Occurrence Of Cerebral Vasospasm Research Articles

Systemic C-Reactive Protein Predicts Cerebral Vasospasm and Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Retrospective Observational Study

Aneurysmal subarachnoid hemorrhage (aSAH) is often complicated by cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI), which significantly impact patient outcomes. The study aimed to investigate the predictive value of systemic serum biomarker levels for CVS and DCI following aSAH. We retrospectively analyzed data for 450 aSAH patients admitted to University Hospital Düsseldorf between January 2011 and October 2021. Serum biomarkers were measured on admission. The occurrence of CVS and DCI was assessed based on clinical and radiological criteria. Multivariate logistic regression analysis was performed to determine the independent association of serum biomarkers with CVS and DCI. We compared the predictive values of various models using the area under the receiver operating characteristic curve. Of the 450 patients, 126 (28.0%) developed CVS, 123 (27.3%) developed DCI, and 62 (13.8%) developed co-occurring CVS and DCI. Patients with CVS, DCI, or both had significantly higher admission C-reactive protein (CRP) levels than those without these complications (P<0.001). Elevated CRP levels were independently associated with an increased risk of CVS, DCI, and co-occurring CVS and DCI (P<0.05). CRP demonstrated a higher predictive value for CVS (area under the curve [AUC]: 0.811) and co-occurring CVS and DCI (AUC: 0.802) compared to DCI alone (AUC: 0.690). Our findings suggest that admission systemic CRP levels can serve as a more valuable predictor for developing CVS than DCI following aSAH. Incorporating CRP into clinical assessments may aid in risk stratification and early intervention strategies for patients at high risk of these complications.

Impact of Early Out-of-Bed Mobilization on Functional Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study

Effects of early mobilization are not well documented in patients with aneurysmal subarachnoid hemorrhage (aSAH). Only a few studies have investigated it through progressive mobilization protocols and suggested that it is safe and feasible. This study aimed to determine the impact of early out-of-bed mobilization (EOM) on 3-month functional outcome and cerebral vasospasm (CVS) occurrence in patients with aSAH. A retrospective review of consecutive patients admitted to the intensive care unit with a diagnosis of aSAH was performed. EOM was defined as out-of-bed (OOB) mobilization performed before or on day 4 after aSAH onset. The primary outcome was 3-month functional independence (i.e., a modified Rankin Scale below 3) and the occurrence of CVS. A total of 179 patients with aSAH met the inclusion criteria. Thirty-one patients constituted the EOM group, and 148 patients were in the delayed out-of-bed mobilization group. Functional independence was more frequent in the EOM group than in the delayed out-of-bed mobilization group (n= 26 [84%] vs. n= 83 [56%], P= 0.004). In a multivariable analysis, EOM was an independent predictor of functional independence (adjusted odds ratio=3.11; 95% confidence interval, 1.11-10.36; P < 0.05). The delay between bleeding and first OOB mobilization was also identified as an independent risk factor for the occurrence of CVS (adjusted odds ratio=1.12; 95% confidence interval=1.06-1.18, P < 0.001). EOM was independently associated with favorable functional outcome after aSAH. The delay between bleeding and OOB mobilization was an independent risk factor for reduced functional independence and CVS occurrence. Prospective randomized trials are necessary to confirm these results and improve clinical practice.

Leukocytosis and C-Reactive Protein May Predict Development of Secondary Cerebral Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage.

