Research Article| Volume 29, ISSUE 4, 104635, April 2020

Association between Enlarged Perivascular Spaces and Internal Carotid Artery Stenosis: A Study in Patients Diagnosed by Digital Subtraction Angiography


      Objective: An enlarged perivascular space (EPVS) is an imaging marker of cerebral small vessel disease, and its relationship with large artery disease is elusive. We investigated the EPVS in patients with internal carotid artery stenosis (ICAS) with the use of digital subtraction angiography (DSA) and tested the relationship between the degree of EPVS and the degree of ICAS; as well as the relationship between the degree of EPVS and white matter hyperintensity (WMH). Method: A total of 202 patients with or without ICAS diagnosed by DSA were enrolled. The maximal ICAS rates, the degrees of EPVS and WMH were measured. The patients’ clinical characteristics and laboratory parameters were recorded. Univariable analysis and multivariable regression were used to test their correlations. In a unilateral stenosis subgroup, the EPVSs in the ipsilateral hemisphere of stenosis and in the contralateral hemisphere were compared. Results: According to univariable analysis, there were significant differences in age (P = .000), Hg1bc (P = .035) and folic acid (P = .008) among the subgroups based on the degrees of EPVS in the basal ganglia (BG). Age (P = .000) and the level of fibrinogen (P = .018) differed statistically among the subgroups based on the degrees of EPVS in the white matter (WM). The correlation between the degrees of WM-EPVS and the ICAS levels was tested with a gamma test: G = .280, P = .001. The ordinal multivariable regression model showed that age was independently associated with both BG-EPVSs and WM-EPVSs. A current smoker status was also independently associated with WM-EPVSs. ICAS level was associated with the severity of WM-EPVSs after adjusting for other risk factors. The degree of BG-EPVS was not correlated with the degree of stenosis. (P = .101). In 59 patients with unilateral ICAS, as tested by the Wilcoxon signed ranks test, the WM-EPVS scores in the ipsilateral hemisphere of stenosis were higher than those in the contralateral hemisphere. (P = .004), but there was no difference in BG-EPVSs (P = .070). Both BG-EPVSs and WM-EPVSs were independently correlated with WMH. Conclusions: BG-EPVSs and WM-EPVSs have different risk factors. WM-EPVSs but not BG-EPVSs are correlated with ICAS.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Stroke and Cerebrovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Pantoni L.
        Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges.
        Lancet Neurol. 2010; 9: 689-701
        • Wardlaw J.M.
        • Smith E.E.
        • Biessels G.J.
        • et al.
        Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.
        Lancet Neurol. 2013; 12: 822-838
        • Gutierrez J.
        • Rundek T.
        • Ekind M.S.V.
        • et al.
        Perivascular spaces are associated with atherosclerosis: an insight from the Northern Manhattan Study.
        AJNR Am J Neuroradiol. 2013; 34: 1711-1716
        • Zhu Y.-C.
        • Tzourio C.
        • Soumare A.
        • et al.
        Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease a population-based study.
        Stroke. 2010; 41: 2483-2490
        • Chutinet A.
        • Biffi A.
        • Kanakis A.
        • et al.
        Severity of leukoaraiosis in large vessel atherosclerotic disease.
        AJNR Am J Neuroradiol. 2012; 33: 1591-1595
        • Schulz U.G.
        • Grüter B.E.
        • Briley D.
        • et al.
        Leukoaraiosis and increased cerebral susceptibility to ischemia: lack of confounding by carotid disease.
        J Am Heart Assoc. 2013; 2e000261
        • Enzinger C.
        • Ropele S.
        • Gattringer T.
        • et al.
        High-grade internal carotid artery stenosis and chronic brain damage: a volumetric magnetic resonance imaging study.
        Cerebrovasc Dis. 2010; 30: 540-546
        • Duan W.
        • Pu Y.
        • Liu H.
        • et al.
        Association between leukoaraiosis and symptomatic intracranial large artery stenoses and occlusions: the Chinese Intracranial Atherosclerosis (CICAS) Study.
        Aging Dis. 2018; 9: 1074-1083
        • Boulouis G.
        • Charidimou A.
        • Auriel E.
        • et al.
        Intracranial atherosclerosis and cerebral small vessel disease in intracerebral hemorrhage patients.
        J Neurol Sci. 2016; 369: 324-329
        • Romero J.R.
        • Preis S.R.
        • Beiser A.
        • et al.
        Atherosclerosis and cerebral microbleeds: the Framingham Heart Study.
        J Am Heart Assoc. 2016; 5e002377
        • Sahin N.
        • Solak A.
        • Genc B.
        • et al.
        Dilatation of the Virchow-Robin spaces as an indicator of unilateral carotid artery stenosis: correlation with white matter lesions.
        Acta Radiol. 2015; 56: 852-859
        • Zhai F.F.
        • Ye Y.C.
        • Chen S.Y.
        • et al.
        Arterial stiffness and cerebral small vessel disease.
        Front Neurol. 2018; 9: 723
        • Riba-Llena I.
        • Jimenez-Balado J.
