Hostname: page-component-cd9895bd7-gvvz8 Total loading time: 0 Render date: 2024-12-26T17:42:23.215Z Has data issue: false hasContentIssue false
  • English
  • Français

Small vessel cerebrovascular disease in older adults

Published online by Cambridge University Press:  17 April 2012

Helen Slavin ,
Julie McManus  and
David J Stott
Helen Slavin
Affiliation:
Department of Medicine for the Elderly, Hairmyres Hospital, East Kilbride, Scotland
Julie McManus*
Affiliation:
Department of Medicine for the Elderly, Victoria Infirmary, Glasgow, Scotland
David J Stott
Affiliation:
Academic Section of Geriatric Medicine, University of Glasgow, Scotland
*
Address for correspondence: Dr Julie McManus, Consultant Physician in Medicine for the Elderly and Stroke, Mansionhouse Unit, 100 Mansionhouse Road, Victoria Infirmary, Glasgow G41 3DX. Email: julie.mcmanus@ggc.scot.nhs.uk
Get access Rights & Permissions [Opens in a new window]

Summary

‘Cerebral small vessel disease’ is common in older adults and is an important cause of morbidity, functional impairment and cognitive decline. Small vessel disease is a collective term used to describe a number of underlying pathological processes and neuroimaging findings, such as lacunar infarcts, white matter lesions and microhaemorrhages.

With readily available neuroimaging, diagnostic accuracy has improved; however, the management of small vessel disease and prevention of cognitive decline remains uncertain. Treatment of conventional vascular risk factors may be appropriate, but future research is required to provide definitive answers. We have conducted a comprehensive literature review of cerebral small vessel disease in older adults. This highlights the clinical sequelae and underlying pathological processes, whilst discussing novel diagnostic neuroimaging and therapeutic strategies.

Keywords

elderlyolder adultcerebral small vessel diseasecognitive impairmentdementianeuroimagingwhite matter hyperintensities
Type
Clinical geriatrics
Information
Reviews in Clinical Gerontology , Volume 22 , Issue 3 , August 2012 , pp. 184 - 194
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Wardlaw, JM. Blood–brain barrier and cerebral small vessel disease. J Neurol Sci 2010; 299: 66–71.CrossRefGoogle ScholarPubMed
2Pohjasvaara, T, Mantyla, R, Ylikoski, R, Kaste, M, Erkinjuntti, T. Clinical features of MRI defined subcortical vascular disease. Alzheimers Dis Assoc Disord 2003; 17: 236–42.CrossRefGoogle ScholarPubMed
3Jokinen, H, Kalska, H, Ylikoski, R, Madureira, S, Verdelho, A, Gouw, A, Scheltens, P, Barkhof, F, Visser, MC, Fazekas, F, Schmidt, R, O'Brien, J, Hennerici, M, Baezner, H, Waldemar, G, Wallin, A, Chabriat, H, Pantoni, L, Inzitari, D, Erkinjuntti, T; LADIS group. MRI defined subcortical vascular disease: baseline clinical and neuropsychological findings. The LADIS study. Cerebrovasc Dis 2009; 27: 336–44.CrossRefGoogle ScholarPubMed
4Jokinen, H, Kalska, H, Mäntylä, R, Pohjasvaara, T, Ylikoski, R, Hietanen, M, Salonen, O, Kaste, M, Erkinjuntti, T. Cognitive profile of subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry 2006; 77: 28–33.CrossRefGoogle ScholarPubMed
5Jokinen, 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 group. Longitudinal cognitive decline in subcortical ischaemic vascular disease – the LADIS study. Cerebrovasc Dis 2009; 27: 384–91.CrossRefGoogle ScholarPubMed
