Prognosis Of Intracerebral Hemorrhage Research Articles

Unveiling the Hidden Impact: Hematoma Volumes Unravel Circuit Disruptions in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) imposes a significant burden on patients, and the volume of hematoma plays a crucial role in determining the severity and prognosis of ICH. Although significant recent progress has been made in understanding the cellular and molecular mechanisms of surrounding brain tissue in ICH, our current knowledge regarding the precise impact of hematoma volumes on neural circuit damage remains limited. Here, using a viral tracing technique in a mouse model of striatum ICH, two distinct patterns of injury response were observed in upstream connectivity, characterized by both linear and nonlinear trends in specific brain areas. Notably, even low-volume hematomas had a substantial impact on downstream connectivity. Neurons in the striatum-ICH region exhibited heightened excitability, evidenced by electrophysiological measurements and changes in metabolic markers. Furthermore, a strong linear relationship (R2 = 0.91) was observed between hematoma volumes and NFL damage, suggesting a novel biochemical index for evaluating changes in neural injury. RNA sequencing analysis revealed the activation of the MAPK signaling pathway following hematoma, and the addition of MAPK inhibitor revealed a decrease in neuronal circuit damage, leading to alleviation of motor dysfunction in mice. Taken together, our study highlights the crucial role of hematoma size as a determinant of circuit injury in ICH. These findings have important implications for clinical evaluations and treatment strategies, offering opportunities for precise therapeutic approaches to mitigate the detrimental effects of ICH and improve patient outcomes.

Multimodal image fusion-assisted endoscopic evacuation of spontaneous intracerebral hemorrhage

PurposeAlthough traditional craniotomy (TC) surgery has failed to show benefits for the functional outcome of intracerebral hemorrhage (ICH). However, a minimally invasive hematoma removal plan to avoid white matter fiber damage may be a safer and more feasible surgical approach, which may improve the prognosis of ICH. We conducted a historical cohort study on the use of multimodal image fusion-assisted neuroendoscopic surgery (MINS) for the treatment of ICH, and compared its safety and effectiveness with traditional methods. MethodsThis is a historical cohort study involving 241 patients with cerebral hemorrhage. Divided into MINS group and TC group based on surgical methods. Multimodal images (CT skull, CT angiography, and white matter fiber of MRI diffusion-tensor imaging) were fused into 3 dimensional images for preoperative planning and intraoperative guidance of endoscopic hematoma removal in the MINS group. Clinical features, operative efficiency, perioperative complications, and prognoses between 2 groups were compared. Normally distributed data were analyzed using t-test of 2 independent samples, Non-normally distributed data were compared using the Kruskal-Wallis test. Meanwhile categorical data were analyzed via the Chi-square test or Fisher’s exact test. All statistical tests were two-sided, and p < 0.05 was considered statistically significant. ResultsA total of 42 patients with ICH were enrolled, who underwent TC surgery or MINS. Patients who underwent MINS had shorter operative time (p < 0.001), less blood loss (p < 0.001), better hematoma evacuation (p = 0.003), and a shorter stay in the intensive care unit (p = 0.002) than patients who underwent TC. Based on clinical characteristics and analysis of perioperative complications, there is no significant difference between the 2 surgical methods. Modified Rankin scale scores at 180 days were better in the MINS than in the TC group (p = 0.014). ConclusionsCompared with TC for the treatment of ICH, MINS is safer and more efficient in cleaning ICH, which improved the prognosis of the patients. In the future, a larger sample size clinical trial will be needed to evaluate its efficacy.

Utilizing the International Normalized Ratio-Platelet Index for Predicting Hospital Outcomes After Spontaneous Supratentorial Intracerebral Hemorrhage

