Early Blood-Brain Barrier Dysfunction Predicts Neurological Outcome Following Aneurysmal Subarachnoid Hemorrhage

Abstract

Background: Disease progression and delayed neurological complications are common after aneurysmal subarachnoid hemorrhage (aSAH). We explored the potential of quantitative blood-brain barrier (BBB) imaging to predict disease progression and neurological outcome. Methods: Data were collected as part of the Co-Operative Studies of Brain Injury Depolarizations (COSBID). We analyzed retrospectively, blindly and semi-automatically magnetic resonance images from 124 aSAH patients scanned at 4 time points (24-48 h, 6-8 days, 12-15 days and 6-12 months) after the initial hemorrhage. Volume of brain with apparent pathology and BBB dysfunction (BBBD), subarachnoid space and lateral ventricles were measured. Neurological status on admission was assessed using the Fisher grades, World Federation of Neurosurgical Societies and Rosen-Macdonald (RMS) scores. Clinical outcome at 6 months or later was assessed using the extended Glasgow outcome scale. Findings: Based on repeated volumetric measures of pathological brain tissue and CSF, patients were categorized as having either progressive (increased pathology; 64%) or nonprogressive (36%) disease course. No differences were found between the two groups in aneurysm locations, neurological status on admission, initial brain pathology or treatment (coiling or clipping). Females were older and more likely to have a non-progressive course compared to males (p=0·01). Progressive course was associated with worse outcome at ≥6 months. A substantial brain volume with BBBD was found already 24-48 h after admission, and persisted at all time points. Brain volume with BBBD was significantly larger in patients with progressive course. BBBD increased the likelihood of a normal brain tissue to become pathological (p<0·001). A multi-linear regression model revealed a significant power for BBBD in combination with RMS at 24-48 h in predicting outcome (receiver operating characteristic area under the curve, 0·804; p<0·001). Interpretation: We suggest that early identification of BBBD may serve as a key predictive biomarker for neurological outcome in aSAH. Funding Statement: The study was designed and performed as a sub-study within the Co-Operative Study of Brain Injury Depolarizations (COSBID) study group. JPD was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (DFG DR 323/5-1), the Bundesministerium fur Bildung und Forschung (BMBF) Center for Stroke Research Berlin 01 EO 0801 and FP7 no 602150 CENTER-TBI. AF was supported by grants from the DFG (DFG DR 323/5-1), Israel Science Foundation and Canada Institute for Health Research (CIHR). JW was supported by grants from the DFG DR 323/5-1 and DFG WO 1704/1-1. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The protocol was approved by the ethics committees of the Charite University Medicine Berlin, the Goethe-University Frankfurt, the University Hospital Heidelberg and the University of Cologne. Research was conducted in accordance with the Declaration of Helsinki. Patients or their legal representative gave written consent for study inclusion. Results are reported in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.