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Introduction: Plavix resistance is an independent risk factor for thromboembolic complications following carotid artery stent (CAS) placements. The VerifyNow P2Y12 assay is the best studied in gauging for Plavix responsiveness. Its performance is affected when hematocrit (HCT) value is Methods: We included symptomatic carotid artery patients who suffered ischemic strokes and received CAS during the same hospitalization with PRU measured via VerifyNow assay. Therapeutic PRU is defined as ≤180. Primary outcomes were the comparisons of PRU and the proportion of non-responders between low ( Results: 78 of 127 symptomatic carotid artery patients met inclusion criteria. Mean age was 70.5 with 38.5% females. 23 of 78 had HCT < 33. Baseline characteristics between low and high HCT groups were similar except for hemoglobin (9.4 vs. 12.7, p Conclusion: In symptomatic carotid patients receiving CAS, low HCT is associated with increased PRU, resulting in some to be falsely categorized as non-responders receiving more aggressive therapy unnecessarily.

Approximately 30% of subarachnoid hemorrhage (SAH) patients who survive the initial ictus develop delayed cerebral ischemia (DCI) 4 to 10 days following SAH. Multiple clinical studies indicate the cause of DCI is multifactorial and includes vasospasm. 12/15-Lipoxygenase (LOX), enzymes that metabolize arachidonic acid into bioactive lipid metabolites, such as 12-HETE and 15-HETE, are expressed in several cell types of the brain including neurons, and microglia. Previous work has shown that 12/15-LOX has detrimental effects on brain vasculature and neurons, triggers inflammation, and thrombosis. In a previous study, inhibition of 12/15-LOX was beneficial in reducing early brain injury in mice after SAH. We hypothesize that inhibition of 12/15-LOX would attenuate delay vasospasm and reduce DCI in SAH mice. C57BL/6 mice of both sexes were randomized into Sham+Vehicle, SAH+Vehicle, SAH+ML351. Vehicle and ML351 (LOX inhibitor, 25mg/kg) were intravenously injected 15 minutes after SAH. 12/15-LOX -/- mice of both sexes were randomized into sham or SAH. Behavior was assessed daily until euthanasia on day 5 for analysis of vasospasm. Following SAH, there, there was an increased expression of 12/15-LOX in brain endothelial cells. Inhibition of 12/15-LOX in C57BL/6 males reduced large artery vasospasm and microvessel constriction, improved functional outcome, and lowered DCI incidence. In female C57BL/6 mice, inhibition of 12/15-LOX also reduced vasospasm and microvessel constriction, and ameliorated behavioral deficits. 12/15-LOX -/- displayed better behavior and have less delayed vasospasm. The findings of this study suggest that inhibition of 12/15-LOX is therapeutically beneficial for male and female mice after SAH via preventing delay vasospasm and DCI.

Subarachnoid hemorrhage (SAH) induces delayed cerebral ischemia (DCI) in about 30% of patients which is characterized by functional decline. As microthrombi is a cause of DCI, platelets may be a therapeutic target for preventing microthrombi formation and development of DCI. Clinical trials of anti-platelets have been inconclusive for their effect on outcome. However, clinical trials used different anti-platelets. Since platelets have numerous receptors which can each prevent thrombosis, there is no clear choice to target for SAH. Here, we utilize 6 platelet antagonists to identify if any receptor is a therapeutic target for DCI after SAH. Our hypothesis is that P2Y receptor inhibition will prevent microthrombi and reduce DCI after SAH. Male and female mice were randomly assigned into sham, SAH+vehicle, SAH+P2Y antagonism, SAH+PAR4 antagonism, SAH+PAF antagonism, SAH+TPβ-R antagonism, and SAH+GPIIb/IIIa antagonism. Mice were euthanized 2 (n=10/group) or 7 days (n=15/group) post-SAH. All outcomes were performed and data was analyzed by a blinded investigator. Behavior was assessed daily. Brain microthrombi were counted. Both male and female SAH mice treated with inhibitors of PAF and TPβ-R had significantly better day 1 function than vehicle-treated mice. Significantly better function on day 1 was also observed in only male mice treated the P2Y antagonists or GPIIb/IIIa antagonist. Neither sex had improved behavior for the PAR-4 inhibitor. Mice exhibiting better function had fewer brain microthrombi with the exception of the GPIIb/IIIa antagonist which reduced microthrombi in female mice but did not correspond with improved behavior. This suggests there may be another deleterious mechanism which is more prevalent/detrimental in females that is not prevented by GPIIb/IIIa inhibition, such as platelet degranulation. However, this needs to be further investigated. Additionally, inhibition of TPβ-R reduced the incidence of DCI compared to vehicle-treated mice. In conclusion, an anti-platelet drug for SAH needs to be chosen carefully as not all antagonists have a beneficial effect after SAH; of vital importance is that anti-platelet drugs may not have similar beneficial effects in both sexes.

Background and ObjectivesWhile somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms.MethodsWe performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results.ResultsSomatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in theSVILgene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown ofSVILvia the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found thatSVILregulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway.DiscussionWe propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants inSVILresult in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.

Aneurysmal subarachnoid hemorrhage (aSAH) causes a robust inflammatory response which leads worse brain injury and poor outcomes. We investigated if stimulation of nicotinic acetylcholine α7 receptors (α7-AChR) (receptors shown to have anti-inflammatory effects) would reduce inflammation and improve outcomes. To investigate the level of peripheral inflammation after aSAH, inflammatory markers were measured in plasma samples collected in a cohort of aSAH patients. To study the effect of α7-AChR stimulation, SAH was induced in adult mice which were then treated with a α7-AChR agonist, galantamine, or vehicle. A battery of motor and cognitive tests were performed 24 h after subarachnoid hemorrhage. Mice were euthanized and tissue collected for analysis of markers of inflammation or activation of α7-AChR-mediated transduction cascades. A separate cohort of mice was allowed to survive for 28 days to assess long-term neurological deficits and histological outcome. Microglia cell culture subjected to hemoglobin toxicity was used to assess the effects of α7-AChR agonism. Analysis of eighty-two patient plasma samples confirmed enhanced systemic inflammation after aSAH. α7-AChR agonism reduced neuroinflammation at 24 h after SAH in male and female mice, which was associated with improved outcomes. This coincided with JAK2/STAT3 and IRAK-M activity modulations and a robust improvement in neurological/cognitive status that was effectively reversed by interfering with various components of these signaling pathways. Pharmacologic inhibition partially reversed the α7-AChR agonist’s benefits, supporting α7-AChR as a target of the agonist’s therapeutic effect. The cell culture experiment showed that α7-AChR agonism is directly beneficial to microglia. Our results demonstrate that activation of α7-AChR represents an attractive target for treatment of SAH. Our findings suggest that α7-AChR agonists, and specifically galantamine, might provide therapeutic benefit to aSAH patients.

BackgroundTools predicting intracranial dural arteriovenous fistulas (dAVFs) treatment outcomes remain scarce. This study aimed to use a multicenter database comprising more than 1000 dAVFs to develop a practical scoring system that predicts treatment outcomes.MethodsPatients with angiographically confirmed dAVFs who underwent treatment within the Consortium for Dural Arteriovenous Fistula Outcomes Research-participating institutions were retrospectively reviewed. A subset comprising 80% of patients was randomly selected as training dataset, and the remaining 20% was used for validation. Univariable predictors of complete dAVF obliteration were entered into a stepwise multivariable regression model. The components of the proposed score (VEBAS) were weighted based on their ORs. Model performance was assessed using receiver operating curves (ROC) and areas under the ROC.ResultsA total of 880 dAVF patients were included. Venous stenosis (presence vs absence), elderly age (ConclusionThe VEBAS score is a practical grading system that can guide patient counseling when considering dAVF intervention by predicting the likelihood of treatment success, with higher scores portending a greater likelihood of complete obliteration.