ObjectiveSpontaneous intracerebral hemorrhage (ICH) poses a public health issue due to its elevated mortality rates. The International Normalized Ratio-platelet index (INR-Plt index) has recently been recognized as a predictive factor for liver disease progression. The potential of applying the INR-Plt index in forecasting ICH prognosis presents an intriguing subject. This study endeavors to examine the correlation between the INR-Plt index and hospital outcomes in patients with spontaneous supratentorial ICH. MethodsA retrospective examination of 283 adult ICH patients was undertaken. The INR-Plt index was computed using the formula: [INR/platelet counts (1000/μL)]×100. The clinical outcomes evaluated consisted of mortality rates and the Modified Rankin Scale (mRS) at discharge. An unfavorable outcome was defined as an mRS score from 4 to 6. ResultsThe study found a significant correlation between the INR-Plt index and hospital mortality (odds ratio: 4.31, 95% CI: 1.07 - 17.31, p = 0.04). There was a 43% rise in mortality risk for every 0.1 unit increase in the INR-Plt index. Kaplan-Meier survival curves illustrated a considerably lower survival rate at discharge for patients with an INR-Plt index > 0.8 (log-rank test: p = 0.047). Regarding unfavorable outcomes, the INR-Plt index was not a significant factor according to logistic regression analyses. ConclusionsThe INR-Plt index is a predictor of hospital mortality in patients with spontaneous supratentorial ICH. A higher INR-Plt index value is associated with an increased risk of mortality, underlining the potential usefulness of this composite index in guiding clinical decision-making and enabling risk stratification.

Serum IL-31 is related to the severity and 3-month prognosis of patients with Intracerebral hemorrhage.

Interleukin (IL)-31/IL-33 axis has been proved to play an important role in the regulation of inflammation, and serum IL-33 was found to be a novel serum prognostic marker of intracerebral hemorrhage (ICH), while the value of serum IL-31 levels on prognosis in patients with ICH remains unknown. The present study was designed to study the value of serum IL-31 levels on prognosis in ICH patients. A total of 200 ICH patients and 50 healthy people were included in this study. We collected clinical data such as demographic data, laboratory data, admission disease scores and medical histories of these participants. We measured serum IL-31 levels using enzyme-linked immunosorbent assay, and assessed the prognosis of ICH patients 3 months after onset by mRS scale, and mRS > 2 was defined as a 3-month poor outcome. The level of IL-31 in ICH patients were significantly higher than that in healthy control people (211.91 ± 61.61 vs 167.64 ± 27.45 pg/mL, P < .001), and levels of IL-31 in ICH patients with 3-month good outcome were significantly lower than that in ICH patients with 3-month poor outcome (196.09 ± 50.84 vs 248.05 ± 41.41 pg/mL, P < .001). Results of correlation analysis suggested that the level of serum IL-31 was positively related to admission NIHSS score (r = 0.627, P < .001), hematoma volume (r = 0.352, P < .001), mRS score (r = 0.515, P < .001), high-density lipoprotein-cholesterol (r = 0.177, P = .012), serum C-reactive protein levels (r = 0.483, P < .001), and serum tumor necrosis factor α levels (r = 0.389, P < .001) in ICH patients, while the level of serum IL-31 was negatively related to the admission GCS score (r = -0.518, P < .001) and triglycerides (r = -0.147, P = .038). Results of multivariate regression analysis shows that serum IL-31 levels are an independent risk factor affecting NIHSS scores (OR = 1.023, 95% CI = 1.010-2.036) and 3-month prognosis (OR = 1.023, 95% CI = 0.982-1.747) in ICH patients. The receiver operating characteristic curve analysis showed that the sensitivity and specificity of serum IL-31 level in evaluating the prognosis of ICH were 85.2% and 76.7%, respectively. A cutoff value of serum IL-31 level > 185.30 pg/mL may indicate a poor prognosis for ICH. Serum IL-31 levels on admission in ICH patients are associated with patient prognosis, and higher serum IL-31 levels are associated with a higher risk of poor prognosis in ICH patients.

The association between high-oxygen saturation and prognosis for intracerebral hemorrhage.

Concerns about the adverse effects of excessive oxygen have grown over the years. This study investigated the relationship between high oxygen saturation and short-term prognosis of patients with spontaneous intracerebral hemorrhage (sICH) after liberal use of oxygen. This retrospective cohort study collected data from the Medical Information Mart for Intensive Care III (MIMIC-III) database (ICU cohort) and a tertiary stroke center (general ward cohort). The data on pulse oximetry-derived oxygen saturation (SpO2) during the first 24 h in ICU and general wards were respectively extracted. Overall, 1117 and 372 patients were included in the ICU and general ward cohort, respectively. Among the patients from the ICU cohort, a spoon-shaped association was observed between minimum SpO2 and the risk of in-hospital mortality (non-linear P<0.0001). In comparison with minimum SpO2 of 93-97%, the minimum SpO2>97% was associated with a significantly higher risk of in-hospital mortality after adjustment for confounders. Sensitivity analysis conducted using propensity score matching did not change this significance. The same spoon-shaped association between minimum SpO2 and the risk of in-hospital mortality was also detected for the general ward cohort. In comparison with the group with 95-97% SpO2, the group with SpO2>97% showed a stronger association with, but non-significant risk for, in-hospital mortality after adjustment for confounders. The time-weighted average SpO2>97% was associated significantly with in-hospital mortality in both cohorts. Higher SpO2 (especially a minimum SpO2>97%) was unrewarding after liberal use of oxygen among patients with sICH and might even be potentially detrimental.

