Intracerebral Hemorrhage Lesions Research Articles

Veliparib exerts protective effects in intracerebral hemorrhage mice by inhibiting the inflammatory response and accelerating hematoma resolution

Poly (ADP-ribose) polymerase (PARP) inhibitors have potent anti-inflammatory effects, including the suppression of brain microglial activation. Veliparib, a well-known PARP1/2 inhibitor, exhibits particularly high brain penetration, but its effects on stroke outcome is unknown. Here, the effects of veliparib on the short-term outcome of intracerebral hemorrhage (ICH), the most lethal type of stroke, were investigated. Collagenase-induced mice ICH model was applied, and the T2-weighted magnetic resonance imaging was performed to evaluate lesion volume. Motor function and hematoma volume were also measured. We further performed immunofluorescence, enzyme linked immunosorbent assay, flow cytometry, and blood–brain barrier assessment to explore the potential mechanisms. Our results demonstrated veliparib reduced the ICH lesion volume dose-dependently and at a dosage of 5 mg/kg, veliparib significantly improved mouse motor function and promoted hematoma resolution at days 3 and 7 post-ICH. Veliparib inhibited glial activation and downregulated the production of pro-inflammatory cytokines. Veliparib significantly decreased microglia counts and inhibited peripheral immune cell infiltration into the brain on day 3 after ICH. Veliparib improved blood–brain barrier integrity at day 3 after ICH. These findings demonstrate that veliparib improves ICH outcome by inhibiting inflammatory responses and may represent a promising novel therapy for ICH.

Peripheral T cell immune repertoire is associated with the outcomes of acute spontaneous intracerebral hemorrhage.

Systematic immune responses have been identified in patients with acute spontaneous intracerebral hemorrhage (ICH). T cells have been established to participate in central nervous system damage and repair following brain injury. However, their contribution to the prognosis of patients with ICH remains to be elucidated. In this study, peripheral blood mononuclear cells (PBMCs) were collected from 45 patients with acute spontaneous ICH (<24 h from symptom onset). Our results exposed significant negative correlations between hematoma volume/white blood cell (WBC) density and Glasgow Coma Scale (GCS) score. Contrastingly, lymphocyte density was negatively correlated with hematoma volume and positively correlated with GCS score. Moreover, flow cytometry determined that ICH activated T cells despite their proportion being lower in blood. Afterward, immune repertoire sequencing (IR-seq) revealed a significant decrease in VJ, VDJ usage, and TCR clonotypes in ICH patients. Finally, variations in the complementarity-determining region 3 (CDR3) amino acid (aa) were also detected in ICH patients. This study reveals the occurrence of peripheral T-cell diminishment and activation in response to acute hematoma. ICH lesion also alters the T cell receptor (TCR) immune repertoire, which is associated with patient prognosis.

Clinical features and associated factors of coexisting intracerebral hemorrhage in patients with cerebral small vessel disease: a cross-sectional study

Intracerebral hemorrhage (ICH) is generally considered to be closely related to cerebral small vessel disease (CSVD), leading to a poor prognosis. However, the coexistence of ICH in general CSVD patients and related factors remain underreported. In our cross-sectional study, we screened 414 CSVD patients from a database at the Department of Neurology, First Affiliated Hospital of Zhengzhou University (September 2018 to April 2022). Imaging biomarkers of CSVD and coexisting ICH lesion were assessed. Factors associated with coexisting ICH in CSVD were determined using multivariate logistic regression analysis. ICH was observed in 59 patients (14.3%). Multivariate logistic regression showed that previous history of ischemic stroke or transient ischemic attack (OR 5.189, 95%CI 2.572–10.467, P < 0.001), high-grade perivascular space in the basal ganglia (n > 10) (OR 2.051, 95%CI 1.044–4.027, P = 0.037) and low adjusted calcium-phosphorus product (OR 0.728 per 1 [mmol/L]2 increase, 95%CI 0.531–0.998, P = 0.049) were associated with coexisting ICH in CSVD patients. The considerable proportion of coexisting ICH and revelation of associated factors in general CSVD patients alert physicians of the potential risk of the reoccurrence of ICH, and might have a significant impact on therapeutic strategies.

