Cerebrovascular disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2021-326308 on 26 May 2021. Downloaded from Review Lacunar stroke: mechanisms and therapeutic implications Shadi Yaghi ,1 Eytan Raz ,2 Dixon Yang,2,3 Shawna Cutting,1 Brian Mac Grory,4 Mitchell SV Elkind,5 Adam de Havenon 6 1Department of Neurology, ABSTRACT overall prevalence of these risk factors is similar Brown University Warren Alpert Lacunar stroke is a marker of cerebral small vessel between lacunar stroke and other stroke subtypes,8 Medical School, Providence, some studies suggest that smoking, hypertension Rhode Island, USA disease and accounts for up to 25% of ischaemic 2Department of Radiology, NYU stroke. In this narrative review, we provide an overview and diabetes are particularly important risk factors Langone Health, New York, New of potential lacunar stroke mechanisms and discuss for lacunar stroke3 7 and that these risk factors may 9 York, USA be more prevalent in patients with lacunar stroke. 3 therapeutic implications based on the underlying Department of Neurology, NYU mechanism. For this paper, we reviewed the literature Among these risk factors, hypertension is most Langone health, New York, New York, USA from important studies (randomised trials, exploratory common in patients with lacunar stroke (68%), 3 7 9 4Department of Neurology, comparative studies and case series) on lacunar stroke followed by diabetes (30%). These studies were Duke Medicine, Durham, North patients with a focus on more recent studies highlighting performed when the control of risk factors, partic- Carolina, USA mechanisms and stroke prevention strategies in ularly hypertension, was less aggressive and more 5Department of Neurology, patients with lacunar stroke. These studies suggest that recent studies suggest that risk factors for lacunar Columbia University Medical 10 Center, New York, New York, lacunar stroke is a heterogeneous disease with various stroke may be similar to those of other subtypes. USA mechanisms, including most commonly lipohyalinosis In addition to conventional risk factors, rare 6Department of Neurology, and less commonly atheromatous disease and genetic conditions, such as Cerebral Autosomal University of Utah Hospital, Salt cardioembolism, highlighting the importance of a careful Arteriopathy with Subcortical Infarcts and Leuko- Lake City, Utah, USA review of brain and neurovascular imaging, a cardiac encephalopathy (CADASIL) can cause lacunar stroke.11 These typically have other accompanying Correspondence to and systemic evaluation. A better understanding of Dr Shadi Yaghi, Department of pathomechanisms of neurological deterioration may lead manifestations, including a positive family history, copyright. Neurology, Brown University to investigating the utility of novel treatment strategies and the diagnosis is made by clinical suspicion and Warren Alpert Medical School, and optimisation of short-term antithrombotic treatment confirmed by genetic testing (table 1).11 Providence, RI 02903, USA; strategies to reduce the risk of neurological deterioration shadiyaghi@ yahoo. com and prevent long-term disability in patients with lacunar Potential mechanisms Received 4 February 2021 stroke. There are several potential mechanisms described Revised 3 May 2021 12 Accepted 5 May 2021 for the pathogenesis of lacunar stroke. These Published Online First 26 May include lipohyalinosis, atherosclerotic disease and 2021 INTRODUCTION cardiac embolism, which will be discussed sepa- Lacunar stroke is a marker of cerebral small vessel rately below. disease1 and accounts for up to 25% of ischaemic http://jnnp.bmj.com/ stroke. The word lacunar comes from Latin for Lipohyalinosis ‘lacuna’ meaning hole, and it is used to describe a Lipohyalinosis is defined as concentric hyaline small focus of encephalomalacia containing CSF, thickening of the cerebral small vessels leading to which is the end result of liquefactive necrosis. occlusion of the small penetrating arteries13 and is Lacunar stroke is defined as a subcortical infarct one of the first and most common lacunar stroke measuring less than 20 mm in diameter, caused by mechanisms described and pathologically proven 1 occlusion of a perforator of an intracranial artery. to cause lacunar stroke.14 Lipohyalinosis is thought on September 27, 2021 by guest. Protected In this narrative review, we aim to provide an over- to originate from hypertension- related hyper- view of potential lacunar stroke mechanisms and trophy and fibrinoid degeneration of the vessel diagnostic approaches, and discuss therapeutic walls as well as subintimal foam cells obliterating implications targeting the underlying mechanism. the lumen of small penetrating arteries, leading to small subcortical