# paper.pdf ## Metadata - PDFFormatVersion=1.7 - Language=de-DE - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - Author=Neshika Samarasekera - CreationDate=D:20260421190901+05'30' - Creator=Adobe InDesign 15.1 (Windows) - ModDate=D:20260421212139+05'30' - Producer=Adobe PDF Library 15.0 - Subject=DOI: 10.1161/STROKEAHA.125.053991 Stroke, Volume. 57, Issue. 5, BACKGROUND: Perihematomal edema (PHE) after intracerebral hemorrhage (ICH) is a biomarker of secondary brain injury. We aimed to determine the direction, strength, and temporality of the association between PHE and functional outcome after ICH onset. METHODS: We did a systematic review to identify cohort studies or trials that used brain computed tomography (CT) imaging to diagnose ICH, and measured functional outcome. We sought individual participant data if they had a diagnostic CT within 72 hours, a repeat CT within 14 days of the diagnostic scan, and were not treated with surgery or therapy that could affect PHE. We did a 2-stage individual participant data meta-analysis. The primary analysis was the association between the change in absolute PHE volume between the diagnostic CT and repeat CT and the primary outcome of death or dependence (modified Rankin Scale score, 3–6) at 90±14 days after ICH onset. We quantified the association between change in absolute PHE volume at 2 repeat CT time points (24±12 and 72±12 hours) and outcome, both unadjusted and adjusted for age, sex, ICH volume on the diagnostic CT, and intraventricular extension using multivariable logistic regression. RESULTS: From 12 969 studies, 38 were eligible, of which 12 studies (with 1 unpublished cohort and the VISTA [Virtual International Stroke Trials Archive]-ICH databank) provided data. We included 1523 participants, of whom 1347 participants (516 [38%] participants female; median age, 66 [interquartile range, 55–75] years) had repeat CT at 24±12 hours, and 495 (195 [39%] participants female; median age, 66 [interquartile range, 55–74] years) had repeat CT at 72±12 hours. 319 participants contributed to both analyses. Death or dependence was associated with absolute PHE growth both in the first 24±12 hours (unadjusted odds ratio, 1.04 per mL increase [95% CI, 1.01–1.06]; P<0.01; adjusted odds ratio, 1.04 per mL increase [95% CI, 1.01–1.06]; P<0.01) and in the first 72±12 hours (unadjusted odds ratio, 1.03 per mL [95% CI, 1.01–1.04]; P<0.01; adjusted odds ratio, 1.02 [95% CI, 1.01–1.04] per 1 mL increase; P<0.01). CONCLUSIONS: PHE growth within 24 and 72 hours of ICH onset is independently associated with death or dependence after ICH. - Title=Perihematomal Edema and Functional Outcome After Intracerebral Hemorrhage: A Meta-Analysis of Individual Participant Data - Trapped=False - dc:format=application/pdf - dc:title=Perihematomal Edema and Functional Outcome After Intracerebral Hemorrhage: A Meta-Analysis of Individual Participant Data - dc:creator=Neshika Samarasekera,Sharon Tuck,Xia Wang,Craig S. Anderson,Alireza Shirazian,Bastian Volbers,Hagen B. Huttner,Sarah Marchina,Casey Norton,Magdy Selim,Kevin N. Sheth,Guido J. Falcone,Pedro Castro,Grant Mair,Tom J. Moullaali,Mark A. Rodrigues,Adrian Parry-Jones,Nikola Sprigg,Floris H.B.M. Schreuder,Thorsten Steiner,Ken S. Butcher,Daniel Hanley,Wendy Ziai,Andrew Demchuk,David Rodriguez-Luna,Ramon Iglesias Rey,Pablo Hervella,Atte Meretoja,Aaron M. Gusdon,Christopher J. Weir,Rustam Al-Shahi Salman - dc:subject=biomarkers ◼,brain ◼,cerebral hemorrhage ◼,edema ◼,tomography - dc:description=DOI: 10.1161/STROKEAHA.125.053991 Stroke, Volume. 57, Issue. 5, BACKGROUND: Perihematomal edema (PHE) after intracerebral hemorrhage (ICH) is a biomarker of secondary brain injury. We aimed to determine the direction, strength, and temporality of the association between PHE and functional outcome after ICH onset. METHODS: We did a systematic review to identify cohort studies or trials that used brain computed tomography (CT) imaging to diagnose ICH, and measured functional outcome. We sought individual participant data if they had a diagnostic CT within 72 hours, a repeat CT within 14 days of the diagnostic scan, and were not treated with surgery or therapy that could affect PHE. We did a 2-stage individual participant data meta-analysis. The primary analysis was the association between the change in absolute PHE volume between the diagnostic CT and repeat CT and the primary outcome of death or dependence (modified Rankin Scale score, 3–6) at 90±14 days after ICH onset. We quantified the association between change in absolute PHE volume at 2 repeat CT time points (24±12 and 72±12 hours) and outcome, both unadjusted and adjusted for age, sex, ICH volume on the diagnostic CT, and intraventricular extension using multivariable logistic regression. RESULTS: From 12 969 studies, 38 were eligible, of which 12 studies (with 1 unpublished cohort and the VISTA [Virtual International Stroke Trials Archive]-ICH databank) provided data. We included 1523 participants, of whom 1347 participants (516 [38%] participants female; median age, 66 [interquartile range, 55–75] years) had repeat CT at 24±12 hours, and 495 (195 [39%] participants female; median age, 66 [interquartile range, 55–74] years) had repeat CT at 72±12 hours. 319 participants contributed to both analyses. Death or dependence was associated with absolute PHE growth both in the first 24±12 hours (unadjusted odds ratio, 1.04 per mL increase [95% CI, 1.01–1.06]; P<0.01; adjusted odds ratio, 1.04 per mL increase [95% CI, 1.01–1.06]; P<0.01) and in the first 72±12 hours (unadjusted odds ratio, 1.03 per mL [95% CI, 1.01–1.04]; P<0.01; adjusted odds ratio, 1.02 [95% CI, 1.01–1.04] per 1 mL increase; P<0.01). CONCLUSIONS: PHE growth within 24 and 72 hours of ICH onset is independently associated with death or dependence after ICH. - dc:rights=© 2026 The Authors. - xmp:createdate=2026-04-21T19:09:01+05:30 - xmp:creatortool=Adobe InDesign 15.1 (Windows) - xmp:modifydate=2026-04-21T21:21:39+05:30 - xmp:metadatadate=2026-04-21T21:21:39+05:30 - xmpmm:instanceid=uuid:534b0276-87a7-4324-9c73-3a0313cfe37f - xmpmm:originaldocumentid=xmp.did:DE4D607E8A24681180838231FB1F3433 - xmpmm:documentid=xmp.id:840713bc-c977-c343-bff9-9582f7fbe305 - xmpmm:renditionclass=proof:pdf - xmpmm:versionid=1 - xmpmm:derivedfrom=xmp.iid:9886738a-5575-9c4a-b4fe-2541e629cb21xmp.did:b0135995-a6f3-c942-b7b5-87eec4d91eb5default - xmpmm:history=convertedfrom application/x-indesign to application/pdfAdobe InDesign 15.1 (Windows)2026-04-21T19:09:01+05:30converteduuid:064067f5-05cd-48fc-8b7f-750d140d9041converted to PDF/A-3aPreflight2026-04-21T21:21:39+05:30 - xmprights:marked=True - pdf:producer=Adobe PDF Library 15.0 - pdf:trapped=False - pdfuaid:part=1 - pdfaid:part=3 - pdfaid:conformance=A - pdfaextension:schemas=http://ns.adobe.com/xap/1.0/mm/xmpMMXMP Media Management SchemainternalUUID based identifier for specific incarnation of a documentInstanceIDURIinternalThe common identifier for all versions and renditions of a document.OriginalDocumentIDURIhttp://ns.adobe.com/pdf/1.3/pdfAdobe PDF SchemainternalA name object indicating whether the document has been modified to include trapping informationTrappedTexthttp://www.aiim.org/pdfa/ns/id/pdfaidPDF/A ID SchemainternalPart of PDF/A standardpartIntegerinternalAmendment of PDF/A standardamdTextinternalConformance level of PDF/A standardconformanceTexthttp://www.aiim.org/pdfua/ns/id/pdfuaidPDF/UA ID SchemainternalPart of PDF/UA standardpartInteger ## Contents ### Page 1 CLINICAL AND POPULATION SCIENCES # Perihematomal Edema and Functional OutcomeAfter Intracerebral Hemorrhage: A Meta-Analysisof Individual Participant Data Neshika Samarasekera[ ![Equation 1]() ](https://orcid.org/0000-0001-6840-0199) , PhD; Sharon Tuck[ ![Equation 1]() ](https://orcid.org/0000-0002-6186-6794) , MSc; Xia Wang[ ![Equation 1]() ](https://orcid.org/0000-0002-1684-7076) , PhD; Craig S. Anderson[ ![Equation 1]() ](https://orcid.org/0000-0002-7248-4863) , PhD; Alireza Shirazian[ ![Equation 1]() ](https://orcid.org/0000-0002-6029-6822) , MD;Bastian Volbers[ ![Equation 1]() ](https://orcid.org/0000-0003-0453-1530) , MD; Hagen B. Huttner[ ![Equation 1]() ](https://orcid.org/0000-0002-0992-8871) , PhD; Sarah Marchina[ ![Equation 1]() ](https://orcid.org/0000-0002-9969-9362) , PhD; Casey Norton[ ![Equation 1]() ](https://orcid.org/0009-0002-3361-6365) , MS; Magdy Selim[ ![Equation 1]() ](https://orcid.org/0000-0002-1936-3173) , PhD;Kevin N. Sheth[ ![Equation 1]() ](https://orcid.org/0000-0003-2003-5473) , MD; Guido J. Falcone[ ![Equation 1]() ](https://orcid.org/0000-0002-6407-0302) , MD; Pedro Castro[ ![Equation 1]() ](https://orcid.org/0000-0003-1401-2398) , PhD; Grant Mair[ ![Equation 1]() ](https://orcid.org/0000-0003-2189-443X) , MD; Tom J. Moullaali[ ![Equation 1]() ](https://orcid.org/0000-0002-6786-3623) , PhD;Mark A. Rodrigues[ ![Equation 1]() ](https://orcid.org/0000-0002-4507-6872) , PhD; Adrian Parry-Jones[ ![Equation 1]() ](https://orcid.org/0000-0002-4462-3846) , PhD; Nikola Sprigg[ ![Equation 1]() ](https://orcid.org/0000-0002-5871-8168) , DM; Floris H.B.M. Schreuder[ ![Equation 1]() ](https://orcid.org/0000-0002-7815-0207) , PhD;Thorsten Steiner[ ![Equation 1]() ](https://orcid.org/0000-0002-5080-8222) , PhD; Ken S. Butcher[ ![Equation 1]() ](https://orcid.org/0000-0002-0590-7918) , PhD; Daniel Hanley[ ![Equation 1]() ](https://orcid.org/0000-0002-9536-4258) , MD; Wendy Ziai[ ![Equation 1]() ](https://orcid.org/0000-0003-4548-7353) , MD; Andrew Demchuk[ ![Equation 1]() ](https://orcid.org/0000-0002-4930-7789) , MD;David Rodriguez-Luna[ ![Equation 1]() ](https://orcid.org/0000-0001-8053-4536) , PhD; Ramon Iglesias Rey[ ![Equation 1]() ](https://orcid.org/0000-0002-9985-9135) , PhD; Pablo Hervella[ ![Equation 1]() ](https://orcid.org/0000-0003-1249-6333) , PhD; Atte Meretoja[ ![Equation 1]() ](https://orcid.org/0000-0001-6433-1931) , PhD;Aaron M. Gusdon[ ![Equation 1]() ](https://orcid.org/0000-0002-3350-6601) , MD; Christopher J. Weir[ ![Equation 1]() ](https://orcid.org/0000-0002-6494-4903) , PhD; Rustam Al-Shahi Salman[ ![Equation 1]() ](https://orcid.org/0000-0002-2108-9222) , PhD Correspondence to: Neshika Samarasekera, PhD, Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh EH16 4SB, UnitedKingdom, Email; or Rustam Al-Shahi Salman, FMedSci, Institute for Neuroscience and Cardiovascular Research, The University ofEdinburgh, Edinburgh EH16 4SB, United Kingdom, Email This manuscript was sent to Yunyun Xiong, Guest Editor, for review by expert referees, editorial decision, and final disposition. Supplemental Material is available at. © 2026 The Authors. Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under theterms of the License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. BACKGROUND: Perihematomal edema (PHE) after intracerebral hemorrhage (ICH) is a biomarker of secondary brain injury. Weaimed to determine the direction, strength, and temporality of the association between PHE and functional outcome afterICH onset. METHODS: We did a systematic review to identify cohort studies or trials that used brain computed tomography (CT) imaging todiagnose ICH, and measured functional outcome. We sought individual participant data if they had a diagnostic CT within 72hours, a repeat CT within 14 days of the diagnostic scan, and were not treated with surgery or therapy that could affect PHE.We did a 2-stage individual participant data meta-analysis. The primary analysis was the association between the change inabsolute PHE volume between the diagnostic CT and repeat CT and the primary outcome of death or dependence (modifiedRankin Scale score, 3–6) at 90±14 days after ICH onset. We quantified the association between change in absolute PHEvolume at 2 repeat CT time points (24±12 and 72±12 hours) and outcome, both unadjusted and adjusted for age, sex, ICHvolume on the diagnostic CT, and intraventricular extension using multivariable logistic regression. RESULTS: From 12 969 studies, 38 were eligible, of which 12 studies (with 1 unpublished cohort and the VISTA [VirtualInternational Stroke Trials Archive]-ICH databank) provided data. We included 1523 participants, of whom 1347 participants(516 [38%] participants female; median age, 66 [interquartile range, 55–75] years) had repeat CT at 24±12 hours, and495 (195 [39%] participants female; median age, 66 [interquartile range, 55–74] years) had repeat CT at 72±12 hours.319 participants contributed to both analyses. Death or dependence was associated with absolute PHE growth both in thefirst 24±12 hours (unadjusted odds ratio, 1.04 per mL increase [95% CI, 1.01–1.06]; P<0.01; adjusted odds ratio, 1.04per mL increase [95% CI, 1.01–1.06]; P<0.01) and in the first 72±12 hours (unadjusted odds ratio, 1.03 per mL [95% CI,1.01–1.04]; P<0.01; adjusted odds ratio, 1.02 [95% CI, 1.01–1.04] per 1 mL increase; P<0.01). CONCLUSIONS: PHE growth within 24 and 72 hours of ICH onset is independently associated with death or dependence afterICH. GRAPHIC ABSTRACT: A is available for this article. Key Words: biomarkers ◼ brain ◼ cerebral hemorrhage ◼ edema ◼ tomography ### Page 2 ## Nonstandard Abbreviations and Acronyms CT computed tomography ICH intracerebral hemorrhage IQR interquartile range OR odds ratio PHE perihematomal edema VISTA Virtual International Stroke Trials Archive Spontaneous intracerebral hemorrhage (ICH) is adevastating form of stroke whose global burden hasincreased over the last 30 years.1 One promisingtreatment target2 is secondary injury, which evolves soonafter onset and consists of several processes, includingclot retraction, vasogenic edema formation, red cell lysis,and inflammation, and for which perihematomal edema(PHE) is an imaging biomarker.3–5 Two systematic reviews using aggregate data6,7 haveshown an association between PHE and functional out-come after ICH, although these reviews were limited byheterogeneity in the assessment of PHE and functionaloutcome. Growth of PHE after ICH onset (rather thanPHE measured at a specific time point after onset) maybe more strongly associated with outcome.7 However,analyses have been post hoc, combined studies thatassessed PHE growth during different time periods afteronset6 and have not adjusted for other variables that areknown to affect ICH outcome.6,7 There is increasing awareness that the concept oftime is brain applies not only to ischemic stroke but alsoto ICH,8 which led to the Code ICH9 paradigm for improv-ing acute ICH care. Knowing that PHE is independentlyassociated with functional outcome, how PHE evolvesafter ICH onset, and determining when it is associatedwith outcome would inform the design of randomizedcontrolled trials of interventions for PHE. We aimed to do an individual participant data meta-analysis to (1) describe the trajectory of PHE growthafter ICH onset, (2) confirm whether PHE is indepen-dently associated with functional outcome, and (3) deter-mine the strength of this association over time after ICHonset. ## METHODS ### Protocol and Registration We registered the protocol (page 15 in the) with PROSPERO () and agreed on aprespecified statistical analysis plan (unpublished, finalized onJuly 6, 2022; page 25 in the). We usedPRISMA-IPD guidelines for reporting (Preferred ReportingItems for Systematic Reviews and Meta-Analyses-IndividualParticipant Data;). ### Data Availability Contributing cohorts shared data on the condition that the datarecipient (The University of Edinburgh) shall not sublicense,transfer, disclose, or otherwise make available the data in wholeor part to any third party except with specific prior written con-sent from the data provider. Written requests will be assessed byrepresentatives of the contributing cohorts and the correspond-ing author, and a decision will be made about the appropriate-ness of the reuse of data. A data sharing agreement will be putin place before any data are shared. Individual cohort data setsmay be shared according to the terms described by each cohort. ### Study Eligibility Criteria and Methods ofIdentifying Studies We did a systematic review6 to identify studies that used braincomputed tomography (CT) to measure PHE after ICH onsetand would share participant-level data for this meta-analysis. We identified potentially eligible cohorts by searching OVIDMedline (1950-; RRID:SCR_002185) and Embase (1980-;RRID:SCR_001650), ClinicalTrials.gov, ISRCTN Registry, andCochrane Reviews|Cochrane Library (RRID:SCR_013000) toNovember 17, 2021, by using a search strategy comprisingterms for ICH and PHE,6 hand searching the bibliographies ofrelevant studies, and contacting authors of collaborating stud-ies. We included the largest single report of any observationalcohort or randomized trial involving ≥10 participants with ICHthat measured PHE and functional outcome. If an interventionin a randomized trial could have affected PHE (eg, steroids,mannitol, or hypertonic saline), we included the control arm only.We included studies irrespective of the language of publica-tion, but excluded conference abstracts. We excluded stud-ies solely using magnetic resonance imaging to assess PHEbecause CT is the most frequently used imaging modality forparticipants with ICH, is reliable for the semiautomated assess-ment of PHE,10 and we wished to standardize PHE assess-ment. We included eligible participants from the control armof randomized trials in the VISTA (Virtual International StrokeTrials Archive) for ICH () databank. ### Participant Eligibility Criteria We included participants from these studies if they: were maleor female adults (age ≥18 years); had nontraumatic ICH thatwas probably due to cerebral small vessel disease (not knownto be secondary to a structural cause); had a first (diagnostic)CT within 72 hours of ICH symptom onset; and had a repeatCT at least once within 14 days of the diagnostic CT to enableassessment of PHE growth. We excluded participants treated with any form of neurosur-gical intervention for ICH, and participants where the time fromICH onset to diagnostic CT was unknown. We emailed an invitation to collaborate to the correspondingauthors of eligible studies, followed by 1 reminder. We includedstudies if the corresponding author confirmed eligibility, sup-plied a data dictionary with their data explaining the variablesshared, and provided participant-level data on eligibility criteriaand baseline characteristics, including timing of diagnostic andrepeat CTs, ICH and PHE volumes on each CT, and timing andmeasurement of functional outcome. ### Page 3 Research ethics committees overseeing the use of patients’data had approved the collaborating studies. Cohorts sharedonly anonymized data, so individual consent was not required,but we obtained approval from the Edinburgh Medical SchoolResearch Ethics Committee (21-EMREC-019). ### Data Collection Including Assessment of Riskof Bias We collected study-level characteristics and participant-levelcharacteristics (). We used the QUIPStool to assess the risk of bias of studies that supplied data.11We rated studies that we included in the meta-analysis andstudies that supplied data but were excluded, and gave a studyan overall low risk of bias if the most important domains, whichwe selected a priori, had a low risk of bias. We checked datacompleteness and consistency within each cohort and resolvedany queries directly with the corresponding authors. We stan-dardized the format, coding, and units of measurement ofvariables to maximize the number available for analysis in allstudies. We combined data sets from collaborating studies intoa new master data set, which included a variable to indicate theoriginal study. We did not use or request aggregate data fromcohorts that did not share participant-level data. Because methods of measuring PHE volumes may dif-fer and PHE volume is closely associated with ICH volume,we calculated the ratio of ICH-to-PHE volume for each study.We used this as a measure of the consistency of PHE vol-ume measurement between cohorts for a given time point afterICH onset and hypothesized that ratios would be comparable ifmethods of measurement were similar. Blinding did not apply inthis individual participant data meta-analysis in which PHE hadbeen measured by collaborating cohorts. ### Primary and Secondary Analyses We used the modified Rankin Scale score 3 to 6 at 90 (±14)days as the measure of our primary outcome of death or depen-dence, because this was the most frequently used outcomemeasure in the participating studies. We prespecified that the primary analysis would be theassociation between the change in PHE volume between thediagnostic CT and a repeat CT in the first 14 days after the diag-nostic CT and death or dependence. We did not prespecify atime point for the repeat CT after the diagnostic CT because wewanted to select the time point (±12 hours) after the diagnosticCT when we had the most repeat CTs to maximize data avail-ability. We prespecified absolute volume as our PHE measurebecause this is the most frequently used measure of PHE.6,7 The prespecified secondary analyses were (1) the asso-ciation between PHE and functional outcome at different timepoints, between which change in PHE volume was measured,and (2) the association between PHE volume at a time point(±12 hours) in the first 2 weeks after the diagnostic CT anddeath or dependence using the same time point as the primaryanalysis. In a post hoc analysis, we plotted the value of absolutePHE volume at each time point. ### Synthesis of Results We prespecified unadjusted and adjusted models for the pri-mary and secondary analyses. We used a 2-stage randomeffects logistic regression meta-analysis with restricted maxi-mum likelihood estimation and a random intercept and coef-ficient for each study included in the model. As the includedstudies were large, we used a 2-stage approach to enable theuse of restricted maximum likelihood estimation. This reducesthe downward bias in between-study variance estimates, whichis not available under the single-stage approach. In stage 1, alogistic regression model was fitted to the data for each studyto obtain a log-odds ratio (OR) estimate and SE for the asso-ciation between the change in absolute PHE volume and deathor dependence. At stage 2, these study-specific estimateswere combined in a random effects meta-analysis, includinga Hartung-Knapp12 adjustment to control for the uncertainty inbetween-study variance estimates by inflating the width of theCI. Random effects modeling allowed for the true associationto be different for each study, with t2 quantifying the heteroge-neity between studies. In a prespecified sensitivity analysis, wecompared the random effects model with the common effects(fixed-effects) model. #### Model Building and Covariate Selection In the multivariable-adjusted modeling, we sought to prespecifyclinical variables from the ICH score13 on the basis of theirknown association with outcome and clinical relevance. Ofthese prespecified variables, we selected variables accordingto their completeness and availability at the time of diagnosisin the available cohorts, and the extent to which their selec-tion maximized the total sample size available for multivariableanalyses. We sought to include radiological variables (ICH vol-ume, location, and time from onset to baseline imaging) in themultivariable model based on the significance of their univari-ate association with outcome and the completeness of data. Tominimize any bias in the model SE estimates, we did not includevariables such as ICH growth, which are known to be collinearwith the absolute change in PHE volume. #### Model Validation At stage 1, we assessed model fit using the Akaike andBayesian information criteria. We internally validated the modelusing bootstrap validation, which, by resampling from the fulloriginal data set, allows all of the available data to contribute tomodel development and permits optimism-adjusted values ofmodel discrimination (C statistic; Brier score) to be calculated. If there was missing data for a particular variable, thoserecords were removed