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Keywords = delayed cerebral ischemia

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21 pages, 18314 KB  
Article
High-Resolution Spatiotemporal Mapping of Cerebral Metabolism During Middle-Cerebral-Artery Occlusion/Reperfusion Progression: Preliminary Insights
by Zhongcheng Yuan, Minhao Xu, Mingze Lu, Guancheng Wang, Jingyuan Ma, Sitong Ding, Haoan Wu, Yu Zhang and Ming Ma
Biomolecules 2025, 15(11), 1558; https://doi.org/10.3390/biom15111558 - 6 Nov 2025
Viewed by 278
Abstract
Ischemia–reperfusion is a rapidly evolving cascade that involves a variety of metabolic shifts whose precise timing and sequential order are still poorly understood. Clarifying these dynamics is critical for understanding the core injury trajectory of stroke and for refining time-delimited therapeutic interventions. More [...] Read more.
Ischemia–reperfusion is a rapidly evolving cascade that involves a variety of metabolic shifts whose precise timing and sequential order are still poorly understood. Clarifying these dynamics is critical for understanding the core injury trajectory of stroke and for refining time-delimited therapeutic interventions. More broadly, continuous in situ monitoring of the middle-cerebral-artery occlusion process at the system level has not yet been achieved. Here, we report the first single-subject high-resolution spatiotemporal resolution metabolic maps of the ultra-early phase of ischemic stroke in a rodent model. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging mapped a metabolic abnormality area in the ischemic hemisphere that propagates from the striatum to the cortex. Microdialysis probes were then stereotaxically implanted within this metabolic abnormality area, capturing 10,429 metabolites that resolved into 16 temporally distinct trajectories aligned with probe insertion, ischemic injury, and reperfusion injury. Analysis of specific metabolic pathways mainly revealed that the delayed clearance of metabolic waste (urea and tryptamine) during early reperfusion, the transient attenuation of the citrate-to-oxaloacetate buffering gradient within the TCA cycle, and the accumulation of extracellular branched-chain amino acids all play crucial roles in shaping the injury trajectory. Simultaneously, the depletion of cellular repair mechanisms (pyrimidine synthesis) in the early phase of reperfusion also warrants our attention. These findings provide novel insights into the molecular basis and mechanisms of ischemia–reperfusion and offer a comprehensive resource for further investigation. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Novel Treatments of Stroke)
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19 pages, 2674 KB  
Article
Early Prediction of Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage Using a Machine Learning Model and Interactive Web Application
by Maria Gollwitzer, Vanessa Mazanec, Markus Steindl, Baran Atli, Nico Stroh-Holly, Anna Hauser, Gracija Sardi, Tobias Rossmann, Stefan Aspalter, Philip Rauch, Eva Horner, Michael Sonnberger, Andreas Gruber and Matthias Gmeiner
Brain Sci. 2025, 15(11), 1187; https://doi.org/10.3390/brainsci15111187 - 31 Oct 2025
Viewed by 371
Abstract
Background: Cerebral vasospasm is a frequent and severe complication after aneurysmal subarachnoid hemorrhage (aSAH), often causing delayed cerebral ischemia (DCI) and poor outcomes. Despite progress in neurocritical care, early vasospasm prediction after aSAH remains challenging due to its multifactorial nature but is essential [...] Read more.
Background: Cerebral vasospasm is a frequent and severe complication after aneurysmal subarachnoid hemorrhage (aSAH), often causing delayed cerebral ischemia (DCI) and poor outcomes. Despite progress in neurocritical care, early vasospasm prediction after aSAH remains challenging due to its multifactorial nature but is essential for timely intervention. Methods: We retrospectively analyzed 503 consecutive patients with spontaneous subarachnoid hemorrhage (SAH) treated between 2013 and 2018. Of these, 345 with angiographically confirmed aSAH were included in the primary analysis, and 158 SAH cases in a sensitivity analysis. We extracted demographic, clinical, and imaging parameters including age, sex, Hunt and Hess grade, Fisher scale, aneurysm and treatment features, external ventricular drainage (EVD), and central nervous system (CNS) infection. Seven supervised machine learning (ML) models, including logistic regression and gradient-boosted trees, were trained using nested cross-validation and evaluated by AUC-ROC, AUC-PR, accuracy, precision, sensitivity, specificity, and F1 score. Results: Over half of aSAH patients developed moderate to severe vasospasm. Independent predictors included younger age, higher Hunt and Hess and Fisher grades, and EVD placement (all p < 0.001). Logistic regression achieved the best discrimination (AUC-ROC 0.723), while tree-based models reached higher sensitivity (0.867) at the expense of specificity. Aneurysmal etiology further increased vasospasm risk (OR 4.72). Conclusions: Routinely available clinical and imaging parameters enable reliable ML-based vasospasm prediction after aSAH. Logistic regression provided the best balance between accuracy and interpretability, while tree-based models optimized sensitivity. This web-based, interpretable ML tool—one of the first using routine clinical data—may support the bedside prediction of vasospasm and requires prospective validation. Full article
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15 pages, 2096 KB  
Article
Preliminary Experience with Extradural Clinoidectomy and Lamina Terminalis Fenestration in Anterior Communicating Artery Aneurysm Surgery: A Matched Case–Control Study
by Yasmin Sadigh, Joost W. Schouten, Erik H. P. van Putten, Ruben Dammers and Victor Volovici
J. Clin. Med. 2025, 14(20), 7413; https://doi.org/10.3390/jcm14207413 - 20 Oct 2025
Viewed by 398
Abstract
Background/Objectives: The anterior communicating artery (AcomA) is one of the most common sites of intracranial aneurysms. We aimed to investigate the effect of routine extradural anterior clinoidectomy (EAC) and extradural lamina terminalis fenestration (ELTF) on the incidence of shunt-dependent hydrocephalus (SDH) and [...] Read more.
