Intracerebral Hemorrhage Cohort Research Articles

Identification of Genetic Loci Associated With Intracerebral Hemorrhage Using a Multitrait Analysis Approach.

Genome-wide association studies (GWASs) have only 2 loci associated with spontaneous intracerebral hemorrhage (ICH): APOE for lobar and 1q22 for nonlobar ICH. We aimed to discover new loci through an analysis that combines correlated traits (multi-trait analysis of GWAS [MTAG]) and explore a gene-based analysis, transcriptome-wide association study (TWAS), and proteome-wide association study (PWAS) to understand the biological mechanisms of spontaneous ICH providing potential therapeutic targets. We use the published MTAG of ICH (patients with spontaneous intraparenchymal bleeding) and small-vessel ischemic stroke. For all ICH, lobar ICH, and nonlobar ICH, a pairwise MTAG combined ICH with traits related to cardiovascular risk factors, cerebrovascular diseases, or Alzheimer disease (AD). For the analysis, we assembled those traits with a genetic correlation ≥0.3. A new MTAG combining multiple traits was performed with those traits whose pairwise MTAG yielded new GWAS-significant single nucleotide polymorphisms (SNPs), with a posterior-probability of model 3 (GWAS-pairwise) ≥0.6. We perform TWAS and PWAS that correlate the genetic component of expression or protein levels with the genetic component of a trait. We use the ICH cohort from UK Biobank as replication. For all ICH (1,543 ICH, 1,711 controls), the mean age was 72 ± 2 in cases and 70 ± 2 in controls, and half of them were women. Replication cohort: 700 ICH and 399,717 controls. Novel loci were found only for all ICH (the trait containing lobar and nonlobar ICH), combining data of ICH and small vessel stroke, white matter hyperintensities volume, fractional anisotropy, mean diffusivity, and AD. We replicated 6 SNPs belonging to 2q33.2 (ICA1L, β = 0.20, SE = 0.03, p value = 8.91 × 10-12), 10q24.33 (OBFC1, β = -0.12, SE = 0.02, p value = 1.67 × 10-8), 13q34 (COL4A2, β = 0.02, SE = 0.02, p value = 2.34 × 10-11), and 19q13.32 (APOC1, β = -0.19, SE = 0.03, p value = 1.38 × 10-12; APOE, β = 0.21, SE = 0.03, p value = 2.70 × 10-11; PVRL2:CTB-129P6.4, β = 0.15, SE = 0.03, p value = 1.38 × 10-8); 2 genes (SH3PXD2A, Z-score = 4.83, p value = 6.67 × 10-7; and APOC1, Z-score: = 5.11, p value = 1.60 × 10-7); and ICA1L transcript (Z-score = 6.8, p value = 9.1 × 10-12) and protein levels (Z-score = -5.8, p value = 6.7 × 10-9). Our results reinforce the role of APOE in ICH risk, replicate previous ICH-associated loci (2q33 and 13q34), and point to new ICH associations with OBFC1, PVRL2:CTB-129P6.4, APOC1, and SH3PXD2A. Our study used data from European subjects, our main limitation. These molecules could be potential targets for future studies for modulating ICH risk.

Incidence and Outcomes of Patients With Early Cardiac Complications After Intracerebral Hemorrhage: A Report From VISTA.

The incidence and outcomes of early cardiac complications in patients with intracerebral hemorrhage (ICH) are poorly understood. These cardiac complications may be part of the so-called stroke-heart syndrome in patients with ICH. We investigated this issue in an individual patient data pooled analysis from an international repository of clinical trial data. We used the Virtual International Stroke Trials Archive to investigate the incidence of cardiac complications within 30 days post-ICH or acute ischemic stroke (AIS). These complications included acute coronary syndrome encompassing myocardial injury, heart failure/left ventricular dysfunction, atrial fibrillation/atrial flutter, other arrhythmia/ECG abnormalities, and cardiorespiratory arrest. We used propensity score matching to compare the incidence of patients with stroke-heart syndrome in patients with ICH with those following AIS. Factors associated with 90-day mortality were evaluated using multivariate logistic regression analysis in the ICH cohort. We pooled data from 8698 participants recruited in acute stroke trials (mean age, 68±12 years; 56% male), of whom 914 (11%) were patients with ICH. Among the patients with ICH, 123 (13%) had stroke-heart syndrome in patients with ICH. Following propensity score matching, a total of 1828 patients (914 for each of the cohorts) were analyzed. While the overall incidence of cardiac events tended to be lower in the ICH group compared with the AIS group (the cumulative incidence freedom from the event, 86.3% [95% CI, 84.1-88.6] versus 83.6% [95% CI, 81.2-86.0]; P=0.100), the incidences cardiac events other than atrial fibrillation/atrial flutter were comparable between the 2 matched groups. The incidence of atrial fibrillation/atrial flutter was significantly lower in the ICH group than in the AIS group (P<0.001). The multivariate-adjusted analysis found that stroke-heart syndrome in patients with ICH was associated with 90-day mortality (adjusted odds ratio, 1.12 [95% CI, 1.06-1.19]; P<0.001). Cardiac events are common and negatively affect prognosis in patients with ICH, just as seen in AIS.

