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Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.

Abstract BACKGROUND Middle meningeal artery (MMA) embolization is an emerging minimally invasive endovascular technique for chronic subdural hematoma (cSDH). Currently, limited literature exists on its safety and efficacy compared with conventional treatment (open-surgical-evacuation-only). OBJECTIVE To compare MMA embolization to conventional treatment. METHODS Retrospective analysis of patients with cSDHs treated with MMA embolization in a single center from 2018 to 2019 was performed. Comparisons were made with a historical conventional treatment cohort from 2006 to 2016. Propensity score matching analysis was used to assemble a balanced group of subjects. RESULTS A total of 357 conventionally treated cSDH and 45 with MMA embolization were included. After balancing with propensity score matching, a total of 25 pairs of cSDH were analyzed. Comparing the embolization with the conventional treatment group yielded no significant differences in complications (4% vs 4%; P > .99), clinical improvement (82.6% vs 83.3%; P = .95), cSDH recurrence (4.3% vs 21.7%; P = .08), overall re-intervention rates (12% vs 24%; P = .26), modified Rankin scale >2 on last follow-up (17.4% vs 32%; P = .24), as well as mortality (0% vs 12%; P = .09). Radiographic improvement at last follow-up was significantly higher in the open surgery cohort (73.9% vs 95.6%; P = .04). However, there was a trend for lengthier last follow-up for the historical cohort (72 vs 104 d; P = .07). CONCLUSION There was a trend for lower recurrence and mortality rates in the embolization era cohort. There were significantly higher radiological improvement rates on last follow-up in the surgical only cohort era. There were no significant differences in complications and clinical improvement. Graphical Abstract Graphical Abstract

Abstract BACKGROUND In adults with ischemic moyamoya disease (MMD), the efficacy of direct vs indirect revascularization procedures remains a matter of debate. OBJECTIVE To investigate the outcomes of ischemic MMD in a North American cohort treated by direct and indirect revascularizations. METHODS We retrospectively reviewed medical records of adult patients with MMD with ischemic presentation from 1984 to 2018 at the Brigham and Women's Hospital and Massachusetts General Hospital who underwent either direct or indirect bypasses. Early postoperative events and outcome at more than 6 mo postoperatively were evaluated using multivariable logistic regression analyses. Multivariable Cox proportional hazards regression analyses were used to evaluate delayed ischemic and hemorrhagic events. Analyses were performed per hemisphere. RESULTS A total of 95 patients with MMD and 127 hemispheres were included in this study. A total of 3.5% and 8.6% of patients had early surgical complications in the direct and indirect bypass cohorts, respectively (P = .24). Hemispheres with direct bypasses had fewer long-term ischemic and hemorrhagic events at latest follow-up (adjusted hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.058-0.63, P = .007; median follow-up 4.5 [interquartile range, IQR 1-8] yr). There was no difference between the direct and indirect bypass groups when the endpoint was limited to infarction and hemorrhage only (P = .12). There was no difference in outcome (modified Rankin Scale [mRS] ≥ 3) between the 2 cohorts (P = .92). CONCLUSION There was no difference in early postoperative events, long-term infarction or hemorrhage, or clinical outcome between direct and indirect revascularization. However, there was a significant decrease in all ischemic and hemorrhagic events combined in direct revascularizations compared to indirect revascularizations. Graphical Abstract Graphical Abstract

Abstract BACKGROUND: The supplementary grading system for brain arteriovenous malformations (AVMs) was introduced in 2010 as a tool for improving preoperative risk prediction and selecting surgical patients. OBJECTIVE: To demonstrate in this multicenter validation study that supplemented Spetzler-Martin (SM-Supp) grades have greater predictive accuracy than Spetzler-Martin (SM) grades alone. METHODS: Data collected from 1009 AVM patients who underwent AVM resection were used to compare the predictive powers of SM and SM-Supp grades. Patients included the original 300 University of California, San Francisco patients plus those treated thereafter (n = 117) and an additional 592 patients from 3 other centers. RESULTS: In the combined cohort, the SM-Supp system performed better than SM system alone: area under the receiver-operating characteristics curve (AUROC) = 0.75 (95% confidence interval, 0.71–0.78) for SM-Supp and AUROC = 0.69 (95% confidence interval, 0.65-0.73) for SM (P < .001). Stratified analysis fitting models within 3 different follow-up groupings (<6 months, 6 months-2 years, and >2 years) demonstrated that the SM-Supp system performed better than SM system for both medium (AUROC = 0.71 vs 0.62; P = .003) and long (AUROC = 0.69 vs 0.58; P = .001) follow-up. Patients with SM-Supp grades ⩽6 had acceptably low surgical risks (0%-24%), with a significant increase in risk for grades >6 (39%-63%). CONCLUSION: This study validates the predictive accuracy of the SM-Supp system in a multicenter cohort. An SM-Supp grade of 6 is a cutoff or boundary for AVM operability. Supplemented grading is currently the best method of estimating neurological outcomes after AVM surgery, and we recommend it as a starting point in the evaluation of AVM operability.

