Background: White matter changes (WMCs), a surrogate for small-vessel disease (SVD), have been shown to be associated with a major negative influence on cognition, mood and functioning in daily life. We aimed to investigate whether severe WMCs are a risk factor for recurrent ischemic stroke in a long-term follow-up. Methods: 320 consecutive patients admitted to hospital with a first-ever ischemic stroke were included in the study and followed up for 12 years using extensive national registers. Patients were aged between 55 and 85 years, with a mean age of 70.8 years. WMCs were rated using MRI and stratified into two grades: absent to moderate WMCs versus severe WMCs. Univariate analysis was performed using binary logistic regression analysis, Kaplan-Meier log rank analysis and life table function. To control for factors such as age, education and cardiovascular risk factors, a multivariate Cox regression proportional hazards analysis was made with forced entry. Results: At least one recurrent stroke, nonfatal or fatal, was diagnosed in 76 (23.8%) patients at 5 years and in 127 (39.7%) patients at 12 years. In univariate analysis, only advancing age was associated with WMCs. The cumulative 5-year recurrence risk was 24.5% [95% confidence interval (95% CI) 23.8–25.2] for patients with absent to moderate WMCs and 39.1% (95% CI 38.1–40.1) for patients with severe WMCs. The cumulative 12-year recurrence risk was 48.1% (95% CI 45.5–50.7) for patients with absent to moderate WMCs and 60.9% (95% CI 56.7–65.1) for patients with severe WMCs. In Cox regression proportional hazards analysis, independent predictors of recurrent stroke at 5 years were severe WMCs [hazard ratio (HR) 1.80, 95% CI 1.11–2.95], atrial fibrillation (HR 1.81, 95% CI 1.09–3.02), hypertension (HR 1.69, 95% CI 1.05–2.71) and peripheral arterial disease (HR 1.89, 95% CI 1.06–3.38). At 12 years, only increasing age remained as an independent predictor (HR 1.04, 95% CI 1.02–1.07). In receiver operating characteristic analysis, the area under the curve for severe WMCs was 0.58 (95% CI 0.51–0.65) for the prediction of stroke recurrence within 5 years. Conclusions: In our well-defined cohort of poststroke patients, the presence of severe WMCs was an indicator of stroke recurrence up to 5 years after a first-ever ischemic stroke. WMCs can be considered as an SVD marker that summarizes the effects of several classical risk factors on the small-vessel brain network and therefore can be used as a score for risk stratification of stroke recurrence. Our findings further underline the poor long-term prognosis of cerebral SVD.

1.
Leys D, Englund E, Del Ser T, Inzitari D, Fazekas F, Bornstein N, Erkinjuntti T, Bowler JV, Pantoni L, Parnetti L, De Reuck J, Ferro J, Bogousslavsky J: White matter changes in stroke patients: relationship with stroke subtype and outcome. Eur Neurol 1999;42:67–75.
2.
Pohjasvaara T, Mäntylä R, Ylikoski R, Kaste M, Erkinjuntti T: Clinical features of MRI-defined subcortical vascular disease. Alzheimer Dis Assoc Disord 2003;17:236–242.
3.
Wen W, Sachdev PS: Extent and distribution of white matter hyperintensities in stroke patients: the Sydney Stroke Study. Stroke 2004;35:2813–2819.
4.
Erkinjuntti T, Inzitari D, Pantoni L, Wallin A, Scheltens P, Rockwood K, Román GC, Chui HC, Desmond DW: Research criteria for subcortical vascular dementia in clinical trials. J Neural Transm 2000(suppl 59):23–30.
5.
Román G, Erkinjuntti T, Wallin A, Pantoni L, Chui HC: Subcortical ischaemic vascular dementia. Lancet Neurol 2002;1:426–436.
6.
Oksala NK, Oksala A, Pohjasvaara T, Vataja R, Kaste M, Karhunen PJ, Erkinjuntti T: Age-related white matter changes predict stroke death in long-term follow-up. J Neurol Neurosurg Psychiatry 2009;80:762–766.
7.
Pantoni L: Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701.
8.