Model based on single-nucleotide polymorphism to discriminate aspirin resistance patients

BackgroundAspirin is widely used for preventing ischaemic events. About 20%–40% of patients have aspirin resistance (ASR), which prevents them from benefiting from aspirin medication. This study aimed to develop and...

The potential for minimally invasive intracerebral hemorrhage evacuation in routine healthcare: applicability of the ENRICH trial criteria to an unselected cohort

ObjectiveFollowing the favorable outcomes demonstrated by the Early MiNimally-invasive Removal of IntraCerebral Hemorrhage (ENRICH) trial in supratentorial intracerebral hemorrhage (ICH) patients treated with minimally invasive surgery (MIS), and considering the increasing interest in MIS, we aimed to assess the potential eligibility rate for ICH patients in Sweden.MethodsAll patients with spontaneous ICH in the Swedish Stroke Register (RS) during 2017–2020 in Skane county (1.37 million) were assessed. Baseline imaging was used for radiological characterization. Clinical data were obtained from RS. MIS eligibility in the total ICH population meeting ENRICH criteria were estimated and extrapolated to the Swedish population (10.5 million).ResultsOf 1,314 ICH patients, 5.9% met the ENRICH criteria for MIS (ICH volume 30–80 ml). Considering the ENRICH trial results indicating the effectiveness of MIS was mainly attributable to intervention for lobar hemorrhages, we determined that 2.8% of our ICH cohort in Sweden would be eligible for MIS. The estimated rate of neurosurgery for ICH could increase from the current 1.46–1.90 patients/100,000 population/year (in absolute numbers from 154 to 200 interventions out of 2,400 ICHs in Sweden annually).ConclusionsWe show that 2.8% of the Skane ICH population would be eligible for MIS if ENRICH criteria are employed for patients with lobar ICH, corresponding to a 29% increase of current surgical rates for ICH in Sweden. As MIS for ICH is not yet standard practice in Sweden, consideration for its implementation within the neurosurgical organization becomes essential to accommodate the anticipated increase in patient demand.

Short-term functional outcomes of patients with acute intracerebral hemorrhage in the native and expatriate population.

Functional outcomes in patients with intracerebral hemorrhage (ICH) have not been well characterized in the Middle East and North Africa Region. We report the 30 and 90-day clinical outcomes in the native and expatriate of Qatar with ICH. We evaluated the Glasgow Coma Scale (GCS), NIHSS, and imaging in the Qatar Stroke Registry (2013-22). The outcome measures were a modified Rankin Scale (mRS) at 90 days and mortality at 30 and 90 days. Unfavorable outcome was defined as mRS of 4-6. We performed non-parametric ROC analyses to measure the concordance index (C-index) to assess the goodness-of-fit of ICH score for predicting 30 day and 90-day mortality and functional outcome. 1,660 patients (median age of 49 (41.5-58) years; male 83.1%, expatriates 77.5%) with ICH, including supratentorial deep in 65.2%, cortical in 16.2%, infratentorial 16% and primary intraventricular in 2.5% were studied. The median baseline ICH volume was 7.5 (3.2-15.8) ml. An unfavorable outcome was seen in 673 (40.5%) patients at 90 days. The unfavorable 90-day outcome (mRS 4-6) was 49.2% in the native population vs. 44.4% in Africans, 39.0% in South Asian, 35.3% in Far Eastern, and 7.7% in Caucasians, p < 0.001. Mortality at 30 days and 90 days was 10.4 and 15.1%. Increasing age [OR (95% CI), 1.02 (1.00-1.03)], lower GCS [0.77 (0.73-0.80)], prior use of antiplatelet medications [1.82 (1.19-2.08)], higher ICH volume [1.03 (1.02-1.04)], and presence of any intraventricular hemorrhage [1.57(1.19-2.08)], were associated with unfavorable outcome. In this relatively younger ICH cohort more than 75% were expatriates. The ICH volume, 90-day unfavorable outcome and mortality was lower in the expatriates compared to the local Arab population, likely related to the younger age and smaller size of the hemorrhages. Prognostic scoring systems may have to be modified in this population to avoid early withdrawal of care.

