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The impact of cerebral microbleeds on intracerebral hemorrhage and poor functional outcome of acute ischemic stroke patients treated with intravenous thrombolysis: a systematic review and meta-analysis


It is still controversial whether pre-existing cerebral microbleeds (CMBs) increase the risks of intracranial hemorrhage (ICH) and poor functional outcome (PFO) in acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT). Therefore, we performed a systematic review and meta-analysis to determine the impact of CMBs on ICH and PFO of AIS patients with IVT. We searched PubMed, EMBASE and Web of Science from inception to August 3, 2016, with language restriction in English. We included studies that reported the relationship between CMBs and ICH or PFO after thrombolysis. Two retrospective and nine prospective studies met inclusion criteria (total 2702 patients). The overall prevalence of CMBs on pre-IVT MRI scans was 24.0%. Pre-existing CMBs on MRI scans were not significantly associated with a higher risk of early sICH (OR 1.74; 95% CI 0.91–3.33; I 2 = 44.5%). Subgroup analyses did not substantially influence these associations. The presence of CMBs was associated with the increased risk of 3-month PFO (OR 1.58; 95% CI 1.08–2.31; I 2 = 54.2%), PH (OR 2.14; 95% CI 1.34–3.42; I 2 = 11.0%) and any ICH (OR 1.42; 95% CI 1.04–1.95; I 2 = 0.0%), respectively. This meta-analysis showed that CMBs presence was not significantly associated with the increased risk of early sICH after IVT. However, the results also demonstrated that CMBs presence increased the risks of 3-month PFO, PH and any ICH after IVT. Due to a small number of included studies and methodological limitations, the results of this meta-analysis should be interpreted cautiously. CMBs presence should not be a contraindication to IVT for AIS patients based on the existing evidence.

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  1. Endres M, Heuschmann PU, Laufs U, Hakim AM (2011) Primary prevention of stroke: blood pressure, lipids, and heart failure. Eur Heart J 32(5):545–552

    Article  PubMed  Google Scholar 

  2. Emberson J, Lees K, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis S, Donnan G, Stroke Thrombolysis Trialists’ Collaborative Group (2014) Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 384(9958):1929–1935

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Atlantis T (2004) Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 363(9411):768–774

    Article  Google Scholar 

  4. Yaghi S, Boehme AK, Dibu J, Guerrero CRL, Ali S, Martin-Schild S, Sands KA, Noorian AR, Blum CA, Chaudhary S (2015) Treatment and outcome of thrombolysis-related hemorrhage: a multicenter retrospective study. JAMA Neurol 72(12):1451–1457

    Article  PubMed  PubMed Central  Google Scholar 

  5. Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Salman RA-S, Warach S, Launer LJ, Van Buchem MA, Breteler MM, Group MS (2009) Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 8(2):165–174

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cordonnier C, Salman RA-S, Wardlaw J (2007) Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 130(8):1988–2003

    Article  PubMed  Google Scholar 

  7. Poels MMF, Vernooij MW, Ikram MA, Hofman A, Krestin GP, Der Lugt AV, Breteler MMB (2010) Prevalence and risk factors of cerebral microbleeds an update of the Rotterdam scan study. Stroke:41

  8. Gregoire SM, Brown MM, Kallis C, Jager R, Yousry TA, Werring DJ (2010) MRI detection of new microbleeds in patients with ischemic stroke. Five-year cohort follow-up study. Stroke 41(1):184–186

    Article  PubMed  Google Scholar 

  9. Orken DN, Uysal E, Timer E, Kuloglu-Pazarcı N, Mumcu S, Forta H (2013) New cerebral microbleeds in ischemic stroke patients on warfarin treatment: two-year follow-up. Clin Neurol Neurosurg 115(9):1682–1685

    Article  PubMed  Google Scholar 

  10. Huang Y, Cheng Y, Wu J, Li Y, Xu E, Hong Z, Li Z, Zhang W, Ding M, Gao X (2008) Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 7(6):494–499

    CAS  Article  PubMed  Google Scholar 

  11. Yan S, Jin X, Zhang X, Zhang S, Liebeskind DS, Lou M (2015) Extensive cerebral microbleeds predict parenchymal haemorrhage and poor outcome after intravenous thrombolysis. J Neurol Neurosurg Psychiatry 86(11):1267–1272. doi:10.1136/jnnp-2014-309857