We thank the Editors of JNIS for alerting us in advance to the concerns about SELECT2 raised by Jadhav1 and colleagues and appreciate the opportunity to explain the rationale for the study design and clarify the benefits of including perfusion imaging-based selection criteria. We are confident that SELECT2 will provide high-level, reliable data regarding the safety and efficacy of endovascular thrombectomy (EVT) for large core patients. The choice of imaging modality for identifying large core in acute ischemic stroke remains an area of considerable debate. Magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI), computed tomography (CT) or MR perfusion imaging and Alberta Stroke Program Early CT Score (ASPECTS) have all been proposed and studied. At present, there is no clear consensus on which imaging modality is best for identifying patients with large core. It is important to recognize that the early window randomized EVT trials used a broad range of imaging selection criteria. The imaging selection criteria for the initial five pivotal trials ranged from allowing patients to be enrolled regardless of the degree of early infarct signs,2 to studies that required a specific ASPECTS score range in addition to other imaging criteria,3–5 to EXTEND IA6 where the ASPECTS score was not considered, and CT perfusion (CTP) mismatch with a maximum estimated core size was required. All five trials were successful but with substantial variability in the treatment effect, leaving uncertainty as to the optimal imaging approach as well as whether there are patient subgroups who do not benefit. In fact, those utilizing perfusion mismatch criteria (EXTEND-IA, SWIFT PRIME) had higher rates of modified Rankin Scale (mRS) scores 0–2 and larger treatment effects, compared with other trials.2–6 Even if a treatment has a clear benefit in most patients, there can be important subgroups that do not …

ObjectiveTo evaluate the comparative safety and efficacy of direct endovascular thrombectomy (dEVT) compared to bridging therapy (BT; IV tissue plasminogen activator + EVT) and to assess whether BT potential benefit relates to stroke severity, size, and initial presentation to EVT vs non-EVT center.MethodsIn a prospective multicenter cohort study of imaging selection for endovascular thrombectomy (Optimizing Patient Selection for Endovascular Treatment in Acute Ischemic Stroke [SELECT]), patients with anterior circulation large vessel occlusion (LVO) presenting to EVT-capable centers within 4.5 hours from last known well were stratified into BT vs dEVT. The primary outcome was 90-day functional independence (modified Rankin Scale [mRS] score 0–2). Secondary outcomes included a shift across 90-day mRS grades, mortality, and symptomatic intracranial hemorrhage. We also performed subgroup analyses according to initial presentation to EVT-capable center (direct vs transfer), stroke severity, and baseline infarct core volume.ResultsWe identified 226 LVOs (54% men, mean age 65.6 ± 14.6 years, median NIH Stroke Scale [NIHSS] score 17, 28% received dEVT). Median time from arrival to groin puncture did not differ in patients with BT when presenting directly (dEVT 1.43 [interquartile range (IQR) 1.13–1.90] hours vs BT 1.58 [IQR 1.27–2.02] hours, p = 0.40) or transferred to EVT-capable centers (dEVT 1.17 [IQR 0.90–1.48] hours vs BT 1.27 [IQR 0.97–1.87] hours, p = 0.24). BT was associated with higher odds of 90-day functional independence (57% vs 44%, adjusted odds ratio [aOR] 2.02, 95% confidence interval [CI] 1.01–4.03, p = 0.046) and functional improvement (adjusted common OR 2.06, 95% CI 1.18–3.60, p = 0.011) and lower likelihood of 90-day mortality (11% vs 23%, aOR 0.20, 95% CI 0.07–0.58, p = 0.003). No differences in any other outcomes were detected. In subgroup analyses, patients with BT with baseline NIHSS scores p = 0.006); this association was not evident for patients with NIHSS scores ≥15 (aOR 1.05, 95% CI 0.40–2.74, p = 0.92). Similarly, functional outcomes improvements with BT were detected in patients with core volume strata (ischemic core 3: aOR 2.10, 95% CI 1.02–4.33, p = 0.044 vs ischemic core ≥50 cm3: aOR 0.41, 95% CI 0.01–16.02, p = 0.64) and transfer status (transferred: aOR 2.21, 95% CI 0.93–9.65, p = 0.29 vs direct to EVT center: aOR 1.84, 95% CI 0.80–4.23, p = 0.15).ConclusionsBT appears to be associated with better clinical outcomes, especially with milder NIHSS scores, smaller presentation core volumes, and those who were “dripped and shipped.” We did not observe any potential benefit of BT in patients with more severe strokes.Trial Registration InformationClinicalTrials.gov Identifier: NCT02446587.Classification of EvidenceThis study provides Class III evidence that for patients with ischemic stroke from anterior circulation LVO within 4.5 hours from last known well, BT compared to dEVT leads to better 90-day functional outcomes.

Background and Purpose: The optimal endovascular stroke therapy (EVT) care delivery structure is unknown. Here, we present our experience in creating an integrated stroke system (ISS) to expand EVT availability throughout our region while maintaining hospital and physician quality standards. Methods: We identified all consecutive patients with large vessel occlusion acute ischemic stroke treated with EVT from January 2014 to February 2019 in our health care system. In October 2017, we implemented the ISS, in which 3 additional hospitals (4 total) became EVT-performing hospitals (EPHs) and physicians were rotated between all centers. The cohort was divided by time into pre-ISS and post-ISS, and the primary outcome was time from stroke onset to EPH arrival. Secondary outcomes included hospital and procedural quality metrics. We performed an external validation using data from the Southeast Texas Regional Advisory Council. Results: Among 513 patients with large vessel occlusion acute ischemic stroke treated with EVT, 58% were treated pre-ISS and 43% post-ISS. Over the study period, EVT procedural volume increased overall but remained relatively low at the 3 new EPHs (P P P Conclusions: In our system, increasing EVT availability decreased time from stroke onset to EPH arrival. The ISS provides a framework to maintain quality in lower volume hospitals.

BackgroundIt is unknown whether endovascular thrombectomy (EVT) is cost effective in large ischemic core infarcts.MethodsIn the prospective, multicenter, cohort study of imaging selection study (SELECT), large core was defined as computed tomography (CT) ASPECTSResultsFrom 361 patients enrolled in SELECT, 105 had large core on CT or CTP (EVT 62, MM 43). 19 (31%) EVT vs 6 (14%) MM patients achieved modified Rankin Scale (mRS) score 0–2 (OR 3.27, 95% CI 1.11 to 9.62, P=0.03) with a shift towards better mRS (cOR 2.12, 95% CI 1.05 to 4.31, P=0.04). Over the projected lifetime of patients presenting with large core, EVT led to incremental costs of $33 094 and a gain of 1.34 QALYs per patient, resulting in ICER of $24 665 per QALY. EVT has a higher NMB compared with MM at lower (EVT -$42 747, MM -$76 740) and upper (EVT $155 041, MM $57 134) WTP thresholds. PSA confirmed the results and CEAC showed 77% and 92% acceptability of EVT at the WTP of $50 000 and $100 000, respectively. EVT was associated with an increment of $29 225 in societal costs. The pivotal EVT trials (HERMES, DAWN, DEFUSE 3) were dominant in a sensitivity analysis at the same inputs, with societal cost-savings of $37 901, $86 164 and $22 501 and a gain of 1.62, 2.36 and 2.21 QALYs, respectively.ConclusionsIn a non-randomized prospective cohort study, EVT resulted in better outcomes in large core patients with higher QALYs, NMB and high cost-effectiveness acceptability rates at current WTP thresholds. Randomized trials are needed to confirm these results.Clinical trial registrationNCT02446587

