(Stroke. 1997;28:1932-1939.)
© 1997 American Heart Association, Inc.
Articles |
Subcortical Silent Brain Infarction as a Risk Factor for Clinical Stroke
From the Department of Internal Medicine III, Shimane (Japan) Medical University.
Correspondence to Shotai Kobayashi, Department of Internal Medicine III, Shimane Medical University, Izumo, Shimane, 693, Japan. E-mail skdr3nai{at}shimane-med.ac.jp
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Abstract |
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Background and Purpose No prospective studies have examined the rate of symptomatic ischemic or hemorrhagic stroke in patients with subcortical silent brain infarction (SSBI) who were otherwise neurologically normal at entry into the study. This report investigates SSBI, detected by MRI, as a clinical stroke risk factor.
Methods MRI scans were performed in 933 neurologically normal adults (30 to 81 years; mean age, 57.5±9.2 years) without history of cerebrovascular diseases who received our health screening of the brain 1 to 7 years before investigation. We obtained information of their clinical stroke onset through sending out a questionnaire for subjects. We detected SSBI (focal T2 hyperintensities larger than 3 mm with correlative T1 hypointensity), FWT2HL (focal white matter T2 hyperintensity lesions similar to SSBI but without correlative T2-hypointensity), and PVH (periventricular hyperintensity) by MRI. Age, sex, family history of stroke, history of hypertension, diabetes mellitus, lipids, hematocrit, blood pressure, fasting blood sugar, smoking, alcohol habits, ischemic changes on electrocardiogram, and sclerotic changes of retinal arteries were included in the analysis.
Results Incidence of SSBI was 10.6% in all subjects. No
cortical infarct was detected in this series. Multiple logistic
regression analysis showed that hypertension (odds ratio
[OR], 4.07; 95% CI, 2.57 to 6.45), diabetes (OR, 2.41; 95% CI, 1.20
to 4.85), alcohol habits 
58 g/day (OR, 2.58; 95% CI, 1.50 to 4.45),
retinal artery sclerosis (OR, 2.14; 95% CI, 1.32 to 2.38), and age
(OR, 1.77; 95% CI, 1.32 to 2.38) were significant and independent risk
factors for SSBI. For FWT2HL, hypertension (OR, 4.49; 95% CI, 2.54 to
7.96) and age (OR, 2.08; 95% CI, 1.45 to 3.00) were also independent
risk factors. Risk factors for PVH were age (OR, 3.46; 95% CI, 2.23 to
5.36), hypertension (OR, 3.06; 95% CI, 1.62 to 5.78), and retinal
artery sclerosis (OR, 2.25; 95% CI, 1.02 to 4.96). We found 14 brain
infarctions, 4 brain hemorrhages, and 1 subarachnoid
hemorrhage during observation. Annual incidence of clinical
stroke was higher in the subjects with SSBI than in those without focal
lesions (10.1% versus 0.77%). ORs for clinical stroke onset were
10.48 for SSBI (95% CI, 3.63 to 30.21) and 4.81 for FWT2HL (95% CI,
1.13 to 20.58). The PVH did not relate to clinical stroke onset.
Conclusions The strong association of SSBI, FWT2HL, and PVH with hypertension suggests a common underlying mechanism (presumably small-vessel vasculopathy). The SSBI showed the most significant association for clinical subcortical stroke. The FWT2HL was also a risk factor for the stroke but was less significant than SSBI. The subjects with SSBI should be considered at high risk for clinical subcortical brain infarction or brain hemorrhage.