infarcts. In a case series published BACKGROUND by Fisher of 114 lacunar strokes, all but three had The incidence of lacunar stroke varies based on direct or indirect evidence of uncontrolled hyper- the population studied from 25 to 50 per 100 000 tension.14 Previous studies suggested that lipohya- 2 3 © Author(s) (or their people, comprising 15%–25% of ischaemic linosis typically causes infarcts 3–7 mm in size on 2–4 employer(s)) 2021. No stroke. These numbers, however, have been brain imaging and that if the infarct is larger than commercial re- use. See rights declining over time, likely due to better control of 7 mm, other mechanisms should be explored.15 and permissions. Published vascular risk factors such as hypertension.5 In addition to lipohyalinosis, some studies by BMJ. Lacunar stroke shares risk factors with other hypothesised that endothelial dysfunction and To cite: Yaghi S, Raz E, Yang stroke subtypes, namely hypertension, diabetes, impaired autoregulation as well as extravasation of D, et al. J Neurol Neurosurg advanced age, cigarette smoking and hyperlip- blood products into the vessel wall resulting in peri- Psychiatry 2021;92:823–830. idaemia.6 7 While studies have shown that the vascular oedema and damage to the neurovascular Yaghi S, et al. J Neurol Neurosurg Psychiatry 2021;92:823–830. doi:10.1136/jnnp-2021-326308 823 Cerebrovascular disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2021-326308 on 26 May 2021. Downloaded from Table 1 Overview of genetic conditions associated with lacunar stroke Genetic Associated systemic condition Genetic characteristics CNS manifestations Pathognomic neuroimaging and pathological findings manifestations CADASIL NOTCH three gene Migraine, stroke, psychiatric Imaging: white matter disease affecting anterior temporal Myocardial infarction Autosomal dominant manifestations, and dementia lobes and external capsule Pathology: granular osmiophilic material in arterioles CARASIL HTRA1 gene Cognitive deficits and lacunar stroke Imaging: white matter disease affecting anterior temporal Alopecia Autosomal recessive lobes and external capsule Low back pain Pathology: degeneration of vascular smooth muscle cellacunar stroke and mural extracellular matrix reduction COL4A1 COL4A1 gene Migraine, lacunar stroke, cognitive Imaging: evidence of markers of cerebral small vessel Cataracts Autosomal dominant dysfunction, and intracerebral disease Renal disease haemorrhage Pathology: basement membrane defects Retinal haemorrhage Porencephaly FD GLA gene Lacunar stroke, intracerebral Imaging: pulvinar sign, arterial dolichoectesia Corneal opacity X- lined haemorrhage, cognitive dysfunction Pathology: lysososmal storage material deposited in Renal failure endothelial and smooth muscle cellacunar stroke of the Cardiac dysfunction vasculature Angiokeratoma Acroparasthesia RVCL TREX1 gene Lacunar stroke, migraine, cognitive Imaging: white matter disease along with contrast Progressive vision loss Autosomal dominant dysfunction enhancing lesions, calcifications in white matter Renal involvement Pathology: multilaminated basement membranes of the brain and kidney vasculature CNS, central nervous system. unit and surrounding brain tissue may be a contributing factor likely aetiology.23 Furthermore, studies have shown that subcor- to the development of lacunar infarcts.13 This is hypothesised tical infarcts are less likely to occur in the setting of a patent to lead to lacunar stroke and white matter disease.16 This mech- foramen ovale.24 Therefore, current evidence suggests that anism has not been pathologically proven and recently data lacunar stroke is a very rare manifestation of cardioembolism. suggests that endothelial dysfunction may be reactive and less likely to be involved in the pathogenesis of the disease itself.17 copyright. Diagnostic approach Brain imaging and non-invasive intracranial vascular imaging Atherosclerotic disease Infarct location on brain imaging could help determine the There are several potential atherosclerotic mechanisms that mechanism in lacunar stroke. For instance, one study showed could lead to lacunar stroke. The most important mechanism that a lacunar stroke involving the paramedian thalamus could that has been pathologically proven is branch atheromatous be related to a distant cardioaortic embolic source25 but more disease.18 Atherosclerotic plaques of the parent artery could studies are needed to confirm this finding. Obtaining a brain MRI involve the ostium of perforating branches leading to occlu- may be particularly helpful not only to confirm the diagnosis but sion and infarction of distal parenchyma. This mechanism has also to help determine the aetiology. For instance, the presence of been widely described in patients with