Nonlobar Intracerebral Hemorrhage Research Articles

Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage.

ObjectiveTo test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.MethodsWe performed sequencing across 559 Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in United States–based and 1,381 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling.ResultsWe identified 107 rare nonsynonymous variants in sporadic ICH, of which 2 missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the United States–based cohort. The minor allele of rs201716258 was also present in Scottish patients with ICH, and rs138269346 was observed in 2 ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with nonlobar ICH risk (p = 0.05), but not with lobar ICH (p = 0.08), while associations between rs201716258 and ICH subtypes were nonsignificant (p > 0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in European populations), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen).ConclusionsWe identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.

Acute intracerebral haemorrhage and diffusion-weighted imaging lesions: A meta-analysis.

Diffusion-weighted imaging lesions in intracerebral haemorrhage are related to a higher risk of recurrent intracerebral haemorrhage, cognitive damage, and mortality. However, it has been reported that the relationship between the risk of diffusion-weighted imaging lesions and intracerebral haemorrhage subtype or the risk factors for diffusion-weighted imaging lesions is variable. This meta-analysis was performed to evaluate this relationship. A systematic literature search up-to August 2020 was performed and 12 studies included 2815 subjects at the baseline with intracerebral haemorrhage. They were reporting relationships between the diffusion-weighted imaging lesions and intracerebral haemorrhage subtype or investigated the risk factors for diffusion-weighted imaging lesions. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated to evaluate the prognostic role of diffusion-weighted imaging lesions and intracerebral haemorrhage subtype and investigated the risk factors for diffusion-weighted imaging lesions using the dichotomous and continuous method with a random or fixed-effect model. Lobar intracerebral haemorrhage was not significantly related to a higher rate of diffusion-weighted imaging lesions (OR, 1.01; 95% CI, 0.75-1.36, P=.94) compared to the non-lobar intracerebral haemorrhage. Also, history of diabetes mellitus (OR, 1.15; 95% CI, 0.83-1.60, P=.39); history of smoking (OR, 0.95; 95% CI, 0.68-1.33, P=.76); history of hypercholesterolaemia (OR, 1.04; 95% CI, 0.73-1.48, P=.83) and history of ischaemic stroke (OR, 1.63; 95% CI, 0.57-4.66, P=.36) were not significantly related to higher rate of diffusion-weighted imaging lesions compared to no history of those factors. However, the history of hypertension was significantly related to a higher rate of diffusion-weighted imaging lesions (OR, 1.33; 95% CI, 1.04-1.70, P=.02) compared to no history of hypertension. Also, Subjects with diffusion-weighted imaging lesions had a greater decrease in systolic pressure in the acute phase of the intracerebral haemorrhage (OR, 10.23; 95% CI, 7.41-13.06, P<.001) compared to without diffusion-weighted imaging lesions. Based on this meta-analysis, the history of hypertension may have an independent risk relationship with a higher rate of diffusion-weighted imaging lesions. Also, subjects with diffusion-weighted imaging lesions had a greater decrease in systolic pressure in the acute phase of the intracerebral haemorrhage compared to those without diffusion-weighted imaging lesions. This relationship forces us to recommend that identification of diffusion-weighted imaging lesions might add appreciated evidence to evaluate the progression of the underlying micro-angiopathy especially in subjects with a history of hypertension. Though further studies are needed to define the mechanisms by which these lesions may lead to cognitive damage and stroke reappearance.

The Effect of Aging and Small-Vessel Disease Burden on Hematoma Location in Patients with Acute Intracerebral Hemorrhage

