Sex differences in patients with and without high-risk factors associated with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Controversy remains regarding the appropriate screening for intracranial aneurysms or for the treatment of aneurysmal subarachnoid hemorrhage (aSAH) for patients without known high-risk factors for rupture. This study aimed to assess how sex affects both aSAH presentation and outcomes for aSAH treatment. METHOD: A retrospective cohort study was conducted of all patients treated at a single institution for an aSAH during a 12-year period (August 1, 2007-July 31, 2019). An analysis of women with and without high-risk factors was performed, including a propensity adjustment for a poor neurologic outcome (modified Rankin Scale [mRS] score > 2) at follow-up. RESULTS: Data from 1014 patients were analyzed (69% [n = 703] women). Women were significantly older than men (mean ± SD, 56.6 ± 14.1 years vs 53.4 ± 14.2 years, p < 0.001). A significantly lower percentage of women than men had a history of tobacco use (36.6% [n = 257] vs 46% [n = 143], p = 0.005). A significantly higher percentage of women than men had no high-risk factors for aSAH (10% [n = 70] vs 5% [n = 16], p = 0.01). The percentage of women with an mRS score > 2 at the last follow-up was significantly lower among those without high-risk factors (34%, 24/70) versus those with high-risk factors (53%, 334/633) (p = 0.004). Subsequent propensity-adjusted analysis (adjusted for age, Hunt and Hess grade, and Fisher grade) found no statistically significant difference in the odds of a poor outcome for women with or without high-risk factors for aSAH (OR = 0.7, 95% CI = 0.4-1.2, p = 0.18). CONCLUSIONS: A higher percentage of women versus men with aSAH had no known high-risk factors for rupture, supporting more aggressive screening and management of women with unruptured aneurysms.

Propensity-adjusted analysis of ultra-early aneurysmal subarachnoid hemorrhage treatment and patient outcomes.

BACKGROUND: Optimal definitive treatment timing for patients with aneurysmal subarachnoid hemorrhage (aSAH) remains controversial. We compared outcomes for aSAH patients with ultra-early treatment versus later treatment at a single large center. METHOD: Patients who received definitive open surgical or endovascular treatment for aSAH between January 1, 2014, and July 31, 2019, were included. Ultra-early treatment was defined as occurring within 24 h from aneurysm rupture. The primary outcome was poor neurologic outcome (modified Rankin Scale score > 2). Propensity adjustment was performed for age, sex, Charlson Comorbidity Index, Hunt and Hess grade, Fisher grade, aneurysm treatment type, aneurysm type, size, and anterior location. RESULTS: Of the 1013 patients (mean [SD] age, 56 [14] years; 702 [69%] women, 311 [31%] men) included, 94 (9%) had ultra-early treatment. Compared with the non-ultra-early cohort, the ultra-early treatment cohort had a significantly lower percentage of saccular aneurysms (53 of 94 [56%] vs 746 of 919 [81%], P <0 .001), greater frequency of open surgical treatment (72 of 94 [77%] vs 523 of 919 [57%], P <0 .001), and greater percentage of men (38 of 94 [40%] vs 273 of 919 [30%], P = .04). After adjustment, ultra-early treatment was not associated with neurologic outcome in those with at least 180-day follow-up (OR = 0.86), the occurrence of delayed cerebral ischemia (OR = 0.87), or length of stay (exp(ß), 0.13) (P ≥ 0.60). CONCLUSIONS: In a large, single-center cohort of aSAH patients, ultra-early treatment was not associated with better neurologic outcome, fewer cases of delayed cerebral ischemia, or shorter length of stay.

Association between external ventricular drain removal or replacement and prophylactic anticoagulation in patients with aneurysmal subarachnoid hemorrhage: a propensity-adjusted analysis.