Background: Extended endoscopic transsphenoidal (EET) approaches can include complete resection of both superior turbinate (ST) for wider exposure. Moreover, ST resection has been associated with postoperative olfactory impairment. Objective: We sought to determine the impact of bilateral ST resection on olfaction during a transsphenoidal approach. Method: A prospective observational study was conducted on 29 patients undergoing endoscopic skull base surgery sparing the olfactory tracts at a tertiary academic center. Olfactory function was measured with Sniffin’ Sticks at the preoperative visit, 2-weeks and 6 to 8 weeks postoperatively. All components: odor threshold (OT), odor discrimination (OD), odor identification (OI) and composite scores (TDI = OT+OD+OI) were evaluated. Result: Study was completed in 15 patients with 14 excluded due to a variety of reasons. At 2 weeks, a significant decrease was noted in composite scores (32.3 ± 5.4 vs. 23.8 ± 5.8, P Conclusion: Patients undergoing bilateral ST resection during EET procedures experience transient hyposmia postoperatively. However, the olfactory function normalizes to preoperative levels at 6 to 8 weeks. The resection of the bilateral superior turbinate does not appear to decrease olfactory function.

Background: Limited data are available on endovascular thrombectomy (EVT) efficacy and safety in large vessel occlusion (LVO) patients presenting >24hr from last known well (LKW). We compared outcomes between patients receiving EVT and best medical management (MM) in a multicenter international cohort. Methods: Consecutive patients with anterior circulation LVO presenting >24h after LKW from 13 centers from 7/2012-4/2021 were analyzed. Multivariable models for 90d mRS distribution and symptomatic ICH were adjusted for age, NIHSS, glucose, IV tPA, transfer status, clot location, time from LKW, CT ASPECTS and ischemic core (rCBF6s volumes. Results: Of 240 patients with a median (IQR) LKW to presentation 28.3h (24.9-38.2), 153 (64%) received EVT. Baseline characteristics were similar except for NIHSS (EVT: 13 (8-20) vs MM: 17 (10-22), p=0.005), CT ASPECTS (EVT: 8(6-9) vs MM: 4(3-6), p Conclusions: EVT may be associated with better functional outcomes, despite numerically increased risk of sICH in patients presenting with anterior circulation LVO beyond 24 hours. Further prospective studies are warranted.

Subarachnoid hemorrhage (SAH) induces delayed cerebral ischemia (DCI) in about 30% of patients which is characterized by functional decline. Microvascular occlusion, via microvessel constriction or microthrombi, may be a cause of DCI. Our hypothesis is that microvascular occlusion and reduced cerebral blood flow (CBF) precede the onset of delayed deficits in mice with SAH. Mice were randomly assigned into sham, SAH+saline, and SAH+A3P5P+Clopidogrel (platelet antagonists). Laser speckle imaging (to assess large and microvessel perfusion) and behavior were assessed daily. All outcomes were performed and data was analyzed by a blinded investigator. Both large artery and microvessel/tissue perfusion recover to baseline in SAH mice which do not get delayed deficits. However, in SAH mice which develop delayed deficits, microvessel/tissue perfusion has a prolonged reduction (Figure 1A). Interestingly, large artery perfusion recovers in these mice. Antiplatelets prevent microthrombi, attenuating microvessel occlusion, and reduce delayed deficits (Figure 2B-C). Our findings suggest that 1) microvessel occlusion and prolonged tissue perfusion are causative factors for DCI and 2) preventing platelet activation may be a therapeutic target to reduce the incidence of DCI. Our data also suggests a sex difference in the response to platelet antagonists (data not shown).

Background: The effect of anesthesia choice on endovascular thrombectomy (EVT) outcomes is unclear. Collateral status on perfusion imaging may help identify the optimal anesthesia choice. Methods: In a pooled patient level analysis of EXTEND-IA, EXTEND-IA TNK, EXTEND-IA TNK part II and SELECT, EVT Functional outcomes (mRS distribution) were compared between general anesthesia (GA) vs non-general anesthesia (non-GA). Further, we assessed the impact of collateral flow on perfusion imaging evaluated by hypoperfusion intensity ratio (HIR) - Tmax10 sec/Tmax6 sec) on the association between anesthesia type and EVT outcomes. Results: Of 731 treated with EVT, 305 (42%) received GA and 426 (58%) non-GA. The baseline characteristics were similar, except for presentation NIHSS (median [IQR] GA 18 [13-22], non-GA 16[11-20], p Conclusion: GA was associated with worse functional outcomes after EVT, particularly in patients with poor collaterals. These findings have implications for randomized trials of GA vs non-GA.

ImportanceThe role of endovascular thrombectomy is uncertain for patients presenting beyond 24 hours of the time they were last known well.ObjectiveTo evaluate functional and safety outcomes for endovascular thrombectomy (EVT) vs medical management in patients with large-vessel occlusion beyond 24 hours of last known well.Design, Setting, and ParticipantsThis retrospective observational cohort study enrolled patients between July 2012 and December 2021 at 17 centers across the United States, Spain, Australia, and New Zealand. Eligible patients had occlusions in the internal carotid artery or middle cerebral artery (M1 or M2 segment) and were treated with EVT or medical management beyond 24 hours of last known well.InterventionsEndovascular thrombectomy or medical management (control).Main Outcomes and MeasuresPrimary outcome was functional independence (modified Rankin Scale score 0-2). Mortality and symptomatic intracranial hemorrhage (sICH) were safety outcomes. Propensity score (PS)–weighted multivariable logistic regression analyses were adjusted for prespecified clinical characteristics, perfusion parameters, and/or Alberta Stroke Program Early CT Score (ASPECTS) and were repeated in subsequent 1:1 PS-matched cohorts.ResultsOf 301 patients (median [IQR] age, 69 years [59-81]; 149 female), 185 patients (61%) received EVT and 116 (39%) received medical management. In adjusted analyses, EVT was associated with better functional independence (38% vs control, 10%; inverse probability treatment weighting adjusted odds ratio [IPTW aOR], 4.56; 95% CI, 2.28-9.09; P P = .003). This association persisted after PS-based matching on (1) clinical characteristics and ASPECTS (EVT, 35%, vs control, 19%; aOR, 3.14; 95% CI, 1.02-9.72; P = .047); (2) clinical characteristics and perfusion parameters (EVT, 35%, vs control, 17%; aOR, 4.17; 95% CI, 1.15-15.17; P = .03); and (3) clinical characteristics, ASPECTS, and perfusion parameters (EVT, 45%, vs control, 21%; aOR, 4.39; 95% CI, 1.04-18.53; P = .04). Patients receiving EVT had lower odds of mortality (26%) compared with those in the control group (41%; IPTW aOR, 0.49; 95% CI, 0.27-0.89; P = .02).Conclusions and RelevanceIn this study of treatment beyond 24 hours of last known well, EVT was associated with higher odds of functional independence compared with medical management, with consistent results obtained in PS-matched subpopulations and patients with presence of mismatch, despite increased odds of sICH. Our findings support EVT feasibility in selected patients beyond 24 hours. Prospective studies are warranted for confirmation.