Intracerebral Hemorrhage Leads to Anemia By Disrupting Erythropoiesis and Erythromyeloblastic Islands

Intracerebral hemorrhage (ICH), caused by the rupture of a cerebral vessel and subsequent entry of blood into the brain parenchyma, is a major form of acquired brain injury and contributes a remarkable proportion of stroke-related morbidity and mortality. Due to the few proven effective emergency and preventive treatments, patients who survived suffer varying degrees of poor prognosis that affect their quality of life. There is an urgent need to explore the cellular and molecular basis of the differences in the severity and prognosis of ICH. Anemia is a common manifestation of ICH. However, the mechanisms underlying ICH-induced anemia as we as the correlation between anemia and ICH progression/prognosis remain unclear. In this study, we found that approximately 35.1% (39 of 111) of ICH patients exhibited anemia and that decreased hemoglobin levels were positively associated with higher scores on the National Institutes of Health Stroke Scale, which quantifies the degree of neurological deficit, at admission. Furthermore, patients with decreased hemoglobin levels at admission showed higher modified Rankin scale scores at 3 months, which reflect the global disability of daily living at this time, suggesting that anemia was associated with a more severe progression and poor patient prognosis. To investigate the effects of ICH on bone marrow (BM) erythropoiesis, we conducted experiments in 12-month-old mice with collagenase-induced striatal ICH. Our results showed that ICH caused apparent anemia on day 3, associated with larger hematomas in the striatum and more severe neurologic deficits. We first evaluated the phenotype of hematopoietic progenitors and found that mice suffering ICH exhibited increased granulocyte monocyte progenitors but a significant decrease in common myeloid progenitors and megakaryocyte erythrocyte progenitors compared to control mice, suggesting a reduced source of erythroid progenitors. Further analysis revealed that the colony-forming ability of erythroid progenitors and subsequent terminal differentiation was significantly suppressed after ICH. To assess whether ICH-induced suppression of erythropoiesis is associated with erythromyeloblastic islands (EMBIs), the niche for erythropoiesis/myelopoiesis, we performed ICH using 12-month-old EpoR-tdTomato-Cre mice and found that the number of BM EMBIs and EpoR + macrophages decreased significantly. Moreover, the number and proportion of developing erythroid cells surrounding EMBIs decreased while LY6G + cells representing granulocytes increased prominently, indicating an altered microenvironment, with EMBI favoring granulopoiesis over erythropoiesis after ICH. Studies have shown that inflammation plays a crucial role in secondary brain injury after ICH. We hypothesize that inflammatory cytokines may contribute to the suppression of erythropoiesis observed in ICH mouse models. To test this, we measured inflammatory factors in both peripheral blood and BM fluid using Quantibody Mouse Inflammation Array. In particular, IL-6 concentrations in peripheral blood and BM fluid in ICH mice were significantly higher than controls. Treatment with MR16-1, an IL-6 antagonist, alleviated ICH-induced anemia and improved BM erythropoiesis in ICH mice, as evidenced by increased peripheral red blood cells and hemoglobin levels, elevated numbers of erythroid progenitors and terminal erythroblast. MR16-1 treatment also improved BM EMBI formation and increased EpoR + macrophages. In addition, MR16-1 treatment effectively improved neurologic deficits and reduced brain hematoma after ICH. Administration of recombinant IL-6 to wild-type mice resulted in decreased levels of red blood cells and hemoglobin along with suppression of erythropoiesis in the BM. Collectively, these results suggest that ICH modulates erythropoiesis and erythromyeloblastic islands function to ultimately lead to anemia and reveal a possible therapeutic opportunity to reverse ICH-induced anemia and improve ICH prognosis by targeting IL-6.