Background/Objectives: The anterior communicating artery (AcomA) is one of the most common sites of intracranial aneurysms. We aimed to investigate the effect of routine extradural anterior clinoidectomy (EAC) and extradural lamina terminalis fenestration (ELTF) on the incidence of shunt-dependent hydrocephalus (SDH) and gyrus rectus injury in patients undergoing microsurgical clip reconstruction. Methods: This matched case–control study included 15 patients treated with routine EAC/ELTF between July 2023 and June 2025, matched 1:2 to 30 historical controls (2000–2019) by aneurysm size, location, dome-to-neck ratio, and rupture status. The primary outcome was the incidence of SDH. The secondary outcomes included the incidence of gyrus rectus hypodensity/injury and clinical outcomes, as assessed by the modified Rankin Scale (mRS) at discharge and follow-up. Results: Among 15 cases, 6 had ruptured aneurysms, 4 had unruptured aneurysms, and 5 were recanalized post-endovascular treatment. EAC was performed in all cases; ELTF was performed in 83% of ruptured cases. SDH occurred in 33% of ruptured cases versus 90% in controls (p = 0.02). Gyrus rectus hypodensity occurred in 13% of cases vs. 50% of controls (p = 0.01). EAC/ELTF was associated with reduced odds of SDH (OR: 0.06; 95% CI: 0.004–0.80; p = 0.03) and gyrus rectus hypodensity (OR: 0.15; 95% CI: 0.03–0.80; p = 0.03). A poor outcome (mRS >2) was seen in 27% at discharge, improving to 14% at follow-up (with a median of 11 months). Delayed cerebral ischemia occurred in 33% of ruptured cases. Conclusions: Routine EAC/ELTF may reduce SDH and gyrus rectus injury after AComA aneurysm clip reconstruction, particularly in ruptured cases. Prospective multi-center studies are needed to validate these preliminary findings. Full article
(This article belongs to the Section Clinical Neurology)
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11 pages, 238 KB  
Article
Association of Computed Tomography Perfusion Parameters with 90-Day Functional Independence After Endovascular Thrombectomy
by Rahul R. Karamchandani, Liang Wang, Hongmei Yang, Shraddha T. Patel, Karan N. Tarasaria, Dale Strong, Jeremy B. Rhoten, Jonathan D. Clemente, Gary Defilipp and Andrew W. Asimos
J. Clin. Med. 2025, 14(20), 7268; https://doi.org/10.3390/jcm14207268 - 15 Oct 2025
Viewed by 321
Abstract
Background/Objectives: Recently, a novel CT perfusion (CTP) parameter, the compensation index (COMPI; ratio of 4 s delayed perfusion to 6 s delayed perfusion), was shown to correlate more strongly with digital subtraction angiographic collaterals than the cerebral blood volume index (CBVI) and [...] Read more.
