We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Differing risk factors and outcomes in ischemic stroke subtypes: focus on lacunar stroke

    Joanna M Wardlaw

    Brain Research Imaging Centre, Edinburgh, SINAPSE Collaboration, c/o Division of Clinical Neurosciences, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.

    Published Online:https://doi.org/10.2217/fnl.11.1

    Lacunar stroke has been a recognized stroke subtype for many years but its pathophysiology remains unknown, so prevention and treatment are suboptimal. Most lacunar strokes result from an intrinsic cerebral small vessel disease, probably part of a systemic disorder. Hypertension, diabetes and other vascular risk factors (but not atrial fibrillation and ipsilateral carotid stenosis) are equally common in lacunar as in large artery atherothromboembolic stroke, which, together with other factors, suggests that the patient’s response to vascular risk factors, not the vascular risk factors per se, determines whether they develop small vessel or large artery stroke. Inflammation and endothelial failure are probably involved in the pathogenesis of lacunar stroke, but their role needs to be clarified. The cerebral venules as well as arterioles are abnormal in this condition. The disorder may not be primarily ischemic; instead, arteriolar thrombosis may be a late-stage phenomenon secondary to chronic arteriolar wall damage resulting from leakage of plasma components across the BBB. Accurate diagnosis of lacunar stroke, avoiding risk factor-based classifications, is required to underpin future research.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL: Global and regional burden of disease and risk factors, (2001): systematic analysis of population health data. Lancet367,1747–1757 (2006).
    • Sudlow CLM, Warlow CP: Comparable studies of the incidence of stroke and its pathological types. Results from an international collaboration. Stroke28,491–499 (1997).
    • Donnan GA, Norrving B, Bamford JM, Bogousslavsky J: Subcortical infarction: classification and terminology. Cerebrovasc. Dis.3,248–251 (1993).
    • Bamford JM, Warlow CP: Evolution and testing of the lacunar hypothesis. Stroke19(9),1074 (1988).
    • Bamford J, Sandercock P, Dennis M, Burn J, Warlow C: Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet337(8756),1521–1526 (1991).
    • Fisher CM: Lacunar infarcts – a review. Cerebrovasc. Dis.1,311–320 (1991).▪▪ Important review of the pathological knowledge of lacunar infarcts.
    • Futrell N: Lacunar infarction. Embolism is the key. Stroke35,1778–1779 (2004).▪ Along with [8,9], summarizes the debate concerning possible mechanisms for lacunar stroke.
    • Norrving B: Lacunar infarction. Embolism is the key: against. Stroke35,1778–1779 (2004).▪ Along with [7,9], summarizes the debate concerning possible mechanisms for lacunar stroke.
    • Davis SM, Donnan GA: Why lacunar syndromes are different and important. Stroke35,1779–1780 (2004).▪ Along with [7,8], summarizes the debate concerning possible mechanisms for lacunar stroke.
    • 10  Wardlaw JM: What causes lacunar stroke? J. Neurol. Neurosurg. Psychiatry76(5),617–619 (2005).
    • 11  Jackson CA, Sudlow CLM: Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and non-lacunar infarcts. Stroke36,891–904 (2005).▪ Systematic review of common vascular risk factors for lacunar stroke.
    • 12  Samuelsson M, Soderfeldt B, Olsson GB: Functional outcome in patients with lacunar infarction. Stroke27(5),842–846 (1996).
    • 13  Sacco S, Marini C, De Santis F, Baldassarre M, Olivieri L, Carolei A: Risk factors and prognosis of lacunar stroke in a population study. Cerebrovasc. Dis.16(Suppl. 4),4 (2003).
    • 14  Voisin T, Rous de Feneyrols AR, Pavy Le Traon A, Larrue V: Cognitive impairment after first lacunar stroke: clinical features and risk factors. Cerebrovasc. Dis.13(Suppl. 3),297 (2002).
    • 15  Schmidt R, Enzinger C, Ropele S, Schmidt H, Fazekas F: Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet361,2046–2048 (2003).
    • 16  Gouw AA, van der Flier WM, Fazekas F et al.: Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period. The Leukoaraiosis and Disability Study. Stroke39,1414–1420 (2008).
    • 17  Jackson CA, Hutchison A, Dennis MS, Wardlaw JM, Lewis SC, Sudlow CL: Differences between ischemic stroke subtypes in vascular outcomes support a distinct lacunar ischemic stroke arteriopathy. A prospective, hospital-based study. Stroke40,3679–3684 (2009).
    • 18  Leys D, Englund E, Del Ser T et al.: White matter changes in stroke patients. Relationship with stroke subtype and outcome. Eur. Neurol.42(2),67–75 (1999).
    • 19  Wiszniewska M, Devuyst G, Bogousslavsky J, Ghika J, van Melle G: What is the significance of leukoaraiosis in patients with acute iscahemic stroke? Arch. Neurol.57,967–973 (2000).
    • 20  Inzitari D: Leukoaraiosis. An independent risk factor for stroke? Stroke34,2067–2071 (2003).