LADIS Study Group: 2001–2011: a decade of the LADIS (Leukoaraiosis And DISability) Study: what have we learned about white matter changes and small-vessel disease? Cerebrovasc Dis 2011;32:577–588.
9.
Arsava EM, Rahman R, Rosand J, Lu J, Smith EE, Rost NS, Singhal AB, Lev MH, Furie KL, Koroshetz WJ, Sorensen AG, Ay H: Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke. Neurology 2009;72:1403–1410.
10.
Putaala J, Haapaniemi E, Kurkinen M, Salonen O, Kaste M, Tatlisumak T: Silent brain infarcts, leukoaraiosis, and long-term prognosis in young ischemic stroke patients. Neurology 2011;76:1742–1749.
11.
Debette S, Markus HS: The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010;341:3666.
12.
Kerber KA, Whitman GT, Brown DL, Baloh RW: Increased risk of death in community-dwelling older people with white matter hyperintensities on MRI. J Neurol Sci 2006;250:33–38.
13.
Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM: Cerebral white matter and the risk of dementia. Arch Neurol 2004;61:1531–1534.
14.
Inzitari D, Pracucci G, Poggesi A, Carlucci G, Barkhof F, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, Langhorne P, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Pantoni L, LADIS Study Group: Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort. BMJ 2009;339:279–282.
15.
Verdelho A, Madureira S, Moleiro C, Ferro JM, Santos CO, Erkinjuntti T, Pantoni L, Fazekas F, Visser M, Waldemar G, Wallin A, Hennerici M, Inzitari D, LADIS Study Group: White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study. Neurology 2010;75:160–167.
16.
Jokinen H, Kalska H, Ylikoski R, Madureira S, Verdelho A, van der Flier WM, Scheltens P, Barkhof F, Visser MC, Fazekas F, Schmidt R, O’Brien J, Waldemar G, Wallin A, Chabriat H, Pantoni L, Inzitari D, Erkinjuntti T, LADIS Study Group: Longitudinal cognitive decline in subcortical ischemic vascular disease – the LADIS Study. Cerebrovasc Dis 2009;27:384–391.
17.
Teodorczuk A, Firbank MJ, Pantoni L, Poggesi A, Erkinjuntti T, Wallin A, Wahlund LO, Scheltens P, Waldemar G, Schrotter G, Ferro JM, Chabriat H, Bazner H, Visser M, Inzitari D, O’Brien JT, LADIS Study Group: Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study. Psychol Med 2010;40:603–610.
18.
Baezner H, Blahak C, Poggesi A, Pantoni L, Inzitari D, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Langhorne P, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Hennerici MG, LADIS Study G: Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology 2008;70:935–942.
19.
Held V, Szabo K, Bazner H, Hennerici MG: Chronic small vessel disease affects clinical outcome in patients with acute striatocapsular stroke. Cerebrovasc Dis 2012;33:86–91.
20.
Fu JH, Lu CZ, Hong Z, Dong Q, Luo Y, Wong KS: Extent of white matter lesions is related to acute subcortical infarcts and predicts further stroke risk in patients with first ever ischaemic stroke. J Neurol Neurosurg Psychiatry 2005;76:793–796.
21.
Hénon H, Vroylandt P, Durieu I, Pasquier F, Leys D: Leukoaraiosis more than dementia is a predictor of stroke recurrence. Stroke 2003;34:2935–2940.
22.
Pohjasvaara T, Erkinjuntti T, Vataja R, Kaste M: Comparison of stroke features and disability in daily life in patients with ischemic stroke aged 55 to 70 and 71 to 85 years. Stroke 1997;28:729–735.
23.
Oksala NK, Heikkinen M, Mikkelsson J, Pohjasvaara T, Kaste M, Erkinjuntti T, Karhunen PJ: Smoking and the platelet fibrinogen receptor glycoprotein IIb/IIIA PIA1/A2 polymorphism interact in the risk of lacunar stroke and midterm survival. Stroke 2007:38:50–55.
24.
Mantyla R, Aronen HJ, Salonen O, Pohjasvaara T, Korpelainen M, Peltonen T, Standertskjöld-Nordenstam CG, Kaste M, Erkinjuntti T: Magnetic resonance imaging white matter hyperintensities and mechanism of ischemic stroke. Stroke 1999;30:2053–2058.