Abstract WP273: The Association of Social Determinants of Health on Functional Outcome After Intracerebral Hemorrhage

Background: It remains unknown which social determinants of health (SDOH) are impactful or when disparities begin to emerge in intracerebral hemorrhage (ICH). This study aimed to investigate the association between pre-stroke SDOH and post-stroke functional outcome. Methods: Data from the Massachusetts General Hospital (MGH) ICH cohort was used and included age, sex, ICH severity, history of hypertension, tobacco use, diabetes, coronary artery disease, atrial fibrillation, liver disease, history of dementia, and history of prior ICH. SDOH exposures included income bracket, educational attainment, marital status, race, and religion. The primary outcome was the modified Rankin Score (mRS) measured at 12 months. Baseline characteristics, past medical history, and SDOH among those with mild stroke versus severe stroke were compared using the Wilcoxon Rank Sum test and chi-square tests. Factors from the univariate analysis which were associated with stroke severity (p&lt;0.05) were included in a logistic regression model. Results: Of the 315 patients with available 12-month mRS, 180 (57%) had mRS scores &lt;3 or relatively good functional outcomes, and 135 (43%) had mRS scores &gt;=3 or relatively poor functional outcomes. The median age of those with low mRS was 69 compared to 76 for those with high mRS. Those with high mRS were more likely to have high school-only education or a diagnosis of dementia on admission compared to those with low mRS. Those with high school-only education were 2.94 times more likely than college diplomates to have high mRS (OR 2.94, 95% CI 1.57-5.53). Similarly, those with a diagnosis of dementia on admission, were 6.22 times more likely than those without a diagnosis of dementia to have high mRS (OR 6.22, 95% CI 1.70-22.75). Discussion: In addition to clinical determinants of age, ICH severity, and underlying dementia, educational attainment was an independent predictor of poor functional outcome after ICH. We recognize the impact of survival bias in our study design; however, we found differences in recovery despite this bias. Our findings suggest that disparities in outcomes exist even in relatively homogenous patient populations and that SDOH prior to an ICH still have associations with functional outcomes after stroke.

Racial Impact on Inpatient Stroke Quality of Care in Two Community Hospitals.

This analysis was conducted as a part of a quality improvement project aiming at identifying racial disparity in inpatient stroke quality of care. The Get With The Guidelines (GWTG) database was used to identify all patients discharged with any stroke diagnosis between January and December 2021. An additional chart review was conducted to ensure the accuracy of racial/ethnic categorization. The sample was dichotomized into white vs. non-white groups and compared with univariate analysis. The study sample comprised 1408 encounters (1347 patients) with Mean age of 71 ± 15 years, 51% women, 82% white patients, 15% non-white patients, 72% acute ischemic stroke (AIS); 15% transient ischemic attack (TIA), 9% intracerebral hemorrhage (ICH), 3% subarachnoid hemorrhage (SAH), and 1% stroke not otherwise specified. Non-white patients were younger and had fewer concomitant diagnoses, a lower proportion of TIA, and a higher proportion of ICH (p = 0.004). In the AIS cohort, compared to white patients, non-white patients had less frequent ambulance (p = 0.009), arrived at the hospital later than white patients (7.7 h longer; p < 0.001), had more severe strokes, and had less frequent IV thrombolysis utilization (7% vs. 13%; p = 0.042). Similarly, in the TIA cohort, non-white patients' utilization of EMS was lower than that of white patients, and their hospital arrival was delayed. In the ICH cohort, non-white patients were younger and had a lower frequency of atrial fibrillation and a non-significant trend toward higher disease severity. The SAH cohort had only eight non-white patients, six of whom were transferred to a higher level of hospital care within a few hours of arrival. Importantly, the hospital-based quality metrics, such as door-to-CT time, door-to-needle time, and the Joint Commission stroke quality metrics, were similar between the two groups. There is a racial disparity in the pre-hospital phase of the stroke chain of survival of non-white patients, impacting IV thrombolysis utilization. The younger age and worse lipid profile and hemoglobin A1c of non-white patients suggest the need for better preventative care starting at a young age.

Stroke Characteristics in a Cohort of Hmong American Patients.

