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Background and Purpose— EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods— Subjects were World Federation of Neurological Surgeons grades 2–4, modified Fisher grades 2–4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6–8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results— The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83–1.22], P =0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P =0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3–4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94–1.58], P =0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions— There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02790632.

Objective: Gait variability analysis has been adopted in clinical settings to characterize the presentation of various neurological diseases. However, literature and practice lack a comprehensive murine model assessment of the gait deficits that result from subarachnoid hemorrhage (SAH). Further, correlations between gait parameters and the gene expression profiles associated with SAH have yet to be identified. The present study quantitatively assesses gait deficits through a clinically relevant murine model of SAH to determine associations between gait deficits and SAH-related gene expressions. Methods: A total of 159 dynamic and static gait parameters from the endovascular perforation murine model for simulating clinical human SAH were measured using the CatWalk system. Pearson’s correlation analysis was applied, and 88 genes associated with SAH were identified from the Ingenuity Pathway Analysis database to aid the investigation of the relationship between gait variability and gene expression profiles. Results: Eighty gait parameters and the mRNA expression levels of 35 of the 88 SAH-associated genes exhibited significant change in the SAH models (p < 0.05). Totals of 42 and 38 gait parameters correlated with the 35 SAH-associated genes positively and negatively with Pearson’s correlation coefficients of > 0.7 and < -0.7, respectively. p-SP1 453 expression in the motor cortex in SAH animal models displays a significant correlation with a subset of gait parameters associated with muscular strength and coordination of limb movements. Conclusion: This examination of gait variability and its strong correlation to gene expression profiles provides a quantitative and reliable assessment of the SAH model’s motor performance. This research provides valuable insights into the study of disease progression and offers novel therapeutic interventions in the murine modeling of SAH. p-SP1 453 expression could act as a biomarker to monitor SAH pathological development and a therapeutic target for SAH.

Introduction: Subarachnoid hemorrhage (SAH) mortality is decreasing, but data on functional outcomes over time is lacking. Methods: We created trends of good (Glasgow Outcomes Scale [GOS] of 4 or 5) and optimal (GOS of 5) functional outcomes and mortality (GOS of 1) using linear regression in 15 SAH trials and registries from 1982 to 2014. Models adjusted for age, sex, history of hypertension, World Federation of Neurological Surgeons grade, Fisher grade, aneurysm size, location, and repair modality, and whether data was from a clinical trial or registry. Analyses were repeated separately for the clinical trials and registries. Missing data were handled with multiple imputation. Results: Overall, 13,343 SAH patients were included. 9,524 (71%) patients had good functional outcome, while 1,608 (12%) died. There was a 0.6% adjusted improvement (95% confidence interval [CI]: 0.5% to 0.7%; p Conclusions: SAH morbidity and mortality decreased from the 1980s to 2010s. This data can be helpful for researchers planning trials, clinicians discussing expected outcomes with patients and family members, and healthcare administrators planning resource utilization.

Background: Recent evidence indicates the critical role of neuroinflammation in the pathogenesis of SAH. Mesenchymal stem cells represent a new frontier in the treatment of numerous diseases and have been shown to have therapeutic effects in neurological disease model such as ischemic stroke. Methods: We employed a murine model of endovascular filament perforation for experimental SAH and tail vein injections were performed for hypoxic hUC-MSC secretome treatment and phosphate buffer treatment (control). The data were expressed as mean+/-SEM and statistical analyses were performed with IBM SPSS 23.0 software. Results: Microglia exhibited suppressed M1 polarization in hypoxic-hUC-MSC-secretome-treated mice at day 3 as compared to phosphate-buffer-treated mice. mRNA expressions of M1-polarization markers (CD16: 0.59+/-0.07; CD32: 0.62+/-0.11, p=0.024; CD68: 0.72+/-0.07. p=0.049) were downregulated and M2-polarization marker TREM2 expression were upregulated (1.57+/-0.13, p=0.013). Confocal microscopy at day 1 showed decreased CD16/32 expression in hypoxic-hUC-MSC-secretome-treated mice as compared to phosphate-buffer-treated mice, and CD206 positive cells were observed in hypoxic-hUC-MSC-secretome-treated mice. mRNA expression of IL-4 was upregulated in hypoxic-hUC-MSC-secretome-treated mice at day 1 as compared to phosphate-buffer-treated mice. Conclusions: Hypoxic hUC-MSC treatment had a positive effect in the modulation of neuroinflammation in a murine experimental SAH model and should be further investigated.