6Jokinen, H, Gouw, AA, Madureira, S, Ylikoski, R, van Straaten, EC, van der Flier, WM, Barkhof, F, Scheltens, P, Fazekas, F, Schmidt, R, Verdelho, A, Ferro, JM, Pantoni, L, Inzitari, D, Erkinjuntti, T; LADIS Study Group. Incident lacunes influence cognitive decline. Neurology 2011; 76: 1872–78.CrossRefGoogle ScholarPubMed
7Melkas, S, Putaala, J, Oksala, NK, Pohjasvaara, T, Oksala, A, Kaste, M, Karhunen, PJ, Erkinjuntti, T. Small vessel disease relates to poor post stroke survival in a 12 year follow up. Neurology 2011; 76: 734–39.CrossRefGoogle Scholar
8van Dijk, EJ, Prins, ND, Vrooman, HA, Hofman, A, Koudstaal, PJ, Breteler, M. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences – Rotterdam Scam Study. Stroke 2008; 39: 2712–19.CrossRefGoogle Scholar
9Vermeer, SE, Longstreth, WT, Koudstaal, PJ. Silent brain infarcts: a systematic review. Lancet Neurol 2007; 6: 611–19.CrossRefGoogle ScholarPubMed
10Pantoni, L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9: 689–701.CrossRefGoogle ScholarPubMed
11Jellinger, KA. The pathology of ischaemic vascular dementia: an update. J Neurol Sci 2002; 203: 153–57.CrossRefGoogle ScholarPubMed
12Thompson, 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. Stroke 2009; 40: e322–30.CrossRefGoogle ScholarPubMed
13Wong, TY, Klein, R, Sharrett, AR, Nieto, FJ, Boland, LL, Couper, DJ, Mosley, TH, Klein, BE, Hubbard, LD, Szklo, M. Retinal microvascular abnormalities and cognitive impairment in middle aged persons: the Atherosclerosis Risk in Communities Study. Stroke 2002; 33: 1487–92.CrossRefGoogle ScholarPubMed
14Wong, TY, Klein, R, Sharrett, AR, Couper, DJ, Klein, BE, Liao, DP, Hubbard, LD, Mosley, TH; ARIC Investigators. Atheroslerosis Risk in Communities Study. Cerebral white matter lesions, retinopathy and incident clinical stroke. JAMA 2002; 288: 67–74.CrossRefGoogle ScholarPubMed
15Khatri, M, Wright, CB, Nickolas, TL, Yoshita, M, Paik, MC, Kranwinkel, G, Sacco, RL, DeCarli, C. Chronic kidney disease is associated with white matter hyperintensity volume; the Northern Manhattan Study. Stroke 2007; 38: 3121–26.CrossRefGoogle ScholarPubMed
16Wada, M, Nagasawa, H, Iseki, C, Takahashi, Y, Sato, H, Arawaka, S, Kawanami, T, Kurita, K, Daimon, M, Kato, T. Cerebral small vessel disease and chronic kidney disease (CKD); results of a cross sectional study in community based Japanese elderly. J Neurol Sci 2008; 272: 36–42.CrossRefGoogle ScholarPubMed
17Smith, EE, Eichler, F. Cerebral amyloid angiopathy and lobar intracerebral haemorrhage. Arch Neurol 2006; 63: 148–51.CrossRefGoogle Scholar
18Snowdon, DA, Greiner, LH, Mortimer, JA, Riley, KP, Greiner, PA, Markesbery, WR. Brain infarction and the clinical expression of Alzheimer's Disease: The Nun Study. JAMA 1997; 277: 813–17.CrossRefGoogle ScholarPubMed
19Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Pathological correlates of late onset dementia in a multicentre community based population in England and Wales. Lancet 2001; 357: 169–75.CrossRefGoogle Scholar
20Garcia, JH, Brown, GG. Vascular dementia: neuropathologic alteration and metabolic brain changes. J Neurol Sci 2002; 203: 153–57.Google Scholar
