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Background: In patients with intracranial steno-occlusive disease (SOD), the risk of hemodynamic stroke depends on the poststenotic vasodilatory reserve. Cerebrovascular reactivity (CVR) is a test for vasodilatory reserve. We tested for vasodilatory reserve by using PETCO2 as the stressor, and Blood Oxygen Level Dependent (BOLD) MRI as a surrogate of blood flow. We correlate the CVR to the incidence of stroke after a 1-year follow-up in patients with symptomatic intracranial SOD. Methods: In this retrospective study, 100 consecutive patients with symptomatic intracranial SOD that had undergone CVR testing were identified. CVR was measured as % BOLD MR signal intensity/mmHg PETCO2. All patients with normal CVR were treated with optimal medical therapy; those with abnormal CVR were offered revascularization where feasible. We determined the incidence of stroke at 1 year. Results: 83 patients were included in the study. CVR was normal in 14 patients and impaired in 69 patients ipsilateral to the lesion. Of these, 53 underwent surgical revascularization. CVR and symptoms improved in 86% of the latter. The overall incidence of stroke was 4.8 % (4/83). All strokes occurred in patients with impaired CVR (4/69; 2/53 in the surgical group, all in the nonrevascularized hemisphere), and none in patients with normal CVR (0/14). Conclusion: Our study confirms that CO2-BOLD MRI CVR can be used as a brain stress test for the assessment of cerebrovascular reserve. Impaired CVR is associated with a higher incidence of stroke and normal CVR despite significant stenosis is associated with a low risk for stroke.

Introduction: Age is a predictor of functional outcome after acute ischemic stroke (AIS). Frailty increases with age and comorbidities, and imaging markers of brain-frailty (e.g. atrophy, small-vessel-disease) are associated with outcomes. However, the extent to which the association of age and 90-day outcome is mediated by brain-frailty is unknown. We explored this mediation in AIS patients receiving endovascular therapy (EVT), with a particular interest in neuroimaging. Methods: In this post-hoc analysis of the ESCAPE-NA1 trial, in which all patients underwent EVT, we assessed brain atrophy (subcortical/cortical), white-matter disease (periventricular/deep) and the number of lacunes and chronic infarctions. Structural equation modelling (SEM) was used to create 3 latent variables: “imaging-frailty” (above-mentioned markers), “clinical-frailty” (e.g. pre-stroke mRS, cardiovascular risk factors, cancer) and “total-frailty” (imaging + clinical markers). We created 3 models ( figure1) including each latent variable as a potential mediator of the association of age and 90-day outcome, adjusting for baseline ASPECTS, NIHSS, onset-to-puncture-time, nerinetide and alteplase. Results: Among 1,092 patients, the indirect effect of age on 90-day outcome, mediated by imaging-frailty, contributed 96% of the total effect(β=0.047;p=0.02), while the indirect effect through clinical-frailty accounted for only 21%(β=0.01;p=0.001) of the total effect. When including both frailty constructs, the indirect pathway accounted for 86% of the total effect(β=0.06;p Conclusions: Brian frailty mediates the association of age and 90-day outcome after EVT, with most of the effect mediated by imaging as opposed to clinical markers of frailty. This work underscores the importance of considering brain-frailty, as opposed to chronological age alone, in predicting post-stroke outcomes.

Background and ObjectivesSmall iatrogenic brain infarcts are often seen on diffusion-weighted MRI (DWI) following surgical or endovascular procedures, but there are few data on their clinical effects. We examined the association of iatrogenic infarcts with outcomes in the ENACT (Evaluating Neuroprotection in Aneurysm Coiling Therapy) randomized controlled trial of nerinetide in patients undergoing endovascular repair of intracranial aneurysms.MethodsIn this post hoc analysis, we used multivariable models to evaluate the association of the presence and number of iatrogenic infarcts on DWI with neurologic impairment (NIH Stroke Scale [NIHSS]), functional status (modified Rankin Scale [mRS]), and cognitive and neuropsychiatric outcomes (30-minute test battery) at 1–4 days and 30 days postprocedure. We also related infarct number to azscore–derived composite outcome score using quantile regression.ResultsAmong 184 patients (median age 56 years [interquartile range (IQR) 50–64]), 124 (67.4%) had postprocedural DWI lesions (median 4, IQR 2–10.5). Nerinetide treatment was associated with fewer iatrogenic infarcts but no overall significant clinical treatment effects. Patients with infarcts had lower Mini-Mental State Examination (MMSE) scores at 2–4 days (median 28 vs 29, adjusted coefficient [acoef] −1.11, 95% CI −1.88 to −0.34,p= 0.005). Higher lesion counts were associated with worse day 1 NIHSS (adjusted odds ratio for NIHSS ≥1: 1.07, 1.02–1.12,p= 0.009), day 2–4 mRS (adjusted common odds ratio [acOR] 1.05, 1.01–1.09,p= 0.005), and day 2–4 MMSE (acoef −0.07, −0.13 to −0.003,p= 0.040) scores. At 30 days, infarct number remained associated with worse mRS (acOR 1.04, 1.01–1.07,p= 0.016) and Hopkins Verbal Learning Test (HVLT) delayed recall scores (acoef −0.21, −0.39 to −0.03,p= 0.020). Patients with infarcts trended towards lower 30-day Digit Symbol Substitution Test (DSST) scores (acoef −3.73, −7.36 to −0.10,p= 0.044). Higher lesion count was associated with worse composite outcome scores at both 1–4 days and 30 days (30-day acoef −0.12, 95% CI −0.21 to −0.03,p= 0.008). Among those with infarcts, day 1 NIHSS and day 2–4 mRS correlated with 30-day NIHSS, DSST, HVLT, and mRS scores, whereas day 2–4 MMSE correlated with 30-day NIHSS and DSST scores (Spearman ρ 0.47,p= 0.001).DiscussionIatrogenic brain infarcts were associated with subtle differences in postprocedural (1–4 days) and 30-day outcomes on different measures in this middle-aged cohort, with earlier dysfunction correlating with later differences.Trial Registration InformationClinical trials registrationNCT00728182.