Introduction: Subarachnoid hemorrhage (SAH) is a devastating stroke type. Microglia/Macrophage, in neuroinflammation response, are capable of classic M1 and alternative M2 polarization after activation. However, the profile of microglial activation was not well studied in SAH. In this study, we aimed to unravel the polarization-specific dynamic of microglia after SAH. Methods: Wild-type C57BL/6 mice and Cx3cr1 GFP/GFP Ccr2 RFP/RFP mice were used and SAH was induced by endovascular perforation. The Immunohistochemistry and Immunofluorescence were employed to characterize the profile of microglia activation on day 1, day 3, day 5, day 10 (n=6-8). Results: Iba1-positive microglia accumulated significantly in the cortex adjacent to the bleeding site (CAPS) on day 1 and sustained to increase till the delayed phase in SAH. Microglial accumulation was also observed on motor cortex and hippocampus on the early phase. Immunofluorescence showed the CD16/32-positive M1-predominant phenotype appeared in 3 days, then gradually transformed into the CD206-positive M2 phenotype. The functionally microglial polarization advanced along with the morphological changes through ramified to amoeboid shape. The bipolar microglia appeared through the morphological transformation with the colocalization of M1/M2 markers. In addition, Ccr2 low expressed and Cx3Cr1 highly expressed (CCR2 - /Cx3Cr1 + ) cells are observed on CAPS with a co-existing of a small group of CCR2 + /Cx3Cr1 + cell. The results suggested the preponderant microglial activation rather than the infiltrated macrophage. Conclusions: Microglia demonstrated a preponderant and early accumulation and this accumulation showed a centrifugal spreading through CAPS to remote motor cortex. Pro-inflammatory response occurred early and transform to the anti-inflammation on the delayed phase. The dynamic of microglial morphological changes and polarization implied the function-related neuroinflammatory response and pathophysiologic process of restoration upon the hemorrhage attack.

Background Delayed cerebral infarction ( DCI ) is a major cause of morbidities after aneurysmal subarachnoid hemorrhage ( SAH ) and typically starts at day 4 to 7 after initial hemorrhage. Micro RNA s (mi RNAs ) play an important role in posttranscriptional gene expression control, and distinctive patterns of circulating mi RNA changes have been identified for some diseases. We aimed to investigate mi RNA s that characterize SAH patients with DCI compared with those without DCI . Methods and Results Circulating mi RNA s were collected on day 7 after SAH in healthy, SAH ‐free controls (n=20), SAH patients with DCI (n=20), and SAH patients without DCI (n=20). We used the LASSO (least absolute shrinkage and selection operator) method of regression analysis to characterize mi RNA s associated with SAH patients with DCI compared with those without DCI . In the 28 dysregulated mi RNA s associated with DCI and SAH , we found that a combination of 4 mi RNA s (miR‐4532, miR‐4463, miR‐1290, and miR‐4793) could differentiate SAH patients with DCI from those without DCI with an area under the curve of 100% (95% CI 1.000–1.000, P RNA combination could also distinguish SAH patients with or without DCI from healthy controls with areas under the curve of 99.3% (95% CI 0.977–1.000, P CI 0.685–0.955, P Conclusions We found a 4‐mi RNA combination that characterized SAH patients with DCI . The findings could guide future mechanistic study to develop therapeutic targets.

Background and purpose: Disability is common after severe stroke resulting from major cerebral artery occlusion despite adoption of prophylactic decompressive craniectomy. Experimental mesenchymal stem cell treatments are commonly administrated through systemic infusion, with limitations in dosage. In this study, the neuro-modulation effect of topical mesenchymal stem cells (MSCs) was tested in a rodent middle carotid artery occlusion (MCAO) model. Methods: Twenty-four hours after MCAO, craniotomy was made and 0.8 x 10 6 GFP-MSCs were topically applied to the ipsilateral parietal cortex (N=30). In the control group, saline were topically applied to the ipsilateral parietal cortex (N=30). Results: After topical MSC treatment, neurological assessments with Rotarod test (at days 3, 7, and 10) and Morris Water Maze test (at days 3, 7, and 14) were significantly better, as compared to the control group; the infarct volume was also smaller. MSCs were found in the penumbra of the infarct 3 days after topical application. In the PCR array analysis of the RNA extracted from penumbra cortex, topical application of MSCs changed 10 gene expressions in the penumbra at day 3 (fold change >1.25, p Conclusions: Topically applied MSCs reduced cerebral infarction volume and improved the neurological function from cerebral ischemia resulting from a major cerebral artery occlusion in a rodent experimental model.