    Article  PubMed  Google Scholar 

  12. Turc G, Sallem A, Moulin S, Tisserand M, Machet A, Edjlali M, Baron JC, Leclerc X, Leys D, Mas JL, Cordonnier C, Oppenheim C (2015) Microbleed status and 3-month outcome after intravenous thrombolysis in 717 patients with acute ischemic stroke. Stroke 46(9):2458–2463. doi:10.1161/strokeaha.115.009290

    CAS  Article  PubMed  Google Scholar 

  13. Dannenberg S, Scheitz JF, Rozanski M, Erdur H, Brunecker P, Werring DJ, Fiebach JB, Nolte CH (2014) Number of cerebral microbleeds and risk of intracerebral hemorrhage after intravenous thrombolysis. Stroke 45(10):2900–2905. doi:10.1161/strokeaha.114.006448

    Article  PubMed  Google Scholar 

  14. Cai J, Fu J, Yan S, Hu H, Lin C (2015) Clinical outcome in acute ischemic stroke patients with microbleeds after thrombolytic therapy: a meta-Analysis. Medicine 94(52):e2379. doi:10.1097/md.0000000000002379

    Article  PubMed  PubMed Central  Google Scholar 

  15. Charidimou A, Shoamanesh A, Wilson D, Gang Q, Fox Z, Jager HR, Benavente OR, Werring DJ (2015) Cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk updated meta-analysis. Neurology 85(11):927–934. doi:10.1212/wnl.0000000000001923

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tsivgoulis G, Zand R, Katsanos AH, Turc G, Nolte CH, Jung S, Cordonnier C, Fiebach JB, Scheitz JF, Klinger-Gratz PP, Oppenheim C, Goyal N, Safouris A, Mattle HP, Alexandrov AW, Schellinger PD, Alexandrov AV (2016) Risk of symptomatic intracerebral hemorrhage after intravenous thrombolysis in patients with acute ischemic stroke and high cerebral microbleed burden: a meta-analysis. JAMA Neurol 73(6):675–683. doi:10.1001/jamaneurol.2016.0292

    Article  PubMed  Google Scholar 

  17. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(4):264–269. doi:10.7326/0003-4819-151-4-200908180-00135

    Article  PubMed  Google Scholar 

  18. Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, Tugwell P (2000) The Newcastle–Ottawa Scale (NOS) for assessing the quality of non-randomised studies in meta-analyses

  19. Higgins JPT, Thompson S, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed  PubMed Central  Google Scholar 

  20. Egger M, Smith GD, Schneider M, Minder CE (1997) Bias in meta›analysis detected by a simple, graphical test. BMJ 315(7109):629

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Annan M, Cottier JP, Gaudron M, Dejobert M, De Toffol B, Debiais S (2015) Microbleeds: not more hemorrhagic transformation after thrombolysis. Eur J Neurol 22:126

    Google Scholar 

  22. Derex L, Nighoghossian N, Hermier M, Adeleine P, Philippeau F, Honnorat J, Yilmaz H, Dardel P, Froment JC, Trouillas P (2004) Thrombolysis for ischemic stroke in patients with old microbleeds on pretreatment MRI. Cerebrovasc Dis (Basel, Switzerland) 17(2–3):238–241. doi:10.1159/000076123

    CAS  Google Scholar 

  23. Fiehler J, Albers GW, Boulanger JM, Derex L, Gass A, Hjort N, Kim JS, Liebeskind DS, Neumann-Haefelin T, Pedraza S, Rother J, Rothwell P, Rovira A, Schellinger PD, Trenkler J, Grp MS (2007) Bleeding risk analysis in stroke imaging before thrombolysis (BRASIL)—pooled analysis of t2*-weighted magnetic resonance imaging data from 570 patients. Stroke 38(10):2738–2744. doi:10.1161/strokeaha.106.480848

    Article  PubMed  Google Scholar 

  24. Gratz PP, El-Koussy M, Hsieh K, von Arx S, Mono ML, Heldner MR, Fischer U, Mattle HP, Zubler C, Schroth G, Gralla J, Arnold M, Jung S (2014) Preexisting cerebral microbleeds on susceptibility-weighted magnetic resonance imaging and post-thrombolysis bleeding risk in 392 patients. Stroke 45(6):1684–1688. doi:10.1161/strokeaha.114.004796

    Article  PubMed  Google Scholar 

  25. Kakuda W, Thijs VN, Lansberg MG, Bammer R, Wechsler L, Kemp S, Moseley ME, Marks MP, Albers GW, Investigators D (2005) Clinical importance of microbleeds in patients receiving IV thrombolysis. Neurology 65(8):1175–1178. doi:10.1212/01.wnl.0000180519.27680.0f