Successful reperfusion determines the treatment effect of endovascular thrombectomy. We evaluated stent-retriever characteristics and their relation to reperfusion in the ESCAPE-NA1 trial.Independent re-scoring of reperfusion grade for each attempt was conducted. The following characteristics were evaluated: stent-retriever length and diameter, thrombus position within stent-retriever, bypass effect, deployment in the superior or inferior MCA trunk, use of balloon guide catheter and distal access catheter. Primary outcome was successful reperfusion defined as expanded thrombolysis in cerebral infarction (eTICI) 2b-3 per attempt. The secondary outcome was successful reperfusion eTICI 2b-3 after the first attempt. Separate regression models for each stent-retriever characteristic and an exploratory multivariable modeling to test the impact of all characteristics on successful reperfusion were built.Of 1105 patients in the trial, 809 with the stent-retriever use (1241 attempts) were included in the primary analysis. The stent-retriever was used as the first-line approach in 751 attempts. A successful attempt was associated with thrombus position within the proximal or middle third of the stent (OR 2.06; 95% CI: 1.24-3.40 and OR 1.92; 95% CI: 1.16-3.15 compared to the distal third respectively) and with bypass effect (OR 1.7; 95% CI: 1.07-2.72). Thrombus position within the proximal or middle third (OR 2.80; 95% CI: 1.47-5.35 and OR 2.05; 95% CI: 1.09-3.84, respectively) was associated with first-pass eTICI 2b-3 reperfusion. In the exploratory analysis accounting for all characteristics, bypass effect was the only independent predictor of eTICI 2b-3 reperfusion (OR 1.95; 95% CI: 1.10-3.46).The presence of bypass effect and thrombus positioning within the proximal and middle third of the stent-retriever were strongly associated with successful reperfusion.

Neuroprotection in acute stroke has not been successfully translated from animals to humans. Animal research on promising agents continues largely in rats and mice which are commonly available to researchers. However, controversies continue on the most suitable species to model the human situation. Generally, putative agents seem less effective in mice as compared with rats. We hypothesized that this may be due to inter-species differences in stroke response and that this might be manifest at a genetic level. Here we used whole-genome microarrays to examine the differential gene regulation in the ischemic penumbra of mice and rats at 2 and 6 h after permanent middle cerebral artery occlusion (pMCAO; Raw microarray CEL data files are available in the GEO database with an accession number GSE163654). Differentially expressed genes (adj. p ≤ 0.05) were organized by hierarchical clustering, correlation plots, Venn diagrams and pathway analyses in each species and at each time-point. Emphasis was placed on genes already known to be associated with stroke, including validation by RT-PCR. Gene expression patterns in the ischemic penumbra differed strikingly between the species at both 2 h and 6 h. Nearly 90% of significantly regulated genes and most pathways modulated by ischemia differed between mice and rats. These differences were evident globally, among stroke-associated genes, immediate early genes, genes implicated in stress response, inflammation, neuroprotection, ion channels, and signal transduction. The findings of this study may have significant implications for the choice of species for screening putative stroke therapies.