Background and Purpose— To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. Methods— After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. Results— Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. Conclusions— Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

Background Experimental evidence has indicated the benefit of simvastatin in the treatment of subarachnoid hemorrhage. However, no clinical data are available to answer whether a high-dose regimen is more effective than a normal-dose regimen, even though the biochemical actions and related neuroprotective mechanisms are thought to be dose related. Objective To determine whether 80 mg simvastatin daily (high dose) over 3 weeks initiated within 96 hours of the ictus will reduce the incidence of delayed ischemic deficits after subarachnoid hemorrhage compared with 40 mg simvastatin daily (normal dose), leading to improvements in clinical outcomes and thus cost-effectiveness. Methods The study design is a randomized, controlled, double-blind clinical trial (www.ClinicalTrials.gov; identifier: NCT01077206). Two hundred forty patients with aneurysmal subarachnoid hemorrhage (presenting within 96 hours of the ictus) from 6 neurosurgical centers are being recruited over 3 years. The primary outcome measure is the presence of delayed ischemic deficits. Secondary outcome measures include modified Rankin Disability Score at 3 months and cost-effectiveness analysis. Expected outcomes This will be the first study to clarify whether high-dose simvastatin is better than normal-dose simvastatin for patients with acute aneurysmal subarachnoid hemorrhage in terms of neurological outcomes and cost-effectiveness. Discussion In the present trial, we compare high-dose and normal-dose simvastatin; we know that another ongoing phase III multicenter trial (Simvastatin in Aneurysmal Subarachnoid Haemorrhage; http://www.stashtrial.com/home.html) is comparing normal-dose and no simvastatin. When the results are interpreted together, the research question of a possible beneficial effect of high-dose simvastatin in acute aneurysmal subarachnoid hemorrhage could be answered.

A 45-year-old woman complained of a progressive 2-month history of bilateral hearing impairment and diplopia on upward gaze. She had a history of a recurrent pineal region ganglioglioma with repeated tumor excision, adjuvant radiotherapy, and a ventriculo-peritoneal shunt performed 12 years prior. Subsequent imaging studies 6 years ago showed a pineal region cyst with progressive increase in size and a Rickham reservoir (Codman; Johnson & Johnson, Raynham, MA) was placed for percutaneous cyst fluid aspiration. The size of the cystic lesion remained static upon follow-up CT scans for several years.

Background Health-related quality of life has recently been suggested as a supplement to the traditional neurological outcome measures from the patient's perspective according to the World Health Organization model and may capture the effects of other factors such as posttraumatic stress disorder and neuroendocrine dysfunction. Objective To explore the profile and clinical factors of quality of life after aneurysmal subarachnoid hemorrhage using the data we obtained from the recently completed Intravenous Magnesium Sulphate After Aneurysmal Subarachnoid Hemorrhage (IMASH) trial. Methods This study was registered at www.strokecenter.org/trials and www.ClinicalTrials.gov (NCT00124150). Data from a patient cohort obtained with the Short Form-36 questionnaire completed at 6 months were used for analysis. Results Patients with aneurysmal subarachnoid hemorrhage demonstrated a decrease in quality of life according to the Short Form-36 at 6 months. The physical and mental health scores correlated with the Extended Glasgow Outcome Scale and had the potential to avoid the ceiling effect. Multiple regression analyses showed that the physical component scores were related to age, World Federation of Neurological Surgeons grade, and chronic hydrocephalus and that the mental component scores were not related to the traditional prognostic factors. Conclusion Subarachnoid hemorrhage caused a decrease in quality of life. Chronic hydrocephalus is related to a decrease in physical health quality of life.

