COVID-19 and intracranial hemorrhage: a multicenter case series, systematic review and pooled analysis

Abstract Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts on hemostasis and microvasculature. Correspondingly, antithrombotic therapy is frequently used for prophylaxis or treatment of thromboembolic complications as well as in the context of extracorporeal membrane oxygenation (ECMO). However, reports of intracranial hemorrhage (ICH) associated with Coronavirus disease 2019 (COVID-19) have also emerged. In the light of the dilemma between thromboembolic and hemorrhagic complications, we sought to systematically investigate incidence, mortality, radiological subtypes and clinical characteristics of ICH in COVID-19 patients.Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. Furthermore, we performed a pooled analysis including a prospectively collected cohort of critically ill COVID-19 patients with ICH as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive care of COVID-19).Results: Our literature review revealed a total of 217 citations. After selection process, 79 studies and a total of 477 patients were included. Median age was 58.8 years (95% CI 54.8 years-62.9 years; I2 = 85,6%). 23.3% patients experienced critical stage of COVID-19 (95% CI 8.9% − 61.2%, I2 = 53.8%). 62.7% patients were on anticoagulation (95% CI 38.2% − 103.0%, I2 = 82,6%), and 27.5% patients received ECMO (95% CI 5.8% − 130.2%, I2 = 92.7%). Microbleeds (51.1%, 95% CI 31.1% − 84.2%, I2 = 85.1%), subarachnoid hemorrhage (SAH) (26.6%, 95% CI 16.8% − 42.0%, I2 = 61.2%) and intraparenchymal hemorrhage (IPH) (33.7%, 95% CI 23.3% − 48.8%, I2 = 63.7%) were most frequently documented as ICH subtypes. Incidence was at 0.85% (95% CI 0.36%-1.99%; I2 = 97.5%) and mortality at 52.18% (95% CI 40.40%-67.39%; I2 = 51.7%), respectively.Conclusion: ICH in COVID-19 patients is rare, but has a very poor prognosis. Different subtypes of ICH seen in COVID-19 support the assumption of heterogenous and multifactorial pathomechanisms contributing to ICH in COVID-19. Further data and pathophysiological insights are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future.