Safety for cervical corpectomy and diskectomy: univariate and multivariate analysis on predictors for prolonged ICU stay after anterior spinal fusion.

AIM: Cervical anterior spinal fusion (ASF) with corpectomy has risks of catastrophic acute complications such as airway obstruction requiring re-intubation. Our team has adopted a management plan for all cervical corpectomy patients to be admitted to the intensive care unit (ICU) after the operations for overnight observation. Some of these patients were kept intubated after the operations and transferred to the ICU. This study aims to review the outcome of this practice and to identify independent predictors associated with a prolonged ICU stay. METHODS: We reviewed consecutive patients with cervical ASF from January 2010 to June 2018. The primary outcome was the ICU length of stay. Univariate and multivariate analyses were conducted to identify independent risk factors associated with a prolonged ICU stay. In total, 103 patients had ASF during the study period. ICU length of stay for elective ASF was 1.01 day (SD 0.373 days) and was significantly shorter than that for emergency ASF (13.29 days, SD 12.57 days) (p < 0.001). 79.6% (82/103) of the ASF patients were extubated in the operating theatre after surgery. Significantly more corpectomy patients (33.3%) versus ACDF patients (15.1%) were kept intubated to the ICU after the operation (p = 0.037). None required reintubation in the ICU. 90.9% (80/88) of the elective ASF can be discharged from the ICU within 24 hours and only 3.41% (3/88) of the elective ASF had prolonged post-operative stay in the ICU (≥48 hours). RESULTS: For prolonged postoperative ICU stay (≥48 hours), ICU admission airway status of ASF patients who were either extubated in the OT or kept intubated to ICU had no significant association (p = 0.903). Univariate and multivariate analysis had identified emergency admissions (p = 0.043) and the presence of postoperative neurological deficits (p = 0.031) as independent predictors associated with a prolonged postoperative ICU stay. CONCLUSION: In conclusion, cervical corpectomy and ASF were safe with minimal acute complications.

Novel role of STAT3 in microglia-dependent neuroinflammation after experimental subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Signal transducer and activator of transcription 3 (STAT3) may contribute to the proinflammation in the central nervous system diseases by modulating the microglial responses. Thus, this study was intended to investigate the effect of STAT3 on microglia-dependent neuroinflammation and functional outcome after experimental subarachnoid haemorrhage (SAH). METHODS: The SAH model was established by endovascular perforation in the mouse. Real-time PCR (RtPCR) and western blot were used to examine the dynamic STAT3 signalling pathway responses after SAH. To clarify the role of the STAT3 signalling pathway in the microglia-dependent neuroinflammation after SAH, the microglia-specific STAT3 knockout (KO) mice were generated by the Cre-LoxP system. The neurological functions were assessed by Catwalk and Morris water maze tests. Neuronal loss after SAH was determined by immunohistochemistry staining. Microglial polarisation status after STAT3 KO was then examined by RtPCR and immunofluorescence. RESULTS: The STAT3 and Janus kinase-signal transducer 2 activated immediately with the upregulation and phosphorylation after SAH. Downstream factors and related mediators altered dynamically and accordingly. Microglial STAT3 deletion ameliorated the neurological impairment and alleviated the early neuronal loss after SAH. To investigate the underlying mechanism, we examined the microglial reaction after STAT3 KO. STAT3 deletion reversed the increase of microglia after SAH. Loss of STAT3 triggered the early morphological changes of microglia and primed microglia from M1 to M2 polarisation. Functionally, microglial STAT3 deletion suppressed the SAH-induced proinflammation and promoted the anti-inflammation in the early phase. CONCLUSIONS: STAT3 is closely related to the microglial polarisation transition and modulation of microglia-dependent neuroinflammation. Microglial STAT3 deletion improved neurological function and neuronal survival probably through promoting M2 polarisation and anti-inflammatory responses after SAH. STAT3 may serve as a promising therapeutic target to alleviate early brain injury after SAH.

