In this cohort, smaller and larger ILLs were associated with different risk factor profiles, supporting the view that lacunes arise from 2 distinct vascular pathologies. As we hypothesized, diabetes and HbA1c, consistently shown to be risk factors for small-vessel disease in the literature, were significantly associated with smaller ILLs but not with larger ones. Other risk factors associated with smaller lesions were age, nonwhite ethnicity, hypertension, and ever-smoking, but not LDL (). Conversely, LDL levels, age, hypertension, and smoking were positively associated with larger lacunar lesions thought to be caused by microatheromata (). When we limited our analysis to participants with lacunes, LDL levels and history of smoking were linked to ILLs 8–20 mm.
These results shed light on the controversy regarding the differences in risk factor profile between lacunar and nonlacunar strokes. Although treatment of hyperglycemia appears to more successfully reduce microvascular disease than disease due to large-artery atherosclerosis,8
in a recent systematic review diabetes was equally associated with lacunar and nonlacunar ischemic stroke.21
However, in all studies included in this review, lacunar infarction was defined clinically, requiring the presence of lacunar symptoms. Therefore, the lacunes studied tend to represent Fisher's microatheromatous lacunar subtype, which we believe is more similar than smaller lacunes to large-artery cerebral infarctions.
As the lipohyalinotic subtype is more likely to be associated with multiple asymptomatic lacunes, rather than occurring as a single symptomatic lesion, some studies involving patients admitted for a clinical lacunar syndrome used multiplicity as a criterion for differentiating lacunar subtypes.2,3,22,23
An association of diabetes with the lipohyalinotic subtype defined in this way was also described by some,3
but not by others.2,3,22,23
However, as discussed above, since clinical recognition was an inclusion criterion for lacunar infarctions in these studies, most of the patients in both groups would tend to also have the microatheromatous subtype of lacunes, thus potentially weakening the association of risk factors such as diabetes with smaller lesions. Furthermore, a criterion based on multiple lesions would likely miss many lipohyalinotic lesions, thus reducing statistical power for detecting associations with diabetes. For instance, in our study, only 60 of the 215 lipohyalinotic subtype (ILLs ≤7 mm) occurred in participants with multiple lesions.
Studies involving asymptomatic populations should be more comparable to ours than those cited above. However, even in this setting, markers of impaired glucose metabolism were not consistently described in association with lacunes.24
Possible explanations of these negative findings would be the absence of differentiation between the size of lesions as indicators of the lacunar subtype; the inclusion of lesions of potential “nonlacunar” etiology,17
such as those extending to the cerebral cortex; and the exclusion of the smallest lesions, those <3 mm in diameter.17,18
Our data show that lesions <3 mm were significantly associated with diabetes and HbA1
c, justifying their inclusion as a marker of lipohyalinotic disease (). Although in our study there was poor agreement concerning the presence of these small lesions,10
our reported associations are likely to be valid, since the misclassification of these small lesions is nondifferential with respect to diabetes status.25
For example, even if our scans failed to detect 50% of the <3 mm diameter lesions, this would not bias the associations with diabetes or other risk factors unless our failure to detect those lesions depended in some way on the level of the risk factors, and we have no reason to believe that such would be the case. Our MRI definition of ILLs requiring hyperintensity on both spin-density and T2-weighed images tended to select ischemic lesions rather than perivascular spaces, though this criterion could be less reliable for smaller lesions.10,26
Most previous studies excluded lesions <3 mm with the concern that they could represent enlarged perivascular spaces, assuming that they may not be related to cardiovascular risk factors. However, emerging evidence indicates that enlarged Virchow-Robin spaces may also result from small-vessel disease.27,28
Lipohyalinosis is associated with increased blood–brain barrier permeability, leading to leakage of proteins, not only to the arterial wall (causing fibrinoid necrosis) but also to the perivascular brain parenchyma. This could result in protein accumulation, congestion of the extracellular fluid, and enlargement of Virchow-Robin spaces.7
Our findings may have important clinical implications. Each type of lacunar disease may imply a different approach to patient management. Lipohyalinosis is associated with fibrinoid necrosis,5–7
an acute lesion that could lead to vessel rupture and blood extravasation.5–7
Therefore, it seems reasonable to expect that this lacunar subtype would be associated with cerebral microbleeds, and an increased risk of intracerebral hemorrhage, either primarily or with the use of antithrombotic drugs.29
Leukoaraiosis, which is also believed to be more common in the lipohyalinotic subtype of lacunar infarction, has already been associated with an increased risk of intracranial bleeding following the use of anticoagulants30
Future studies might address the prognostic implications of our findings.3,22,23
Due to the cross-sectional nature of this investigation, we cannot determine the temporality of the observed associations. Another limitation of our study is the availability of only a single HbA1c measurement performed approximately 3 years before the MRI scanning, which might underestimate the exposure to increased glucose levels over time. Furthermore, only a few participants had larger lesions, limiting our statistical power for that group. Finally, despite the adjustment for known cardiovascular risk factors, we cannot rule out the possibility of residual confounding.
Strengths of this study are the large community-based population, rigorous measurement of cardiovascular risk factors, standardized and reliable methods to evaluate the outcomes, and the large number of African American participants.15
In summary, this study strongly supports the hypothesis of 2 types of lacunar infarctions, with noncortical lesions divided according to size class. ILLs ≤7 mm (of presumptive lipohyalinotic origin) were associated with diabetes and elevated HbA1c level, age, nonwhite ethnicity, hypertension, and history of smoking, and ILLs 8–20 mm (likely of microatheromatous etiology) were linked to LDL as well as age, hypertension, and smoking. Furthermore, we found that the exclusions of lesions <3 mm as previously done in imaging studies may lead to underestimation of the lacunar burden. These findings might have future impact on the classification of lacunar disease, prognosis, and clinical management of these patients.