    • 21  Mantyla R, Aronen HJ, Salonen O, Pohjasvaara T, Korpelain M, Peltonen T: Magnetic resonance imaging white matter hyperintensities and mechanism of ischemic stroke. Stroke30,2053–2058 (1999).
    • 22  Wen W, Sachdev PS: Extent and distribution of white matter hyperintensities in stroke patients. The Sydney Stroke Study. Stroke35(12),2813–2819 (2004).
    • 23  Boon A, Lodder J, Heuts-van Raak L, Kessels F: Silent brain infarcts in 755 consecutive patients with a first-ever supratentorial ischemic stroke. Relationship with index-stroke subtype, vascular risk factors, and mortality. Stroke25(12),2384–2390 (1994).
    • 24  Vermeer SE, Longstreth WT Jr, Koudstaal PJ: Silent brain infarcts: a systematic review. Lancet Neurol.6(7),611–619 (2007).▪ Systematic review of the frequency and associations of silent infarction (i.e., lacunes).
    • 25  Cordonnier C, Al-Shahi Salman R, Wardlaw J: Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain130(8),1988–2003 (2007).▪ Systematic review of the frequency and associations of microbleeds.
    • 26  Doubal FN, MacLullich AM, Ferguson KJ, Dennis MS, Wardlaw JM: Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke41(3),450–454 (2010).▪ Observational study of enlarged perivascular spaces in lacunar and cortical stroke.
    • 27  Deary IJ, Leaper SA, Murray AD, Staff RT, Whalley LJ: Cerebral white matter abnormalities and lifetime cognitive change: a 67-year follow-up of the Scottish Mental Survey of 1932 . Psychol. Aging18(1),140–148 (2003).
    • 28  Wen HM, Mok VC, Fan YH et al.: Effect of white matter changes on cognitive impairment in patients with lacunar infarcts. Stroke35(8),1826–1830 (2004).
    • 29  Jokinen H, Kalska H, Mantyla R et al.: White matter hyperintensities as a predictor of neuropsychological deficits post-stroke. J. Neurol. Neurosurg. Psychiatry76(9),1229–1233 (2005).
    • 30  Jokinen H, Kalska H, Ylikoski R et al.: Longitudinal cognitive decline in subcortical ischemic vascular disease – the LADIS Study. Cerebrovasc. Dis.27(4),384–391 (2009).
    • 31  Miyao S, Takano A, Teramoto J, Takahashi A: Leukoaraiosis in relation to prognosis for patients with lacunar infarction. Stroke23(10),1434–1438 (1992).
    • 32  Kuller LH, Longstreth WT Jr, Arnold AM, Bernick C, Bryan RN, Beauchamp NJ Jr: White matter hyperintensity on crainal magnetic resonance imaging. A predictor of stroke. Stroke35(8),1821–1825 (2004).
    • 33  Samuelsson M, Lindell D, Olsson G-B: Lacunar infarcts: a 1-year clinical and MRI follow-up study. Cerebrovasc. Dis.4,265–272 (1994).
    • 34  Yamamoto H, Bogousslavsky J: Mechanisms of second and further strokes. J. Neurol. Neurosurg. Psychiatry64(6),771–776 (1998).
    • 35  van Zagten M, Boiten J, Kessels F, Lodder J: Significant progression of white matter lesions and small deep (lacunar) infarcts in patients with stroke. Arch. Neurol.53(7),650–655 (1996).
    • 36  Anderson JF, Saling MM, Srikanth VK, Thrift AG, Donnan GA: Individuals with first-ever clinical presentation of a lacunar infarction syndrome: is there an increased likelihood of developing mild cognitive impairment in the first 12 months after stroke? J. Neuropsychol.2(Pt 2),373–385 (2008).
    • 37  Baloh RW, Vinters HV: White matter lesions and disequilibrium in older people. II. Clinicopathologic correlation. Arch. Neurol.52(10),975–981 (1995).
    • 38  Colledge N, Lewis S, Mead G, Sellar R, Wardlaw J, Wilson J: Magnetic resonance brain imaging in people with dizziness: a comparison with non-dizzy people. J. Neurol. Neurosurg. Psychiatry72(5),587–589 (2002).
    • 39  Lammie GA: Pathology of small vessel stroke. Br. Med. Bull.56(2),296–306 (2000).▪ Review of pathology studies of the causes of lacunar stroke.
    • 40  Ogata J: The arterial lesions underlying cerebral infarction. Neuropathology19,112–118 (1999).
    • 41  Challa VR, Bell MA, Moody DM: A combined hematoxylin-eosin, alkaline phosphatase and high-resolution microradiographic study of lacunes. Clin. Neuropathol.9(4),196–204 (1990).
    • 42  Arboix A, Marti-Vilalta JL: Estudio de los infartos lacunares a partir del analisis de las principales series anatomopatologicas de la literatura. Rev. Neurol.26(151),365–367 (1998).
    • 43  Gouw AA, Seewann A, van der Flier WM et al.: Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J. Neurol. Neurosurg. Psychiatry82(2),126–135 (2011).
