{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:15:13Z","timestamp":1791656113069,"version":"4.3.4"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T00:00:00Z","timestamp":1614470400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T00:00:00Z","timestamp":1614470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl. Stroke Res."],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Intravenous recombinant tissue plasminogen activator (iv-rtPA) has been routinely used to treat ischemic stroke for 25\u00a0years, following large clinical trials. However, there are few prospective studies on the efficacy and safety of this therapy in strokes attributed to cerebral small vessel disease (SVD). We evaluated functional outcome (modified Rankin scale, mRS) and symptomatic intracerebral hemorrhage (sICH) using all available data on the effects of iv-rtPA in SVD-related ischemic stroke (defined either using neuroimaging, clinical features, or both). Using fixed-effect and random-effects models, we calculated the pooled effect estimates with regard to excellent and favorable outcomes (mRS=0\u20131 and 0\u20132 respectively, at 3\u00a0months), and the rate of sICH. Twenty-three studies fulfilled the eligibility criteria, 11 of which were comparative, and there were only 3 randomized clinical trials. In adjusted analyses, there was an increased odds of excellent outcome (adjusted OR=1.53, 95%\u00a0CI:\u00a01.29\u20131.82, I2:\u00a00%) or favorable outcome (adjusted OR=1.68, 95%\u00a0CI:\u00a01.31\u20132.15,I2:\u00a00%) in patients who received iv-rtPA compared with placebo. Across the six studies which reported it, the incidence of sICH was higher in the treatment group (M-H RR\u2009=\u20098.83, 95% CI:\u00a02.76\u201328.27). The pooled rate of sICH in patients with SVD administered iv-rtPA was only 0.72% (95%\u00a0CI:\u00a00.12%\u20131.64%). We conclude that when ischemic stroke attributed to SVD is considered separately, available data on the effects of iv-rtPA therapy are insufficient for the highest level of recommendation, but it seems to be safe. Although further therapeutic trials in SVD-related ischemic stroke appear to be justified, our findings should not prevent its continued use for this group of patients in clinical practice.<\/jats:p>","DOI":"10.1007\/s12975-021-00890-9","type":"journal-article","created":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T07:02:21Z","timestamp":1614495741000},"page":"406-415","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Efficacy and Safety of Intravenous rtPA in Ischemic Strokes Due to Small-Vessel Occlusion: Systematic Review and Meta-Analysis"],"prefix":"10.1007","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2726-0016","authenticated-orcid":false,"given":"Bartosz","family":"Karaszewski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6293-1439","authenticated-orcid":false,"given":"Adam","family":"Wyszomirski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1657-5090","authenticated-orcid":false,"given":"Bartosz","family":"Jab\u0142o\u0144ski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2074-1861","authenticated-orcid":false,"given":"David J.","family":"Werring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominika","family":"Tomaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,28]]},"reference":[{"key":"890_CR1","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1001\/jama.1995.03530130023023","volume":"274","author":"W Hacke","year":"1995","unstructured":"Hacke W, Kaste M, Cesare F, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA. 1995;274:1017\u201325.","journal-title":"JAMA"},{"key":"890_CR2","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1016\/S0140-6736(98)08020-9","volume":"352","author":"W Hacke","year":"1998","unstructured":"Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352:1245\u201351.","journal-title":"Lancet"},{"key":"890_CR3","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1056\/NEJMoa0804656","volume":"359","author":"W Hacke","year":"2008","unstructured":"Hacke W, Kaste M, Bluhmki E, Brozman M, D\u00e1valos A, Guidetti D, et al. Thrombolysis with Alteplase 3 to 4.5 hours after acute ischemic stroke Werner. N Engl J Med. 2008;359:1543\u201354.","journal-title":"N Engl J Med"},{"key":"890_CR4","doi-asserted-by":"publisher","first-page":"2352","DOI":"10.1016\/S0140-6736(12)60768-5","volume":"379","author":"P Sandercock","year":"2012","unstructured":"Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379:2352\u201363.","journal-title":"Lancet"},{"key":"890_CR5","doi-asserted-by":"publisher","first-page":"2019","DOI":"10.1001\/jama.282.21.2019","volume":"282","author":"WM Clark","year":"2003","unstructured":"Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S, et al. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. JAMA. 2003;282:2019\u201326.","journal-title":"JAMA"},{"key":"890_CR6","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1056\/NEJM199512143332401","volume":"333","author":"The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group","year":"1995","unstructured":"The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581\u20137.","journal-title":"N Engl J Med"},{"key":"890_CR7","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1161\/STROKEAHA.114.006573","volume":"46","author":"RI Lindley","year":"2015","unstructured":"Lindley RI, Wardlaw JM, Whiteley WN, Cohen G, Blackwell L, Murray GD, et al. Alteplase for acute ischemic stroke: outcomes by clinically important subgroups in the third international stroke trial. Stroke. 2015;46:746\u201356.","journal-title":"Stroke"},{"key":"890_CR8","doi-asserted-by":"crossref","unstructured":"Barow E, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, et al. Functional outcome of intravenous thrombolysis in patients with lacunar infarcts in the WAKE-UP trial. JAMA Neurol. 2019:1\u20139.","DOI":"10.1001\/jamaneurol.2019.0351"},{"key":"890_CR9","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1056\/NEJMoa1804355","volume":"379","author":"G Thomalla","year":"2018","unstructured":"Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379:611\u201322.","journal-title":"N Engl J Med"},{"key":"890_CR10","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/jcbfm.2015.116","volume":"36","author":"A Poggesi","year":"2016","unstructured":"Poggesi A, Pasi M, Pescini F, Pantoni L, Inzitari D. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: a review. J Cereb Blood Flow Metab. 2016;36:72\u201394.","journal-title":"J Cereb Blood Flow Metab"},{"key":"890_CR11","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/S1474-4422(13)70060-7","volume":"12","author":"JM Wardlaw","year":"2013","unstructured":"Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12:483\u201397.","journal-title":"Lancet Neurol"},{"key":"890_CR12","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/S1474-4422(10)70104-6","volume":"9","author":"L Pantoni","year":"2010","unstructured":"Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689\u2013701.","journal-title":"Lancet Neurol"},{"key":"890_CR13","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1586\/14737175.9.2.179","volume":"9","author":"A Arboix","year":"2009","unstructured":"Arboix A, Mart\u00ed-Vilaita JL. Lacunar stroke. Expert Rev Neurother. 2009;9:179\u201396.","journal-title":"Expert Rev Neurother"},{"key":"890_CR14","doi-asserted-by":"publisher","first-page":"2084","DOI":"10.1161\/STROKEAHA.116.012992","volume":"48","author":"A Charidimou","year":"2017","unstructured":"Charidimou A, Turc G, Oppenheim G, Yan S, Scheitz JF, Erdur H, et al. Microbleeds, cerebral hemorrhage, and functional outcome after stroke thrombolysis: individual patient data meta-analysis. Stroke. 2017;48:2084\u201390.","journal-title":"Stroke"},{"key":"890_CR15","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1016\/j.jclinepi.2009.06.006","volume":"62","author":"A Liberati","year":"2009","unstructured":"Liberati A, Altman DG, Tetzlaff J, Mulrow C, G\u00f8tzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62:e1\u201334.","journal-title":"J Clin Epidemiol"},{"key":"890_CR16","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1177\/003693305700200504","volume":"2","author":"J Rankin","year":"1957","unstructured":"Rankin J. Cerebral vascular accidents in patients over the age of 60: II. Prognosis. Scott Med J. 1957;2:200\u201315.","journal-title":"Scott Med J"},{"key":"890_CR17","doi-asserted-by":"publisher","first-page":"d5928","DOI":"10.1136\/bmj.d5928","volume":"343","author":"JPT Higgins","year":"2011","unstructured":"Higgins JPT, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration\u2019s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.","journal-title":"BMJ"},{"key":"890_CR18","unstructured":"Wells GA, Shea B, O\u2019Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses http:\/\/www.ohri.ca\/programs\/clinical_epidemiology\/oxford.htm. Accessed February 27, 2020."