Background Prior studies have indicated high rates of vascular risk factors, but little is known about stroke in Hmong. Methods and Results The institutional Get With The Guidelines (GWTG) database was used to identify patients discharged with acute ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage between 2010 and 2019. Hmong patients were identified using clan names and primary language. Univariate analysis was used to compare Hmong and White patients. A subarachnoid hemorrhage comparison was not conducted because of the small sample size. We identified 128 Hmong patients and 3084 White patients. Hmong patients had more prevalent hemorrhagic stroke (31% versus 15%; P<0.0016). In the acute ischemic stroke cohort, compared with White patients, Hmong patients were younger (60±13 versus 71±15 years; P<0.0001), presented to the emergency department almost 4 hours later; and had a lower thrombolysis usage rate (6% versus 14%; P=0.03496), worse lipid profile, higher hemoglobin A1C, similar stroke severity, and less frequent discharge to rehabilitation facilities. The most common ischemic stroke mechanism for Hmong patients was small-vessel disease. In the intracerebral hemorrhage cohort, Hmong patients were younger (55±13 versus 70±15 years; P<0.0001), had higher blood pressure, and had a lower rate of independent ambulation on discharge (9% versus 30%; P=0.0041). Conclusions Hmong patients with stroke were younger and had poorer risk factor control compared with White patients. There was a significant delay in emergency department arrival and low use of acute therapies among the Hmong acute ischemic stroke cohort. Larger studies are needed to confirm these observations, but action is urgently needed to close gaps in primary care and stroke health literacy.

Association of candidate genetic variants and circulating levels of ApoE/ApoJ with common neuroimaging features of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-β (Aβ) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aβ is also accumulated in Alzheimer's disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins. The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA. We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS. This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral β-amyloidosis.

Abstract TP119: Relationships Of Female Sex With Intracerebral Hemorrhage Characteristics And Outcomes

Introduction: Biological sex is known to impact cerebrovascular disease characteristics and clinical outcomes. While in intracerebral hemorrhage (ICH) it is known that biological sex impacts ICH incidence, it is less clear whether biological sex impacts ICH outcomes. Hypothesis: Female sex will be associated with ICH characteristics and clinical outcomes. Methods: Spontaneous ICH patients enrolled into a prospective observational ICH cohort study between 2009-2020 were assessed. Patients with prior anticoagulant use and secondary etiologies of ICH were excluded from the analysis. Female sex was assessed as the primary exposure variable. Primary analyses assessed relationships of female sex with radiographic outcomes: ICH location, ICH volume, hematoma expansion (&gt;33% and/or &gt;6mL). Secondary analyses assessed relationships of female sex with clinical outcomes: poor discharge neurological outcome (modified Rankin 4-6), and poor discharge disposition (skilled nursing facility, hospice, or inpatient death). Separate multivariable regression models assessed these relationships after adjusting for relevant covariates. Results: Of 504 ICH patients analyzed, mean age was 67 (SD 14.9), 46% were female, and median baseline ICH volume was 14.6 mL (IQR 4.98-35.0). In primary analyses, female sex was not associated with ICH volume or hematoma expansion but was associated with lobar ICH location (adjusted OR 1.72, 95% CI: 1.09-2.70). In secondary analyses, female sex was not associated with poor discharge neurological outcomes (adjusted OR 1.40, 95% CI: 0.74-2.64) after adjusting for race, ICH severity, and ICH location. However, there was an association of female sex with poor discharge disposition (adjusted OR 1.91, 95% CI: 1.15-3.16) after adjusting for similar covariates. Conclusions: While there were no clear intergroup sex differences in ICH severity or neurological outcomes, female sex was associated with worse discharge disposition. Further work is required to clarify whether these disposition differences are due to disease specific complications, characteristics, or if there are other social disparities responsible for these outcome differences.

Abstract TP125: Relationships Of Female Sex With Viscoelastic Hemostatic Assay Coagulation Characteristics After Intracerebral Hemorrhage