Background and Objectives: Secondary cerebral vasospasm (CV) with subsequent delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains an unpredictable pathology. The aim of this retrospective study was to investigate the association between inflammatory parameters, white blood cell (WBC) count, and C-reactive protein plasma levels (CRP) and the occurrence of secondary CV in patients with aSAH. Materials and Methods: The medical records of 201 Intensive Care Unit patients in Riga East University Hospital with aSAH were retrospectively reviewed in a 24-month period. WBC count and CRP values were observed at admission to the hospital and on the third day. According to the inclusion criteria, 117 (48 males) participants were enrolled for further analysis, with average age of 56 ± 15 years (mean ± SD). In total, secondary CV was diagnosed in 21.4% of cases, and DCI in 22.4% of cases. The patients were classified into three groups: SAH-CV group (n = 25), SAH-DCI group (n = 12), and SAH or control group (n = 80), for comparative analysis. Results: We found that SAH-CV patients demonstrated notably higher inflammatory parameters compared to controls: WBC 13.2 ± 3.3 × 109/L vs. 11.2 ± 3.7 × 109/L; p = 0.01 and CRP median 9.3 mg/L vs. 1.9 mg/L; p < 0.001, respectively. We found that the odds of developing CV increased by 5% for each CRP increase of 1 mg/L at admission (OR, 1.05; CI, 1.014–1.087; p = 0.006). Concomitantly, the odds increased by 16% for every rise in WBC count of 1 × 109/L (OR, 1.16; CI, 1.02–1.32; p = 0.02). WBC count was associated with the occurrence of CV with 96% sensitivity and 40% specificity, with a cut off level of 10.015 × 109/L and AUC 0.683; p = 0.006. CRP displayed 54% sensitivity and 90% specificity with a cut off value of 8.9 mg/L and AUC 0.751; p < 0.001. Moreover, higher values of inflammatory parameters at admission correlated with a longer stay in ICU (r = 0.3, p = 0.002 for WBC count and r = 0.305, p = 0.002 for CRP values), and poor outcome (death) was significantly associated with higher CRP values at admission and on the third day (16.1. vs. 2.2. and 57.4. vs. 11.1, p < 0.001, respectively). Higher mortality was detected in SAH-CV patients (32%) compared to controls (6.3%; p < 0.001). Conclusions: Inflammatory parameters such as WBC count and CRP values at admission might be helpful to predict the development of secondary CV.

Meta-analysis of associations of genetic polymorphisms with cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are among the most hazardous complications of aneurysmal subarachnoid hemorrhage (aSAH). Genetic factors are thought to play a significant role in the development of both complications. To perform a comprehensive meta-analysis of studies that study the association between different genetic polymorphisms and development of DCI and/or CV. We searched MEDLINE and Science Direct databases on May 29, 2021, using iterations of the keywords "subarachnoid hemorrhage", "vasospasm", "delayed cerebral ischemia", and "gene". After duplicates were removed, the two reviewers screened the titles of the articles and abstracts independently. A random-effect model was used to calculate the relative risk with 95% CI; a fixed-effect model was additionally explored. We pooled data from 16 articles that reported an association between eNOS, apolipoprotein E4 (ApoE4), haptoglobin (Hp), or ryanodine-1 (RYR-1) and CV, DCI, or both. Presence of Hp 2-2 was associated both with CV (RR 2.10, 95% CI 1.33-3.31, p = 0.0014) and DCI (RR 1.57, 95%CI 1.06-2.34, p = 0.026). ApoE4 allele had a borderline association with CV (RR 1.48, 95%CI 0.99-2.21, p = 0.054). Our meta-analysis supports the association between the presence of the Hp2-2 allele and the occurrence of CV and DCI after aSAH. Further studies investigating this association are needed to reinforce this finding.

Nimodipine reduces delayed cerebral vasospasm after intracranial tumour surgery: A Retrospective Study.

Cerebral vasospasm (CVS) is a frequent and serious neurosurgical complication, without sufficient therapy. This retrospective study was performed to analyze if nimodipine can improve prognosis and reduce ischaemia secondary to delayed CVS after intracranial tumour surgery. A retrospective review was performed over the years 2011 to 2012 for patients with an anterior cranial fossa tumour and underwent intracranial tumour surgery. The surgical field was soaked with nimodipine solution or normal saline. Transcranial Doppler ultrasonography was used to measure velocity in the middle cerebral artery (MCA) and the distal extracranial internal carotid artery (eICA). Follow-up was performed using the Glasgow Outcome Scale (GOS) after discharge. There were 94 patients that met the inclusion criteria. They included 50males and 44 females, with a mean age of 49.6years. In the nimodipine group, CVS occurred in 13 patients; 9 patients had CVS between 4 and 7days, and 4had CVS between 8 and 14days. In the normal saline group, 19 patients had CVS, 3 presented with CVS within 3days, 11 between 4-7days and 5 between 8-14days. A significant difference in the occurrence of CVS was observed between the two groups. Preoperative and postoperative the MCA velocities were compared, revealing a significant change in the normal saline group but not in the nimodipine group. Nimodipine markedly improves prognosis and significantly reduces ischaemia secondary to delayed CVS after intracranial tumour surgery, as well as the risks of mortality and morbidity.

