Risk of Symptomatic Intracerebral Hemorrhage After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke and High Cerebral Microbleed Burden: A Meta-analysis

JAMA Neurol. 2016 Jun 1;73(6):675-83. doi: 10.1001/jamaneurol.2016.0292.


Importance: Cerebral microbleeds (CMBs) have been established as an independent predictor of cerebral bleeding. There are contradictory data regarding the potential association of CMB burden with the risk of symptomatic intracerebral hemorrhage (sICH) in patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT).

Objective: To investigate the association of high CMB burden (>10 CMBs on a pre-IVT magnetic image resonance [MRI] scan) with the risk of sICH following IVT for AIS.

Data sources: Eligible studies were identified by searching Medline and Scopus databases. No language or other restrictions were imposed. The literature search was conducted on October 7, 2015. This meta-analysis has adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) proposal.

Study selection: Eligible prospective study protocols that reported sICH rates in patients with AIS who underwent MRI for CMB screening prior to IVT.

Data extraction and synthesis: The reported rates of sICH complicating IVT in patients with AIS with pretreatment MRI were extracted independently for groups of patients with 0 CMBs (CMB absence), 1 or more CMBs (CMB presence), 1 to 10 CMBs (low to moderate CMB burden), and more than 10 CMBs (high CMB burden). An individual-patient data meta-analysis was also performed in the included studies that provided complete patient data sets.

Main outcomes and measures: Symptomatic intracerebral hemorrhage based on the European Cooperative Acute Stroke Study-II definition (any intracranial bleed with ≥4 points worsening on the National Institutes of Health Stroke Scale score).

Results: We included 9 studies comprising 2479 patients with AIS. The risk of sICH after IVT was found to be higher in patients with evidence of CMB presence, compared with patients without CMBs (risk ratio [RR], 2.36; 95% CI, 1.21-4.61; P = .01). A higher risk for sICH after IVT was detected in patients with high CMB burden (>10 CMBs) when compared with patients with 0 to 10 CMBs (RR, 12.10; 95% CI, 4.36-33.57; P < .001) or 1 to 10 CMBs (RR, 7.01; 95% CI, 3.20-15.38; P < .001) on pretreatment MRI. In the individual-patient data meta-analysis, high CMB burden was associated with increased likelihood of sICH before (unadjusted odds ratio, 31.06; 95% CI, 7.12-135.44; P < .001) and after (adjusted odds ratio, 18.17; 95% CI, 2.39-138.22; P = .005) adjusting for potential confounders.

Conclusions and relevance: Presence of CMB and high CMB burdens on pretreatment MRI were independently associated with sICH in patients with AIS treated with IVT. High CMB burden may be included in individual risk stratification scores predicting sICH risk following IVT for AIS.

Publication types

  • Meta-Analysis

MeSH terms

  • Administration, Intravenous
  • Brain Ischemia / complications
  • Brain Ischemia / diagnostic imaging
  • Cerebral Hemorrhage / chemically induced*
  • Cerebral Hemorrhage / diagnostic imaging
  • Cerebral Hemorrhage / epidemiology
  • Databases, Bibliographic / statistics & numerical data
  • Fibrinolytic Agents / adverse effects*
  • Humans
  • Magnetic Resonance Imaging
  • Risk Factors
  • Stroke / diagnostic imaging
  • Stroke / drug therapy
  • Stroke / etiology


  • Fibrinolytic Agents