Introduction: There are described differences in coagulation between females and males. Specifically, female sex is associated with greater platelet activation and stronger clotting characteristics. It is unclear whether there are relevant coagulation differences identifiable between female and male patients suffering from intracerebral hemorrhage (ICH). Hypothesis: Female sex will be associated with stronger clotting characteristics on whole blood viscoelastic hemostatic assay testing. Methods: Spontaneous ICH patients admitted and enrolled into a prospective observational ICH cohort study between 2009-2020 and who received baseline viscoelastic hemostatic assay testing (Rotational Thromboelastometry: ROTEM) were assessed. Patients with prior anticoagulant use, patients receiving hemorrhage control therapies prior to ROTEM, and secondary etiologies of ICH were excluded from the analysis. Female sex was assessed as the primary exposure variable. The following ROTEM clotting parameters were assessed as the outcome: Coagulation Time (CT) and Maximum Clot Firmness (MCF). We assessed relationships of female sex with these separate ROTEM parameters using multivariable linear regression analyses after adjusting for relevant covariates. Results: Of 57 ICH patients included for analyses, mean age was 65 (SD 14.1), 47% were female, and the median ICH volume was 20.6 mL (IQR 10.1-43.3). There were no baseline intergroup sex differences in demographics, age, or ICH characteristics. Female sex was associated with increased EXTEM MCF (ß 0.323, p&lt;0.05), signifying greater clotting strength, after adjusting for age, race, baseline hematoma volume, and ICH location. Female sex was not associated with other ROTEM parameters. Conclusions: We identified that female sex was associated with stronger clotting characteristics on ROTEM viscoelastic testing. Further work is required to clarify the clinical significance of these findings and their potential specific impacts on radiographic, complication, and clinical outcomes after ICH.

Abstract TP87: Predictors Of Diffusion-weighted Imaging Lesion Burden In Patients After Minimally Invasive Surgery For Intracerebral Hemorrhage

Introduction: The etiology of diffusion-weighted imaging (DWI) lesions in patients after minimally invasive surgery (MIS) for acute intracerebral hemorrhage (ICH) remains unclear. Methods: Postoperative brain MRIs of patients with spontaneous ICH from 2016-2021 who underwent imaging within one month of MIS were reviewed. DWI lesions were quantified. Lesions within 10 mm of the hematoma were excluded. Siderosis and microbleeds were identified. Leukoaraiosis was quantified using the Fazekas score. Univariate analyses were conducted to determine predictors of DWI lesion burden, and variables with P≤0.1 were included in multivariate analyses. Results: DWI lesions were present in 84 (49%) postoperative MRIs. The average number of DWI lesions was 2.11 (range 0-74, SD 6.50). Factors associated with DWI burden in univariate analyses included increased presenting systolic blood pressure (SBP) (P=0.003), Fazekas score (P=0.004), delta SBP on day of admission (P=0.034), preoperative angiogram (P=0.062), microbleeds on MRI (P=0.065), increased presenting National Institutes of Health Stroke Score (P=0.066), presence of intraventricular hemorrhage (P=0.069), and decreased presenting Glasgow Coma Scale (P=0.076). Upon multivariate analysis, increased Fazekas score (OR 2.04, 95% CI 1.21-3.43, P=0.008), presenting SBP (OR 1.04, 95% CI 1.00-1.06, P=0.014), and preoperative angiogram (OR 10.35, 95% CI 1.44-74.36], P=0.020) were predictive of DWI burden. Conclusions: In this unique postoperative ICH cohort, white matter changes, presenting SBP, and preoperative angiogram predicted DWI lesion burden. Larger studies are needed to understand the implications of DWI burden after MIS for ICH recovery.

Apolipoprotein E ɛ2 Is Associated with the White Matter Hyperintensity Multispot Pattern in Spontaneous Intracerebral Hemorrhage.

The white matter hyperintensity (WMH) multispot pattern, as multiple punctate subcortical foci, could differentiate cerebral amyloid angiopathy (CAA) from hypertensive arteriolopathy. Nevertheless, the pathophysiology underlying the multispot sign is still inexplicit. We aimed to explore risk factors for multispot patterns in cerebral small vessel disease (CSVD)-related intracerebral hemorrhage (ICH). Between June 2018 and January 2020, we retrospectively rated the WMH multispot pattern while blinded to our prospective spontaneous ICH cohort's clinical data. Demographic, genetic, and neuroimaging characteristics were applied in establishing the multispot pattern models via multiple logistic regression. In total, 268 participants were selected from our cohort. The possession of apolipoprotein E (APOE) ε2 (P = 0.051) was associated with multispot WMH in univariate analysis. Multispot WMHs were accompanied by multiple CAA features, such as centrum semiovale (CSO)-perivascular space (PVS) predominance (P = 0.032) and severe CSO-PVS (P < 0.001). After adjusting for confounding factors, APOE ε2 possession (OR 2.99, 95% CI [1.07, 8.40]; P = 0.037), severe CSO-PVS (OR 2.39, 95% CI [1.09, 5.26]; P = 0.031), and large posterior subcortical patches (P = 0.001) were independently correlated with the multispot pattern in multivariate analysis. Moreover, APOE ε2 possession (OR 4.34, 95% CI [1.20, 15.62]; P = 0.025) and severe CSO-PVS (OR 3.39, 95% CI [1.23, 9.34]; P = 0.018) remained statistically significant among the participants older than 55years of age and with categorizable CSVD. APOE ε2 and severe CSO-PVS contribute to the presence of WMH multispot patterns. Because the multispot pattern is a potential diagnostic biomarker in CAA, genetics-driven effects shed light on its underlying vasculopathy. Clinical Trial Registration: URL- http://www.chictr.org.cn . Unique identifier: ChiCTR-ROC-2000039365. Registration date 2020/10/24 (retrospectively registered).