Statins Improve Clinical Outcome After Non-aneurysmal Subarachnoid Hemorrhage: A Translational Insight From a Systematic Review of Experimental Studies

The efficacy of statin-treatment in aneurysmal subarachnoid hemorrhage (SAH) remains controversial. We aimed to investigate the effects of statin-treatment in non-aneurysmal (na)SAH in accordance with animal research data illustrating the pathophysiology of naSAH. We systematically searched PubMed using PRISMA-guidelines and selected experimental studies assessing the statin-effect on SAH. Detecting the accordance of the applied experimental models with the pathophysiology of naSAH, we analyzed our institutional database of naSAH patients between 1999 and 2018, regarding the effect of statin treatment in these patients and creating a translational concept. Patient characteristics such as statin-treatment (simvastatin 40 mg/d), the occurrence of cerebral vasospasm (CVS), delayed infarction (DI), delayed cerebral ischemia (DCI), and clinical outcome were recorded. In our systematic review of experimental studies, we found 13 studies among 18 titles using blood-injection-animal-models to assess the statin-effect in accordance with the pathophysiology of naSAH. All selected studies differ on study-setting concerning drug-administration, evaluation methods, and neurological tests. Patients from the Back to Bedside project, including 293 naSAH-patients and 51 patients with simvastatin-treatment, were recruited for this analysis. Patients under treatment were affected by a significantly lower risk of CVS (p < 0.01; OR 3.7), DI (p < 0.05; OR 2.6), and DCI (p < 0.05; OR 3). Furthermore, there was a significant association between simvastatin-treatment and favorable-outcome (p < 0.05; OR 3). However, dividing patients with statin-treatment in pre-SAH (n = 31) and post-SAH (n = 20) treatment groups, we only detected a tenuously significant higher chance for a favorable outcome (p < 0.05; OR 0.05) in the small group of 20 patients with statin post-SAH treatment. Using a multivariate-analysis, we detected female gender (55%; p < 0.001; OR 4.9), Hunt&Hess ≤III at admission (p < 0.002; OR 4), no anticoagulant-therapy (p < 0.0001; OR 0.16), and statin-treatment (p < 0.0001; OR 24.2) as the main factors improving the clinical outcome. In conclusion, we detected a significantly lower risk for CVS, DCI, and DI in naSAH patients under statin treatment. Additionally, a significant association between statin treatment and favorable outcome 6 months after naSAH onset could be confirmed. Nevertheless, unified animal experiments should be considered to create the basis for developing new therapeutic schemes.

Activation of Platelets and Occurrence of Cerebral Vasospasm and Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage in &#x0D; a Prospective Pilot-Trial

Aneurysmal subarachnoid hemorrhage (SAH) often leads to poor outcome. The aim of the study was to assess platelet function in patients after SAH. In this prospective observational study in patients suffering from SAH, platelet count and aggregability were assessed by multiple electrode aggregometry (MEA) over 14 days. In 12 of 18 patients, cerebral vasospasms (CVS) were diagnosed; of those, five developed delayed cerebral ischemia (DCI). We observed a significant increase in the platelet count compared to baseline from day 8 onwards (p < 0.037) and, in patients with CVS and DCI, a significant difference in outcome classified by the mRS (p = 0.047). Repeated measures ANOVA determined no differences in platelet aggregability in patients with or without CVS/DCI. Besides an increase in platelet count, we detected no increase in platelet aggregability. Nevertheless, patients after SAH may have increased platelet aggregability, which is not reflected by MEA.

Assessment of two prophylactic fluid strategies in aneurysmal subarachnoid hemorrhage: A randomized trial.

