The association between perihaematomal oedema and functional outcome after spontaneous intracerebral haemorrhage: A systematic review and meta-analysis.

PURPOSE: Perihaematomal oedema (PHO) formation has gained increasing interest as a therapeutic target after spontaneous intracerebral haemorrhage (ICH). Whether PHO contributes to poor outcome is unclear. We aimed to determine the association between PHO and outcome in patients with spontaneous ICH. METHOD: We searched five databases up to 17 November 2021 for studies of ⩾10 adults with ICH reporting the presence of PHO and outcome. We assessed risk of bias, extracted aggregate data and used random effects meta-analysis to pool studies that reported odds ratios (OR) with 95% confidence intervals (CI). Primary outcome was poor functional outcome defined as modified Rankin Scale score of 3-6 at 3 months. Additionally, we assessed PHO growth and poor outcome at any time of follow-up. We prospectively registered the protocol in PROSPERO (CRD42020157088). FINDINGS: We identified 12,968 articles, of which we included 27 studies (n = 9534). Eighteen studies reported an association between larger PHO volume and poor outcome, six a neutral result and three an inverse relationship. Larger absolute PHO volume was associated with poor functional outcome at 3 months (OR per mL increase of absolute PHO 1.03, 95% CI 1.00-1.06, I2 44%, four studies). Additionally, PHO growth was associated with poor outcome (OR 1.04, 95% CI 1.02-1.06, I2 0%, seven studies). DISCUSSION: In patients with spontaneous ICH, larger PHO volume is associated with poor functional outcome at 3 months. These findings support the development and investigation of new therapeutic interventions targeting PHO formation to evaluate if reduction of PHO improves outcome after ICH.

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

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

Differences in cerebral small vessel disease magnetic resonance imaging markers between lacunar stroke and non-Lobar intracerebral hemorrhage.

INTRODUCTION: It is unclear why cerebral small vessel disease (SVD) leads to lacunar stroke in some and to non-lobar intracerebral hemorrhage (ICH) in others. We investigated differences in MRI markers of SVD in patients with lacunar stroke or non-lobar ICH. PATIENTS AND METHODS: We included patients from two prospective cohort studies with either lacunar stroke (RUN DMC) or non-lobar ICH (FETCH). Differences in SVD markers (white matter hyperintensities [WMH], lacunes, cerebral microbleeds [CMB]) between groups were investigated with univariable tests; multivariable logistic regression analysis, adjusted for age, sex, and vascular risk factors; spatial correlation analysis and voxel-wise lesion symptom mapping. RESULTS: We included 82 patients with lacunar stroke (median age 63, IQR 57-72) and 54 with non-lobar ICH (66, 59-75). WMH volumes and distribution were not different between groups. Lacunes were more frequent in patients with a lacunar stroke (44% vs. 17%, adjusted odds ratio [aOR] 5.69, 95% CI [1.66-22.75]) compared to patients with a non-lobar ICH. CMB were more frequent in patients with a non-lobar ICH (71% vs. 23%, aOR for lacunar stroke vs non-lobar ICH 0.08 95% CI [0.02-0.26]), and more often located in non-lobar regions compared to CMB in lacunar stroke. DISCUSSION: Although we obserd different types of MRI markers of SVD within the same patient, ischemic markers of SVD were more frequent in the ischemic type of lacunar stroke, and hemorrhagic markers were more prevalent in the hemorrhagic phenotype of non-lobar ICH. CONCLUSION: There are differences between MRI markers of SVD between patients with a lacunar stroke and those with a non-lobar ICH.

Variation in medical management and neurosurgical treatment of patients with supratentorial spontaneous intracerebral haemorrhage.