from any statistical analysis relating tothat variable, unless otherwise specified. There is no universally accepted method for determiningsample size in multivariable regression, but we used the maxi-mum sample size available for multivariable analyses. We didnot use a power calculation. We did analyses using R (version 4.2.2, R Core Team,2023).14 ## RESULTS We screened 12 968 articles identified by databasesearching and identified 1 additional study15 and a fur-ther unpublished cohort from Sheth et al through contactwith researchers. We assessed 159 full-text articles foreligibility. We excluded 22 studies which included par-ticipants in a cohort published elsewhere,16–37 19 review ### Page 4 articles,38–56 16 studies which had measured PHE on thediagnostic scan only,57–72 13 studies which did not reportan outcome measure,73–85 12 studies which assessedPHE using magnetic resonance imaging,86–97 12 stud-ies in which some/all participants had received an inter-vention which might affect PHE,98–109 11 participantsin which some/all had surgery,110–120 8 in which brainedema or cerebral blood flow was measured rather thanPHE,121–128 6 which included ICH with ischemic stroke orother intracranial hemorrhage,129–134 and 2 studies whichhad<10 participants.135,136 These differ from the system-atic review,6 which (unlike this individual participant datameta-analysis) excluded studies that assessed PHE anda functional outcome in a single cohort but did not reportan association between them or assessed functional out-come using alternatives to the modified Rankin Scale. We invited 38 eligible studies to share data. 26 eligiblestudies did not respond to the invitation ().137–162Twelve studies (32%), the VISTA databank, and 1 unpub-lished cohort by Sheth et al, shared individual participantdata on 8369 participants (Figure 1). We then excluded6 studies which shared data for the following reasons: 1measured PHE on their repeat CT as the maximum lengthof PHE on the axial CT image slice with most edema vis-ible,163 1 did not measure PHE volume on the diagnosticscan,164 2 did not assess functional outcome using themodified Rankin Scale score at 90 days,15,165 which wasthe most commonly used time point for assessing out-come, one study did not pass data consistency checks,166and one, which due to a small number of eligible par-ticipants, produced large CIs and SEs.167 The remainingstudies () contributed 1523 participants from 9cohorts: 3 randomized trials (the control and interven-tion arms of the first 2 intensive blood pressure reduc-tion in acute cerebral hemorrhage trials [INTERACT 1(Intensive Blood Pressure Reduction in Acute CerebralHemorrhage Trial) and INTERACT 2 (The Second Inten-sive Blood Pressure Reduction in Acute Cerebral Hem-orrhage Trial)] comprising participants predominantly inAsia,168 the control arm of the i-DEF trial [DeferoxamineMesylate in Patients With Intracerebral Hemorrhage],from United States169), 4 published observational cohorts(from United States,170 United Kingdom,171 Germany,172and Spain173), 1 unpublished cohort from United States(Sheth et al), and the VISTA databank. We identified 2 groups for analysis: 1347 participantswith repeat brain CT at 24±12 hours (Table;)and 495 with repeat brain CT at 72±12 hours (); 319 participants contributed to both analy-ses. All published cohorts except one, which used theABC/2 formula,170 used semiautomated planimetricmethods to measure ICH and PHE volumes ().We found that each published cohort contributing datahad a moderate risk of bias for the study participationdomain because they were retrospective (including ret-rospective analyses of prospective cohorts)34,168,170,173 orsusceptible to selection bias,169,171 and 2 studies had amoderate risk of bias in functional outcome measure-ment because outcome was assessed by review of med-ical records170 or the method of ascertainment was notreported ().173 The participant charac-teristics of those included were similar to those of thoseexcluded (). Of 1347 participants with repeat CT at 24±12 hours(Table), 516 participants (38%) were female, and themedian age was 66 years (interquartile range [IQR],55–75 years). ICH locations in 1347 participants weresupratentorial deep (n=908, 67%), lobar (n=262, 19%),infratentorial (n=77, 6%), and unknown (n=100, 7%).VISTA-ICH did not provide an ICH location, and 94(94%) of the participants with an unknown ICH locationwere from VISTA-ICH. Another cohort did not provide theadmission Glasgow Coma Scale score.170 The median time from symptom onset to diagnosticCT was 2 hours (IQR, 1·4–2·9 hours). On the diagnosticCT, median ICH volume was 11 mL (IQR, 6–22 mL) andmedian absolute PHE volume was 4 mL (IQR, 2–11mL), which increased to 7 mL (IQR, 3–16 mL) on the24±12 hour repeat CT. The median ratio of ICH: PHEvolume on CTs at 24±12 hours after ICH onset was1.8 mL (IQR, 0.9–3.5 mL), and only 1 cohort168 had ahigher ratio (3.3 mL; IQR, 2.1–5.6 mL) in comparison tothe rest (). Of 495 participants with repeat CT at 72 ±12 hours(page 18 in the), 195 participants(39%) were female, and the median age was 66 years(IQR, 55–74 years). ICH locations were supratentorialdeep (n=287, 58%), lobar (n=78, 16%), infratentorial(n=31, 6.3%), and unknown (n=99, 20%). The median absolute PHE volume was 4.0 mL (IQR,1.6–11.0 mL) within 12 hours of ICH onset, 14.8 mL(IQR, 8.8–23.7 mL) between 36 and 48 hours, and 19.1mL (IQR, 8.2–43.0 mL) between 60 and 72 hours of ICHonset (Figure 2). For the primary analysis, using an unadjusted randomeffects logistic regression model, growth in absolutePHE volume between the diagnostic CT and a repeatCT 24±12 hours after onset was associated with deathor dependence (OR, 1.04 per mL [95% CI, 1.01–1.06];I2=25%) with a fixed-effects model showing similarresults (OR, 1.04 per mL [95% CI, 1.02–1.05];). These results were unchanged after adjustment forage, sex, ICH volume, and intraventricular extension inboth random and fixed-effects models (OR, 1.04 per mL[95% CI, 1.01–1.06]; I2=0%; Figure 3). In an unadjusted logistic regression analysis, growthin absolute PHE volume between the diagnostic CT and72±12 hours after onset was associated with death ordependence (OR, 1.03 per mL [95% CI, 1.01–1.04];I2=0%), with random and fixed-effects models pro-ducing the same result (). This associationremained after adjustment for age, sex, ICH volume, and ### Page 5 ![Figure 1]() ### Page 6 mRS scores 3 to 6 denote poor outcome. CT indicates computed tomography; IQR, interquartile range; mRS, modified Rankin Scale; and PHE, perihema-tomal edema. *Missing in 239 participants (34 in the good outcome and 205 in the poor outcome group). ![Figure 2]() intraventricular extension (OR, 1.02 per mL [95% CI,1.01–1.04]; I2=0%) with random and fixed-effects mod-els producing the same result (Figure 4). In an unadjusted logistic regression model, absolutePHE volume at 24±12 hours after onset was associ-ated with death or dependence in both random effects(OR, 1.05 per mL [95% CI, 1.03–1.07]; I2=20%) andfixed-effects (OR, 1.05 per mL [95% CI, 1.04–1.06])models (). This association did not remain inan adjusted random effects model (OR, 1.02 per mL[95% CI, 0.98–1.07]; I2=53%), but it persisted in a fixed-effects model (OR, 1.02 per mL [95% CI, 1.01–1.04];). ## DISCUSSION In this international individual participant data meta-analysis, absolute PHE growth assessed on CT in boththe first 24 and 72 hours after ICH onset was associatedwith death or dependence at 90 days. We found thatthe increase in the odds of death or dependence at 90days was 4% (95% CI, 1%–6%) for each l mL increasein PHE growth in the first 24 hours and 2% (95% CI,1%–4%) in the first 72 hours after onset. Two previous systematic reviews suggested thatPHE growth was associated with worse outcomes.6,7In the review that analyzed PHE growth by time7 worse ### Page 7 ![Figure 3]() ![Figure 4]() functional outcome was associated with PHE growth inthe first 72 hours but not with PHE growth in the first24 hours after ICH onset; however, the 3 contributingstudies were heterogeneous,153,160,168 and 90% of partici-pants in these studies had deep ICH, which leads to lessPHE growth than lobar ICH.171 Therefore, our findingsprovide additional support for quantifying PHE growth asearly as 24 hours, or as late as 72 hours, for investigat-ing associations with death or dependence at 90 days.Our findings also advance current research in this areaby providing the first individual participant data meta-analytic justification for PHE as an imaging biomarker ofoutcome and at least a 24h time window for clinical trialsof interventions targeting secondary injury to reducePHE and reduce the risk of death or dependence afterICH. Our study has some strengths. We included 66% ofthe available data and more than twice the number of par-ticipants with lobar ICHs in our primary outcome analysisthan was possible in 2 recent systematic reviews,6,7 mak-ing our results applicable to both supratentorial deep andlobar ICH. The large sample size permitted multivariableanalysis with adjustment for confounders. We adhered toa prespecified protocol and statistical analysis plan. Weadjusted for ICH volume and intraventricular extension,which are closely related to Glasgow Coma Scale score ### Page 8 (although we were unable to include Glasgow Coma Scalescore in a multivariable analysis because this was notprovided by 1 cohort170). Our results for the overall asso-ciation between PHE growth and the primary outcomewere consistent in unadjusted and adjusted analyses, infixed-effects and random effects models, and consistentwith a previous systematic review of aggregate data.6 Thewidespread availability of CT means that these findingsare broadly applicable in a range of healthcare settings. Our study has some limitations. The initial system-atic review included studies published until November17, 2021. We updated the literature search on August19, 2025, and identified 5 new cohorts containing 586participants,174–178 which might have been eligible for thisindividual participant data meta-analysis. However, thelargest of these174 (n=246) is likely ineligible, becausetheir data has been included in VISTA-ICH, so may havealready been included in the individual participant datameta-analysis. Whether their data was definitely includedin the data supplied by VISTA-ICH is uncertain becauseVISTA-ICH does not tell users which trials their data hascome from. We acknowledge the possibility of selection biasbecause 3 of the included cohorts were randomized tri-als, although this would not be expected to bias the asso-ciation between PHE and outcome. Although only 18%of the shared individual participant data were used in themeta-analysis, characteristics of those included weresimilar to those who were not. We did not use aggregatedata from cohorts which did not provide individual par-ticipant data; however, only 3 cohorts comprising 474 eli-gible participants provided a measure of the associationbetween PHE growth in the first 24 hours and death ordependence which could have contributed to the primaryoutcome, and only 1 cohort provided a measure of theassociation between PHE growth in the first 72 hoursand outcome (). The IQR of ICHvolumes in this data set was 6 to 21 mL, so we may notbe able to make outcome predictions from the modelsfor large hematoma volumes. We also did not adjust forICH growth for 2 reasons. First, a previous meta-analysisof ICH growth showed a linear relationship between ICHvolumes of this size on the diagnostic scan and the prob-ability of growth,179 indicating that a change in ICH volumewould likely be collinear with a change in PHE volume.Second, we wished to adhere to the prespecified statisti-cal analysis plan. Although we sought to exclude par-ticipants treated with drugs that could affect PHE, moststudies lacked these data. We were unable to explore theeffect of newer imaging signs, such as PHE shape,180or other variables, such as drugs with an inflammation-modulating effect, on the association between PHE