Risk factors and a prediction model for the prognosis of intracerebral hemorrhage using cerebral microhemorrhage and clinical factors

BackgroundThis study aimed to identify the risk factors and construct a prediction model for the prognosis of intracerebral hemorrhage (ICH) at discharge, 3 months, and 12 months.MethodsA total of 269 patients with ICH were retrospectively enrolled at our hospital between January 2014 and August 2016. The prognosis of ICH was assessed using the modified Rankin Scale (mRS); an mRS score &amp;gt; 2 was considered a poor outcome. The primary endpoint was the 3-month mRS, whereas the secondary endpoints included the mRS scores at discharge and 12 months, and mortality.ResultsThe Glasgow Coma Scale (GCS), National Institutes of Health (NIH) stroke scale, International Normalized Ratio (INR), blood urea nitrogen (BUN), epencephalon hemorrhage, and primary hematoma volume were significantly associated with a poor mRS score at 3 months. The predictive value of the prediction model based on these factors for a poor mRS score was 87.8%. Furthermore, a poor mRS score at discharge was affected by the GCS, NIH stroke scale, and primary hematoma volume; the constructed model based on these factors had a predictive value of 87.6%. In addition, the GCS, NIH stroke scale, and surgery were significantly related to a poor mRS score at 12 months; the predictive value of the constructed model based on the aforementioned factors for a poor mRS score was 86.5%. Finally, primary hematoma volume is significantly associated with the risk of 12 months mortality.ConclusionsThe study identified risk factors and constructed a prediction model for poor mRS scores and mortality at discharge, 3 and 12 months in patients with ICH. The prediction models for mRS scores showed a relatively high predictive performance.

Role of serum alkaline phosphatase as a potential biomarker of severity and prognosis in intracerebral hemorrhage

ObjectivesAlkaline phosphatase (ALP) catalyzes the hydrolysis of pyrophosphate and facilitates vascular calcification. We aimed at investigating serum ALP levels in intracerebral hemorrhage (ICH) patients and ascertaining its relationship to severity and prognosis. MethodsSerum ALP levels from 148 patients and 148 healthy controls were detected. Glasgow coma scale (GCS) score and hematoma volume at admission were recorded to evaluate hemorrhagic severity. Modified Rankin Scale (mRS) score > 2 at 90 days after onset was judged as a poor prognosis. ResultsSerum ALP levels in patients with ICH were substantially elevated compared with healthy controls, and were significantly related to hematoma volume and GCS score. Serum ALP levels significantly distinguished ICH patients at risk for unfavorable prognosis. Serum ALP levels > 78.5 U/L in ICH patients may indicated a unfavorable prognosis with 69.1 % sensitivity and 83.6 % specificity, and served as an independent predictor for unfavorable prognosis. ConlusionsElevated serum ALP levels were intimately connected with increased severity and 90-day unfavorable prognosis in patients with ICH. Serum ALP could be a potential biomarker for severity and prognosis of ICH.

A Radiomics Model Based on CT Images Combined with Multiple Machine Learning Models to Predict the Prognosis of Spontaneous Intracerebral Hemorrhage

PurposeWe aimed to construct three predictive models, including a clinical model, a radiomics model, and a combined model, to forecast the discharge prognosis of patients with intracerebral hemorrhage on admission. MethodsA retrospective study was conducted, involving a total of 161 patients with intracerebral hemorrhage (ICH). At a ratio of 7:3, 115 of these patients were assigned to the training cohort, and 46 of these patients were assigned to the validation cohort. To produce the radionics signature and pick the features to use in its construction, the least absolute shrinkage and selection operator (LASSO) regression was applied. Five machine models were applied, and the optimal model was chosen to construct the radionics model. A clinical model was constructed using univariate and stepwise analysis to identify independent risk variables for poor outcomes at discharge. A predictive combined model nomogram was generated by integrating the clinical model and radiomics model. The performance of the nomogram was assessed in the training cohort and validated in the validation cohort. Analyses of the receiver operating characteristic curve (ROC), the calibration curve, and the decision curve were performed to assess the performance of the combined model. ResultsThis study encompassed a cohort of 161 individuals diagnosed with intracerebral hemorrhage (ICH), consisting of 110 males and 51 females. Utilizing the modified Rankin Scale (mRS) at discharge, the analysis revealed that 89 patients (55.3%) had a good prognosis, while 72 patients (44.7%) had a poor prognosis. Only 8 out of 1130 radiomics features were selected and used in conjunction with the LR algorithm to develop the radiomics model. Sex, IVH, GCS score, and ICH volume were determined to be independent predictors of poor outcomes at the time of discharge. The AUC values of the combined model, radiomics model, and clinical model were 0.8583, 0.8364, and 0.7579 in the training cohort, and 0.9153, 0.8692, and 0.7114 in the validation cohort, respectively. The combined model nomogram exhibited good calibration and clinical benefit in both the training and validation cohorts. The decision curve analysis (DCA) displays that the combined model obtained the highest net benefit compared to the radiomics model and clinics model in the training cohort. ConclusionThe combined model demonstrates reliability and efficacy in predicting the discharge prognosis of ICH, enabling physicians to perform individualized risk assessments and make optimal choices about patients with ICH.