        • Castane X.
        • et al.
        Arterial stiffness is associated with basal ganglia enlarged perivascular spaces and cerebral small vessel disease load.
        Stroke. 2018; 49: 1279-1281
        • Del Brutto O.H.
        • Mera R.M.
        Enlarged perivascular spaces in the basal ganglia are independently associated with intracranial atherosclerosis in the elderly.
        Atherosclerosis. 2017; 267: 34-38
        • Lu T.
        • Liang J.
        • Wei N.
        • et al.
        Extracranial artery stenosis is associated with total MRI burden of cerebral small vessel disease in ischemic stroke patients of suspected small or large artery origins.
        Front Neurol. 2019; 10: 243
        • Doubal F.N.
        • MacLullich A.M.
        • Ferguson K.J.
        • et al.
        Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease.
        Stroke. 2010; 41: 450-454
        • Brown R.
        • Benveniste H.
        • Black S.E.
        • et al.
        Understanding the role of the perivascular space in cerebral small vessel disease.
        Cardiovasc Res. 2018; 114: 1462-1473
        • Yang H.
        • Shen R.
        • Jin Z.
        • et al.
        Dilated Virchow-Robin spaces in first-ever lacunar stroke patients: topography and clinical correlations.
        J Stroke Cerebrovasc Dis. 2016; 25: 306-311
        • Yamada S.
        • Ishikawa M.
        • Yamamoto K.
        • et al.
        Location-specific characteristics of perivascular spaces as the brain's interstitial fluid drainage system.
        J Neurol Sci. 2019; 398: 9-15
        • Rasmussen M.K.
        • Mestre H.
        • Nedergaard M.
        The glymphatic pathway in neurological disorders.
        Lancet Neurol. 2018; 17: 1016-1024
        • Mestre H.
        • Tithof J.
        • Du T.
        • et al.
        Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension.
        Nat Commun. 2018; 9: 4878
        • Zhai F.F.
        • Yan S.
        • Li M.L.
        • et al.
        Intracranial arterial dolichoectasia and stenosis: risk factors and relation to cerebral small vessel disease.
        Stroke. 2018; 49: 1135-1140
        • Committee NASCETNS
        North American symptomatic carotid endarterectomy trial methods, patient characteristics, and progress.
        Stroke. 1991; 22: 711-720
        • Inzitari D.
        • Pracucci G.
        • Poggesi A.
        • et al.
        Changes in white matter as determinant of global functional decline in older independent outpatients: three year followup of LADIS (leukoaraiosis and disability) study cohort.
        BMJ. 2009; 339: b2477
        • Zhang C.
        • Chen Q.
        • Wang Y.
        • et al.
        Risk factors of dilated Virchow-Robin spaces are different in various brain regions.
        PLoS One. 2014; 9e105505
        • Duperron M.G.
        • Tzourio C.
        • Sargurupremraj M.
        • et al.
        Burden of dilated perivascular spaces, an emerging marker of cerebral small vessel disease, is highly heritable.
        Stroke. 2018; 49: 282-287
        • Shams S.
        • Martola J.
        • Charidimou A.
        • et al.
        Topography and determinants of Magnetic Resonance Imaging (MRI)-visible perivascular spaces in a large memory clinic cohort.
        J Am Heart Assoc. 2017; 6e006279
        • Shi Y.
        • Thrippleton M.J.
        • Blair G.W.
        • et al.
        Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow.
        J Cereb Blood Flow Metab. 2020; 40: 85-99
        • Pollock H.
        • Hutchings M.
        • Weller R.O.
        • et al.
        Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes.
        J Anat. 1997; 191: 337-346
        • Ishikawa M.
        • Yamada S.
        • Yamamoto K.
        Three-dimensional observation of Virchow-Robin spaces in the basal ganglia and white matter and their relevance to idiopathic normal pressure hydrocephalus.
        Fluids Barriers CNS. 2015; 12: 15
        • Park A.Y.
        • Chung T.-S.
        • Suh S.H.
        • et al.
        Asymmetric Dilatation of Virchow-Robin space in unilateral internal carotid artery steno-occlusive disease.
        J Comput Assist Tomogr. 2011; 35: 298-302
        • Charidimou A.
        • Jaunmuktane Z.
        • Baron J.-C.
        • et al.
        White matter perivascular spaces An MRI marker in pathology-proven cerebral amyloid angiopathy?.
        Neurology. 2014; 82: 57-62
        • Roher A.E.
        • Kuo Y.-M.
        • Esh C.
        • et al.
        Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's Disease.
        Mol Med. 2003; 9: 112-122
        • Saji N.
        • Ogama N.
        • Toba K.
        • et al.
        White matter hyperintensities and geriatric syndrome: an important role of arterial stiffness.
        Geriatr Gerontol Int. 2015; 15: 17-25
        • Lau K.K.
        • Pego P.
        • Mazzucco S.
        • et al.
        Age and sex-specific associations of carotid pulsatility with small vessel disease burden in transient ischemic attack and ischemic stroke.
        Int J Stroke. 2018; 13: 832-839