Background Intracranial hemorrhage is a known complication after endovascular treatment in patients with acute ischemic stroke due to large vessel occlusion, but the association between radiologic hemorrhage severity and outcome is controversial. Purpose To investigate the prevalence and impact on outcome of intracranial hemorrhage and hemorrhage severity after endovascular stroke treatment. Materials and Methods The Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke (ESCAPE-NA1) trial enrolled participants with acute large vessel occlusion stroke who underwent endovascular treatment from March 1, 2017, to August 12, 2019. Evidence of any intracranial hemorrhage, hemorrhage multiplicity, and radiologic severity, according to the Heidelberg classification (hemorrhagic infarction type 1 [HI1], hemorrhagic infarction type 2 [HI2], parenchymal hematoma type 1 [PH1], and parenchymal hematoma type 2 [PH2]) was assessed at CT or MRI 24 hours after endovascular treatment. Good functional outcome, defined as a modified Rankin score of 0-2 at 90 days, was compared between participants with intracranial hemorrhage and those without intracranial hemorrhage at follow-up imaging and between hemorrhage subtypes. Poisson regression was performed to obtain adjusted effect size estimates for the presence of any intracranial hemorrhage and hemorrhage subtypes at good functional outcome. Results Of 1097 evaluated participants (mean age, 69 years ± 14 [standard deviation]; 551 men), any degree of intracranial hemorrhage was observed in 372 (34%). Good outcomes were less often achieved among participants with hemorrhage than among those without hemorrhage at follow-up imaging (164 of 372 participants [44%] vs 500 of 720 [69%], respectively; P < .01). After adjusting for baseline variables and infarct volume, intracranial hemorrhage was not associated with decreased chances of good outcome (adjusted risk ratio [RR] = 0.91 [95% CI: 0.82, 1.02], P = .10), but there was a graded relationship of radiologic hemorrhage severity and outcomes, whereby PH1 (RR = 0.77 [95% CI: 0.61, 0.97], P = .03) and PH2 (RR = 0.41 [95% CI: 0.21, 0.81], P = .01) were associated with decreased chances of good outcome. Conclusion Any degree of intracranial hemorrhage after endovascular treatment was seen in one-third of participants. A graded association existed between radiologic hemorrhage severity and outcome. Hemorrhagic infarction was not associated with outcome, whereas parenchymal hematoma was strongly associated with poor outcome, independent of infarct volume. © RSNA, 2021 Clinical trial registration no. NCT01778335 Online supplemental material is available for this article.

Background The effect of infarct pattern on functional outcome in acute ischemic stroke is incompletely understood. Purpose To investigate the association of qualitative and quantitative infarct variables at 24-hour follow-up noncontrast CT and diffusion-weighted MRI with 90-day clinical outcome. Materials and Methods The Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke, or ESCAPE-NA1, randomized controlled trial enrolled patients with large-vessel-occlusion stroke undergoing mechanical thrombectomy from March 1, 2017, to August 12, 2019. In this post hoc analysis of the trial, qualitative infarct variables (predominantly gray [vs gray and white] matter involvement, corticospinal tract involvement, infarct structure [scattered vs territorial]) and total infarct volume were assessed at 24-hour follow-up noncontrast CT or diffusion-weighted MRI. White and gray matter infarct volumes were assessed in patients by using follow-up diffusion-weighted MRI. Infarct variables were compared between patients with and those without good outcome, defined as a modified Rankin Scale score of 0-2 at 90 days. The association of infarct variables with good outcome was determined with use of multivariable logistic regression. Separate regression models were used to report effect size estimates with adjustment for total infarct volume. Results Qualitative infarct variables were assessed in 1026 patients (mean age ± standard deviation, 69 years ± 13; 522 men) and quantitative infarct variables were assessed in a subgroup of 358 of 1026 patients (mean age, 67 years ± 13; 190 women). Patients with gray and white matter involvement (odds ratio [OR] after multivariable adjustment, 0.19; 95% CI: 0.14, 0.25; P < .001), corticospinal tract involvement (OR after multivariable adjustment, 0.06; 95% CI: 0.04, 0.10; P < .001), and territorial infarcts (OR after multivariable adjustment, 0.22; 95% CI: 0.14, 0.32; P < .001) were less likely to achieve good outcome, independent of total infarct volume. Conclusion Infarct confinement to the gray matter, corticospinal tract sparing, and scattered infarct structure at 24-hour noncontrast CT and diffusion-weighted MRI were highly predictive of good 90-day clinical outcome, independent of total infarct volume. Clinical trial registration no. NCT02930018 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Mossa-Basha in this issue.