Abstract TP170: An Explainable Deep Learning Method to Quantitatively Predict Hematoma Progression After Intracerebral Hemorrhage

In patients with intracerebral hemorrhage (ICH), it is important to quickly and accurately individualize the treatment decision by quantitatively predicting the hematoma progression using medical information collected on admission. Current approaches only qualitatively predict ICH progression trends leveraging anatomical features extracted from non-contrast computed tomography (NCCT) images. However, these approaches do not consider the hemodynamics of the cerebral circulation system, cannot quantitatively predict ICH progression, and lack the needed explainability. To address these technical challenges, in this work, we developed an explainable deep learning method to quantitatively predict hematoma progression after ICH, which quantitatively predicts ICH progression leveraging (i) deep anatomical features (baseline ICH lesion volume) derived from NCCT images, and (ii) deep hemodynamic features focusing veins-of-interest derived from time-resolved CT images collected on admission. A total of 73 patients categorized into the training data set (containing 58 patients) and the test data set (containing 15 patients), with 216 sets of images, were used in the development and validation of the model. For the ICH lesion volume predicted by this model, the mean difference with respect to the reference volume is -0.96 mL, and the agreement limits are [-9.64 mL, +7.71 mL] (Figure 1). In conclusions, by simultaneously leveraging deep anatomical and hemodynamic features, our model can quantitatively predict ICH progression using multimodal CT images collected on admission and hence help individualize the treatment decision during hospitalization.

Abstract TP306: Anemia Causes Hematoma Expansion, Cerebral Hypoxia-Driven Microglial Activation, and Early Mortality in Mice With Intracerebral Hemorrhage

Anemic intracerebral hemorrhage (ICH) patients are observed to have poor clinical outcomes with increased risk of hematoma expansion (HE) and impaired cerebral oxygenation. To assess whether anemia causes these observations, we assessed neuroimaging evidence of HE and neuropathological changes of hypoxia and blood brain barrier (BBB) dysfunction in anemic vs non-anemic mice with ICH. Anemia was generated in 3 month old female C57/BL6 mice using iron-deficient chow. Age and sex-matched controls were fed iron-replete control diet. Anemia was verified using modified Drabkin assays. Collagenase was used to induce ICH. ICH volume and HE were quantified using serial T2-weighed MRI at 1, 4, and 24 hours after ICH. Early 24 hour mortality was recorded. After the last MRI, surviving mice were euthanized by intracardiac perfusion and the brain was processed for histological analysis of vascular permeability (IgG), microglia number and activation (Iba1 and CD68), and response to hypoxia (HIF1α). Statistical analyses were performed using two-tailed ANOVA. Compared to controls, anemic mice displayed larger final ICH lesion volumes (anemia: 7.7 mm 3 vs control: 6.1 mm 3 ), greater HE at 24 hours (anemia: 111.4% vs control: 23.6%) and increased early mortality (anemia: 30% vs control: 0%). Histological analyses revealed that, while microglial activation and BBB permeability to serum IgGs in control mice were restricted to the ipsilateral hemisphere and mostly localized perilesionally, anemic mice had increased immune infiltration and increased BBB permeability in both hemispheres. Similarly, non-ICH anemic mice showed increased and widespread immune cell infiltration and increased BBB permeability compared to non-ICH control mice, suggesting that consistently low hemoglobin concentrations may increase cerebrovascular susceptibility to injury.Future studies will be needed to further clarify cellular and molecular mechanisms driving our findings and whether anemia can be a treatable target to improve ICH outcomes.