    CAS  Article  PubMed  Google Scholar 

  26. Kimura K, Aoki J, Shibazaki K, Saji N, Uemura J, Sakamoto Y (2013) New appearance of extraischemic microbleeds on T2*-weighted magnetic resonance imaging 24 hours after tissue-type plasminogen activator administration. Stroke 44(10):2776–2781. doi:10.1161/strokeaha.113.001778

    CAS  Article  PubMed  Google Scholar 

  27. Moriya Y, Takahashi W, Kijima C, Yutani S, Iijima E, Mizuma A, Honma K, Uesugi T, Ohnuki Y, Nagata E, Yanagimachi N, Takizawa S (2013) Predictors for hemorrhagic transformation with intravenous tissue plasminogen activator in acute ischemic stroke. Tokai J Exp Clin Med 38(1):24–27

    PubMed  Google Scholar 

  28. Takahashi Y, Morihara R, Narai H, Omori N, Manabe Y (2014) Acute neuroimaging analysis of the risk of hemorrhagic complications in acute ischemic stroke patients with microbleeds after intravenous recombinant tissue plasminogen activator therapy. Int J Stroke 9:57–58

    Article  Google Scholar 

  29. Shoamanesh A, Kwok CS, Lim PA, Benavente OR (2013) Postthrombolysis intracranial hemorrhage risk of cerebral microbleeds in acute stroke patients: a systematic review and meta-analysis. Int J Stroke 8(5):348–356. doi:10.1111/j.1747-4949.2012.00869.x

    Article  PubMed  Google Scholar 

  30. Wu Y, Chen T (2016) An Up-To-Date Review On Cerebral Microbleeds. J Stroke Cerebrovasc Dis 25(6):1301–1306. doi:10.1016/j.jstrokecerebrovasdis.2016.03.005

    Article  PubMed  Google Scholar 

  31. Smith EE, Greenberg SM (2001) Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 56(4):537–539

    Article  Google Scholar 

  32. Yakushiji Y (2015) Cerebral microbleeds: detection, associations and clinical implications. Front Neurol Neurosci 37:78–92. doi:10.1159/000437115

    Article  PubMed  Google Scholar 

  33. Viswanathan M, Salman RA-S, Steven Warach M, Lenore J (2009) Cerebral microbleeds: a field guide to their detection and interpretation. Lancet Neurol 8(2):165–174

    Article  PubMed  PubMed Central  Google Scholar 

  34. Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, Hartung HP (1999) Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. Am J Neuroradiol 20(4):637–642

    CAS  PubMed  Google Scholar 

  35. Dzialowski I, Pexman JW, Barber PA, Demchuk AM, Buchan AM, Hill MD, Investigators C (2007) Asymptomatic hemorrhage after thrombolysis may not be benign prognosis by hemorrhage type in the Canadian Alteplase for Stroke Effectiveness Study Registry. Stroke 38(1):75–79

    Article  PubMed  Google Scholar 

  36. Thorlund K, Imberger G, Walsh M, Chu R, Gluud C, Wetterslev J, Guyatt G, Devereaux PJ, Thabane L (2011) The number of patients and events required to limit the risk of overestimation of intervention effects in meta-analysis—a simulation study. PLoS One 6(10):e25491

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Dávalos A, Erilä T, Ford GA, Grond M, Hacke W (2008) Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials safe implementation of thrombolysis in stroke-monitoring study (SITS-MOST). Stroke 39(12):3316–3322

    Article  PubMed  Google Scholar 

  38. Arsava E, Rahman R, Rosand J, Lu J, Smith E, Rost N, Singhal A, Lev M, Furie K, Koroshetz W (2009) Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke. Neurology 72(16):1403–1410

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Cheng A-L, Batool S, McCreary CR, Lauzon M, Frayne R, Goyal M, Smith EE (2013) Susceptibility-weighted imaging is more reliable than T2*-weighted gradient-recalled echo MRI for detecting microbleeds. Stroke 44(10):2782–2786

    Article  PubMed  Google Scholar 

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Correspondence to Hui-Sheng Chen.

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S. Wang and Y. Lv equally contributed to this article.

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Wang, S., Lv, Y., Zheng, X. et al. The impact of cerebral microbleeds on intracerebral hemorrhage and poor functional outcome of acute ischemic stroke patients treated with intravenous thrombolysis: a systematic review and meta-analysis. J Neurol 264, 1309–1319 (2017).

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  • Cerebral microbleeds
  • Magnetic resonance imaging
  • Acute ischemic stroke
  • Recombinant tissue plasminogen activator
  • Thrombolytic therapy
  • Cerebral hemorrhage