andoutcome, as we did not access participants’ scans, andfew collaborating cohorts provided these data. Whether blood pressure lowering modifies PHE andits association with outcome remains uncertain. Althoughwe included participants in both the intervention and con-trol arms of INTERACT 1 and 2, acute blood pressurelowering in INTERACT 1 did not affect PHE,181 makingit unlikely that including the intervention arms from thesetrials affected the results. If it did, it may be more likely toreduce PHE, so this might have reduced the effect sizeof the association between PHE growth in the 0 to 24hperiod and death or dependency, rather than leading to atype 1 error. It was not feasible to do a sensitivity analysisby removing the intervention arms of the INTERACT 1and 2 cohorts because both the intervention and controlarms used the same range of antihypertensive medica-tions, which were based on prespecified treatment proto-cols devised according to local availability of medications.The difference between the control and interventionarms was that the intensity of blood pressure loweringwas greater in the intervention arm, but we did not haveinformation on the intensity of blood pressure loweringreceived by individual participants in the 2 groups. Although intensive blood pressure lowering in theATACH-2 trial (Antihypertensive Treatment of AcuteCerebral Hemorrhage II) was associated with reducedPHE growth in the 24 hours after ICH onset,160 meansystolic blood pressures in the 2 hours after random-ization were lower in the treatment arm of ATACH-IIcompared with INTERACT2 (128.9 vs 150 mm Hg,respectively), so extent of BP reduction may affect PHEand further investigation of the effects of intensive bloodpressure lowering on PHE are warranted. Our findings raise questions for future research intoPHE. Future research should verify these findings in anindependent data set and develop a prediction model todetermine those at greatest risk of PHE growth afterICH. PHE growth beyond 72 hours after ICH onset mayalso be associated with death or dependence, but giventhe shortage of participants who had repeat imagingbeyond 72 hours, this requires further exploration. Wewere unable to fully examine the PHE trajectory (includ-ing whether the trajectory of PHE differs by ICH loca-tion) because we lacked longitudinal data and only 2published cohorts34,171 had these data. Future prospec-tive studies should examine PHE evolution over timebecause it would further inform the duration of an inter-vention for PHE and help to target a PHE intervention atthose most likely to benefit. Our findings also have implications for the use ofPHE as a potential imaging biomarker of outcome andtreatment effect in randomized trials targeting second-ary injury after ICH. Neuropathological studies show ironscavenging and apoptosis during the first 72 hours, withinterleukin-1 and tumor necrosis factor production inperihematomal brain tissue; future studies could identifycandidate drugs targeting these pathways.182,183 Previous studies of corticosteroids for ICH have notimproved outcome after ICH,184 but studies have beenlimited by small sample sizes with heterogeneity in the ### Page 9 dose, timing, and duration of therapy. Minimally invasiveneurosurgery185 improves outcome after ICH, and thismay in part be because of the removal of blood products,which can perpetuate secondary injury, therefore wors-ening PHE, but this requires further study. Trials of interventions for PHE should consider repeatassessment of PHE within 72±12 hours, which maybecome feasible with the advent of both CT186 and mag-netic resonance imaging187–based automated methodsfor measuring PHE. To date 2 small proof-of-concept tri-als have targeted PHE,99,188 of which one did not repeatbrain imaging within 72 hours of ICH onset.99 Of 9 ongo-ing drug trials targeting PHE (accessed on March 15,2025), 6 studies investigating Mirabegron (URL:; Unique identifier: NCT05369351),Celecoxib (URL:; Uniqueidentifier: NCT05434065), Ir-CPI (Ixodes ricinus Con-tact Phase Inhibitor; URL:;Unique identifier: NCT05970224), MW01-6-189WH(a suppressor of inflammatory cytokine production;URL:; Unique identifier:NCT05020535), CN-105 (a neuroprotective peptide;URL:; Unique identifier:NCT06255977), and Edavarone (URL:; Unique identifier: NCT05953103) planrepeat imaging to assess PHE growth within 72 hours,and these could investigate proof of concept that PHE isan intermediate outcome of treatment effect. These findings provide support for PHE as an imagingbiomarker of functional outcome, and establish a timewindow of at least 24 hours for clinical trials of interven-tions targeting secondary injury to reduce PHE and therisk of death or dependence. In clinical practice, absolutePHE growth both in the first 24±12 and 72±12 hoursmight help to determine eligibility for randomized trialsof treatments targeting secondary injury to reduce theglobal burden of death and disability attributable to ICH. ## ARTICLE INFORMATION Received September 30, 2025; final revision received January 4, 2026; acceptedFebruary 12, 2026. Presented in part at the European Stroke Organisation Conference, Munich,Germany, May 24–26, 2023, and Basel, Switzerland, May 15–17, 2024. ### Affiliations Institute for Neuroscience and Cardiovascular Research (N. Samarasekera, G.M.,T.J.M., M.A.R., R.A.-S.S.) and Edinburgh Clinical Trials Unit, Usher Institute (S.T.,C.J.W., R.A.-S.S.), The University of Edinburgh, United Kingdom. The George In-stitute for Global Health, Faculty of Medicine (X.W., C.S.A., R.A.-S.S.) and Schoolof Clinical Medicine (K.S.B.), University of New South Wales, Sydney, Australia.Department of Neurology, University of Chicago Medical Center, IL (A.S.). Depart-ment of Neurology, University Hospital Erlangen, Friedrich-Alexander-UniversitätErlangen-Nürnbergt Erlangen-Nrnberg, Germany (B.V., H.B.H.). Department ofNeurology, Beth Israel Deaconess Medical Center, Stroke Division, Boston, MA(S.M., C.N., M.S.). Department of Neurology, Yale University School of Medicine,New Haven, CT (K.N.S., G.J.F.). Department of Clinical Neurosciences and Men-tal Health, Faculty of Medicine, University of Porto, Portugal (P.C.). Departmentof Neurology, Centro Hospitalar Universitário de São Joãorio de So Joo, Porto,Portugal (P.C.). Geoffrey Jefferson Brain Research Centre, Manchester AcademicHealth Science Centre, Northern Care Alliance NHS Foundation Trust & Univer-sity of Manchester, United Kingdom (A.P.-J.). Stroke Trials Unit, Mental Health andClinical Neuroscience, University of Nottingham, Queens Medical Centre Hos-pital Campus, United Kingdom (N. Sprigg). Department of Neurology, DondersInstitute for Brain, Cognition and Behaviour, Radboud University Medical Cen-tre, Nijmegen, the Netherlands (F.H.B.M.S.). Department of Neurology, KlinikumFrankfurt Höchst, Germany (T.S.). Division of Neurology, University of Alberta,Edmonton, Canada (K.S.B.). Division of Brain Injury Outcomes, Johns HopkinsUniversity, Baltimore, MD (D.H., W.Z.). Department of Clinical Neurosciences andRadiology, Hotchkiss Brain Institute, University of Calgary, Alberta, Canada (A.D.).Department of Neurology, Vall d’Hebron University Hospital, Barcelona, Spain(D.R.-L.). Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neu-rosciences Research Laboratory, Health Research Institute of Santiago de Com-postela, Spain (R.I.R., P.H.). Department of Neurology, Helsinki University Hospital,Finland (A.M.). Department of Neurosurgery, University of Texas Health ScienceCenter, McGovern School of Medicine, Houston (A.M.G.). ### Sources of Funding Dr Samarasekera had full access to all the data in the study and takes respon-sibility for the integrity of the data and the accuracy of the data analysis. Theindividual participant data meta-analysis was funded by the British Heart Foun-dation Research Excellence Award (round 3) to The University of Edinburgh(RE/18/5/34216) and a Stroke Association priority program award (TSA PPA2017/01). Dr Samarasekera is funded by a National Health Service ResearchScotland fellowship and a Stroke Association Senior Clinical Lectureship (SASCLM 23\100002). Dr Iglesias Rey (CP22/00061) receives funding fromthe Miguel Servet Program of Instituto de Salud Carlos III and the EuropeanUnion, ISCIII/PI21/01256. The i-DEF trial was funded by the National Insti-tutes of Health/National Institute of Neurological Disorders and Stroke (U01NS074425). Dr Anderson receives project and fellowship support from the Na-tional Health and Medical Research Council of Australia. ### Disclosures Dr Samarasekera reports grants from the National Health Service (NHS) Re-search Scotland and grants from Stroke Association. Dr Volbers reports personalfees from Pfizer AG/Bristol Myers Squibb SA, personal fees from Bayer AG,personal fees from Ipsen Pharma, personal fees from CSL Behring, personal feesfrom Pfizer AG/Bristol Myers Squibb SA, personal fees from AstraZeneca, nonfi-nancial support from AbbVie, outside the submitted work. Dr Selim reports grantsfrom National Institutes of Health (NIH)/National Institute of Neurological Disor-ders and Stroke (NINDS) and National Institute on Aging (NIA; U01NS102289;UF1NS120871; UG3NS128397); royalties for UpToDate Inc, authored a sectionon secondary prevention of ICH; and Oxford University Press; compensation fromBioxodes Inc for consultant services; compensation from EMVision Medical De-vices Ltd for consultant services; grants from NIH/NIA; stock holdings in NeuGelInc; compensation from Alnylam Pharmaceuticals for data and safety monitoringservices; compensation from MedRhythms, Inc for consultant services; and com-pensation from AegisCN, LLC for consultant services. Dr Sheth reports a patentpending for Stroke wearables licensed to Alva Health; compensation from Philipsfor data and safety monitoring services; grants from Genentech Inc; compensa-tion from Bexorg for consultant services; stock options in BrainQ; compensationfrom Rhaeos for consultant services; grants from Hyperfine; and compensationfrom Astrocyte for consultant services. Dr Mair reports grants from British HeartFoundation; compensation from Canon Medical Systems Corporation for con-sultant services; and grants from Medical Research Council. Dr Moullaali reportsgrants from Scottish Heart and Arterial Risk Prevention (SHARP). Dr Parry-Jonesreports compensation from Alveron for consultant services. Dr Sprigg reportsgrants from National Institute for Health Research. Dr Schreuder reports grantsfrom the Netherlands Heart Foundation; grants from Swedish Orphan Biovit-rum AB; and grants from ZonMw. Dr Steiner reports compensation from Dai-ichi Sankyo Company for consultant services; compensation from AstraZenecafor consultant services; compensation from Bristol Myers Squibb for consultantservices; compensation from Bayer for consultant services; compensation fromChiesi USA Inc for other services; and compensation from Boehringer Ingelheimfor consultant services. Dr Butcher reports compensation from AstraZeneca Aus-tralia for consultant services and compensation from Boehringer Ingelheim forconsultant services. Dr Hanley reports stock options in EpiWatch; compensationfrom HiCatalyst for consultant services; and gifts from Jeffrey and Harriet Le-gum Professorship in Acute Neurological Medicine at Johns Hopkins University.Dr Ziai reports grant support from the National Institute of Neurological Disor-ders and Stroke (NINDS) and compensation from Neurocritical Care Society forconsultant services. Dr Demchuk reports grants from SFJ Pharmaceuticals toother; compensation from Boehringer Ingelheim for consultant services; compen-sation from NovaSignal for consultant services; compensation from Medtronic ### Page 10 for consultant services; compensation from Lumosa for data and safety monitor-ing services; a patent issued for Stroke imaging software licensed to Circle NVI;stock holdings in Circle NVI; compensation from Hoffmann-La Roche Limited forconsultant services; compensation from Philips for data and safety monitoringservices; grants from AstraZeneca; compensation from AstraZeneca Canada forother services; grants from Sense Neuro Diagnostics to other; and compensationfrom Novo Nordisk AS for other services. Dr Weir reports grants from the BritishHeart Foundation. Dr R.A.