Association of Prior Intracerebral Hemorrhage With Major Adverse Cardiovascular Events

Patients with stroke due to nontraumatic (spontaneous) intracerebral hemorrhage (ICH) often harbor vascular risk factors and comorbidities, but it is unclear which major adverse cardiovascular events (MACEs) occur more frequently among patients with a prior ICH than the general population. To evaluate the risk of a MACE for patients with a prior ICH compared with the general population. This cohort study identified 8991 patients with a first ICH in the Danish Stroke Registry from January 1, 2005, to June 30, 2018, who were aged 45 years or older and survived more than 30 days after an ICH. Patients in this ICH cohort were matched 1:40 on age, sex, and ICH-onset date with a comparison cohort of 359 185 individuals from the general population without a prior ICH. Both cohorts were followed up for 6 months or more until December 31, 2018, for outcomes using registry data. Data were analyzed from October 1, 2021, to July 19, 2022. Intracerebral hemorrhage identified by a nationwide clinical database. The main outcomes were ICH, ischemic stroke, myocardial infarction, and a composite of MACEs. For each outcome, a case-control study nested within the cohorts was also performed, adjusting for time-varying exposures and potential confounders. Crude absolute event rates per 100 person-years, adjusted hazard ratios (aHRs) and 95% CIs and, in the nested case-control analyses, crude and adjusted odds ratios and 95% CIs were calculated. The ICH cohort (n = 8991; 4814 men [53.5%]; mean [SD] age, 70.7 [11.5] years) had higher event rates than the comparison cohort (n = 359 185; 192 256 men [53.5%]; mean [SD] age, 70.7 [11.5] years) for MACEs (4.16 [95% CI, 3.96-4.37] per 100 person-years vs 1.35 [95% CI, 1.33-1.36] per 100 person-years; aHR, 3.13 [95% CI, 2.97-3.30]), ischemic stroke (1.52 [95% CI, 1.40-1.65] per 100 person-years vs 0.56 [95% CI, 0.55-0.57] per 100 person-years; aHR, 2.64 [95% CI, 2.43-2.88]), and ICH (1.44 [95% CI, 1.32-1.56] per 100 person-years vs 0.06 [95% CI, 0.06-0.07] per 100 person-years; aHR, 23.49 [95% CI, 21.12-26.13]) but not myocardial infarction (0.52 [95% CI, 0.45-0.60] per 100 person-years vs 0.48 [95% CI, 0.47-0.49] per 100 person-years; aHR, 1.12 [95% CI, 0.97-1.29]). Nested case-control analyses returned risk estimates of similar magnitude as the cohort analyses. The findings of this cohort study suggest that Danish patients with a prior ICH had statistically significantly higher rates of MACEs than the general population, indicating a need for attention to optimal secondary prevention with blood pressure lowering and antithrombotic and statin therapies after an ICH in clinical research and practice.

Clinical and neuroimaging risk factors associated with the development of intracerebral hemorrhage while taking direct oral anticoagulants.

Intracerebral hemorrhage (ICH) associated with direct oral anticoagulant (DOAC) usage confers significant mortality/disability. We aimed to understand the clinical and neuroimaging features associated with developing ICH among DOAC users. Clinical and radiological data were collected from consecutive DOAC users with ICH (DOAC-ICH) and age-matched controls without ICH from a single referral center. The frequency/distribution of MRI markers of hemorrhage risk were assessed. Baseline demographics and neuroimaging markers were compared in univariate tests. Significant associations (p < 0.1) were entered into a multivariable regression model to determine predictors of ICH. 86 DOAC-ICH and 94 ICH-free patients were included. Diabetes, coronary artery disease, prior ischemic stroke, smoking history, and antiplatelet usage were more common in ICH patients than ICH-free DOAC users. In the neuroimaging analyses, severe white matter hyperintensities (WMHs), lacunes, cortical superficial siderosis (cSS), and cerebral microbleeds (CMBs) were more common in the ICH cohort than the ICH-free cohort. In the multivariable regression, diabetes [OR 3.53 95% CI (1.05-11.87)], prior ischemic stroke [OR 14.80 95% CI (3.33-65.77)], smoking history [OR 3.08 95% CI (1.05-9.01)], CMBs [OR 4.07 95% CI (1.45-11.39)], and cSS [OR 39.73 95% CI (3.43-460.24)] were independently associated with ICH. Risk factors including diabetes, prior stroke, and smoking history as well as MRI biomarkers including CMBs and cSS are associated with ICH in DOAC users. Although screening MRIs are not typically performed prior to initiating DOAC therapy, these data suggest that patients of high-hemorrhagic risk may be identified.

