0.16
0.15
0.19
0.28a

Both sexes
0.05
0.10
0.18
0.18
0.27
0.20a

aEstimated from the data in each reference.
Appendix 2 Age-specific stroke incidence rates per 1000 population in selected communities (group B)

Community
Year
Sex
Age-specific incidence (age group)

35–44
45–54
55–64
65–74
75+

All strokes
Shibata (Niigata, Japan)
1976–78
Male
0.51
2.28
5.49
13.80
22.13

Female
0.18
0.58
2.22
5.12
15.31

Both sexes
0.34
1.39
3.64
8.90
17.90

Jerusalem (Israel)
1960–67
Male
0.21
1.26
3.93
9.15
10.04

Female
0.23
0.64
3.20
6.50
9.08

Both sexes
0.22
0.94
3.49
7.78
9.52

Fargo, ND – Moorhead, MN (USA)
1965–66
Male
0.81
1.91
4.42
11.51
34.94

Female
0.46
1.45
2.63
10.18
39.08

Both sexes
0.64
1.68
3.49
10.82
37.16

Mid-Missouri (USA)
1964–65

White

Male
0
0.26
3.92
7.43
29.27

Female
0
0
2.55
4.61
26.93

Both sexes
0
0.13
3.19
5.86
27.92
Nonwhite

Male
0
10.26
7.55
27.78
38.46

Female
0
7.43
0
19.31
19.11

Both sexes
0
8.62
3.72
23.16
28.75

Middlesex, CT (USA)
1957–58
Male
0
1.2
4.6
11.9
26.3a

Female
0.2
1.0
3.5
7.2
28.9a

Both sexes
0.1
1.1
4.0
9.4
27.9a

Community
Year
Sex
Age-specific incidence (age group)

35–44
45–54
55–64
65–74
75+

Taiwan
1986–90
Male
(0.60)b
1.07
5.17
7.90
12.93

Female
(0)
1.35
4.41
5.53
15.38

Both sexes
(0.26)
1.22
4.82
6.89
14.17

Copenhagen (Denmark)
1976–88
Male
0.66
1.78
5.18
10.10
(20.37)c

Female
0.41
0.85
1.87
5.45
(10.85)

Both sexes
0.53a
1.3a
3.3a
7.5a
(15)a

Malmö (Sweden)
1989
Male
(0.14)d
1.13
2.07
7.68
13.3

Female
(0.06)
0.37
1.62
3.78
11.9

Both sexes
(0.10)
0.74
1.83
5.46
12.4

Warsaw (Poland)
1991–92
Male
(0.53)e
0.98
4.08
7.61
13a

Female
(0.19)
0.96
1.89
4.35
15a

Both sexes
(0.35)
0.97
2.89
5.75
14a

Finland
1983–85

North Karelia

Male
0.83
2.58
5.09
9.71

Female
0.39
0.70
2.51
8.37

Both sexes
0.62a
1.7a
3.7a
8.9a

Kuopio Province

Male
1.27
2.64
5.98
12.48

Female
0.65
1.37
3.15
8.79

Both sexes
0.98a
2.0a
4.4a
10a

Turku/Loimaa

Male
0.57
1.33
4.42
9.07

Female
0.34
0.73
2.12
6.37

Both sexes
0.46a
1.0a
3.1a
7.4a

Community
Year
Sex
Age-specific incidence (age group)

35–44
45–54
55–64
65–74
75+

Rochester, MN (USA)
1980–84
Both sexes
(0.10)d
1.04
2.09
6.81
13a

1975–79
Both sexes
(0.11)
0.71
1.79
5.61
11a

1970–74
Both sexes
(0.05)
0.65
2.47
5.96
12a

1965–69
Both sexes
(0.07)
1.20
3.14
6.13
13a

1960–64
Both sexes
(0.07)
0.93
3.20
7.83
19a

1955–59
Both sexes
(0.10)
1.08
4.38
8.52
21a

1950–54
Both sexes
(0.10)
1.69
2.99
10.40
23a

1945–49
Both sexes
(0.06)
1.26
4.06
9.95
22a

1945–54
Both sexes
0.34
1.59
3.69
10.81
24.94

1955–69
Male
0.43
1.58
5.11
10.82
25.04

Female
0.27
0.71
2.61
6.03
19.88

Both sexes
0.35
1.10
3.64
7.91
21.56

Auckland (New Zealand)
1991
Male
0.50
1.04
4.23
11.32
20.08a

Female
0.40
0.97
2.56
7.12
21.45a

Both sexes
0.45
1.00
3.39
9.02
20.98a

1991
Male
0.44
0.85
2.76
7.59
11.94c

Female
0.37
0.76
2.05
5.15
11.90c

1981
Male
0.52
1.18
2.14
6.82
16.85c

Female
0.31
0.82
1.88
3.56
13.66c

Arcadia (Greece)
1994–95
Male
0.31
1.13
2.40
6.62
17.01a

Female
0.18
0.48
1.96
4.78
13.85a

Both sexes
0.25
0.82
2.18
5.68
15.41a

Shanghai (China)

Rural

Male
0.14
0.66
3.48
9.36

Female
0.16
0.75
1.78
6.87

Urban

Male
0.05
0.39
3.17
8.62

Female
0.06
0.48
2.51
7.34

Rural and urban

Male
0.1
0.50
3.32
8.98

Female
0.12
0.61
2.15
7.09

Both sexes
0.11
0.56
2.71
7.92

Community
Year
Sex
Age-specific incidence (age group)