Background/Objectives: Recently, a novel CT perfusion (CTP) parameter, the compensation index (COMPI; ratio of 4 s delayed perfusion to 6 s delayed perfusion), was shown to correlate more strongly with digital subtraction angiographic collaterals than the cerebral blood volume index (CBVI) and hypoperfusion intensity ratio. Methods: We retrospectively analyzed all anterior circulation large vessel occlusion patients treated at multiple thrombectomy centers from January to December 2024 to determine the relationship of COMPI and other CTP parameters with the primary outcome: a 90-day modified Rankin Scale (mRS) score of 0–2. Univariable logistic regression was performed to assess the association between each CTP parameter and the primary outcome in the full cohort and in those achieving endovascular reperfusion (modified treatment in cerebral ischemia 2b-3). Multivariable logistic regression was performed to determine factors independently associated with a 90-day mRS score of 0–2. Results: 323 subjects (median age 69 [57–78] years, median of National Institutes of Health Stroke Scale 15 [10–19.5]) were included, of whom 146/302 (48.3%) were functionally independent at 90 days. The COMPI was not associated with the primary outcome in the univariate analysis. CBVI was the only CTP parameter independently associated with a 90-day mRS score of 0–2 in the full cohort (per 0.1-point increase, odds ratio 1.349, 95% confidence interval 1.099–1.655, p = 0.004) and in those achieving reperfusion. Conclusions: The COMPI was not associated with a 90-day mRS score of 0–2. CBVI was associated with independent neurological function in the full cohort and in reperfused patients, supporting its role as a CTP collateral biomarker and potential risk stratification tool before thrombectomy. Full article
(This article belongs to the Special Issue Acute Ischemic Stroke: Current Status and Future Challenges)
19 pages, 1166 KB  
Review
Bidirectional Regulation of Nitric Oxide and Endothelin-1 in Cerebral Vasospasm: Mechanisms and Therapeutic Perspectives
by Katrin Becker and Kaihui Lu
Future Pharmacol. 2025, 5(4), 59; https://doi.org/10.3390/futurepharmacol5040059 - 10 Oct 2025
Cited by 1 | Viewed by 604
Abstract
Cerebral vasospasm (CVS) following a subarachnoid hemorrhage (SAH) is a critical complication driven by imbalances between vasodilators and vasoconstrictors. This review explores the bidirectional interplay between nitric oxide (NO) and endothelin-1 (ET-1) in CVS pathogenesis. NO, a potent vasodilator mainly produced by endothelial [...] Read more.
Cerebral vasospasm (CVS) following a subarachnoid hemorrhage (SAH) is a critical complication driven by imbalances between vasodilators and vasoconstrictors. This review explores the bidirectional interplay between nitric oxide (NO) and endothelin-1 (ET-1) in CVS pathogenesis. NO, a potent vasodilator mainly produced by endothelial and neuronal nitric oxide synthase (eNOS/nNOS) under normal physiological conditions, is scavenged early after SAH by hemoglobin derivatives, leading to microcirculatory dysfunction, pericyte constriction, and impaired neurovascular coupling. Conversely, ET-1 exacerbates vasoconstriction by suppressing NO synthesis via ROS-dependent eNOS uncoupling and Rho-kinase activation. The NO/ET-1 axis further influences delayed cerebral ischemia (DCI) through mechanisms like 20-HETE-mediated cGMP suppression and oxidative stress. Emerging therapies—including NO donors, NOS gene therapy, and ET-1 receptor antagonists—aim to restore this balance. Understanding these pathways offers translational potential for mitigating CVS and improving outcomes post-SAH. Full article
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13 pages, 873 KB  
Article
A Closer Look at Potential Underlying Factors Related to Possible Disparity Between Sexes in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage
by Michael Veldeman, Tobias Philip Schmidt, Katharina Seyfried, Charlotte Weyland, Karlijn Hakvoort, Tobias Rossmann, Laura Victoria Vossen, Anke Hoellig and Catharina Conzen-Dilger
J. Clin. Med. 2025, 14(19), 6856; https://doi.org/10.3390/jcm14196856 - 27 Sep 2025
Viewed by 624
Abstract
Background: Aneurysmal subarachnoid hemorrhage (SAH) is over twice as common in females compared to males, who may also experience more severe hemorrhages and worse outcomes. Differences in SAH severity, susceptibility to delayed cerebral ischemia (DCI), and treatment responsiveness may underlie this disparity. [...] Read more.
Background: Aneurysmal subarachnoid hemorrhage (SAH) is over twice as common in females compared to males, who may also experience more severe hemorrhages and worse outcomes. Differences in SAH severity, susceptibility to delayed cerebral ischemia (DCI), and treatment responsiveness may underlie this disparity. This study evaluated sex-based differences in DCI timing, severity, treatment responsiveness, and outcomes after SAH. Methods: We analyzed 650 consecutive SAH patients admitted to RWTH Aachen University Hospital (2006–2021). SAH severity was assessed via the (World Federation of Neurological Surgeons) WFNS and modified Fisher scales. DCI-related infarction was defined as new infarcts on CT not present initially or within 48 h post-aneurysm occlusion. Endovascular rescue therapy (ERT) was used for treatment-resistant DCI. Outcomes were assessed at discharge and 12 months using the modified Rankin Scale (mRS). Generalized linear mixed-effects models adjusted for confounders. Results: Of 650 patients, 455 (70%) were female. DCI rates did not differ significantly between sexes (41.5% female vs. 36.4% male; p = 0.361). DCI-related infarction occurred in 19.4% of patients, with no sex-based differences in infarct volume (median 115 mL; p = 0.670) or location. ERT use was similar in females (22.4%) and males (23.9%; p = 0.825). Lower age, poor-grade SAH, and higher mFisher scores were associated with DCI and poor outcomes, but sex was not an independent predictor. Conclusions: Female sex was not associated with more severe SAH, a higher incidence of DCI, or more severe DCI manifestations. Although small effect sizes may become statistically significant in larger cohorts, our findings indicate that such effects are unlikely to be driven by differences in DCI timing, infarct size, or treatment responsiveness. Full article
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20 pages, 3439 KB  
Article
A Comparison of Three Perfusion Algorithms in Patients at Risk of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage
by Lea Katharina Falter, Dirk Halama, Cordula Scherlach, Felix Arlt, Kristin Starke, Karl-Titus Hoffmann and Cindy Richter
Diagnostics 2025, 15(17), 2236; https://doi.org/10.3390/diagnostics15172236 - 3 Sep 2025
Viewed by 1102
Abstract
Background/Objectives: Delayed cerebral ischemia (DCI) after an aneurysmal subarachnoid hemorrhage (aSAH) often presents with bilateral vasospasm and cortical spreading depolarizations. Computer tomography perfusion (CTP) is the prevailing screening method for detecting early changes in the cerebral blood flow. Commonly used CTP thresholds [...] Read more.