INTRODUCTION: The role of surgery in spontaneous intracerebral haemorrhage (sICH) remains controversial. This leads to variation in the percentage of patients who are treated with surgery between countries. PATIENTS AND METHODS: We sent an online survey to all neurosurgeons (n = 140) and to a sample of neurologists (n = 378) in Dutch hospitals, with questions on management in supratentorial sICH in general, and on treatment in six patients, to explore current variation in medical and neurosurgical management. We assessed patient and haemorrhage characteristics influencing treatment decisions. RESULTS: Twenty-nine (21%) neurosurgeons and 92 (24%) neurologists responded. Prior to surgery, neurosurgeons would more frequently administer platelet-transfusion in patients on clopidogrel (64% versus 13%; p = 0.000) or acetylsalicylic acid (61% versus 11%; p = 0.000) than neurologists. In the cases, neurosurgeons and neurologists were similar in their choice for surgery as initial treatment (24% and 31%; p = 0.12), however variation existed amongst physicians in specific cases. Neurosurgeons preferred craniotomy with haematoma evacuation (74%) above minimally-invasive techniques (5%). Age, Glasgow Coma Scale score and ICH location were important factors influencing decisions on treatment for neurosurgeons and neurologists. 69% of neurosurgeons and 80% of neurologists would randomise patients in a trial evaluating the effect of minimally-invasive surgery on functional outcome. DISCUSSION: Our results reflect the lack of evidence about the right treatment strategy in patients with sICH. CONCLUSION: New high quality evidence is needed to guide treatment decisions for patients with ICH. The willingness to randomise patients into a clinical trial on minimally-invasive surgery, contributes to the feasibility of such studies in the future.

Long-term prognosis after intracerebral haemorrhage.

INTRODUCTION: The aim of this study was to determine the risk of recurrent intracerebral haemorrhage (ICH), ischaemic stroke, all stroke, any vascular event and all-cause mortality in 30-day survivors of ICH, according to age and sex. PATIENTS AND METHODS: We linked national hospital discharge, population and cause of death registers to obtain a cohort of Dutch 30-day survivors of ICH from 1998 to 2010. We calculated cumulative incidences of recurrent ICH, ischaemic stroke, all stroke and composite vascular outcome, adjusted for competing risk of death and all-cause mortality. Additionally, we compared survival with the general population. RESULTS: We included 19,444 ICH-survivors (52% male; median age 72 years, interquartile range 61-79; 78,654 patient-years of follow-up). First-year cumulative incidence of recurrent ICH ranged from 1.5% (95% confidence interval 0.9-2.3; men 35-54 years) to 2.4% (2.0-2.9; women 75-94 years). Depending on age and sex, 10-year risk of recurrent ICH ranged from 3.7% (2.6-5.1; men 35-54 years) to 8.1% (6.9-9.4; women 55-74 years); ischaemic stroke 2.6% to 7.0%, of all stroke 9.9% to 26.2% and of any vascular event 15.0% to 40.4%. Ten-year mortality ranged from 16.7% (35-54 years) to 90.0% (75-94 years). Relative survival was lower in all age-groups of both sexes, ranging from 0.83 (0.80-0.87) in 35- to 54-year-old men to 0.28 (0.24-0.32) in 75- to 94-year-old women. DISCUSSION: ICH-survivors are at high risk of recurrent ICH, of ischaemic stroke and other vascular events, and have a sustained reduced survival rate compared to the general population. CONCLUSION: The high risk of recurrent ICH, other vascular events and prolonged reduced survival-rates warrant clinical trials to determine optimal secondary prevention treatment after ICH.

Contrast leakage distant from the hematoma in patients with spontaneous ICH: A 7 T MRI study.

Disruption of the blood-brain barrier (BBB) might play a role in the pathophysiology of cerebral small vessel disease-related ICH. The aim of this study was to assess presence and extent of contrast agent leakage distant from the hematoma as a marker of BBB disruption in patients with spontaneous ICH. We prospectively performed 7 tesla MRI in adult patients with spontaneous ICH and assessed contrast leakage distant from the hematoma on 3D FLAIR images. Thirty-one patients were included (mean age 60 years, 29% women). Median time between ICH and MRI was 20 days (IQR 9-67 days). Seventeen patients (54%; seven lobar, nine deep, one infratentorial ICH) had contrast leakage, located cortical in 16 and cortical and deep in one patient. Patients with contrast leakage more often had lobar cerebral microbleeds (CMBs; 77%) than those without (36%; RR 2.5, 95% CI 1.1-5.7) and a higher number of lobar CMBs (patients with contrast leakage: median 2, IQR 1-8 versus those without: median 0, IQR 0-2; p = 0.02). This study shows that contrast leakage distant from the hematoma is common in days to weeks after spontaneous ICH. It is located predominantly cortical and related to lobar CMBs and therefore possibly to cerebral amyloid angiopathy.