Key Words: magnetic resonance imaging • cerebral infarction • cerebral hemorrhage • risk factors
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Introduction |
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The silent brain lesions detected by CT or MRI were fairly common not only in first-ever stroke but also in normal elderly subjects.1 2 3 4 5 6 7 Lechner et al8 has demonstrated that a significantly higher incidence of white matter lesions exist in neurologically normal people with multiple risk factors for stroke than in those without. They also emphasized that there was significant superiority of MRI over CT for detection of white matter lesions.However, classification of the silent lesions detected by MRI was different among the authors, and clinical significance of these has also remained unclear. Tuszynski et al9 demonstrated that as many as 81% of the patients with pathologically verified lacunes were asymptomatic. The Hisayama community-based study showed that the incidence of silent infarction (86% of them were small) was 12.9%.10 Most of the silent infarctions observed in acute stroke patients were small and deep.2 11 Okada et al12 have reported that 89% of patients with initial hypertensive brain hemorrhage had silent lacunes indicated on MRI. These results suggest that possible lacunar lesions within the silent brain lesions on MRI may be a risk factor for clinical stroke. However, there has been no reported prospective study of the incidence of clinical stroke in a sufficient number of neurologically normal subjects with silent brain lesions detected by MRI. In 1988 at the Shimane Institute of Health Science we began health screening of the brain, using MRI, for people who desire to maintain their brain health. We have already reported3 that the incidence of SSBI was 13% in neurologically normal adults without history of CVD and that the most important risk factor was hypertension. In this article, we report the incidence of clinical stroke onset in subjects with silent brain lesions compared with control subjects without brain lesions but in the same state of health otherwise.
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Subjects and Methods |
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Subjects were 933 neurologically normal adults without history of CVD aged 30 to 81 years (mean age, 57.5±9.2 years). There were 536 men (mean age, 57.3±10 years) and 397 women (57.6±8.1 years). The subjects wished to receive health screening of the brain at their own expense. Eighty percent of them were supported by mutual aid associations, such as of public school teachers. This was not a population-based study; therefore, the follow-up period was varied: 217 subjects were followed up for 1 to 2 years, 160 for 2 to 3 years, 164 for 3 to 4 years, 142 for 5 to 6 years, and 250 for more than 6 years. We obtained information about their clinical stroke onset through sending out a questionnaire for subjects who received our health screening of the brain 1 to 7 years before this investigation. We continued this investigation from 1992. This report was based on the results of a 1992 to 1995 survey. We sent questionnaires to 1003 subjects in 1995, and confirmed health information from 93% of these subjects. We confirmed details for subjects with clinical stroke onset by telephone interview or direct examination with CT/MRI as soon as we could.
MRI was performed by using 0.15-T MRI (MT-15, Toshiba Co) (1988 to 1992) and 0.2-T MRI (Magnetom P-8, Siemens Co) (1992 to 1995). We used moderate T2WI (TR, 2000 ms; TE, 50 ms) at the transverse plane parallel to the orbitomeatal line and T1-weighted image (T1WI) (inversion recovery, TR of 2000 ms/TE of 40 ms; inversion time, 400 ms) at coronal slices with 1-cm intervals in the former period. We used T2WI (TR, 2000 ms; TE, 24 ms) and proton density–weighted (TR, 5000 ms; TE, 96 ms) at the transverse plane, and T1WI (TR, 350 ms; TE, 15 ms; flip angle 82°) at coronal slices (7 mm thick) in the latter period. In this series, we could not detect cortical infarction or brain stem or cerebellar infarction. Therefore, all silent brain infarctions were SSBI. We classified silent brain hyperintense lesions on T2WI according to the following: (1) SSBI, (2) FWT2HL, and (3) PVH. We considered a focal and sharply demarcated high intensity on T2WI larger than 3 mm to be SSBI that coincided with low density area of the T1WI. We called small demarcated hyperintensities in basal ganglia and white matter possible lacunes if they measured 3 to 15 mm and had correlative T1 hypointensity. The term "lacune" as we use it is not intended to infer the vascular pathoanatomy (lipohyalinosis versus arteriosclerosis). Most of the SSBIs were less than 10 mm in size, and no SSBI larger than 15 mm was observed in this series. The FWT2HL were defined as focal T2 hyperintensities similar to SSBI but without correlative T1 hypointensity. In addition, we defined the FWT2HL as a T2 hyperintensity lesion with correlative high intensity on proton density image in the latter period, We considered very small punctate (1 to 2 mm) hyperintensities detected in only T2WI to be perivascular enlargements according to histopathological study13 and excluded them from statistical analysis. The PVH was classified as grade 0 to 4 as follows: grade 0, almost no or unclear PVH; grade 1, a thin but apparent PVH restricted at the frontal horn; grade 2, smooth PVH surrounding the entire lateral ventricle or horns; grade 3, thick and irregular PVH surrounding the lateral ventricle and horns; and grade 4, marked diffuse PVH. Nonfocal vague T2 hyperintense lesions apart from periventricular were not included in the analysis.