BACKGROUND: Withholding prophylactic anticoagulation from patients with aneurysmal subarachnoid hemorrhage (aSAH) before external ventricular drain (EVD) removal or replacement remains controversial. This study analyzed whether prophylactic anticoagulation was associated with hemorrhagic complications related to EVD removal. METHOD: All aSAH patients treated from January 1, 2014, to July 31, 2019, with an EVD placed were retrospectively analyzed. Patients were compared based on the number of prophylactic anticoagulant doses withheld for EVD removal (> 1 vs. ≤ 1). The primary outcome analyzed was deep venous thrombosis (DVT) or pulmonary embolism (PE) after EVD removal. A propensity-adjusted logistic-regression analysis was performed for confounding variables. RESULTS: A total of 271 patients were analyzed. For EVD removal, > 1 dose was withheld from 116 (42.8%) patients. Six (2.2%) patients had a hemorrhage associated with EVD removal, and 17 (6.3%) patients had a DVT or PE. No significant difference in EVD-related hemorrhage after EVD removal was found between patients with > 1 versus ≤ 1 dose of anticoagulant withheld (4 of 116 [3.5%] vs. 2 of 155 [1.3%]; p = 0.41) or between those with no doses withheld compared to ≥ 1 dose withheld (1 of 100 [1.0%] vs. 5 of 171 [2.9%]; p = 0.32). After adjustment, withholding > 1 dose of anticoagulant versus ≤ 1 dose was associated with the occurrence of DVT or PE (OR 4.8; 95% CI, 1.5-15.7; p = 0.009). CONCLUSIONS: In aSAH patients with EVDs, withholding > 1 dose of prophylactic anticoagulant for EVD removal was associated with an increased risk of DVT or PE and no reduction in catheter removal-associated hemorrhage.

Cerebrospinal Fluid Biomarkers for Diagnosis and the Prognostication of Acute Ischemic Stroke: A Systematic Review.

Despite the high incidence and burden of stroke, biological biomarkers are not used routinely in clinical practice to diagnose, determine progression, or prognosticate outcomes of acute ischemic stroke (AIS). Because of its direct interface with neural tissue, cerebrospinal fluid (CSF) is a potentially valuable source for biomarker development. This systematic review was conducted using three databases. All trials investigating clinical and preclinical models for CSF biomarkers for AIS diagnosis, prognostication, and severity grading were included, yielding 22 human trials and five animal studies for analysis. In total, 21 biomarkers and other multiomic proteomic markers were identified. S100B, inflammatory markers (including tumor necrosis factor-alpha and interleukin 6), and free fatty acids were the most frequently studied biomarkers. The review showed that CSF is an effective medium for biomarker acquisition for AIS. Although CSF is not routinely clinically obtained, a potential benefit of CSF studies is identifying valuable biomarkers from the pathophysiologic microenvironment that ultimately inform optimization of targeted low-abundance assays from peripheral biofluid samples (e.g., plasma). Several important catabolic and anabolic markers can serve as effective measures of diagnosis, etiology identification, prognostication, and severity grading. Trials with large cohorts studying the efficacy of biomarkers in altering clinical management are still needed.

Nanoliposomes Reduce Stroke Injury Following Middle Cerebral Artery Occlusion in Mice.

BACKGROUND AND PURPOSE: Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phosphatidylcholine, cholesterol, and monosialogangliosides (nanoliposomes) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that nanoliposomes will preserve human neuroblastoma (SH-SY5Y) and human brain microvascular endothelial cells viability following oxygen-glucose deprivation (OGD)-reoxygenation and will reduce injury in mice following middle cerebral artery occlusion. METHODS: SH-SY5Y and human brain microvascular endothelial cells were exposed to oxygen-glucose deprivation-reoxygenation (3 hours 0.5%-1% oxygen and glucose-free media followed by 20-hour ambient air/regular media) without or with nanoliposomes (300 µg/mL). Viability was measured (calcein-acetoxymethyl fluorescence) and protein expression of antioxidant proteins HO-1 (heme oxygenase-1), NQO1 (NAD[P]H quinone dehydrogenase 1), and SOD1 (superoxide dismutase 1) were measured by Western blot. C57BL/6J mice were treated with saline (n=8) or nanoliposomes (10 mg/mL lipid, 200 µL, n=7) while undergoing 60-minute middle cerebral artery occlusion followed by reperfusion. Day 2 postinjury neurological impairment score and infarction size were compared. RESULTS: SH-SY5Y and human brain microvascular endothelial cells showed reduced viability post-oxygen-glucose deprivation-reoxygenation that was reversed by nanoliposomes. Nanoliposomes increased protein expressions of HO-1, NQO1 in both cell types and SOD1 in human brain microvascular endothelial cells. Nanoliposomes-treated mice showed reduced neurological impairment and brain infarct size (18.8±2% versus 27.3±2.3%, P=0.017) versus controls. CONCLUSIONS: Nanoliposomes reduced stroke injury in mice subjected to middle cerebral artery occlusion likely through induction of an antioxidant protective response. Nanoliposome is a candidate novel agent for stroke.