The objective of this study was to evaluate functional and safety outcomes of endovascular thrombectomy (EVT) versus medical management (MM) in patients with M2 occlusion and examine their association with perfusion imaging mismatch and stroke severity.In a pooled, patient-level analysis of 3 randomized controlled trials (EXTEND-IA, EXTEND-and IA-TNK parts 1 and 2) and 2 prospective nonrandomized studies (INSPIRE and SELECT), we evaluated EVT association with 90-day functional independence (modified Rankin Scale [mRS] = 0-2) in isolated M2 occlusions as compared to medical management overall and in subgroups by mismatch profile status and stroke severity.We included 517 patients (EVT = 195 and MM = 322), baseline median (interquartile range [IQR]) National Institutes of Health Stroke Scale (NIHSS) was 13 (8-19) in EVT versus 10 (6-15) in MM, p 0.001. Pretreatment ischemic core did not differ (EVT = 10 [0-24] ml vs MM = 9 [3-21] ml, p = 0.59). Compared to MM, EVT was more frequently associated with functional independence (68.3 vs 61.6%, adjusted odds ratio [aOR] = 2.42, 95% confidence interval [CI] = 1.25-4.67, p = 0.008, inverse probability of treatment weights [IPTW]-OR = 1.75, 95% CI = 1.00-3.75, p = 0.05) with a shift toward better mRS outcomes (adjusted cOR = 2.02, 95% CI:1.23-3.29, p = 0.005), and lower mortality (5 vs 10%, aOR = 0.32, 95% CI = 0.12-0.87, p = 0.025). EVT was associated with higher functional independence in patients with a perfusion mismatch profile (EVT = 70.7% vs MM = 61.3%, aOR = 2.29, 95% CI = 1.09-4.79, p = 0.029, IPTW-OR = 2.02, 1.08-3.78, p = 0.029), whereas no difference was found in those without mismatch (EVT = 43.8% vs MM = 62.7%, p = 0.17, IPTW-OR: 0.71, 95% CI = 0.18-2.78, p = 0.62). Functional independence was more frequent with EVT in patients with moderate or severe strokes, as defined by baseline NIHSS above any thresholds from 6 to 10, whereas there was no difference between groups with milder strokes below these thresholds.In patients with M2 occlusion, EVT was associated with improved clinical outcomes when compared to MM. This association was primarily observed in patients with a mismatch profile and those with higher stroke severity. ANN NEUROL 2022;91:629-639.

Delayed cerebral ischemia (DCI) continues to be a sequela of aneurysmal subarachnoid hemorrhage (aSAH) that carries significant morbidity and mortality. Aside from nimodipine, no therapeutic agents are available to reduce the incidence of DCI. Pathophysiologic mechanisms contributing to DCI are poorly understood, but accumulating evidence over the years implicates several factors. Those have included microvessel vasoconstriction, microthrombosis, oxidative tissue damage, and cortical spreading depolarization as well as large vessel vasospasm. Common to these processes is red blood cell leakage into the cerebrospinal fluids (CSF) and subsequent lysis which releases hemoglobin, a central instigator in these events. This has led to the hypothesis that early blood removal may improve clinical outcome and reduce DCI. This paper will provide a narrative review of the evidence of hemoglobin as an instigator of DCI. It will also elaborate on available human data that discuss blood clearance and CSF drainage as a treatment of DCI. Finally, we will address a recent novel device that is currently being tested, the Neurapheresis CSF Management System™. This is an automated dual-lumen lumbar drainage system that has an option to filter CSF and return it to the patient.

This meeting abstract was removed due to the OA licensing requirements of this journal. The full abstract is listed here : https://www.svin.org/files/SVIN_2021_Abstracts_for_Web.pdf

Objective: the aim of this study was to provide the evidence base to guide interconversion of the modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS) in neurological research. Methods: a retrospective analysis of paired mRS and GOS recordings was conducted using datasets with the following selection criteria: (1) patients had haemorrhagic stroke, (2) simultaneous mRS and GOS measurements were available, and (3) data sharing was possible. The relationship between mRS and GOS was assessed using correlation analysis. The optimum dichotomisation thresholds for agreement between the mRS and GOS were identified using Cohen's kappa coefficient. Two-way conversion tables between mRS and GOS were developed based on the highest agreement between scores. Finally, to identify which direction of conversion (mRS to GOS or vice versa) was better, the Kolmogorov-Smirnov D statistic was calculated. Results: using 3474 paired recordings the mRS and GOS were shown to be highly correlated (ρ = 0.90, p < 0.0001). The greatest agreement between the two scoring systems occurred when mRS=0-2 and GOS=4-5 was used to define good outcome (κ=0.83, 95% confidence interval: 0.81–0.85). Converting from mRS to GOS was better than the reverse direction as evidenced by a lower Kolmogorov-Smirnov statistic (D=0.054 compared to D=0.157). Conclusions: this study demonstrates that the mRS and GOS are highly correlated, establishes the optimum dichotomisation threshold for agreement, provides a method for interconversion and shows that mRS to GOS conversion is superior to the reverse direction if a choice is available.

BACKGROUND Large pituitary adenomas can rarely cause compression of the cavernous internal carotid artery (ICA) due to chronic tumor compression or invasion. Here, the authors present a case of pituitary apoplexy causing acute bilateral ICA occlusion with resultant stroke. Our middle-aged patient presented with sudden vision loss and experienced rapid deterioration requiring intubation. Computed tomography (CT) angiography revealed a large pituitary mass causing severe stenosis of the bilateral ICAs. CT perfusion revealed a significant perfusion delay in the anterior circulation. The patient was taken for cerebral angiography, and balloon angioplasty was attempted with no improvement in arterial flow. Resection of the tumor was then performed, with successful restoration of blood flow. Despite restoration of luminal patency, the patient experienced bilateral ICA infarcts. OBSERVATIONS Pituitary apoplexy can present as an acute stroke due to flow-limiting carotid compression. Balloon angioplasty is ineffective for the treatment of this type of compression. Surgical removal of the tumor restores the flow and luminal caliber of the ICA. LESSONS Pituitary apoplexy can be a rare presentation of acute stroke and should be managed with immediate surgical decompression rather than attempted angioplasty in order to restore blood flow and prevent the development of cerebral ischemia.

Aneurysmal subarachnoid haemorrhage (aSAH) results in persistent clinical deficits which prevent survivors from returning to normal daily functioning. Only a small fraction of the variation in clinical outcome following aSAH is explained by known clinical, demographic and imaging variables; meaning additional unknown factors must play a key role in clinical outcome. There is a growing body of evidence that genetic variation is important in determining outcome following aSAH. Understanding genetic determinants of outcome will help to improve prognostic modelling, stratify patients in clinical trials and target novel strategies to treat this devastating disease. This protocol details a two-stage genome-wide association study to identify susceptibility loci for clinical outcome after aSAH using individual patient-level data from multiple international cohorts. Clinical outcome will be assessed using the modified Rankin Scale or Glasgow Outcome Scale at 1–24 months. The stage 1 discovery will involve meta-analysis of individual-level genotypes from different cohorts, controlling for key covariates. Based on statistical significance, supplemented by biological relevance, top single nucleotide polymorphisms will be selected for replication at stage 2. The study has national and local ethical approval. The results of this study will be rapidly communicated to clinicians, researchers and patients through open-access publication(s), presentation(s) at international conferences and via our patient and public network.

Brain arteriovenous malformations (bAVMs) have long been considered to be congenital, developing between the third and eighth weeks of embryogenesis. However, cases reporting their de novo formation suggest that these lesions can develop after birth and have challenged this concept. We present a case of a 6-year-old boy with a history of a brainstem cavernous malformation diagnosed after birth who later developed a de novo bAVM. The de novo occurrence of this bAVM distant to the site of the cavernous malformation and a prior negative catheter angiography contributes to the uncertainty of the dynamics and pathophysiology of bAVMs.

