Risk factor profile of cerebral small vessel disease and its subtypes

Background

The mechanisms of cerebral small vessel disease (SVD) are unclear. Both atherosclerosis and a non‐atherosclerotic diffuse arteriopathy have been reported pathologically. Two pathological and radiological subtypes have been suggested: localised atherosclerotic disease in larger perforating arteries causing larger lacunar infarcts without leukoaraiosis, and diffuse disease in smaller arterioles causing multiple smaller lacunar infarcts with leukoaraiosis. If atherosclerosis were important in SVD as a whole or in one particular subtype, one would expect the risk factor profile to be similar to that of cerebral large vessel disease (LVD).

Methods

Risk factor profiles were compared in Caucasian stroke patients with SVD (n = 414), LVD (n = 471) and 734 stroke‐free Caucasian population controls. Patients with SVD were subdivided according to the presence or absence of confluent leukoaraiosis, into isolated lacunar infarction (ILI) and ischaemic leukoaraiosis (ILA).

Results

Hypertension was commoner in SVD than LVD (odds ratio (OR) 3.43 (2.32 to 5.07); p<0.001) whereas hypercholesterolaemia (OR 0.34 (0.24 to 0.48); p<0.001), smoking (OR 0.63 (0.44 to 0.91); p = 0.012), myocardial infarction (OR 0.35 (0.20 to 0.59); p<0.001) and peripheral vascular disease (OR 0.32 (0.20 to 0.50); p<0.001) were commoner in LVD. Among SVD patients, age (OR 1.11 (1.09 to 1.14); p<0.001) and hypertension (OR 3.32 (1.56 to 7.07); p = 0.002) were associated with ILA and hypercholesterolaemia (OR 0.45 (0.28 to 0.74); p = 0.002), diabetes (OR 0.42 (0.21 to 0.84); p = 0.014) and myocardial infarction (OR 0.18 (0.06 to 0.52); p = 0.001) with ILI.

Conclusion

SVD has a different risk factor profile from the typical atherosclerotic profile found in LVD, with hypertension being important. There are differences in the risk factor profile between the SVD subtypes; the association of ILI with hypercholesterolaemia, diabetes and myocardial infarction may be consistent with a more atherosclerotic aetiology.The pathogenesis of cerebral small vessel disease (SVD) is incompletely understood. Hypertension is a major risk factor but fails to account for all of the risk.¹ Neuropathological data, particularly soon after a lacunar stroke, are limited because of low case fatality. Pathological vascular abnormalities reported include both a diffuse arteriopathy of the perforating arteries with hyaline deposition, an appearance referred to as lipohyalinosis, and microatheroma.²Based on pathological studies, it has been suggested that there may be two types of SVD that can be differentiated on brain imaging.³ The first involves atheroma at the origins or proximal portions of the larger (200–800 μm diameter) perforating arteries. This is associated with single or a few larger lacunar infarcts without leukoaraiosis. The second involves a diffuse arteriopathy of the smaller perforating arteries, 40–200 μm in diameter, resulting in multiple smaller lacunar infarcts with leukoaraiosis. Endothelial dysfunction may play an important role in the pathogenesis of this SVD subtype. A reduction in white matter cerebral blood flow⁴ and autoregulation,⁵ both dependent on nitric oxide released from the endothelium, has been reported in lacunar infarction with leukoaraiosis. Furthermore, circulating markers of endothelial activation are elevated in lacunar infarction with leukoaraiosis,⁶ and specific associations have been reported with homocysteine, which is toxic to the endothelium.⁷One way of obtaining information on pathogenesis is to compare the risk factor profile between different stroke subtypes. If atherosclerosis plays an important role in SVD, one would expect the risk factor profile to be similar to that seen in patients with large artery atherosclerotic stroke. Furthermore, as suggested by pathological studies in SVD, if atherosclerosis is more important in lacunar infarction without leukoaraiosis compared with lacunar infarction with leukoaraiosis, one might expect differences in the risk factor profile between the two proposed subtypes of lacunar stroke, with a more atherosclerotic profile seen in lacunar infarction without leukoaraiosis.A meta‐analysis of four community based clinical studies demonstrated that there are differences in the risk factor profile between ischaemic stroke subtypes.⁸ Large vessel disease (LVD) stroke was associated with male sex, smoking and raised cholesterol, while SVD was associated with hypertension. However, there were several limitations to these studies, including small SVD and LVD sample sizes, lack of MRI imaging in all studies, variability in risk factor definition between studies, inclusion of hypertension and diabetes in the SVD definition by some studies which may result in biased risk factor–stroke subtype associations, and failure to prospectively subtype patients using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria in one large stroke cohort used in the meta‐analysis. In this same cohort, a significant proportion of patients did not have carotid imaging. It has been shown that subtyping based on clinical presentation alone without imaging of the large arteries cannot reliably distinguish SVD from LVD.⁹ Studies have also suggested there may be differences in the risk factor profile between the two subtypes of cerebral SVD but data are limited and most studies have been small,^{3,10,11,12,13,14} and this was not covered in the meta‐analysis above.In this study, we used a large well‐phenotyped group of patients with SVD and LVD to determine differences in the risk factor profile between the two groups. All patients had brain imaging and imaging of the extracranial cerebral arteries. In addition, differences in the risk factor profile between the two proposed subtypes of SVD were determined.