BACKGROUND AND PURPOSE: Infarct volume is an important predictor of clinical outcome in acute stroke. We hypothesized that the association of infarct volume and clinical outcome changes with the magnitude of infarct size. MATERIALS AND METHODS: Data were derived from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, in which patients with acute stroke with large-vessel occlusion were randomized to endovascular treatment plus either nerinetide or a placebo. Infarct volume was manually segmented on 24-hour noncontrast CT or DWI. The relationship between infarct volume and good outcome, defined as mRS 0–2 at 90 days, was plotted. Patients were categorized on the basis of visual grouping at the curve shoulders of the infarct volume/outcome plot. The relationship between infarct volume and adjusted probability of good outcome was fitted with linear or polynomial functions as appropriate in each group. RESULTS: We included 1099 individuals in the study. Median infarct volume at 24 hours was 24.9 mL (interquartile range [IQR] = 6.6–92.2 mL). On the basis of the infarct volume/outcome plot, 4 infarct volume groups were defined (IQR = 0–15 mL, 15.1–70 mL, 70.1–200 mL, >200 mL). Proportions of good outcome in the 4 groups were 359/431 (83.3%), 219/337 (65.0%), 71/201 (35.3%), and 16/130 (12.3%), respectively. In small infarcts (IQR = 0–15 mL), no relationship with outcome was appreciated. In patients with intermediate infarct volume (IQR = 15–200 mL), there was progressive importance of volume as an outcome predictor. In infarcts of > 200 mL, outcomes were overall poor. CONCLUSIONS: The relationship between infarct volume and clinical outcome varies nonlinearly with the magnitude of infarct size. Infarct volume was linearly associated with decreased chances of achieving good outcome in patients with moderate-to-large infarcts, but not in those with small infarcts. In very large infarcts, a near-deterministic association with poor outcome was seen.

Background and purpose: Endovascular treatment (EVT) is a powerful treatment for large vessel occlusion (LVO) stroke if reperfusion can be achieved, while in cases with failed reperfusion, EVT may cause harm, as procedure-related complications may occur. We hypothesized that EVT with failed recanalization does not result in worse outcomes compared to best medical management and compared clinical outcomes of LVO stroke patients who underwent EVT with failed reperfusion to those who were treated with best medical management. Methods: We included patients with failed reperfusion from the control (EVT-only) arm of the ESCAPE-NA1 trial and the EVT arm of the ESCAPE trial and patients of the ESCAPE control arm who were treated with best medical management. Failed reperfusion following EVT was defined as modified thrombolysis in cerebral infarction score 0–2a. Proportions of good outcome (modified Rankin scale 0–2) were compared between patients who did and did not undergo EVT, and adjusted effect size estimates for EVT on outcomes were obtained. Results: We included 260 patients (110 failed EVT and 150 non-EVT patients). Proportions of good outcome were 38/110 (34.6%) with failed EVT vs.43/147 (29.3%) without EVT (adjusted odds ratio[aOR]: 1.48 [95%CI: 0.81–2.68]). Mortality and proportions of sICH in the failed EVT group vs. patients treated with best medical management were 26/110 (23.6%) vs. 28/147 (19.1%), aOR: 1.12 (95%CI: 0.56–2.24), and 7/110 (6.4%) vs. 4/150 (2.7%), aOR: 2.34 (95%CI: 0.00–22.97). Conclusion: Clinical outcomes of EVT patients with failed reperfusion did not differ significantly from patients treated with best medical management.

There are few data on the prevalence and impact of isolated deep grey matter infarction in acute stroke. In this study, we aimed to investigate the prevalence of isolated deep grey matter infarcts and their impact on the outcome. Infarcts on 24-h follow-up imaging (non-contrast head CT or diffusion-weighted MRI) in the ESCAPE-NA1 trial were categorized into predominantly deep grey matter infarcts vs. infarcts involving additional territories (“other infarcts”). Total infarct volume was manually segmented. Baseline characteristics and proportions of good outcome (primary outcome, defined as modified Rankin Score [mRS] 0–2 at 90 days), excellent outcome (mRS 0–1) and mortality were compared between patients with and without predominantly deep grey matter infarcts. Multivariable logistic regression with adjustment for baseline variables and total infarct volume was used to determine a possible association of predominantly deep grey matter infarcts and clinical outcome. Predominantly deep grey matter infarcts were seen in 316/1026 patients (30.8%). Compared to other patients, their ASPECTS was higher, collateral status and reperfusion quality were better and time to treatment was shorter. Good outcome was seen in 239/316 (75.6%) with vs. 374/704 (53.1%) without predominantly deep grey matter infarcts. After adjusting for baseline variables and total infarct volume, predominantly deep grey matter infarcts were independently associated with excellent outcome (adjOR: 1.45 [CI95: 1.04–2.02]), but not with good outcome (adjOR: 1.24 [CI95: 0.86–1.80]) or mortality (adjOR: 0.73 [CI95:0.39–1.35]) Predominantly deep grey matter infarct patterns were seen in 1/3rd of patients and were significantly associated with increased chances of excellent outcome, independent of patient baseline status and infarct size.