The magnetic field strength of the MRI that was used in the former period was low and had lower spacial resolution than that used in the latter period. Therefore, most of the perivascular enlargements were likely to be undetected. The MRI in the latter period was also of low magnetic field strength, but it had enough spatial resolution to detect the perivascular enlargements 1 to 2 mm in diameter. We confirmed these findings by comparing them with scans made with 1.5-T MRI. Evaluation of the lesions on MRI was made by the same two authors independently in a blinded fashion. The interobserver agreement was high (94%). We discussed the diagnosis and made a group decision when there was disagreement. Blood pressure was measured by the standard sphygmomanometric method at supine position after 15 minutes of rest. Hematocrit, serum lipids (total cholesterol, triglyceride level, and HDL-C), fasting blood sugar, and ECG were measured on the same day. Sclerotic changes of retinal arteries were also examined with an ophthalmoscopic camera, and we defined retinal artery sclerosis as positive if judged to be Keith-Wegener's grade 1 or more. We defined a history of hypertension and diabetes that was diagnosed by physician with or without treatment according to the subject's information. One-time hypertension was not included the history. We obtained information of a family history of CVD from personal interview by a neurologist. We defined a smoker as any subject whose smoking index (number of cigarettes/day x number of years) was more than 200, and alcohol habits were graded as none or occasional drinker, 28 to 57 g of alcohol/d, 58 to 85 g/d, and 86 g/d or more. Informed consent for this study was obtained from all subjects according to our institutional guidelines.
Statistical Analysis
Group differences among subjects, characteristics, and risk
factors were tested for statistical significance using ANOVA and
contingency table analysis.
Group differences in risk factors between the subjects with clinical stroke onset and those without were tested using the Mann-Whitney U test. Survival free of clinical stroke was determined by Kaplan-Meier lifetable analysis beginning at the time of the first examination of MRI for the observation period.
Annual incidence of clinical stroke onset was calculated by the
following formula: % ratio=case number/
(observation days of each
subject/365.25)x100. Stepwise multiple logistic regression
analysis was performed for determination of multifactorial
significance. Data were presented as mean±SD. These
analyses were performed using the SPSS software package on a
Macintosh.
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Results |
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Background of the 933 Subjects
Distribution of age was as follows: number of the subjects under 40 years was 45, 40 to 49 was 81, 50 to 59 was 406, 60 to 69 was 325, and over 70 years was 76. A history of hypertension was observed in 28.8%, a history of diabetes in 7.1%, and a family history of CVD in 54.3%. Hypercholesterolemia (
220
mg/dL) was observed in 31.6%,
hypertriglyceridemia (180 mg/dL)
in 10.1%, low level of HDL-C (<35 mg/dL) in 6.7%, and
hyperglycemia (fasting blood sugar 110 mg/dL) in 17.2%. A
history of smoking was observed in 23.7% (38% in men and 3.3% in
women) and habitual alcohol drinker was 40.7% for 28 to 57 g of
alcohol/d, 12.3% for 58 to 85 g/d, and 2.1% for 86
g/d or more. Ischemic changes in ECG were observed in
12.4% and atrial fibrillation in 0.6%. Sclerotic changes of retinal
arteries were observed in 27%. Two subjects with SSBI and 8 without
SBI died during the observation period. The causes of death were cancer
for 4 subjects, heart failure for 1, respiratory failure for 3, traffic
accident for 1, and unknown for 1. There were no subjects who died of
clinical stroke.
Incidence of Silent Brain Lesions
SSBI was detected in 99 of 933 subjects, an incidence of 10.6%.
This incidence was significantly increased with advancing age. The
FWT2HL were observed in 56 subjects (6%) and also increased with age.
The incidence of grades 2 and 3 of PVH was 14.8% and 5.1%,
respectively, and was also increased with age. There was no subject who
had grade 4 PVH. Incidence of grade 3 PVH was higher in SSBI: 28%
compared with 9% in FWT2HL and 2% in the nonfocal lesion group
(P=.0001).