21Steingart, A, Hachinski, VC, Lau, C, Fox, AJ, Diaz, F, Cape, R, Lee, D, Inzitari, D, Merskey, H. Cognitive and neurologic findings in subjects with diffuse white matter lucencies on CT scan. Arch Neurol 1987; 44: 32–35.CrossRefGoogle Scholar
22Rossi, R, Joachim, C, Geroldi, C, Combrinck, M, Esiri, MM, Smith, AD, Frisoni, GB. Association between subcortical vascular disease on CT and neuropathological findings. Int J Geriatr Psychiatry 2004; 19: 690–95.CrossRefGoogle Scholar
23Gouw, AA, Seewann, A, van der Flier, WM, Barkhof, F, Rozemuller, AM, Scheltens, P, Geurts, JJ. Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J Neurol Neurosurg Psychiatry 2011; 82: 126–35.CrossRefGoogle ScholarPubMed
24Hunt, AL, Orrison, WW, Yeo, RA, Haaland, KY, Rhyne, RL, Garry, PJ, Rosenberg, GA. Clinical significance of MRI white matter lesions in the elderly. Neurology 1989; 39: 1470–74.CrossRefGoogle ScholarPubMed
25Longstreth, WT Jr, Arnold, AM, Beauchamp, NJ Jr, Manolio, TA, Lefkowitz, D, Jungreis, C, Hirsch, CH, O'Leary, DH, Furberg, CD. Incidence, manifestations, and predictors of worsening white matter on serial cranial MR imaging in the elderly: the Cardiovascular Health Study. Stroke 2005; 36: 56–61.CrossRefGoogle ScholarPubMed
26Patel, B, Markus, H. Magnetic resonance imaging in cerebral small vessel disease and its use as a surrogate disease marker. Int J Stroke 2011; 6: 47–59.CrossRefGoogle ScholarPubMed
27Werring, DJ, Gregoire, SM, Cipolotti, L. Cerebral microbleeds and vascular cognitive impairment. J Neurol Sci 2010; 299: 131–35.CrossRefGoogle ScholarPubMed
28Altmann-Schneider, I, Trompet, S, de Craen, AJ, van Es, AC, Jukema, JW, Stott, DJ, Sattar, N, Westendorp, RG, van Buchem, MA, van der Grond, J. Cerebral microbleeds are predictive of mortality in the elderly. Stroke 2011; 42: 638–44.CrossRefGoogle ScholarPubMed
29van Norden, AG, de Laat, KF, Gons, RA, van Uden, IW, van Dijk, EJ, van Oudheusden, LJ, Esselink, RA, Bloem, BR, van Engelen, BG, Zwarts, MJ, Tendolkar, I, Olde-Rikkert, MG, van der Vlugt, MJ, Zwiers, MP, Norris, DG, de Leeuw, FE. Causes and consequences of cerebral small vessel disease. The RUN DMC study: a prospective cohort study. Study rationale and protocol. BMC Neurology 2011; 11: 29.CrossRefGoogle ScholarPubMed
30Erkinjuntti, T, Ostbye, T, Steenhuis, R, Hachinski, V. The effect of different diagnostic criteria on the prevalence of dementia. N Eng J Med 1997; 337: 1667–74.CrossRefGoogle ScholarPubMed
31Price, CC, Jefferson, AL, Merino, JG, Heilman, KM, Libon, DJ. Subcortical vascular dementia: integrating neuropsychological and neuroradiologic data. Neurology 2005; 65: 376–82.CrossRefGoogle ScholarPubMed
32Reed, BR, Mungas, DM, Kramer, JH, Ellis, W, Vinters, HV, Zarow, C, Jagust, WJ, Chui, HC. Profiles of neuropsychological impairment in autopsy defined Alzheimer's disease and cerebrovascular disease. Brain 2007; 130: 731–39.CrossRefGoogle ScholarPubMed
33Román, GC, Tatemichi, TK, Erkinjuntti, T, Cummings, JL, Masdeu, JC, Garcia, JH, Amaducci, L, Orgogozo, JM, Brun, A, Hofman, A et al. Vascular dementia: diagnostic criteria for research studies. Neurology 1993; 43: 250–60.CrossRefGoogle ScholarPubMed