Early fever in patients with primary intracerebral hemorrhage is associated with worse long-term functional outcomes: a prospective study

BackgroundPrimary intracerebral hemorrhage (ICH) accounts for 85% of ICH cases and is associated with high morbidity and mortality rates. Fever can cause secondary injury after ICH; however, relevant studies have reported inconsistent results regarding the effects of fever on functional outcomes after ICH. This study examined the effects of early fever on the prognosis of ICH, particularly on long-term functional outcomes.MethodsThis prospective study recruited patients with primary ICH at a tertiary medical center between 2019 and 2021. Early fever was defined as a tympanic body temperature of ≥ 38 °C upon admission. Barthel Index (BI) and modified Rankin scale (mRS) were examined at 1 year after ICH. A BI of ≤ 60 or mRS of ≥ 4 was considered as indicating severe disability.ResultsWe included 100 patients, and early fever was significantly associated with less functional independence at 1 year post-ICH, as determined using the mRS (p = 0.048; odds ratio [OR] = 0.23), and with severe functional dependency at 1 year post-ICH, as determined using the BI (p = 0.043; OR = 3) and mRS (p = 0.045; OR = 3). In addition, patients with early fever had a longer length of hospital stay (p = 0.002; 95% confidence interval = 21.80–95.91).ConclusionsFever is common among patients with primary ICH. Our data indicate a significant association between early fever and worse functional outcomes in ICH survivors at 1 year after ICH. Additionally, patients with early fever had a significantly longer length of hospital stay after ICH.

More severe initial manifestations and worse short-term functional outcome of intracerebral hemorrhage in the plateau than in the plain

Intracerebral hemorrhage (ICH) is one of the most devastating forms of stroke. However, studies on ICH at high altitude are insufficient. We aimed to compare the initial manifestations, imaging features and short-term functional outcomes of ICH at different altitudes, and further explore the effect of altitude on the severity and prognosis of ICH. We retrospectively recruited ICH patients from January 2018 to July 2021 from two centers at different altitudes in China. Information regarding to clinical manifestations, neuroimages, and functional outcomes at discharge were collected and analyzed. Association between altitude and initial severity, neuroimages, and short-term prognosis of ICH were also investigated. A total of 724 patients with 400 lowlanders and 324 highlanders were enrolled. Compared with patients from the plain, those at high altitude were characterized by more severe preliminary manifestations (P < 0.0001), larger hematoma volume (P < 0.001) and poorer short-term functional outcome (P < 0.0001). High altitude was independently associated with dependency at discharge (adjusted P = 0.024), in-hospital mortality (adjusted P = 0.049) and gastrointestinal hemorrhage incidence (adjusted P = 0.017). ICH patients from high altitude suffered from more serious initial manifestations and worse short-term functional outcome than lowlanders. Control of blood pressure, oxygen supplementation and inhibition of inflammation may be critical for ICH at high altitude.

Inhibition of BACE1 attenuates microglia-induced neuroinflammation after intracerebral hemorrhage by suppressing STAT3 activation.

