Background: Few pathological data have focused on the causal link between intracranial atherosclerotic disease and parent artery stroke. The objective of this study was to investigate the cause of middle cerebral artery (MCA) atherosclerotic disease in patients with fatal stroke. Methods and Results: In 123 patients with unilateral MCA territory infarction we performed a case-control autopsy study evaluating the frequency of atherosclerotic plaque and moderate (<70%) or severe (≧70%) stenosis in the ipsilateral and contralateral MCA. Clinical history, risk factors, imaging data and general autopsy reports were available. The entire cerebral arterial tree was studied pathologically. MCA atherosclerosis (either moderate or severe stenosis) was more frequent in the ipsilateral (21.1%, n = 26) than the contralateral MCA (8.1%, n = 10). The corresponding odds ratio (OR) for the presence of atherosclerosis in the ipsilateral MCA relative to the contralateral MCA was 6.33 [95% confidence interval (CI) = 1.87–21.40]. This difference was found with both moderate (OR = 5.75, 95% CI = 1.45–22.76) and severe (OR = 7.18, 95% CI = 1.58–32.73) stenosis. Conclusions: Moderate MCA atherosclerotic stenosis may be responsible for parent territorial stroke. Novel arterial wall magnetic resonance imaging techniques should now be used to investigate in vivo the hypothesis that moderate MCA stenosis is a possible explanation in patients with nonfatal stroke of unknown cause.

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