Introduction: Intracerebral hemorrhage (ICH) is a devastating hemorrhagic event and is associated with high mortality or severe neurological sequelae. Age-associated differences in hematoma location for nonlobar ICH are not well known. The aims of the present study were to elucidate the relationship between age and hematoma location and to assess the differences in small-vessel disease (SVD) burden as a potential surrogate marker for longstanding hypertension among various hematoma locations. Methods: From September 2014 through July 2019, consecutive patients with acute, spontaneous ICH were retrospectively enrolled from a prospective registry. Magnetic resonance imaging was performed during admission, and the total SVD burden score (including microbleeds, lacunes, enlarged perivascular spaces, and white matter hyperintensities) was calculated. The relationships of hematoma location with aging and SVD burden were assessed by using multivariate logistic regression analyses. Results: A total of 444 patients (156 women [35%]; median age 69 [interquartile range 59–79] years; National Institutes of Health Stroke Scale score 9 [17][3–17]) were enrolled in the present study. Multivariate logistic regression analyses showed that advanced age was independently associated with thalamic (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.19–1.84, p < 0.001 for 10-year increment) and lobar hemorrhage (OR: 1.58, 95% CI: 1.19–2.09, p = 0.002) and was independently and negatively related to putaminal hemorrhage (OR: 0.55, 95% CI: 0.44–0.68, p < 0.001). The total SVD burden score was independently and positively associated with thalamic hemorrhage (OR: 1.27, 95% CI: 1.01–1.59, p = 0.045) and negatively with lobar hemorrhage (OR: 0.74, 95% CI: 0.55–0.99, p = 0.042), even after adjusting by age, but not with putaminal hemorrhage (OR: 0.91, 95% CI: 0.73–1.14, p = 0.395). Conclusion: Putaminal, thalamic, and lobar hemorrhages are prone to occur in specific ages and SVD states: putaminal in young patients, thalamic in old and high SVD burden patients, and lobar hemorrhages in old and low SVD burden patients. Susceptibility to bleeding with aging or severe SVD accumulation seems to differ considerably among brain locations.

The relation between acute intracerebral hemorrhage and diffusion-weighted imaging lesions: a meta-analysis.

Diffusion-weighted imaging lesions in intracerebral hemorrhage are related to a higher risk of recurrent intracerebral hemorrhage, cognitive damage, and mortality. However, it has been reported that the relationship between the risk of diffusion-weighted imaging lesions and intracerebral hemorrhage subtype or the possible risk factors for diffusion-weighted imaging lesions is variable. This meta-analysis was performed to evaluate this relationship. A systematic literature search up-to August 2020 was performed and 12 studies included 2815 subjects at the baseline with intracerebral hemorrhage. Odds ratio (OR) or mean difference (MD) with 95% confidence intervals (CIs) was calculated to evaluate the prognostic role of diffusion-weighted imaging lesions and intracerebral hemorrhage subtype and investigated the possible risk factors for diffusion-weighted imaging lesions using the dichotomous and continuous methods with a random or fixed-effect model. Lobar intracerebral hemorrhage was not significantly related to a higher rate of diffusion-weighted imaging lesions (OR, 1.01; 95% CI, 0.75-1.36, p = 0.94) compared to the non-lobar intracerebral hemorrhage. Also, history of diabetes mellitus (OR, 1.15; 95% CI, 0.83-1.60, p = 0.39); history of smoking (OR, 0.95; 95% CI, 0.68-1.33, p = 0.76); history of hypercholesterolemia (OR, 1.04; 95% CI, 0.73-1.48, p = 0.83); and history of ischemic stroke (OR, 1.63; 95% CI, 0.57-4.66, p = 0.36) were not significantly related to higher rate of diffusion-weighted imaging lesions compared to no history of those factors. However, the history of hypertension was significantly related to a higher rate of diffusion-weighted imaging lesions (OR, 1.33; 95% CI, 1.04-1.70, p = 0.02) compared to no history of hypertension. Also, Subjects with diffusion-weighted imaging lesions had a greater decrease in systolic pressure in the acute phase of the intracerebral hemorrhage (MD, 10.23; 95% CI, 7.41-13.06, p < 0.001) compared to without diffusion-weighted imaging lesions. Based on this meta-analysis, the history of hypertension may have an independent risk relationship with a higher rate of diffusion-weighted imaging lesions. Also, subjects with diffusion-weighted imaging lesions had a greater decrease in systolic pressure in the acute phase of the intracerebral hemorrhage compared to those without diffusion-weighted imaging lesions. This relationship forces us to recommend that identification of diffusion-weighted imaging lesions might add appreciated evidence to evaluate the progression of the underlying micro-angiopathy especially in subjects with a history of hypertension. Though further studies are needed to define the mechanisms by which these lesions may lead to cognitive damage and stroke reappearance.