34Hachinski, V, Iadecola, C, Petersen, RC, Breteler, MM, Nyenhuis, DL, Black, SE, Powers, WJ, DeCarli, C, Merino, JG, Kalaria, RN, Vinters, HV, Holtzman, DM, Rosenberg, GA, Wallin, A, Dichgans, M, Marler, JR, Leblanc, GG. National Institute of Neurological Disorders and Stroke – Canadian Stroke Network vascular cognitive impairment harmonisation standards. Stroke 2006; 37: 2220–41.CrossRefGoogle Scholar
35Ishii, N, Nishihara, Y, Imamura, T. Why do frontal lobe symptoms predominate in vascular dementia with lacunes? Neurology 1986; 36: 340–45.CrossRefGoogle ScholarPubMed
36Critchley, M. Arteriosclerotic Parkinsonism. Brain 1929; 52: 23–83.CrossRefGoogle Scholar
37Nutt, JG, Marsden, CD, Thompson, PD. Human walking and higher level gait disorders, particularly in the elderly. Neurology 1993; 43: 268–79.CrossRefGoogle ScholarPubMed
38Liston, R, Mickelborough, J, Bene, J, Tallis, R. A new classification of higher level gait disorders in patients with cerebral multi infarct states. Age Ageing 2003; 32: 252–58.CrossRefGoogle ScholarPubMed
39Bazner, H, Oster, M, Daffertshofer, M, Hennerici, M. Assessment of gait in subcortical vascular encephalopathy by computerised analysis: a cross sectional and longitudinal study. J Neurol 2000; 247: 841–49.CrossRefGoogle ScholarPubMed
40Van Zagten, M, Lodder, J, Kessels, F. Gait disorder and parkinsonian signs in patients with stroke related to small deep infarcts and white matter lesions. Mov Disord 1998; 13: 89–95.CrossRefGoogle ScholarPubMed
41Villardita, C. Alzheimer's disease compared with cerebrovascular dementia. Neuropsychological similarities and differences. Acta Neurol Scand 1993; 87: 299–308.CrossRefGoogle ScholarPubMed
42Lafosse, JM, Reed, BR, Mungas, D, Sterling, SB, Jagust, WJ. Fluency and memory differences between ischaemic vascular dementia and Alzheimer's disease. Neuropsychology 1997; 11: 514–22.CrossRefGoogle ScholarPubMed
43Carew, TG, Lamar, M, Cloud, BS, Grossman, M, Libon, DJ. Impairment in category fluency in ischaemic vascular dementia. Neuropsychology 1997; 11: 400–12.CrossRefGoogle Scholar
44Gelber, DA, Good, DC, Laven, LJ, Velhurst, SJ. Causes of urinary incontinence after acute hemispheric stroke. Stroke 1993; 24: 378–82.CrossRefGoogle ScholarPubMed
45Resnick, NM, Yalla, SV, Laurino, E. The pathophysiology of urinary incontinence among institutionalised elderly persons. N Eng J Med 1989; 320: 1–7.CrossRefGoogle Scholar
46Molska, PK, Paljarvi, L, Rinne, JO, Rinne, UK, Salko, E. Validity of clinical diagnosis in dementia. A prospective clinicopathological study. J Neurol Neurosurg Psych 1985; 48: 1085–90.CrossRefGoogle Scholar
47Hickie, I, Scott, L. Late onset depressive disorders: a preventable variant of cerebrovascular disease? Psychol Med 1998; 48: 1007–13.CrossRefGoogle Scholar
48Babikian, V, Ropper, AH. Binswangers Disease: a review. Stroke 1987: 18: 2–12.CrossRefGoogle Scholar
49Skoog, I, Lernfelt, B, Landahl, S, Palmertz, B, Andreasson, LA, Nilsson, L, Persson, G, Odén, A, Svanborg, A. Fifteen year longitudinal study of blood pressure and dementia. Lancet 1996; 347: 1141–45.CrossRefGoogle Scholar
50Tohgi, H, Chiba, K, Kiamura, M. 24 hour variation of blood pressure in vascular dementia of the Binswanger type. Stroke 1991; 22: 603–8.CrossRefGoogle ScholarPubMed
51Zimerbaum, P, Frishman, W, Aronson, M. Lipids, vascular disease and dementia with advancing age: Epidemiological considerations. Arch Int Med 1991; 151: 240–44.CrossRefGoogle Scholar