COVID-19 and Its Long-Term Neurological and Cognitive Implications: A Literature Review

Introduction: COVID-19 is an infectious disease resulting from severe acute respiratory syndrome. Individuals with prior COVID-19 infection have had neurological complaints of impaired attention, fatigue, and “brain fog”. This review seeks to summarize the associations between COVID-19 infection and the development of the neurocognitive elements of post-acute COVID syndrome (PACS) which is relevant to healthcare workers for the efficient treatment and management of the long-term effects of COVID. Methods: Literature that examines the neurocognitive complaints caused by COVID-19 infection, including brain fog, attention deficits, psychiatric impairment, and fatigue were selected. Google Scholar and PubMed were the primary databases used to obtain relevant literature. After preliminary searching, 21 articles were analyzed as part of this review. Results: The following symptoms of PACS were persistently reported by a large majority (approximately ⅓ to ½) of patients: breathlessness, cough, fatigue, and brain fog. PACS neurological symptoms were more prevalent in females than in males. Reported psychiatric symptoms from prior COVID-19 infection were ADHD, depression, and insomnia. Discussion: The causes of these neurocognitive symptoms were attributed to neuroinflammation of the choroid plexus, intracerebral hemorrhagic lesions, and hypoactivity in the anterior and posterior cingulate cortex. These possible pathways were confirmed with magnetic resonance imaging (MRI) findings, computed tomography (CT) scans, and positron emission tomography (PET) scans. Conclusion: This paper will add to the evidence regarding the association between COVID-19 and the development of neurocognitive PACS. It is hoped that future research will build on a clearer understanding of the etiology of neurocognitive issues associated with viral infection.

Prevalence and clinical predictors of spasticity after intracerebral hemorrhage.

Spasticity is a common complication of intracerebral hemorrhage (ICH). However, no consensus exists on the relation between spasticity and initial clinical findings after ICH. This retrospective study enrolled adult patients with a history of ICH between January 2012 and October 2020. The modified Ashworth scale was used to assess spasticity. A trained image analyst traced all ICH lesions. Multivariable logistic regression was used to examine the association between ICH lesion sites and spasticity. We finally analyzed 304 patients (mean age 54.86±12.93 years; 72.04% men). The incidence of spasticity in patients with ICH was 30.92%. Higher National Institutes of Health stroke scale (NIHSS) scores were associated with an increased predicted probability for spasticity (odds ratio, OR=1.153 [95% confidence interval, CI 1.093-1.216], p < .001). Logistic regression analysis revealed that lower age, higher NIHSS scores, and drinking were associated with an increased risk of moderate-to-severe spasticity (OR=0.965 [95% CI 0.939-0.992], p = .013; OR=1.068 [95% CI 1.008-1.130], p = .025; OR=4.809 [95% CI 1.671-13.840], p = .004, respectively). However, smoking and ICH in the thalamus were associated with a reduced risk of moderate-to-severe spasticity (OR=0.200 [95% CI 0.071-0.563], p = .002; OR=0.405 [95% CI 0.140-1.174], p = .046, respectively) compared with ICH in the basal ganglia. Our results suggest that ICH lesion locations are at least partly associated with post-stroke spasticity rather than the latter simply being a physiological reaction to ICH itself. The predictors for spasticity after ICH were age, NIHSS scores, past medical history, and ICH lesion sites.

Endothelial cell TRPA1 activity exacerbates cerebral hemorrhage during severe hypertension.