-S. Salman reports grants paid to his institution from The Stroke As-sociation, British Heart Foundation and Chief Scientist Office of the ScottishGovernment Health Department; consulting fees paid to his institution fromRecursion Pharmaceuticals; honoraria paid to their institution from EuropeanStroke Masters (European Stroke Organisation); participation on Novo NordiskNN9931-4553 and NN9931-4554 end point adjudication committee; and per-sonal payment as clinical director of UK Clinical Research Collaboration networkof registered Clinical Trials Units. The other authors report no conflicts. ### Supplemental Material Tables S1–S9 Figures S1–S4 Protocol Statistical Analysis Plan ## REFERENCES 1. GBD 2021 Stroke Risk Factor Collaborators. Global, regional, and nationalburden of stroke and its risk factors, 1990-2021: a systematic analysis forthe Global Burden of Disease Study 2021. Lancet Neurol. 2024;23:973–1003. doi: 10.1016/S1474-4422(24)00369-7 2. Hemorrhagic Stroke Academia Industry (HEADS) Roundtable Participants;Second HEADS Roundtable Participants. Recommendations for clinical tri-als in ICH: the Second Hemorrhagic Stroke Academia Industry Roundtable.Stroke. 2020;51:1333–1338. doi: 10.1161/STROKEAHA.119.027882 3. Xue M, Yong VW. Neuroinflammation in intracerebral haemorrhage: immu-notherapies with potential for translation. Lancet Neurol. 2020;19:1023–1032. doi: 10.1016/S1474-4422(20)30364-1 4. Tschoe C, Bushnell CD, Duncan PW, Alexander-Miller MA, Wolfe SQ. Neu-roinflammation after intracerebral hemorrhage and potential therapeutictargets. J Stroke. 2020;22:29–46. doi: 10.5853/jos.2019.02236 5. Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms ofinjury and therapeutic targets. Lancet Neurol. 2012;11:720–731. doi:10.1016/S1474-4422(12)70104-7 6. Cliteur MP, Sondag L, Cunningham L, Al-Shahi Salman R, Samarasekera N,Klijn CJM, Schreuder FHBM. The association between perihaematomaloedema and functional outcome after spontaneous intracerebral haemor-rhage: a systematic review and meta-analysis. Eur Stroke J. 2023;8:423–433. doi: 10.1177/23969873231157884 7. Marchina S, Lee KH, Lioutas VA, Carvalho F, Incontri D, Heistand E,Lin D, Selim M. An updated systematic review and meta-analysis inves-tigating perihematomal edema and clinical outcome after intracere-bral hemorrhage. J Stroke Cerebrovasc Dis. 2023;32:107204. doi:10.1016/j.jstrokecerebrovasdis.2023.107204 8. Puy L, Parry-Jones AR, Sandset EC, Dowlatshahi D, Ziai W,Cordonnier C. Intracerebral haemorrhage. Nat Rev Dis Primers. 2023;9:14.doi: 10.1038/s41572-023-00424-7 9. Li Q, Yakhkind A, Alexandrov AW, Alexandrov AV, Anderson CS, Dowlatshahi D,Frontera JA, Hemphill JC, Ganti L, Kellner C, et al. Code ICH: a call to action.Stroke. 2024;55:494–505. doi: 10.1161/STROKEAHA.123.043033 10. Volbers B, Staykov D, Wagner I, Dörfler A, Saake M, Schwab S,Bardutzky J. Semi-automatic volumetric assessment of perihemorrhagicedema with computed tomography. Eur J Neurol. 2011;18:1323–1328. doi:10.1111/j.1468-1331.2011.03395.x 11. Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C. Assess-ing bias in studies of prognostic factors. Ann Intern Med. 2013;158:280–286. doi: 10.7326/0003-4819-158-4-201302190-00009 12. Hartung J, Knapp G. A refined method for the meta-analysis of controlledclinical trials with binary outcome. Stat Med. 2001;20:3875–3889. doi:10.1002/sim.1009 13. Hemphill JC III, Bonovich DC, Besmertis L, Manley GT, Johnston SC. TheICH score: a simple, reliable grading scale for intracerebral hemorrhage.Stroke. 2001;32:891–897. doi: 10.1161/01.str.32.4.891 14. R Core Team. A language and environment for statistical computing.Accessed June 25, 2025. 15. Hanley DF, Thompson RE, Rosenblum M, Yenokyan G, Lane K, McBee N,Mao SW, Bistran-Hall AJ, Gandhi D, Mould WA, et al. Efficacy and safetyof Minimally Invasive Surgery With Thrombolysis in Intracerebral Haem-orrhage Evacuation (MISTIE III): a randomised, controlled, open-label,blinded endpoint phase 3 trial. Lancet. 2019;393:1021–1032. doi:10.1016/S0140-6736(19)30195-3 16. Abilleira S, Montaner J, Molina CA, Monasterio J, Castillo J, Alvarez-Sabin J.Matrix metalloproteinase-9 concentration after spontaneous intracerebralhemorrhage. J Neurosurg. 2003;99:65–70. doi: 10.3171/jns.2003.99.1.0065 17. Arima H, Wang JG, Huang Y, Heeley E, Skulina C, Parsons MW, Peng B,Li Q, Su S, Tao QL, et al; INTERACT Investigators. Significance of perihema-tomal edema in acute intracerebral hemorrhage: the INTERACT trial. Neu-rology. 2009;73:1963–1968. doi: 10.1212/WNL.0b013e3181c55ed3 18. Carcel C, Sato S, Zheng D, Heeley E, Arima H, Yang J, Wu G, Chen G,Zhang S, Delcourt C, et al; Intensive Blood Pressure Reduction in AcuteCerebral Hemorrhage Trial 2 Investigators. Prognostic significance of hypo-natremia in acute intracerebral hemorrhage: pooled analysis of the intensiveblood pressure reduction in acute cerebral hemorrhage trial studies. CritCare Med. 2016;44:1388–1394. doi: 10.1097/CCM.0000000000001628 19. Castillo J, Davalos A, Alvarez-Sabin J, Pumar JM, Leira R, Silva Y, Montaner J,Kase CS. Molecular signatures of brain injury after intracerebral hemor-rhage. Neurology. 2002;58:624–629. doi: 10.1212/wnl.58.4.624 20. Delgado P, Cuadrado E, Rosell A, Alvarez-Sabin J, Ortega-Aznar A,Hernandez-Guillamon M, Penalba A, Molina C, Montaner J. Fas system acti-vation in perihematomal areas after spontaneous intracerebral hemorrhage.Stroke. 2008;39:1730–1734. 21. Grunwald Z, Beslow LA, Urday S, Vashkevich A, Ayres A, Greenberg SM,Goldstein JN, Leasure A, Shi FD, Kahle KT, et al. Perihematomal edema expan-sion rates and patient outcomes in deep and lobar intracerebral hemorrhage.Neurocrit Care. 2017;26:205–212. doi: 10.1007/s12028-016-0321-3 22. Gusdon AM, Gialdini G, Baradaran H, Merkler AE, Iadecola C, Navi B,Gupta A, Kamel H, Murthy S. Association between leucocyte count andperihematomal edema growth after primary intracerebral hemorrhage. Neu-rology. 2017;88: doi: 10.1212/wnl.88.16_supplement.n8.001 23. Hervella P, Rodriguez-Yanez M, Pumar JM, Avila-Gomez P, da Silva-Candal A, Lopez-Loureiro I, Rodriguez-Maqueda E, Correa-Paz C,Castillo J, Sobrino T, et al. Antihyperthermic treatment decreases peri-hematomal hypodensity. Neurology. 2020;94:e1738–e1748. doi:10.1212/WNL.0000000000009288 24. Howe MD, Zhu L, Sansing LH, Gonzales NR, McCullough LD, Edwards NJ.Serum markers of blood-brain barrier remodeling and fibrosis as predictorsof etiology and clinicoradiologic outcome in intracerebral hemorrhage. FrontNeurol. 2018;9:746. doi: 10.3389/fneur.2018.00746 25. Hurford R, Vail A, Heal C, Ziai WC, Dawson J, Murthy SB, Wang X,Anderson CS, Hanley DF, Parry-Jones AR; VISTA-ICH Collaborators. Oedemaextension distance in intracerebral haemorrhage: association with baselinecharacteristics and long-term outcome. Eur Stroke J. 2019;4:263–270. doi:10.1177/2396987319848203 26. Lord AS, Gilmore E, Choi HA, Mayer SA; VISTA-ICH Collaboration. Timecourse and predictors of neurological deterioration after intracerebral hemor-rhage. Stroke. 2015;46:647–652. doi: 10.1161/STROKEAHA.114.007704 27. Murthy SB, Moradiya Y, Dawson J, Lees KR, Hanley DF, Ziai WC; VISTA-ICH Collaborators. Perihematomal edema and functional outcomes in intra-cerebral hemorrhage: influence of hematoma volume and location. Stroke.2015;46:3088–3092. doi: 10.1161/STROKEAHA.115.010054 28. Murthy SB, Urday S, Beslow LA, Dawson J, Lees K, Kimberly WT, Iadecola C,Kamel H, Hanley DF, Sheth KN, et al; VISTA ICH Collaborators. Rate of peri-haematomal oedema expansion is associated with poor clinical outcomes inintracerebral hemorrhage. J Neurol Neurosurg Psychiatry. 2016;87:1169–1173. doi: 10.1136/jnnp-2016-313653 29. Qureshi AI, Majidi S, Gilani WI, Palesch YY, Martin R, Novitzke J, Cruz-Flores S,Ehtisham A, Goldstein JN, Kirmani JF, et al; Antihypertensive Treatment ofAcute Cerebral Hemorrhage Study Investigators. Increased brain volumeamong good grade patients with intracerebral hemorrhage. Results from theAntihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) study.Neurocrit Care. 2014;20:470–475. doi: 10.1007/s12028-013-9842-1 30. Qureshi AI, Palesch YY, Martin R, Novitzke J, Cruz-Flores S, Ehtisham A,Ezzeddine MA, Goldstein JN, Kirmani JF, Hussein HM, et al; ATACH Investi-gators. Association of serum glucose concentrations during acute hospital-ization with hematoma expansion, perihematomal edema, and three monthoutcome among patients with intracerebral hemorrhage. Neurocrit Care.2011;15:428–435. doi: 10.1007/s12028-011-9541-8 31. Sansing LH, Messe SR, Cucchiara BL, Cohen SN, Lyden PD, Kasner SE;CHANT Investigators. Prior antiplatelet use does not affect hemorrhage ### Page 11 growth or outcome after ICH. Neurology. 2009;72:1397–1402. doi:10.1212/01.wnl.0000342709.31341.88 32. Staykov D, Volbers B, Doerfler A, Schwab S, Willfarth W, Wagner I. Influenceof perihemorrhagic edema evolution on clinical outcome after intracerebralhemorrhage. Neurocrit Care. 2012;S139. 33. Staykov D, Wagner I, Volbers B, Hauer EM, Doerfler A, Schwab S, Bardutzky J.Natural course of perihemorrhagic edema after intracerebral hemorrhage.Stroke. 2011;42:2625–2629. doi: 10.1161/STROKEAHA.111.618611 34. Sprugel MI, Kuramatsu JB, Volbers B, Gerner ST, Sembill JA, Madzar D,Bobinger T, Kolbl K, Hoelter P, Lucking H, et al. Perihemorrhagic edema: revis-iting hematoma volume, location, and surface. Neurology. 2019;93:e1159–e1170. doi: 10.1212/WNL.0000000000008129 35. Volbers B, Willfarth W, Kuramatsu JB, Struffert T, Dorfler A, Huttner HB,Schwab S, Staykov D. Impact of perihemorrhagic edema on short-term out-come after intracerebral hemorrhage. Neurocrit Care. 2016;24:404–412.doi: 10.1007/s12028-015-0185-y 36. Wang X, Arima H, Yang J, Zhang S, Wu G, Woodward M, Munoz-Venturelli P,Lavados PM, Stapf C, Robinson T, et al; INTERACT2 Investigators. Mannitoland outcome in intracerebral hemorrhage: propensity score and multivariableintensive blood pressure reduction in acute cerebral hemorrhage trial 2 results.Stroke. 2015;46:2762–2767. doi: 10.1161/STROKEAHA.115.009357 37. Wu TY, Putaala J, Sharma G, Strbian D, Tatlisumak T, Davis SM,Meretoja A. Persistent hyperglycemia is associated with increased mor-tality after intracerebral hemorrhage. J Am Heart Assoc. 2017;6:02. doi:10.1161/jaha.117.005760 38. Adeoye O, Broderick JP. Advances in the management of intracerebral hemor-rhage. Nat Rev Neurol. 2010;6:593–601. doi: 10.1038/nrneurol.2010.146 39. Alcauskas M, Galetta S. Editors’ note: peak perihemorrhagic edema cor-relates with functional outcome in intracerebral hemorrhage. Neurology.2018;91:673–673. doi: 10.1212/wnl.0000000000006274 40. Babadjouni RM, Radwanski RE, Walcott BP, Patel A, Durazo R,Hodis DM, Emanuel BA, Mack WJ. Neuroprotective strategies followingintraparenchymal hemorrhage. J Neurointerv Surg. 2017;9:1202–1207. doi:10.1136/neurintsurg-2017-013197 41. Babi MA, James ML. Peri-hemorrhagic edema and secondary hematomaexpansion after intracerebral hemorrhage: from benchwork to practicalaspects. Front Neurol. 2017;8:645. doi: 10.3389/fneur.2017.00645 42. Ho ML, Rojas R, Eisenberg RL. Cerebral edema. AJR Am J Roentgenol.2012;199:W258–W273. doi: 10.2214/AJR.11.8081 43. Ironside N, Chen CJ, Ding D, Mayer SA, Connolly ES. Perihematomal edemaafter spontaneous intracerebral hemorrhage. Stroke. 2019;50:1626–1633.doi: 10.1161/STROKEAHA.119.024965 44. Jiang YS, Feng Y, Zhang JJ. Effectiveness and safety of intensive bloodpressure lowering for intracerebral hemorrhage: a systematic review. [Chi-nese]. Chin J Evid Based Med. 2014;14:974–983. 45. Kim H, Edwards NJ, Choi HA, Chang TR, Jo KW, Lee K. Treatment strategiesto attenuate perihematomal edema in patients with intracerebral hemor-rhage. World Neurosurg. 