Treatment Approaches to Lacunar Stroke
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ARTICLE IN PRESS Review Article Treatment Approaches to Lacunar Stroke , , Alvin S. Das, MD,* † Robert W. Regenhardt, MD, PhD,* † Steven K. Feske, MD,† and Mahmut Edip Gurol, MD* Lacunar strokes are appropriately named for their ability to cavitate and form ponds or “little lakes” (Latin: lacune -ae meaning pond or pit is a diminutive form of lacus meaning lake). They account for a substantial proportion of both symptomatic and asymptomatic ischemic strokes. In recent years, there have been several advan- ces in the management of large vessel occlusions. New therapies such as non-vita- min K antagonist oral anticoagulants and left atrial appendage closure have recently been developed to improve stroke prevention in atrial fibrillation; how- ever, the treatment of small vessel disease-related strokes lags frustratingly behind. Since Fisher characterized the lacunar syndromes and associated infarcts in the late 1960s, there have been no therapies specifically targeting lacunar stroke. Unfortu- nately, many therapeutic agents used for the treatment of ischemic stroke in general offer only a modest benefit in reducing recurrent stroke while adding to the risk of intracerebral hemorrhage and systemic bleeding. Escalation of antithrombotic treat- ments beyond standard single antiplatelet agents has not been effective in long- term lacunar stroke prevention efforts, unequivocally increasing intracerebral hem- orrhage risk without providing a significant benefit. In this review, we critically review the available treatments for lacunar stroke based on evidence from clinical trials. For several of the major drugs, we summarize the adverse effects in the con- text of this unique patient population. We also discuss the role of neuroprotective therapies and neural repair strategies as they may relate to recovery from lacunar stroke. Key Words: Cerebrovascular diseases—stroke—lacunar stroke—cerebral small vessel disease © 2019 Elsevier Inc. All rights reserved. Introduction and Basic Definitions Lacunar strokes (LS), which account for approximately From the *Department of Neurology, Massachusetts General Hos- 20%-30% of all ischemic strokes,1,2 are largely due to the pital, Harvard Medical School, Boston, Massachusetts; and †Depart- pathologic consequences of underlying cerebral small ves- ment of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. sel disease (cSVD). While LS is one sequela of cSVD, cSVD Received January 21, 2019; revision received April 15, 2019; is a major contributor to several neurological comorbid- accepted May 2, 2019. ities, including vascular cognitive impairment, gait disor- Funding: Funding for this study was provided by grants from the ders, and intracerebral hemorrhage (ICH).3-8 In addition National Institutes of Health (M. Edip Gurol, NS083711; Robert W. to lacunar cavitations, cSVD has many neuroimaging Regenhardt, NS065743). Address correspondence to M. Edip Gurol, MD, Department of manifestations including white matter hyperintensities Neurology, Hemorrhagic Stroke Research Program, Massachusetts (WMH), cerebral microbleeds, dilated perivascular General Hospital, 175 Cambridge Street, Suite 300, Boston, MA spaces, superficial cortical siderosis, and brain atrophy. 02114. E-mail address: [email protected]. By the historical classification schema outlined in the Trial 1052-3057/$ - see front matter of Org 10172 in Acute Stroke Treatment (TOAST), small © 2019 Elsevier Inc. All rights reserved. fi https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.05.004 artery occlusions (LS) were de ned as meeting the Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2019: &&À&& 1 ARTICLE IN PRESS 2 A.S. DAS ET AL. ACRONYM DEFINITION FMS Fugl-Meyer motor scale FOCUS Functional Outcomes after Acute ACTIVE Atrial Fibrillation Clopidogrel Trial Stroke with Irbesartan for Prevention GABA g-aminobutyric acid of Vascular Events GI gastrointestinal ADC apparent diffusion coefficient GOS Glasgow Outcome Scale aICH asymptomatic intracerebral HbA1c hemoglobinA1c hemorrhage HR hazard ratio fi AICLA Accidents Ischemiques Cerebraux ICD International Classi cation of Lies a l’Atherosclerose Diseases ALIAS Albumin Treatment for Ischemic ICH intracerebral hemorrhage Stroke INR international normalized ratio AMPA a-amino-3-hydroxy-5-methyl-4-iso- IRIS Insulin Resistance Intervention after xazolepropionic acid Stroke ASA aspirin IS ischemic stroke ATC Antithrombotic Trialists IST-3 Third International Stroke Trial Collaboration IU International Unit ATLANTIS Alteplase ThromboLysis for Acute IV intravenous Noninterventional Therapy in JCS Joint Committee for Stroke Ischemic Stroke LAA large artery atherosclerosis BI Barthel index LAAC left atrial appendage