Background and Purpose— The PILLAR (Extracorporeal Filtration of Subarachnoid Hemorrhage via Spinal Catheter) study is a first-in-human trial of cerebrospinal fluid (CSF) filtration in aneurysmal subarachnoid hemorrhage. The study evaluates the safety and feasibility of a novel filtration system to rapidly remove blood and blood breakdown products from CSF after securement of a ruptured aneurysm. Methods— Patients with aneurysmal subarachnoid hemorrhage had a dual-lumen lumbar, intrathecal catheter placed after aneurysm securement and received up to 24 hours of CSF filtration (neurapheresis therapy). The catheter aspirated blood-contaminated CSF from the lumbar cistern and returned filtered CSF to the thoracic subarachnoid space. Neuro checks were performed q2 hours, and CSF samples were collected for cell counts, total protein, and gram stain. Computed tomography scans were acquired at baseline and post-filtration. Clinical follow-up occurred at 2 weeks and 30 days. Results— Thirteen patients had a catheter placed (mean time 24:13 hours after ictus). The system processed 632.0 mL (180.6–1447.6 mL) CSF in 15:07 hours (5:32–24:00 hours) of filtration. The mean initial CSF red blood cell count, 2.78×10 5 cells/µL, reduced to 1.17×10 5 cells/µL after filtration (52.9% reduction), and total protein reduced 71%. Independent analysis of baseline and postfiltration computed tomographies found notable cisternal blood decrease, with 46.5% mean Hijdra Score reduction. Three mild, anticipated adverse events were reported. Conclusions— The initial safety and feasibility of Neurapheresis therapy in aneurysmal subarachnoid hemorrhage demonstrated the potential to safely filter CSF and remove blood and blood byproducts. Future studies are warranted. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT0287263.

Rationale Randomized evidence for endovascular thrombectomy safety and efficacy in patients with large core strokes is lacking. Aims To demonstrate endovascular thrombectomy efficacy and safety in patients with large core on non-contrast CT or perfusion imaging (CT/MR) and determine if there is heterogeneity of treatment effect in large cores based on the imaging modality. Design SELECT2 is a prospective, randomized, multi-center, assessor-blinded controlled trial with adaptive enrichment design, enrolling up to 560 patients. Procedure Patients who meet the clinical criteria and have anterior circulation large vessel occlusions with large core on either NCCT (ASPECTS 3–5) or perfusion imaging (CTP [rCBF Study outcomes The distribution of 90-day mRS scores is the primary outcome. Functional independence (mRS = 0–2) rate is a secondary outcome. Other secondary outcomes include safety (symptomatic ICH, neurological worsening, mortality) and imaging outcomes. Analysis A normal approximation of the Wilcoxon-Mann-Whitney test (the generalized likelihood ratio test) to assess the primary outcome. Functional independence rates, safety and imaging outcomes will also be compared. Discussion The SELECT2 trial will evaluate endovascular thrombectomy safety and efficacy in large cores on either CT or perfusion imaging and may provide randomized evidence to extend endovascular thrombectomy eligibility to larger population. Registration: ClinicalTrials.gov–NCT03876457

Aneurysmal subarachnoid hemorrhage (aSAH) patients develop delayed cerebral ischemia and delayed deficits (DCI) within 2 weeks of aneurysm rupture at a rate of approximately 30%. DCI is a major contributor to morbidity and mortality after SAH. The cause of DCI is multi-factorial with contributions from microthrombi, blood vessel constriction, inflammation, and cortical spreading depolarizations. Platelets play central roles in hemostasis, inflammation, and vascular function. Within this review, we examine the potential roles of platelets in microthrombi formation, large artery vasospasm, microvessel constriction, inflammation, and cortical spreading depolarization. Evidence from experimental and clinical studies is provided to support the role(s) of platelets in each pathophysiology which contributes to DCI. The review concludes with a suggestion for future therapeutic targets to prevent DCI after aSAH.

Objective: Current guidelines recommend active surveillance with serial magnetic resonance angiography (MRA) for management of small, asymptomatic unruptured anterior circulation aneurysms (UIAs). We sought to determine the cost-effectiveness of active surveillance compared to immediate surgery. Methods: We developed a Markov cost-effectiveness model simulating patients with small (Results: Immediate surgical treatment was the most cost-effective management strategy for small UIAs with ICER of USD 45,772 relative to active surveillance. Sensitivity analysis demonstrated immediate surgery was the preferred strategy, if rupture rate was >0.1%/year and if the diagnosis age was 11%. Probabilistic sensitivity analysis demonstrated that at a willingness-to-pay of USD 100,000/QALY, immediate surgical treatment was the most cost-effective strategy in 64% of iterations. Conclusion: Immediate surgical treatment is a cost-effective strategy for initial management of small UIAs in patients

Subarachnoid hemorrhage induces neuronal apoptosis which causes acute and long-term memory deficits. Ourhypothesis is that agonism of α7-acetylcholine receptors attenuates neuronal apoptosis and improves memorydeficits in SAH mice. Mice were randomly assigned into the experimental groups. One cohort was euthanizedone day after SAH to assess neuronal apoptosis and signaling pathways. A second cohort survived for 30 dayspost-SAH to test long-term memory function. Inhibitors and an α7-acetylcholine receptor knockout mouse wereused. Neurobehavioral performance was assessed on days 1-3, 5, 7, and 23-28. All outcomes were performedand all data was analyzed by a blinded investigator. The α7-acetylcholine receptor agonist prevented neuronalapoptosis and improved acute memory deficits caused by SAH via activation of the PI3K/Akt pathway in neurons.Agonism of the α7-acetylcholine receptor was beneficial in both male and female mice, although the protectionin females was significantly better than in male mice. α7-acetylcholine receptor agonism did not provide anybenefit in α7-acetylcholine receptor knockout mice subjected to SAH. Treatment with the α7-acetylcholinereceptor agonist for 3 days after SAH led to improved working memory one month after SAH suggesting thatacutely improving neuronal survival can have long-lasting benefits. The α7-acetylcholine receptor may be atherapeutic target for SAH which can promote neuronal survival acutely after SAH, but also confer long-lastingmemory benefits. The findings of this study support the α7-acetylcholine receptor as a treatment target whichmay attenuate the long-term memory deficits which SAH patients suffer from.

Background: Acute ischemic strokes outcomes may be less favorable in elderly patients. Whether transferring octogenarians with large vessel occlusion (LVO) for endovascular thrombectomy (EVT) results in similar outcomes to younger patients is uncertain. Methods: A pooled cohort from 6 centers (Europe, US) from 1/2014 to 5/2020 of pts with (ICA, M1, M2) LVO transferred for EVT ≤ 24 hrs from LKW. Patients were stratified into < 80 vs ≥ 80 years old. We compared 90 day functional independence and safety outcomes and assessed for predictors of good outcome (mRS 0-2) and profound disability (mRS 5-6). Results: Of 1176 pts received EVT as transfers, 216 (18%) were octogenarians. Baseline NIHSS was higher in octogenarians [19 (14, 22) vs 17 (12, 21), p Milder strokes (aOR 0.88, 95%CI 0.86-0.91, p Conclusion: EVT may be associated with lower independence rates in transferred octogenarians with LVO. Milder stroke severity, earlier presentation and IV thrombolysis increased the odds of good outcomes in octogenarians. Severe strokes and later treatment were associated with profound disability. Optimized selection and workflow is warranted in transferring elderly patients for EVT.

