Silent Brain Infarcts and Transient Ischemic Attacks
A Three-Year Study of First-Ever Ischemic Stroke Patients: The Klosterneuburg Stroke Data Bank
Background and Purpose We undertook to study the clinical relevance of silent strokes and history of transient ischemic attacks (TIAs) and their individual and combined effects on outcome variables of neurological and epidemiological interest in first-ever stroke patients.
Methods We performed univariate and multivariate analyses of data prospectively collected in the Klosterneuburg Stroke Data Bank, a hospital-based registry in Austria that includes a 3-year follow-up program.
Results Of 728 patients (mean age, 68±10 years) with a first-ever ischemic stroke, 110 (15%) had had a previous TIA, and 66/618 (11%) patients did not have a history of TIA but showed evidence of silent brain infarct on CT. Outcome variables of neurological interest were not significantly different between groups, including time between stroke and study entry, activities of daily living status at first presentation, median time of hospitalization, 30-day mortality, or 3-year mortality. Univariate analyses of epidemiologically important risk factors showed either history of TIA or evidence of silent infarct to be more frequently associated with hypertension (P=.007). Cox models of survival showed that neither history of TIA nor evidence of silent infarct were significantly associated with an increase in 3-year mortality.
Conclusions Over a period of 3 years, neither history of TIA nor evidence of silent infarct diagnosed at the time of the presenting major stroke in first-ever ischemic stroke patients exert an important influence on neurological or epidemiological outcome variables.
Silent infarcts are a common finding of neuroimaging or necropsy. The prevalence of clinically silent cerebral ischemia in the general population is unknown, as is its influence on risk for stroke recurrence. Whether clinically silent strokes bear an influence on the severity of a subsequent stroke, on long-term mortality, or on any other long-term outcome measure has rarely been the object of systematic studies. Only three studies of silent infarcts in first-ever stroke patients have included mortality data for their patients, and these studies did not find a notable influence of a silent stroke on 28-day mortality1 2 3 ; two of these studies showed that the 12-month mortality is not influenced by silent strokes.2 3
We report a 3-year longitudinal study of a series of hospitalized stroke patients from the Klosterneuburg Stroke Data Bank in Austria.4 Examining risk factor patterns, clinical characteristics at presentation, and outcome measures, we compared groups of patients who had previously suffered a clinically silent stroke or had a history of TIA, both individually and combined, with a group of first-ever stroke patients who had neither a history of TIA nor evidence of a clinically silent stroke.
Subjects and Methods
The KSDB is a single-center, hospital-based stroke registry that was established in 1988 and systematically collects data on all consecutive stroke patients regardless of age or previous stroke. The time of entry into the KSDB was originally defined from day 0 through day 28 after the stroke event; since 1991 it has been narrowed down to day 0 through day 7. This wide range of entry time was selected to include a wide variety of stroke patients coming either from rural areas or as referred from general wards from other hospitals, either for treatment of specific neurological conditions or for rehabilitation. This accounts for the delay between stroke and study entry as well as for a comparatively low total mortality (see “Results”). Patients presenting with TIAs or subarachnoid hemorrhage were not included. The project background, design, and methods, the many definitions used, and patient characteristics have been previously published.4 This stroke registry adheres to the criteria considered important for clinical research.5 In short, a total of 327 items are collected within a specified time frame for medical history and description of stroke onset, social status, neurological status, neuroimaging and vessel examinations, results of cardiac and laboratory tests, complications, and functional status. The diagnosis is made according to predefined categories6 and according to the clinical syndrome. The diagnosis of lesion type, location, and size as determined by CT scan is made according to a diagnostic scale tested in seven institutions by 10 neuroradiologists and has an excellent interobserver agreement.7 Special efforts are given to completeness of investigation as well as to yearly follow-up examinations for a total of 3 years. Follow-up investigations (either personal or by telephone) include a set of 44 additional items, which includes information on the end points of recurring stroke or death from all causes.