BackgroundThe DAWN and DEFUSE-3 trials showed the benefit of endovascular treatment (EVT) in acute ischemic stroke patients presenting beyond 6 hours from last known well (LKW) and selected by perfusion imaging criteria. The ESCAPE NA1-trial selected patients based on non-contrast CT (NCCT) Alberta Stroke Program Early CT Score (ASPECTS) and multiphase CT angiography (CTA) collateral status. This study compares baseline characteristics, workflow, and outcomes in the EVT arms of DAWN and DEFUSE-3 with late-window patients from the EVT-only arm of ESCAPE-NA1.MethodsAggregate data on baseline characteristics, workflow, reperfusion quality, final infarct volume, and clinical outcomes (modified Rankin Score [mRS] at 90 days) in subjects enrolled in the DAWN and DEFUSE-3 EVT arms were compared with similar data from the ESCAPE-NA1 control arm (EVT-only arm) presenting beyond 6 hours from LKW using descriptive statistics.ResultsBaseline characteristics among late-window patients in the ESCAPE NA1 trial were similar to those in the DAWN and DEFUSE-3 EVT arms. Median time from LKW-to-puncture in subjects enrolled in the ESCAPE NA1 trial was 9 hrs (IQR: 7.5–11 hours) when compared with DAWN (n=107; 12.8 hours, IQR: 10.6–16.7 hours) and DEFUSE-3 (n=92; 11.5 hours, IQR: 9.2–12.8 hours). Median post-treatment infarct-volume was largest in the ESCAPE NA1-patients (47 mL [IQR: 19–146] vs median 8 mL [IQR: 0–48] in the DAWN group and 35 mL [IQR: 18–82] in DEFUSE-3), while % mRS 0–2 at 90 days were similar across the three trials (ESCAPE NA1: 50/111 [45%], DAWN: 52/107 [49%], DEFUSE-3: 41/92 [45%]).ConclusionPatients enrolled beyond 6 hours from LKW in the ESCAPE-NA1 trial based on NCCT-ASPECTS and mCTA had similar clinical outcomes when compared with patients selected by perfusion imaging in the DAWN and DEFUSE-3 trials.

OBJECTIVEThe evolution of microsurgical and endoscopic techniques has allowed the development of less invasive transcranial approaches. The authors describe a purely endoscopic transpterional port craniotomy to access lesions involving the cavernous sinus and the anterolateral skull base.METHODSThrough single- or dual-port incisions and with direct endoscopic visualization, the authors performed an endoscopic transpterional port approach (ETPA) using a 4-mm straight endoscope in 8 sides of 4 formalin-fixed cadaveric heads injected with colored latex. A main working port incision is made just below the superior temporal line and behind the hairline. An optional 0.5- to 1-cm second skin port incision is made on the lateral supraorbital region, allowing multiangle endoscopic visualization and maneuverability. A 1.5- to 2-cm craniotomy centered over the pterion is done through the main port, which allows an extradural exposure of the cavernous sinus region and extra/intradural exposure of the frontal and temporal cranial fossae. The authors present a pilot surgical series of 17 ETPA procedures and analyze the surgical indications and clinical outcomes retrospectively.RESULTSThe initial stage of this work on cadavers provided familiarity with the technique, standardized its steps, and showed its anatomical limits. The clinical ETPA was applied to gain access into the cavernous sinus, as well as for aneurysm clipping and meningioma resection. Overall, perioperative complications occurred in 1 patient (6%), there was no mortality, and at last follow-up all patients had a modified Rankin Scale score of 0 or 1.CONCLUSIONSThe ETPA provides a less invasive, focused, and direct route to the cavernous sinus, and to the frontal and temporal cranial fossae, and it is feasible in clinical practice for selected indications with good results.

Background Statistical models to predict outcomes after endovascular therapy for acute ischemic stroke often incorporate baseline (pretreatment) variables only. We assessed the performance of stroke outcome prediction models for endovascular therapy in stroke in an iterative fashion using baseline, treatment‐related, and posttreatment variables. Methods Data from the ESCAPE‐NA1 (Safety and Efficacy of Nerinetide [NA‐1] in Subjects Undergoing Endovascular Thrombectomy for Stroke) trial were used to build 4 outcome prediction models using multivariable logistic regression: model 1 included baseline variables available before treatment decision making, model 2 included additional treatment‐related variables, model 3 additional posttreatment variables that become available early (within 24–48 hours), and model 4 later (beyond 48 hours) after endovascular therapy. The primary outcome was functional independence (90‐day Modified Rankin Scale score 0–2). Model performance was compared using the area under the receiver operating characteristic curve (AUC). Shapley values were used to determine marginal contributions of variables to outcome variance in the regression models. Results Among 1105 patients, functional independence was achieved by 666 (60.3%). When using baseline variables only (model 1), the AUC was 0.74 (95% CI, 0.71–0.77); this iteratively improved when treatment and posttreatment variables were added to the models (model 2: AUC, 0.77; 95% CI, 0.74–0.80; model 3: AUC, 0.80; 95% CI, 0.77–0.83; model 4: AUC, 0.82; 95% CI, 0.79–0.85). With baseline variables alone, 26% of patients who achieved functional independence were erroneously classified as not achieving functional independence. Even with the most comprehensive model, 19.8% of patients were misclassified as such. Patient age contributed most to outcome variance (Shapley value, 0.28), followed by severe adverse events including pneumonia (0.16) and intracranial hemorrhage at 24‐hours imaging (0.13). Conclusions A substantial contribution to outcomes after endovascular therapy comes from factors unrelated to currently collected baseline patient variables. One‐fifth of patients achieving functional independence were misclassified as not achieving independence, even with the most comprehensive model. Our findings suggest that the achievable accuracy of current outcome prediction models is limited, and caution should be used when applying them in clinical practice.