ObjectiveTo compare the effect of two prophylactic euvolemic fluid strategy regimens on the incidence of cerebral vasospasm and clinical outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH).MethodsNinety-six patients with a basal intravenous intake of 15 mL/kg/day of Ringer’s lactate solution were included, and an additional 15 to 50 mL/kg/day Ringer’s lactate (RL-group) or hydroxyethyl starch 130/0.4 solution (HES-group) was administered to maintain the targeted mean arterial pressure. The primary end point was the occurrence of cerebral vasospasm during the first 14 days. The secondary end points were case fatality, Barthel’s index, and Glasgow Outcome Scores (GOS) at 30 days after SAH.ResultsCerebral vasospasm developed in 42 patients (43.7%), and nine of these events were severe. The vasospasm rate among the RL- and HES-based groups was 25/48 and 17/48, respectively. For the secondary endpoint, four patients (4%) died by the end of follow-up (two in each group). Unfavorable outcome cases were not different in the RL and HES groups (9 vs. 14, respectively). There was no difference between the Barthel’s scores at 30 days between the two groups.ConclusionsUsing starches in a prophylactic treatment strategy in aneurysmal SAH in not supported by the study.The trial was registered at Clinicaltrials.gov under the number NCT02064075

Small vessel disease in patients with subarachnoid hemorrhage: Prevalence and associations with vasospasm occurrence, severity and clinical outcomes

Investigating the associations between cerebral small vessel disease (cSVD) burden and cerebral vasospasm (CVS), delayed cerebral ischemia (DCI) and clinical outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH). Consecutive aSAH patients with initial (<7 days after onset) and 3-month follow-up brain magnetic resonance imaging (MRI) and clinical evaluation at 6 months were included. The cSVD burden score was built using MRI criteria. CVS was defined according to transcranial Doppler examination and computed tomography (CT) or digital subtraction angiography. DCI was defined by the appearance of hyperintense fluid-attenuated inversion recovery lesions, with territorial or cortico-subcortical distribution, between initial MRI and 3-month MRI. The modified Rankin scale of ≤2 at 6 months was considered a favorable outcome. Using univariate and multivariable analyses, we investigated the associations between cSVD and CVS, DCI and clinical outcome. A total of 113 patients were included in the study sample (median age 49.1 years (IQR 42.1-60.8), 70/113 females). The burden of cSVD was mild with a median of 0 (IQR 0-1). When comparing patients with no/mild versus those with moderate/severe cSVD burden, we did not find a univariable difference regarding vasospasm occurrence (60% versus 46.1%, p = 0.54), DCI (20.2% versus 23%, p = 0.66) or favorable outcome at 3 months (94% versus 83.3%, p = 0.20). There was a univariable trend towards more frequent favorable outcome in patients with no/milde white matter hyperintensities versus those with moderate/severe white matter hyperintensities (92% versus 85%, p = 0.09). In multivariable models, cSVD markers were not associated with CVS occurrence and severity, DCI or clinical outcome. In patients with mild aSAH, the burden of cSVD as assessed by MRI is minimal and is not associated with CVS, DCI or clinical outcome.

Temporal profile of serum mitochondrial DNA (mtDNA) in patients with aneurysmal subarachnoid hemorrhage (aSAH)

Aneurysmal subarachnoid hemorrhage (aSAH) is a highly complex disease. Majority of aSAH survivors confront post-SAH complications including cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) that mainly influence the clinical outcome. Tissue damage during early brain injury may lead to release of damage associated molecular pattern molecules (DAMPs) that may initiate and sustain inflammation during the course of aSAH through activation of pattern recognition receptors. Mitochondrial DNA (mtDNA) due to unmethylated CpG motifs acts as a DAMP via binding to toll-like receptor-9. The aim of this study was to investigate the cell free circulating mtDNA in the systemic circulation of aSAH patients and its association with post-SAH complications and clinical outcome.The DNA was extracted from the serum of 80 aSAH patients at days 1, 3, 5, 7, 9, 11, 13 and from 18 healthy controls. Three representative mitochondrial gene fragments including Cytochrome B (CytB), D-Loop and Cytochrome c oxidase subunit-1 (COX-1) were quantified using a Taqman-probes based qPCR. Levels of mtDNA were quantified from standard curves generated using mtDNA extracted from HepG2 cell mitochondria. Clinical outcome of the patients was assessed by Glasgow outcome scale (GOS) and modified Rankin scale (mRS). Clinical data and post-SAH complications were recorded from patient's record file.Serum D-Loop and COX-1 were significantly elevated early after aSAH and remained high over first 2 weeks. CytB levels were however, initially unchanged but elevated later at day 7 as compared to healthy controls. Cumulative levels measured over two weeks showed significant correlations with post-SAH complications including a negative correlation of D-Loop with pneumonia infection, hydrocephalus and occurrence of epilepsy, a positive correlation of Cyt B with occurrence of CVS and a negative correlation of COX-1 with occurrence of systemic infections and seizures. Cumulative D-Loop values negatively correlated with clinical outcome. Our data suggest that mtDNA may directly or indirectly influence post-SAH complications and clinical outcome.