Introduction: Hypoxia-induced dilation of cerebral arteries orchestrated by Ca2+-permeable transient receptor potential ankyrin 1 (TRPA1) cation channels on endothelial cells is neuroprotective during ischemic stroke, but it is unknown if the channel has a similar impact during hemorrhagic stroke. TRPA1 channels are endogenously activated by lipid peroxide metabolites generated by reactive oxygen species (ROS). Uncontrolled hypertension, a primary risk factor for the development of hemorrhagic stroke, is associated with increased ROS production and oxidative stress. Therefore, we hypothesized that TRPA1 channel activity is increased during hemorrhagic stroke. Methods: Severe, chronic hypertension was induced in control (Trpa1 fl/fl) and endothelial cell-specific TRPA1 knockout (Trpa1-ecKO) mice using a combination of chronic angiotensin II administration, a high-salt diet, and the addition of a nitric oxide synthase inhibitor to drinking water. Blood pressure was measured in awake, freely-moving mice using surgically placed radiotelemetry transmitters. TRPA1-dependent cerebral artery dilation was evaluated with pressure myography, and expression of TRPA1 and NADPH oxidase (NOX) isoforms in arteries from both groups was determined using PCR and Western blotting techniques. In addition, ROS generation capacity was evaluated using a lucigenin assay. Histology was performed to examine intracerebral hemorrhage lesion size and location. Results: All animals became hypertensive, and a majority developed intracerebral hemorrhages or died of unknown causes. Baseline blood pressure and responses to the hypertensive stimulus did not differ between groups. Expression of TRPA1 in cerebral arteries from control mice was not altered after 28 days of treatment, but expression of three NOX isoforms and the capacity for ROS generation was increased in hypertensive animals. NOX-dependent activation of TRPA1 channels dilated cerebral arteries from hypertensive animals to a greater extent compared with controls. The number of intracerebral hemorrhage lesions in hypertensive animals did not differ between control and Trpa1-ecKO animals but were significantly smaller in Trpa1-ecKO mice. Morbidity and mortality did not differ between groups. Discussion: We conclude that endothelial cell TRPA1 channel activity increases cerebral blood flow during hypertension resulting in increased extravasation of blood during intracerebral hemorrhage events; however, this effect does not impact overall survival. Our data suggest that blocking TRPA1 channels may not be helpful for treating hypertension-associated hemorrhagic stroke in a clinical setting.

A symmetric prior knowledge based deep learning model for intracerebral hemorrhage lesion segmentation.

Background: Accurate localization and classification of intracerebral hemorrhage (ICH) lesions are of great significance for the treatment and prognosis of patients with ICH. The purpose of this study is to develop a symmetric prior knowledge based deep learning model to segment ICH lesions in computed tomography (CT). Methods: A novel symmetric Transformer network (Sym-TransNet) is designed to segment ICH lesions in CT images. A cohort of 1,157 patients diagnosed with ICH is established to train (n = 857), validate (n = 100), and test (n = 200) the Sym-TransNet. A healthy cohort of 200 subjects is added, establishing a test set with balanced positive and negative cases (n = 400), to further evaluate the accuracy, sensitivity, and specificity of the diagnosis of ICH. The segmentation results are obtained after data pre-processing and Sym-TransNet. The DICE coefficient is used to evaluate the similarity between the segmentation results and the segmentation gold standard. Furthermore, some recent deep learning methods are reproduced to compare with Sym-TransNet, and statistical analysis is performed to prove the statistical significance of the proposed method. Ablation experiments are conducted to prove that each component in Sym-TransNet could effectively improve the DICE coefficient of ICH lesions. Results: For the segmentation of ICH lesions, the DICE coefficient of Sym-TransNet is 0.716 0.031 in the test set which contains 200 CT images of ICH. The DICE coefficients of five subtypes of ICH, including intraparenchymal hemorrhage (IPH), intraventricular hemorrhage (IVH), extradural hemorrhage (EDH), subdural hemorrhage (SDH), and subarachnoid hemorrhage (SAH), are 0.784 0.039, 0.680 0.049, 0.359 0.186, 0.534 0.455, and 0.337 0.044, respectively. Statistical results show that the proposed Sym-TransNet can significantly improve the DICE coefficient of ICH lesions in most cases. In addition, the accuracy, sensitivity, and specificity of Sym-TransNet in the diagnosis of ICH in 400 CT images are 91.25%, 98.50%, and 84.00%, respectively. Conclusion: Compared with recent mainstream deep learning methods, the proposed Sym-TransNet can segment and identify different types of lesions from CT images of ICH patients more effectively. Moreover, the Sym-TransNet can diagnose ICH more stably and efficiently, which has clinical application prospects.

