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(Stroke. 1995;26:380-385.)
© 1995 American Heart Association, Inc.

Articles

Silent Cerebral Infarction in a Community-Based Autopsy Series in Japan

The Hisayama Study

Atsushi Shinkawa, MD; Kazuo Ueda, MD; Yutaka Kiyohara, MD; Isao Kato, MD; Katsuo Sueishi, MD; Masazumi Tsuneyoshi, MD Masatoshi Fujishima, MD

From the Second Department of Internal Medicine (A.S., K.U., Y.K., I.K., M.F.) and the First (K.S.) and Second (M.T.) Departments of Pathology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

Correspondence to Atsushi Shinkawa, MD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812 Japan.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose The purpose of this study was to assess the prevalence and characteristics of silent cerebral infarction in a population-based consecutive autopsy series of residents of Hisayama, Kyushu, Japan.

Methods Autopsy records, cerebral pathological findings, and clinical charts of 966 Hisayama residents recorded during the 26 years from 1961 to 1987 were examined (autopsy rate, 82.4%). The subjects were divided into three groups: those with both clinically apparent strokes and pathologically verified cerebral infarcts (stroke group), those having pathological evidence of cerebral infarction in the brain but without clinical stroke episodes (silent infarction group), and those with neither infarction nor stroke episode (noninfarction group). Risk factors and brain pathology in the three groups were compared.

Results Silent cerebral infarction was found in 12.9% of the 966 subjects who had undergone autopsy, and its frequency increased with age. The subjects with silent infarcts were older, had higher systolic or diastolic blood pressure, and had atrial fibrillation more frequently than subjects in the noninfarction group. There were no significant differences in the locations of infarcts between the stroke and silent infarction groups, although infarcts tended to be located in the deeper area of the brain in the latter. The number and size of infarcts were smaller in the silent infarction group than in the stroke group.

Conclusions Diastolic blood pressure and atrial fibrillation appear to be strong predictors of silent cerebral infarction in the Japanese general population. Stroke becomes clinically apparent as infarct volume increases.

Key Words: autopsy • cerebral infarction • Japan • risk factors

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Evidence of prior silent cerebral infarction is commonly found by computed tomography (CT) and magnetic resonance imaging (MRI) in hospitalized stroke patients. On the other hand, it is unclear how many people have silent cerebral infarction while appearing to be healthy or at least without cerebrovascular symptoms. Very few studies have addressed this issue in terms of the frequency and characteristics of silent cerebrovascular lesions in the general population. Although several studies have reported the prevalence of silent stroke, most only describe the frequency of prior asymptomatic or unreported cerebral infarction on CT among patients with stroke.^{1 2 3 4} Other studies have reported the prevalence of silent stroke in patients with risk factors for stroke: ie, atrial fibrillation,^{5 6 7} extracranial carotid disease,^{8 9 10 11 12} transient ischemic attacks,^{13 14} or cigarette smoking.¹⁴ One autopsy study focused on silent lacunar infarction,¹⁵ but it scarcely examined relatively larger cerebral infarcts. Thus, the prevalence of silent cerebral infarction in the general population remains unknown, especially among subjects without cerebrovascular symptoms.

The purpose of this study was to investigate the prevalence, characteristics, and factors related to silent cerebral infarction in the general population using data from a population-based autopsy study conducted in a Japanese suburban community, Hisayama.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hisayama is a suburban area adjacent to Fukuoka City on Kyushu Island in southern Japan. The population of Hisayama is about 7000 and has scarcely changed during the past 30 years; sex and age distributions have been similar to those for all of Japan at each national census. A prospective population-based study has been conducted in the town since 1961 to elucidate the incidence of cerebrovascular disease in the general population and to explore risk factors for stroke.¹⁶ In November 1961, 1621 men and women aged 40 years or older were recruited from Hisayama as the inception cohort (about 90% of all residents in this age group). Patients with stroke diagnosed before the entry examination were excluded from the cohort. Information about new cerebrovascular disease has been collected through weekly visits to physicians' clinics in Hisayama or by telephone if a patient relocated to another town. Whenever new neurological symptoms occurred, the patient was carefully evaluated by the study physician as soon as possible, either at home or at the hospital. At 13 and 22 years after the start of the study, new population cohorts were selected from Hisayama residents aged 40 years or over, who underwent cross-sectional examinations before inclusion in the study. The ancillary diagnostic methods of detecting stroke have changed greatly during the long-term follow-up. In brief, the use of CT scanning has gradually increased since 1976, and now almost all stroke patients undergo this procedure. However, few patients in Hisayama have had MRI or carotid Doppler scanning, because these instruments are not yet available in the hospitals near the town. Cerebral angiography has only been performed in stroke patients who were admitted to University Hospital in Fukuoka, less than 10% of all stroke patients. Autopsies were performed for most of the residents who died, and the causes of death were ascertained. The autopsy rate was 82.4% through the whole follow-up period. Details of the methods of examination and follow-up have been described elsewhere.^{16 17 18 19}