Abstract P417: Critical Knowledge Gaps in Characterizing Cognitive Impairment Among Intracerebral Hemorrhage Patients: Systematic Review of Contemporary Literature

Introduction: Despite emerging evidence, trajectories of cognitive impairment (CI) among patients with spontaneous intracerebral hemorrhage (ICH) are not well characterized. Methods: We conducted a systematic review of literature within PubMed, using keywords [“Intracerebral hemorrhage” OR “ICH”] AND “Cognitive Impairment,” after 2010. Articles reporting assessments of post ICH CI were included. Articles limited to pre-clinical (animal) studies, non-English literature, other intracranial hemorrhages, traumatic ICH, narrative reviews, and patient under 18 years were excluded. Results: Based on selection criteria, we included 16 articles (graphic) that provide an assessment of post-ICH CI. Post-ICH CI had a reported incidence of up to 85% within the first 2 weeks. The proportion of ICH patients who experience an incident CI across a longer follow up time period have been reported with a high degree of variability; with reports at 3 (32.5 - 71%), 4 (78%), 6 (37 - 63.3%), 9 (47.1 - 100%), 18 (51%), 30 (25.8%), 40 (23%), 45.6 (52 - 64%) and 60 (37.4%) months. Though the assessment scales utilized are variable; 12 (75%) reports employed a version of Montreal Cognitive Assessment or Information Questionnaire on Cognitive Decline in the Elderly. Lobar ICH was well identified, while non-lobar ICHs were variably grouped. Imaging markers have been reported in 10 (62.5%) reports. Though most studies report comorbidities and sociodemographic factors; stroke-specific severity / functional scales and genetic factors have only been considered by 2 (12.5%) articles each. Conclusions: At least 1 in 3 ICH survivors experience post-ICH CI over 12 months. There is an overall paucity of data on post-ICH CI, which highlights a critical need to characterize the natural history of post ICH CI in prospective cohorts and develop standardized assessment protocols for CI among ICH patients.

Abstract MP40: Klotho -vS Heterozygosity is Associated With Lower Risk of Lobar Intracerebral Hemorrhage

Introduction: Klotho is a transmembrane protein highly expressed in the kidneys and choroid plexus. Klotho modulates insulin sensitivity and suppresses oxidative stress. Two missense variants in the Klotho gene ( KL ) form the functional haplotype KL-VS . Heterozygosity for KL-VS ( KL-VS-Het+ ) increases serum levels of Klotho and attenuates the excess risk of Alzheimer’s Disease conferred by APOE epsilon 4. We tested the hypothesis that KL-VS-Het+ lowers the risk of spontaneous intracerebral hemorrhage (ICH) and the excess in this risk conferred by the APOE epsilon variants. Methods: We conducted a genetic association study that combined publicly available data from 3 case-control studies of ICH in Europeans. We identified the two genetic variants that define KL-VS (rs9536314 and rs9527025) and the two genetic variants that define the APOE epsilon alleles (rs429358 and rs7412). We tested for association between KL-VS-Het+ and ICH risk via study-specific logistic regression followed by fixed-effects, inverse-variance weighted meta-analysis using I 2 to quantify heterogeneity. Given the known biological differences between lobar and non-lobar ICH, we conducted stratified analyses based on location. Additionally, we evaluated the role of KL-VS-Het+ in carriers of APOE epsilon 2 and 4 variants. Results: A total of 1066 ICH cases (464 lobar and 602 non-lobar) and 1073 controls were included in the study (mean age 69 [SD 14], female sex 919 [47%]). KL-VS-Het+, present in 554 (26%) participants, was associated with a lower risk of ICH (OR 0.81, 95%CI 0.67-0.99; p=0.04) without heterogeneity across studies (I 2 =0%). Stratified analyses indicated that KL-VS-Het+ was associated with a lower risk of lobar ICH (OR 0.68, 95%CI 0.52-0.88; p=0.004) but not of non-lobar ICH (OR 0.92, 95%CI 0.73-1.16; p=0.48). In secondary analyses, KL-VS-Het+ was associated with a lower risk of ICH in carriers of APOE epsilon 2 (OR 0.52, 95%CI 0.28-0.96; p=0.037; I 2 =0%) but not epsilon 4 (OR 0.82, 95%CI 0.5-1.33; p=0.42). Conclusion: KL-VS -Het+ is associated with a lower risk of ICH. This protective association was stronger in lobar hemorrhages and in carriers of APOE epsilon 2. Further research should evaluate these associations in non-Europeans and identify the mediating molecular pathways.

