Location and Timing of Recurrent, Nontraumatic Intracerebral Hemorrhage

IMPORTANCE: : The spatial and temporal distribution of intracerebral hemorrhage (ICH) recurrence are largely unknown. OBJECTIVE: To assess timing and location of recurrent ICH events in relation to the index ICH event (adjacent ICH [adjICH] vs remote ICH [remICH]). DESIGN, SETTING, AND PARTICIPANTS: This cohort study was a pooled analysis of individual cohort studies from 2002 to 2021 among hospital-based European cohorts. Patients with 2 or more clinically distinguishable (≥1 recurrent) small vessel disease-related ICH events were included. Data analysis was performed from December 2023 to December 2024. EXPOSURES: ICH location and underlying small vessel disease type. MAIN OUTCOMES AND MEASURES: The primary outcome was adjICH, defined by anatomical ICH location and side, and the secondary outcome was time to recurrence. Multivariable regression analyses were conducted adjusting for ICH location, cerebral amyloid angiopathy according to Boston 2.0 or simplified Edinburgh criteria, convexity subarachnoid hemorrhage extension, hypertension, and antihypertensive treatment, including an interaction term for hypertension and antihypertensive treatment. RESULTS: Among 733 patients (median [IQR] age, 72.4 [65.2 to 79.0] years; 346 female [47.2%]), there were 1616 ICH events, including 733 index and 883 recurrent ICH events (range, 1 to 6 recurrences) over a median (IQR) follow-up of 2.53 (0.66 to 4.92) years. There were 340 patients (46.4%) with adjICH and 393 patients (53.6%) with remICH. Among recurrent ICH events, there were 476 adjICH events and 407 remICH events. In multivariable regression analyses, lobar index ICH (adjusted odds ratio [aOR], 2.08; 95% CI, 1.32 to 3.27) and cerebral amyloid angiopathy at index ICH (aOR, 2.21; 95% CI, 1.57 to 3.11) were associated with higher odds of adjICH, while cerebellar index ICH was associated with lower odds of adjICH (aOR, 0.25; 95% CI, 0.07 to 0.89). The median (IQR) time to recurrence was 1.25 (0.36 to 3.38) years for adjICH and 2.21 (0.66 to 4.85) years for remICH. Previous lobar or convexity subarachnoid hemorrhage (coefficient, -0.75; 95% CI, -1.25 to -0.25; P = .003 ), adjICH (coefficient, -0.60; 95% CI, -1.02 to -0.18; P = .005), and the number of previous ICH events (coefficient per 1-event increase, -0.62; 95% CI, -0.93 to -0.32; P < .001) were independently associated with a shorter time to recurrence. CONCLUSIONS AND RELEVANCE: This study found that early recurrence and cerebral amyloid angiopathy were associated with adjICH. These findings suggest that regional, tissue-based factors may facilitate recurrence and that identifying and targeting local vasculopathic changes may represent potential novel treatment targets

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [&lt;1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None