closure C controlled LACI lacunar infarction CAA cerebral amyloid angiopathy LACI-2 LACunar Intervention-2 CAPRIE Clopidogrel versus AsPirin in LS lacunar stroke patients at Risk of Ischaemic Events MATCH Management of AtheroThrombosis CASISP Cilostazol versus Aspirin for Sec- with Clopidogrel in High-risk ondary Ischemic Stroke Prevention patients CAST Chinese Acute Stroke Trial MC multicenter CD clopidogrel mg milligram CE cardioembolic MI myocardial infarction CHANCE Clopidogrel in High-Risk Patients mm millimeter with Acute Nondisabling mmHg millimeter of mercury Cerebrovascular Events MRI magnetic resonance imaging fi CI confidence interval mRS modi ed Rankin scale CS cilostazol NE neurological examination CSPS Cilostazol Stroke Prevention Study NIHSS National Institutes of Health Stroke CSPS.com Cilostazol Stroke Prevention Study for Scale Antiplatelet Combination (CSPS.com) NINDS National Institute of Neurological cSVD cerebral small vessel disease Disorders and Stroke CT computed tomography NMDA N-methyl-D-aspartate receptor À DAPT dual antiplatelet therapy NOAC non vitamin K antagonist oral DB double-blind anticoagulants DP dipyridamole NOGO neurite outgrowth inhibitor DWI diffusion-weighted imaging NR not reported ECASS European Cooperative Acute Stroke O other Study OCSP Oxfordshire Community Stroke EPITHET EchoPlanar Imaging Thrombolytic Project Evaluation Trial OHS Oxford Handicap Scale ESPRIT European/Australasian Stroke Pre- PACI partial anterior circulation infarct vention in Reversible Ischaemia Trial PE physical exam ESPS-2 European Stroke Prevention Study-2 PI pulsatility index FLAIR fluid-attenuated inversion recovery PLATO Platelet Inhibition and Patient FLAME Fluoxetine for Motor Recovery after Outcomes Acute Ischemic Stroke POCI posterior circulation infarct ARTICLE IN PRESS TREATMENT APPROACHES TO LACUNAR STROKE 3 separates the lesion attributed to small vessel disease into POINT Platelet-Oriented Inhibition in New several subtypes: recent small subcortical infarct and TIA and minor ischemic stroke lacune of presumed vascular origin.10 This terminology PRoFESS Prevention Regimen for Effectively reflects a more complete understanding of the dynamic Avoiding Second Strokes nature of cSVD such that not all subcortical infarcts form PS prospective lacunar cavities but instead may form acute and chronic R randomized WMH.11,12 Furthermore, while subcortical infarctions are RRR relative risk reduction often accompanied by the clinical syndromes originally RS retrospective described by Fisher and others,13 subcortical infarctions RT randomized can be identified incidentally by diffusion-weighted imag- SATURN StATins Use in IntRacerebral Hem- ing (DWI) sequences on MRI scans.14-17 orrhage PatieNts By consensus definitions set forth by the STRIVE con- SC single-center sortium, recent small subcortical infarcts can be up to sICH asymptomatic intracerebral 20 mm in axial diameter on MRI and are attributed to hemorrhage infarcts in the territory of the arteriole perforator.10 SOCRATES Acute Stroke or Transient Ischemic Lesions larger than 20 mm in the basal ganglia are Attack Treated with Aspirin or Tica- excluded from this definition, because they may be caused grelor and Patient Outcomes by an infarct affecting several arteriolar penetrators. SPARCL Stroke Prevention by Aggressive Lacunes of presumed vascular origin are the end products Reduction in Cholesterol Levels of small subcortical infarcts (Fig 1), although they can SPIRIT Stroke Prevention in Reversible sometimes be difficult to distinguish from old hemor- Ischemia Trial rhages or large perivascular spaces. These lacunes are fre- SPS3 Secondary Prevention of Small Sub- quently observed on neuroimaging scans of cortical Strokes 3 neurologically “healthy” individuals, although they con- SSRI selective serotonin reuptake fer an increased risk of symptomatic stroke and vascular inhibitors cognitive impairment.5,18-23 Lacunes of presumed vascu- STRIVE STandards for ReportIng Vascular lar origin are subcortical, round, fluid-filled spaces changes on nEuroimaging between 3 mm and 15 mm (smaller than subcortical SWI susceptibility-weighted imaging infarcts due to chronic involution of tissue). Compared to TACI total anterior cerebral infarct dilated perivascular spaces, lacunes have a surrounding TIA transient ischemic attack T2 hyperintense rim and are usually larger than the 3 mm TOAST Trial of ORG 10172 in Acute Stroke size cutoff for these lesions.10,24,25 Lacunes are classically Treatment found in deep locations, although lobar lacunes have been TP ticlopidine recently characterized,26 and are likely associated with tPA tissue plasminogen activator cerebral amyloid angiopathy (CAA) (Fig 2). For purposes UD undetermined of this review, small subcortical infarcts and their accom-