Background and Purpose— Conflicting data have been obtained on optimal plasma magnesium concentrations for clinical outcomes in patients with aneurysmal subarachnoid hemorrhage. Methods— Adults (aged 18 years or older) who had acute aneurysmal subarachnoid hemorrhage diagnosed were randomly assigned to receive either an intravenous MgSO 4 infusion (80 mmol in 500 mL normal saline per day) or a placebo (500 mL normal saline per day) for up to 14 days. Post hoc multivariable binary logistic regression analyses were performed by dividing mean plasma magnesium concentrations into 4 quartiles according to treatment group and then comparing with the lowest quartiles. Results— The worst clinical outcomes at 6 months were seen in MgSO 4 group patients, with mean plasma magnesium concentrations in the fourth quartile, and in placebo group patients, with mean such concentrations in the third and fourth quartiles. Conclusions— No evidence was found to suggest that a higher mean plasma magnesium concentration improves clinical outcomes. On the contrary, we found an association between high plasma magnesium concentration and worse clinical outcomes.

We performed a randomized, double-blind, pilot study on magnesium sulfate (MgSO4) infusion for aneurysmal subarachnoid hemorrhage (SAH).Sixty patients with SAH were randomly allocated to receive either MgSO4 80 mmol/day or saline infusion for 14 days. Patients also received intravenous nimodipine. Episodes of vasospasm were treated with hypertensive and hypervolemic therapy. Neurologic status was assessed 6 months after hemorrhage using the Barthel index and Glasgow Outcome Scale. Incidences of cardiac and pulmonary complications were also recorded. Patient characteristics, severity of SAH, and surgical treatment did not differ between groups. The incidence of symptomatic vasospasm decreased from 43% in the saline group to 23% in patients receiving MgSO4 infusion, but it did not reach statistical significance, P=0.06. For patients who had transcranial Doppler-detected vasospasm, defined as mean flow velocity >120 cm/s and a Lindegaard index >3, the duration was shorter in the magnesium group compared with controls (P

Background and Purpose — Active management of ruptured intracranial aneurysm in subarachnoid hemorrhage is indicated in patients with favorable prognosis. Outcome prediction is based on patient characteristics and clinical and radiological factors. Current clinical grading scales are imprecise, with low interobserver reproducibility. Therefore, outcome prediction remains inconsistent and decision making becomes difficult, especially for patients with poor clinical grade. Methods — The possible relationship between apolipoprotein E genotype and the outcome of patients suffering spontaneous subarachnoid hemorrhage was investigated. A prospective study was conducted on all patients with spontaneous aneurysmal subarachnoid hemorrhage admitted to our unit during a 2-year period. All patients were managed according to standard protocol, and treatments were given according to their clinical grading. Patient characteristics, clinical grade, radiological grade, and apolipoprotein E genotype were documented. The focus of the study was the 6-month neurological outcome for this group of patients after they were discharged. Results — Seventy-two patients with aneurysmal subarachnoid hemorrhage were admitted to the Prince of Wales Hospital in Shatin, Hong Kong, China, from February 1998 to February 2000. Their ages ranged from 24 to 95 years of age, with a mean (SD) age of 58.3 (15.0) years. Apolipoprotein E ε4 was found in 15 patients (21%). At 6 months, Glasgow Outcome Scale score ≤3 was found in 29 patients (40%). Univariate analysis showed that older patients (odds ratio [OR], 1.03; 95% CI, 1.00 to 1.07; P =0.07) and patients with poor Fisher’s grade (OR, 4.5; 95% CI, 1.3 to 15.2; P =0.01), poor World Federation of Neurological Surgeons grade (OR, 5.8; 95% CI, 1.9 to 17.8; P =0.002), or apolipoprotein E ε4 (OR, 6.0; 95% CI, 1.7 to 21.3; P =0.006) were more likely to attain unfavorable outcome at 6 months. The additional effect of apolipoprotein E ε4 remained significant in the multiple logistic regression model (OR, 11.3; 95% CI, 2.2 to 57.0; P =0.003); the gain in predictive performance was not significant ( P =0.26). Conclusions — Apolipoprotein E ε4 genotype is related to poor outcome in patients with subarachnoid hemorrhage.

We report a case of a 33-year-old male with a history of complex posterior fossa arteriovenous malformation (AVM) with partial resection done in China; at follow-up in our unit, he presented with a 1-day history of acute deterioration of consciousness level after minor head injury. The clinical and radiologic features were compatible with spontaneous hemorrhage from the AVM, and the patient died 1 day after admission. However, postmortem examination revealed the direct cause of death was due to Klebsiella meningitis. The clinical catch is highlighted, and the importance of early and prompt detection of this condition is emphasized.