The first 1000 consecutive patients treated for completed stroke at the Department of Neurology at the Landesnervenklinik Gugging between March 1988 and September 1992 represented the data set for this analysis. These patients were grouped according to the following criteria. (1) Group 1A included patients who had suffered a TIA before the onset of their presenting stroke. A history of the TIA was taken from the patient and/or spouse according to a semistructured interview, which included the time elapsed since their (last) TIA, number of attacks, type of TIA, and vascular territory involved. (2) Group 1B included patients with evidence of a previous silent stroke, ie, those who to their knowledge (and to the knowledge of their spouse) had not previously suffered a TIA or stroke and were admitted for a first-ever stroke but whose CT scan showed evidence of a previous ischemic infarction that was not thought to relate to their presenting stroke. A silent infarct was defined as any circumscribed low attenuation consistent with cerebral infarction. The analysis of CT scans for the detection of additional ischemic lesions that were not attributable to the presenting stroke syndrome was planned as an integral part of the prospective data acquisition and performed to the best of our knowledge.4 Despite this, it is clear that retrospective analysis of CT scans in patients who have recently suffered a major stroke cannot exclude patients with early stroke recurrence, especially recurring embolism. Although virtually all patients had at least one CT (99.6%), patients with CTs performed within 24 hours had, as a rule, a second CT within the first week. To avoid false-negative interpretations of CT scans performed after day 14 (due to the “fogging effect”), contrast-enhanced scans are routinely performed. Since 1990 many patients also had had an MRI, especially in cases of brain stem strokes but also in other cases of diagnostic relevance. The MRI data are not considered in this analysis, although it would be tempting to do so because the rates for silent ischemia would be expected to be higher. On the other hand, MRI-anatomic correlations are still largely lacking, and therefore no definite conclusions can be drawn from such data. (3) Group 2 included all first-ever stroke patients without a history of TIA or signs of silent cerebral ischemia as seen by means of CT.
Group comparisons for risk factors and outcome characteristics were made by univariate methods applying χ2 tests, ANOVA, and nonparametric statistical methods as appropriate. Multiple logistic regression analysis was used to examine for associations between risk factors and silent strokes. Statistical significance was defined as P<.05, although because many tests were performed and no multiple comparison adjustments were made to control the overall type I error rate, significant results should be interpreted descriptively. To compare survival across groups, nonparametric estimates of the survival functions were computed using the Kaplan-Meier method. Losses to follow-up were censored at the date of the last contact. The log-rank test was used to test for overall group differences in survival, without adjusting for other covariates. Multivariate analyses to assess the effects of covariates on survival were performed using Cox proportional hazards regression. Incorporation of indicator variables for group membership (after checking the proportional hazards assumption) allowed for testing of group differences after adjusting for other covariates. Point estimates and confidence intervals for relative risks associated with various covariates were obtained from the resulting regression coefficients and their standard errors.
From 1000 patients, 272 were excluded for the following single or multiple reasons: 187 had had a previous stroke, 86 had primary intracerebral hemorrhages, in 26 no history of TIA could be established (either the patient was in a clouded state of consciousness, died early, or was severely aphasic or demented and no other source of information was obtainable), and in 4 no CT and no autopsy data were available.
The demographic characteristics of the remaining 728 patients are summarized in Table 1⇓. The ANOVA test for age showed no significant group differences.
Group 1A comprised 110 patients. Sixty-seven of them (60.9%) had had a single TIA, 32 (29.1%) had had between two and five attacks, 5 (4.5%) had a history of more than five attacks, and in 6 cases (5.4%) no frequency could be determined. The TIA types were pure motor hemiparesis (31), pure sensory hemiparesis (18), isolated anarthria or dysphasia (17), brachiocephalic motor paresis (11), monocular blindness (10), brain stem syndrome (4), other (7), and unspecified (12). Additional ischemic lesions (not attributed to their presenting stroke syndrome) seen on CT showed a left-sided preponderance: 14 left-sided versus 7 on the right, mostly small, deep and small cerebellar infarctions. Altogether, the rate of ischemic lesions as either the correlate of the TIA or the result of an additional silent stroke was 20.0% (22/110 patients). Two of those patients had two ischemic lesions. In only five cases was the presenting stroke located within the same vascular territory as one of the additional lesions seen on CT. The laterality of lesions of the presenting stroke was evenly distributed between the hemispheres (40 left, 38 right, 9 bilateral, 2 median) and did not differ from the other groups.