From November 1, 1961, to December 31, 1987, 1069 subjects underwent autopsy at the Department of Pathology of Kyushu University. We reviewed the autopsy records and hospital charts of these patients, including the medical history, laboratory data, and other test results. One hundred and three patients with hemorrhagic stroke as the initial stroke episode were excluded from the present study to simplify analysis. The remaining 966 subjects were divided into three groups according to clinical history and pathological findings: (1) a stroke group with both a clinical history of stroke and pathological evidence of cerebral infarction; (2) a silent infarction group with cerebral infarction on pathological examination but no clinical history, symptoms, or signs of stroke; and (3) a noninfarction group with neither clinical episodes of stroke nor pathological evidence of cerebral infarction.

We did not distinguish cerebral embolism from cerebral thrombosis within the category of cerebral infarction, because this difference was sometimes difficult to establish even upon pathological examination.

Infarcts were classified as being in the following areas according to anatomy and blood supply²⁰ : (1) cerebral cortex and subcortical white matter of the anterior cerebral artery territory (ACA), (2) middle cerebral artery and anterior choroidal artery territory, except for the basal ganglia and internal capsule (MCA), (3) posterior cerebral artery territory (PCA), (4) basal ganglia and internal capsule (BGL), (5) thalamus (TLM), (6) pons, and (7) cerebellum. Watershed infarcts between the middle and anterior or posterior cerebral arteries were considered as being in the MCA because the blood supply to such infarcts is often difficult to determine.

At the usual pathological examination, brains were cut into 1- to 3-cm slices. We could not actually measure the infarct size in all cases because autopsy materials were not available. We referred to the photographs of the brain slices in the autopsy documents and divided the infarcts into four size categories: small, medium, large, and massive. The approximate diameter of infarcts in each category was <1 cm, 1 to 3 cm, 3 to 5 cm, and >5 cm, respectively. We examined the laterality of the infarcts (right or left) only in the supratentorial area (ACA, MCA, PCA, BGL, and TLM), and additionally divided the lesions into "superficial" (involvement of the cerebral cortex) and "deep" (involvement of white matter).

Seven hundred fifty-four subjects (78.1%) among the 966 who had undergone autopsy were members of the prospective follow-up cohort of the Hisayama study. For the purpose of studying risk factors for silent or overt cerebral infarction in this population, we obtained data, including blood pressure, serum cholesterol concentration, electrocardiographic (ECG) findings, and glucose tolerance (normal or not), for these subjects as early in the study as possible. It was hoped that such data on risk factors could thus be recorded before the formation of silent cerebral infarction. ECG abnormalities included Q-wave myocardial infarction (Minnesota code 1-1,2), left ventricular hypertrophy (Minnesota code 3-1), and ST depression (Minnesota code 4-1,2,3). We assessed the cumulative frequency of atrial fibrillation separately from the sequential follow-up data in each group because paroxysmal atrial fibrillation, in addition to persistent atrial fibrillation, could be determined by this procedure. In 1961, the oral glucose tolerance test was only performed for subjects with glycosuria, using a solution containing 100 g glucose or an equivalent test meal. The criteria for glucose intolerance were as follows: (1) a 1-hour capillary blood glucose level exceeding 200 mg/dL and a 2-hour level of more than 150 mg/dL after oral administration of 100 g glucose, or (2) both 2- and 3-hour blood glucose values greater than 140 mg/dL after the test meal. In the cross-sectional examination in 1973 to 1974, only plasma glucose concentration was measured and all subjects were tested. Glucose intolerance was defined as a fasting plasma glucose greater than 140 mg/dL, a previous diagnosis of diabetes mellitus, or current treatment with insulin or an oral hypoglycemic agent.

During the 26-year study period, treatment for hypertension increased among Hisayama residents. Subjects taking antihypertensive drugs comprised less than 5% of the population at the cross-sectional examination in 1961, but that proportion increased to more than 50% in 1988. In response to treatment, the prevalence of hypertension decreased from 27.2% to 14.4% for men and from 25.0% to 14.2% for women during the period from 1961 to 1988. Because the question of whether antihypertensive agents or anticoagulants should be used as primary prevention had not been settled in the mid-1980s in Hisayama, there were very few patients with atrial fibrillation who took these medicines. Thus, we had no definite information on the effects of these treatments in the study population.