2016;94:32–41. doi: 10.1016/j.wneu.2016.06.093 46. Lattanzi S, Silvestrini M. Reader response: peak perihemorrhagic edemacorrelates with functional outcome in intracerebral hemorrhage. Neurology.2018;91:673–674. doi: 10.1212/WNL.0000000000006275 47. Munakomi S. Reader response: peak perihemorrhagic edema corre-lates with functional outcome in intracerebral hemorrhage. Neurology.2018;91:674–675. doi: 10.1212/WNL.0000000000006273 48. Qureshi A, Mendelow A, Hanley DF. Intracerebral haemorrhage. Lancet.2009;373:1632–1644. doi: 10.1016/S0140-6736(09)60371-8 49. Selim M, Norton C. Perihematomal edema: implications for intracere-bral hemorrhage research and therapeutic advances. J Neurosci Res.2020;98:212–218. doi: 10.1002/jnr.24372 50. Selim M, Sheth KN. Perihematoma edema: a potential translational targetin intracerebral hemorrhage? Transl Stroke Res. 2015;6:104–106. doi:10.1007/s12975-015-0389-7 51. Sun S, Li Y, Zhang H, Wang X, She L, Yan Z, Lu G. The effect of mannitolin the early stage of supratentorial hypertensive intracerebral hemorrhage:a systematic review and meta-analysis. World Neurosurg. 2019;124:386–396. doi: 10.1016/j.wneu.2018.11.249 52. Urday S, Kimberly WT, Beslow LA, Vortmeyer AO, Selim MH,Rosand J, Simard JM, Sheth KN. Targeting secondary injury in intracerebralhaemorrhage-perihaematomal oedema. Nat Rev Neurol. 2015;11:111–122. doi: 10.1038/nrneurol.2014.264 53. Yu Z, Ma L, Zheng J, You C. Prognostic role of perihematomal edema inintracerebral hemorrhage: a systematic review. Turk Neurosurg. 2017;25:25.doi: 10.5137/1019-5149.jtn.19659-16.0 54. Zhao XQ, Wang CX, Wang YJ. Brain edema and nervous system injury dueto cerebral hemorrhage. Chin J Clin Rehab. 2005;9:196–199. 55. Zheng H, Chen C, Zhang J, Hu Z. Mechanism and therapy of brain edemaafter intracerebral hemorrhage. Cerebrovasc Dis. 2016;42:155–169. doi:10.1159/000445170 56. Ziai WC, Carhuapoma JR. Intracerebral hemorrhage. Continuum.2018;24:1603–1622. doi: 10.1212/CON.0000000000000672 57. Appelboom G, Bruce SS, Hickman ZL, Zacharia BE, Carpenter AM,Vaughan KA, Duren A, Hwang R, Piazza M, Lee K, et al. Volume-dependenteffect of perihaematomal oedema on outcome for spontaneous intracere-bral haemorrhages. J Neurol Neurosurg Psychiatry. 2013;84:488–493. doi:10.1136/jnnp-2012-303160 58. Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S, Spilker J,Tomsick TA, Duldner J, Broderick JP. Relative edema volume is a predictor ofoutcome in patients with hyperacute spontaneous intracerebral hemorrhage.Stroke. 2002;33:2636–2641. doi: 10.1161/01.str.0000035283.34109.ea 59. Gupta M, Verma R, Parihar A, Garg RK, Singh MK, Malhotra HS. Perihemato-mal edema as predictor of outcome in spontaneous intracerebral hemorrhage.J Neurosci Rural Pract. 2014;5:48–54. doi: 10.4103/0976-3147.127873 60. Irvine H, Male S, Robertson J, Bell C, Bentho O, Streib C. Reduced intra-cerebral hemorrhage and perihematomal edema volumes in diabeticson sulfonylureas: a case-control study. Stroke. 2019;50:995–998. doi:10.1161/STROKEAHA.118.022301 61. Jingjing Z, Bo H, Le W, Jingya W, Dong W, Fang Y, Wen J. Pretreatmentof sulfonylureas reducing perihematomal edema in diabetic patients withbasal ganglia hemorrhage: a retrospective case-control study. Front Neurol.2021;12. doi: 10.3389/fneur.2021.736383 62. Junttila EK, Koskenkari J, Romppainen N, Ohtonen PP, Karttunen A,Ala-Kokko TI. Risk factors for 1-year mortality in patients with nontraumaticintracranial hemorrhage requiring intensive care. Acta Anaesthesiol Scand.2011;55:1052–1060. doi: 10.1111/j.1399-6576.2011.02512.x 63. Kemal B, Talip A, Nermin T, Yahya C, Ufuk U. Volume of perihemato-mal edema in diabetic patients. Turk Beyin Damar Hastaliklar Dergisi.2006;12:73–76. 64. Leasure AC, Kuohn LR, Vanent KN, Bevers MB, Kimberly WT, Steiner T,Mayer SA, Matouk CC, Sansing LH, Falcone GJ, et al. Association of serumIL-6 (interleukin 6) with functional outcome after intracerebral hemorrhage.Stroke. 2021;52:1733–1740. doi: 10.1161/strokeaha.120.032888 65. Levine JM, Snider R, Finkelstein D, Gurol ME, Chanderraj R,Smith EE, Greenberg SM, Rosand J. Early edema in warfarin-relatedintracerebral hemorrhage. Neurocrit Care. 2007;7:58–63. doi:10.1007/s12028-007-0039-3 66. Loan JJ, Gane AB, Middleton L, Sargent B, Moullaali TJ, Rodrigues MA,Cunningham L, Wardlaw JM, Al-Shahi Salman R, Samarasekera N. Asso-ciation of baseline hematoma and edema volumes with one-year outcomeand long-term survival after spontaneous intracerebral hemorrhage: acommunity-based inception cohort study. Int J Stroke. 2020;16:828–839.doi: 10.1177/1747493020974282 67. McCarron MO, Hoffmann KL, DeLong DM, Gray L, Saunders AM,Alberts MJ. Intracerebral hemorrhage outcome: apolipoprotein E genotype,hematoma, and edema volumes. Neurology. 1999;53:2176–2179. doi:10.1212/wnl.53.9.2176 68. Nawabi J, Elsayed S, Morotti A, Speth A, Liu M, Kniep H, McDonough R,Broocks G, Faizy T, Can E, et al. Perihematomal edema and clinical outcomein intracerebral hemorrhage related to different oral anticoagulants. J ClinMed. 2021;10:2234. doi: 10.3390/jcm10112234 69. Ozdinc S, Unlu E, Karakaya Z, Turamanlar O, Dogan N, Isler Y, Gonul Y,Boyaci MG. Prognostic value of perihematomal edema area at the initialED presentation in patients with intracranial hematoma. Am J Emerg Med.2016;34:1241–1246. doi: 10.1016/j.ajem.2016.03.048 70. Pinho J, Silva L, Quintas-Neves M, Marques L, Amorim JM, Reich A,Ferreira C. Red cell distribution width is associated with 30-day mortalityin patients with spontaneous intracerebral hemorrhage. Neurocrit Care.2020;34:825–832. doi: 10.1007/s12028-020-01103-1 71. Thatikonda AK, Natuva SSK. Predictors of outcome of primary spontaneousintracerebral hemorrhage along the seacoast population of South India. IntJ Stroke. 2016;11(Supplement 3):120. 72. Zubkov AY, Mandrekar JN, Claassen DO, Manno EM,Wijdicks EF, Rabinstein AA. Predictors of outcome in warfarin-relatedintracerebral hemorrhage. Arch Neurol. 2008;65:1320–1325. doi:10.1001/archneur.65.10.1320 73. Appelboom G, Bruce S, Duren A, Piazza M, Monahan A, Christophe B,Zoller S, LoPresti M, Connolly ES. Aquaporin-4 gene variant independentlyassociated with oedema after intracerebral haemorrhage. Neurol Res.2015;37:657–661. doi: 10.1179/1743132815Y.0000000047 74. Cao D, Liu F, Liu Q, Feng J. Correlation analysis between TSP2, MMP-9 andperihematoma edema, as well as the short-term prognosis of patients with ### Page 12 hypertensive intracerebral hemorrhage. Ann Palliat Med. 2021;10:10930–10937. doi: 10.21037/apm-21-2553 75. Castellazzi M, Tamborino C, De Santis G, Garofano F, Lupato A, Ramponi V,Trentini A, Casetta I, Bellini T, Fainardi E. Timing of serum active MMP-9and MMP-2 levels in acute and subacute phases after spontaneous intra-cerebral hemorrhage. Acta Neurochir Suppl. 2010;106:137–140. doi:10.1007/978-3-211-98811-4_24 76. Chang JJ, Kim-Tenser M, Emanuel BA, Jones GM, Chapple K, Alikhani A,Sanossian N, Mack WJ, Tsivgoulis G, Alexandrov AV, et al. Minocycline andmatrix metalloproteinase inhibition in acute intracerebral hemorrhage: apilot study. Eur J Neurol. 2017;24:1384–1391. doi: 10.1111/ene.13403 77. Dhar R, Falcone GJ, Chen Y, Hamzehloo A, Kirsch EP, Noche RB,Roth K, Acosta J, Ruiz A, Phuah CL, et al. Deep learning for automatedmeasurement of hemorrhage and perihematomal edema in supra-tentorial intracerebral hemorrhage. Stroke. 2020;51:648–651. doi:10.1161/STROKEAHA.119.027657 78. Feng H, Jin Z, He W, Zhao X. Cerebral venous outflow participates inperihematomal edema after spontaneous intracerebral hemorrhage:a cross-sectional study. Medicine (Baltimore). 2018;97:e12034. doi:10.1097/MD.0000000000012034 79. Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L,Salisbury S, Spilker J, Tomsick TA, Duldner J, Broderick JP. Naturalhistory of perihematomal edema in patients with hyperacute sponta-neous intracerebral hemorrhage. Stroke. 2002;33:2631–2635. doi:10.1161/01.str.0000035284.12699.84 80. Gu S, Zhang J, Han L, Qian J, Li Q, Sha D. Analysis of relevant fac-tors for delayed cerebral edema and plasma matrix metalloproteinase9 after intracerebral hemorrhage. [Chinese]. Chin J Cerebrovasc Dis.2015;12:297–301. 81. Gusdon AM, Gialdini G, Kone G, Baradaran H, Merkler AE, Mangat HS,Navi BB, Iadecola C, Gupta A, Kamel H, et al. Neutrophil-lymphocyte ratioand perihematomal edema growth in intracerebral hemorrhage. Stroke.2017;48:2589–2592. doi: 10.1161/STROKEAHA.117.018120 82. Liu QX, Wang FR, Zhang SM, Wang YP. Expression of platelet CD42b andCD62p in cerebral hemorrhage associated encephaledema. Chin J ClinRehab. 2003;7:2282–2283. 83. Mould WA, Carhuapoma JR, Muschelli J, Lane K, Morgan TC, McBee NA,Bistran-Hall AJ, Ullman NL, Vespa P, Martin NA, et al; MISTIE Investigators.Minimally invasive surgery plus recombinant tissue-type plasminogen activatorfor intracerebral hemorrhage evacuation decreases perihematomal edema.Stroke. 2013;44:627–634. doi: 10.1161/STROKEAHA.111.000411 84. Naval NS, Abdelhak TA, Urrunaga N, Zeballos P, Mirski MA, Carhuapoma JR.An association of prior statin use with decreased perihematomal edema.Neurocrit Care. 2008;8:13–18. doi: 10.1007/s12028-007-0081-1 85. Wang MD, Wang Y, Xia YP, Dai JW, Gao L, Wang SQ, Wang HJ, Mao L,Li M, Yu SM, et al. High serum MiR-130a levels are associated with severeperihematomal edema and predict adverse outcome in acute ICH. Mol Neu-robiol. 2016;53:1310–1321. doi: 10.1007/s12035-015-9099-0 86. Aksoy D, Bammer R, Mlynash M, Venkatasubramanian C, Eyngorn I,Snider RW, Gupta SN, Narayana R, Fischbein N, Wijman CAC. Magneticresonance imaging profile of blood-brain barrier injury in patients withacute intracerebral hemorrhage. J Am Heart Assoc. 2013;2:e000161. doi:10.1161/JAHA.113.000161 87. Butcher KS, Baird T, MacGregor L, Desmond P, Tress B, Davis S. Perihema-tomal edema in primary intracerebral hemorrhage is plasma derived. Stroke.2004;35:1879–1885. doi: 10.1161/01.STR.0000131807.54742.1a 88. Fainardi E, Borrelli M, Saletti A, Sarubbo S, Roversi G, Bernardoni A, Latini F,Azzini C, Borgatti L, de Vito A, et al. Temporal changes in perihematomalapparent diffusion coefficient values during the transition from acute tosubacute phases in patients with spontaneous intracerebral hemorrhage.Neuroradiology. 2013;55:145–156. doi: 10.1007/s00234-012-1093-x 89. Li N, Worthmann H, Heeren M, Schuppner R, Deb M, Tryc AB, Bueltmann E,Lanfermann H, Donnerstag F, Weissenborn K, et al. Temporal pattern ofcytotoxic edema in the perihematomal region after intracerebral hemor-rhage: a serial magnetic resonance imaging study. Stroke. 2013;44:1144–1146. doi: 10.1161/STROKEAHA.111.000056 90. Lin WM, Yang TY, Weng HH, Chen CF, Lee MH, Yang JT, Jao SYN, Tsai YH.Brain microbleeds: distribution and influence on hematoma and perihema-tomal edema in patients with primary intracerebral hemorrhage. NeuroradiolJ. 2013;26:184–190. doi: 10.1177/197140091302600208 91. Puig J, Blasco G, Terceno M, Daunis IEP, Schlaug G, Hernandez-Perez M,Cuba V, Carbo G, Serena J, Essig M, et al. Predicting motor outcome inacute intracerebral hemorrhage. Am J Neuroradiol. 2019;40:769–775. doi:10.3174/ajnr.A6038 92. Schneider T, Frieling D, Schroeder J, Regelsberger J, Schoen G,Fiehler J, Gellissen S. Perihematomal diffusion restriction as a commonfinding in large intracerebral hemorrhages in the hyperacute phase. PLoSOne. 2017;12:e0184518. doi: 10.1371/journal.pone.0184518 93. Stosser S, Neugebauer H, Althaus K, Ludolph AC, Kassubek J, Schocke M.Perihematomal diffusion restriction in intracerebral hemorrhage dependson hematoma volume, but does not predict outcome. Cerebrovasc Dis.2016;42:280–287. doi: 10.1159/000446549 94. Sykora M, Diedler J, Turcani P, Rupp A, Steiner T. Subacute perihema-tomal edema in intracerebral hemorrhage is associated with impairedblood pressure regulation. J Neurol Sci. 2009;284:108–112. doi:10.1016/j.jns.2009.04.028 95. Tsai YH, Hsu LM, Weng HH, Lee MH, Yang JT, Lin CP. Functional diffu-sion map as an imaging predictor of functional outcome in patients withprimary intracerebral haemorrhage. Br J Radiol. 2013;86:20110644. doi:10.1259/bjr.20110644 96. Venkatasubramanian C, Mlynash M, Finley-Caulfield A, Eyngorn I,Kalimuthu R, Snider RW, Wijman CA. Natural history of perihematomal edemaafter intracerebral hemorrhage measured by serial magnetic resonance im-aging. Stroke. 