Rescue therapy for vasospasm following aneurysmal subarachnoid hemorrhage: a propensity score-matched analysis with machine learning.

OBJECTIVE: Rescue therapies have been recommended for patients with angiographic vasospasm (aVSP) and delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). However, there is little evidence from randomized clinical trials that these therapies are safe and effective. The primary aim of this study was to apply game theory-based methods in explainable machine learning (ML) and propensity score matching to determine if rescue therapy was associated with better 3-month outcomes following post-SAH aVSP and DCI. The authors also sought to use these explainable ML methods to identify patient populations that were more likely to receive rescue therapy and factors associated with better outcomes after rescue therapy. METHODS: Data for patients with aVSP or DCI after SAH were obtained from 8 clinical trials and 1 observational study in the Subarachnoid Hemorrhage International Trialists repository. Gradient boosting ML models were constructed for each patient to predict the probability of receiving rescue therapy and the 3-month Glasgow Outcome Scale (GOS) score. Favorable outcome was defined as a 3-month GOS score of 4 or 5. Shapley Additive Explanation (SHAP) values were calculated for each patient-derived model to quantify feature importance and interaction effects. Variables with high SHAP importance in predicting rescue therapy administration were used in a propensity score-matched analysis of rescue therapy and 3-month GOS scores. RESULTS: The authors identified 1532 patients with aVSP or DCI. Predictive, explainable ML models revealed that aneurysm characteristics and neurological complications, but not admission neurological scores, carried the highest relative importance rankings in predicting whether rescue therapy was administered. Younger age and absence of cerebral ischemia/infarction were invariably linked to better rescue outcomes, whereas the other important predictors of outcome varied by rescue type (interventional or noninterventional). In a propensity score-matched analysis guided by SHAP-based variable selection, rescue therapy was associated with higher odds of 3-month GOS scores of 4-5 (OR 1.63, 95% CI 1.22-2.17). CONCLUSIONS: Rescue therapy may increase the odds of good outcome in patients with aVSP or DCI after SAH. Given the strong association between cerebral ischemia/infarction and poor outcome, trials focusing on preventative or therapeutic interventions in these patients may be most able to demonstrate improvements in clinical outcomes. Insights developed from these models may be helpful for improving patient selection and trial design.

Risk of Rupture After Intracranial Aneurysm Growth.

Importance: Unruptured intracranial aneurysms not undergoing preventive endovascular or neurosurgical treatment are often monitored radiologically to detect aneurysm growth, which is associated with an increase in risk of rupture. However, the absolute risk of aneurysm rupture after detection of growth remains unclear. Objective: To determine the absolute risk of rupture of an aneurysm after detection of growth during follow-up and to develop a prediction model for rupture. Design, Setting, and Participants: Individual patient data were obtained from 15 international cohorts. Patients 18 years and older who had follow-up imaging for at least 1 untreated unruptured intracranial aneurysm with growth detected at follow-up imaging and with 1 day or longer of follow-up after growth were included. Fusiform or arteriovenous malformation-related aneurysms were excluded. Of the 5166 eligible patients who had follow-up imaging for intracranial aneurysms, 4827 were excluded because no aneurysm growth was detected, and 27 were excluded because they had less than 1 day follow-up after detection of growth. Exposures: All included aneurysms had growth, defined as 1 mm or greater increase in 1 direction at follow-up imaging. Main Outcomes and Measures: The primary outcome was aneurysm rupture. The absolute risk of rupture was measured with the Kaplan-Meier estimate at 3 time points (6 months, 1 year, and 2 years) after initial growth. Cox proportional hazards regression was used to identify predictors of rupture after growth detection. Results: A total of 312 patients were included (223 [71%] were women; mean [SD] age, 61 [12] years) with 329 aneurysms with growth. During 864 aneurysm-years of follow-up, 25 (7.6%) of these aneurysms ruptured. The absolute risk of rupture after growth was 2.9% (95% CI, 0.9-4.9) at 6 months, 4.3% (95% CI, 1.9-6.7) at 1 year, and 6.0% (95% CI, 2.9-9.1) at 2 years. In multivariable analyses, predictors of rupture were size (7 mm or larger hazard ratio, 3.1; 95% CI, 1.4-7.2), shape (irregular hazard ratio, 2.9; 95% CI, 1.3-6.5), and site (middle cerebral artery hazard ratio, 3.6; 95% CI, 0.8-16.3; anterior cerebral artery, posterior communicating artery, or posterior circulation hazard ratio, 2.8; 95% CI, 0.6-13.0). In the triple-S (size, site, shape) prediction model, the 1-year risk of rupture ranged from 2.1% to 10.6%. Conclusion and Relevance: Within 1 year after growth detection, rupture occurred in approximately 1 of 25 aneurysms. The triple-S risk prediction model can be used to estimate absolute risk of rupture for the initial period after detection of growth.