Background: Efficacy and safety of endovascular thrombectomy (EVT) in large vessel occlusion (LVO) patients with mild deficits is unclear. Methods: Pooled cohort of pts with mild deficits (NIHSS Results: Of 371 pts, 189 (51%) had EVT. Time LKW to EVT center: EVT 165 (70- 416) vs MM 200 (72-564) min, p=0.35 were similar. EVT pts had larger perfusion lesions (51 cc (23-86) vs 30.1 (5, 65), p0.99, neuro-worsening 17% vs 6%, p=0.30) and mortality 5% vs 3%, p>0.99). Without target profile, excellent outcomes were similar without a shift, Fig 1C. Safety was worse with EVT: sICH 8% vs 0%, p=0.001; neuro-worsening 20% vs 3%, p Conclusion: EVT was not associated with improved outcomes in patients with mild deficits; safety was worse. However, EVT was safe and associated with improved outcomes in target profile patients.

Introduction: Successful and fast reperfusion with endovascular thrombectomy (EVT) improves outcomes in acute ischemic strokes due to large vessel occlusion (LVO). While complete reperfusion (mTICI 3) is the ideal target, multiple passes could prolong EVT and increase complications likelihood without improving clinical outcomes. We hypothesized that pts with a single pass mTICI2b would have similar good outcomes to those with multiple passes mTICI3 with a better safety profile. Methods: From the prospective multicenter cohort study of imaging selection (SELECT), EVT pts who achieved mTICI2b and mTICI3 were stratified into those with single pass vs multiple passes. Functional independence rates at 90 day mRS and safety (sICH, neuro-worsening and mortality) were compared between pts with single pass mTICI 2b and multiple passes mTICI 3. Results: Of 361 pts enrolled, 285 received EVT, of those 70 (25%) achieved mTICI 2b and 159 (56%) mTICI 3. 89 (31%) achieved mTICI 3 with single pass, 70 (25%) with multiple passes, 33 (12%) had mTICI 2b with a single pass and 37 (13%) with multiple passes. Baseline characteristics were similar between the two groups except for larger perfusion deficit (Tmax >6s) volume in pts with multiple passes mTICI3 55 (25, 99) cc vs first pass mTICI 2b 43 (4, 79), p=0.047). Functional independence rates were higher with single pass mTICI 2b as compared to multiple passes mTICI 3 (70% vs 56%, aOR=1.51, 95% CI=0.48-4.76, p=0.78), fig 1 but did not reach statistical significance. Multiple passes mTICI 3 was associated with numerically higher mortality (13% vs 3%, p=0.16) and Neuro-worsening (13% vs 3%, p=0.16) with similar sICH: 4% vs 3%, p=1.00 rates. Conclusion: Complete reperfusion with multiple passes did not confer better outcome rates than single pass mTICI 2b and was associated with worse safety profiles. These results suggest that in the absence of complete reperfusion on first attempt, a single pass mTICI 2b may be sufficient for a successful thrombectomy.

Background: Direct To Angio (DTA) for transferred large vessel occlusions (LVO) lowers time to endovascular thrombectomy (EVT), reperfusion and potentially improves outcomes. Safety and efficacy of DTA in late time window and on-call hours is unknown. Methods: Pooled cohort from 6 centers (EU, US) from 1/14-5/20 (ICA, M1, M2) LVO pts transferred for EVT≤24 hrs from LKW. Pts stratified into with repeat imaging (RI) (CT+/- CTA/CTP) and without RI (DTA). We compared time metrics, good outcome (90 day mRS 0-2), safety (sICH, mortality) and assessed the impact of arrival for EVT; regular (M-F, 8am-5pm) vs on-call hrs. Propensity matched analysis was done. Results: Of 1178 EVT transfers, 334 (28%) were DTA. DTA pts had more tPA (61% vs 51%, p=0.002), trended to lower NIHSS 17 (12, 20) vs 17 (13, 21), p=0.07 and lower LKW to arrival 268 (190, 430) min vs 280 (190, 518), p=0.097. Groin puncture (GP) was faster with DTA (p6-24, p=0.88 for interaction). In propensity matched 75 pairs, DTA had shorter time to EVT (19 min vs 52, p Conclusion: In pooled, non-randomized data DTA may result in faster treatment, safe and better functional outcomes, during all hours and treatment windows. Repeat imaging may be reasonable with prolonged transfer times. Optimal EVT workflow in transfers may result in faster, safe reperfusion with higher good outcomes.

Background: The efficacy of endovascular thrombectomy (EVT) in M2 occlusions is uncertain. Methods: In a pooled patient level analysis of the prospective multicenter cohort study of imaging selection (SELECT) and the INternational Stroke Perfusion Imaging REgistry (INSPIRE) EVT outcomes were compared to medical management (MM) in M2 occlusions. Further, we assessed for potential treatment benefit in patients with higher stroke severity (NIHSS). The primary outcome was excellent outcome (mRS 0-1). Results: 387 patients with isolated M2 occlusion (EVT 112, MM 275) met the inclusion criteria. Baseline NIHSS median (IQR) (EVT: 13 (9-19), MM: 10 (6-15), p10 had a trend towards higher excellent outcome rates outcomes with EVT (43%) vs MM (27%), aOR=3.11, 95% CI=0.81-11.95, p=0.098) as shown in figure 1. Conclusion: EVT may result in better rates of excellent outcomes in isolated M2 occlusions, especially those with more severe strokes who are more likely to have worse outcomes without emergent reperfusion.

Background and Purpose: Time elapsed from last-known well (LKW) and baseline imaging results are influential on endovascular thrombectomy (EVT) outcomes. Methods: In a prospective multicenter cohort study of imaging selection for endovascular thrombectomy (SELECT [Optimizing Patient’s Selection for Endovascular Treatment in Acute Ischemic Stroke], the early infarct growth rate (EIGR) was defined as ischemic core volume on perfusion imaging (relative cerebral blood flow2. The primary outcome was 90-day functional independence (modified Rankin Scale score =0–2). Results: Of 445 consented, 361 (285 EVT, 76 medical management only) patients met the study inclusion criteria. The optimal EIGR was P P P P =0.001). EIGR independently correlated with functional independence after EVT, adjusting for age, National Institutes of Health Stroke Scale, time LKW to groin puncture, reperfusion (modified Thrombolysis in Cerebral Infarction score of ≥2b), IV-tPA (intravenous tissue-type plasminogen activator), and transfer status (aOR: 0.78 [0.65–0.94], P =0.01). Slow progressors had higher functional independence rates (121 [61%] versus 30 [35%], P P =0.001) as compared to fast progressors, who had substantially worse clinical outcomes both in early and late time window. The odds of good outcome decreased by 14% for each 5 mL/h increase in EIGR (aOR, 0.87 [0.80–0.94], P Conclusions: The EIGR strongly correlates with both collateral status and clinical outcomes after EVT. Fast progressors demonstrated worse outcomes when receiving EVT beyond 6 hours of stroke onset as compared to those who received EVT within 6 hours. Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT02446587.

The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via strong tight junctions, specific transporters, and limited endocytosis which combine to protect the brain from toxins and maintains brain homeostasis. Blood–brain barrier (BBB) leakage is a serious secondary injury in various CNS disorders like stroke, brain tumors, and neurodegenerative disorders. Currently, there are no drugs or therapeutics available to treat specifically BBB damage after a brain injury. Growing knowledge in the field of epigenetics can enhance the understanding of gene level of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. In this brief review, we summarize the epigenetic mechanisms or regulators that have a protective or disruptive role for components of BBB, along with the promising approaches to regain the integrity of BBB.