52Stewart, R, Liolitsa, D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med 1999; 16: 93–112.CrossRefGoogle ScholarPubMed
53Ott, A, Slooter, AJ, Hofman, A, van Harskamp, F, Witteman, JC, Van Broeckhoven, C, van Duijn, CM, Breteler, MM. Smoking and risk of dementia and Alzheimer's disease in a population based cohort study. The Rotterdam study. Lancet 1998; 351: 1840–43.CrossRefGoogle Scholar
54Schmidt, R, Schmidt, H, Curb, JD, Masaki, K, White, LR, Launer, LJ. Early inflammation and dementia: a 25 year follow up of the Honolulu-Asia Ageing Study. Ann Neurol 2002; 52: 168–74.CrossRefGoogle Scholar
55Godin, O, Tzourio, C, Malliard, P, Mazoyer, B, Dofouil, C. Antihypertensive treatment and change in blood pressure are associated with the progression of white matter lesion volumes.The Three-City (3C)–Dijon Magnetic Resonance Imaging Study. Circulation 2011; 123: 266–73.CrossRefGoogle Scholar
56Tzourio, C, Anderson, C, Chapman, N, Woodward, M, Neal, B, MacMahon, S, Chalmers, J; PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Int Med 2003; 163: 1069–75.Google Scholar
57Forette, F, Seux, ML, Staessen, JA, Thijs, L, Babarskiene, MR, Babeanu, S, Bossini, A, Fagard, R, Gil-Extremera, B, Laks, T, Kobalava, Z, Sarti, C, Tuomilehto, J, Vanhanen, H, Webster, J, Yodfat, Y, Birkenhäger, WH; Systolic Hypertension in Europe Investigators. The prevention of dementia with antihypertensive treatment: new evidence from the systolic hypertension in Europe (syst-eur) study. Arch Int Med 2002; 162: 2046–52.CrossRefGoogle ScholarPubMed
58Pantoni, L, del Ser, T, Soglian, AG, Amigoni, S, Spadari, G, Binelli, D, Inzitari, D. Efficacy and safety of nimodipine in subcortical vascular dementia. A randomised placebo controlled trial. Stroke 2005; 36: 619–24.CrossRefGoogle Scholar
59McGuinness, B, Todd, S, Passmore, A, Bullock, R. Systematic review: blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. J Neurol Neurosurg Psychiatry 2008; 79: 4–5.CrossRefGoogle ScholarPubMed
60Euser, SM, van Bemmel, T, Schram, MT, Gussekloo, J, Hofman, A, Westendorp, RG, Breteler, MM. The effect of age on the association between blood pressure and cognitive function later in life. J Am Geriatr Soc 2009; 57: 1232–37.CrossRefGoogle ScholarPubMed
61Amarenco, P, Benavente, O, Goldstein, LB, Callahan, A 3rd, Sillesen, H, Hennerici, MG, Gilbert, S, Rudolph, AE, Simunovic, L, Zivin, JA, Welch, KM; Stroke Prevention by Aggressive Reduction in Cholesterol Levels Investigators. Results of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial by stroke subtypes. Stroke 2009; 40: 1405–9.CrossRefGoogle ScholarPubMed
62Houx, PJ, Shepherd, J, Blauw, GJ, Murphy, MB, Ford, I, Bollen, EL, Buckley, B, Stott, DJ, Jukema, W, Hyland, M, Gaw, A, Norrie, J, Kamper, AM, Perry, IJ, MacFarlane, PW, Meinders, AE, Sweeney, BJ, Packard, CJ, Twomey, C, Cobbe, SM, Westendorp, RG. Testing cognitive function in elderly populations: The PROSPER study. J Neurol Neurosurg Psychiatry 2002; 73: 385–89.CrossRefGoogle ScholarPubMed
63Bernick, C, Katz, R, Smith, NL, Rapp, S, Bhadelia, R, Carlson, M, Kuller, L; Cardiovascular Health Study Collaborative Research Group. Statins and cognitive function in the elderly: the Cardiovascular Health Study. Neurology 2005; 65: 1388–94.CrossRefGoogle ScholarPubMed
