Pathophysiology of Lacunar Stroke: History's Mysteries and Modern Interpretations

Abstract

Since the term "lacune" was adopted in the 1800s to describe infarctions from cerebral small vessels, their underlying pathophysiological basis remained obscure until the 1960s when Charles Miller Fisher performed several autopsy studies of stroke patients. He observed that the vessels displayed segmental arteriolar disorganization that was associated with vessel enlargement, hemorrhage, and fibrinoid deposition. He coined the term "lipohyalinosis" to describe the microvascular mechanism that engenders small subcortical infarcts in the absence of a compelling embolic source. Since Fisher's early descriptions of lipohyalinosis and lacunar stroke (LS), there have been many advancements in the understanding of this disease process. Herein, we review lipohyalinosis as it relates to modern concepts of cerebral small vessel disease (cSVD). We discuss clinical classifications of LS as well as radiographic definitions based on modern neuroimaging techniques. We provide a broad and comprehensive overview of LS pathophysiology both at the vessel and parenchymal levels. We also comment on the role of biomarkers, the possibility of systemic disease processes, and advancements in the genetics of cSVD. Lastly, we assess preclinical models that can aid in studying LS disease pathogenesis. Enhanced understanding of this highly prevalent disease will allow for the identification of novel therapeutic targets capable of mitigating disease sequelae.

Keywords: Stroke; cerebral small vessel disease; genetics; lacunar stroke.

Figure 1.

Small infarcts on DWI sequences within the right subcortical white matter (A), left thalamus (B), and left pons (C) consistent with acute lacunar strokes. Panel D shows T2 FLAIR sequence with white matter hyperintensities in the subcortical white matte (yellow arrow) and periventricular white matter (blue arrow). Panel E shows T2 FLAIR sequence with white matter hyperintensities on in the basal ganglia (yellow arrow) and deep chronic lacune with a rim of hyperintensity (blue arrow). Panel F shows susceptibility weighted imaging with superficial microbleed (blue arrow) and deep microbleed (yellow arrow).

Figure 2.

Illustration of a coronal brain section with parenchymal findings of cerebral small vessel disease. The right hemisphere includes findings suggestive of hypertension-related small vessel disease, including a peri-basal ganglia white matter hyperintensity (blue arrow), dilated perivascular space (yellow arrow), microinfarct (green arrow), deep lacune (gray arrow), and microbleed (red arrow). The left hemisphere includes findings suggestive of cerebral amyloid angiopathy, including a microbleed (red arrow), sulcal siderosis (purple arrow), dilated perivascular space (yellow arrow), subcortical white matter hyperintensity spots (double blue arrow), lobar lacune (gray arrow), and microinfarct (green arrow). There is also perivascular white matter hyperintensity (triple blue arrow), which is associated with both small vessel diseases.

Figure 3.

Lacunar stroke timeline, portraying both the vessel and parenchymal disease processes. These processes can be thought of separate therapeutic targets for intervention, but they are intimately related.