Differences in mean values between the groups were assessed by ANOVA and Bonferroni's t test for multiple comparisons. Differences in frequencies for ordinal variables were tested by the simple ² test and confirmed by the Mann-Whitney U test and the Kruskal-Wallis test. In addition, we used stepwise multiple logistic regression analysis to identify significant factors discriminating the silent infarction group from the stroke group and the noninfarction group. All calculations were performed on a FACOM M780/20 mainframe computer at the Kyushu University Computer Center using SAS software.^{21 22 23}

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Characteristics of the Subjects With Silent Infarcts
Among the 966 subjects who underwent autopsy, 125 (12.9%) had pathological evidence of cerebral infarction, although they never experienced clinical stroke. Two hundred fifty-eight (26.2%) had clinical stroke, and compatible infarcts in their brains were verified at autopsy. The remaining 588 patients (60.9%) had neither clinical stroke nor cerebral infarcts at autopsy. The silent infarction group comprised 63 men and 62 women whose ages ranged from 42 to 97 years at death (mean±SD, 78.3±9.5 years). Mean age at death in the silent infarction group was significantly greater than that in the noninfarction group (67.1±17.9 years), but the difference was not significant compared with that in the stroke group (76.9±9.6 years). The percentage of subjects with silent infarcts increased with advancing age, from 4.4% of those aged 40 to 49 years to 19.3% of those more than 80 years old (Table 1). The proportion of subjects belonging in the stroke group also increased with age, from 6.5% in those aged 40 to 49 years to 32.8% for those more than 80 years old. The causes of death in the three groups differed. Most of the vascular deaths in the silent infarction and noninfarction groups were cardiac. More than half of the stroke group died of cerebrovascular causes, and cardiac deaths were less frequent in this group compared with the other two.

View this table: [in this window] [in a new window]   Table 1. Basic Characteristics of the Study Subjects by Group

The traditional risk factors for stroke in the three groups at entry and during follow-up were compared using data obtained from the 754 participants (103 in the silent infarction group, 211 in the stroke group, and 440 in the noninfarction group) on cross-sectional examinations. The mean age at death in both the silent infarction and stroke groups (79.4±7.9 and 78.0±9.0 years, respectively) was similar to that of the original subjects, but the noninfarction group was skewed to a higher age (72.5±11.9 years) because subjects less than 40 years old were eliminated from the original autopsy population. All parameters examined for the silent infarction group (including mean values of systolic and diastolic blood pressure, mean serum cholesterol concentration, frequency of ECG abnormalities [Q-wave myocardial infarction, left ventricular hypertrophy, and ST depression], atrial fibrillation, and glucose intolerance) were midway between those of the other two groups, being higher than those for the noninfarction group and lower than those for the stroke group, with or without significant differences (Figure). Differences between the silent infarction group and the noninfarction group were significant for the mean values of systolic and diastolic blood pressure (systolic, 154 mm Hg in the silent infarction group versus 138 mm Hg in the noninfarction group, P<.01; diastolic, 84 versus 78 mm Hg, respectively, P<.01) and the frequency of atrial fibrillation (10.7% versus 3.9%, respectively, P<.05). In addition, the silent infarction group and the stroke group showed significant differences in the mean diastolic blood pressure (84 versus 89 mm Hg, respectively, P<.01) and in the frequency of ECG abnormalities (22.3% versus 35.1%, respectively, P<.05).

View larger version (33K): [in this window] [in a new window]   Figure 1. Bar graph showing prevalence of traditional risk factors for stroke in three groups (noninfarction, silent infarction, and stroke). Electrocardiogram abnormality was defined as Q-wave myocardial infarction (Minnesota code 1-1,2), left ventricular hypertrophy (Minnesota code 3-1), or ST depression (Minnesota code 4-1,2,3).

Characteristics of Infarcts in the Silent Infarction Group
On autopsy, 280 infarcts were detected in 125 brains from the silent infarction group, with an average of 2.2 infarcts per subject. Seventy percent or more of the silent infarction group had 2 infarcts or less. However, 120 subjects (47%) in the stroke group had 3 or more infarcts, with an average of 2.9 infarcts per case. The silent infarction group thus had significantly fewer lesions than the stroke group on average (P<.01). Eighty-six percent of the infarcts in the silent infarction group were small, and there were no massive lesions. At most, 52% of the infarcts in the stroke group were small, and massive infarcts were found in 4% of the infarcts in this group. Infarcts in the silent infarction group were thus significantly smaller than those in the stroke group (P<.01, ² test). Infarct location, however, was similar in the silent infarction and stroke groups. More than 40% of the infarcts were in the BGL and 20% were in the MCA in both the silent infarction group and the stroke group.