Abstract BACKGROUND Thromboembolic and hemorrhagic complications are among the most feared adverse events in the endovascular treatment of aneurysms, and this is particularly the case for flow diverter devices. Dual antiplatelet therapy has become standard of care; however, the safety, efficacy, and cost profiles of newer antiplatelet agents are not well characterized in the neurovascular context. OBJECTIVE To compare the safety, efficacy, and cost of one of these newer agents, ticagrelor, to the most frequently used agent, clopidogrel. METHODS A multicenter, retrospective, cohort comparison study design of consecutively treated aneurysms with flow diverter embolization device and treated with either ticagrelor or clopidogrel was performed. Data were collected on patient demographics and risk factors, procedural details, antiplatelet treatment regime, complications, and angiographic and functional outcomes. RESULTS Fifty patients undergoing flow diverter device deployment and treatment with ticagrelor were compared to 53 patients undergoing flow diversion and treatment with clopidogrel. The patients’ age, sex, smoking status, aneurismal morphology and size, and procedural details did not differ between the 2 groups; neither did the rate of thromboembolic and hemorrhagic complications, angiographical, and functional outcomes. Ticagrelor was more expensive when compared to clopidogrel. CONCLUSION Ticagrelor is a safe and effective agent for prevention of thromboembolic complications following flow diverter deployment when compared to clopidogrel. However, ticagrelor remains significantly more expensive than clopidogrel, and, thus, we would advise ticagrelor be reserved for patients who are hyporesponsive to clopidogrel.

Intracranial aneurysms are common, and the risk of rupture is influenced by size, location, morphology, and factors such as hypertension, smoking, and family history. Management options and risks are discussed.

A recent systematic review indicated that gut–microbiota–brain axis contributes to growth and rupture of intracranial aneurysms. However, gaps were detected in the role of intestinal microbiome in cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH). This is the first pilot study aiming to test study feasibility and identify differences in gut microbiota between subjects with and without CVS following aSAH. A prospective nested case–control pilot study with 1:1 matching was conducted recruiting subjects with aSAH: cases with CVS; and controls without CVS based on the clinical picture and structured bedside transcranial Doppler (TCD). Fecal samples for microbiota analyses by means of 16S rRNA gene amplicon sequencing were collected within the first 96 h after ictus. Operational taxonomic unit tables were constructed, diversity metrics calculated, phylogenetic trees built, and differential abundance analysis (DAA) performed. At baseline, the groups did not differ significantly in basic demographic and aneurysm-related characteristics ( p  > 0.05). Alpha-diversity (richness and Shannon Index) was significantly reduced in cases of middle cerebral artery (MCA) vasospasm ( p  < 0.05). In DAA, relative abundance of genus Acidaminococcus was associated with MCA vasospasm ( p  = 0.00013). Two butyrate-producing genera, Intestinimonas and Butyricimonas , as well as [ Clostridium ] innocuum group had the strongest negative correlation with the mean blood flow velocity in anterior cerebral arteries ( p  < 0.01; rho = − 0.63; − 0.57, and − 0.57, respectively). In total, 16 gut microbial genera were identified to correlate with TCD parameters, and two intestinal genera correlated with outcome upon discharge. In this pilot study, we prove study feasibility and present the first preliminary evidence of gut microbiome signature associating with CVS as a significant cause of stroke in subjects with aSAH.

