Secondary injury and inflammation after intracerebral haemorrhage: a systematic review and meta-analysis of molecular markers in patient brain tissue.

BACKGROUND: Inflammatory responses to intracerebral haemorrhage (ICH) are potential therapeutic targets. We aimed to quantify molecular markers of inflammation in human brain tissue after ICH compared with controls using meta-analysis. METHODS: We searched OVID MEDLINE (1946-) and Embase (1974-) in June 2020 for studies that reported any measure of a molecular marker of inflammation in brain tissue from five or more adults after ICH. We assessed risk of bias using a modified Newcastle-Ottawa Scale (mNOS; mNOS score 0-9; 9 indicates low bias), extracted aggregate data, and used random effects meta-analysis to pool associations of molecules where more than two independent case-control studies reported the same outcome and Gene Ontology enrichment analysis to identify over-represented biological processes in pooled sets of differentially expressed molecules (International Prospective Register of Systematic Reviews ID: CRD42018110204). RESULTS: Of 7501 studies identified, 44 were included: 6 were case series and 38 were case-control studies (median mNOS score 4, IQR 3-5). We extracted data from 21 491 analyses of 20 951 molecules reported by 38 case-control studies. Only one molecule (interleukin-1ß protein) was quantified in three case-control studies (127 ICH cases vs 41 ICH-free controls), which found increased abundance of interleukin-1ß protein after ICH (corrected standardised mean difference 1.74, 95% CI 0.28 to 3.21, p=0.036, I2=46%). Processes associated with interleukin-1ß signalling were enriched in sets of molecules that were more abundant after ICH. CONCLUSION: Interleukin-1ß abundance is increased after ICH, but analyses of other inflammatory molecules after ICH lack replication. Interleukin-1ß pathway modulators may optimise inflammatory responses to ICH and merit testing in clinical trials.

Association of baseline hematoma and edema volumes with one-year outcome and long-term survival after spontaneous intracerebral hemorrhage: A community-based inception cohort study.

BACKGROUND: Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. AIMS: In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. METHODS: We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3-6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. RESULTS: Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68-83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9-21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear (R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08-2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63-1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11-1.42); p = 0.0004). CONCLUSION: Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. DATA ACCESS STATEMENT: Anonymized summary data may be requested from the corresponding author.