A difference in laterality of infarcts was seen only in the ACA area; subjects in the silent infarction group had fewer infarcts on the right side compared with those in the stroke group (20% versus 58%, P<.05). In addition, some differences in the distribution of infarcts were seen in the MCA territory, in which infarcts in subjects in the silent infarction group were more deeply situated than those in subjects in the stroke group (60% versus 40%, P<.05).

Factors Distinguishing the Three Groups
To identify factors related to silent infarction, we performed three stepwise multiple logistic regression analyses using data obtained at the entry examination in 1961 or in 1973 through 1974. The first analysis was of the silent infarction group compared with the stroke group (Table 2). The dependent variable was a history of stroke (silent infarction group=0, stroke group=1). For predictive variables, we chose the age at death, sex (female=0, male=1), diastolic blood pressure, serum cholesterol concentration, ECG abnormality (present=1, absent=0), atrial fibrillation (present=1, absent=0), glucose intolerance (present=1, absent=0), the number of infarcts, and the size of the largest lesion. A higher diastolic blood pressure, greater number of infarcts, and larger size of the most extensive lesion were independently related to an increased risk of symptomatic stroke (Table 2). A second analysis excluding size and number of lesions from the potential predictive variables indicated that a higher diastolic blood pressure was independently related to an increased risk of symptomatic infarction (P<.01, odds ratio=1.25, for each 10-mm Hg increment). A third analysis was performed to compare the noninfarction group and the silent infarction group. The dependent variable was presence of infarcts (absent=0, present=1) and the predictive variables were the same as in the first analysis, except that the number and size of infarcts were excluded. Increasing age, a higher diastolic blood pressure, and atrial fibrillation were independent risk factors for silent cerebral infarction (Table 3).

View this table: [in this window] [in a new window]   Table 2. Factors Separating the Silent Infarction Group From the Stroke Group on Stepwise Multiple Logistic Regression Analysis

View this table: [in this window] [in a new window]   Table 3. Factors Separating the Noninfarction Group From the Silent Infarction Group on Multiple Logistic Regression Analysis

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study revealed that about 13% of the subjects in a consecutive autopsy series from Hisayama had cerebral infarcts without clinical stroke during their lives. In the Framingham study, the prevalence of silent cerebral infarction was 10.5% in subjects who were investigated for acute stroke symptoms.¹ There are also a few studies on the prevalence of silent cerebral infarction in the whole population of stroke patients. The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) Stroke Data Bank reported that silent cerebral infarction was observed in 11% of stroke patients.² An MRI study on silent infarction was performed in 246 normal Japanese adults, 13% of whom had silent lacunar lesions.²⁴ Recently, in SEPIVAC, a community-based survey of the incidence and outcome of cerebrovascular diseases in the Sixth Local Health Unit of Umbria in central Italy, up to 38% of 209 patients with an initial ischemic stroke had unrelated ischemic lesions documented upon CT examination within 30 days after the episode.³ The Dutch TIA Trial, a secondary prevention trial with vascular death, stroke, and myocardial infarction as the main outcome events, included patients with transient ischemic attack (TIA) or minor stroke without disability. Silent stroke was observed in 13% of the 2329 patients in this study.¹⁴ Although these prevalence figures are similar to ours, it may be inappropriate to directly compare these data with our results, because in other studies the prevalence of silent cerebral infarction was based on subjects who had experienced clinical stroke or on normal volunteers. The sex and age distributions and the other demographic factors of subjects in other studies might therefore be quite different from those of the general population. The present study may be the first report on the prevalence of silent cerebral infarction based on an unselected autopsy series drawn from the general population. Dismissal of fleeting and minor symptoms by either the patient or the physician might help explain the apparent absence of symptoms in some of our subjects. In this sense, the present study may have limitations regarding the precise detection of clinical symptoms. There also remains a possibility that very small, millimeter-sized silent infarcts were buried in the thickness of the brain slices and not observed despite the pathologist's efforts. If so, the prevalence of silent cerebral infarction might be somewhat underestimated by our data.