},{"key":"890_CR19","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1001\/jama.280.19.1690","volume":"280","author":"J Zhang","year":"1998","unstructured":"Zhang J, Yu KF. What\u2019s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998;280:1690\u20131.","journal-title":"JAMA"},{"key":"890_CR20","doi-asserted-by":"crossref","unstructured":"Matusevicius M, Paciaroni M, Caso V, Bottai M, Khurana D, de Bastos M, et al. Outcome after intravenous thrombolysis in patients with acute lacunar stroke: an observational study based on SITS international registry and a meta-analysis. Int J Stroke 2019;0:1\u20139.","DOI":"10.1177\/1747493019840947"},{"key":"890_CR21","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1007\/s00415-013-7212-8","volume":"261","author":"M Griebe","year":"2014","unstructured":"Griebe M, Fischer E, Kablau M, Eisele P, Wolf ME, Chatzikonstantinou A, et al. Thrombolysis in patients with lacunar stroke is safe: an observational study. J Neurol. 2014;261:405\u201311.","journal-title":"J Neurol"},{"key":"890_CR22","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1111\/ene.13288","volume":"24","author":"CCJ Eggers","year":"2017","unstructured":"Eggers CCJ, Bocksrucker C, Seyfang L. The efficacy of thrombolysis in lacunar stroke \u2013 evidence from the Austrian stroke unit registry. Eur J Neurol. 2017;24:780\u20137.","journal-title":"Eur J Neurol"},{"key":"890_CR23","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1159\/000151638","volume":"26","author":"Y-H Hwang","year":"2008","unstructured":"Hwang Y-H, Seo J-G, Lee H-W, Park S-P, Suh C-K. Early neurological deterioration following intravenous recombinant tissue plasminogen activator therapy in patients with acute lacunar stroke. Cerebrovasc Dis. 2008;26:355\u20139.","journal-title":"Cerebrovasc Dis"},{"key":"890_CR24","doi-asserted-by":"publisher","first-page":"2722","DOI":"10.1161\/STROKEAHA.114.005757","volume":"45","author":"S Lahoti","year":"2014","unstructured":"Lahoti S, Gokhale S, Caplan L, Michel P, Samson Y, Rosso C, et al. Thrombolysis in ischemic stroke without arterial occlusion at presentation. Stroke. 2014;45:2722\u20137.","journal-title":"Stroke"},{"key":"890_CR25","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1111\/j.1747-4949.2012.00932.x","volume":"8","author":"N Shobha","year":"2013","unstructured":"Shobha N, Fang J, Hill MD. Do lacunar strokes benefit from thrombolysis? Evidence from the registry of the Canadian stroke network. Int J Stroke. 2013;8:45\u20139.","journal-title":"Int J Stroke"},{"key":"890_CR26","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.jocn.2019.03.036","volume":"64","author":"YM Paek","year":"2019","unstructured":"Paek YM, Lee JS, Park HK, Cho YJ, Bae HJ, Kim BJ, et al. Intravenous thrombolysis with tissue-plasminogen activator in small vessel occlusion. J Clin Neurosci. 2019;64:134\u201340.","journal-title":"J Clin Neurosci"},{"key":"890_CR27","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.jns.2016.03.048","volume":"365","author":"L Yang","year":"2016","unstructured":"Yang L, Cao W, Wu F, Ling Y, Cheng X, Dong Q. Predictors of clinical outcome in patients with acute perforating artery infarction. J Neurol Sci. 2016;365:108\u201313.","journal-title":"J Neurol Sci"},{"key":"890_CR28","doi-asserted-by":"publisher","first-page":"e492","DOI":"10.1016\/j.jstrokecerebrovasdis.2013.05.022","volume":"22","author":"JJ Chang","year":"2013","unstructured":"Chang JJ, Chiem T, Alderazi YJ, Chapple K, Restrepo L. Clinical outcomes after intravenous fibrinolysis in cryptogenic strokes with or without patent foramen ovale. J Stroke Cerebrovasc Dis. 2013;22:e492\u20139.","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"890_CR29","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jns.2012.10.003","volume":"324","author":"S-F Sung","year":"2013","unstructured":"Sung S-F, Wu C-S, Hsu Y-C, Tseng M-C, Chen Y-W. Oxfordshire community stroke project classification but not NIHSS predicts symptomatic intracerebral hemorrhage following thrombolysis. J Neurol Sci. 2013;324:65\u20139.","journal-title":"J Neurol Sci"},{"key":"890_CR30","first-page":"2587","volume":"41","author":"SJ Lee","year":"2011","unstructured":"Lee SJ, Saver JL, Liebeskind DS, Ali L, Ovbiagele B, Kim D, et al. Safety of intravenous fibrinolysis in imaging-confirmed single penetrator artery infarcts. Imaging. 