BackgroundPrior studies on rupture risk of brain arteriovenous malformations (AVMs) in women undergoing pregnancy and delivery have reported conflicting findings, but also have not accounted for AVM morphology and heterogeneity. Here, we assess the association between pregnancy and the risk of intracranial hemorrhage (ICH) in women with AVMs using a cohort-crossover design in which each woman serves as her own control.MethodsWomen who underwent pregnancy and delivery were identified using DRG codes from the Healthcare Cost and Utilization Project State Inpatient Databases for California (2005–2011), Florida (2005–2014), and New York (2005–2014). The presence of AVM and ICH was determined using ICD 9 codes. Pregnancy was defined as the 40 weeks prior to delivery, and postpartum as 12 weeks after. We defined a non-exposure control period as a 52-week period prior to pregnancy. The relative risks of ICH during pregnancy were compared against the non-exposure period using conditional Poisson regression.ResultsAmong 4 022 811 women identified with an eligible delivery hospitalization (median age, 28 years; 7.3% with gestational diabetes; 4.5% with preeclampsia/eclampsia), 568 (0.014%) had an AVM. The rates of ICH during pregnancy and puerperium were 6355.4 (95% CI 4279.4 to 8431.5) and 14.4 (95% CI 13.3 to 15.6) per 100 000 person-years for women with and without AVM, respectively. In cohort-crossover analysis, in women with AVMs the risk of ICH increased 3.27-fold (RR, 95% CI 1.67 to 6.43) during pregnancy and puerperium compared with a non-pregnant period.ConclusionsAmong women with AVM, pregnancy and puerperium were associated with a greater than 3-fold risk of ICH.

Background and Purpose: Noncontrast head CT and CT perfusion (CTP) are both used to screen for endovascular stroke therapy (EST), but the impact of imaging strategy on likelihood of EST is undetermined. Here, we examine the influence of CTP utilization on likelihood of EST in patients with large vessel occlusion (LVO). Methods: We identified patients with acute ischemic stroke at 4 comprehensive stroke centers. All 4 hospitals had 24/7 CTP and EST capability and were covered by a single physician group (Neurology, NeuroIntervention, NeuroICU). All centers performed noncontrast head CT and CT angiography in the initial evaluation. One center also performed CTP routinely with high CTP utilization (CTP-H), and the others performed CTP optionally with lower utilization (CTP-L). Primary outcome was likelihood of EST. Multivariable logistic regression was used to determine whether facility type (CTP-H versus CTP-L) was associated with EST adjusting for age, prestroke mRS, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT Score, LVO location, time window, and intravenous tPA (tissue-type plasminogen activator). Results: Among 3107 patients with acute ischemic stroke, 715 had LVO, of which 403 (56%) presented to CTP-H and 312 (44%) presented to CTP-L. CTP utilization among LVO patients was greater at CTP-H centers (72% versus 18%, CTP-H versus CTP-L, P Conclusions: We identified an increased likelihood for undergoing EST in centers with lower CTP utilization, which was not associated with worse clinical outcomes or increased hemorrhage. These findings suggest under-treatment bias with routine CTP.

Patient: Female, 44-year-old Final Diagnosis: Pituitary adenoma Symptoms: Depression and anxiety Medication:— Clinical Procedure: — Specialty: Neurosurgery • Psychiatry Objective: Unusual clinical course Background: Few case reports exist in the literature of patients with pituitary adenoma presenting with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD). Complete remission of persistent PMDD symptoms after surgical removal of a pituitary lesion has not been reported. Case Report: We report a case of a 44-year-old woman with childbearing potential who underwent transsphenoidal surgery (TSS) in December 2017 to remove a non-functioning pituitary adenoma. The surgery resulted in full remission of her PMDD symptoms. The patient’s hormone levels remained stable before and after the TSS procedure. During 28 months of follow-up, the woman has been asymptomatic for periods of 6 consecutive months or longer without taking antidepressants. Given the patient’s current condition, a durable remission from PMDD is anticipated. Conclusions: We believe that refractory PMS/PMDD associated with pituitary lesions is under-diagnosed and under reported. As demonstrated in this case, surgical intervention for a sellar mass has the potential to be effective or even curative for patients with PMS/PMDD. We recommend that physicians consider magnetic resonance imaging of the brain in patients with PMS/PMDD.

Background: Haptoglobin (Hp) binds to and facilitates clearance of heme. Compared with HP 1-1 and 1-2 genotypes, HP 2-2 has a weaker binding affinity and has been linked with increased inflammation and vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Objective: This study aims to assess levels of inflammatory cytokines in the context of different HP genotypes. Methods: Patients were enrolled among those presenting with spontaneous aneurysmal SAH. Blood was drawn at four time points; Results: Fifty-seven patients were enrolled. Compared with HP 1-1 and 1-2, subjects encoding HP 2-2 had elevated levels of the following cytokines at all time points: FLT3L, IFNγ, IL-17A, TGFα, and VEGF-A. Elevations were also seen at some time points for IL-8, CSF2, FGF2, IL-7, IL-12p70, and TNFγ. This study was not powered to detect differences in the functional outcome; however, there were no significant differences in dichotomized mRS scores between patients with HP 1-1/1-2 or HP 2-2. Conclusion: Our findings indicate that HP 2-2 genotype leads to increased proinflammatory cytokine levels compared with HP 1-1/1-2 genotypes. These data may provide guidance for further studies seeking to identify testable markers for functional prognosis or targets for treatment.

Background and Purpose: Delayed neurological deficits are a devastating consequence of subarachnoid hemorrhage (SAH), which affects about 30% of surviving patients. Although a very serious concern, delayed deficits are understudied in experimental SAH models; it is not known whether rodents recapitulate the delayed clinical decline seen in SAH patients. We hypothesized that mice with SAH develop delayed functional deficits and that microthrombi and infarction correlate with delayed decline. Methods: Adult C57BL/6J mice of both sexes were subjected to endovascular perforation to induce SAH. Mice were allowed to survive for up to 1 week post-ictus and behavioral performance was assessed daily. Postmortem microthrombi, large artery diameters (to assess vasospasm), and infarct volume were measured. These measures were analyzed for differences between SAH mice that developed delayed deficits and SAH mice that did not get delayed deficits. Correlation analyses were performed to identify which measures correlated with delayed neurological deficits, sex, and infarction. Results: Twenty-three percent of males and 47% of females developed delayed deficits 3 to 6 days post-SAH. Female mice subjected to SAH had a significantly higher incidence of delayed deficits than male mice with SAH. Mice that developed delayed deficits had significantly more microthrombi and larger infarct volumes than SAH mice that did not get delayed deficits. Microthrombi positively correlated with infarct volume, and both microthrombi and infarction correlated with delayed functional deficits. Vasospasm did not correlate with either infarction delayed functional deficits. Conclusions: We discovered that delayed functional deficits occur in mice following SAH. Sex differences were seen in the prevalence of delayed deficits. The mechanism by which microthrombi cause delayed deficits may be via formation of infarcts.