Background/Objectives: Delayed cerebral ischemia (DCI) after an aneurysmal subarachnoid hemorrhage (aSAH) often presents with bilateral vasospasm and cortical spreading depolarizations. Computer tomography perfusion (CTP) is the prevailing screening method for detecting early changes in the cerebral blood flow. Commonly used CTP thresholds include an rCBF < 30% for the core volume and a Tmax > 6 s for hypoperfused tissue detection in acute ischemic stroke. These stroke algorithm computing thresholds compared to the contralateral hemisphere may or may not apply to detect tissue at risk of DCI. We aimed to quantify the volumetric agreement of three different stroke algorithms compared to the final infarct volumes as the standard. Methods: Furthermore, 123 CTP datasets of 75 patients with aSAH suspicious of DCI were processed using Intellispace Portal (ISP), Cercare Threshold, and Cercare Artificial Intelligence (AI) to calculate the tissue-at-risk (hypoperfused) and non-viable tissue (core) volumes. CT infarct volumes in plain CTs were segmented in the follow-up study by using a 3D slicer. Results: The calculated core volumes corresponded best to the final infarct volumes if DCI-related treatment was performed subsequently. Additional postprocessing improved the calculation of core volumes but overestimated the tissue at risk of hypoperfusion in DCI. Whereas the accuracy of tissue-at-risk prediction accelerated without treatment, underlining the importance of intra-arterial spasmolysis and induced hypertension in the prevention of DCI. Conclusions: Cercare AI and ISP revealed a sensitivity of 100% each, with a serious low specificity of <5% that was independent of treatment. Overall, the Cercare Threshold, applying the commonly used stroke thresholds, performed the best in predicting tissue at risk of hypoperfusion in DCI. Full article
(This article belongs to the Special Issue Optimization of Clinical Imaging: From Diagnosis to Prognosis)
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20 pages, 1819 KB  
Article
Cerebrospinal Fluid MicroRNAs as Early Biomarker Candidates for Predicting Vasospasm Following Aneurysmal Subarachnoid Hemorrhage
by Emre Ozkara, Ozlem Aykac, Ebru Erzurumluoglu Gokalp, Nazli Durmaz Celik, Sara Khadem Ansari, Zehra Uysal Kocabas, Ertugrul Colak, Sinem Kocagil, Zuhtu Ozbek, Oguz Cilingir, Ali Arslantas, Atilla Ozcan Ozdemir and Sevilhan Artan
Genes 2025, 16(9), 1025; https://doi.org/10.3390/genes16091025 - 29 Aug 2025
Viewed by 810
Abstract
Background/Objectives: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently complicated by cerebral vasospasm, a major contributor to delayed cerebral ischemia and poor neurological outcomes. Early prediction remains challenging, and there is a critical need for reliable biomarkers. MicroRNAs (miRNAs) in cerebrospinal fluid (CSF) have [...] Read more.