Diagnostic Value of Susceptibility-Weighted Imaging Combined with Diffusion-Weighted Imaging in Early Intracerebral Hemorrhage.

Objective The incidence of early intracerebral hemorrhage (ICH) is gradually increasing and has been shown to affect an increasing number of younger people. Conventional imaging modalities might have a low detection rate of early and small ICH lesions. This study aimed to investigate the diagnostic value of susceptibility-weighted imaging (SWI) combined with diffusion-weighted imaging (DWI) in early ICH. Materials and Methods The data of 61 patients with early ICH diagnosed by computed tomography (CT) scan between January 2019 and February 2020 were assessed. Using CT as the gold standard, we compared the diagnostic sensitivity, accuracy, and imaging characteristics of SWI + DWI versus SWI or DWI alone. Results A total of 78 lesions were detected by CT in 61 patients with early ICH. The diagnostic sensitivity and accuracy of SWI + DWI were significantly higher than those of SWI or DWI alone. In terms of imaging characteristics, DWI demonstrated very low signal intensity in the hematoma center at different stages of early ICH with high signal intensity in the surrounding tissue, and the signal range gradually increased over time. By contrast, SWI displayed very low signal intensity at different stages, and the signal intensity also gradually increased over time. Conclusion Compared with SWI or DWI alone, SWI combined with DWI could improve the detection rate of hematoma lesions in patients with early ICH.

Abstract WMP82: Diffusion Tensor Imaging Is Independently Associated With Mobility After Intracerebral Hemorrhage

Background: Intracerebral hemorrhage (ICH) patients may appear disabled despite intact cortical spinal tracts (CST). ICH lesions may also vary in volume and location relative to the CST with differential impacts on motor outcome. In this study, we evaluated whether diffusion tensor imaging (DTI) integrity of CST fiber tracking associates with mobility three months post ICH. Methods: The Recovery and Outcomes from StrokE (ROSE) Study is a prospective, multi-center study of ICH serially assessed with motor, cognitive, and functional outcomes and MRI/DTI. Outcome data were collected by hospital chart review and interview/exam. Acute MRI images were analyzed by a central neuroimaging core for ICH location, size, intraventricular hemorrhage, and fractional anisotropy (FA) derived from DTI of the CST. Mobility was assessed at 3-month follow-up using the Barthel Mobility Index. We computed single variable logistic regression analyses (outcome = Barthel mobility at 3 months). We also computed a stepwise logistic model, with and without age, sex, and race, including variables that met P&lt;0.1 to best fit. Results: There were 76 ICH patients with DTI FA data available for analysis; 61 with complete data for the multivariate model. Poor mobility after ICH (N = 21; 27.6%) was associated with ICH volume, presence of IVH, Glasgow coma score, ipsilesional CST FA, ipsilesional CP FA and CP FA asymmetry index (Table 1). The multivariate model that adjusted for age, sex, and race identified ipsilesional CP FA, admission GCS and presence of IVH as associated with poor mobility at 3 months; notably, log ICH volume was not associated after controlling for CST injury (Table 1). Conclusions: The presence of IVH and the GCS score at baseline were associated with poor mobility. In addition, the CP FA asymmetry index was independently associated with poor mobility even after accounting for log ICH volume, suggesting that DTI is informative of outcome beyond classic ICH outcome predictors.

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139mm Hg versus 140-179mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90days. Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90days, compared with patients without lesions. Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

Effects of insular involvement on functional outcome after intracerebral hemorrhage.