2011;41:2587\u201391.","journal-title":"Imaging"},{"key":"890_CR31","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1111\/j.1468-1331.2010.02961.x","volume":"17","author":"F Fluri","year":"2010","unstructured":"Fluri F, Hatz F, Rutgers MP, Georgiadis D, Sekoranja L, Schwegler G, et al. Intravenous thrombolysis in patients with stroke attributable to small artery occlusion. Eur J Neurol. 2010;17:1054\u201360.","journal-title":"Eur J Neurol"},{"key":"890_CR32","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1159\/000185607","volume":"27","author":"M Kohrmann","year":"2009","unstructured":"Kohrmann M, Nowe T, Huttner HB, Engelhorn T, Struffert T, Kollmar R, et al. Safety and outcome after thrombolysis in stroke patients with mild symptoms. Cerebrovasc Dis. 2009;27:160\u20136.","journal-title":"Cerebrovasc Dis"},{"key":"890_CR33","doi-asserted-by":"publisher","first-page":"46","DOI":"10.4103\/0028-3886.30426","volume":"55","author":"MV Padma","year":"2007","unstructured":"Padma MV, Singh MB, Bhatia R, Srivastava A, Tripathi M, Shukla G, et al. Hyperacute thrombolysis with IV rtPA of acute ischemic stroke: efficacy and safety profile of 54 patients at a tertiary referral center in a developing country. Neurol India. 2007;55:46\u20139.","journal-title":"Neurol India"},{"key":"890_CR34","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1159\/000091982","volume":"55","author":"D Cocho","year":"2006","unstructured":"Cocho D, Belvis R, Marti-Fabregas J, Bravo Y, Aleu A, Pagonabarraga J, et al. Does thrombolysis benefit patients with lacunar syndrome? Eur Neurol. 2006;55:70\u20133.","journal-title":"Eur Neurol"},{"key":"890_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12883-016-0617-0","volume":"16","author":"I Miedema","year":"2016","unstructured":"Miedema I, Luijckx GJ, Brouns R, De Keyser J, Uyttenboogaart M. Admission hyperglycemia and outcome after intravenous thrombolysis: is there a difference among the stroke-subtypes? BMC Neurol. 2016;16:1\u20135.","journal-title":"BMC Neurol"},{"key":"890_CR36","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1177\/1747493016650454","volume":"11","author":"CZ Simonsen","year":"2016","unstructured":"Simonsen CZ, Schmitz ML, Madsen MH, Mikkelsen IK, Chandra RV, Leslie-Mazwi T, et al. Early neurological deterioration after thrombolysis: clinical and imaging predictors. Int J Stroke. 2016;11:776\u201382.","journal-title":"Int J Stroke"},{"key":"890_CR37","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s40064-016-1666-y","volume":"5","author":"Y-T Pan","year":"2016","unstructured":"Pan Y-T, Lee J-D, Lin Y-H, Huang Y-C, Weng H-H, Lee M, et al. Comparisons of outcomes in stroke subtypes after intravenous thrombolysis. Springerplus. 2016;5:47.","journal-title":"Springerplus"},{"key":"890_CR38","unstructured":"Zivanovic Z, Gubi M, Vlahovic D, Milicevic M, Jovicevic M, Lucic A, et al. Patients with acute lacunar infarction have benefit from intravenous thrombolysis. J Stroke Cerebrovasc Dis 2018;1\u20136."},{"key":"890_CR39","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s12883-018-1033-4","volume":"18","author":"DH Kim","year":"2018","unstructured":"Kim DH, Lee DS, Nah HW, Cha JK. Clinical and radiological factors associated with unfavorable outcome after intravenous thrombolysis in patients with mild ischemic stroke. BMC Neurol. 2018;18:3\u201310.","journal-title":"BMC Neurol"},{"key":"890_CR40","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/S1474-4422(13)70124-8","volume":"12","author":"JM Wardlaw","year":"2013","unstructured":"Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822\u201338.","journal-title":"Lancet Neurol"},{"issue":"3","key":"890_CR41","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1136\/svn-2016-000035","volume":"1","author":"Y Shi","year":"2016","unstructured":"Shi Y, Wardlaw JM. Update on cerebral small vessel disease: a dynamic whole-brain disease. Stroke Vasc Neurol. 2016;1(3):83\u201392.","journal-title":"Stroke Vasc Neurol"},{"issue":"1","key":"890_CR42","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1161\/STROKEAHA.110.597534","volume":"42","author":"S Mustanoja","year":"2011","unstructured":"Mustanoja S, Meretoja A, Putaala J, Viitanen V, Curtze S, Atula S, et al. Outcome by stroke etiology in patients receiving thrombolytic treatment: descriptive subtype analysis. Stroke. 