Cerebral Small Vessel Disease and Functional Outcome Prediction After Intracerebral Hemorrhage.

To determine whether CT-based cerebral small vessel disease (SVD) biomarkers are associated with 6-month functional outcome after intracerebral hemorrhage (ICH) and whether these biomarkers improve the performance of the preexisting ICH prediction score. We included 864 patients with acute ICH from a multicenter, hospital-based prospective cohort study. We evaluated CT-based SVD biomarkers (white matter hypodensities [WMH], lacunes, brain atrophy, and a composite SVD burden score) and their associations with poor 6-month functional outcome (modified Rankin Scale score >2). The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow test were used to assess discrimination and calibration of the ICH score with and without SVD biomarkers. In multivariable models (adjusted for ICH score components), WMH presence (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.12-2.06), cortical atrophy presence (OR 1.80, 95% CI 1.19-2.73), deep atrophy presence (OR 1.66, 95% CI 1.17-2.34), and severe atrophy (either deep or cortical) (OR 1.94, 95% CI 1.36-2.74) were independently associated with poor functional outcome. For the revised ICH score, the AUROC was 0.71 (95% CI 0.68-0.74). Adding SVD markers did not significantly improve ICH score discrimination; for the best model (adding severe atrophy), the AUROC was 0.73 (95% CI 0.69-0.76). These results were confirmed when lobar and nonlobar ICH were considered separately. The ICH score has acceptable discrimination for predicting 6-month functional outcome after ICH. CT biomarkers of SVD are associated with functional outcome, but adding them does not significantly improve ICH score discrimination. ClinicalTrials.gov Identifier: NCT02513316.

Risk of intracerebral haemorrhage from hypertension is greatest at an early age.

The risk of intracerebral haemorrhage (ICH) associated with hypertension (HTN) is well documented. While the prevalence of HTN increases with age, the greatest odds ratio (OR) for HTN as a risk for ischemic stroke is at an early age. We sought to evaluate if the risk for ICH from HTN was higher in the youngest patients of each race. The Ethnic/Racial Variations of ICH (ERICH) study is a prospective multicenter case-control study of ICH among whites, blacks, and Hispanics. Participants were divided into age groups based on race-specific quartiles. Cases in each race/age group were compared to controls using logistic regression (i.e., cases and controls unmatched). The probability of ICH among cases and controls for each race were compared against independent variables of HTN, quartile of age and interaction of quartile and age also using logistic regression. Overall, 2033 non-lobar ICH cases and 2060 controls, and 913 lobar ICH cases with 927 controls were included. ORs were highest in the youngest age quartile for non-lobar haemorrhage for blacks and Hispanics and highest in the youngest quartile for lobar haemorrhage for all races. The formal test of interaction between age and HTN was significant in all races for all locations with the exception of lobar ICH in whites (p = 0.2935). Hypertension is a strong independent risk factor for ICH irrespective of location among persons of younger age, consistent with the hypothesis that first exposure to HTN is a particularly sensitive time for all locations of ICH.

Mutation analysis of the GLA gene in Chinese patients with intracerebral hemorrhage

Fabry disease (FD) is an important underlying condition in young cryptogenic stroke patients and has also been implicated in cerebral small vessel disease. However, the contributions of causative GLA mutations in patients with intracerebral hemorrhage (ICH) remain unclear. In this study, GLA sequences were analyzed in a Chinese ICH cohort comprising 373 patients with computed tomography-confirmed ICH and 563 in-house controls and East Asians from public databases. Only one previously reported mutation, p. Ala15Val, responsible for Fabry disease was identified in a female patient with nonlobar ICH. Therefore, this definitive GLA mutation accounted for 0.27% (1/373) of Chinese patients with ICH. Another functional variant, rs2071225 (c.-10C>T), was present at minor allele frequency (MAF) of 9.1%, indicating no association with ICH, despite a trend of an association for male patients with lobar ICH. In conclusion, our results indicate that the GLA mutation is an uncommon genetic etiology of ICH in China.

Impact of Statins on Hematoma, Edema, Seizures, Vascular Events, and Functional Recovery After Intracerebral Hemorrhage.