Activation of Cytotoxic Natural Killer Cells After Aneurysmal Subarachnoid Hemorrhage.

Cell-mediated inflammation is critical in the development of cerebrovascular complications after aneurysmal subarachnoid hemorrhage. We analyzed the course for activated CD16brightCD56dim cytotoxic natural killer (NK) cells in cerebrospinal fluid of 15 patients. Patients were classified by occurrence of cerebral vasospasm (CV) and delayed cerebral ischemia. NK were monitored by flow cytometry between day 1 and 14 after hemorrhage. Twelve patients (80%) developed CV with a mean day of detection at 3.9 ± 1.6. In those patients, cell count for NK increased from 1.40 ± 1.42 cells/μL on day 1 to a peak of 11.66 ± 11.56 cells/μL on day 6.1 ± 2.9 (P=0.001). An increase of mean cerebral blood flow velocity in transcranial Doppler from 71.33 ± 12.93 cm/second to 166.20 ± 20.19 cm/second (P < 0.01) and an increase in number of vascular axes affected by CV was detected (P<0.01). In patients with grade 3 CV (n= 4, 33.3%), activated NK counts were significantly higher than in patients who did not have CV (23.18 ± 13.92 cells/μL vs. 0.02 ± 0.01 cells/μL; P= 0.029). NK counts were significantly different between patients with grade 1 and grade 3 CV (P= 0.04). Patients who did not have CV who showed low NK counts achieved better functional outcome (GlasgowOutcome Scale [GOS] score, 4.6 ± 0.6) at discharge than did patients with CV grade 2 (GOS score, 3.3± 0.5) and CV grade 3 (GOS score, 2.3 ± 0.5) who showed increased NK cell counts (CV grade 0 vs. CV grade 2, P= 0.048; CV grade 0 vs. CV grade 3, P= 0.001). Activated CD16brightCD56dim cytotoxic NKCSF cell counts showed a mean maximum (14.15 ± 12.21 cells/μL) when delayed cerebral ischemia occurred. The increase of activated CD16brightCD56dim cytotoxic NK cells in cerebrospinal fluid after aneurysmal subarachnoid hemorrhage suggests an increased risk of CV and delayed cerebral ischemia.

ω-3 Fatty Acids Ethyl Esters Suppress Cerebral Vasospasm and Improve Clinical Outcome Following Aneurysmal Subarachnoid Hemorrhage.

Occurrence of cerebral vasospasm after onset of aneurysmal subarachnoid hemorrhage (SAH) is a critical factor determining clinical prognosis. Eicosapentaenoic acid and docosahexaenoic acid, both ω-3 fatty acids (ω-3FA), can suppress cerebral vasospasm, and docosahexaenoic acid can relax vessel vasoconstriction and have neuroprotective effects. We investigated whether administration of ω-3FA prevented cerebral vasospasm occurrence and improved clinical outcomes after aneurysmal SAH. From 2012 to 2015, 100 consecutive patients with aneurysmal SAH were divided into 2 periods. Between 2012 and 2013 (control period), 45 patients received standard management. Between 2014 and 2015 (ω-3FA period), 55 patients were prospectively treated with additional ω-3FA. Occurrence of cerebral vasospasm, occurrence of cerebral infarction caused by vasospasm, and modified Rankin Scale scores at 30 days and 90 days after onset of SAH for each period were evaluated and compared. The frequency of angiographic cerebral vasospasm in the ω-3FA period was significantly lower than in the control period (12 patients vs. 23 patients, P=0.004). The frequency of new infarction caused by vasospasm in the ω-3FA period was also significantly lower than in the control period (5 patients vs. 14 patients, P= 0.011). There was a significant difference in modified Rankin Scale scores at 90 days after onset of SAH between the groups (P= 0.031). No adverse events were associated with ω-3FA administration. Administration of ω-3FA after aneurysmal SAH may reduce the frequency of cerebral vasospasm and may improve clinical outcomes.