    • 44  Mead GE, Lewis S, Wardlaw JM, Dennis MS, Warlow CP: Should computed tomography appearance of lacunar stroke influence patient management? J. Neurol. Neurosurg. Psychiatry67,682–684 (1999).
    • 45  Lindgren A, Staaf G, Geijer B et al.: Clinical lacunar syndromes as predictors of lacunar infarcts. A comparison of acute clinical lacunar syndromes and findings on diffusion-weighted MRI. Acta Neurol. Scand.101(2),128–134 (2000).
    • 46  Toni D, Iweins F, von Kummer R et al.: Identification of lacunar infarcts before thrombolysis in the ECASS I study. Neurology54(3),684–688 (2000).
    • 47  Potter G, Doubal F, Jackson C, Sudlow C, Dennis M, Wardlaw J: Associations of clinical stroke misclassification (‘clinical-imaging dissociation’) in acute ischemic stroke. Cerebrovasc. Dis.29(4),395–402 (2010).
    • 48  Adams HP, Jr., Bendixen BH, Kappelle LJ et al.: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of ORG 10172 in Acute Stroke Treatment. Stroke24(1),35–41 (1993).
    • 49  Landau WM, Nassief A: Editorial comment – time to burn the TOAST. Stroke36(4),902–904 (2005).
    • 50  Thompson CS, Hakim AM: Living beyond our physiological means. Small vessel disease of the brain is an expression of a systemic failure in arteriolar function: a unifying hypothesis. Stroke40,E322–E330 (2009).▪▪ Review of systemic abnormalities in cerebral small vessel disease.
    • 51  Pantoni L, Sarti C, Alafuzoff I et al.: Postmortem examination of vascular lesions in cognitive impairment: a survey among neuropathological services. Stroke37(4),1005–1009 (2006).
    • 52  Potter GM, Marlborough FJ, Wardlaw JM: Wide variation in definition, detection and description of lacunar lesions on imaging. Stroke42(2),359–366 (2011).▪ Systematic review and survey of experts on the definitions and diagnosis of imaging features of lacunar stroke.
    • 53  Wardlaw JM: What is a lacune? Stroke39,2921–2922 (2008).▪ Discussion about lacunes and their relevance to the wider picture of small vessel disease.
    • 54  Potter GM, Doubal FN, Jackson CA et al.: Counting cavitating lacunes underestimates the burden of lacunar infarction. Stroke41,267–272 (2010).
    • 55  Fisher CM: Lacunes: small, deep cerebral infarcts. Neurology15,774–784 (1965).
    • 56  Jackson CA, Hutchison A, Dennis MS et al.: Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy? Stroke41,624–629 (2010).▪▪ Systematic review and individual patient data meta-analysis of common vascular risk factors for small vessel and large artery ischemic stroke.
    • 57  Adachi T, Kobayashi S, Yamaguchi S, Okada K: MRI findings of small subcortical ‘lacunar-like’ infarction resulting from large vessel disease. J. Neurol.247,280–285 (2002).
    • 58  Baumgartner RW, Sidler C, Mosso M, Georgiadis D: Ischemic lacunar stroke in patients with and without potential mechanism other than small-artery disease. Stroke34,653–659 (2003).
    • 59  Tegeler CH, Shi F, Morgan T: Carotid stenosis in lacunar stroke. Stroke22(9),1124 (1991).
    • 60  Kazui S, Levi CR, Jones EF, Quang L, Calafiore P, Donnan G: Lacunar stroke: transoesophageal echocardiographic factors influencing long-term prognosis. Cerebrovasc. Dis.12,325–330 (2001).
    • 61  Mead GE, Lewis SC, Wardlaw JM, Dennis MS, Warlow CP: Severe ipsilateral carotid stenosis and middle cerebral artery disease in lacunar ischemic stroke: innocent bystanders? J. Neurol.249(3),266–271 (2002).
    • 62  Ay H, Oliveira-Filho J, Buonanno FS et al.: Diffusion-weighted imaging identifies a subset of lacunar infarction associated with embolic source. Stroke30(12),2644–2650 (1999).
    • 63  Uehara T, Tabuchi M, Mori E: Occlusive lesions of carotid and intracranial arteries in patients with symptomatic lacunar infarction – evaluation by MR angiography. Rinsho Shinkeigaku37,796–801 (1997).
    • 64  Tejada J, Diez-Tejedor E, Hernandez-Echebarria L, Balboa O: Does a relationship exist between carotid stenosis and lacunar infarction? Stroke34,1404–1411 (2003).
    • 65  Read SJ, Pettigrew L, Schimmel L et al.: White matter medullary infarcts: acute subcortical infarction in the centrum ovale. Cerebrovasc. Dis.8(5),289–295 (1998).
    • 66  Seifert T, Enzinger C, Storch MK, Pichler G, Niederkorn K, Fazekas F: Acute small subcortical infarctions on diffusion weighted MRI: clinical presentation and aetiology. J. Neurol. Neurosurg. Psychiatry76(11),1520–1524 (2005).
    • 67  Norrving B: Are multiple acute small subcortical infarctions caused by embolic mechanisms? J. Neurol. Neurosurg. Psychiatry75(10),1375 (2004).