To the Editor: We read with great interest the study by W.M. van den Bergh regarding the randomized controlled trial on Magnesium Sulfate in Aneurysmal Subarachnoid Hemorrhage1. In essence, it was a negative study using delayed cerebral ischemia (DCI) and poor outcome at three months from the data provided. The methodology raised concerns us. The author, for some unexplained reason, truncated out the aspirin group’s case selection as well as data to carry out the analysis. As noted in the MASH group’s trial protocol published in the Internet Stroke Center,2 the way would be to add aspirin to the group that had aneurysm intervention within 4 days. If the aspirin group were actually excluded, the study population would be undoubtedly focused on patients with delayed aneurysm treatment. The study used DCI as the primary outcome measure and used CT evidence of infarct. Magnesium is thought to be neuroprotective and reverse cerebral vasospasm in animal models. Thus, it would be of interest to look at their clinical vasospasm data and blood flow study data as Transcranial Doppler USG and SPECT. It would certainly enlighten about the possible actions of magnesium. The other reasons for the above data would be that some patterns of CT infarct may not be related to cerebral vasospasm, and some infarct may actually be masked by edema or metallic artifact as quoted by Rabinstein et al.3 The outcome was made in 3 months. From our experience, some of the poor-grade subarachnoid hemorrhage patients would show …

To the Editor: We read with great interest the article by angiotensin-converting enzyme investigators entitled “Does Impaired Cerebrovascular Reactivity Predict Stroke Risk in Asymptomatic Carotid Stenosis? A Prospective Substudy of the Asymptomatic Carotid Emboli Study.”1 The authors carried out a 7-center prospective study to investigate whether impaired carbon dioxide cerebrovascular reactivity (CO2 CVR) by transcranial Doppler ultrasound predicted ischemic events in 106 patients with asymptomatic carotid stenosis. Although meta-analysis suggested an association between impaired CO2 CVR, …

Response: We thank Drs Keller and Muroi for their interest in our article and their comments.1 We share the same disappointment with the negative result of intravenous magnesium sulfate for aneurysmal subarachnoid hemorrhage and the excitement in improvement of clinical outcome brought by specialized neurocritical care in recent years.2,3 The design of intravenous magnesium sulfate for aneurysmal subarachnoid hemorrhage involved adding prophylactic hypermagnesemic treatment …

To the Editor: We read with great interest the article by Katayama et al.1 In concordance with their previous pilot study,2 the authors showed that hydrocortisone 1200 mg/d …

To the Editor: In the Magnesium and Acetylsalicylic acid in Subarachnoid Hemorrhage (MASH) trial, van den Bergh and colleagues reported no significant difference in the incidence of delayed cerebral ischemia after magnesium sulfate or placebo in patients with aneurysmal subarachnoid hemorrhage.1 More recently, they reported similar findings with acetylsalicylic acid (ASA) in the same cohort of patients.2 Given that patients in this factorial study were …

To the Editor: We read with great interest the article by Kastrup et al.1 The authors showed that the proportion of patients with any new ipsilateral diffusion-weighted imaging (DWI) lesion (49% versus 67%; P

To the Editor: We read with great interest the article by Taschner et al.1 The authors presented their philosophy in case selection for aneurysm occlusion using matrix detachable coils and their clinical results. Of the 25 total procedures, 5 were complicated with a thrombus formation …

To the Editor: We would like to congratulate Tseng et al1 for the article titled “Effects of acute treatment with Pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: A phase II randomized placebo-controlled trial”. The authors hypothesized that statins might improve cerebral vasomotor activity through cholesterol-dependent and -independent mechanisms. They randomized aneurysmal subarachnoid hemorrhage patients (18 to 84 years of age) within 72 hours from the ictus to receive either oral pravastatin (40 mg) or placebo daily for up to 14 days. They were able to show a decrease in incidence of vasospasm, duration of severe vasospasm, duration of impaired autoregulation, incidence of vasospasm-related delayed ischemic deficits and mortality with pravastatin treatment impressively in this 80-patient study. The authors’ center …

To the Editor: We read with great interest the article by Naidech et al.1 The authors started from the abstract statement that “Phenytoin is routinely used for seizure prophylaxis after subarachnoid hemorrhage … … ” and went on to investigate the possible harmful effects on cognitive and neurological outcome. After a study of 527 subarachnoid hemorrhage patients, the authors concluded that higher quartiles of phenytoin burden were associated with worse telephone interviews for cognitive status scores at hospital discharge ( P