Electroencephalography for detection of vasospasm and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a retrospective analysis and systematic review.

OBJECTIVE: Good functional outcomes after aneurysmal subarachnoid hemorrhage (aSAH) are often dependent on early detection and treatment of cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI). There is growing evidence that continuous monitoring with cranial electroencephalography (cEEG) can predict CVS and DCI. Therefore, the authors sought to assess the value of continuous cEEG monitoring for the detection of CVS and DCI in aSAH. METHODS: The cerebrovascular database of a quaternary center was reviewed for patients with aSAH and cEEG monitoring between January 1, 2017, and July 31, 2019. Demographic data, cardiovascular risk factors, Glasgow Coma Scale score at admission, aneurysm characteristics, and outcomes were abstracted from the medical record. Patient data were retrospectively analyzed for DCI and angiographically assessed CVS. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and odds ratio for cEEG, transcranial Doppler ultrasonography (TCDS), CTA, and DSA in detecting DCI and angiographic CVS were calculated. A systematic literature review was conducted in accordance with PRISMA guidelines querying the PubMed, Cochrane Controlled Trials Register, Web of Science, and Embase databases. RESULTS: A total of 77 patients (mean age 60 years [SD 15 years]; female sex, n = 54) were included in the study. Continuous cEEG monitoring detected DCI and angiographically assessed CVS with specificities of 82.9% (95% CI 66.4%-93.4%) and 94.4% (95% CI 72.7%-99.9%), respectively. The sensitivities were 11.1% (95% CI 3.1%-26.1%) for DCI (n = 71) and 18.8% (95% CI 7.2%-36.4%) for angiographically assessed CVS (n = 50). Furthermore, TCDS detected angiographically determined CVS with a sensitivity of 87.5% (95% CI 71.0%-96.5%) and specificity of 25.0% (95% CI 7.3%-52.4%). In patients with DCI, TCDS detected vasospasm with a sensitivity of 85.7% (95% CI 69.7%-95.2%) and a specificity of 18.8% (95% CI 7.2%-36.4%). DSA detected vasospasm with a sensitivity of 73.9% (95% CI 51.6%-89.8%) and a specificity of 47.8% (95% CI 26.8%-69.4%). CONCLUSIONS: The study results suggest that continuous cEEG monitoring is highly specific in detecting DCI as well as angiographically assessed CVS. More prospective studies with predetermined thresholds and endpoints are needed to assess the predictive role of cEEG in aSAH.

Microsurgical treatment of ruptured aneurysms beyond 72 hours after rupture: implications for advanced management.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) patients admitted to primary stroke centers are often transferred to neurosurgical and endovascular services at tertiary centers. The effect on microsurgical outcomes of the resultant delay in treatment is unknown. We evaluated microsurgical aSAH treatment > 72 h after the ictus. METHODS: All aSAH patients treated at a single tertiary center between August 1, 2007, and July 31, 2019, were retrospectively reviewed. The additional inclusion criterion was the availability of treatment data relative to time of bleed. Patients were grouped based on bleed-to-treatment time as having acute treatment (on or before postbleed day [PBD] 3) or delayed treatment (on or after PBD 4). Propensity adjustments were used to correct for statistically significant confounding covariables. RESULTS: Among 956 aSAH patients, 92 (10%) received delayed surgical treatment (delayed group), and 864 (90%) received acute endovascular or surgical treatment (acute group). Reruptures occurred in 3% (26/864) of the acute group and 1% (1/92) of the delayed group (p = 0.51). After propensity adjustments, the odds of residual aneurysm (OR = 0.09; 95% CI = 0.04-0.17; p < 0.001) or retreatment (OR = 0.14; 95% CI = 0.06-0.29; p < 0.001) was significantly lower among the delayed group. The OR was 0.50 for rerupture, after propensity adjustments, in the delayed setting (p = 0.03). Mean Glasgow Coma Scale scores at admission in the acute and delayed groups were 11.5 and 13.2, respectively (p < 0.001). CONCLUSIONS: Delayed microsurgical management of aSAH, if required for definitive treatment, appeared to be noninferior with respect to retreatment, residual, and rerupture events in our cohort after adjusting for initial disease severity and significant confounding variables.