The relationship between IL-6, ET-1 and cerebral vasospasm, in experimental rabbit subarachnoid hemorrhage.

In subarachnoid hemorrhage (SAH), occurrence of cerebral vasospasm (CVS) mediated by endothelin (ET)-1 might be a result of a compartmental inflammatory response with interleukin (IL)-6 release. We aim to investigate the relationship between ET-1 and IL-6 in association of CVS. A total of 24 New Zealand white rabbits where randomly allocated into 3 groups: SAH (N.=10), IL-6 (N.=10), and sham (N.=4). SAH was induced by a closed cranium extracranial-intracranial shunt model. In the IL-6 group, IL-6 was injected into the cisterna magna. CVS of the basilar artery was assessed by digital subtraction angiography. IL-6 and ET-1 concentrations were measured using enzyme-linked immunosorbent assay. Neuronal damage was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling. A significant increase between baseline (day 0) and follow-up (day 3) was found in CSF IL-6 levels of animals in the SAH and IL-6 group. There was a statistically significant correlation between IL-6 and ET-1 levels in the CSF (Pearson's r=0.454, P=0.003). CVS at day 3 was more pronounced in the SAH than in the IL-6 group: 26.0 ±7.2 % and 16.7 ±5.0 % respectively. TUNEL positive apoptotic neurons in the hippocampal formation were present in the SAH group and in a lesser degree in the IL-6 group. The results indicate that IL-6 triggered CVS after SAH is ET-1 dependent. IL-6 may be a target for new therapeutic approaches.

Effects of Toll-Like Receptor 4 Antagonists Against Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage in Mice.

Toll-like receptor 4 (TLR4) signaling may play a crucial role in the occurrence of cerebral vasospasm after subarachnoid hemorrhage (SAH). The main purpose of this study was to assess if selective blockage of TLR4 on cerebral arteries prevents cerebral vasospasm development and neurological impairments after SAH in mice. One hundred fourteen mice underwent endovascular perforation SAH or sham operation and were randomly divided into the following 6 groups: sham+vehicle, sham+LPS-RS ultrapure 8μg, sham+LPS-RS ultrapure 40μg, SAH+vehicle, SAH+LPS-RS ultrapure 8μg, and SAH+LPS-RS ultrapure 40μg. A selective TLR4 antagonist, LPS-RS ultrapure (8 or 40μg), was administered intracerebroventricularly to mice at 30min, and the effects were evaluated by neurobehavioral tests and India-ink angiography at 24-48h, and Western blotting and immunohistochemistry on cerebral arteries at 24h post-SAH. Higher but not lower dosages of LPS-RS ultrapure significantly prevented post-SAH neurological impairments and ameliorated cerebral vasospasm. SAH caused TLR4 activation and cyclooxygenase-1 (COX1) upregulation in the endothelial cells and smooth muscle cells of spastic cerebral arteries, both of which were significantly suppressed by LPS-RS ultrapure. Another selective TLR4 antagonist, IAXO-102, which has a different binding site from LPS-RS ultrapure, also showed similar protective effects to LPS-RS ultrapure. These findings suggest that TLR4 signaling is implicated in cerebral vasospasm development at least partly via COX1 upregulation, and that TLR4 antagonists have therapeutic potential as a new therapy against cerebral vasospasm.

Apolipoprotein E polymorphism in aneurysmal subarachnoid haemorrhage in West Sweden.