Ischemic stroke, as well as intracerebral hemorrhage (ICH), involving the insular cortex tends to be more severe. The impact of insular involvement on outcome of ICH remains enigmatic. We analyzed 159 patients with supratentorial ICH. Depending on insular involvement the patients were classified into two groups (ICHnon-insular vs. ICHinsular ). Volume and symptom severity of ICH were assessed. Electrocardiography, chest X-ray, and laboratory examinations including myocardial enzymes and inflammatory markers were made. In-hospital death and outcome at discharge from hospital were assessed on the modified Rankin scale (mRS). The main finding was an association of insular involvement of ICH with worse short-term outcome as measured by mRS (common odds ratio: 4.08 (95% CI: 2.09-7.92); p<.001). This association survived adjustment to relevant covariates such as age, sex, ICH volume, intraventricular hemorrhage, pneumonia, and length of stay (adjusted common odds ratio: 2.51 (95% CI: 1.21-5.21); p=.014) but had no predictive value for side of ICH or rate of atrial fibrillation. There was no association of ICH localization with in-hospital death rate. Insular localization of ICH lesions predicts worse short-term functional outcome independent of side of bleeding or cardiac dysfunction such as new AF. These findings need clarification in larger prospective cohorts assessed by detailed autonomic/cardiac testing, as well as neuroimaging sub-localization of ICH within the insular region.

Asymptomatic acute ischemic lesions in intracerebral hemorrhage: Its frequency, MRI features, and risk factors

BackgroundAsymptomatic acute ischemic lesions (AIL) may be coincidentally found on brain magnetic resonance imaging (MRI) obtained during the acute phase of intracerebral hemorrhage, but its clinical significance has yet to be determined. The objective of this study is to determine the frequency of asymptomatic AIL, its characteristic features of brain MRI and risk factors in patients with acute intracerebral hemorrhage. MethodsWe retrospectively reviewed the clinical information of 108 patients with intracerebral hemorrhage who underwent brain MRIs within 30 days of hospitalization between April 2013 and January 2018. We determined the frequency of asymptomatic AIL, its brain MRI features, and risk factors. ResultsAIL was found in 26 of 108 patients; symptomatic in 2 and asymptomatic in 24 (22.2%). Asymptomatic AIL were small, multiple, mainly distributed to the white matter in the anterior circulation (22/24, 91.7%), and occasionally seen in deep watershed areas (15/24, 62.5%). Only 2 patients had severe major vessel stenosis. Asymptomatic AIL was associated with high mean blood pressure (BP) on admission (> 145 mmHg), excessive drug-induced reduction in mean BP (≥ 55 mmHg), and large hemorrhage (> 31 mL in volume). ConclusionsAsymptomatic AIL were found in 22.2% of patients with intracerebral hemorrhage within 30 days of hospitalization. Asymptomatic AIL were often small, multiple and occasionally developed in deep watershed areas despite the absence of major vessel stenosis. High mean BP on admission, excessive drug-induced BP reduction, and larger hemorrhage may be a risk factor for development of asymptomatic AIL.

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.

Observation of Collagen-Containing Lesions After Hematoma Resolution in Intracerebral Hemorrhage.

The classic presentation of chronic (stage III) hemorrhagic stroke lesions is a fluid-filled cavity. In one of the most commonly used animal models of intracerebral hemorrhage (ICH), we noticed additional solid material within the chronic lesion. We examined the composition of those chronic ICH lesions and compared them with human autopsy cases. ICH was induced in rats by the injection of collagenase in the striatum. Tissue sections after hematoma resolution corresponding to 3 different chronic time points—28, 42, and 73 to 85 days post-ICH—were selected. Human autopsy reports at the University Hospital of Zurich were searched between 1990 and 2019 for ICH, and 3 chronic cases were found. The rat and human sections were stained with a variety of histopathologic markers. Extensive collagenous material was observed in the chronic lesion after hematoma resolution in both the rat model and human autopsy cases. Additional immunostaining revealed that the material consisted primarily of a loose network of collagen 3 intermingled with occasional GFAP (glial fibrillary acidic protein)-positive processes and collagen 4. A key feature of the chronic ICH lesion is a loose network of collagen 3. The collagenase rat model reproduces the morphology and composition of the chronic human ICH lesion. While identifying new features of ICH lesion pathology, these results are important for treatment and recovery strategies.