Delays in presentation and mortality among Black patients with mechanical thrombectomy after large-vessel stroke at a US hospital.

OBJECTIVE: The incidence and severity of stroke are disproportionately greater among Black patients. In this study, the authors sought to examine clinical outcomes among Black versus White patients after mechanical thrombectomy for stroke at a single US institution. METHODS: All patients who underwent mechanical thrombectomy at a single center from January 1, 2014, through March 31, 2020, were retrospectively analyzed. Patients were grouped based on race, and demographic characteristics, preexisting conditions, clinical presentation, treatment, and stroke outcomes were compared. The association of race with mortality was analyzed in multivariable logistic regression analysis adjusted for potential confounders. RESULTS: In total, 401 patients (233 males) with a reported race of Black (n = 28) or White (n = 373) underwent mechanical thrombectomy during the study period. Tobacco use was more prevalent among Black patients (43% vs 24%, p = 0.04), but there were no significant differences between the groups with respect to insurance, coronary artery disease, diabetes, illicit drug use, hypertension, or hyperlipidemia. The mean time from stroke onset to hospital presentation was significantly greater among Black patients (604.6 vs 333.4 minutes) (p = 0.007). There were no differences in fluoroscopy time, procedural success (Thrombolysis in Cerebral Infarction grade 2b or 3), hospital length of stay, or prevalence of hemicraniectomy. In multivariable analysis, Black race was strongly associated with higher mortality (32.1% vs 14.5%, p = 0.01). The disparity in mortality rates resolved after adjusting for the average time from stroke onset to presentation (p = 0.14). CONCLUSIONS: Black race was associated with an increased risk of death after mechanical thrombectomy for stroke. The increased risk may be associated with access-related factors, including delayed presentation to stroke centers.

Small intracranial aneurysms in the Barrow Ruptured Aneurysm Trial (BRAT).

BACKGROUND: Treatment of small ruptured aneurysms (SRAs) remains controversial, with literature reporting difficulty with endovascular versus microsurgical approaches. This paper analyzes outcomes after endovascular coiling and microsurgical clipping among patients with SRAs prospectively enrolled in the Barrow Ruptured Aneurysm Trial (BRAT). METHOD: All BRAT patients were included in this study. Patient demographics, aneurysm size, aneurysm characteristics, procedure-related complications, and outcomes at discharge and at 1-year and 6-year follow-up were evaluated. A modified Rankin scale (mRS) score > 2 was considered a poor outcome. RESULTS: Of 73 patients with SRAs, 40 were initially randomly assigned to endovascular coiling and 33 to microsurgical clipping. The rate of treatment crossover was significantly different between coiling and clipping; 25 patients who were assigned to coiling crossed over to clipping, and no clipping patients crossed over to coiling (P < 0.001). Among SRA patients, 15 underwent coiling and 58 underwent clipping; groups did not differ significantly in demographic characteristics or aneurysm type (P ≥ 0.11). Mean aneurysm diameter was significantly greater in the endovascular group (3.0 ± 0.3 vs 2.6 ± 0.6; P = 0.02). The incidence of procedure-related complications was similar for endovascular and microsurgical treatments (odds ratio [95% confidence interval], 1.0 [0.1-10.0], P = 0.98). Both groups had comparable overall outcome (mRS score > 2) at discharge and 1-year and 6-year follow-up (P = 0.48 and 0.73, respectively). CONCLUSIONS: Most SRA patients in the BRAT underwent surgical clipping, with a high rate of crossover from endovascular approaches. Endovascular treatment was equivalent to surgical clipping with regard to procedure-related complications and neurologic outcomes.

Treatment of octogenarians and nonagenarians with aneurysmal subarachnoid hemorrhage: a 17-year institutional analysis.