    • 68  Kappelle LJ, Koudstaal PJ, van Gijn J, Ramos LM, Keunen JE: Carotid angiography in patients with lacunar infarction. A prospective study. Stroke19(9),1093–1096 (1988).
    • 69  Macdonald RL, Kowalczuk A, Johns L: Emboli enter penetrating arteries of monkey brain in relation to their size. Stroke26,1247–1251 (1995).
    • 70  de Jong G, Kessels F, Lodder J: Two types of lacunar infarcts: further arguments from a study on prognosis. Stroke33(8),2072–2076 (2002).
    • 71  Jung DK, Devuyst G, Maeder P, Bogousslavsky J: Atrial fibrillation with small subcortical infarcts. J. Neurol. Neurosurg. Psychiatry70,344–349 (2001).
    • 72  Fisher CM: Capsular infarcts: the underlying vascular lesions. Arch. Neurol.36,65 (1979).
    • 73  Chowdhury D, Wardlaw JM, Dennis MS: Are multiple acute small subcortical infarctions caused by embolic mechanisms? J. Neurol. Neurosurg. Psychiatry75(10),1416–1420 (2004).
    • 74  Bots ML, van Swieten JC, Breteler MM et al.: Cerebral white matter lesions and atherosclerosis in the Rotterdam Study. Lancet341(8855),1232–1237 (1993).
    • 75  Manolio TA, Burke GL, O’Leary DH et al.: Relationships of cerebral MRI findings to ultrasonographic carotid atherosclerosis in older adults: the Cardiovascular Health Study. CHS Collaborative Research Group. Arterioscler. Thromb. Vasc. Biol.19(2),356–365 (1999).
    • 76  Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJM; for the Carotid Endarterectomy Trialists’ Collaboration: Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroup and timing of surgery. Lancet363,915–924 (2004).
    • 77  Amarenco P, Cohen A, Tzourio C et al.: Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N. Engl. J. Med.331(22),1474–1479 (1994).
    • 78  Nguyen TN, Kidwell CS, Rubenstein E, Saver JL: Cardioembolism as a potential cause of single penetrator (lacunar) strokes. Stroke34(1),271 (2003).
    • 79  Li H, Wong KS: Racial distribution of intracranial and extracranial atherosclerosis. J. Clin. Neurosci.10(1),30–34 (2003).
    • 80  Wong KS, Li H: Long-term mortality and recurrent stroke risk among Chinese stroke patients with predominant intracranial atherosclerosis. Stroke34(10),2361–2366 (2003).
    • 81  Huang HW, Guo MH, Lin RJ et al.: Prevalence and risk factors of middle cerebral artery stenosis in asymptomatic residents in Rongqi County, Guangdong. Cerebrovasc. Dis.24(1),111–115 (2007).
    • 82  Lyrer PA, Engelter S, Radu EW, Steck AJ: Cerebral infarcts related to isolated middle cerebral artery stenosis. Stroke28(5),1022–1027 (1997).
    • 83  Lee PH, Oh SH, Bang OY, Joo SY, Joo IS, Huh K: Infarct patterns in atherosclerotic middle cerebral artery versus internal carotid artery disease. Neurology62(8),1291–1296 (2004).
    • 84  Bang OY, Joo SY, Lee PH et al.: The course of patients with lacunar infarcts and a parent arterial lesion: similarities to large artery vs small artery disease. Arch. Neurol.61,514–519 (2004).
    • 85  Bang OY, Heo JH, Kim JY, Park JH, Huh K: Middle cerebral artery stenosis is a major clinical determinant in striatocapsular small, deep infarction. Arch. Neurol.59(2),259–263 (2002).
    • 86  Baracchini C, Manara R, Ermani M, Meneghetti G: The quest for early predictors of stroke evolution: can TCD be a guiding light? Stroke31(12),2942–2947 (2000).
    • 87  Mead GE, Wardlaw JM, Dennis MS, Lewis SC, Warlow CP: Relationship between pattern of intracranial artery abnormalities on transcranial Doppler and Oxfordshire Community Stroke Project clinical classification of ischemic stroke. Stroke31(3),714–719 (2000).
    • 88  Allendoerfer J, Goertler M, von Reutern GM: Prognostic relevance of ultra-early doppler sonography in acute ischemic stroke: a prospective multicentre study. Lancet Neurol.5(10),835–840 (2006).
    • 89  Zanette EM, Fieschi C, Bozzao L et al.: Comparison of cerebral angiography and transcranial Doppler sonography in acute stroke. Stroke20(7),899–903 (1989).
    • 90  Mazighi M, Labreuche J, Gongora-Rivera F, Duyckaerts C, Hauw JJ, Amarenco P: Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke. Stroke39(4),1142–1147 (2008).
    • 91  Klein IF, Labreuche J, Lavallee PC et al.: Is moderate atherosclerotic stenosis in the middle cerebral artery a cause of or a coincidental finding in ischemic stroke? Cerebrovasc. Dis.29(2),140–145 (2010).