Topical application of adipose tissue-derived mesenchymal stem cells (ADMSCs) reduced cerebral edema in experimental traumatic brain injury (TBI)-a preliminary study.

BACKGROUND: Our previous studies showed that topical application of mesenchymal stem cells (MSCs) improved functional recovery in rat traumatic brain injury (TBI) model, and hypoxic precondition further enhanced the therapeutic effects of MSCs. There was no previous study on the attenuation of cerebral edema by MSCs. We investigated whether topical application of normoxic and hypoxic MSCs could reduce cerebral edema in an experimental TBI model. METHODS: Two million normoxic (N = 24) and hypoxic (N = 24) MSCs were applied topically to exposed the cerebral cortex in a controlled cortical impact (CCI) model. The MSCs were fixed in position with fibrin glue. No treatment was given to control animals (TBI only: n = 24). After surgery, four animals in each group were sacrificed daily (day 1 to day 6) for edema evaluation. Normal animals without TBI were used as reference (n = 4). The expressions of GFAP, AQP4, and MMP9 were also investigated by immunofluorescence staining and RT-PCR at day 3. RESULTS: The edema peaked within 3 days after TBI. Compared with the control, hypoxic MSCs reduced brain water content significantly (p < 0.05). Both hypoxic and normoxic MSCs downregulated the expression of MMP9 and normalized AQP4 distribution to astrocyte end feet. CONCLUSION: Our preliminary study showed that topical application of hypoxic MSCs suppressed both vasogenic and cytotoxic edema formation.

Long term treatment efficacy & complications of hypofractionated stereotactic radiosurgery in brain arteriovenous malformations.

OBJECTIVE: To evaluate long term treatment efficacy and complications of hypofractionated stereotactic radiosurgery (hfSRS) and identify factors that predict outcomes. METHODS: A retrospective review was conducted on 34 consecutive patients who received hfSRS from 2008 to 2017. Demographic, clinical, angio-architectural characteristics, and radiosurgery data were extracted from the Clinical Data Analysis and Reporting System and our unit's iPlan (BrainLAB, Munich) system. Data was analysed using SPSS. RESULTS: 5-year obliteration rate was 39.1%. Most patients (n = 29, 85.3%) recovered well with GOS of 4-5. 26.9% (n = 9) patients have at least one post-radiosurgery complication including hemorrhage, neurological deficits, radionecrosis. Neurological morbidity and mortality was 17.6% (n = 6). A higher modified radiosurgery arteriovenous malformation score (mRBAS) is associated with a lower 5-year obliteration rate (Rho = -0.486, p = 0.025). None of the bAVM were obliterated once mRBAS exceeds 5.35. As expected, a larger 20-Gy volume outside lesion is associated with more complications and poorer GOS. Interestingly, irradiated drainage vein volume indexed to AVM volume (iiDVV) correlates with increased risks of post-hfSRS haemorrhage (Rho = 0.472, p = 0.031) and reduced event-free survival (Rho = -0.472, p = 0.031). Once iiDVV exceeds 20%, a high rebleeding rate after hfSRS is anticipated (AUC under ROC 0.889). CONCLUSION: Hypofractionated stereotactic radiosurgery is an alternative radiosurgery treatment for bAVM unsuitable for single-fraction SRS. mRBAS predicts obliteration rate and morbidity in hfSRS. Index irradiated drainage vein volume (iiDVV) is associated with event-free survival and rebleeding and should be minimized if feasible.