Aneurysmal subarachnoid haemorrhage (aSAH) is associated with high morbidity and mortality despite novel treatments. Genetic variability may explain outcome differences. Apolipoprotein E (ApoE) is a glycoprotein with a major role in brain lipoprotein metabolism. It has three isoforms encoded by distinct alleles: APOEε2, APOEε3 and APOEε4. The APOEε4 allele is associated with Alzheimer's disease and worse outcome after traumatic brain injury and ischaemic stroke. This prospective blinded study explored the influence of the APOEε4 polymorphism on the risk of aSAH, risk of cerebral vasospasm (CVS) and 1-year neurological outcome. The APOΕε4 polymorphism was analysed in 147 patients with aSAH. Allele and genotype frequencies were compared to those found in a gender- and area-matched control group of healthy individuals (n = 211). Early CVS was identified and treated according to neurointensive care unit (NICU) guidelines. Neurological deficit(s) at admittance and at 1-year follow-up visit was recorded. Neurological outcome was assessed by the National Institute of Health Stroke Scale, Barthel Index and the Extended Glasgow Outcome Scale. APOEε4 and non-APOEε4 allele frequencies were similar in aSAH patients and healthy individuals. The presence of APOEε4 was not associated with the development of early CVS. We could not find an influence of the APOE polymorphism on 1-year neurological outcome between groups. Subgroup analyses of patients treated with surgical clipping vs endovascular coiling did not reveal any associations. The APOEε4 polymorphism has no major influence on risk of aSAH, the occurrence of CVS or long-term neurological outcome after aSAH.

Optimal hemoglobin concentration in patients with aneurysmal subarachnoid hemorrhage after surgical treatment to prevent symptomatic cerebral vasospasm.

Medical complications occur frequently after aneurismal subarachnoid hemorrhage (aSAH), such as cerebral vasospasm (CVS), anemia, etc. The relationship between hemoglobin (Hgb) concentration and the occurrence of CVS after aSAH remains largely elusive. A total of 218 patients with postoperative aSAH were recruited. Symptomatic cerebral vasospasm (SCVS) was initially diagnosed on the basis of their clinical signs and symptoms, and confirmed by imaging tests. The patients were then divided into four groups on the basis of the postoperative mean Hgb concentration (<11, 11-12, 12-13, and >13 g/dl). The possible influential factors that were statistically significant in the initial univariate analysis were subjected to a multivariable logistic regression analysis. Univariate analysis showed that Hunt and Hess neurological grade on admission, intraoperative aneurysm rupture, CT Fisher grade, and postoperative mean Hgb were associated significantly with SCVS in aSAH patients after surgical treatment (P<0.05). Subsequent multivariable analysis showed that postoperative mean Hgb remained significant after adjustment for Hunt and Hess neurological grade on admission and CT fisher grade. The incidence of SCVS in the group with an Hgb concentration 11-12 g/dl was found to be the lowest among all groups [odds ratio (OR), 3.29, 95% confidence interval (CI), 1.43-7.58, P=0.005; OR, 3.63, 95% CI, 1.41-9.34, P=0.007; OR, 5.34, 95% CI, 1.85-15.43, P=0.002]. Postoperative Hgb concentration is an independent risk factor for SCVS in aSAH patients following surgery, and maintaining the concentration at 11-12 g/dl may reduce the incidence of SCVS.

Toll-like Receptor 4 (TLR4) is Associated with Cerebral Vasospasm and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage.

In the present prospective study, the Toll-like receptor 4 (TLR4) levels on peripheral blood mononuclear cells (PBMCs) were investigated in 30 patients with aneurysmal subarachnoid hemorrhage (aSAH) and in 20 healthy controls (HCs). The relationship between TLR4 levels and the occurrence of cerebral vasospasm (CVS) was also analyzed. TLR4 expression level on cell surface of PBMCs on days 1, 3, and 7 after admission was determined by flow cytometry. Results showed that patients with aSAH presented a significantly higher TLR4 levels. For patients with Hunt-Hess grades IV–V, higher TLR4 levels were also observed; higher TLR4 levels have already been seen in patients developing CVS and/or delayed cerebral ischemia (DCI). Higher TLR4 levels were also associated with modified Fisher score, occurrence of dCVS, DCI, cerebral infarction (CT), and poor neurological functional recovery. Binary logistic regression analysis indicated that high TLR4 expression on blood monocytes was an independent predictive factor of the occurrence of dCVS, DCI, and poor neurological functional recovery. Taken together, TLR4 levels on PBMCs is significantly altered in the early stage of aSAH, especially in those patients experiencing CVS and DCI. Furthermore, higher TLR4 levels in the early stage of aSAH is also associated with the neurological function outcome. As far as we know, this is the first clinical study about TLR4's significance for patients with aSAH.

Cerebral vasospasm after selective amygdalohippocampectomy.