    • 92  Bos MJ, Koudstaal PJ, Hofman A, Witteman JCM, Breteler MMB: Transcranial Doppler hemodynamic parameters and risk of stroke: the Rotterdam study. Stroke38(9),2453–2458 (2007).
    • 93  van Popele NM, Grobbee DE, Bots ML et al.: Association between arterial stiffness and atherosclerosis: the Rotterdam Study. Stroke32(2),454–460 (2001).
    • 94  Cupini LM, Pasqualetti P, Diomedi M et al.: Carotid artery intima-media thickness and lacunar versus nonlacunar infarcts. Stroke33(3),689–694 (2002).
    • 95  Fulton A, Stanton A, Moroney J: Direct comparison of microvascular endothelial function and carotid intima–media thickness in patients with large vessel and small vessel ischemic stroke. Cerebrovasc. Dis.21(Suppl. 4),22 (2006).
    • 96  Shenkin SD, Bastin ME, MacGillivray TJ et al.: Carotid intima media thickness and cerebrovascular disease in community-dwelling older people without stroke. Stroke41(9),2083–2086 (2010).
    • 97  Paternoster L, Gonzalez NA, Lewis S, Sudlow C: Association between apolipoprotein E genotype and carotid intima–media thickness may suggest a specific effect on large artery atherothrombotic stroke. Stroke39(1),48–54 (2008).
    • 98  Pico F, Labreuche J, Seilhean D, Duyckaerts C, Hauw J-J, Amarenco P: Association of small-vessel disease with dilatative arteriopathy of the brain: neuropathological evidence. Stroke38,1197–1202 (2007).
    • 99  Ince B, Petty GW, Brown RD, Chu CP, Sicks JD, Whisnant JP: Dolichoectasia of the intracranial arteries in patients with first ischemic stroke: a population-based study. Neurology50(6),1694–1698 (1998).
    • 100  Pico F, Labreuche J, Touboul P-J, Amarenco P: Intracranial arterial dolichoectasia and its relation with atherosclerosis and stroke subtype. Neurology61,1736–1742 (2003).
    • 101  Bailey EL, McCulloch J, Sudlow C, Wardlaw JM: Potential animal models of lacunar stroke. A systematic review. Stroke40,E451–E458 (2009).▪ Along with [165], presents a systematic review of potential models of lacunar stroke and what they tell us about potential mechanisms.
    • 102  Wong TY: Is retinal photography useful in the measurement of stroke risk? Lancet Neurol.3(3),179–183 (2004).
    • 103  Patton N, Aslam T, MacGillivray T, Pattie A, Deary IJ, Dhillon B: Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J. Anat.206(4),319–348 (2005).
    • 104  Doubal FN, Hokke PE, Wardlaw JM: Retinal microvascular abnormalities and stroke: a systematic review. J. Neurol. Neurosurg. Psychiatry80,158–165 (2009).▪ Along with [105], presents a systematic reviews of retinal vascular signs and stroke.
    • 105  Baker ML, Hand PJ, Wang JJ, Wong TY: Retinal signs and stroke: revisiting the link between the eye and brain. Stroke39(4),1371–1379 (2008).▪ Along with [104], presents a systematic reviews of retinal vascular signs and stroke.
    • 106  Wong TY, Klein R, Couper DJ et al.: Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet358(9288),1134–1140 (2001).
    • 107  Mitchell P, Wang JJ, Wong TY, Smith W, Klein R, Leeder SR: Retinal microvascular signs and risk of stroke and stroke mortality. Neurology65(7),1005–1009 (2005).
    • 108  Kwa VIH, van der Sande JJ, Stam J, Tijmes N, Vrooland JL: Retinal arterial changes correlate with cerebral small-vessel disease. Neurology59,1536–1540 (2002).
    • 109  Wong TY, Klein R, Sharrett AR et al.: Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA288(1),67–74 (2002).
    • 110  Klein R, Sharrett AR, Klein BEK et al.: Are retinal arteriolar abnormalities related to atherosclerosis? The Atherosclerosis Risk in Communities Study. Arterioscler. Thromb. Vasc. Biol.20,1644–1650 (2000).
    • 111  Doubal FN, Dhillon B, Dennis MS, Wardlaw JM: Retinopathy in ischemic stroke subtypes. Stroke40,389–393 (2009).
    • 112  Doubal FN, MacGillivray TJ, Hokke PE, Dhillon B, Dennis MS, Wardlaw JM: Differences in retinal vessels support a distinct vasculopathy causing lacunar stroke. Neurology72,1773–1778 (2009).▪ Along with [113], consists of two parallel but independent cohort studies of retinal vessels in lacunar and cortical stroke.
    • 113  Lindley RI, Wang JJ, Wong MC et al.: Retinal microvasculature in acute lacunar stroke: a cross-sectional study. Lancet Neurol.8(7),628–634 (2009).▪ Along with [112], consists of two parallel but independent cohort studies of retinal vessels in lacunar and cortical stroke.
    • 114  Doubal F, De Haan R, MacGillivray T et al.: Retinal arteriolar geometry is associated with cerebral white matter hyperintensities on MRI. Int. J. Stroke5(6),434–439 (2010).