Risk Factors for Silent Brain Lesions
To investigate significant items for logistic regression
analysis, we performed contingency table analysis for
risk factors between the subgroups with focal silent brain lesions and
those without (Table 1
). Hypertension was
observed to be twofold higher in SSBI and FWT2HL groups than in those
without. The prevalence of diabetes was significantly higher in the
SSBI group than in those without. Men showed significantly higher
incidence of SSBI than women. A habit of alcohol drinking of more than
58 g/d was observed to be significantly higher in the SSBI group
than in those without. A smoking habit was significantly higher in the
SSBI and FWT2HL groups than those without in all the subjects. We
reexamined these results, because 94% of the smokers were men. Smoking
habits in men with SSBI and FWT2HL were observed in 44.9% and 50%,
respectively, versus 36.7% in men without. There was no significant
difference among them. Retinal artery sclerosis was more often observed
in the SSBI group. Ischemic changes on ECG were more frequent
in the SSBI and FWT2HL groups than in those without. Systolic
and diastolic blood pressures were significantly higher in
the SSBI and FWT2HL groups than in those without. Incidence of
hyperglycemia was significantly higher in the former than in the
latter. There was no significant differences in
hypercholesterolemia,
hypertriglyceridemia, low level of HDL-C,
and hyperhematocrit among the groups. Other risk factors were not
significant.
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For PVH grade 3, hypertension and retinal sclerotic change were significant risk factors (11.2% in those with hypertension and 2.7% in those without, P=.0001, and 18.0% in those with retinal artery sclerosis and 4.2% in those without, P=.0001). PVH grade 3 was observed more often in the subjects with ischemic change in ECG than in those without (10.3% versus 4.4%, P=.0145).
Multiple logistic regression analysis for the subtypes of
silent brain lesions including significant items mentioned above
revealed that hypertension, diabetes, alcohol habits, retinal artery
sclerosis, and age were significant and independent risk factors for
SSBI (Table 2).
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For FWT2HL, hypertension and age were the only significant and
independent risk factors. These odds ratios mean that there is a
strength of independent effect of the risk factor after adjusting for
the effect of other factors (Table 3).
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Contingency table analysis for PVH showed that hypertension was
significantly more frequent in PVH grade 3 than in PVH grades 0 to 2.
Ischemic changes on ECG and retinal artery sclerosis were also
significantly increased with PVH grade (Table 4).
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Distribution of blood pressure according to PVH grade was as follows: systolic blood pressure of 140 to 159 mm Hg (n=139) was observed in 13.5% of PVH grades 0 to 1, 19.3% of PVH grade 2, and 22.9% of PVH grade 3 group. systolic blood pressures >160 mm Hg (n=66) were seen in 4.3% of grade 0 to 1, 16.4% of grade 2, and 22.9% of grade 3 (P=.0001) and diastolic blood pressures of 81 to 94 mm Hg (n=221) in 22.9% of grade 0 to 1, 25.7% of grade 2, and 29.2% of grade 3; diastolic blood pressures >95 mm Hg (n=44) in 3.4% of grade 0 to 1, 7.9% of grade 2, and 16.7% of grade 3 (P=.0001).
Logistic regression analysis for PVH grade 3 including selected items mentioned above showed that hypertension, age, and sclerotic change of retinal arteries were significant and independent risk factors for PVH. Odds ratios (ORs) for PVH grade 3 was 3.06 for hypertension, 3.46 for age, and 2.25 for retinal artery sclerosis.
Incidence of Clinical Stroke Onset
Incidence of clinical stroke onset during the observation was
significantly higher in the SSBI group (10 of 99; 10.1%) and the
FWT2HL group (3 of 56, 5.4%) than that in the nonfocal lesion group (6
of 779; 0.77%) (P=.0001). Annual incidence of clinical
stroke was 2.79% in the SSBI group, 1.50% in the FWT2HL group, and
0.21% in those without either focal lesion (0.55% in totals).
In these patients with clinical stroke onset, there were 14 brain
infarction, 4 brain hemorrhages, and 1 SAH. The earliest onset
of clinical stroke occurred 2.5 months and latest 7.3 years after the
brain examination. Details of these cases are shown in Table 5.