Key Points Question Why do some patients have poor outcomes despite small infarcts after endovascular therapy, while others with large infarcts fare better? Findings In this cohort study of 1091 patients who received endovascular therapy as part of a randomized clinical trial, discrepancies between infarct volume and functional outcome were associated with prespecified pretreatment factors, such as age, cancer, and vascular risk factors, as well as posttreatment factors, such as infarct in new territory, stroke progression, intracerebral hemorrhage, recurrent stroke, pneumonia, and heart failure. Models including these factors performed similar to those derived from stepwise regressions. Meaning In this study, discrepancies between outcome and infarct volume were associated with pretreatment and posttreatment factors, including complications related to index stroke evolution, secondary prevention, and quality of stroke unit care., This cohort study validates exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment, and posttreatment factors associated with discrepancies between follow-up infarct volume and 90-day functional outcome., Importance Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes. Objective To validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome. Design, Setting, and Participants This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included. Exposures Small FIV (volume ≤25th percentile) and large FIV (volume ≥75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score ≥3 despite small FIV or those with mRS scores ≤2 despite large FIV) and nondiscrepant cases. Main Outcomes and Measures Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression–derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score. Results Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women; median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, ≤25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, ≥75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (AUC, 0.92 [95% CI, 0.90-0.95] vs 0.94 [95% CI, 0.91-0.96]; P = .14). Younger age was associated with high FIV and lower mRS score; stepwise models identified absence of diabetes and higher baseline hemoglobin as additional pretreatment factors (AUC, 0.76 [95% CI, 0.70-0.82] vs 0.77 [95% CI, 0.71-0.83]; P = .82). Absence of SAEs, especially stroke progression, symptomatic intracerebral hemorrhage, and pneumonia, was associated with high FIV and lower mRS score2; stepwise models also identified 24-hour hemoglobin level, glucose, and diastolic blood pressure as posttreatment factors associated with discrepant cases (AUC, 0.80 [95% CI, 0.74-0.87] vs 0.79 [95% CI, 0.72-0.86]; P = .92). Conclusions and Relevance In this study, discrepancies between functional outcome and post-EVT infarct volume were associated with differences in pretreatment factors, such as age and comorbidities, and posttreatment complications related to index stroke evolution, secondary prevention, and quality of stroke unit care. Besides preventing such complications, optimization of blood pressure, glucose levels, and hemoglobin levels are potentially modifiable factors meriting further study.

OBJECTIVEThe goal of this study was to describe changes in the angioarchitecture of brain arteriovenous malformations (bAVMs) between acute and delayed cerebral digital subtraction angiography (DSA) obtained after hemorrhage, and to examine bAVM characteristics predicting change.METHODSThis is a retrospective study of a prospective institutional bAVM database. The authors included all patients with ruptured bAVMs who had DSA in both acute and delayed phases, with no interval treatment of their bAVM, between January 2000 and April 2017. The authors evaluated the existence or absence of angioarchitectural changes. Demographic data, radiological characteristics of hemorrhages, and angioarchitectural features of the bAVMs of the two patients’ groups were analyzed. Univariate and multivariate logistic analyses were performed to identify predictors of angioarchitectural change.RESULTSA total of 42 patients were included in the series. Seventeen (40.5%) patients had angioarchitectural changes including bAVM only visible on the delayed DSA study (n = 8), spontaneous thrombosis of the AVM (n = 3), or alteration of the size or the opacification of the nidus (n = 6). The factors associated with angioarchitectural changes were a small nidus (3.8 ± 7.9 ml vs 6.1 ± 9.5 ml, p = 0.046), a superficial location (94.1% vs 5.9%, p = 0.016), and a single superficial draining vein (58.8% vs 24.0%, p = 0.029).CONCLUSIONSAngioarchitectural changes can be seen in 40% of ruptured bAVMs between the acute- and delayed-phase DSA. A small nidus, a superficial location, and a single superficial draining vein were statistically associated with the occurrence of angioarchitectural changes. These changes included either enlargement or spontaneous occlusion of the bAVM, as well as subsequent diagnosis of a bAVM following an initial negative DSA study.