    • 115  Baker ML, Wang JJ, Liew G et al.: Differential associations of cortical and subcortical cerebral atrophy with retinal vascular signs in patients with acute stroke. Stroke41,2143–2150 (2010).
    • 116  de Jong FJ, Ikram MK, Witteman JC, Hofman A, de Jong PT, Breteler MM: Retinal vessel diameters and the role of inflammation in cerebrovascular disease. Ann. Neurol.61(5),491–495 (2007).
    • 117  Black S, Gao F, Bilbao J: Understanding white matter disease. Imaging–pathological correlations in vascular cognitive impairment. Stroke40(Suppl. 1),S48–S52 (2009).▪▪ Review of pathology, including venular disease, in cerebral small vessel disease.
    • 118  Brown WR, Moody DM, Challa VR, Thore CR, Anstrom JA: Venous collagenosis and arteriolar tortuosity in leukoaraiosis. J. Neurol. Sci203–204, 159–163 (2002).
    • 119  McGeechan K, Liew G, Macaskill P et al.: Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis. Am. J. Epidemiol.170(11),1323–1332 (2009).
    • 120  Tanoi Y, Okeda R, Budka H: Binswanger’s encephalopathy: serial sections and morphometry of the cerebral arteries. Acta Neuropathol.100(4),347–355 (2000).
    • 121  Matsushita K, Kuriyama Y, Nagatsuka K, Nakamura M, Sawada T, Omae T: Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients. Hypertension23(5),565–568 (1994).
    • 122  Bakker SLM, de Leeuw F-E, de Groot JC, Hofman A, Koudstaal PJ, Breteler MMB: Cerebral vasomotor reactivity and cerebral white matter lesions in the elderly. Neurology52,578–583 (1999).
    • 123  Terborg C, Gora F, Weiller C, Rother J: Reduced vasomotor reactivity in cerebral microangiopathy: a study with near-infrared spectroscopy and transcranial Doppler sonography. Stroke31(4),924–929 (2000).
    • 124  O’Sullivan M, Lythgoe DJ, Pereira AC et al.: Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis. Neurology59(3),321–326 (2002).
    • 125  Kobari M, Meyer JS, Ichijo M, Oravez WT: Leukoaraiosis: correlation of MR and CT findings with blood flow, atrophy, and cognition. Am. J. Neuroradiol.11,273–281 (1990).
    • 126  Appelman APA, van der Graaf Y, Vincken KL et al.: Total cerebral blood flow, white matter lesions and brain atrophy: the SMART-MR study. J. Cereb. Blood Flow Metab.28,633–639 (2008).
    • 127  Herholz K, Heindel W, Rackl A et al.: Regional cerebral blood flow in patients with leuko-araiosis and atherosclerotic carotid artery disease. Arch. Neurol.47,392–396 (1990).
    • 128  Capizzano AA, Schuff N, Amend DL et al.: Subcortical ischemic vascular dementia: assessment with quantitative MR imaging and 1H MR spectroscopy. Am. J. Neuroradiol.21,621–630 (2000).
    • 129  Yao H, Yuzuriha T, Fukuda K et al.: Cerebral blood flow in nondemented elderly subjects with extensive deep white matter lesions on magnetic resonance imaging. J. Stroke Cerebrovasc. Dis.9(4),172–175 (2000).
    • 130  Calamante F, Gadian DG, Connelly A: Quantification of perfusion using bolus tracking magnetic resonance imaging in stroke: assumptions, limitations, and potential implications for clinical use. Stroke33(4),1146–1151 (2002).
    • 131  Carpenter T, Armitage PA, Bastin ME, Wardlaw JM: DSC perfusion MRI – quantification and reduction of systematic errors arising in areas of reduced cerebral blood flow. Magn. Reson. Med.55(6),1342–1349 (2006).
    • 132  Blamire A, Styles P: Does contrast based perfusion imaging give the right answer in pathological tissue? A Monte Carlo simulation study. Proc. Int. Soc. Magn. Reson. Med.9,1586 (2001).
    • 133  Wardlaw JM, Doubal FN, Eadie E, Chappell F, Shuler K, Cvoro V: Little association between intracranial arterial stenosis and lacunar stroke. Cerebrovasc. Dis.31,12–18 (2011).
    • 134  Knottnerus ILH, Ten Cate H, Lodder J, Kessels F, van Oostenbrugge RJ: Endothelial dysfunction in lacunar stroke: a systematic review. Cerebrovasc. Dis.27,519–526 (2009).▪ Along with [135], consists of two systematic reviews of endothelial function in lacunar stroke.
    • 135  Stevenson SF, Doubal FN, Shuler K, Wardlaw JM: A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls. Stroke41,E434–E442 (2010).▪ Along with [134], consists of two systematic reviews of endothelial function in lacunar stroke.
    • 136  Girouard H, Iadecola C: Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J. Appl. Physiol.100(1),328–335 (2006).
    • 137  Webb DJ: The pharmacology of human blood vessels in vivo. J. Vasc. Res.32(1),2–15 (1995).