BACKGROUND: Outcomes for octogenarians and nonagenarians after an aneurysmal subarachnoid hemorrhage (aSAH) are particularly ominous, with mortality rates well above 50%. The present analysis examines the neurologic outcomes of patients ≥ 80 years of age treated for aSAH. METHOD: A retrospective review was performed of all aSAH patients treated at Barrow Neurological Institute from January 1, 2003, to July 31, 2019. Patients were placed in 2 groups by age, < 80 vs ≥ 80 years. The ≥ 80-year-old group of octogenarians and nonagenarians was subsequently analyzed to compare treatment modalities. Poor neurologic outcome was defined as a modified Rankin Scale (mRS) score of > 2. RESULTS: During the study period, 1418 patients were treated for aSAH. The mean (standard deviation) age was 55.1 (13.6) years, the mean follow-up was 24.6 (40.0) months, and the rate of functional independence (mRS 0-2) at follow-up was 54% (751/1395). Logistic regression analysis found increasing age strongly associated with declining functional independence (R2 = 0.929, p < 0.001). Forty-three patients ≥ 80 years old were significantly more likely to be managed endovascularly than with open microsurgery (67% [n = 29] vs 33% [n = 14], p < 0.001). Compared with younger patients, those ≥ 80 years old had an increased risk of mortality and poor neurologic outcomes at follow-up. In the ≥ 80-year-old group, only 4 patients had good outcomes; none of the 4 had preexisting comorbidities, and all 4 were treated endovascularly. CONCLUSIONS: Age is a significant prognostic indicator of functional outcomes and mortality after aSAH. Most octogenarians and nonagenarians with aSAH will become severely disabled or die.

IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage.

Background and Purpose- Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods- Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15tg). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results- In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1ß, and TNF-α is markedly increased in GFAP-IL-15tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15tg mice. Conclusions- Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.

Nationwide Trends in Carotid Endarterectomy and Carotid Artery Stenting in the Post-CREST Era.

Background and Purpose- The CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) demonstrated equivalent composite outcomes between carotid endarterectomy (CEA) and carotid artery stenting (CAS) for treating carotid stenosis. We investigated nationwide trends in these procedures and associated periprocedural stroke, myocardial infarction, death, cost, and readmission rates since CREST outcomes were published. Methods- We queried the Nationwide Readmissions Database to identify patients undergoing CEA and CAS for asymptomatic and symptomatic carotid stenosis from 2010 to 2015. Patients were matched based on demographics, comorbidities, and severity of illness. Results- In total, 378 354 CEA and 57 273 CAS patients were treated during this 6-year period. CEA volume decreased by an average of 2669 procedures annually (P=0.001) with stable CAS volume (P=0.225). After matching, CEA patients had a higher rate of periprocedural stroke than CAS patients, driven by increased stroke risk in symptomatic CEA patients (8.1% versus 5.6%; odds ratio, 1.47 [CI, 1.29-1.68]; P<0.001) but a lower rate of overall inpatient mortality (0.8% versus 1.4%; odds ratio, 0.57 [CI, 0.48-0.68]; P<0.001). CEA patients were less likely to be readmitted within 30 days (7.2% versus 8.0%; odds ratio, 0.90 [CI, 0.84-0.96]; P=0.018) and 90 days (12.3% versus 14.1%; odds ratio, 0.86 [CI, 0.81-0.90]; P<0.001), and mean hospital costs were lower for CEA compared with CAS ($14 433 versus $19 172; P<0.001). Conclusions- The procedural treatment of carotid stenosis has changed dramatically in the post-CREST era. When matched for characteristics and illness severity, patients undergoing CEA had a higher rate of perioperative stroke than patients undergoing CAS, primarily among symptomatic patients. These findings are in contrast to the findings of CREST, which showed nearly twice the risk of stroke in CAS patients compared with CEA patients. CEA was associated with lower procedure cost and readmission rate.

Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage.

Delayed cognitive decline commonly occurs following intracerebral hemorrhage (ICH), but the mechanisms underlying this phenomenon remain obscure. We therefore investigated the potential mechanisms responsible for impaired cognitive function in a mouse collagenase model of ICH. Following recovery of motor and sensory deficits in the chronic phase of ICH, we noted significant cognitive impairment, which was assessed by the Morris water maze. This finding was accompanied by reduced dendrite spine density of ipsilateral hippocampal CA1 neurons. Reduced synaptic plasticity, manifested by impaired long-term potentiation in hippocampal neurons, was also evident in both ipsilateral and contralateral hemispheres, suggesting that ICH also induces functional alterations in distal brain regions remote from the site of injury. In addition, the accumulation of microglia, infiltration of peripheral immune cells, and generation of reactive oxygen species were observed in both contralateral and ipsilateral hemispheres up to 5 wk post-ICH. Furthermore, depletion of microglia using PLX3397, which inhibits colony stimulating factor 1 receptor, ameliorated this delayed cognitive impairment. Collectively, these results suggest that persistent and diffuse brain inflammation may contribute to cognitive impairment in the chronic stage of ICH recovery.-Shi, E., Shi, K., Qiu, S., Sheth, K. N., Lawton, M. T., Ducruet, A. F. Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage.