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We could confirm MRI or CT findings after clinical stroke onset in 15
of 19 cases. Details are shown in Table 4
. Lacunar infarctions in basal
ganglia and deep white matter were commonly observed in the patients
with brain infarction, but 1 patient had a 2.5-cm–sized corona radiata
lesion associated with ipsilateral internal carotid artery occlusion.
In the cases of brain hemorrhage, 3 patients showed
hypertensive putaminal hemorrhage and 1 showed
temporo-occipital lobar hemorrhage. The case of lobar
hemorrhage was clinically suspected to be associated with
amyloid angiopathy. The subject showed a low level of cystatin C in
cerebrospinal fluid, which indicated amyloid angiopathy with deposition
of cystatin C as we reported before.14 In these 15
subjects, as confirmed by CT or MRI, SSBI increased in 1 subject and
confluent lesions increased in 2. All 3 of these subjects had SSBI and
hypertension, and 2 of them also had diabetes. The rate of diabetes
complication was significantly higher in these 3 subjects than in
another 12 subjects (P=.037). Intervals from examination to
stroke were 1044±731 days in the former period and 1356±579 days in
the latter (NS). Clinical diagnosis of another 4 subjects without
imaging data was confirmed by information from the physicians who
treated these patients.
Lifetable analysis showed that occurrence of the clinical
stroke was earlier and most frequent in the SSBI group among all
subjects (P<.0001) (see the
Figure). The FWT2HL group had the second
most frequent occurrence as compared with the nonfocal lesion group. In
this table, stroke incidence was rather amplified for later periods
because the number of follow-up subjects was decreased.
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Background of Clinical Stroke Onset
Contingency table analysis for risk factors against CVD
between the group with clinical stroke onset and stroke-free group was
performed for selected items. The stroke group was significantly older
(66±6 versus 57±9 years, P=.0001) and showed significantly
higher frequency of hypertension (69% versus 28%, P=.0003)
and family history of CVD (79% versus 54%, P=.0307) than
the stroke-free group. There was no significant difference in other
risk factors, including diabetes, between the two groups.
The incidence of clinical stroke was significantly higher in the subjects with a history of hypertension than in those without it (4.8% versus 0.9%, P=.0003). Observation periods in the two groups were as follows: less than 2 years, 21.2% versus 23.2%; 2 to 3 years,15.8% versus 17.1%; 3 to 4 years, 15.8% versus 17.6%; 4 to 5 years, 26.3% versus 15%; 6 to 7 years, 21.1% versus 27.1%. None of the six cases with atrial fibrillation showed clinical stroke.
Silent Brain Lesions as Risk Factors for Clinical Stroke
Onset
Multiple logistic regression comparison for clinical stroke onset
in each group adjusted for age, sex, hypertension, diabetes, alcohol
habits, ECG ischemia, and retinal artery sclerosis showed that
SSBI was the most significant risk factor (OR, 10.48; 95% CI, 3.63 to
30.21; P=.0001), and FWT2HL was the second most significant
risk factor (OR, 4.81; 95% CI, 1.13 to 20.58). The PVH grade 3 was not
a significant risk factor for stroke onset (Table 6).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The incidence of SSBI was 10.6% in this study, and this result was coincidently almost the same as in our previous report3 and as the incidence of small infarction in a community based autopsy study in Hisayama.10 Lindgren et al15 reported that 62.3% of 77 adults (mean age, 65 years) without a history of focal brain lesion in the community showed white matter hyperintensities on 0.2 T MRI. Their incidence included all white matter lesions. We defined SSBI as a focal and demarcated T2 hyperintensity larger than 3 mm that had correlative T1 hypointensity. Therefore, most of them could be considered to be lacunes. As regards silent deep infarcts on MRI, Ylikoski et al7 reported that the incidence of deep infarct was 2.6% in young-old (n=76) and 15.4% in old-old (n=52) by community based study using 0.02 T MRI. The Japanese community based studies using MRI revealed more higher incidence of lacunes as 47% in the elderly 4 5