Intracerebral Hemorrhage in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prevalence, Clinical and Neuroimaging Features and Risk Factors.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic cerebral small vessel disease. The role of intracerebral hemorrhage (ICH) in CADASIL remains elusive. The present study aims to investigate the prevalence, characteristics, and risk factors for ICH in CADASIL. This retrospective cross-sectional study investigated ICH and cerebral microbleeds (CMBs) in brain susceptibility-weighted imaging or T2*-weighted gradient-recalled echo images of 127 Taiwanese patients with genetically confirmed CADASIL. We analyzed CMBs, lacunes, white matter hyperintensity, and perivascular space. The total small vessel disease score (range, 0-4) was calculated to estimate the overall magnetic resonance imaging burden of small vessel disease. Multivariate regression analysis was performed to identify factors related to ICH lesions in CADASIL. Thirty-seven ICH lesions, including 15 symptomatic and 22 asymptomatic lesions, were found in 27 (21.3% [95% CI, 14.0%-30.9%]) of the 127 patients with CADASIL. The thalamus and lobar regions were the most common ICH locations, and 72.7% of the lobar hemorrhages occurred silently. Patients with CADASIL with ICH lesions more often had hypertension and a higher total small vessel disease score than those without ICH (odds ratio [95% CI]: 3.22 [1.25-8.30] and 3.79 [1.51-9.51]). The presence of CMBs in the brain stem and a total CMB count >10 were independently associated with ICH lesions in patients with CADASIL, with odds ratio (95% CI) of 5.82 (1.80-18.80) and 3.83 (1.08-13.67), respectively. ICH is an underestimated but important manifestation of CADASIL. The location and number of CMBs are associated with the presence of ICH lesions in patients with CADASIL.

A Pooled Analysis of Diffusion-Weighted Imaging Lesions in Patients With Acute Intracerebral Hemorrhage

The etiology and significance of diffusion-weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. To evaluate which factors are associated with DWI lesions, whether associated factors differ by ICH location, and whether DWI lesions are associated with functional outcomes. This analysis pooled individual patient data from 3 randomized clinical trials (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, and Intracerebral Hemorrhage Deferoxamine phase 2 trial) and 1 multicenter prospective study (Ethnic/Racial Variations of Intracerebral Hemorrhage). Patients were enrolled from August 1, 2010, to September 30, 2018. Of the 4782 patients, 1788 who underwent magnetic resonance imaging scans of the brain were included. Data were analyzed from July 1 to December 31, 2019. The primary outcome consisted of factors associated with DWI lesions. Secondary outcomes were poor functional outcome, defined as a modified Rankin score (mRS) of 4 to 6, and mortality, both assessed at 3 months. Mixed-effects logistic regression was used to evaluate the association between exposures and outcomes. Subgroup analyses stratified by hematoma location were performed. After exclusion of 36 patients with missing data on DWI lesions, 1752 patients were included in the analysis (1019 men [58.2%]; mean [SD] age, 60.8 [13.3] years). Diffusion-weighted imaging lesions occurred in 549 patients (31.3%). In mixed-effects regression models, factors associated with DWI lesions included younger age (odds ratio [OR] per year, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.64; 95% CI, 1.17-2.30), admission systolic blood pressure (OR per 10-mm Hg increase, 1.13; 95% CI, 1.08-1.18), baseline hematoma volume (OR per 10-mL increase, 1.12; 95% CI, 1.02-1.22), cerebral microbleeds (OR, 1.85; 95% CI, 1.39-2.46), and leukoaraiosis (OR, 1.59; 95% CI, 1.67-2.17). Diffusion-weighted imaging lesions were independently associated with poor mRS (OR, 1.50; 95% CI, 1.13-2.00), but not with mortality (OR, 1.11; 95% CI, 0.72-1.71). In subgroup analyses, similar factors were associated with DWI lesions in lobar and deep ICH. Diffusion-weighted imaging lesions were associated with poor mRS in deep but not lobar ICH. In a large, heterogeneous cohort of prospectively identified patients with ICH, results were consistent with the hypothesis that DWI lesions represent acute sequelae of chronic cerebral small vessel disease, particularly hypertensive vasculopathy. Diffusion-weighted imaging lesions portend a worse prognosis after ICH, mainly deep hemorrhages.