Background/Objectives: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently complicated by cerebral vasospasm, a major contributor to delayed cerebral ischemia and poor neurological outcomes. Early prediction remains challenging, and there is a critical need for reliable biomarkers. MicroRNAs (miRNAs) in cerebrospinal fluid (CSF) have emerged as promising indicators of acute neuropathological changes. This study aimed to evaluate CSF miRNA expression profiles in patients with aSAH to identify early predictors of vasospasm and improve clinical risk stratification. Methods: We conducted a prospective observational study involving 48 patients (40 patients with aSAH (20 who developed vasospasm, 20 who did not) and 8 healthy controls). A panel of 20 candidate miRNAs was analyzed in CSF samples collected on days 1 and 5 post−hemorrhage using quantitative real−time PCR. Expression differences between groups were assessed, and receiver operating characteristic (ROC) curves were used to evaluate diagnostic performance. Results: Several miRNAs were differentially expressed in patients who developed vasospasm. On day 1, miR−221−3p and miR−183−5p were significantly upregulated (p = 0.014, p = 0.009), while miR−126, miR−29a, and miR−27b−3p were downregulated (p = 0.006, 0.021, 0.028) compared with controls. MiR−126 remained suppressed on day 5 (p = 0.002). These early changes showed high predictive accuracy (e.g., day 1 AUC for miR−221−3p ≈ 0.98, 95% CI 0.83–1.00). Compared with non−vasospasm patients, miR−221−3p was lower (0.12−fold), while miR−9−3p and miR−183−5p were higher (13.4−fold and 2.7−fold, respectively; all p < 0.01). MiR−24 and miR−21−5p correlated with more severe grades and poorer outcomes (p < 0.05). Conclusions: Specific CSF miRNAs—particularly miR−221−3p, miR−9−3p, and miR−183−5p—may serve as early biomarkers for vasospasm, warranting further validation in larger cohorts. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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15 pages, 763 KB  
Article
Immune Checkpoint Dysregulation in Aneurysmal Subarachnoid Hemorrhage: A Prospective Study of sCTLA-4 and sPD-L1 as Biomarkers of Symptomatic Vasospasm
by Reka Varnai, Gábor J. Szebeni, Nikolett Gémes, Attila Schwarcz, Tihamer Molnar, Csaba Olah and Peter Csecsei
Int. J. Mol. Sci. 2025, 26(17), 8228; https://doi.org/10.3390/ijms26178228 - 25 Aug 2025
Viewed by 871
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) is a severe stroke subtype often complicated by symptomatic cerebral vasospasm (sVP), contributing to delayed cerebral ischemia and poor outcomes. Immune dysregulation, particularly T-cell imbalances and pro-inflammatory cytokines, is implicated in vasospasm development. Soluble immune checkpoint proteins—CTLA-4 (sCTLA-4) and [...] Read more.
Aneurysmal subarachnoid hemorrhage (aSAH) is a severe stroke subtype often complicated by symptomatic cerebral vasospasm (sVP), contributing to delayed cerebral ischemia and poor outcomes. Immune dysregulation, particularly T-cell imbalances and pro-inflammatory cytokines, is implicated in vasospasm development. Soluble immune checkpoint proteins—CTLA-4 (sCTLA-4) and PD-L1 (sPD-L1)—regulate immune homeostasis and may serve as biomarkers or modulators of inflammation in aSAH. This prospective cohort study included 179 aSAH patients, divided into sVP+ (n = 48) and sVP− (n = 131), plus 50 healthy controls. Serum sCTLA-4 and sPD-L1 levels were measured on days 1, 5, and 9 post-ictus using Luminex xMAP. Associations with clinical outcomes were analyzed using non-parametric statistics and hierarchical clustering. Both sCTLA-4 and sPD-L1 were significantly elevated in sVP+ patients versus sVP− and controls, increasing over time. sCTLA-4 was significantly higher in sVP+ on days 5 (p = 0.001) and 9 (p < 0.001), and sPD-L1 on days 5 and 9 (both p < 0.001). Clustering revealed distinct expression patterns between sVP+ and sVP− groups. Elevated sCTLA-4 and sPD-L1 levels are associated with sVP after aSAH and may serve as biomarkers for early immune dysfunction, offering insights into potential therapeutic targets. Full article
(This article belongs to the Section Molecular Neurobiology)
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14 pages, 3149 KB  
Article
CSF-Exosomal miRNAs and Delayed Cerebral Ischemia: Insights into Pathophysiology but No Definitive Biomarkers
by Chathathayil M. Shafeeque, Devin W. McBride, Yuanqing Yan, Hussein A. Zeineddine, John P. Hagen, H. Alex Choi, Jude P. Savarraj, Ari Dienel, Spiros L. Blackburn and Peeyush Kumar Thankamani
Biomolecules 2025, 15(8), 1161; https://doi.org/10.3390/biom15081161 - 13 Aug 2025
Viewed by 829
Abstract
Background: Aneurysmal subarachnoid hemorrhage (aSAH) is notoriously known for its high mortality and morbidity. Approximately one-third of the patients who survive aneurysm rupture are reported to develop delayed cerebral ischemia (DCI), which contributes to a poor clinical outcome. Currently, there are no biomarkers [...] Read more.
