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

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.