    • 138  Newby DE, McLeod AL, Uren NG et al.: Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. Circulation103(15),1936–1941 (2001).
    • 139  Hassan A, Hunt BJ, O’Sullivan M et al.: Markers of endothelial dysfunction in lacunar infarction and ischemic leukoaraiosis. Brain126,424–432 (2003).
    • 140  Di Napoli M, Papa F: C-reactive protein and cerebral small-vessel disease: an opportunity to reassess small-vessel disease physiopathology? Circulation112(6),781–785 (2005).
    • 141  Markus HS, Hunt B, Palmer K, Enzinger C, Schmidt H, Schmidt R: Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities. Longitudinal results of the Austrian Stroke Prevention Study. Stroke36(7),1410–1414 (2005).
    • 142  Lowe GDO, Lee AJ, Rumley A, Price JF, Fowkes FGR: Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br. J. Haematol.96,168–173 (1997).
    • 143  Smith FB, Lee AJ, Fowkes FGR, Price JF, Rumley A, Lowe GDO: Haemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler. Thromb. Vasc. Biol.17,3321–3325 (1997).
    • 144  Woodward M, Lowe GD, Campbell DJ et al.: Associations of inflammatory and hemostatic variables with the risk of recurrent stroke. Stroke36(10),2143–2147 (2005).
    • 145  Knottnerus ILH, Govers-Riemslag JWP, Hamulyak K et al.: Endothelial activation in lacunar stroke subtypes. Stroke41(8),1617–1622 (2010).
    • 146  Lowe GDO, Foulds WS: Rheology of retinal disorders. In: Clinical Blood Rheology (Volume 2). Lowe GDO (Ed.). CRC Press, FL, USA, 189–202 (1988).
    • 147  de Lau LM, Smith AD, Refsum H, Johnston C, Breteler MM: Plasma vitamin B12 status and cerebral white-matter lesions. J. Neurol. Neurosurg. Psychiatry80(2),149–157 (2009).
    • 148  Laloux P, Gospodaru N, Cornil V, Ossemann M, Jamart J: Is hyperhomocysteinemia associated with a specific ischemic stroke subtype? Cerebrovasc. Dis.21(Suppl. 4),91 (2006).
    • 149  de Jager J, Kooy A, Lehert P et al.: Long term treatment with metformin in patients with Type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ340,C2181 (2010).
    • 150  Kooy A, de Jager J, Lehert P et al.: Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with Type 2 diabetes mellitus. Arch. Intern. Med.169(6),616–625 (2009).
    • 151  de Jager J, Dekker JM, Kooy A et al.: Endothelial dysfunction and low-grade inflammation explain much of the excess cardiovascular mortality in individuals with Type 2 diabetes: the Hoorn Study. Arterioscler. Thromb. Vasc. Biol.26(5),1086–1093 (2006).
    • 152  Nomura E, Kohriyama T, Kozuka K, Kajikawa H, Nakamura S, Matsumoto M: Significance of serum soluable thrombomodulin level in acute cerebral infarction. Eur. J. Neurol.11,329–334 (2004).
    • 153  Whiteley W, Jackson C, Lewis S et al.: Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med.6(9),E1000145 (2009).▪▪ Cohort study of plasma biomarkers of inflammation and thrombosis and outcomes after stroke.
    • 154  Bechmann I, Galea I, Perry VH: What is the blood–brain barrier (not)? Brain29(1),5–11 (2007).
    • 155  Wardlaw JM, Dennis MS, Warlow CP, Sandercock PA: Imaging appearance of the symptomatic perforating artery in patients with lacunar infarction: occlusion or other vascular pathology? Ann. Neurol.50(2),208–215 (2001).▪▪ Original description of imaging of abnormal perforating arterioles in lacunar stroke.
    • 156  Lammie GA, Brannan F, Wardlaw JM: Incomplete lacunar infarction (type 1b lacunes). Acta Neuropathol.96,163–171 (1998).
    • 157  Ma K-C, Olsson Y: Structural and vascular permeability abnormalities associated with lacunes of the human brain. Acta Neurol. Scand.88,100–107 (1993).
    • 158  Young VG, Halliday GM, Kril JJ: Neuropathologic correlates of white matter hyperintensities. Neurology71(11),804–811 (2008).
    • 159  Tomimoto H, Akiguchi I, Suenaga T et al.: Alterations of the blood–brain barrier and glial cells in white matter lesions in cerebrovascular and Alzheimer’s disease patients. Stroke27,2069–2074 (1996).
    • 160  Farrall AJ, Wardlaw JM: Blood brain barrier: ageing and microvascular disease – systemic review and meta-analysis. Neurobiol. Aging30(3),337–352 (2007).▪▪ Systematic review of changes in the BBB with aging and in dementia and white matter lesions.
    • 161  Wardlaw JM, Doubal F, Armitage P et al.: Lacunar stroke is associated with diffuse blood–brain barrier dysfunction. Ann. Neurol.65(2),194–202 (2009).▪▪ Observational study of BBB function in lacunar and cortical stroke.