Infarct volume in acute ischemic stroke is closely linked with clinical outcome, with larger infarct volumes being associated with a worse prognosis. Small iatrogenic infarcts, which can occur as a result of surgical or endovascular procedures, are often only seen on diffusion-weighted MR imaging. They often do not lead to any overtly appreciable clinical deficits, hence the term covert or silent infarcts. There is relative paucity of data on the clinical impact of periprocedural hyperintense diffusion-weighted MR imaging lesions, partly because they commonly remain undiagnosed. Clearly, a better understanding of iatrogenic periprocedural diffusion-weighted MR imaging lesions and their clinical significance is needed. In this article, we describe the current limitations of our understanding of the significance of iatrogenic diffusion-weighted MR imaging lesions using exemplary data from the ENACT trial (Safety and Efficacy of NA-1 in Patients With Iatrogenic Stroke After Endovascular Aneurysm Repair) and outline a framework for how to investigate their clinical impact.

Endovascular treatment (EVT) is a powerful treatment for large vessel occlusion (LVO) stroke if reperfusion can be achieved, while in cases with failed reperfusion, EVT may cause harm, as procedure-related complications may occur. We hypothesized that EVT with failed recanalization does not result in worse outcomes compared to best medical management and compared clinical outcomes of LVO stroke patients who underwent EVT with failed reperfusion to those who were treated with best medical management.We included patients with failed reperfusion from the control (EVT-only) arm of the ESCAPE-NA1 trial and the EVT arm of the ESCAPE trial and patients of the ESCAPE control arm who were treated with best medical management. Failed reperfusion following EVT was defined as modified thrombolysis in cerebral infarction score 0-2a. Proportions of good outcome (modified Rankin scale 0-2) were compared between patients who did and did not undergo EVT, and adjusted effect size estimates for EVT on outcomes were obtained.We included 260 patients (110 failed EVT and 150 non-EVT patients). Proportions of good outcome were 38/110 (34.6%) with failed EVT vs.43/147 (29.3%) without EVT (adjusted odds ratio[aOR]: 1.48 [95%CI: 0.81-2.68]). Mortality and proportions of sICH in the failed EVT group vs. patients treated with best medical management were 26/110 (23.6%) vs. 28/147 (19.1%), aOR: 1.12 (95%CI: 0.56-2.24), and 7/110 (6.4%) vs. 4/150 (2.7%), aOR: 2.34 (95%CI: 0.00-22.97).Clinical outcomes of EVT patients with failed reperfusion did not differ significantly from patients treated with best medical management.

BackgroundThe optimal treatment and prognosis for stroke patients with tandem cervical carotid occlusion are unclear. We analyzed outcomes and treatment strategies of tandem occlusion patients in the ESCAPE-NA1 trial.MethodsESCAPE-NA1 was a multicenter international randomized trial of nerinetide versus placebo in 1105 patients with acute ischemic stroke who underwent endovascular treatment. We defined tandem occlusions as complete occlusion of the cervical internal carotid artery (ICA) on catheter angiography, in addition to a proximal ipsilateral intracranial large vessel occlusion. Baseline characteristics and outcome parameters were compared between patients with tandem occlusions versus those without, and between patients with tandem occlusion who underwent ICA stenting versus those who did not. The influence of tandem occlusions on functional outcome was analyzed using multivariable regression modeling.ResultsAmong 115/1105 patients (10.4%) with tandem occlusions, 62 (53.9%) received stenting for the cervical ICA occlusion. Of these, 46 (74.2%) were stented after and 16 (25.8%) before the intracranial thrombectomy. A modified Rankin Score (mRS) of 0–2 at 90 days was achieved in 82/115 patients (71.3%) with tandem occlusions compared with 579/981 (59.5%) patients without tandem occlusions. Tandem occlusion did not impact functional outcome in the adjusted analysis (OR 1.5, 95% CI 0.95 to 2.4). Among the subgroup of patients with tandem occlusion, cervical carotid stenting was not associated with different outcomes compared with no stenting (mRS 0–2: 75.8% vs 66.0%, adjusted OR 2.0, 95% CI 0.8 to 5.1).ConclusionsTandem cervical carotid occlusion in patients with acute large vessel stroke did not lower the odds of good functional outcome in our study. Functional outcomes were similar irrespective of the management of the cervical ICA occlusion (stenting vs not stenting).