Hematoma-induced neuroinflammation is the cause of poor prognosis in intracerebral hemorrhage (ICH); therefore, promoting blood clearance and blocking overactivated inflammation are rational approaches for ICH treatment. β-site amyloid precursor protein (APP) lyase-1 (BACE1) is a key molecule regulating the microglial phenotype transition in neurodegenerative diseases. Therefore, the aim of this study was to investigate the role of BACE1 in microglial phagocytosis and inflammatory features in ICH. Here, we demonstrated the unique advantages of targeting BACE1 in microglia using an autologous blood model and primary microglia hemoglobin stimulation. When BACE1 was inhibited early in ICH, fewer residual hematomas remained, consistent with an increase in genetic features that favor phagocytosis and anti-inflammation. In addition, inhibition of BACE1 enhanced the secretion of anti-inflammatory cytokines and substantially reduced the expression of proinflammatory genes, which was regulated by signal transduction and phosphorylation of activator of transcription 3 (STAT3). Further pharmacological inhibition of STAT3 phosphorylation effectively blocked the proinflammatory and weak phagocytic phenotype of microglia due to BACE1 induction. In summary, BACE1 is the critical molecule regulating the inflammatory and phagocytic phenotypes of microglia after ICH, and targeted inhibition of the BACE1/STAT3 pathway is an important strategy for the future treatment of ICH-induced neurological injury.

Oxytocin Improves Intracerebral Hemorrhage Outcomes by Suppressing Neuronal Pyroptosis and Mitochondrial Fission.

Intracerebral hemorrhage (ICH) causes severe sensorimotor dysfunction and cognitive decline which are aggravated by secondary brain injury, yet there are no effective management to alleviate these outcomes. Pyroptosis is strongly related to neuroinflammation, which plays a crucial role in the pathophysiological processes of secondary brain injury after ICH. OXT (oxytocin), as a pleiotropic neuropeptide, has multiple functions including anti-inflammation and antioxidation. This study aims to investigate the role of OXT in improving ICH outcomes and the underlying mechanisms. C57BL/6 mice were used to establish the ICH model by autologous blood injection. OXT was administered intranasally (0.2 μg/g) after ICH. Combing behavioral tests, Western blot, immunofluorescence staining, electron microscopy, and pharmacological approaches, we evaluated the effect of intranasal OXT application on neurological outcomes after ICH and explored the underlying mechanism. Endogenous OXT level was decreased, whereas OXTR (oxytocin receptor) expression was increased after ICH. OXT treatment improved the short-term and long-term neurological functions and alleviated neuronal pyroptosis and neuroinflammation. In addition, OXT reduced excessive mitochondrial fission and mitochondrial-derived oxidative stress 3 days after ICH. OXT decreased the expression of pyroptotic and proinflammatory factors including NLRP3 (NOD-like receptor protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), GSDMD (gasdermin D), caspase-1, IL (interleukin)-1β, and IL-18 and increased the expression of p-PKA (phospho-protein kinase A) and p-DRP1 (S637; DRP1 [dynamin-related protein 1] phosphorylation at Ser637). OXT-induced neuroprotective effects were blocked by either OXTR inhibitor or PKA inhibitor. Intranasal application of OXT can ameliorate neurological deficits and alleviate neural pyroptosis, inflammation, and excessive mitochondrial fission via OXTR/p-PKA/DRP1 signaling pathway after ICH. Thus, OXT administration may be a potential therapeutic strategy to improve the prognosis of ICH.

Nox4-and Tf/TfR-mediated peroxidation and iron overload exacerbate neuronal ferroptosis after intracerebral hemorrhage: Involvement of EAAT3 dysfunction.

Intracerebral hemorrhage (ICH) induces high mortality and disability. Neuronal death is the principal factor to unfavourable prognosis in ICH. However, the mechanisms underlying this association remain unclear. In this study, we investigated the molecular mechanisms by which neuronal ferroptosis occurs after ICH and whether the use of corresponding modulators can inhibit neuronal death and improve early outcomes in a rat ICH model. Our findings indicated that Nox4 and TF/TfR were upregulated in the perihematomal tissues of ICH rats. Oxidative stress and iron overload induced by Nox4 and TF/TfR promoted neuronal ferroptosis post-ICH. In contrast, application of Nox4-siRNA and the deferoxamine (DFO) attenuated peroxidation and iron deposition in the hemorrhagic brain, alleviated neuronal ferroptosis, and improved sensorimotor function in ICH rats. Additionally, our findings indicated that the post-ICH neuronal reduced glutathione (GSH) depletion were not related to dysfunctional glutamine delivery in astrocytes but rather to downregulation of EAAT3 due to lipid peroxidation-induced dysfunction in the neuronal membrane. These findings indicate that ferroptosis is involved in neuronal death in model rats with collagenase-induced ICH. Oxidative stress and iron overload induced by Nox4 and TF/TfR exacerbate ferroptosis after ICH, while Nox4 downregulation and iron chelation exert neuroprotective effects. The present results highlight the cysteine importer EAAT3 as a potential biomarker of ferroptosis and provide insight into the neuronal death process that occurs following ICH, which may aid in the development of translational treatment strategies for ICH.