Onyx embolization of skull base paragangliomas: a single-center experience.

BACKGROUND: Skull base paragangliomas are highly vascular tumors that are often embolized before surgical resection; however, the safety and efficacy of preoperative embolization using an ethylene vinyl alcohol copolymer (Onyx; Medtronic, Dublin, Republic of Ireland) in these tumors is unknown. This retrospective cohort study evaluated patient outcomes after preoperative embolization of skull base paragangliomas using Onyx. METHODS: We retrospectively analyzed data from all patients with skull base paragangliomas who underwent preoperative Onyx embolization at our institution (January 01, 2005-December 31, 2017). Patient, tumor, embolization, and outcomes data were extracted by reviewing inpatient and outpatient clinical and imaging records. RESULTS: Seven patients were studied (5/7 [71%] female), 6 with glomus jugulares and 1 with a glomus vagale. The median age was 52 years, and the most common presenting symptom was cranial neuropathy (6/7 [86%]). The tumor vascular supply was from the ascending pharyngeal artery in all 7 cases (100%) with additional feeders including the occipital artery in 5 (71%); internal carotid artery in 3 (43%); middle meningeal, vertebral, and internal maxillary artery each in 2 (29%); and posterior auricular artery in 1 (14%). The median postembolization tumor devascularization was 80% (range, 64-95%). The only postembolization complication was a facial palsy in 1 patient. CONCLUSION: Preoperative embolization with Onyx affords excellent devascularization for the majority of skull base paragangliomas, and it may facilitate resection of these hypervascular lesions. The advantages provided by Onyx with respect to penetration of intratumoral vessels must be weighed against the risk of cranial neuropathy.

Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow.

OBJECTIVE: The present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window. METHODS: This was a prospective, randomized, open-label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingolimod. All patients underwent pretreatment and 24-hour noncontrast computed tomography (CT)/perfusion CT/CT angiography. The coprimary endpoints were the decrease of National Institutes of Health Stroke Scale scores over 24 hours and the favorable shift of modified Rankin Scale score (mRS) distribution at day 90. Exploratory outcomes included vessel recanalization, anterograde reperfusion, and retrograde reperfusion of collateral flow. RESULTS: Each treatment group included 23 patients. Compared with alteplase alone, patients receiving fingolimod plus alteplase exhibited better early clinical improvement at 24 hours and a favorable shift of mRS distribution at day 90. In addition, patients who received fingolimod and alteplase exhibited a greater reduction in the perfusion lesion accompanied by suppressed infarct growth by 24 hours. Fingolimod in conjunction with alteplase significantly improved anterograde reperfusion of downstream territory and prevented the failure of retrograde reperfusion from collateral circulation. INTERPRETATION: Fingolimod may enhance the efficacy of alteplase administration in the 4.5- to 6-hour time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow. These findings are instructive for the design of future trials of recanalization therapies in extended time windows. Ann Neurol 2018;84:725-736.

Activation of JAK/STAT3 restores NK-cell function and improves immune defense after brain ischemia.