Background: Aneurysmal subarachnoid hemorrhage (aSAH) is notoriously known for its high mortality and morbidity. Approximately one-third of the patients who survive aneurysm rupture are reported to develop delayed cerebral ischemia (DCI), which contributes to a poor clinical outcome. Currently, there are no biomarkers for identifying which aSAH patients are at risk of developing DCI. We aimed to determine the feasibility of cerebrospinal fluid (CSF) exosomal microRNAs (miRNAs) for predicting DCI post-aSAH. Methods: aSAH patients were prospectively enrolled, and CSF samples were collected at two time points (<24 h and 72 h post-aSAH) from individuals undergoing external ventricular drainage. Exosomal miRNAs were isolated from the CSF for analysis. In the initial group of patients (discovery cohort), an exploratory analysis was conducted using a CSF panel containing 84 miRNAs, assessed by quantitative real-time PCR (RT-qPCR). Based on this analysis, 27 miRNAs were selected for further evaluation in a second group of patients (validation cohort). Among these, 10 miRNAs had previously been reported in SAH-related CSF studies, supporting their relevance for continued investigation. Results: In this study, RT-qPCR analysis of 84 miRNAs in CSF samples from aSAH patients (n = 10 DCI, n = 16 no DCI) and non-aSAH controls (n = 5) identified 9 upregulated and 13 downregulated miRNAs in the DCI group, and 7 upregulated and 18 downregulated miRNAs in the no-DCI group, compared to the controls. When comparing DCI to no-DCI patients, 13 miRNAs were found to be upregulated in the DCI group. Additionally, seven miRNAs showed temporal upregulation in DCI patients between early (<24 h/T1) and later (72 h/T3) time points across both discovery and validation cohorts. However, no miRNAs were uniquely expressed in either DCI or no-DCI groups, limiting their potential as specific biomarkers for DCI. Conclusions: Despite analyses in both the discovery and validation phases, no miRNAs emerged as consistent and reliable biomarkers for distinguishing DCI from no-DCI patients. However, the identified miRNAs are involved in the key KEGG pathways that regulate vascular integrity, neuronal survival, and inflammatory processes central to DCI pathophysiology. These findings highlight the complexity of miRNA regulation following aSAH, as reflected by the variability in differentially expressed miRNAs between cohorts. This variability may be influenced by factors such as limited sample size, patient heterogeneity, individual biological differences, and experimental variability. Comprehensive profiling using larger, well-characterized cohorts, along with rigorous validation, is essential to determine the predictive value and mechanistic significance of candidate miRNAs in DCI. Full article
(This article belongs to the Special Issue Barrier Formation and Homeostasis in the Vertebrate Brain)
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18 pages, 4222 KB  
Systematic Review
The Safety and Efficacy of Glibenclamide in Managing Cerebral Edema After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis
by Majd M. AlBarakat, Rana B. Altawalbeh, Khaled Mohamed Hamam, Ahmed A. Lashin, Ahmed Wadaa-Allah, Ayah J. Alkrarha, Mohamed Abuelazm and James Robert Brašić
Brain Sci. 2025, 15(7), 677; https://doi.org/10.3390/brainsci15070677 - 24 Jun 2025
Viewed by 1433
Abstract
Background/Objectives: We sought to determine if glibenclamide, a sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel blocker, reduces cerebral edema and improves neurological functioning in aneurysmal subarachnoid hemorrhage (aSAH). Methods: Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a [...] Read more.
Background/Objectives: We sought to determine if glibenclamide, a sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel blocker, reduces cerebral edema and improves neurological functioning in aneurysmal subarachnoid hemorrhage (aSAH). Methods: Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a systematic search was conducted in PubMed, Cochrane Library, Web of Science, and SCOPUS for studies evaluating glibenclamide in aSAH patients. Primary outcomes included scores on the modified Rankin Scale (mRS) at discharge and the Subarachnoid Hemorrhage Early Brain Edema Score (SEBES) at ten days post-intervention. Secondary outcomes included adverse events, and safety and efficacy endpoints. Random-effects models were employed for meta-analyses. Results: Three studies utilizing oral glibenclamide (n = 245) met inclusion criteria. Oral glibenclamide demonstrated no significant improvements in mRS scores [MD −0.19 with 95% CI (−2.05, 1.66)] at discharge, [MD 0.06, (−0.60, 0.71)] at 3 months, and [MD 0.4, (−0.67, 0.87)] at 6 months; functional independence [risk ratio (RR) 1.05, (0.81, 1.36)]; independent ambulation [RR 1.07, (0.77, 1.48)]; mortality [RR 0.79, (0.42, 1.50)]; or delayed cerebral ischemia [RR 0.58, (0.31, 1.09]). Hypoglycemia risk was significantly higher in the glibenclamide group [RR 3.92, (1.14, 13.49)]. Conclusions: Oral glibenclamide offers a novel approach to addressing cerebral edema in aSAH but shows limited clinical efficacy in improving functional and neurological outcomes in subtherapeutic doses. Its safety profile is acceptable, though hypoglycemia risk necessitates careful monitoring. Further research is required to optimize dosing, timing of intervention, and patient selection to enhance therapeutic outcomes. By contrast, intravenous administration of therapeutic doses of glibenclamide offers a promising avenue for future studies in the management of aSAH by taking advantage of the favorable pharmacokinetics of this route of administration. Full article
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8 pages, 515 KB  
Article
Attention Test as a Predictive Marker of Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage
by Helaina Lehrer, Ankit Bansal, Nicki Mohammadi, Anmol Mittal, John Liang and Alexandra S. Reynolds
Clin. Transl. Neurosci. 2025, 9(2), 28; https://doi.org/10.3390/ctn9020028 - 18 Jun 2025
Viewed by 805
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) has high morbidity and mortality in part due to vasospasm and delayed cerebral ischemia (DCI). This retrospective, single-center, case–control study evaluates the accuracy of an attention test, counting backwards from twenty to one (TTO), for detecting vasospasm and DCI [...] Read more.