Systemic inflammation and immune index predicting outcomes in patients with intracerebral hemorrhage.

Recent evidence has suggested that systemic inflammatory and immune index (SIRI) and systematic inflammation index (SII) could predict prognosis in stroke patients. This study aimed to determine the effects of SIRI and SII on predicting in-hospital infections and unfavorable outcomes in patients with acute intracerebral hemorrhage (ICH). We used the data from a prospective and registry-based study recruiting ICH patients between January 2014 and September 2016 in a single comprehensive stroke center. All patients were stratified by quartiles of SIRI or SII. Logistic regression analysis was used to estimate the associations with follow-up prognosis. The receiver operating characteristics (ROC) curves were performed to examine the predictive utility of these indexes for infections and prognosis. Six hundred and forty spontaneous ICH patients were enrolled in this study. Compared with the lowest quartile (Q1), SIRI or SII values both showed positive correlations with increased risks for poor 1-month outcomes (adjusted ORs in Q4 was 2.162 [95% CI: 1.240-3.772] for SIRI, 1.797 [95% CI: 1.052-3.070] for SII). Additionally, a higher level of SIRI, but not SII, was independently associated with a higher risk of infections and an unfavorable 3-month prognosis. The C-statistic for the combined SIRI and ICH score was higher than SIRI or ICH score alone for predicting in-hospital infections and poor outcomes. Elevated SIRI values were associated with in-hospital infections and poor functional outcomes. It may provide a new biomarker for ICH prognosis prediction, especially in the acute stage.

Association of sex and age with in-hospital mortality and complications of patients with intracerebral hemorrhage: A study from the Chinese Stroke Center Alliance.

The impact of sex and age on prognosis in patients with intracerebral hemorrhage (ICH) in the Chinese population remains unclear. Our study aimed to investigate the relationship between sex and age of Chinese ICH patients and adverse prognosis. We used the Chinese Stroke Center Alliance database with in-hospital mortality as the primary outcome and hospital complications as the secondary outcome. Patients were divided into four groups by sex and age. Logistic regression analyses were performed to assess the association between sex and age and the prognosis of ICH patients. We enrolled 60,911 ICH patients, including 22,284 young and middle-aged males, 15,651 older males, 11,948 young and middle-aged females, and 11,028 older females. After adjusting for variables, older male patients had a higher mortality rate (OR=1.21, 95% CI 1.01-1.45), combined with more frequent hematoma expansion (OR=1.14, 95% CI 1.03-1.26), pneumonia (OR=1.91, 95% CI 1.81-2.03), and hydrocephalus (OR=1.28, 95% CI 1.04-1.59). Young and middle-aged female patients had a lower mortality rate (OR=0.74, 95% CI 0.58-0.95) and less frequent combined pneumonia (OR=0.81, 95% CI 0.75-0.87). In-hospital mortality was not significantly different in older females compared with young and middle-aged males, but the odds of deep vein thrombosis, swallowing disorders, urinary tract infections, and gastrointestinal bleeding were significantly higher. Among young and middle-aged patients, females are related to a lower in-hospital mortality rate from ICH. Older patients are at an increased risk of ICH complications, with higher in-hospital mortality in older men.

Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke.

Promoting microglial/macrophage (M/Mφ) phagocytosis accelerates hematoma clearance and improves the prognosis of intracerebral hemorrhagic stroke (ICH). Cation channels such as Piezo1 modulate bacterial clearance by regulating M/Mφ. Whether LRRC8A, an anion channel, affects M/Mφ erythrophagocytosis and functional recovery after ICH was investigated here. We found that LRRC8A is highly expressed on M/Mφ in the perihematomal region of ICH mice. Conditional knockout of Lrrc8a in M/Mφ or treatment with an LRRC8A channel blocker accelerated hematoma clearance, reduced neuronal death, and improved functional recovery after ICH. Mechanistically, the LRRC8A channel inhibition promoted M/Mφ phagocytosis by activating AMP-activated protein kinase (AMPK), thereby inducing nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2) and increasing Cd36 transcription. Our findings illuminate the regulation of M/Mφ phagocytosis by the LRRC8A channel via the AMPK-Nrf2-CD36 pathway after ICH, suggesting that LRRC8A is a potential target for hematoma clearance in ICH treatment.