Stroke-induced immune suppression predisposes the host to infections and can contribute to high morbidity and mortality in stroke patients. Because ischemic stroke has a profound effect on the systemic immune response, which may explain the increased susceptibility of stroke patients to infection, an urgent need persists for a better understanding of mechanisms associated with immune suppression; new and effective treatments for stroke can then be identified. NK cells play a key role in early host defense against pathogens by killing infected cells and/or producing cytokines such as IFN-γ. Because the phenotype and function of peripheral NK cells have been widely investigated in ischemic stroke, nCounter Inflammation Gene Array Analysis was used to build immune-related gene profiles of NK cells to comprehensively analyze the molecular signature of NK cells after ischemic brain injury. We observed distinct gene expression profiles reflecting different splenic NK-cell phenotypes and functional properties across the time course of transient middle cerebral artery occlusion (MCAO). Based on gene expression and pathway-network analysis, lower expression levels of signal transducer and activator of transcription-3 (STAT3) were observed in animals with MCAO compared with sham control animals. Genetic activation of STAT3 through the introduction of STAT3 clustered regularly interspaced short palindromic repeats (CRISPR) plasmid prevented the loss of NK-cell-derived IFN-γ production after MCAO, together with reduced bacterial burden and mortality. Our data suggest that brain ischemia impairs NK-cell-mediated immune defense in the periphery, at least in part through the JAK-STAT3 pathway, which can be readdressed by modulating STAT3 activation status.-Jin, W.-N., Ducruet, A. F., Liu, Q., Shi, S. X.-Y., Waters, M., Zou, M., Sheth, K. N., Gonzales, R., Shi, F.-D. Activation of JAK/STAT3 restores NK-cell function and improves immune defense after brain ischemia.

Role of matrix metalloproteinases in the pathogenesis of intracranial aneurysms.

Intracranial aneurysms (IAs) are a result of complex interactions between biochemical and mechanical forces and can lead to significant morbidity if they rupture and cause subarachnoid hemorrhage. This review explores the role of matrix metalloproteinases (MMPs) in the pathogenesis and progression of IAs. In addition to providing a review of the normal function of MMPs, it is intended to explore the interaction between inflammation and abnormal blood flow and the resultant pathological vascular remodeling processes seen in the development and rupture of IAs. Also reviewed is the potential for the use of MMPs as a diagnostic tool for assessment of aneurysm development and progression.

Iatrogenic pseudoaneurysm rupture of the anterior cerebral artery after placement of an external ventricular drain, treated with clip-wrapping: a case report and review of the literature.

External ventricular drains (EVDs) are often placed emergently for patients with hydrocephalus, which carries a risk of hemorrhage. Rarely, rupture of a pseudoaneurysm originating from an EVD placement precipitates such a hemorrhage. An EVD was placed in a patient with a ruptured left posterior communicating artery aneurysm who later underwent endovascular coil embolization. On post-bleed day 20, a distal right anterior cerebral artery pseudoaneurysm along the EVD tract ruptured, which was successfully treated via clip-wrapping. Although EVD-associated pseudoaneurysms are rare, they have a high propensity for rupture. Early treatment of these lesions should be considered to prevent neurologic deterioration.

Interfacility Transfer Directly to the Neuroangiography Suite in Acute Ischemic Stroke Patients Undergoing Thrombectomy.

BACKGROUND AND PURPOSE: In patients identified at referring facilities with acute ischemic stroke caused by a large vessel occlusion, bypassing the emergency department (ED) with direct transport to the neuroangiography suite may safely shorten reperfusion times. METHODS: We conducted a single-center retrospective review of consecutive patients transferred to our facility for consideration of endovascular therapy. Patients were identified as admitted directly to the neuroangiography suite (DAN), transferred to the ED before intra-arterial therapy (ED-IA), and transferred to the ED but did not receive IA therapy (ED-IV). RESULTS: A retrospective review of a prospectively maintained database of transfer patients between January 2013 and October 2016 with large vessel occlusions identified 108 ED-IV patients and 261 patients who underwent mechanical thrombectomy (DAN=111 patients and ED-IA=150 patients). There were no differences in baseline characteristics among the 3 groups. The median computed tomography ASPECTS (Alberta Stroke Program Early CT Score) was lower in the ED-IV group versus the ED-IA and DAN groups (8 versus 9; P=0.001). In the DAN versus ED-IA cohort, there were comparable rates of TICI2b/3 recanalization and access to recanalization time. There was significantly faster hospital arrival to groin access time in the DAN cohort (81 minutes versus 22 minutes; P=0.001). Functional independence at 90 days was comparable in the DAN versus ED-IA cohorts but worse in the ED-IV group (43% versus 44% versus 22%; P=0.001). CONCLUSIONS: DAN is safe, feasible, and associated with faster times of hospital arrival to recanalization. The clinical benefit of this approach should be assessed in a prospective randomized trial.