At the beginning of this study, we expected that some cortical infarcts due to atherothrombosis or embolism may be included in silent brain infarctions, but we could detect only SSBI in this series. The reason may be that most of our subjects were healthy and relatively young people without severe complications that were often observed in symptomatic stroke patients. For example, only six subjects had atrial fibrillation in this series. We also evaluated the clinical significance of nonspecific focal T2 hyperintensities. Clinical significance of nonspecific T2 hyperintenisties, except very small punctate lesions (suspected of being mostly perivascular enlargement), was not fully elucidated. Our results indicate that the most important and common underlying mechanism for SSBI, FWT2HL, and PVH is hypertensive small-vessel vasculopathy. The second most important risk factors for SSBI were diabetes and alcohol habits. On the other hand, only hypertension and age were significant risk factors for FWT2HL and PVH. Kase et al1 emphasized that diabetes was the sole risk factor for silent stroke in the Framingham study, but these silent lesions included cortical infarcts in 7 of 15 lesions. Initial stroke subtype in these patients with silent stroke was mainly atherothrombotic infarcts and embolism (10/13). On the other hand, Boon et al2 reported that advanced age and hypertension were the only risk factors for silent infarcts in their patients with initial ischemic stroke. This discrepancy may be caused by a difference in the type of silent infarction, because 82% of silent infarcts were small and deep in the study of Boon et al. Tuszynski et al9 reported that hypertension (64%) and diabetes (34%) were the most important risk factors in pathologically verified lacunar infarctions. It has been known that lacunar infarction caused not only by hypertensive small-vessel vasculopathy but also by atherosclerotic stenosis of the middle cerebral artery or embolism.16 However, hypertensive small-vessel vasculopathy was considered to be the most common cause of lacunar infarction.17 18 Shimada et al5 reported that silent lacunar infarctions were detected in 47% of 73 normal elderly subjects (40 of them were hypertensive), and SBP during sleep was significantly associated to silent lacunar infarctions. Our results showed heavy alcohol habits was also a significant risk factor for SSBI. A J-shaped relationship between alcohol intake and risk of stroke has been reported.19 The Hisayama study showed that hypertensive heavy drinkers were in a high-risk group for hemorrhagic and ischemic strokes.20 They suggested that the synergistic effect of heavy alcohol use and hypertension may be related to SSBI.
Boon et al2 reported that silent infarcts were found in 27% of 755 ischemic stroke cases on CT and that these lesions were significantly more strongly associated with a lacunar than an atherothrombotic infarction.
Chamorro et al11 reported that silent infarctions on MRI were observed in 33% of 249 ischemic or hemorrhagic stroke patients. Okada et al12 reported that the incidence of silent lacunes was 89% in 65 patients with hypertensive brain hemorrhage on MRI. However, no prospective study has been performed to investigate the rate of clinical stroke onset in neurologically normal subjects with SSBI. We have examined more than 1400 neurologically normal adults without any stroke history since 1988. We investigated clinical stroke onset of these subjects by questionnaire every year since 1992, and confirmed clinical stroke onset in 19 of 933 subjects during the observation period. Annual incidence of clinical stroke in our total subjects was 0.55% per year. Stroke incidence was estimated as 0.1% to 0.2% per year in the general population.21 It was reported that the age- and sex-adjusted average annual incidence rate of lacunar cerebral infarction was 13.4/100 000 persons.22 Our results demonstrated that the subjects with SSBI showed an apparently higher annual incidence of clinical stroke, 2.79% compared with 0.21% in those without SSBI. Kaplan-Meier lifetable analysis showed early and frequent clinical stroke onset in the subjects with SSBI. The subjects with FWT2HL showed an incidence median between those with SSBI and those without focal lesions. Retinal artery sclerosis was significantly related to SSBI but not to FWT2HL. This result suggested that SSBI was related to more long-standing hypertension than that in FWT2HL. We suppose that noncystic infarcts may be involved in FWT2HL to some extent, because focal subcortical T2 hyperintensity lesions with proton hyperintensity were possibly noncystic infarction if they had no correlative T1 hypointensity.13 The FWT2HL may have included so-called "unidentified bright objects" (UBO), which has been proposed by Kertesz et al.23 They showed that UBO was significantly related to hypertension, and they commented that UBO should be differentiated from the white matter confluent lesions. Therefore, FWT2HL should be included in the analysis of prospective study for stroke onset. Although the number of cases with clinical stroke onset was relatively small, our results