    • 162  Wardlaw JM, Sandercock PA, Dennis MS, Starr J: Is breakdown of the blood–brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke34(3),806–812 (2003).
    • 163  Wardlaw JM, Farrall A, Armitage PA et al.: Changes in background blood–brain barrier integrity between lacunar and cortical ischemic stroke subtypes. Stroke39,1327–1332 (2008).
    • 164  Topakian R, Barrick TR, Charlton RA, Schiavone F, Howe FA, Markus HS: Increased blood–brain permeability in normal-appearing white matter in subjects with small vessel disease. A MRI study. Cerebrovasc. Dis.25(Suppl. 2),21 (2008).▪▪ Observational study of BBB function in lacunar stroke.
    • 165  Hainsworth AH, Markus HS: Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review. J. Cereb. Blood Flow Metab.28(12),1877–1891 (2008).▪ Along with [101], presents a systematic review of potential models of lacunar stroke and what they tell us about potential mechanisms.
    • 166  Kemper TL, Blatt GJ, Killiany RJ, Moss MB: Neuropathology of progressive cognitive decline in chronically hypertensive rhesus monkeys. Acta Neuropathol.101(2),145–153 (2001).
    • 167  Fredriksson K, Kalimo H, Westergren I, Kahstrom J, Johansson BB: Blood–brain barrier leakage and brain edema in stroke-prone spontaneously hypertensive rats: effect of chronic sympathectomy and low protein/high salt diet. Acta Neuropathol.74,259–268 (1987).
    • 168  Sironi L, Guerrini U, Tremoli E et al.: Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach. J. Neurosci. Res.78(1),115–122 (2004).
    • 169  Viswanathan A, Patel P, Rahman R et al.: Tissue microstructural changes are independently associated with cognitive impairment in cerebral amyloid angiopathy. Stroke39(7),1988–1992 (2008).
    • 170  Greenberg SM, Vernooij MW, Cordonnier C et al.: Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol.8(2),165–174 (2009).
    • 171  Gurol ME, Irizarry MC, Smith EE et al.: Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy. Neurology66(1),23–29 (2006).
    • 172  Valdez Hernandez M, Armitage P, Doubal F, Wardlaw J: Leakage of intravenously injected gadolinium contrast into CSF on FLAIR MR imaging predates progression of white matter lesions at long term follow up in patients with mild stroke. Cerebrovasc. Dis.29(Suppl. 2),55 (2010).
    • 173  Doubal F, Armitage P, Sandeman E, Shuler K, Dennis M, Wardlaw J: Associations of baseline white matter disease and blood–brain barrier permeability with functional outcome three years after minor stroke. Cerebrovasc. Dis.29(Suppl. 2),55 (2010).
    • 174  Skoog I, Wallin A, Fredman P et al.: A population study on blood–brain barrier function in 85-year-olds: relation to Alzheimer’s disease and vascular dementia. Neurology50(4),966–971 (1998).
    • 175  Debette S, Markus HS: The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ341,C3666 (2010).
    • 176  Abbott NJ: Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem. Int.45(4),545–552 (2004).▪ Discusses the importance of perivascular spaces to the circulation of interstitial fluid in the brain.
    • 177  Fazekas F, Kleinert R, Offenbacher H et al.: The morphologic correlate of incidental punctate white matter hyperintensities on MR images. Am. J. Neuroradiol.12,915–921 (1991).
    • 178  Wuerfel J, Haertle M, Waiczies H et al.: Perivascular spaces – MRI marker of inflammatory activity in the brain? Brain131(Pt 9),2332–2340 (2008).▪ Discusses the relationship between enlarged perivascular spaces and inflammation in multiple sclerosis.
    • 179  Rouhl RPW, van Oostenbrugge RJ, Knottnerus ILH, Staals JEA, Lodder J: Virchow–Robin spaces relate to cerebral small vessel disease severity. J. Neurol.255(5),692–696 (2008).
    • 180  MacLullich AM, Wardlaw JM, Ferguson KJ, Starr JM, Seckl JR, Deary IJ: Enlarged perivascular spaces are associated with cognitive function in healthy elderly men. J. Neurol. Neurosurg. Psychiatry75(11),1519–1523 (2004).
    • 181  Patankar TF, Mitra D, Varma A, Snowden J, Neary D, Jackson A: Dilatation of the Virchow-Robin space is a sensitive indicator of cerebral microvascular disease: study in elderly patients with dementia. Am. J. Neuroradiol.26(6),1512–1520 (2005).
    • 182  Rosenberg GA: Inflammation and white matter damage in vascular cognitive impairment. Stroke40(Suppl. 1),S20–S23 (2009).▪▪ Review of the role of inflammation in vascular dementia.
    • 183  Boiten J, Lodder J, Kessels F: Two clinically distinct lacunar infarct entities? A hypothesis. Stroke24(5),652 (1993).
    • 184  Donnan GA, Bladin PF, Berkovic SF, Longley WA, Saling MM: The stroke syndrome of striatocapsular infarction. Brain114(Pt 1A),51–70 (1991).