Higher Cerebral Small Vessel Disease Burden in Patients With Small Intracerebral Hemorrhage.

ObjectiveTo investigate the association between cerebral small vessel disease (SVD) and hematoma volume in primary intracerebral hemorrhage (ICH).MethodsPatients from a prospective ICH cohort were enrolled. Admission and follow-up CT scan within 72 h after onset were reviewed to calculate the final hematoma volume. We evaluated cortical superficial siderosis and the global SVD score, including white matter hyperintensities, lacunes, enlarged perivascular space, and cerebral microbleeds on MRI. We conducted the multivariate logistic regression analyses to explore the association between SVD markers and small ICH, as well as hematoma volume. Hematoma location was stratified into lobar and non-lobar for subgroup analysis.ResultsA total of 187 patients with primary ICH (mean age 62.4 ± 13.4 years, 67.9% male) were enrolled. 94 (50.2%) patients had small ICH. The multivariate logistic regression analysis showed an association between global SVD score and small ICH [adjusted odds ratio (aOR) 1.27, 95% CI 1.03–1.57, p = 0.027] and a trend of higher global SVD score towards non-lobar small ICH (aOR 1.23, 95% CI 0.95–1.58, p = 0.122). In the multivariate linear regression analysis, global SVD score was inversely related to hematoma volume of all ICH (β = −0.084, 95% CI −0.142 to −0.025, p = 0.005) and non-lobar ICH (β = −0.112, 95% CI −0.186 to −0.037, p = 0.004). Lacune (β = −0.245, 95% CI −0.487 to −0.004, p = 0.046) was associated with lower non-lobar ICH volume.ConclusionGlobal SVD score is associated with small ICH and inversely correlated with hematoma volume. This finding predominantly exists in non-lobar ICH.

Immune Thrombocytopenic Purpura and Intracerebral Hemorrhage, Incidence, and Mortality.

Introduction: Intracerebral hemorrhage (ICH) is a devastating complication of immune thrombocytopenic purpura (ITP). Using a large database, we sought to determine its incidence and mortality.Methods: We used a de-identified database (TriNetX) to gather information on patients with ITP with subsequent ICH (cohort 1), propensity score-matched with patients with ITP and no ICH (cohort 2). Primary endpoint was mortality, with secondary endpoints of percutaneous endoscopic gastrostomy (PEG) placement, craniotomy, palliative care encounters, intensive care unit (ICU) management, seizure, falls, pulmonary embolism (PE), myocardial infarction (MI), deep venous thrombosis (DVT), ischemic stroke (IS), and other venous embolism and thrombosis (VTE).Results: Incidence of ICH in patients with ITP was 1.540% in all ages, and 0.774% in those under age 18. After matching, 942 patients from each cohort were identified. Mean age was 58.3 years versus 61.2 years in cohort 1 and 2, respectively. Mortality rate was 34.076% vs. 20.17% (p <0.0001, OR 2.046 with 95% CI 1.661,2.520) at five years. Thirty-day survival was 83.46% vs. 95.17% (p<0.0001), and 365-day survival 68.59% vs. 85.33% (p<0.0001). PEG placement was seen in 21 (2.229%) patients in cohort 1, and less than 10 patients (<1.062%) in cohort 2 (p<0.0464). 2.442% vs. 0% underwent craniotomy (p<0.0001), palliative care was involved in 15.711% vs. 7.962% (p<0.0001), ICU care was seen in 27.389% vs. 11.783% (p<0.0001), with a mean ICU stay of 8.075 vs. 5.812 days (p=0.0537). 6.582% vs. 3.715% had PE (p=0.0049), 7.643% vs. 7.113% experienced MI (p=0.6595), 9.236% vs. 4.883% had DVTs (p=0.0002), 23.673% vs. 5.732% had seizures (p<0.0001), 9.023% vs. 6.582% suffered falls (p=0.0482), 7.537% vs. 3.503% suffered IS (p<0.0001), and 15.074% vs. 8.174% experienced other VTE (p<0.0001).Conclusion: ICH occurs in approximately 1.54% of ITP patients, and is associated with a 34% mortality rate, increased PEG tube placement rates, palliative care involvement, ICU care, craniotomy, PE, IS, DVT, seizures, and falls.