indicate that the subjects with SSBI should be considered to be at high risk for clinical stroke. Seventy-four percent of the cases who developed clinical stroke were ischemic stroke, however, hemorrhagic stroke was also observed in 26% of subjects in our study. Most cases of brain infarction were lacunar infarction except 1. In cases of brain hemorrhage, 3 of 4 cases showed typical hypertensive putaminal hemorrhage similar to SSBI. This type of hemorrhage is considered to be caused by fibrinoid necrosis of a small perforating artery.24 It has been known that a common cause of lacunes is lipohyalinosis of the perforating arteries.25 However, fibrinoid necrosis of perforating arteries also is often observed in hypertensive elderly people with not only brain hemorrhage but also lacunar stroke.26 Therefore, it must be considered that SSBI puts one not only at high risk for subcortical brain infarction but also for hypertensive brain hemorrhage. On the other hand, PVH was not a significant risk for clinical stroke onset in this study. Our results showed that hypertension was the most significant risk factor for PVH. Although detailed pathogenesis of PVH or leukoaraiosis was not fully elucidated, it is supposed to be caused by chronic ischemia in the terminal zones of the medullary arteries related to hypertensive arteriolosclerosis.27 A large cooperative study with MRI in 3301 elderly showed that white matter findings correlated with age, hypertension, silent stroke, and impaired cognitive function.28 We have reported that frontal white matter lesions are significantly related to cognitive impairment in patients with multiple lacunar infarction.29 Silent diffuse white matter lesions are supposed to be a risk factor for mental deterioration rather than clinical stroke.
One of our hemorrhagic cases showed lobar hemorrhage associated with probable amyloid angiopathy. It is well known that amyloid angiopathy causes lobar hemorrhage in elderly people.30 Moreover, Vinters30 reported that amyloid angiopathy was often observed in dementia of Binswanger's type. We also reported a case of amyloid angiopathy with marked leukoaraiosis found on autopsy of an elderly subject who had been diagnosed by low level of cystatin C in cerebrospinal fluid.31 Therefore, antiplatelet therapy is not recommended for SSBI in elderly subjects with apparent PVH.
Thirty years ago in Japan the death rate from brain hemorrhage was one of the highest in the world, but it has dramatically decreased with management of hypertension and improvement of nutrition.32
Reed et al33 reported that Japanese men living in Japan more often had intracerebral small artery lesions than those in Hawaii. This result suggests that Japanese living in Japan have small cerebral artery disease more often than people in Western countries.
The incidence of clinical stroke differed according to distribution of age, sex, and other risk factors for stroke such as hypertension. As regards the recurrence rate of stroke, it was much higher than that of initial stroke. Alter et al34 reported that the recurrence rate of stroke was significantly higher in hypertensive patients (43% compared with 19%) than in normotensives during 24 months in a population-based cohort of 662 stroke patients. Lai et al35 also showed that the recurrence rate of stroke for 4 years was 24% in hypertensives and 9% in normotensives. On the other hand, primary stroke prevention by antihypertensive drugs has been proved in a large clinical trial.36 Our results showed that SSBI was the most important risk factor for subcortical clinical stroke, OR of 10.48, suggesting that SSBI may be considered to be a prestroke stage if these subjects leave risk factors, such as hypertension, as they are, untreated.
In conclusion, the subjects with SSBI should be considered to be a high-risk group for clinical stroke not only for subcortical brain infarction but also for brain hemorrhage. Further prospective, controlled studies are needed to clarify the effect of management of risk factors on prevention of clinical stroke onset in the subjects with SSBI.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by fund of research for "Etiology and Treatment of Silent Brain Infarction (#6-2, 1994-1996)" from Japanese Ministry of Health and Welfare and by fund of "Research for Geriatric Disorders (26th, 1994)" from Foundation of Welfare of Mitsui Life Insurance Enterprise. The authors are grateful to Yuko Kanetsuki who assisted health screening of the brain and data management of this study.
Received January 14, 1997; revision received June 18, 1997; accepted June 18, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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