2011;42:73–80. doi: 10.1161/STROKEAHA.110.590646 97. Worthmann H, Li N, Martens-Lobenhoffer J, Dirks M, Schuppner R,Lichtinghagen R, Kielstein JT, Raab P, Lanfermann H, Bode-Boger SM, etal. Dimethylarginines in patients with intracerebral hemorrhage: associationwith outcome, hematoma enlargement, and edema. J Neuroinflammation.2017;14:247. doi: 10.1186/s12974-017-1016-1 98. Fouda AY, Newsome AS, Spellicy S, Waller JL, Zhi W, Hess DC, Ergul A,Edwards DJ, Fagan SC, Switzer JA. Minocycline in acute cerebral hemor-rhage: an early phase randomized trial. Stroke. 2017;48:2885–2887. doi:10.1161/STROKEAHA.117.018658 99. Fu Y, Hao J, Zhang N, Ren L, Sun N, Li YJ, Yan Y, Huang DR,Yu C, Shi FD. Fingolimod for the treatment of intracerebral hemorrhage:a 2-arm proof-of-concept study. JAMA Neurol. 2014;71:1092–1101. doi:10.1001/jamaneurol.2014.1065 100. Huang YJ. Effect of Xingnaojing injection combined with minimally inva-sive percutaneous drainage in treating brain edema and content of serumAQP4 in patients with moderate hypertensive basal ganglia hemorrhage.[Chinese]. Zhongguo Zhongyao Zazhi. 2014;39:2564–2568. 101. Kollmar R, Staykov D, Dorfler A, Schellinger PD, Schwab S, Bardutzky J.Hypothermia reduces perihemorrhagic edema after intracerebral hemorrhage.Stroke. 2010;41:1684–1689. doi: 10.1161/STROKEAHA.110.587758 102. Lee SH, Park HK, Ryu WS, Lee JS, Bae HJ, Han MK, Lee YS, Kwon HM,Kim CK, Park ES, et al. Effects of celecoxib on hematoma and ede-ma volumes in primary intracerebral hemorrhage: a multicenter ran-domized controlled trial. Eur J Neurol. 2013;20:1161–1169. doi:10.1111/ene.12140 103. Park HK, Lee SH, Chu K, Roh JK. Effects of celecoxib on volumes ofhematoma and edema in patients with primary intracerebral hemorrhage. JNeurol Sci. 2009;279:43–46. doi: 10.1016/j.jns.2008.12.020 104. Soldo A, Koruga N, Butkovic Soldo S, Stimac D, Hecimovic I. Treatmentpossibilities of basal ganglia hemorrhage: retrospective trial of fifty-fourpatients. J Neurol Sci. 2013;333:e243. doi: 10.1016/j.jns.2013.07.943 105. Song J, Nie Y, Qin X, Wang P, Lu H, Gao L. Efficacy of Naoxueshu in acutespontaneous intracerebral hemorrhage: a multicenter observational study.Neurol Sci. 2021;43:1885–1891. doi: 10.1007/s10072-021-05582-8 106. Staykov D, Schwab S, Dorfler A, Kollmar R. Hypothermia reduces peri-hemorrhagic edema after intracerebral hemorrhage: but does it influ-ence functional outcome and mortality? Ther Hypothermia Temp Manag.2011;1:105–106. doi: 10.1089/ther.2011.0004 107. Volbers B, Herrmann S, Willfarth W, Lucking H, Kloska SP,Doerfler A, Huttner HB, Kuramatsu JB, Schwab S, Staykov D. Impact ofhypothermia initiation and duration on perihemorrhagic edema evolu-tion after intracerebral hemorrhage. Stroke. 2016;47:2249–2255. doi:10.1161/STROKEAHA.116.013486 108. Yu Y, Zhao W, Zhu C, Kong Z, Xu Y, Liu G, Gao X. The clinical effect ofdeferoxamine mesylate on edema after intracerebral hemorrhage. PLoSOne. 2015;10:e0122371. doi: 10.1371/journal.pone.0122371 109. Shah M, Birnbaum L, Rasmussen J, Sekar P, Moomaw CJ, Osborne J,Vashkevich A, Woo D. Effect of hyperosmolar therapy on outcome fol-lowing spontaneous intracerebral hemorrhage: Ethnic/Racial Variationsof Intracerebral Hemorrhage (ERICH) study. J Stroke Cerebrovasc Dis.2018;27:1061–1067. doi: 10.1016/j.jstrokecerebrovasdis.2017.11.013 110. Baixiang H, Shouxun L, Maode W. Clinical research on brain edema afteroperations on hypertensive cerebral hemorrhage. J Xi’an Med Univ Chin Ed.1998;19:625–627. ### Page 13 111. Fung C, Murek M, Klinger-Gratz PP, Fiechter M, Z’Graggen WJ,Gautschi OP, El-Koussy M, Gralla J, Schaller K, Zbinden M, et al. Effectof decompressive craniectomy on perihematomal edema in patientswith intracerebral hemorrhage. PLoS One. 2016;11:e0149169. doi:10.1371/journal.pone.0149169 112. Huang CF, Tsai ZP, Li CS, Wang KL, Wang YC. Surgical improvement ofbrain edema related to hypertensive intracerebral hemorrhage. ZhonghuaYi Xue Za Zhi. 2002;65:241–246. 113. Lian L, Xu F, Hu Q, Liang Q, Zhu W, Kang H, Liu X, Tang Z, Zhu S. No exac-erbation of perihematomal edema with intraclot urokinase in patients withspontaneous intracerebral hemorrhage. Acta Neurochir. 2014;156:1735–1744. doi: 10.1007/s00701-014-2130-9 114. Lian LF, Xu F, Tang ZP, Xue Z, Liang QM, Hu Q, Zhu WH, Kang HC, Liu XY,Wang FR, et al. Intraclot recombinant tissue-type plasminogen activatorreduces perihematomal edema and mortality in patients with spontane-ous intracerebral hemorrhage. J Huazhong Univ Sci Technolog Med Sci.2014;34:165–171. doi: 10.1007/s11596-014-1252-x 115. Ning X, Liu Q, Zhao H. Nimodipine for treatment of perifocal edema follow-ing aspiration and drainage in patients with cerebral hemorrhage. NeuralRegener Res. 2007;2:310–313. 116. Volbers B, Wagner I, Willfarth W, Doerfler A, Schwab S,Staykov D. Intraventricular fibrinolysis does not increase perihemorrhagicedema after intracerebral hemorrhage. Stroke. 2013;44:362–366. doi:10.1161/STROKEAHA.112.673228 117. Wang X, Yang S, Huang Y, Sun M, Zhao L, Zhuo J, Gao M. Effects ofcraniopuncture and drainage of intracerebral hemorrhage on brain edemaand neurological outcome. [Chinese]. Chin J Contemp Neurol Neurosurg.2011;11:230–235. 118. Ziai W, Moullaali T, Nekoovaght-Tak S, Ullman N, Brooks JS,Morgan TC, Hanley DF. No exacerbation of perihematomal edema withintraventricular tissue plasminogen activator in patients with spontane-ous intraventricular hemorrhage. Neurocrit Care. 2013;18:354–361. doi:10.1007/s12028-013-9826-1 119. Zuo Y, Cheng G, Gao DK, Zhang X, Zhen HN, Zhang W,Xiao SC. Gross-total hematoma removal of hypertensive basal gangliahemorrhages: a long-term follow-up. J Neurol Sci. 2009;287:100–104.doi: 10.1016/j.jns.2009.08.046 120. Ye G, Huang S, Chen R, Zheng Y, Huang W, Gao Z, Cai L, Zhao M, Ma K, He Q,et al. Early predictors of the increase in perihematomal edema volume afterintracerebral hemorrhage: a retrospective analysis from the Risa-MIS-ICHstudy. Front Neurol. 2021;12:700166. doi: 10.3389/fneur.2021.700166 121. Al-Khaled M, Eggers J; QugSS2 Study. Prognosis of intracerebralhemorrhage after conservative treatment. J Stroke Cerebrovasc Dis.2014;23:230–234. doi: 10.1016/j.jstrokecerebrovasdis.2012.12.018 122. James ML, Blessing R, Bennett E, Laskowitz DT. Apolipoprotein E modi-fies neurological outcome by affecting cerebral edema but not hematomasize after intracerebral hemorrhage in humans. J Stroke Cerebrovasc Dis.2009;18:144–149. doi: 10.1016/j.jstrokecerebrovasdis.2008.09.012 123. Kiphuth IC, Huttner HB, Breuer L, Schwab S, Kohrmann M. Sonographicmonitoring of midline shift predicts outcome after intracerebral hemor-rhage. Cerebrovasc Dis. 2012;34:297–304. doi: 10.1159/000343224 124. Lietke S, Zausinger S, Patzig M, Holtmanspotter M, Kunz M. CT-Based clas-sification of acute cerebral edema: association with intracranial pressureand outcome. J Neuroimaging. 2020;30:640–647. doi: 10.1111/jon.12736 125. Muiz AJ, Abdullah J, Naing NN, Ghazaime G, Ariff AR. Spontaneous intra-cerebral hemorrhage in northeast Malaysian patients: a four-year study.Neuroepidemiology. 2003;22:184–195. doi: 10.1159/000069894 126. Sun W, Pan W, Kranz PG, Hailey CE, Williamson RA, Laskowitz DT,James ML. Predictors of late neurological deterioration after spontane-ous intracerebral hemorrhage. Neurocrit Care. 2013;19:299–305. doi:10.1007/s12028-013-9894-2 127. Tayal AH, Gupta R, Yonas H, Jovin T, Uchino K, Hammer M,Wechsler L, Gebel JM. Quantitative perihematomal blood flow in sponta-neous intracerebral hemorrhage predicts in-hospital functional outcome.Stroke. 2007;38:319–324. doi: 10.1161/01.STR.0000254492.35504.db 128. Zazulia AR, Diringer MN, Derdeyn CP, Powers WJ. Progression of masseffect after intracerebral hemorrhage. Stroke. 1999;30:1167–1173. doi:10.1161/01.str.30.6.1167 129. Statham PF, Todd NV. Intracerebral haematoma: aetiology and haematomavolume determine the amount and progression of brain oedema. ActaNeurochir. 1990;Supplementum 51:289–291. 130. Modrego PJ, Boned B, Berlanga JJ, Serrano M. Plasmatic B-type na-triuretic peptide and C-reactive protein in hyperacute stroke as mark-ers of CT-evidence of brain edema. Int J Med Sci. 2008;5:18–23. doi:10.7150/ijms.5.18 131. Guo ZY, Zhang Y, Dai YQ, Wu ZT, Hao DN, Gao JZ. A multicenter, random-ized, controlled clinical trial for application of Naoxueshu oral liquid in thetreatment of cerebral edema after stroke. [Chinese]. Chin J New Drugs.2019;28:2126–2129. 132. Praveen Kumar B, Udaykumar P. Study of drugs used in cerebral oede-ma in patients with stroke at a tertiary care centre. Indian J Pharmacol.2013;45:S91. 133. Vemmos KN, Tsivgoulis G, Spengos K, Zakopoulos N,Synetos A, Kotsis V, Vassilopoulos D, Mavrikakis M. Association between24-h blood pressure monitoring variables and brain oedema in pa-tients with hyperacute stroke. J Hypertens. 2003;21:2167–2173. doi:10.1097/00004872-200311000-00027 134. Viderman D, Issanov A, Temirov T, Goligher E, la Fleur P. Outcome pre-dictors of stroke mortality in the neurocritical care unit. Front Neurol.2020;11:579733. doi: 10.3389/fneur.2020.579733 135. Aksay Koyuncu B, Gur Ozmen S, Tavukcu Ozkan S, Altindag E, Tolun R,Krespi Y. Steroid-responsive late symptomatic perihematomal edema inintracerebral hemorrhage. Noro psikiyatri arsivi. 2015;52:423–424. doi:10.5152/npa.2015.9918 136. Lim SY, Wesley Thevathasan A, Gonzales M, Mitchell PJ, Evans A.Vasogenic oedema with no mass lesion. J Clin Neurosci. 2008;15:1048,75–1048, 76. doi: 10.1016/j.jocn.2006.11.024 137. Alvarez-Sabin J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribo M,Santamarina E, Quintana M, Monasterio J, Montaner J. Temporal profile ofmatrix metalloproteinases and their inhibitors after spontaneous intracere-bral hemorrhage: relationship to clinical and radiological outcome. Stroke.2004;35:1316–1322. doi: 10.1161/01.STR.0000126827.69286.90 138. Bakhshayesh B, Hosseininezhad M, Saadat SN, Ansar MM, Ramezani H,Saadat SM. Iron overload is associated with perihematoma edema growthfollowing intracerebral hemorrhage that may contribute to in-hospitalmortality and long-term functional outcome. Curr Neurovasc Res.2014;11:248–253. doi: 10.2174/1567202611666140530124855 139. Chen L, Xu M, Yan S, Luo Z, Tong L, Lou M. Insufficient cerebral venous drain-age predicts early edema in acute intracerebral hemorrhage. Neurology.2019;93:e1463–e1473. doi: 10.1212/WNL.0000000000008242 140. Delgado P, Alvarez Sabin J, Santamarina E, Molina CA,Quintana M, Rosell A, Montaner J. Plasma S100B level after acute spon-taneous intracerebral hemorrhage. Stroke. 2006;37:2837–2839. doi:10.1161/01.STR.0000245085.58807.ad 141. Halstead MR, Mould WA, Sheth KN, Rosand J, Thompson R,Levy A, Hanley DF, Goldstein JN, Nyquist P. Haptoglobin is associ-ated with increased early perihematoma edema progression in spon-taneous intracranial hemorrhage. Int J Stroke. 2020;15:899–908. doi:10.1177/1747493020912602 142. Huan R, Li Y, Tan J, Tang J, Huang N, Cheng Y. The Hounsfield unit ofperihematomal edema is associated with poor clinical outcomes in in-tracerebral hemorrhage. World Neurosurg. 2021;146:e829–e836. doi:10.1016/j.wneu.2020.11.025 143. Inaji M, Tomita H, Tone O, Tamaki M, Suzuki R, Ohno K. Chronological changesof perihematomal edema of human intracerebral hematoma. Acta NeurochirSuppl. 2003;86:445–448. doi: 10.1007/978-3-7091-0651-8_91 144. Roy-O’Reilly M, Zhu L, Atadja L, Torres G, Aronowski J,McCullough L, Edwards NJ. Soluble CD163 in intracerebral hemorrhage:biomarker for perihematomal edema. Ann Clin Transl Neurol. 2017;4:793–800. doi: 10.1002/acn3.485 145. Sansing LH, Kaznatcheeva EA, Perkins CJ, Komaroff E, Gutman FB,Newman GC. Edema after intracerebral hemorrhage: correlations with co-agulation parameters and treatment. J Neurosurg. 2003;98:985–992. doi:10.3171/jns.2003.98.5.0985 146. Feng W, Tauhid S, Goel S, Sidorov EV, Selim M. Hyperglycemia andoutcome in intracerebral hemorrhage: from bedside to bench-morestudy is needed. Transl Stroke Res. 2012;3(SUPPL. 