Group 1B comprised 66 patients. The distribution of silent lesions (58 patients had one silent lesion and 8 patients had two) was deep, small periventricular (14), putamen or globus pallidus (4), small, deep thalamic (3), caudate head (9), cortical ACA (1), cortical MCA (4), cortical-subcortical MCA (2), median PCA (1), lateral PCA (2), corona radiata (1), pontine (3), midbrain (1), cerebellar (7), and other infarcts (8); border zones: internal MCA (4), external MCA anterior (1), external MCA posterior (5); multiple lesions: lacunar state (1) and Binswanger (3). The distribution between hemispheres was 33 on the left and 30 on the right, 7 bilateral and 4 median. Of the 49 patients with single hemispheric lesions, 19 patients had their presenting stroke in the same hemisphere as their silent stroke lesion.
Group 2 comprised 552 patients according to the definition above.
Group comparisons of variables of neurological interest showed no significant differences for the time between stroke and study entry (median for all groups, 13±9 days; Kruskal-Wallis rank sum test, P=.06, NS), as well as for the length of hospital stay (median for all groups, 39±23 days; Kruskal-Wallis rank sum test, P=.08, NS). No significant group differences were found for stroke severity (applying a simplified six-grade stroke severity scale, moderate deficits found in groups 1A, 1B, and 2 were 60.9%, 66.7%, and 56.9%, respectively [NS]; severe deficits found were 11.8%, 4.5%, and 13.0%, respectively [NS]), median values of the ADL status at presentation (median for all groups, 50±34; Kruskal-Wallis rank sum test, P=.17, NS), or for 30-day mortality (overall mortality, 5.6%). The laterality of the lesion of the presenting stroke showed no group difference by brain hemisphere or by infratentorial location of the presenting stroke. When comparing stroke etiologies between groups, group 1A showed a suggestive preponderance of atherothrombotic strokes versus cryptogenic, cardiac embolic, and lacunar strokes, but no differences occurred in an overall test for differences among the three groups (P=.28). Also, no major differences were found when comparing the most frequent stroke syndromes among groups.
Group comparisons of variables of epidemiological interest included the prevalence of single and combined potential risk factors for silent infarcts and TIAs and their relation to the characteristics of the presenting stroke (Tables 2⇓ and 3⇓). No group differences were found, but group 1A tended to have a higher rate of atherothrombotic strokes in combination with a higher prevalence of peripheral arterial disease, although the rates in all three groups were rather low.
In a combined analysis of groups 1A and 1B versus group 2, only a history of hypertension was more common in patients with either a history of TIA or evidence of silent infarct (P=.007) (Table 4⇓). In a multiple logistic regression analysis relating various risk factors to the presence of silent stroke lesions, old age (>65 years) and a history of myocardial infarction were significantly associated with the presence of silent strokes, even after adjusting for sex, hypertension, and diabetes, none of which were significantly associated with the presence of silent strokes.
Follow-up investigations were performed on all but 4 patients. Survival rates in the three groups were compared, and the effects of various covariates on survival were examined. A log-rank test for differences in survival among the three groups, without taking into consideration additional covariates, showed no statistically significant difference. Using available covariate information from before the index stroke, Cox proportional hazards regression techniques identified old age, diabetes, and ischemic heart disease as important negative predictors for survival, although hypertension was not a significant contributor to mortality (Table 5⇓). A second model included additional information known at the time of the presenting stroke and showed the diagnosis of a lacunar stroke (versus nonlacunar stroke) and an ADL level >50 (versus ADL level <50) to be significant positive prognostic indicators for survival (Table 6⇓). In both models, neither silent infarcts nor history of TIA played a major role in survival after adjusting for other covariates.