64Bousser, MG, Eschwege, E, Haguenau, M, Lefaucconnier, JM, Thibult, N, Touboul, D, Touboul, PJ. AICLA controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischaemia. Stroke 1983; 14: 5–14.CrossRefGoogle Scholar
65CAST (Chinese Acute Stroke Trial) Collaborative group. CAST: randomised placebo controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–49.CrossRefGoogle Scholar
66Meyer, JS, Rogers, RL, McClintic, K, Mortel, KF, Lotfi, J. Randomised clinical trial of daily aspirin therapy in multi-infarct dementia. J Am Ger Soc 1989; 37: 549–55.CrossRefGoogle ScholarPubMed
67Diener, HC, Sacco, RL, Yusuf, S, Cotton, D, Ounpuu, S, Lawton, WA, Palesch, Y, Martin, RH, Albers, GW, Bath, P, Bornstein, N, Chan, BP, Chen, ST, Cunha, L, Dahlöf, B, De Keyser, J, Donnan, GA, Estol, C, Gorelick, P, Gu, V, Hermansson, K, Hilbrich, L, Kaste, M, Lu, C, Machnig, T, Pais, P, Roberts, R, Skvortsova, V, Teal, P, Toni, D, VanderMaelen, C, Voigt, T, Weber, M, Yoon, BW; Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group. Effects of aspirin plus extended release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the prevention regimen for effectively avoiding second strokes (ProFESS) trial: a double blind, active and placebo controlled study. Lancet Neurol 2008; 7: 875–84.CrossRefGoogle Scholar
68Black, S, Román, GC, Geldmacher, DS, Salloway, S, Hecker, J, Burns, A, Perdomo, C, Kumar, D, Pratt, R; Donepezil 307 Vascular Dementia Study Group. Efficacy and tolerability of donepezil in vascular dementia positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke 2003; 34: 2323–30.CrossRefGoogle Scholar
69Erkinjuntti, T, Kurz, A, Gauthier, S, Bullock, R, Lilienfeld, S, Damaraju, CV. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet 2002; 359: 1283–90.CrossRefGoogle ScholarPubMed
70Wilkinson, D, Doody, R, Helme, R et al. Donepezil 308 Study Group. Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology 2003; 61: 479–86.CrossRefGoogle Scholar
71Wilcock, G, Möbius, HJ, Stöffler, A; MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol 2002; 17: 297–305.CrossRefGoogle ScholarPubMed
72Orgogozo, JM, Rigaud, AS, Stöffler, A, Möbius, HJ, Forette, F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002; 33: 1834–39.CrossRefGoogle ScholarPubMed
73Hacke, W, Kaste, M, Bluhmki, E, Brozman, M, Dávalos, A, Guidetti, D, Larrue, V, Lees, KR, Medeghri, Z, Machnig, T, Schneider, D, von Kummer, R, Wahlgren, N, Toni, D; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischaemic stroke. N Engl J Med 2008; 359: 1317–29.CrossRefGoogle Scholar
74The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. New Eng J Med 1995; 333: 1581–87.CrossRefGoogle Scholar
75Palumbo, V, Boulanger, JM, Hill, MD, Inzitari, D, Buchan, AM; CASES Investigators. Leukoariosis and intracerebral haemorrhage after thrombolysis in acute stroke. Neurology 2007; 68: 1020–24.CrossRefGoogle Scholar
76Gorter, JW, for the stroke prevention in reversible ischaemia trial (SPIRIT) and European Atrial Fibrillation trial (EAFT) study groups. Major bleeding during anticoagulation after cerebral ischaemia: patterns and risk factors. Neurology 1999; 53: 1319–27.CrossRefGoogle ScholarPubMed