It is interesting that our subjects with silent infarction had higher levels of certain risk factors compared with those without stroke but lower levels than those with a history of clinical stroke. This suggests that individuals with silent infarcts may be ranked as a moderate risk group. The mean diastolic blood pressure of the silent infarction group was significantly higher than that of the noninfarction group and significantly lower than that of the stroke group. In addition, both of our multiple logistic regression analyses indicated that diastolic blood pressure was an independent risk factor for both formation of silent infarction and the appearance of stroke. Diastolic blood pressure thus seems to be the key factor distinguishing our three groups of subjects. Hypertension^{3 13 14 15 24} and ECG abnormalities³ have been reported as factors contributing to the occurrence of silent cerebral infarction. We reported that the incidence of intracerebral hemorrhage,¹⁷ as well as that of lacunar infarction, has recently decreased in the Hisayama population,²⁵ and this is possibly related to the decreased prevalence of hypertension. The question then arises as to whether silent infarction decreases with symptomatic infarction or, on the contrary, increases because of a shift of symptomatic infarcts to silent infarcts in a population under treatment for hypertension. In the present study, we could not analyze a direct effect of hypertension management on the frequency of silent infarction because of incomplete information on blood pressure control in each individual. Silent cerebral infarction has previously been studied in relation to atrial fibrillation,^{5 6 7} and it was found more frequently in the patients with atrial fibrillation than in control subjects without atrial fibrillation. We also found that the cumulative frequency of atrial fibrillation was higher in the subjects with silent cerebral infarction than in those without infarction. As already mentioned, we have no data on the use of antiplatelet agents or anticoagulants in patients with atrial fibrillation, and therefore the question of whether antiplatelet or anticoagulant therapy could prevent silent cerebral infarction should be solved by further studies. Some reports on Caucasians have indicated that silent cerebral infarction is closely related to TIA or carotid stenosis.^{11 14} We did not examine whether TIA is a risk factor for silent cerebral infarction because of the relatively small number of TIA patients in Hisayama.²⁶ However, in the Hisayama population, we found that severe carotid lesions were less frequent in TIA patients, and that their transient cerebral signs could be related to lacunes in the basal ganglia.²⁶ Therefore, we consider that hypertension may induce lesions of the perforating arteries rather than carotid atherosclerosis in patients with silent infarction. In an autopsy review of nearly 3000 patients, 81% of lacunes were asymptomatic; their etiology was varied and included hemodynamic and embolic causes.¹⁵ However, we could not obtain any direct evidence that silent infarcts were caused by microemboli from the heart or by carotid atherosclerosis.

Another point of interest is that the clinical symptoms of cerebral infarction were related to the size and number of the pathologically demonstrated infarcts. The more lesions present, the greater the risk of clinical stroke. Although the silent infarcts were relatively small, accumulation of small infarcts increases the total volume of involved brain and consequently may cause symptoms to appear.

Silent infarction that occurred before or after symptomatic infarct would be hidden clinically but visible at autopsy. It is very difficult to determine which lesion was responsible for a patient's symptoms if infarcts clustered in the same functional area. The coexistence of silent infarcts with symptomatic ones would also make the difference in the location of infarcts between the silent infarction and stroke groups less distinct. There was in fact no difference in the location of infarcts between the two groups in the present study. Apart from the small size of these infarcts, there may be other reasons for their silent nature.

The frequency of silent infarcts increased with advancing age. Silent infarction is reported to be more related to impaired cognition²⁷ and depression²⁸ than to impairments in activities of daily living.¹⁴ Because the elderly population is gradually increasing in developed countries, silent cerebral infarction may become an important social problem, especially if it is proven to lead to vascular dementia. Future MRI-based prospective follow-up studies will answer questions about the role of silent infarction as a risk factor for symptomatic cerebral infarction and vascular dementia.

	Acknowledgments

 
This study was partially supported by research grants for cardiovascular disease from the Ministry of Health and Welfare and from the Ministry of Education (No. 04670539), Japan. It was facilitated by the Japan-US cooperative agreement in the cardiovascular area; by the Japanese National Cardiovascular Center, Osaka; and the National Heart, Lung, and Blood Institute, Bethesda, Md. The authors are grateful to Yutaka Hasuo, MD; Junichi Wada, MD; Takao Omura, MD; Hiromitu Iwamoto, MD; and Keizo Nakayama, MD, all active members devoted to the Hisayama study. They also greatly appreciate the assistance of Emeritus Professor Shibanosuke Katsuki, MD; Teruo Omae, MD, President of the National Cardiovascular Disease Center, Osaka; Yasuo Hirota, MD, Professor of Kyushu Dental College; Moriyuki Takeshita, MD, Director of the Health Center, Kyushu Rosai Hospital; and Emeritus Professors Kenzo Tanaka, MD, and Munetomo Enjoji, MD, Department of Pathology, Kyushu University, Fukuoka, Japan.

Received August 16, 1994; revision received December 12, 1994; accepted December 21, 1994.

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