Slightly Elevated Lymphocyte to Monocyte Ratio Predicting Favorable Outcomes in Patients with Spontaneous Intracerebral Hemorrhage.

This study was designed to determine the association between admission lymphocyte to monocyte ratio (LMR) values and clinical outcomes in patients with spontaneous intracerebral hemorrhage (ICH). We used a prospective and registry-based database, and ICH patients were consecutively recruited in Beijing Tiantan Hospital between January 2014 and September 2016. All participants were stratified by quartiles of the LMR. Univariable and multivariable logistic regression analyses were plotted to evaluate the association between LMR levels and functional outcomes. Kaplan-Meier survival curves and Cox regression analysis were also performed to examine the relevance between different LMR quartiles and case fatality at follow-up. Six hundred and forty patients with spontaneous ICH were finally included in this study. Compared with the patients with LMR values in quartile 1 (Q1), slightly elevated LMR values showed a negative correlation with risks of poor short-term outcomes (adjusted ORs in Q2 were 0.572 [95% CI: 0.338-0.968] at 1 month, 0.515 [95% CI: 0.305-0.871] at 3 months). Patients with LMR values in Q1 had the highest cumulative death rate. A slightly elevated LMR was also independently relevant to a deduced mortality rate compared to that in Q1 (adjusted HRs in Q2 were 0.471 [95% CI: 0.274-0.809] at 1 month, 0.474 [95% CI: 0.283-0.793] at 3 months, 0.575 [95% CI: 0.361-0.917] at 1 year). Additionally, a higher LMR value was associated with a lower risk of in-hospital infections. This study suggests that a lower LMR value is associated with higher risks of in-hospital infections, poor functional outcomes, and follow-up mortality in patients with ICH. However, a slightly elevated LMR value, especially in Q2, relates to a favorable prognosis, which may reflect an inner balance between inflammation and immunodepression and thus provides a promising marker for predicting ICH prognosis.

Ozanimod-Dependent Activation of SIRT3/NF-κB/AIM2 Pathway Attenuates Secondary Injury After Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is characterized by poor prognosis and high mortality rates. To date, satisfactory therapeutic approaches for ICH remain limited, so it is urgently needed to develop a safer and more effective prescription. Secondary inflammatory response has been acknowledged as an aggravating factor to neurological deterioration after ICH. As a component of inflammasome sensors, absent in melanoma 2 (AIM2) plays an important role in the neuroinflammation process. Here, ozanimod, a novel selective sphingosine 1-phosphate receptor modulator, has gained much attention, which alleviates the resultant neuroinflammation and improves functional recovery derived from ICH. In this study, ozanimod improved neurological functions of ICH mice via reduction of hematoma size. Furthermore, both microglial and AIM2 inflammasome activations were reversed by ozanimod, which are confirmed by the downregulation of related inflammatory proteins and cytokines (IL-1β, IL-6, and TNF-α), coupled with the upregulation of SIRT3, by leveraging the Western blot and enzyme-linked immunosorbent assay. Additionally, we find that ozanimod decreases nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression. Notably, in vitro cell experiments induced by lipopolysaccharide confirms that the anti-inflammatory effect of ozanimod could be abolished by the SIRT3 inhibitor. In conclusion, these results indicate that ozanimod mitigates ICH-induced secondary inflammatory responses by modulating AIM2 inflammasome mediated by SIRT3/NF-κB/AIM2 pathway. This demonstrates ozanimod orchestrates ICH-induced neuroinflammation and could be a targeted therapy for improving prognosis of ICH.

Therapeutic strategies for intracerebral hemorrhage.

Stroke is the second highest cause of death globally, with an increasing incidence in developing countries. Intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes. ICH is associated with poor neurological outcomes and high mortality due to the combination of primary and secondary injury. Fortunately, experimental therapies are available that may improve functional outcomes in patients with ICH. These therapies targeting secondary brain injury have attracted substantial attention in their translational potential. Here, we summarize recent advances in therapeutic strategies and directions for ICH and discuss the barriers and issues that need to be overcome to improve ICH prognosis.