2011;42(1):102\u20136.","journal-title":"Stroke"},{"key":"890_CR43","unstructured":"OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence Oxford Centre for Evidence-Based Medicine 2011. https:\/\/www.cebm.net\/wp-content\/uploads\/2014\/06\/CEBM-Levels-of-Evidence-2.1.pdf. Accessed 15 Nov 2020."},{"key":"890_CR44","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1161\/01.STR.18.3.545","volume":"18","author":"J Bamford","year":"1987","unstructured":"Bamford J, Sandercock P, Jones L, Warlow C. The natural history of lacunar infarction: the oxfordshire community stroke project. Stroke. 1987;18:545\u201351.","journal-title":"Stroke"},{"key":"890_CR45","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1159\/000108704","volume":"3","author":"J Boiten","year":"1993","unstructured":"Boiten J, Lodder J. Prognosis for survival, handicap and recurrence of stroke in lacunar and superficial infarction. Cerebrovasc Dis. 1993;3:221\u20136.","journal-title":"Cerebrovasc Dis"},{"key":"890_CR46","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1001\/jama.2018.8496","volume":"320","author":"P Khatri","year":"2018","unstructured":"Khatri P, Kleindorfer DO, Devlin T, Sawyer RN, Starr M, Mejilla J, et al. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits the PRISMS randomized clinical trial. JAMA. 2018;320:156\u201366.","journal-title":"JAMA"},{"key":"890_CR47","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1161\/01.STR.27.5.842","volume":"27","author":"M Samuelsson","year":"1996","unstructured":"Samuelsson M, S\u00f6derfeldt B, Olsson GB. Functional outcome in patients with lacunar infraction. Stroke. 1996;27:842\u20136.","journal-title":"Stroke"},{"key":"890_CR48","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1161\/01.STR.22.10.1236","volume":"22","author":"SE Sacco","year":"1991","unstructured":"Sacco SE, Whisnant JP, Broderick JP, Phillips SJ, Michael WOF. Epidemiological characteristics of lacunar infarcts in a population. Stroke. 1991;22:1236\u201341.","journal-title":"Stroke"},{"issue":"2","key":"890_CR49","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1080\/03610926.2015.1006778","volume":"46","author":"S Burgess","year":"2016","unstructured":"Burgess S. Estimating and contextualizing the attenuation of odds ratios due to non-collapsibility. Communications in Statistics - Theory and Methods. 2016;46(2):786\u2013804.","journal-title":"Communications in Statistics - Theory and Methods"},{"key":"890_CR50","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1136\/jnnp.68.5.558","volume":"68","author":"GE Mead","year":"2000","unstructured":"Mead GE, Lewis SD, Wardlaw JM, Dennis MS, Warlow CP. How well does the Oxfordshire community stroke project classification predict the site and size of the infarct on brain imaging? J Neurol Neurosurg Psychiatry. 2000;68:558\u201362.","journal-title":"J Neurol Neurosurg Psychiatry"}],"container-title":["Translational Stroke Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12975-021-00890-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12975-021-00890-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12975-021-00890-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,29]],"date-time":"2023-01-29T17:32:34Z","timestamp":1675013554000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12975-021-00890-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,28]]},"references-count":50,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["890"],"URL":"https:\/\/doi.org\/10.1007\/s12975-021-00890-9","relation":{},"ISSN":["1868-4483","1868-601X"],"issn-type":[{"value":"1868-4483","type":"print"},{"value":"1868-601X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,28]]},"assertion":[{"value":"8 May 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 January 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"BK received salaries for providing lectures at the Boehringer Ingelheim sponsored symposia within larger scientific or clinical conferences. All information provided by BK during his lectures is solely and exclusively based on systematic evidence-based knowledge on the subject, and do not contain any commercial promotional data. DJW has received personal fees from Bayer, Alnylam and Portola.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of Interest and Competing Interests"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code Availability"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Not applicable","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}}]}}