Injectable Gelatin Hydrogel Suppresses Inflammation and Enhances Functional Recovery in a Mouse Model of Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high morbidity and mortality. However, there is no effective therapy method to improve its clinical outcomes to date. Here we report an injectable gelatin hydrogel that is capable of suppressing inflammation and enhancing functional recovery in a mouse model of ICH. Thiolated gelatin was synthesized by EDC chemistry and then the hydrogel was formed through Michael addition reaction between the thiolated gelatin and polyethylene glycol diacrylate. The hydrogel was characterized by scanning electron microscopy, porosity, rheology, and cytotoxicity before evaluating in a mouse model of ICH. The in vivo study showed that the hydrogel injection into the ICH lesion reduced the neuron loss, attenuated the neurological deficit post-operation, and decreased the activation of the microglia/macrophages and astrocytes. More importantly, the pro-inflammatory M1 microglia/macrophages polarization was suppressed while the anti-inflammatory M2 phenotype was promoted after the hydrogel injection. Besides, the hydrogel injection reduced the release of inflammatory cytokines (IL-1β and TNF-α). Moreover, integrin β1 was confirmed up-regulated around the lesion that is positively correlated with the M2 microglia/macrophages. The related mechanism was proposed and discussed. Taken together, the injectable gelatin hydrogel suppressed the inflammation which might contribute to enhance the functional recovery of the ICH mouse, making it a promising application in the clinic.

Brain MRI Findings in Severe COVID-19: A Retrospective Observational Study.

BackgroundBrain MRI parenchymal signal abnormalities have been in association with SARS-CoV-2.PurposeDescribe the neuroimaging findings (excluding ischemic infarcts) in patients with severe COVID-19 infection.MethodsThis was a retrospective study of patients evaluated from March 23th, 2020 to April 27th, 2020 at 16 hospitals. Inclusion criteria were: (i) positive nasopharyngeal or lower respiratory tract reverse transcriptase-polymerase chain reaction assays; (ii) severe COVID infection defined as requirement for hospitalization and oxygen therapy; (iii) neurologic manifestations; (iv) abnormal brain MRI. Exclusion criteria were patients with missing or non-contributory data regarding brain MRI or a brain MRI showing ischemic infarcts, cerebral venous thrombosis, or chronic lesions unrelated to the current event. Categorical data were compared using Fisher exact test. Quantitative data were compared using Student’s t-test or Wilcoxon test. A p-value lower than 0.05 was considered significant.ResultsThirty men (81%) and 7 women (19%) met inclusion criteria, with a mean age of 61+/- 12 years (range: 8-78). The most common neurologic manifestations were alteration of consciousness (27/37, 73%), pathological wakefulness when the sedation was stopped (15/37, 41%), confusion (12/37, 32%), and agitation (7/37, 19%). The most frequent MRI findings were: signal abnormalities located in the medial temporal lobe in 16/37 (43%, 95% CI 27-59%) patients, non-confluent multifocal white matter hyperintense lesions on FLAIR and diffusion sequences, with variable enhancement, with associated hemorrhagic lesions in 11/37 patients (30%, 95% CI 15-45%), and extensive and isolated white matter microhemorrhages in 9/37 patients (24%, 95% CI 10-38%). A majority of patients (20/37, 54%) had intracerebral hemorrhagic lesions with a more severe clinical presentation: higher admission rate in intensive care units, 20/20 patients, 100% versus 12/17 patients, 71%, p=0.01; development of the acute respiratory distress syndrome in 20/20 patients, 100% versus 11/17 patients, 65%, p=0.005. Only one patient was positive for SARS-CoV-2 RNA in the cerebrospinal fluid.ConclusionPatients with severe COVID-19 and without ischemic infarcts had a wide range of neurologic manifestations that were be associated with abnormal brain MRIs. Eight distinctive neuroradiological patterns were described.