35–44
45–54
55–64
65–74
75+

MONICA Project Populations

Beijing (China)
1985–87
Male
0.18
1.47
4.33

Female
0.19
1.03
3.08

Glostrup (Denmark)
1985–87
Male
0.29
1.45
2.82

Female
0.26
0.72
1.57

Kuopio Province (Finland)
1985–87
Male
0.9
2.40
6.39

Female
0.55
1.60
3.31

North Karelia (Finland)
1985–87
Male
0.97
2.15
4.96

Female
0.24
0.93
2.34

Turku/Loima (Finland)
1985–87
Male
0.54
1.64
4.71

Female
0.31
0.70
2.02

Halle County (Germany)
1985–87
Male
0.23
0.95
3.00

Female
0.25
0.60
1.41

Karl Marx Stadt (Germany)
1985–87
Male
0.27
1.08
2.93

Female
0.29
0.54
1.87

Rest of DDR MONICA (Germany)
1985–87
Male
0.11
0.83
2.93

Female
0.22
0.53
1.02

Rhein–Neckar Region (Germany)
1985–87
Male
0.25
0.85
2.39

Female
0.16
0.33
1.11

Friuli (Italy)
1985–87
Male
0.26
0.89
2.31

Female
0.22
0.44
1.19

Kaunas (Lithuania)
1985–87
Male
0.56
1.96
4.75

Female
0.41
1.17
2.64

Warsaw (Poland)
1985–87
Male
0.35
1.06
2.66

Female
0.15
0.51
1.33

Moscow (control, Russia)
1985–87
Male
0.31
1.63
3.67

Female
0.08
0.91
2.03

Moscow (intervention, Russia)
1985–87
Male
0.21
1.24
3.44

Female
0.11
0.57
2.03

Novosibirsk (intervention, Russia)
1985–87
Male
0.62
2.03
5.50

Female
0.36
2.03
4.34

Göteborg (Sweden)
1985–87
Male
0.28
0.88
2.63

Female
0.26
0.48
1.25

Northern Sweden
1985–87
Male
0.39
1.36
4.09

Female
0.33
0.65
2.16

Novi Sad (Yugoslavia)
1985–87
Male
0.39
1.64
4.15

Female
0.23
0.76
2.09

Community
Year
Sex
Age-specific incidence (age group)

35–44
45–54
55–64
65–74
75+

Cerebral haemorrhage
Shibata (Niigata, Japan)
1976–78
Male
0.19
0.82
1.19
3.45
2.11

Female
0.06
0.35
0.91
1.56
1.08

Both sexes
0.12
0.57
1.03
2.38
1.47
Rochester, MN (USA)
1945–54
Both sexes
0.13
0.24
0.42
1.31
0.96

Middlesex, CT (USA)
1957–58
Male
0
0.2
1.6
5.4
7.1a

Female
0
0.4
1.5
2.5
10.3a

Both sexes
0
0.3
1.6
3.8
9.0

Manitoba (Canada)
1970–71

Urban area

Male
0.11
0.37
0.50

Female
0.22
0.42
0.78

Both sexes
0.16
0.39
0.65

Rural area

Male
0.31
0.54
0.46

Female
0.13
0.13
0.39

Both sexes
0.22
0.33
0.43

Malmö (Sweden)
1989
Both sexes
(0.02)d
0.07
0.19
0.62
1.0a

Arcadia (Greece)
1994–95
Male
0.00
0.17
0.40
1.52
2.26a

Female
0.09
0.19
0.54
0.43
0.91a

Both sexes
0.04
0.18
0.47
0.96
1.57a

Community
Year
Sex
Age-specific incidence (age group)

35–44
45–54
55–64
65–74
75+

Cerebral infarction
Shibata (Niigata, Japan)
1976–78
Male
0
0.70
3.12
8.77
17.91

Female
0
0.12
0.66
2.34
12.29

Both sexes
0
0.39
1.73
5.14
14.43
Rochester, MN (USA)
1955–69
Male
0.32
1.18
4.08
8.98
21.05

Female
0.03
0.36
1.84
4.61
16.33

Both sexes
0.17
0.72
2.77
6.32
17.86

1945–54
Both sexes
0.08
1.14
2.66
8.33
21.57

Manitoba (Canada)
1970–71

Urban area

Male
0.11
0.67
2.84

Female
0.15
0.40
1.14

Both sexes
0.13
0.52
1.94

Rural area

Male
0.12
0.47
1.99

Female
0
0.33
1.80

Both sexes
0.16
0.39
0.65

Malmö (Sweden)
1989
Both sexes
(0.06)d
0.48
1.12
3.46
4.8a

Arcadia (Greece)
1994–95
Male
0.23
0.95
1.87
5.01
14.28a

Female
0.09
0.19
1.28
3.50
12.12a

Both sexes
0.17
0.59
1.58
4.23
13.18a

Community
Year
Sex
Age-specific incidence (age group)

35–44
45–54
55–64
65–74
75+

Subarachnoid infarction
Shibata (Niigata, Japan)
1976–78
Both sexes
0.22
0.18
0.56
0.38
0

Rochester, MN (USA)
1945–54
Both sexes
0.13
0.15
0.42
0.37
0.36

Malmö (Sweden)
1989
Both sexes
(0.02)d
0.15
0.11
0
0.21a

Auckland (New Zealand)
1981–83
Male
0.16
0.20
0.13

Female
0.22
0.28
0.35

Both sexes
0.19
0.24
0.24

1991–93
Male
0.04
0.16
0.21

Female
0.14
0.28
0.38

Both sexes
0.09
0.22
0.29

Arcadia (Greece)
1994–95
Male
0.08
0.00
0.13
0.09
0.19a

Female
0.00
0.09
0.07
0.43
0.09a

Both sexes
0.04
0.05
0.10
0.26
0.14a

aEstimated from the data in each reference.
b36–44 years.
c75–84 years.
d0–44 years.
e30–44 years.
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