Abstract BACKGROUND Flow diversion for basilar apex aneurysms has rarely been reported. OBJECTIVE To assess flow diversion for basilar apex aneurysms in a multicenter cohort. METHODS Retrospective review of prospectively maintained databases at 8 academic institutions was performed from 2009 to 2016 to identify patients with basilar apex aneurysms treated with flow diversion. Clinical and radiographic data were analyzed. RESULTS Sixteen consecutive patients (median age 54.5 yr) underwent 18 procedures to treat 16 basilar apex aneurysms with either the Pipeline Embolization Device (Medtronic Inc, Dublin, Ireland) or Flow Redirection Endoluminal Device (Microvention, Tustin, California). Five aneurysms (31.3%) were treated in the setting of subarachnoid hemorrhage. Seven aneurysms (43.8%) were treated with flow diversion alone, while 9 (56.2%) underwent flow diversion and adjunctive coiling. At a median follow-up of 6 mo, complete (100%) and near-complete (90%-99%) occlusion was noted in 11 (68.8%) aneurysms. Incomplete occlusion occurred more commonly in patients treated with flow diversion alone compared to those with adjunctive coiling. Patients with partial occlusion were significantly younger. Retreatment with an additional flow diverter and adjunctive coiling occurred in 2 aneurysms with wide necks. There was 1 mortality in a patient (6.3%) who experienced posterior cerebral artery and cerebellar strokes as well as subarachnoid hemorrhage after the placement of a flow diverter. Minor complications occurred in 2 patients (12.5%). CONCLUSION Flow diversion for the treatment of basilar apex aneurysms results in acceptable occlusion rates in highly selected cases. Both primary flow diversion and rescue after failed clipping or coiling resulted in a modified Rankin Scale score that was either equal or better than at presentation and the technology represents a viable alternative or adjunctive option.

Abstract BACKGROUND Patients with bilateral chronic subdural hematoma (bCSDH) undergo unilateral evacuation for the large or symptomatic side because the contralateral hematoma is either small or asymptomatic. However, the contralateral hematoma may subsequently grow and require evacuation. OBJECTIVE To characterize factors that predict contralateral hematoma growth and need for evacuation. METHODS A retrospective study on 128 surgically treated bCSDHs. RESULTS Fifty-one and 77 were bilaterally and unilaterally evacuated, respectively. Glasgow Coma Scale was lower and midline shift was higher in those evacuated unilaterally compared to those evacuated bilaterally. Hematoma size was a significant determinant of decision for unilateral vs bilateral evacuation. The contralateral side needed evacuation at a later stage in 7 cases (9.1%). There was no significant difference in terms of reoperation rate between those evacuated unilaterally and bilaterally. Greater contralateral hematoma thickness on the first postoperative day computed tomography (CT) and more postoperative midline shift reversal had higher rates of operation in the opposite side. There was no difference between the daily pace of hematoma decrease in the operated and nonoperated sides (0.7% decrease per day vs 0.9% for the operated and nonoperated sides, respectively). CONCLUSION Results of this study show that most bCSDHs evacuated unilaterally do not experience growth in the nonoperated side and unilateral evacuation results in hematoma resolution for both sides in most cases. Hematoma thickness on the opposite side on the first postoperative day CT and amount of midline shift reversal after surgery are the most important factors predicting the need for surgery on the opposite side.

Abstract BACKGROUND There is ongoing controversy regarding the optimal antiplatelet regimen, and extent or even need for platelet function testing surrounding Pipeline flow diverter (Medtronic Inc, Dublin, Ireland) embolization of cerebral aneurysms. OBJECTIVE To compare a unique pharmacy-mediated antiplatelet medication management protocol to a 1-time platelet function testing strategy prior to Pipeline placement. METHODS A retrospective review of patients with cerebral aneurysms who underwent Pipeline embolization at 2 academic institutions was performed. The first line antiplatelet regimen consisted of aspirin and clopidogrel at both institutions. At institution A, the pharmacy-mediated antiplatelet medication management protocol consisted of repeat platelet function testing using VerifyNow (Accriva Diagnostics, San Diego, California), and dosing adjustments prior to and after Pipeline placement. At institution B, a 1-time platelet function test using light transmission aggregometry was obtained prior to Pipeline placement. Both strategies were compared using propensity score matching. RESULTS A total of 63 and 165 Pipeline embolization procedures were performed at institutions A and B, respectively. Baseline characteristics differed in aneurysm location and aneurysm maximal diameter. Propensity score matching resulted in 25 matched pairs and demonstrated that the number of procedures in which the patient was switched to an alternative platelet agent was significantly smaller at institution A. There were no differences between the sites with regard to aneurysm occlusion rate, the incidence of thromboembolic and hemorrhagic complications, and modified Rankin scale at last follow-up after propensity score matching. CONCLUSION Pharmacy-mediated antiplatelet management using VerifyNow is a safe and efficacious alternative to a more traditional approach, and significantly reduces the need to utilize other, potentially more expensive antiplatelet agents.