25.
Pantoni L, Basile AM, Pracucci G, Asplund K, Bogousslavsky J, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D: Impact of age-related cerebral white matter changes on the transition to disability – the LADIS study: rationale, design and methodology. Neuroepidemiology 2005;24:51–62.
26.
Mantyla R, Erkinjuntti T, Salonen O, Aronen OJ, Peltonen T, Pohjasvaara T, Standertskjöld-Nordenstam CG: Variable agreement between visual rating scales for white matter hyperintensities on MRI. Comparison of 13 rating scales in a poststroke cohort. Stroke 1997;28:1614–1623.
27.
Mantyla R, Aronen HJ, Salonen O, Korpelainen M, Peltonen T, Standertskjold-Nordenstam C, Erkinjuntti T: The prevalence and distribution of white matter changes on different MRI pulse sequences in a post-stroke cohort. Neuroradiology 1999b;41:657–665.
28.
Scheltens P, Erkinjuntti T, Leys D, Wahlund LO, Inzitari D, del Ser T, Pasquier F. Barkhof F, Mantyla R, Bowler J, Wallin A, Ghika J, Fazekas F, Pantoni L: White matter changes on CT and MRI: an overview of visual rating scales. European Task Force on Age-Related White Matter Changes. Eur Neurol 1998;39:80–89.
29.
Streifler JY, Eliasziw M, Benavente OR, Alamowitch S, Fox AJ, Hachinski VC, Barnett HJ, North American Symptomatic Carotid Endarterectomy Trial Group: Prognostic importance of leukoaraiosis in patients with symptomatic internal carotid artery stenosis. Stroke 2002;33:1651–1655.
30.
van Swieten JC, Kappelle LJ, Algra A, van Latum JC, Koudstaal PJ, van Gijn J: Hypodensity of the cerebral white matter in patients with transient ischemic attack or minor stroke. Influence on the rate of subsequent stroke. Ann Neurol 1992;32:177–183.
31.
Miyao S, Takano A, Teramoto J, Takahashi A: Leukoaraiosis in relation to prognosis for patients with lacunar infarction. Stroke 1992;23:1434–1438.
32.
Patankar T, Widjaja E, Chant H, McCollum C, Baldwin R, Jeffries S, Sutcliffe C, Burns A, Jackson A: Relationship of deep white matter hyperintensities and cerebral blood flow in severe carotid artery stenosis. Eur J Neurol 2006;13:10–16.
33.
Mawet J, Vahedi K, Aout M, Vicaut E, Duering M, Touboul PJ, Dichgans M, Chabriat H: Carotid atherosclerotic markers in CADASIL. Cerebrovasc Dis 2011;31:246–252.
34.
Altaf N, Daniels L, Morgan PS, Lowe J, Gladman J, MacSweeney ST, Moody A, Auer DP: Cerebral white matter hyperintense lesions are associated with unstable carotid plaques. Eur J Vasc Endovasc Surg 2006;31:8–13.
35.
Fu JH, Chen YK, Chen XY, Mok V, Wong KS: Coexisting small vessel disease predicts poor long-term outcome in stroke patients with intracranial large artery atherosclerosis. Cerebrovasc Dis 2010;30:433–439.
36.
Melkas S, Putaala J, Oksala NK, Pohjasvaara T, Oksala A, Kaste M, Karhunen PJ, Erkinjuntti T: Small-vessel disease relates to poor poststroke survival in a 12-year follow-up. Neurology 2011;76:734–739.
37.
Potter GM, Román G: Cerebral small-vessel disease. What lies beyond the early years? Neurology 2011;76:684–685.
38.
Leppala JM, Virtamo J, Heinonen OP: Validation of stroke diagnosis in the National Hospital Discharge Register and the Register of Causes of Death in Finland. Eur J Epidemiol 1999;15:155–160.
39.
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421.
40.
Wannamethee SG, Shaper AG, Lennon L, Morris RW: Metabolic syndrome vs. Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med 2005;165:2644–2650.
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