CN-105 in Participants with Acute Supratentorial Intracerebral Hemorrhage (CATCH) Trial.

Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH. Eligible patients were aged 30-80years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0mg/kg every 6h for 72h) within 12h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30days after ICH were compared. In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31-5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort. CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.

Disability-Adjusted Life-Years Associated With Intracerebral Hemorrhage and Secondary Injury

Intracerebral hemorrhage (ICH) contributes significantly to the global burden of disease. To examine the association of ICH and secondary injury with disability-adjusted life-years (DALYs) for the individual patient. This cohort study was conducted using data from the Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage study. Consecutive patients admitted to a single tertiary care center from January 1, 2006, to December 31, 2015, were included. The sample comprised patients with oral anticoagulation-associated ICH (OAC-ICH) or primary spontaneous ICH (non-OAC-ICH). Statistical analysis was conducted from October 1 to December 31, 2020. ICH occurrence and secondary injury. DALYs, years of life lost (YLL), and years lived with disability (YLD) were analyzed by hematoma location, ICH volume, and secondary injury (ie, hematoma expansion [HE], intraventricular hemorrhage [IVH], and perihemorrhagic edema [PHE]). Among 1322 patients with ICH, 615 (46.5%) were women and the mean (SD) age at hospital admission was 71 (13) years; ICH was associated with a mean (SD) of 9.46 (8.08) DALYs, 5.72 (8.29) YLL, and 3.74 (5.95) YLD. There were statistically significant differences in mean (SD) DALYs by extent of hematoma volume (< 10 mL ICH: 7.05 [6.79] DALYs; 10-30 mL ICH: 9.91 [8.35] DALYs; >30 mL ICH: 12.42 [8.47] DALYs; P < .001) and ICH location (deep location: 10.60 [8.35] DALYs; lobar location: 8.18 [7.63] DALYs; cerebellum: 8.14 [6.80] DALYs; brainstem: 12.63 [9.21] DALYs; P < .001). Regarding population-level disease burden of secondary injuries after ICH, there was a statistically significant difference in mean (SD) by injury type, with 0.94 (3.19) DALYs for HE, 2.45 (4.16) DALYs for IVH, and 1.96 (2.66) DALYs for PHE (P < .001) among the entire ICH cohort. Regarding individual-level exposure to secondary injuries after ICH, there were a mean (SD) 7.14 (6.62) DALYs for HE, 4.58 (4.75) DALYs for IVH, and 3.35 (3.28) DALYs for PHE among patients with ICH affected by secondary injuries. These findings suggest that there is a high burden of disability associated with ICH and secondary injuries, and the findings may guide public health strategies. The study findings further suggest that IVH and PHE may be relevant for the overall outcome of patients with ICH, that DALYs may represent a viable outcome parameter for studies to evaluate treatment outcomes in ICH research, and that IVH and PHE may represent potential treatment targets.

Circulating AQP4 Levels in Patients with Cerebral Amyloid Angiopathy-Associated Intracerebral Hemorrhage.

Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage (ICH) in elderly patients. Growing evidence suggests a potential role of aquaporin 4 (AQP4) in amyloid-beta-associated diseases, including CAA pathology. Our aim was to investigate the circulating levels of AQP4 in a cohort of patients who had suffered a lobar ICH with a clinical diagnosis of CAA. AQP4 levels were analyzed in the serum of 60 CAA-related ICH patients and 19 non-stroke subjects by enzyme-linked immunosorbent assay (ELISA). The CAA–ICH cohort was divided according to the time point of the functional outcome evaluation: mid-term (12 ± 18.6 months) and long-term (38.5 ± 32.9 months) after the last ICH. Although no differences were found in AQP4 serum levels between cases and controls, lower levels were found in CAA patients presenting specific hemorrhagic features such as ≥2 lobar ICHs and ≥5 lobar microbleeds detected by magnetic resonance imaging (MRI). In addition, CAA-related ICH patients who presented a long-term good functional outcome had higher circulating AQP4 levels than subjects with a poor outcome or controls. Our data suggest that AQP4 could potentially predict a long-term functional outcome and may play a protective role after a lobar ICH.