Lacunar stroke accounts for roughly one in four of all ischemic strokes, approximately 35,000 cases per year in the UK alone. These small, deep brain infarcts are routinely treated with antiplatelet drugs such as aspirin and clopidogrel, on the assumption that they are caused by the same atherosclerotic plaque buildup that drives other types of stroke.
That assumption may be wrong.
A study published in Circulation by researchers at the University of Edinburgh finds that lacunar stroke is not caused by narrowing of the large arteries feeding the brain, but by an intrinsic disease of the brain’s smallest blood vessels, specifically, a condition called dolichoectasia, in which the tiny vessels become abnormally widened, elongated, and tortuous.
The finding explains why antiplatelet drugs have been largely ineffective at preventing recurrent lacunar strokes, and points toward the need for entirely different treatment strategies.
The study
The research team, led by Professor Joanna Wardlaw at the University of Edinburgh’s Center for Clinical Brain Sciences, studied 229 patients with mild stroke (mean age 65.9 years), of whom 131 had lacunar stroke and the remainder had other types of mild stroke. All patients underwent detailed brain imaging to measure the diameter and condition of both large and small cerebral arteries.
The conventional picture predicts that lacunar stroke should be associated with large-artery stenosis, narrowing of at least 50 percent. But the data showed the opposite: patients with large-artery stenosis had lower odds of lacunar stroke (odds ratio 0.49), meaning stenosis was not a risk factor.
Instead, the strongest predictor was basilar artery dolichoectasia, or BADE, an abnormal widening of the basilar artery, the main vessel supplying the back of the brain. Patients with BADE were more than four times as likely to have lacunar stroke (odds ratio 4.67), and more than twice as likely to develop new “silent” strokes (odds ratio 2.29) and white matter damage progression over one year.
More than one in four participants developed new silent strokes during the study despite receiving standard preventive antiplatelet treatment.
A different disease mechanism
The results point toward what the authors call “segmental arteriolar disorganization”, an intrinsic structural disease of the brain’s microvessels, not a clot-blocking problem in a narrowed artery.
“This study provides strong evidence that lacunar stroke is not caused by fatty blockage of larger arteries, but by disease of the small vessels within the brain itself,” Wardlaw said. “Recognizing this distinction is crucial, because it explains why conventional treatments like antiplatelet drugs are not as effective for this type of stroke and highlights the urgent need to develop new therapies that target the underlying microvascular damage.”
The mechanism appears to involve the breakdown of the structural integrity of the small vessel walls, the same process that, on a larger scale, produces aneurysm-like widening in the basilar artery. The microvessels become disorganized, leaky, and unable to properly regulate blood flow to the deep brain structures they supply.
What comes next
A clinical trial is already underway. The LACunar Intervention Trial 3 (LACI-3) is testing two drugs that target small blood vessel function directly: cilostazol, a phosphodiesterase III inhibitor that dilates blood vessels, and isosorbide mononitrate, a nitrate vasodilator. The goal is to protect the brain, reduce recurrent stroke, and prevent the cognitive decline and dementia that often follow lacunar strokes.
“The findings support a non-atheromatous, intrinsic microvascular pathology as the principal mechanism of lacunar stroke and cerebral small-vessel disease,” the authors wrote. “Mechanism-specific diagnostic and therapeutic strategies are warranted.”
For the estimated 35,000 people who have a lacunar stroke each year in the UK alone, and the millions more who live with the risk of cognitive decline from silent small-vessel disease, this reframing of the underlying cause could eventually change how they are diagnosed and treated.
Maeva May, Director of Policy at the Stroke Association, noted the broader context: “Stroke research is chronically underfunded, with less than 1 percent of total UK research funding spent on the condition. Yet these findings illustrate the value of research and the potential it has to change the lives of stroke patients.”