NEWTON-2 Cisternal (Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage): A Phase 2, Multicenter, Randomized, Open-Label Safety Study of Intracisternal EG-1962 in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE: To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. METHODS: Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. RESULTS: The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups. CONCLUSION: Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.

Impact of metformin on immunological markers: Implication in its anti-tumor mechanism.

Metformin, an anti-hyperglycemic drug, has been known to have antitumor properties for around 15 years. Although there are a number of reports attributing the antitumor function of metformin to its impact on energy homeostasis and oxygen re-distribution in tumor microenvironment, detailed mechanisms remain largely unknown. In the past several years, there is an increasing number of publications indicating that metformin can affect various immunological components including lymphocytes, macrophages, cytokines and several key immunological molecules in both human and animal studies. These interesting results appear to be in line with emerging data that suggest associations between immune responses and energy homeostasis/oxygen re-distribution, which may explain effective impacts of metformin on immunotherapies against autoimmune diseases as well as cancers. This review article is to analyse and discuss recent development in the above areas with aim to justify metformin as a new adjuvant for immunotherapy against human cancers. We hope that our summary will help to optimize the application of metformin for various types of human cancers.

Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage.

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.

Common Data Elements for Unruptured Intracranial Aneurysms and Subarachnoid Hemorrhage Clinical Research: A National Institute for Neurological Disorders and Stroke and National Library of Medicine Project.

OBJECTIVES: The goal for this project was to develop a comprehensive set of common data elements (CDEs), data definitions, case report forms and guidelines for use in unruptured intracranial aneurysm (UIA) and subarachnoid hemorrhage (SAH) clinical research, as part of a new joint effort between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Library of Medicine of the US National Institutes of Health. These UIA and SAH CDEs will join several other neurological disease-specific CDEs that have already been developed and are available for use by research investigators. METHODS: A Working Group (WG) divided into eight sub-groups and a Steering Committee comprised of international UIA and SAH experts reviewed existing NINDS CDEs and instruments, created new elements when needed and provided recommendations for UIA and SAH clinical research. The recommendations were compiled, internally reviewed by the entire UIA and SAH WG and posted online for 6 weeks for external public comments. The UIA and SAH WG and the NINDS CDE team reviewed the final version before posting the SAH Version 1.0 CDE recommendations. RESULTS: The NINDS UIA and SAH CDEs and supporting documents are publicly available on the NINDS CDE ( https://www.commondataelements.ninds.nih.gov/#page=Default ) and NIH Repository ( https://cde.nlm.nih.gov/home ) websites. The recommendations are organized into domains including Participant Characteristics and Outcomes and Endpoints. CONCLUSION: Dissemination and widespread use of CDEs can facilitate UIA and SAH clinical research and clinical trial design, data sharing, and analyses of observational retrospective and prospective data. It is vital to maintain an international and multidisciplinary collaboration to ensure that these CDEs are implemented and updated when new information becomes available.

Common Data Elements for Unruptured Intracranial Aneurysm and Subarachnoid Hemorrhage Clinical Research: Recommendations from the Working Group on Long-Term Therapies.