The impact of statins on hematoma characteristics, perihemorrhagic edema (PHE), cardiovascular events, seizures, and functional recovery in patients with intracerebral hemorrhage (ICH) is insufficiently studied. Patients with ICH of the prospective UKER-ICH (Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage) study (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03183167) were analyzed by multivariable regression modeling and propensity score matching, and PHE volumes were volumetrically assessed. Outcomes comprised hematoma characteristics, the impact of continuation, discontinuation, and initiation of statins on peak PHE extent, and the influence of statin treatment on the occurrence of seizures, cardiovascular adverse events, and functional recovery after ICH. A total of 1275 patients with ICH with information on statin treatment were analyzed. Statin treatment on hospital admission (21.7%) was associated with higher rates of lobar versus nonlobar ICH (odds ratio, 1.57 [1.03-2.40]; P=0.038). Initiation of statins after ICH was associated with increased peak PHE (β=0.12, SE=0.06, P=0.008), whereas continuation versus discontinuation of prior statin treatment was not significantly associated with edema formation (P>0.10). There were no significant differences in the incidence of remote symptomatic seizures according to statin exposure during follow-up (statins: 11.5% versus no statins: 7.8%, subdistribution hazard ratio: 1.15 [0.80-1.66]; P=0.512). Patients on statins revealed less cardiovascular adverse events and more frequently functional recovery after 12 months (functional recovery: 57.7% versus 45.0%, odds ratio 1.67 [1.09-2.56]; P=0.019). Among statin users, lobar ICH occurs more frequently as compared with nonstatin users. While continuation of prior statin treatment appears to be safe regarding PHE formation, the initiation of statins during the first days after ICH may increase PHE extent. However, statins should be initiated thereafter (eg, at hospital discharge) to prevent cardiovascular events and potentially improve functional recovery.

Location-specific risk factors for intracerebral hemorrhage: Systematic review and meta-analysis.

To conduct a systematic review and meta-analysis of studies reporting on risk factors according to location of the intracerebral hemorrhage. We searched PubMed and Embase for cohort and case-control studies reporting ≥100 patients with spontaneous intracerebral hemorrhage that specified the location of the hematoma and reported associations with risk factors published until June 27, 2019. Two authors independently extracted data on risk factors. Estimates were pooled with the generic variance-based random-effects method. After screening 10,013 articles, we included 42 studies totaling 26,174 patients with intracerebral hemorrhage (9,141 lobar and 17,033 nonlobar). Risk factors for nonlobar intracerebral hemorrhage were hypertension (risk ratio [RR] 4.25, 95% confidence interval [CI] 3.05-5.91, I 2 = 92%), diabetes mellitus (RR 1.35, 95% CI 1.11-1.64, I 2 = 37%), male sex (RR 1.63, 95% CI 1.25-2.14, I 2 = 61%), alcohol overuse (RR 1.48, 95% CI 1.21-1.81, I 2 = 19%), underweight (RR 2.12, 95% CI 1.12-4.01, I 2 = 31%), and being a Black (RR 2.83, 95% CI 1.02-7.84, I 2 = 96%) or Hispanic (RR 2.95, 95% CI 1.69-5.14, I 2 = 71%) participant compared with being a White participant. Hypertension, but not any of the other risk factors, was also a risk factor for lobar intracerebral hemorrhage (RR 1.83, 95% CI 1.39-2.42, I 2 = 76%). Smoking, hypercholesterolemia, and obesity were associated with neither nonlobar nor lobar intracerebral hemorrhage. Hypertension is a risk factor for both nonlobar and lobar intracerebral hemorrhage, although with double the effect for nonlobar intracerebral hemorrhage. Diabetes mellitus, male sex, alcohol overuse, underweight, and being a Black or Hispanic person are risk factors for nonlobar intracerebral hemorrhage only. Hence, the term hypertensive intracerebral hemorrhage for nonlobar intracerebral hemorrhage is not appropriate.

Clinical value of perilesional perfusion deficit measured by Technetium-99m-ECD single-photon emission computed tomography in hypertensive intracerebral hemorrhage.