Aneurysmal subarachnoid hemorrhage (aSAH) has high morbidity and mortality in part due to vasospasm and delayed cerebral ischemia (DCI). This retrospective, single-center, case–control study evaluates the accuracy of an attention test, counting backwards from twenty to one (TTO), for detecting vasospasm and DCI in patients admitted to the ICU with aSAH over one year. The odds of symptomatic vasospasm and hospital outcomes were compared between the inattention and control groups. A subgroup analysis included accuracy tests comparing TTO to radiographic vasospasm. Of 44 subjects, 24 had inattention during their ICU course. Compared to controls, the inattention group had increased odds of vasospasm (OR 72 [7.6–677.7], p = 0.001), with significantly longer ICU (5.9 days) and hospital (6.6 days) lengths of stay, and higher odds of discharge to other healthcare facilities (OR 11.4 [2.8 to 46.8], p < 0.001). Errors on TTO testing had a specificity and sensitivity of 78%, and a positive predictive value (PPV) of 91%, for radiographic vasospasm, primarily in the anterior circulation. This study provides support for future prospective research to help elucidate the utility of TTO testing for monitoring and treatment of patients with aSAH. Full article
(This article belongs to the Topic Neurological Updates in Neurocritical Care)
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9 pages, 1026 KB  
Article
Perimesencephalic Subarachnoid Hemorrhage Bleeding Patterns Are Not Always Benign: Prognostic Impact of an Aneurysmal Pathology
by Emily Hoffmann, Công Dùy Bui, David Ventura, Manfred Musigmann, Alexandra Valls Chavarria, Markus Holling, Vivek S. Yedavalli, Jeremy J. Heit, Christian Paul Stracke, Tobias D. Faizy, Hermann Krähling and Burak Han Akkurt
Biomedicines 2025, 13(6), 1444; https://doi.org/10.3390/biomedicines13061444 - 12 Jun 2025
Viewed by 949
Abstract
Background/Objectives: Perimesencephalic subarachnoid hemorrhage (pmSAH) is generally considered to be a benign variant of spontaneous SAH. However, in rare cases, an underlying aneurysm may be present, altering both clinical management and prognosis. The aim of this study was to evaluate the prognostic [...] Read more.
Background/Objectives: Perimesencephalic subarachnoid hemorrhage (pmSAH) is generally considered to be a benign variant of spontaneous SAH. However, in rare cases, an underlying aneurysm may be present, altering both clinical management and prognosis. The aim of this study was to evaluate the prognostic impact of aneurysmal pathology in patients presenting with perimesencephalic hemorrhage, focusing on the occurrence of complications and functional outcomes. Methods: This single-center, retrospective study included 77 patients diagnosed with perimesencephalic hemorrhage between 2012 and 2022. Clinical and radiological data were extracted, including demographics, risk factors, complications (hydrocephalus, vasospasm, and delayed cerebral ischemia (DCI)), and outcome scores (Glasgow Outcome Scale (GOS) and modified Rankin scale (mRS) at discharge). Patients were divided into two groups based on the presence or absence of an aneurysm confirmed through digital subtraction angiography (DSA). Results: Of the 77 patients, 7 (9.1%) were found to have an aneurysm. While rates of complications such as hydrocephalus and DCI were higher in the aneurysm group, these differences did not reach statistical significance. However, patients with aneurysms had significantly worse functional outcomes, with higher mRS and lower GOS scores at discharge. Logistic regression confirmed the presence of aneurysms as an independent factor associated with poor outcomes (OR = 21.6; 95% CI: 1.00−467.3; p = 0.050), while other variables such as age, sex, and World Federation of Neurosurgical Societies (WFNS) score were not statistically significant. ROC analysis showed moderate discriminative power of aneurysm presence for poor outcomes (AUC = 0.72). Conclusions: The presence of an aneurysm, although rare in pmSAH, significantly worsens functional outcomes. These findings highlight the necessity of early and sensitive vascular diagnostics—particularly DSA—to reliably exclude aneurysms. Differentiating between aneurysmal and non-aneurysmal perimesencephalic bleeding is essential not only for clinical decision-making but also for optimizing resource allocation in neurocritical care. Full article
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10 pages, 1305 KB  
Article
Japanese Nationwide Questionnaire Survey on the Treatment and Management of Subarachnoid Hemorrhage Due to Ruptured Cerebral Aneurysm
by Toshikazu Hidaka, Junichiro Ochiai, Yusuke Inoue, Yuichiro Kawamoto, Nobutaka Horie, Yusuke Nishikawa, Mitsuhito Mase, Motohiro Morioka, Jun C. Takahashi, Hiroaki Shimizu and Fusao Ikawa
J. Clin. Med. 2025, 14(12), 4107; https://doi.org/10.3390/jcm14124107 - 10 Jun 2025
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Abstract
Background: Since clazosentan was approved for insurance coverage in Japan, the postoperative management of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has changed as each facility gains experience. Here, we investigate the prevention, treatment, and management of DCI after SAH throughout [...] Read more.