OBJECTIVES: The goal for the long-term therapies (LTT) working group (WG) of the Unruptured Intracranial Aneurysm (UIA) and Subarachnoid Hemorrhage (SAH) common data elements (CDEs) was to develop a comprehensive set of CDEs, data definitions, case report forms, and guidelines for use in UIA and SAH LTT clinical research, as part of a new joint effort between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Library of Medicine of the US National Institutes of Health. These UIA and SAH CDEs will join other neurological disease-specific CDEs already developed and available for use by research investigators. METHODS: The eight LTT WG members comprised international UIA, and SAH experts reviewed existing NINDS CDEs and instruments, created new elements when needed, and provided recommendations for future LTT clinical research. The recommendations were compiled, internally reviewed by the all UIA and SAH WGs and steering committee members. The NINDS CDE team also reviewed the final version before posting the SAH Version 1.0 CDE recommendations on the NINDS CDE website. RESULTS: The NINDS UIA and SAH LTT CDEs and supporting documents are publicly available on the NINDS CDE ( https://www.commondataelements.ninds.nih.gov/#page=Default ) and NIH Repository ( https://cde.nlm.nih.gov/home ) websites. The subcommittee members discussed and reviewed various parameters, outcomes, and endpoints in UIA and SAH LTT studies. The following meetings with WG members, the LTT WG's recommendations are incorporated into the disease/injury-related events, assessments and examinations, and treatment/intervention data domains. CONCLUSIONS: Noting gaps in the literature regarding medication and rehabilitation parameters in UIA and SAH clinical studies, the current CDE recommendations aim to arouse interest to explore the impact of medication and rehabilitation treatments and therapies and encourage the convergence of LTT clinical study parameters to develop a harmonized standard.

Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage: the SAHIT multinational cohort study.

OBJECTIVE: To develop and validate a set of practical prediction tools that reliably estimate the outcome of subarachnoid haemorrhage from ruptured intracranial aneurysms (SAH). DESIGN: Cohort study with logistic regression analysis to combine predictors and treatment modality. SETTING: Subarachnoid Haemorrhage International Trialists' (SAHIT) data repository, including randomised clinical trials, prospective observational studies, and hospital registries. PARTICIPANTS: Researchers collaborated to pool datasets of prospective observational studies, hospital registries, and randomised clinical trials of SAH from multiple geographical regions to develop and validate clinical prediction models. MAIN OUTCOME MEASURE: Predicted risk of mortality or functional outcome at three months according to score on the Glasgow outcome scale. RESULTS: Clinical prediction models were developed with individual patient data from 10 936 patients and validated with data from 3355 patients after development of the model. In the validation cohort, a core model including patient age, premorbid hypertension, and neurological grade on admission to predict risk of functional outcome had good discrimination, with an area under the receiver operator characteristics curve (AUC) of 0.80 (95% confidence interval 0.78 to 0.82). When the core model was extended to a "neuroimaging model," with inclusion of clot volume, aneurysm size, and location, the AUC improved to 0.81 (0.79 to 0.84). A full model that extended the neuroimaging model by including treatment modality had AUC of 0.81 (0.79 to 0.83). Discrimination was lower for a similar set of models to predict risk of mortality (AUC for full model 0.76, 0.69 to 0.82). All models showed satisfactory calibration in the validation cohort. CONCLUSION: The prediction models reliably estimate the outcome of patients who were managed in various settings for ruptured intracranial aneurysms that caused subarachnoid haemorrhage. The predictor items are readily derived at hospital admission. The web based SAHIT prognostic calculator (http://sahitscore.com) and the related app could be adjunctive tools to support management of patients.

Interactome and reciprocal activation of pathways in topical mesenchymal stem cells and the recipient cerebral cortex following traumatic brain injury.

In this study, GFP-MSCs were topically applied to the surface of cerebral cortex within 1 hour of experimental TBI. No treatment was given to the control group. Three days after topical application, the MSCs homed to the injured parenchyma and improved the neurological function. Topical MSCs triggered earlier astrocytosis and reactive microglia. TBI penumbra and hippocampus had higher cellular proliferation. Apoptosis was suppressed at hippocampus at 1 week and reduced neuronal damaged was found in the penumbral at day 14 apoptosis. Proteolytic neuronal injury biomarkers (alphaII-spectrin breakdown products, SBDPs) and glial cell injury biomarker, glial fibrillary acidic protein (GFAP)-breakdown product (GBDPs) in injured cortex were also attenuated by MSCs. In the penumbra, six genes related to axongenesis (Erbb2); growth factors (Artn, Ptn); cytokine (IL3); cell cycle (Hdac4); and notch signaling (Hes1) were up-regulated three days after MSC transplant. Transcriptome analysis demonstrated that 7,943 genes were differentially expressed and 94 signaling pathways were activated in the topical MSCs transplanted onto the cortex of brain injured rats with TBI. In conclusion, topical application offers a direct and efficient delivery of MSCs to the brain.

ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms.

OBJECTIVE: To develop a risk score that estimates 3-year and 5-year absolute risks for aneurysm growth. METHODS: From 10 cohorts of patients with unruptured intracranial aneurysms and follow-up imaging, we pooled individual data on sex, population, age, hypertension, history of subarachnoid hemorrhage, and aneurysm location, size, aspect ratio, and shape but not on smoking during follow-up and family history of intracranial aneurysms in 1,507 patients with 1,909 unruptured intracranial aneurysms and used aneurysm growth as outcome. With aneurysm-based multivariable Cox regression analysis, we determined predictors for aneurysm growth, which were presented as a risk score to calculate 3-year and 5-year risks for aneurysm growth by risk factor status. RESULTS: Aneurysm growth occurred in 257 patients (17%) and 267 aneurysms (14%) during 5,782 patient-years of follow-up. Predictors for aneurysm growth were earlier subarachnoid hemorrhage, location of the aneurysm, age >60 years, population, size of the aneurysm, and shape of the aneurysm (ELAPSS). The 3-year growth risk ranged from <5% to >42% and the 5-year growth risk from <9% to >60%, depending on the risk factor status. CONCLUSIONS: The ELAPSS score consists of 6 easily retrievable predictors and can help physicians in decision making on the need for and timing of follow-up imaging in patients with unruptured intracranial aneurysms.

Clinically important difference of Stroke-Specific Quality of Life Scale for aneurysmal subarachnoid hemorrhage.

Health-related quality of life measurements, are commonly used to quantify burden of disease, to evaluate treatment method, and to facilitate benchmarking. The aim of the current study was to determine the Clinically Important Difference (CID) for a Chinese version of Stroke-specific Quality of Life (SS-QOL) in an aneurysmal subarachnoid hemorrhage (SAH) patient cohort. The study recruited SAH patients in a neurosurgical unit in Hong Kong. SAH patients who completed both 3-month and 1-year assessments were included in the analysis. The study received ethical approvals from the joint CUHK-NTEC Clinical Ethics Committee and written informed consent was obtained from all participants or their next of kins. Over a 2-year period, 65 eligible patients were included in the study. Employing the anchor-based approach with global rating of change, the CID estimate of SS-QOL total score was 4.7 (95% confidence interval [CI]: 2.5-5.3), the CID estimate for SSQOL physical subscore was 2.1 (95% CI: 0.3-2.4), and the CID estimate for SS-QOL psychosocial subscore change was 2.8 (95% CI: 1.8-3.7). In conclusion, our study defined the CID for SS-QOL applied to SAH patients and should be further validated in another SAH patient population.

Topical Therapy with Mesenchymal Stem Cells Following an Acute Experimental Head Injury Has Benefits in Motor-Behavioral Tests for Rodents.