1):113–118. doi:10.1007/s12975-012-0163-z. 147. Sansing LH, Messe SR, Cucchiara BL, Lyden PD, Kasner SE. Anti-adrenergicmedications and edema development after intracerebral hemorrhage.Neurocrit Care. 2011;14:395–400. doi: 10.1007/s12028-010-9498-z 148. Suarez-Pinilla M, Fernandez-Rodriguez A, Benavente-Fernandez L,Calleja-Puerta S. Vitamin K antagonist-associated intracerebral hem-orrhage: lessons from a devastating disease in the dawn of the neworal anticoagulants. J Stroke Cerebrovasc Dis. 2014;23:732–742. doi:10.1016/j.jstrokecerebrovasdis.2013.06.034 149. Li N, Liu YF, Ma L, Worthmann H, Wang YL, Wang YJ, Gao YP, Raab P,Dengler R, Weissenborn K, et al. Association of molecular markers withperihematomal edema and clinical outcome in intracerebral hemorrhage.Stroke. 2013;44:658–663. doi: 10.1161/STROKEAHA.112.673590 ### Page 14 150. Leira R, Davalos A, Silva Y, Gil-Peralta A, Tejada J, Garcia M,Castillo J; Stroke Project, Cerebrovascular Diseases Group of the SpanishNeurological Society. Early neurologic deterioration in intracerebral hemor-rhage: predictors and associated factors. Neurology. 2004;63:461–467.doi: 10.1212/01.wnl.0000133204.81153.ac 151. Zang Y, Zhang C, Song Q, Zhang J, Li H, Zhang C, Feng S, Fang G.Therapeutic effect of early intensive antihypertensive treatment on re-bleeding and perihematomal edema in acute intracerebral hemorrhage. JClin Hypertens. 2019;21:1325–1331. doi: 10.1111/jch.13629 152. Peng WJ, Li Q, Tang JH, Reis C, Araujo C, Feng R, Yuan MH, Jin LY,Cheng YL, Jia YJ, et al. The risk factors and prognosis of delayed perihe-matomal edema in patients with spontaneous intracerebral hemorrhage.CNS Neurosci Ther. 2019;25:1189–1194. doi: 10.1111/cns.13219 153. Lv XN, Li ZQ, Deng L, Yang WS, Li YL, Huang YJ, Shen YQ, Xie XF, Li XH,Wang ZJ, et al. Early perihematomal edema expansion: definition, signifi-cance, and association with outcomes after intracerebral hemorrhage. OxidMed Cell Longev. 2021;2021:6249509. doi: 10.1155/2021/6249509 154. Kim M, Byun J, Chung Y, Lee SU, Park JE, Park W, Park JC, Ahn S, Lee S.Reactive oxygen species scavenger in acute intracerebral hemorrhagepatients: a multicenter, randomized controlled trial. Stroke. 2021;52:1172–1181. doi: 10.1161/STROKEAHA.120.032266 155. Li XAO, Liu SH, Zhuang SJ, Guo SF, Pang SL. Effects of oxiracetam com-bined with ginkgo biloba extract in the treatment of acute intracerebral hem-orrhage: a clinical study. Brain Behav. 2020;10. doi: 10.1002/brb3.1661 156. Tan Y, Gu Y, Zhao Y, Lu Y, Liu X, Zhao Y. Effects of hemodialysis onprognosis in individuals with comorbid ERSD and ICH: a retrospectivesingle-center study. J Stroke Cerebrovasc Dis. 2021;30:105686. doi:10.1016/j.jstrokecerebrovasdis.2021.105686 157. Zhao WAO, Jiang F, Li S, Liu G, Wu C, Wang Y, Ren C, Zhang J, Gu F, Zhang Q,et al. Safety and efficacy of remote ischemic conditioning for the treatmentof intracerebral hemorrhage: a proof-of-concept randomized controlledtrial. Int J Stroke. 2022;17:425–433. doi: 10.1177/17474930211006580 158. Kashiwazaki D, Tomita T, Shibata T, Yamamoto S, Hori E,Akioka N, Kuwayama N, Nakatsuji Y, Noguchi K, Kuroda S. Impact of peri-hematomal edema on infectious complications after spontaneous intra-cerebral hemorrhage. J Stroke Cerebrovasc Dis. 2021;30:105827. doi:10.1016/j.jstrokecerebrovasdis.2021.105827 159. Urday S, Beslow LA, Dai F, Zhang F, Battey TW, Vashkevich A, Ayres AM,Leasure AC, Selim MH, Simard JM, et al. Rate of perihematomal edemaexpansion predicts outcome after intracerebral hemorrhage. Crit Care Med.2016;44:790–797. doi: 10.1097/CCM.0000000000001553 160. Leasure AC, Qureshi AI, Murthy SB, Kamel H, Goldstein JN, Walsh KB,Woo D, Shi FD, Huttner H, Ziai WC, et al. Intensive blood pressure reductionand perihematomal edema expansion in deep intracerebral hemorrhage.Stroke. 2019;50:2016–2022. doi: 10.1161/STROKEAHA.119.024838 161. Rendevski V, Aleksovski B, Stojanov D, Rendevska AM,Aleksovski V, Gjorgoski I. Modeling prognostic factors for poor neurologi-cal outcome in conservatively treated patients with intracerebral hemor-rhage: a focus on TNF-alpha. Clin Neurol Neurosurg. 2018;172:51–58. doi:10.1016/j.clineuro.2018.06.027 162. Zhang C, Zhong J, Chen WX, Zhang XY, Li YH, Zhou TY, Zou YJ, Lan C,Li L, Lai ZP, et al. Usage of angiotensin-converting enzyme inhibitor orangiotensin II receptor blocker in hypertension intracerebral hemorrhage.Neuropsychiatr Dis Treat. 2021;9:355–363. doi: 10.2147/NDT.S291624 163. Rodriguez-Luna D, Stewart T, Dowlatshahi D, Kosior JC, Aviv RI, Molina CA,Silva Y, Dzialowski I, Lum C, Czlonkowska A, et al; PREDICT/SunnybrookICH CTA Study Group. Perihematomal edema is greater in the presence ofa spot sign but does not predict intracerebral hematoma expansion. Stroke.2016;47:350–355. doi: 10.1161/STROKEAHA.115.011295 164. Iglesias-Rey R, Rodriguez-Yanez M, Arias S, Santamaria M,Rodriguez-Castro E, Lopez-Dequidt I, Hervella P, Sobrino T, Campos J,Castillo J. Inflammation, edema and poor outcome are associated withhyperthermia in hypertensive intracerebral hemorrhages. Eur J Neurol.2018;25:1161–1168. doi: 10.1111/ene.13677 165. Wu TY, Sharma G, Strbian D, Putaala J, Desmond PM, Tatlisumak T,Davis SM, Meretoja A. Natural history of perihematomal edema and impacton outcome after intracerebral hemorrhage. Stroke. 2017;48:873–879.doi: 10.1161/STROKEAHA.116.014416 166. Gusdon AM, Nyquist PA, Torres-Lopez VM, Leasure AC, Falcone GJ,Sheth KN, Sansing LH, Hanley DF, Malani R. Perihematomal edema af-ter intracerebral hemorrhage in patients with active malignancy. Stroke.2020;51:129–136. doi: 10.1161/STROKEAHA.119.027085 167. Gioia LC, Kate M, McCourt R, Gould B, Coutts SB, Dowlatshahi D, Asdaghi N,Jeerakathil T, Hill MD, Demchuk A, et al. Perihematoma cerebral blood flow isunaffected by statin use in acute intracerebral hemorrhage patients. J CerebBlood Flow Metab. 2015;35:1175–1180. doi: 10.1038/jcbfm.2015.36 168. Yang J, Arima H, Wu G, Heeley E, Delcourt C, Zhou J, Chen G, Wang X,Zhang S, Yu S, et al; INTERACT Investigators. Prognostic significanceof perihematomal edema in acute intracerebral hemorrhage: pooledanalysis from the intensive blood pressure reduction in acute ce-rebral hemorrhage trial studies. Stroke. 2015;46:1009–1013. doi:10.1161/STROKEAHA.114.007154 169. Selim M, Foster LD, Moy CS, Xi G, Hill MD, Morgenstern L,Greenberg SM, James ML, Singh V, Clark WM, et al. Deferoxamine me-sylate in patients with intracerebral haemorrhage (i-DEF): a multicentre,randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol.2019;18:428–438. doi: 10.1016/S1474-4422(19)30069-9 170. Shirazian A, Peralta-Cuervo AF, Aguilera-Pena MP, Cannizzaro L, Tran V,Nguyen D, Iwuchukwu I. Sustained Low-efficiency dialysis is associatedwith worsening cerebral edema and outcomes in intracerebral hemorrhage.Neurocrit Care. 2021;35:221–231. doi: 10.1007/s12028-020-01155-3 171. Samarasekera N, Ferguson K, Parry-Jones AR, Rodrigues M,Loan J, Moullaali T, Hughes J, Shoveller L, Wardlaw J, McColl B, et al.Perihaematomal oedema evolution over 2 weeks after spontaneous intra-cerebral haemorrhage and association with outcome: a prospective cohortstudy. Cerebrovasc Dis. 2024;54:298–307. doi: 10.1159/000540099 172. Volbers B, Giede-Jeppe A, Gerner ST, Sembill JA, Kuramatsu JB, Lang S,Lucking H, Staykov D, Huttner HB. Peak perihemorrhagic edema cor-relates with functional outcome in intracerebral hemorrhage. Neurology.2018;90:e1005–e1012. doi: 10.1212/WNL.0000000000005167 173. Fonseca S, Costa F, Seabra M, Dias R, Soares A, Dias C, Azevedo E,Castro P. Systemic inflammation status at admission affects the outcomeof intracerebral hemorrhage by increasing perihematomal edema butnot the hematoma growth. Acta Neurol Belg. 2020;121:649–659. doi:10.1007/s13760-019-01269-2 174. Witsch J, Cao Q, Song JW, Luo Y, Sloane KL, Rothstein A, Favilla CG,Cucchiara BL, Kasner SE, Messe SR, et al. Sex differences in perihemato-mal edema volume and outcome after intracerebral hemorrhage. Neurocritcare. 2024;41:208–217. doi: 10.1007/s12028-024-01945-z 175. Kakarla R, Bhangoo G, Pandian J, Shuaib A, Kate MP. Remote ischemicconditioning to reduce perihematoma edema in patients with intracere-bral hemorrhage (RICOCHET): a randomized control trial. J Clin Med.2024;13:2696. doi: 10.3390/jcm13092696 176. Bevers MB, Booraem C, Li K, Sreekrishnan A, Sastre C, Falcone GJ,Sheth KN, Sansing LH, Kimberly WT. Association of soluble ST2 withfunctional outcome, perihematomal edema, and immune response afterintraparenchymal hemorrhage. Neurology. 2023;100:e1329–e1338. doi:10.1212/WNL.0000000000206764 177. Wang S, Wang X, Zhao X, Chen L, Sun S. Peak perihematomal edema ex-pansion predicts poor outcome in patients with intracerebral haemorrhage.Brain Haemorrhages. 2024;6:148-153. doi: 10.1016/j.hest.2024.10.005 178. Huang Q, Wu L, Song Z, Zhang Z, Kuang H, Zhu Y, Zeng C, Zhang L,Zhang H, Xu Z, et al. Hematoma, perihematomal edema, and total lesionpredict outcome in patients with intracerebral hemorrhage. Brain Behav.0340;15:e7. doi: 10.1002/brb3.70340 179. Al-Shahi Salman R, Frantzias J, Lee RJ, Lyden PD, Battey TWK,Ayres AM, Goldstein JN, Mayer SA, Steiner T, Wang X, et al; VISTA-ICH Collaboration. Absolute risk and predictors of the growth of acutespontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data. Lancet Neurol. 2018;17:885–894. doi:10.1016/S1474-4422(18)30253-9 180. Dierksen F, Tran AT, Zeevi T, Maier I, Qureshi A, Sanelli P,Werring DJ, Malhotra A, Falcone G, Sheth K, et al. Peri-hematomal ede-ma shape features related to 3-month outcome in acute supratento-rial intracerebral hemorrhage. Eur Stroke J. 2024;9:383–390. doi:10.1177/23969873231223814 181. Anderson CS, Huang Y, Arima H, Heeley E, Skulina C, Parsons MW,Peng B, Qiang L, Su S, Tao QL, et al. Effects of early intensive bloodpressure-lowering treatment on the growth of hematoma and perihe-matomal edema in acute intracerebral hemorrhage: the Intensive BloodPressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT).Stroke. 2010;41:307–312. doi: 10.1161/STROKEAHA.109.561795 182. Loan J, Kirby C, Emelianova K, Dando OR, Poon MTC, Pimenova L,Hardingham GE, McColl BW, Klijn CJM, Al-Shahi Salman R, et al. Secondaryinjury and inflammation after intracerebral haemorrhage: a system-atic review and meta-analysis of molecular markers in patient braintissue. J Neurol Neurosurg Psychiatry. 2022;93:126–132. doi:10.1136/jnnp-2021-327098 ### Page 15 183. Ohashi S, DeLong J, Kozberg M, Mazur-Hart DJ, van Veluw SJ, Alkayed NJ,Sansing LH. Role of inflammatory processes in hemorrhagic stroke. Stroke.2023;54:605–619. doi: 10.1161/STROKEAHA.122.037155 184. Wang Y, Huang L, Li J, Duan J, Pan X, Menon B, Anderson CS, Liu M,Wu S. Efficacy and safety of corticosteroids for stroke and traumatic braininjury: a systematic review and meta-analysis. Syst Rev. 2025;14:54. doi:10.1186/s13643-025-02803-5 185. Pradilla G, Ratcliff JJ, Hall AJ, Saville BR, Allen JW, Paulon G, McGlothlin A,Lewis RJ, Fitzgerald M, Caveney AF, et al; ENRICH trial investigators. Trialof early minimally invasive removal of intracerebral hemorrhage. N Engl JMed. 2024;390:1277–1289. doi: 10.1056/NEJMoa2308440 186. Ironside N, Chen CJ, Mutasa S, Sim JL, Ding D, Marfatiah S, Roh D,Mukherjee S, Johnston KC, Southerland AM, et al. Fully automatedsegmentation algorithm for perihematomal edema volumetry afterspontaneous intracerebral hemorrhage. Stroke. 2020;51:815–823. doi:10.1161/STROKEAHA.119.026764 187. Pszczolkowski S, Law ZK, Gallagher RG, Meng D, Swienton DJ,Morgan PS, Bath PM, Sprigg N, Dineen RA. Automated segmentation ofhaematoma and perihaematomal oedema in MRI of acute spontaneousintracerebral haemorrhage. Comput Biol Med. 2019;106:126–139. doi:10.1016/j.compbiomed.2019.01.022 188. Parry-Jones A, Stocking K, MacLeod MJ, Clarke B, Werring DJ,Muir KW, Vail A. Phase II randomised, placebo-controlled, clinical trial ofinterleukin-1 receptor antagonist in intracerebral haemorrhage: Blockingthe Cytokine IL-1 in ICH (BLOC-ICH). Eur Stroke J. 2023;8:819–827. doi:10.1177/23969873231185208