Symptomatic cerebral vasospasm (CV) is a frequently observed complication after aneurysmal subarachnoid haemorrhage (SAH).[1] Infrequently, it is known to occur after skull base surgeries and surgeries for medically intractable epilepsy (viz., temporal lobectomy and selective amygdalo-hippocampectomy (AHE).[2] Factors predicting the occurrence of CV after AHE have been described.[3] Transcranial Doppler (TCD) has been suggested as an invaluable modality for the detection of CV after epilepsy surgery.[3] We report a case of AHE where the patient developed symptoms of CV even in the absence of predictive factors and normal TCD findings.

Cerebral Vasospasm in Critically III Patients with Aneurysmal Subarachnoid Hemorrhage: Does the Evidence Support the Ever-Growing List of Potential Pharmacotherapy Interventions?

The occurrence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a significant event resulting in decreased cerebral blood flow and oxygen delivery. Prevention and treatment of cerebral vasospasm is vital to avert neurological damage and reduced functional outcomes. A variety of pharmacotherapy interventions for the prevention and treatment of cerebral vasospasm have been evaluated. Unfortunately, very few large randomized trials exist to date, making it difficult to make clear recommendations regarding the efficacy and safety of most pharmacologic interventions. Considerable debate exists regarding the efficacy and safety of hypervolemia, hemodilution, and hypertension (triple-H therapy), and the implementation of each component varies substantially amongst institutions. There is a new focus on euvolemic-induced hypertension as a potentially preferred mechanism of hemodynamic augmentation. Nimodipine is the one pharmacologic intervention that has demonstrated favorable effects on patient outcomes and should be routinely administered unless contraindications are present. Intravenous nicardipine may offer an alternative to oral nimodipine. The addition of high-dose magnesium or statin therapy has shown promise, but results of ongoing large prospective studies are needed before they can be routinely recommended. Tirilazad and clazosentan offer new pharmacologic mechanisms, but clinical outcome results from prospective randomized studies have largely been unfavorable. Locally administered pharmacotherapy provides a targeted approach to the treatment of cerebral vasospasm. However, the paucity of data makes it challenging to determine the most appropriate therapy and implementation strategy. Further studies are needed for most pharmacologic therapies to determine whether meaningful efficacy exists.

Effects of intravenous infusion of hydrogen-rich fluid combined with intra-cisternal infusion of magnesium sulfate in severe aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial.

BackgroundThe failures of recent studies intended to prevent cerebral vasospasm have moved the focus of research into delayed cerebral ischemia away from cerebral artery constriction towards other mechanisms. Recent accumulating evidence has suggested that early brain injury is also involved in the development of delayed cerebral ischemia, and that hydrogen can prevent early brain injury. Therefore, we have established a combination therapy of intravenous hydrogen infusion and intra-cisternal magnesium sulfate infusion for the treatment of both early brain injury and cerebral vasospasm. The present randomized controlled clinical trial is designed to investigate the effects of this novel therapeutic strategy on the occurrence of cerebral vasospasm, delayed cerebral ischemia, and clinical outcomes after high-grade subarachnoid hemorrhage.MethodsThis study is a randomized, double-blind, placebo-controlled design to be conducted in two hospitals. A total of 450 patients with high-grade subarachnoid hemorrhage will be randomized to one of three arms: (i) Mg + H2 group, (ii) Mg group, and (iii) control group. Patients who are assigned to the Mg + H2 group will receive intra-cisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days and intravenous hydrogen-rich fluid infusion (200 mL) twice a day for 14 days. Patients who are assigned to the Mg group will receive intra-cisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days and intravenous normal glucose-electrolyte solution (200 mL) without added hydrogen twice a day for 14 days. Patients who are assigned to the control group will receive intra-cisternal Ringer solution without magnesium sulfate at 20 mL/h for 14 days and intravenous normal glucose-electrolyte solution (200 mL) without added hydrogen twice a day for 14 days. Primary outcome measures will be occurrence of delayed cerebral ischemia and cerebral vasospasm. Secondary outcome measures will be modified Rankin scale score at 3, 6, and 12 months and biochemical markers.DiscussionThe present protocol for a randomized, placebo-controlled study of intravenous hydrogen therapy with intra-cisternal magnesium infusion is expected to establish the efficacy and safety of this therapeutic strategy.Trial registrationUMIN-CTR: UMIN000014696