BACKGROUND: The neuroprotective effects of mesenchymal stem cells (MSCs) have been reported in rodent and in preliminary clinical studies. MSCs are usually transplanted to patients by systemic infusion. However, only a few of the infused MSCs are delivered to the brain because of pulmonary trapping and the blood-brain barrier. In this study, MSCs were topically applied to the site of traumatic brain injury (TBI) and the neuroprotective effects were assessed. MATERIALS AND METHODS: TBI was induced in Sprague-Dawley (SD) rats with an electromagnetically controlled cortical impact device after craniotomy was performed between the bregma and lambda, 1 mm lateral to the midline. We applied 1.5 million MSCs, derived from the adipose tissue of transgenic green fluorescent protein (GFP)-SD rats, to the exposed cerebral cortex at the injured site. The MSCs were held in position by a thin layer of fibrin. Neurological function in the test (n = 10) and control (n = 10) animals was evaluated using the rotarod test, the water maze test, and gait analysis at different time points. RESULTS: Within 5 days following topical application, GFP-positive cells were found in the brain parenchyma. These cells co-expressed with markers of Glial fibrillary acidic protein (GFAP), nestin, and NeuN. There was less neuronal death in CA1 and CA3 of the hippocampus in the test animals. Neurological functional recovery was significantly improved. CONCLUSION: Topically applied MSCs can migrate to the injured brain parenchyma and offer neuroprotective effects.

Screening for intracranial aneurysms? Prevalence of unruptured intracranial aneurysms in Hong Kong Chinese.

OBJECT The objective of this study was to generate data on the local prevalence of unruptured intracranial aneurysms (UIAs) in asymptomatic Hong Kong Chinese individuals. First-degree relatives of patients with aneurysmal subarachnoid hemorrhage (aSAH) were recruited as surrogates of the general population and to explore the potential role of screening in this locality. METHODS The authors identified first-degree relatives of consecutive patients with subarachnoid hemorrhage from a ruptured aneurysm who were admitted to a university hospital in Hong Kong from June 2008 to December 2010. Magnetic resonance angiography (MRA) was the imaging modality used to screen the cerebral vasculature of these asymptomatic individuals. If MRA showed abnormal findings, CT angiography was performed to confirm the MRA findings. RESULTS In total, 7 UIAs were identified from the 305 MR angiograms obtained. The prevalence of UIAs in first-degree relatives of patients with aSAH in the Hong Kong Chinese population was 2.30% (95% CI1.02%-4.76%). This percentage was lower than the prevalence rate of 3.2% from a meta-analysis of the literature. The sizes of the UIAs detected ranged from 1.4 mm to 7.5 mm; 85.7% of the UIAs detected in this study were < 5 mm, in contrast to 66% noted in the literature. One of the UIAs identified underwent endovascular stent placement with a flow diverter. None of the UIAs identified ruptured or became symptomatic during a median follow-up period of 3.5 years. CONCLUSIONS The prevalence of UIAs in first-degree relatives of patients with aSAH in the Hong Kong Chinese population was lower than that in Caucasians. At the same time, most of the UIAs detected in this study were small (85.7% were < 5 mm, vs 66% in a meta-analysis). With a similar incidence of aSAH in Hong Kong (7.5 per 100,000 person-years) as compared with data cited in the literature, the hypothesis that UIA rupture risk size threshold is different in Chinese patients should be further investigated.

Early Magnesium Treatment After Aneurysmal Subarachnoid Hemorrhage: Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Trials of magnesium treatment starting <4 days after symptom onset found no effect on poor outcome or DCI in SAH. Earlier installment of treatment might be more effective, but individual trials had not enough power for such a subanalysis. We performed an individual patient data meta-analysis to study whether magnesium is effective when given within different time frames within 24 hours after the SAH. METHODS: Patients were divided into categories according to the delay between symptom onset and start of the study medication: <6, 6 to 12, 12 to 24, and >24 hours. We calculated adjusted risk ratios with corresponding 95% confidence intervals for magnesium versus placebo treatment for poor outcome and DCI. RESULTS: We included 5 trials totaling 1981 patients; 83 patients started treatment<6 hours. For poor outcome, the adjusted risk ratios of magnesium treatment for start <6 hours were 1.44 (95% confidence interval, 0.83-2.51); for 6 to 12 hours 1.03 (0.65-1.63), for 12 to 24 hours 0.84 (0.65-1.09), and for >24 hours 1.06 (0.87-1.31), and for DCI, <6 hours 1.76 (0.68-4.58), for 6 to 12 hours 2.09 (0.99-4.39), for 12 to 24 hours 0.80 (0.56-1.16), and for >24 hours 1.08 (0.88-1.32). CONCLUSIONS: This meta-analysis suggests no beneficial effect of magnesium treatment on poor outcome or DCI when started early after SAH onset. Although the number of patients was small and a beneficial effect cannot be definitively excluded, we found no justification for a new trial with early magnesium treatment after SAH.