Background: Since clazosentan was approved for insurance coverage in Japan, the postoperative management of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has changed as each facility gains experience. Here, we investigate the prevention, treatment, and management of DCI after SAH throughout Japan in 2023. Methods: In 2024, we conducted an anonymous questionnaire survey—emailed to certified neurosurgeons in hospitals across Japan—regarding management for preventing DCI after aneurysmal SAH. Of them, 78 hospitals responded and were included in this study. These results were compared with the findings of a survey conducted prior to the approval of clazosentan in Japan (2022). Results: The proportion of institutions with a standardized protocol for DCI after aneurysmal SAH at a level of ≥50% was 93.0%. For both craniotomy and endovascular surgery, clazosentan was used most frequently, followed by cilostazol, fasudil, and statins. The most common drug for both direct and endovascular procedures was clazosentan. The predominant reason for discontinuing clazosentan was respiratory complications—such as pulmonary edema—followed by cardiac complications. However, 62.1% of facilities felt that the number of cases wherein clazosentan was discontinued was deceasing. While 77.5% of respondents felt that clazosentan was effective for preventing DCI after aneurysmal SAH, only 49.3% felt that it improved outcomes. Conclusions: Since its approval, clazosentan has been the most common treatment for DCI prevention after aneurysmal SAH. The impression of the effectiveness in preventing DCI and the outcomes of clazosentan have been mixed. As data accumulate, clazosentan use and management protocols will be refined and developed. Full article
(This article belongs to the Special Issue Clinical Updates and Perspectives on Subarachnoid Hemorrhage)
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14 pages, 1321 KB  
Article
Infection Associated with Global Cerebral Edema and Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage
by Daina Kashiwazaki, Kunitaka Maruyama, Saori Hamada, Shusuke Yamamoto, Emiko Hori, Naoki Akioka, Kyo Noguchi and Satoshi Kuroda
J. Clin. Med. 2025, 14(11), 3808; https://doi.org/10.3390/jcm14113808 - 29 May 2025
Viewed by 782
Abstract
Background/Objectives: Patients with aneurysmal subarachnoid hemorrhage (SAH) experience functional impairment due to early brain injury and delayed complications. We aimed to clarify the association between cerebral edema and post-SAH infection. We investigated whether this association leads to delayed cerebral ischemia (DCI) and poor [...] Read more.
Background/Objectives: Patients with aneurysmal subarachnoid hemorrhage (SAH) experience functional impairment due to early brain injury and delayed complications. We aimed to clarify the association between cerebral edema and post-SAH infection. We investigated whether this association leads to delayed cerebral ischemia (DCI) and poor clinical outcomes. Methods: We included 189 patients diagnosed with aneurysmal SAH at our institution. Demographic data and data on World Federation of Neurological Surgeons (WFNS) grade, modified Fisher grade, aneurysm location, treatment methods, global cerebral edema (GCE) assessed according to Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), DCI, infection, duration of hospital stay, and modified Rankin Scale at 3 months were collected. Results: Overall, 88 patients (46.6%) developed GCE ([SEBES] 3 or 4), while 101 patients (53.4%) did not. DCI was observed in 58 (30.7%) patients. Infectious complications occurred in 80 (42.3%) patients. Kaplan–Meier analysis results suggested a higher frequency of DCI among patients with GCE and infection than those without (p < 0.01). Logistic regression analysis identified GCE (p < 0.001, odds ratio [OR] 3.3, 95% confidence interval [CI] [1.3–8.6]), older age (p = 0.02, OR 2.5, 95%CI [1.2–4.9]), higher WFNS grade (p = 0.01, OR 3.9, 95%CI [1.5–9.5]), and mechanical ventilation use (p = 0.04, OR 1.4, 95%CI [1.1–3.9]) as risk factors for infection, while age (p = 0.03, OR 2.3, 95%CI [1.1–4.6]), WFNS grade (p < 0.001, OR 4.5, 95%CI [1.5–9.2]), and GCE + infection (p < 0.001, OR 4.1, 95%CI [1.3–8.9]) were independent risk factors for DCI. Conclusions: GCE–infection linkage is associated with DCI, poor clinical outcomes, and longer hospital stays in patients with aneurysmal SAH. Therefore, the EBI-DCI chain plays an important role in the postsurgical management of these patients. Full article
(This article belongs to the Section Clinical Neurology)
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