Pathological and experimental studies indicate the existence of a “penumbra” of progressive tissue damage and edema in regions immediately surrounding a hematoma in patients of intracerebral hemorrhage (ICH). This zone of oligemia surrounding ICH has a potential for perfusion recovery. Improved understanding of the pathophysiology of perilesional blood flow changes and brain injury after ICH may result in improved treatment strategies. The aim was to study perilesional blood flow changes in ICH by perfusion deficit (PD) measured by single-photon emission computed tomography (SPECT) and to correlate it with the severity of ICH and outcome. Forty-four patients of computed tomography (CT) documented nonlobar deep ICH suggestive of hypertensive hematoma of <7 days duration were subjected to 99mTc-ethylene diacetate SPECT scans of the brain. Patients with significant midline shift (0.5 cm) or global blood flow reduction were excluded from the analysis. SPECT scan of the brain was analyzed by segmental analysis, a semi-quantitative method of cerebral blood flow. A difference of radiotracer uptake of >10% between the region of interest of ICH cases and the ratio between the two ROI below 0.9 was taken as a significant PD. A correlation of PD was analyzed with that of various parameters such as the severity of stroke, duration from onset of ictus, and imaging including CT scan of the brain and SPECT scan. A statistically significant difference in the percentage of radiotracer uptake on comparison of ipsilateral and contralateral to ICH (P < 0.001) was observed, suggesting a significant hypoperfusion in the perilesional area in patients with ICH. A statistically significant correlation was noted between the severity of stroke and PD indicated by various parameters such as the National Institutes of Health Stroke Scale (NIHSS) score at admission (r = 0.328, P = 0.016), Glasgow Coma Scale (GCS) score at admission (r = −0.388, P = 0.005), and ICH score at admission (r = 0.314, P = 0.020). This study demonstrated more severe hypoperfusion in clinically severe ICH which is a possible explanation of poor outcomes in severe ICH cases. We observed hypoperfusion on SPECT study in 25 of 34 (73.5%) patients with subacute ICH and 5 of 10 patients (50%) with acute ICH. The mean time from the onset of ictus to SPECT scan done was 5.04 ± 1.75 days with a range of 1–7 days, suggesting the persistence of hypoperfusion in subacute stages too. This finding may be of clinical importance for identifying the salvageable area surrounding ICH for any possible intervention in future to improve the outcome. This study demonstrates that perilesional PD occurs in acute and subacute cases of ICH. This hypoperfusion is possibly time related and appears to be more severe in patients having major ICH with poor clinical and imaging parameters. This area of hypoperfusion or ischemic penumbra is a potential site for perfusion recovery to improve clinical outcomes and to reduce long-term neurological deficits.

Longer term stroke risk in intracerebral haemorrhage survivors

ObjectiveTo evaluate the influence of intracerebral haemorrhage (ICH) location on stroke outcomes.MethodsWe included patients recruited to a UK hospital-based, multicentre observational study of adults with imaging confirmed spontaneous ICH. The...

Risk factors for intracerebral haemorrhage - Results from a prospective population-based study.

IntroductionWhile the relationship between hypertension and incident intracerebral haemorrhage is well established, other risk factors are less clear. This study examined risk factors for primary intracerebral haemorrhage, separately for lobar and non-lobar intracerebral haemorrhage.Patients and methodsIncidence of intracerebral haemorrhage was studied among 28,416 individuals from the population-based Malmö Diet and Cancer cohort. Intracerebral haemorrhage cases were ascertained using the Swedish Hospital Discharge Register and the Stroke Register of Malmö, validated by review of hospital records and images, and classified by location by a neuroradiologist. Multivariable Cox regression was used.ResultsThree hundred and thirty-three intracerebral haemorrhages occurred, mean follow-up time was 18.4 years. Systolic blood pressure (hazard ratio per 10 mmHg 1.19 [95% confidence interval 1.13–1.26], diastolic blood pressure (hazard ratio 1.42 [1.27–1.59]), oral anticoagulants (hazard ratio 4.26 [2.17–8.38]), smoking (hazard ratio 1.45 [1.14–1.87]), living alone (hazard ratio 1.32 [1.04–1.69]) and low apolipoprotein B (hazard ratio per 10 mg/dL: 0.94 [0.90–0.99]) were significantly associated with incident intracerebral haemorrhage after multivariable adjustment. Systolic blood pressure, smoking and oral anticoagulants were associated with lobar intracerebral haemorrhage. Systolic blood pressure, diastolic blood pressure, living alone and diabetes were associated with non-lobar intracerebral haemorrhage. Diabetes and diastolic blood pressure showed significantly different relationships with lobar and non-lobar intracerebral haemorrhage. Alcohol, apolipoprotein A1, body mass index, waist circumference, physical activity and education were not independently associated with intracerebral haemorrhage.Discussion and conclusions: Blood pressure, smoking, low apolipoprotein B, oral anticoagulants and living alone were associated with intracerebral haemorrhage. Diabetes was associated with non-lobar intracerebral haemorrhage only. Further research is required on differences between lobar and non-lobar intracerebral haemorrhage.

