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. 2025 Mar 3;82(4):355-363.
doi: 10.1001/jamaneurol.2025.0026. Online ahead of print.

Location and Timing of Recurrent, Nontraumatic Intracerebral Hemorrhage

Martina B Goeldlin  1 , Simon Fandler-Höfler  2   3 , Alessandro Pezzini  4   5 , Anusha Manikantan  1 , Janis Rauch  1 , Stine Munk Hald  6 , Mona Løgtholt Kristensen  7 , Lena Obergottsberger  2 , Jochen A Sembill  8 , David Haupenthal  8 , Kristin Tveitan Larsen  9 , Nikolaos S Avramiotis  10 , Alexandros A Polymeris  10 , Charlotte Periole  11 , Kitti Thiankhaw  3 , Ida Rangus  12 , Laurent Puy  13 , Marco Pasi  14 , Andrea Morotti  15 , Giorgio Silvestrelli  16 , Giacomo Giacalone  17 , Maurizio Paciaroni  18 , Marialuisa Zedde  19 , Elisa Giorli  20 , Rossana Tassi  21 , Marc Delgado-Romeu  22 , Urs Fischer  1 , Bastian Volbers  1 , Arsany Hakim  23 , Werner J Z'Graggen  1   24 , Christian H Nolte  12   25 , David J Werring  3 , Nicolas Raposo  11   26 , Stefan T Engelter  10   27 , Espen S Kristoffersen  9 , Joji Kuramatsu  8   28 , Thomas Gattringer  2 , David Gaist  6 , David J Seiffge  1 ; EURECA collaborators
Collaborators, Affiliations

Location and Timing of Recurrent, Nontraumatic Intracerebral Hemorrhage

Martina B Goeldlin et al. JAMA Neurol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Goeldlin reported receiving grants from Inselgruppe AG, Swiss Stroke Society, Bangerter-Rhyner-Foundation/Swiss Academy of Medical Sciences, and European Stroke Organisation; congress registration and hotel from the European Academy of Neurology; and a travel grant from Pfizer to Inselspital Bern outside the submitted work. Dr Fandler-Höfler reported receiving personal fees from AstraZeneca outside the submitted work. Dr Puy reported receiving personal fees from Novo Nordisk outside the submitted work. Dr Morotti reported receiving personal fees from the Emergency Cardiac Research and Education Group and AstraZeneca outside the submitted work. Dr Fischer reported receiving grants from Medtronic, Stryker, Penumbra, Phenox, Rapid Medical, Boehringer Ingelheim, Swiss National Science Foundation, and Swiss Heart Foundation to Inselspital Bern outside the submitted work and personal fees from Medtronic, AstraZeneca (formerly, Alexion/Portola), Bayer, Boehringer Ingelheim, Biogen, AbbVie, and Siemens to Inselspital Bern and serving as a member of a clinical event committee of the COATING study (Phenox) and data and safety monitoring committee of the TITAN, LATE_MT, IN EXTREMIS, and RapidPulse trials and president of the Swiss Neurological Society and president-elect of the European Stroke Organisation. Dr Volbers reported receiving personal fees from Pfizer AG/Bristol Myers Squibb SA, Bayer AG, Ipsen Pharma, CSL Behring, and AstraZeneca and education and training from AbbVie outside the submitted work. Dr Werring reported receiving personal fees from Bayer, Alnylam, and AstraZeneca outside the submitted work. Dr Engelter reported receiving grants from Daiichi Sankyo to Felix Platter Spital Basel and grants from Bayer and Boehringer Ingelheim during the conduct of the study. Dr Kuramatsu reported receiving personal fees from Boehringer Ingelheim and AstraZeneca outside the submitted work. Dr Gattringer reported receiving grants from the Austrian Science Fund and personal fees from Bayer, Bristol Myers Squibb-Pfizer, Boehringer Ingelheim, Novartis, and AstraZeneca outside the submitted work. Dr Gaist reported receiving personal fees from Pfizer and Bristol Myers Squibb and participating in research funded by Bayer paid to Odense University Hospital outside the submitted work. Dr Seiffge reported receiving grants from AstraZeneca, Swiss National Science Foundation, Swiss Heart Foundation, and Bangerter Rhyner Foundation outside the submitted work and personal fees from AstraZeneca, Bayer AG, Bioxodes, and VarmX to Inselspital Bern. No other disclosures were reported.

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