Cognitive outcome in acute simvastatin treatment for aneurysmal subarachnoid hemorrhage: A propensity matched analysis.

OBJECTIVES: Experimental evidence has indicated the benefit of simvastatin in the treatment of subarachnoid hemorrhage (SAH). Recently, acute simvastatin treatment was not shown to be beneficial in neurological outcome using modified Rankin Scale. Cognitive function is another important dimension of outcome assessment and yet had not been investigated in statin studies for aneurysmal subarachnoid hemorrhage. We therefore explored whether acute simvastatin treatment would improve cognitive outcomes. METHODS: The study recruited SAH patients with acute simvastatin treatment enrolled in a randomized controlled double-blinded clinical trial (ClinicalTrials.gov Identifier: NCT01038193). A control cohort of SAH patients without simvastatin treatment was identified with propensity score matching of age and admission grade. Primary outcome measure was Montreal Cognitive Assessment (MoCA). Secondary outcome measures were delayed ischaemic deficit (DID), delayed cerebral infarction, modified Rankin Scale (mRS), and Mini-Mental State Examination (MMSE). RESULTS: Fifty-one SAH patients with acute simvastatin treatment and 51 SAH patients without simvastatin treatment were recruited for analysis. At 3 months, there were no differences in MoCA scores (MoCA: 21+/-6 vs. 21+/-5, p=0.772). MoCA-assessed cognitive impairment (MoCA<26) was not different (75% vs. 80%, OR 0.7, 95%CI 0.3 to 1.8, p=0.477). There were also no differences in DID, delayed cerebral infarction, favorable mRS outcome, and MMSE scores, and MMSE-assessed cognitive impairment between both groups. CONCLUSIONS: The current study does not support that acute simvastatin treatment improves cognitive outcome after aneurysmal subarachnoid hemorrhage.

High-dose simvastatin for aneurysmal subarachnoid hemorrhage: multicenter randomized controlled double-blinded clinical trial.

BACKGROUND AND PURPOSE: Experimental evidence has indicated the benefits of simvastatin for the treatment of subarachnoid hemorrhage. Two randomized placebo-controlled pilot trials that used the highest clinically approved dose of simvastatin (80 mg daily) gave positive results despite the fact that a lower dose of simvastatin (40 mg daily) did not improve clinical outcomes. We hypothesized that a high dose of 80 mg of simvastatin daily for 3 weeks would reduce the incidence of delayed ischemic deficits after subarachnoid hemorrhage compared with a lower dose (40 mg of simvastatin daily) and lead to improved clinical outcomes. METHODS: The study design was a randomized controlled double-blinded clinical trial. Patients with aneurysmal subarachnoid hemorrhage (presenting within 96 hours of the ictus) from 6 neurosurgical centers were recruited for 3 years. The primary outcome measure was the presence of delayed ischemic deficits, and secondary outcome measures included a modified Rankin disability score at 3 months and an analysis of cost-effectiveness. RESULTS: No difference was observed between the groups treated with the higher dose or the lower dose of simvastatin in the incidence of delayed ischemic deficits (27% versus 24%; odds ratio, 1.2; 95% confidence interval, 0.7-2.0; P=0.586) or in the rate of favorable outcomes (modified Rankin Scale score, 0-2) at 3 months (73% versus 72%; odds ratio, 1.1; 95% confidence interval, 0.6-1.9; P=0.770). CONCLUSIONS: High-dose simvastatin treatment should not be prescribed routinely for aneurysmal subarachnoid hemorrhage. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01077206.