Subarachnoid Extension Predicts Lobar Intracerebral Hemorrhage Expansion.

Background and Purpose- We investigated whether subarachnoid extension (SAHE) of intracerebral hemorrhage (ICH) is associated with hematoma expansion (HE). Methods- Retrospective analysis of patients with primary spontaneous ICH admitted at 3 academic hospitals in Italy. The study population was divided into a development and a replication cohort. SAHE was rated on baseline noncontrast computed tomography by investigators blinded to clinical data. The main outcome of interest was HE, defined as ICH growth >33% mL and/or >6 mL. Predictors of HE were explored with multivariable logistic regression stratified by ICH location (lobar versus nonlobar). Results- A total of 360 and 192 patients were included in the development and replication cohort, respectively. SAHE was identified with good interrater reliability (K=0.82), and its frequency was 27.8% in the development and 24.5% in the replication cohort. In univariate analysis, HE was more common in patients with SAHE (52.0% versus 27.3%; P<0.001). When controlling for confounders in logistic regression, SAHE was an independent predictor of lobar HE (odds ratio, 6.00 [95% CI, 2.16-16.64]; P=0.001) whereas there was no association with HE in nonlobar ICH (odds ratio, 0.55 [95% CI, 0.17-1.84]; P=0.334). The increased risk of HE in lobar ICH with SAHE was confirmed in the replication cohort (odds ratio, 3.46 [95% CI, 1.07-11.20]; P=0.038). Conclusions- SAHE predicts HE in lobar ICH. This may improve the stratification of HE risk in clinical practice or future trials targeting HE. Further research is needed to confirm our findings and characterize the underlying biological mechanisms.

Ten-year risks of recurrent stroke, disability, dementia and cost in relation to site of primary intracerebral haemorrhage: population-based study

BackgroundPatients with primary intracerebral haemorrhage (ICH) are at increased long-term risks of recurrent stroke and other comorbidities. However, available estimates come predominantly from hospital-based studies with relatively short follow-up. Moreover,...

Abstract WP408: Risk of Lobar Intracerebral Hemorrhage From Hypertension is Greatest at an Early Age

Background: The risk of intracerebral hemorrhage (ICH) with hypertension (HTN) is well documented, with prior studies showing that HTN is the most important risk factor associated with ICH. Prior studies have shown that while the prevalence of HTN increases with age, the odds ratio (OR) of HTN for non-lobar ICH is greater earlier in life. We have previously found a lack of Apolipoprotein E allele association with lobar ICH in minority populations. Here we seek to determine if, similar to non-lobar ICH, the odds ratio of HTN for lobar ICH is greater at an earlier age. Methods: The Ethnic/Racial Variations of ICH (ERICH) study is a prospective multicenter case-control study of ICH among whites, blacks, and Hispanics. Cases were enrolled from 42 sites. Controls matched to cases 1:1 by age (±5 years), sex, ethnicity/race, and metropolitan area were identified by random-digit dialing. Participants were interviewed to determine history of HTN. Participants were divided into age groups based on ethnicity-specific quartiles. Cases in each ethnic/age group were compared to controls using logistic regression (i.e., cases and controls unmatched). ORs were calculated to show the risk of lobar ICH associated with HTN by quartile. Results: Overall, 917 lobar ICH cases and 932 controls were included. The Table shows the multivariable OR. ORs were highest in the youngest age quartile across all races (6.47 for blacks, 5.72 for Hispanics and 2.74 for whites). HTN produced a significant increase in risk for the youngest two quartiles in blacks and Hispanics, but only the youngest quartile in whites. However, the age of the lowest quartile in whites was equivalent to the bottom two quartiles in minorities. Discussion: Similar to non-lobar ICH, HTN earlier in life bears a greater risk of lobar ICH than later in life and this risk is across a greater range in disproportionately affected minorities. Research into how new onset or early life HTN leads to disproportionate risk compared to late life is needed.