In our hospitalized cohort of patients with first-ever stroke in a lifetime, we found an 11% prevalence of silent strokes, which compares with the prevalence from previous studies of stroke patients in Framingham (10%)8 and the National Institute of Neurological Disorders and Stroke Stroke Data Bank (11%).9 Other studies in stroke patients report higher prevalence rates. The highest rate was reported from Umbria, Italy, where a 38% prevalence was found.2 This high rate is surprising, considering the fact that about one third of the patients did not have a CT scan and that these patients who did not undergo CT were older (78 versus 71 years). Other reported rates were 19% from a hospital-based series of either stroke or TIA patients,10 27% from another hospital-based series that included only supratentorial strokes,3 22.5% from a multicenter hospital-based series of stroke patients,11 and 29.4% from the hospital-based community study in Copenhagen.1 Only the latter study reports age-specific prevalence rates and shows the highest prevalence of 33% silent strokes occurring in stroke patients over 75 years old. The relatively low prevalence reported in this cohort probably is due to the comparatively low age of our hospitalized patients (68±10 years). As was the case in our cohort, the Copenhagen study found no evidence for any role of silent infarcts for the 28-day mortality after acute stroke, but this study did not include long-term follow-up data.
With the exception of two studies,2 3 all others were cross-sectional and did not evaluate follow-up examinations of their stroke patients. Ricci et al2 found that the 12-month outcome was not influenced by the presence of a silent infarct. Boon et al3 do not specify their follow-up data but state globally that they found no influence of silent infarcts on the 12-month mortality in their cohort of 755 patients. The present study represents the longest follow-up study of stroke patients with evidence of a silent stroke and does not show any differences in mortality between patients with a silent stroke and those with a first-ever stroke and no evidence of a silent infarct within 3 years of the index stroke. In addition, we did not find differences in the severity of the presenting index stroke that would be reflected in the ADL status or the stroke severity. These findings are corroborated by the study of Boon et al, who measured the initial handicap by means of the Rankin Scale. Our study also found no differences in the duration of hospitalization, which is an important indicator for the costs of health care for stroke patients.
Due to individual differences in the observation and self-recognition of such short-lasting or nonspecific signs, a variable number of pathophysiologically identical episodes associated with cerebral infarction might pass either as silent stroke or TIA. Since it has been shown that the majority of TIAs also are associated with cerebral infarcts, especially when investigated by means of MRI,12 13 14 15 16 such a continuum might be postulated. Although cerebral infarcts are most often seen when TIA lasts longer than 1 hour, when signs during attacks clear more slowly, when the TIAs are multiple versus single, and in those with speech dysfunction as a component of the attack,17 18 no strict separation in terms of pathophysiology has been possible to determine which TIA in a single patient will be associated with an infarct. Similarly, in studies of patients who have suffered a TIA, no single important factor indicated whether a patient is going to suffer a further vascular event.19 One other study showed that risk of cardiac death in patients who have suffered a TIA depends mainly on the cardiac risk factors and that none of the neurological variables predict cardiac death.20 21
In conclusion, neither clinically silent infarcts nor TIAs exert an important influence on neurological or epidemiological outcome variables when studied in first-ever stroke patients over a period of 3 years. This also holds for a combined analysis when first-ever ischemic stroke patients that had either previously suffered a TIA or showed evidence of a silent infarct on CT were grouped together and compared with first-ever ischemic stroke patients without a previous TIA and without a silent stroke. No influence on the severity of a first-ever ischemic stroke, the many characteristics of the presenting stroke, or duration of hospital stay was found. The predictors of mortality are the same as in most studies of ischemic stroke. It remains to be studied, however, whether silent infarcts exert an influence on prognosis for asymptomatic individuals who have not yet suffered a stroke.
Selected Abbreviations and Acronyms
|ACA||=||anterior cerebral artery|
|ADL||=||activities of daily living|
|KSDB||=||Klosterneuburg Stroke Data Bank|
|MCA||=||middle cerebral artery|
|PCA||=||posterior cerebral artery|
|TIA||=||transient ischemic attack|
We thankfully acknowledge the assistance of Jack Panossian with data management.
- Received March 30, 1995.
- Revision received May 11, 1995.
- Accepted May 12, 1995.
- Copyright © 1995 by American Heart Association
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