The blood brain barrier (BBB), unique to the central nervous system (CNS) vessels, tightly controls the passage of molecules between the blood and the brain. BBB breakdown is documented in many pathological conditions including, stroke, and contributes to the severity of disease and poor outcome. Currently, there is no efficient treatment strategy to prevent BBB breakdown or restore disrupted BBB . Despite BBB’s importance in the CNS function, t he genetic program and mechanism, that regulates BBB formation and maintenance is poorly characterized. To understand the molecular features underlying BBB gene regulation during development we utilize endothelial cell (EC) cultures derived from brain of both embryonic (E-13.5) and adult mice and investigated differences in BBB gene expression and epigenetic status using real time PCR analysis and ChIP-qPCR. We found that a distinct BBB profile exist in the CNS ECs during BBB formation and maintenance . When compared to embryonic ECs, adult ECs showed a significant down regulation in expression of tight junction (TJ) genes such as CLDN-1 , CLDN -11 , ZO-1 and OCLN . Conversely, another important TJ gene CLDN- 5 shows a significant increase in adult ECs. Further, we found that epigenetic-histone modifications are involved in the repression in the TJ gene in adult ECs. To more fully understand the role of Wnt/β-catenin in BBB formation and maintenance we block the downstream of the Wnt/β-catenin signaling pathway using LF3 (block the interaction of β-catenin and transcription factor TCF4) in developing ECs. This results in a adult BBB phenotype in developing ECs indicating, silencing of Wnt/β-catenin pathway is required for BBB maturation . Further, epigenetic component HDAC2 was increased significantly in developing ECs when Wnt/β-catenin signaling is blocked demonstrating this pathway can modulate the epigenetics of CNS ECs . In summary, we describe that BBB genes have distinguished expression pattern during BBB formation and maintenance, guided by the Wnt/β-catenin pathway through epigenetic modifications. Understanding the fundamental epigenetic and regulatory mechanisms of BBB formation and maintenance is critical for developing therapeutic interventions against BBB breakdown.

Background: The effect of anesthesia choice on endovascular thrombectomy (EVT) outcomes is unclear. Methods: In the prospective multicenter cohort study of imaging selection for EVT (SELECT), patients were stratified based on their anesthesia type into general anesthesia (GA) and conscious sedation (CS). EVT times and outcomes were compared. Further we assessed the impact of ischemic core size (rCBF Results: Of 361 enrolled, 285 received EVT. 129 (45%%) received GA and 156 (54%) CS. The baseline characteristics were similar, except for presentation NIHSS (GA 17(13-21), CS 15(11-20), p=0.027) and ischemic core volume (GA 14.1 cc (0-38) vs CS 6.3(0-26.1), p=0.034). GA was associated with numerically longer arrival to GP times 92 (68—115) vs. 85(60-117) mins, p=0.58. After adjustment for baseline imbalances, patients who received CS had a shift toward better outcome (adj cOR 1.72, 95% CI=1.08-2.75, p=0.022) with higher functional independence rates 56.8% vs 48.8%, p=0.75. Furthermore, GA was associated with higher mortality rates (19% vs 9%, p=0.017), figure 1A. In patients with core volume ≥ 50 cc, there was a trend for a shift towards better outcomes (adj cOR=5.84, 95%CI= 0.90-38.00, P=0.065), figure 1B while there was no difference in patients with core volume < 50 cc (adj cOR=1.01 (95%CI 0.53-1.94, P=0.96), figure 1C. There was an interaction between core volume size and anesthesia type on functional outcome (p=0.042). For every 10cc increase in the core volume, the odds of attaining better functional outcome decreased by 29% (adjusted cOR: 0.71, 95% CI=0.61-0.83, p Conclusion: Conscious sedation was associated with a shift towards better EVT outcomes. This effect was driven by patients with larger ischemic core volumes and has implications for randomized trials of conscious sedation vs general anesthesia.

Introduction: Prior studies suggest that patients with large vessel occlusion (LVO) who undergo endovascular stroke therapy (EST) after inter-hospital transfer (IHT) have worse outcomes than those who present directly to EST centers. However, these studies were largely derived from clinical trials or registries and may not be representative of real-world clinical practice. Methods: We performed a multicenter, observational cohort study on acute ischemic stroke (AIS) patients with LVO that presented to EST-capable centers directly (LVO-D) or after IHT (LVO-T) between 1/1/2018 to 2/1/2019. The study included 11 hospitals in the Houston area, of which 4 are EST-capable. Clinical data were collected using our cerebrovascular data registry. All transfers were from non-EST capable hospitals to EST-capable hospitals. Logistic regression adjusted for age, NIHSS, occlusion location and direct vs transfer arrival was used to assess the likelihood of good outcome, defined as discharge to home or rehabilitation. Results are given as median [IQR] and OR [95% CI]. Results: Among 4,313 patients with AIS, 772 (18%) patients had LVO. Among LVO patients, median age was 68 [59-79], 47% were female, 51% were white, 378 (49%) were LVO-D and 394 (51%) were LVO-T. Median IHT time was 152 min [114-198]. LVO-D patients arrived at EST-treating hospitals with superior ASPECTS compared to LVO-T (9 [7-10] vs 7 [6-9], p Conclusion: In this real-world cohort of a multi-center stroke network, IHT was not associated with worse outcomes for patients with LVO, for both patients who did receive EST and those that did not.

Background: Whether IV tPA has adjunctive benefit to endovascular thrombectomy (EVT) is unclear. Methods: In a prospective multicenter cohort study of imaging selection for EVT (SELECT), patients who received IV tPA vs. no IV tPA were compared stratified by stroke severity and ischemic core size (rCBF Results: Of 361 enrolled, 285 received EVT; 226 presented within 4.5 hrs, 162 (72%) received IV tPA. IV tPA patients had lower median ASPECTS (8 vs 9, p=0.007) and larger ischemic core size (11.4 (1.5-37) vs 3.9 (0-32.15), p=0.042, otherwise similar at baseline. There were no delays in EVT delivery associated with tPA: median time (IQR) from arrival to groin puncture 95.0 min (66.0, 118.0) tPA vs 81.5 (63.5, 107.5) no tPA, p=0.21. IV tPA use was associated with higher mRS 0-2 rates (57% vs 44%), aOR 2.02 (95% CI 1.01-4.03, p=0.046) after adjustment for baseline differences with a shift towards better outcomes on all mRS levels (cOR 2.06, 95% CI 1.18-3.59, p=0.01) with lower mortality (11% vs 22%, p=0.026) and similar sICH rates (and 6% vs 6%, p=1.0). In patients with NIHSS Conclusion: IV tPA did not result in thrombectomy delivery delays and may result in better outcomes. Patients with less severe strokes and smaller infarct size had a stronger association between the use of IV tPA and favorable outcomes.

Background: The efficacy of endovascular thrombectomy (EVT) in M2 occlusions is uncertain. Methods: In a prospective multicenter cohort study of imaging selection (SELECT), EVT outcomes were compared to medical managment (MM) in M2 occlusions. Further, we assessed for potential treatment benefit in patients with higher stroke severity (NIHSS) and a larger perfusion deficit on CTP (Tmax > 6 sec - ischemic core volume)The primary outcome was excellent outcome (mRS 0-1). Results: of 361 patients enrolled in SELECT, 87 had isolated M2 occlusion (EVT 59, MM 28). Baseline NIHSS median (IQR) (EVT 14 (10-20), MM 15 (9.5-19.5), p=0.72) and infarct volume rCBF10 had better outcomes with EVT (46%) vs MM (10%), aOR=11.39, 95% CI=1.80-72.11, p=0.01 as shown in figure 1. As perfusion deficit lesion size increased, the odds of achieving excellent outcomes was reduced (for each 10cc by 11%, aOR: 0.89, 95% CI=0.79-1.00, p=0.05). Excellent outcomes declined in patients with MM as perfusion deficit lesion size increased, yet in the EVT they were maintained as shown in figure 2. Similar results were obtained for mRS 0-2. Conclusion: EVT may result in better rates of excellent outcomes in isolated M2 occlusions, especially those with more severe strokes and larger perfusion deficits who are more likely to have worse outcomes without emergent reperfusion.