Abstract TP331: The Effect of Intradialytic Blood Pressure Variability Prior to Intracerebral Hemorrhage on Outcomes

Introduction: Increased blood pressure variability (BPV) during chronic hemodialysis (HD) is associated with cardiovascular event and all-cause mortality. However, it is largely unknown whether pre-admission intradialytic BPV affects functional outcomes in patients with acute intracerebral hemorrhage (ICH). Methods: We examined consecutive patients with acute spontaneous ICH who had received HD from our prospective stroke registry between January 2012 and March 2019. Patients with premorbid modified Rankin Scale (mRS) score of 5 and patients who could not be obtained either pre-admission or post-admission blood pressure were excluded from the study. Pre-admission intradialytic BPV was quantified by systolic blood pressure successive variation (SBP-SV) from the last pre-admission dialysis record prior to ICH. Post-admission BPV during initial 24 hours was also quantified using SBP-SV. The clinical outcomes were hematoma expansion and unfavorable outcome at 3-months (mRS score of 5 to 6). Results: Of 54 ICH patients who had received HD, 45 patients were analyzed (median age, 68 years; male, 64%; non-lobar ICH, 93 %).Unfavorable outcome was observed in 26 (58%) patients.Increased pre-admission intradialytic SBP-SV was associated with only post-admission SBP-SV, but not associated with National Institute of Health Stroke Scale (NIHSS) score, hematoma volume, or hematoma expansion.In univariate analysis, both of pre- and post-admission SBP-SV were associated with unfavorable outcome. In analysis adjusting for age, NIHSS score, and hematoma volume, pre-admission SBP-SV (per SD; odds ratio, 3.70; 95% confidence interval, 1.01-13.6) was associated with unfavorable outcome, while post-admission SBP-SV was not independently associated with unfavorable outcome. Conclusions: In ICH patients who had received chronic HD, pre-admission intradialytic BPV was independently associated with unfavorable outcome after ICH, suggesting that BP control during HD may be a therapeutic target for avoiding further neurological aggravation even once ICH has occurred.

Underlying Small Vessel Disease Associated With Mixed Cerebral Microbleeds.

Background and Purpose: Whether patients with both lobar and deep cerebral microbleeds (mixed CMB) have advanced cerebral amyloid angiopathy (CAA), hypertensive angiopathy (HA) or both is uncertain. To get insight into the underlying small vessel disease (SVD) associated with mixed CMB, we explored its association with cortical superficial siderosis (cSS), a key marker of CAA and other MRI markers of SVD in patients with intracerebral hemorrhage (ICH).Methods: Of 425 consecutive patients with acute ICH who had received brain MRIs, 260 had ≥1 CMB and were included in the analysis. They were categorized as strictly lobar CMB (suggesting CAA), strictly deep CMB (suggesting HA) or mixed CMB. Clinical and imaging characteristics were compared (1) between the three CMB groups and (2) within mixed CMB patients according to the symptomatic ICH location.Results: Overall, 111 (26%) patients had mixed CMB. Compared to strictly lobar CMB (n = 111) and strictly deep CMB (n = 38), patients with mixed CMB had a more severe burden of lacune, white matter hyperintensities and CMB. cSS was observed in 24.3% of patients with mixed CMB compared to 44.1% in strictly lobar CMB and 10.5% in strictly deep CMB (p < 0.0001). Among patients with mixed CMB, 44 (39.6%) had a lobar symptomatic ICH and 67 (60.4%) had a non-lobar ICH. Patients with non-lobar ICH were more likely to have hypertension, whereas those with lobar ICH were more likely to have cSS and chronic lobar ICH and had higher ratio lobar CMB count/total CMB count.Conclusions: Mixed CMB is frequently encountered in patients with ICH and appears as a heterogeneous group, suggesting that both CAA and HA may be contributing to mixed CMB. Neuroimaging markers including ICH location, cSS, and CMB distribution may indicate the predominant underlying vasculopathy, with potential prognostic implications.

Genome-wide association study of cerebral small vessel disease reveals established and novel loci.

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.