Purpose: In this post-hoc analysis of the ESCAPE-NA1 trial, we investigated the prevalence of deep grey matter infarcts and their influence on clinical outcome. Methods: Infarcts on 24 hour follow up imaging (non contrast head CT or diffusion-weighted MRI) were categorized as predominantly deep grey matter infarcts (caudate and/or lentiform nucleus infarcts with sparing of the superficial grey matter and white matter) vs. other infarcts. Total infarct volume was manually segmented in all patients. When MRI follow-up was available, deep grey matter and grey matter infarct volumes were segmented separately. Multivariable logistic regression with adjustment for key minimization variables and by infarct volume was used to assess the association of predominantly deep grey matter infarcts and good outcome. Results: Of the 1026 included patients, 316 (30.8%) had predominantly deep grey matter infarcts. Cumulative proportions of good outcome for overall, grey matter, deep grey matter, and superficial grey matter infarct volumes are shown in the figure. Good outcomes were more frequently achieved in patients with predominantly deep grey matter infarcts (239/316 [75.6%] vs. 374/704 [53.1%]). Deep infarcts were tightly correlated with infarct volume (Pearson rho -0.35) and in multivariable analysis deep grey matter infarcts were predictive of outcome overall; when examined in volume percentiles, there was no effect of deep infarct location. Conclusion: Predominantly deep grey matter infarcts are associated with good outcomes. Deep grey matter infarct location favorable prognosis is associated with small overall infarct size.

Purpose: We investigated the prevalence and prognostic impact on outcome of any intracranial hemorrhage, hemorrhage morphology, type and volume in acute ischemic stroke patients undergoing mechanical thrombectomy. Methods: Prevalence of intracranial hemorrhage, hemorrhage type, morphology and volume was determined on 24h follow-up imaging (non contrast head CT or gradient-echo/susceptibility-weighted MRI). Proportions of good outcome (mRS 0-2 at 90 days) were reported for patients with vs. without any intracranial hemorrhage. Multivariable logistic regression with adjustment for key minimization variables and total infarct volume was performed to obtain adjusted effect size estimates for hemorrhage type and volume on good outcome. Results: Hemorrhage on follow up-imaging was seen in 372/1097 (33.9%) patients, among them 126 (33.9%) with hemorrhagic infarction (HI) type 1, 108 (29.0%) with HI-2, 72 /19.4%) with parenchymal hematoma (PH) type 1, 37 (10.0) with PH2, 8 (2.2%) with remote PH and 21 (5.7%) with extra-parenchymal/intraventricular hemorrhage. Good outcomes were less often achieved by patients with hemorrhage on follow-up imaging (164/369 [44.4%] vs. 500/720 [69.4%]). Any type of intracranial hemorrhage was strongly associated with decreased chances of good outcome ( adj OR 0.62 [CI 95 0.44 - 0.87]). The effect of hemorrhage was driven by both PH hemorrhage sub-type [PH-1 ( adj OR 0.39 [CI 95 0.21 - 0.72]), PH-2 ( adj OR 0.15 [CI 95 0.05 - 0.50])] and extra-parenchymal/intraventricular hemorrhage ( adj OR 0.60 (0.20-1.78) Petechial hemorrhages (HI-1 and HI-2) were not associated with poorer outcomes. Hemorrhage volume ( adj OR 0.97 [CI 95 0.05 - 0.99] per ml increase) was significantly associated with decreased chances of good outcome. Conclusion: Presence of any hemorrhage on follow-up imaging was seen in one third of patients and strongly associated with decreased chances of good outcome.

There are few data on the prevalence and impact of isolated deep grey matter infarction in acute stroke. In this study, we aimed to investigate the prevalence of isolated deep grey matter infarcts and their impact on the outcome.Infarcts on 24-h follow-up imaging (non-contrast head CT or diffusion-weighted MRI) in the ESCAPE-NA1 trial were categorized into predominantly deep grey matter infarcts vs. infarcts involving additional territories ("other infarcts"). Total infarct volume was manually segmented. Baseline characteristics and proportions of good outcome (primary outcome, defined as modified Rankin Score [mRS] 0-2 at 90 days), excellent outcome (mRS 0-1) and mortality were compared between patients with and without predominantly deep grey matter infarcts. Multivariable logistic regression with adjustment for baseline variables and total infarct volume was used to determine a possible association of predominantly deep grey matter infarcts and clinical outcome.Predominantly deep grey matter infarcts were seen in 316/1026 patients (30.8%). Compared to other patients, their ASPECTS was higher, collateral status and reperfusion quality were better and time to treatment was shorter. Good outcome was seen in 239/316 (75.6%) with vs. 374/704 (53.1%) without predominantly deep grey matter infarcts. After adjusting for baseline variables and total infarct volume, predominantly deep grey matter infarcts were independently associated with excellent outcome (

Neuroprotection in acute stroke has not been successfully translated from animals to humans. Animal research on promising agents continues largely in rats and mice which are commonly available to researchers. However, controversies continue on the most suitable species to model the human situation. Generally, putative agents seem less effective in mice as compared with rats. We hypothesized that this may be due to inter-species differences in stroke response and that this might be manifest at a genetic level. Here we used whole-genome microarrays to examine the differential gene regulation in the ischemic penumbra of mice and rats at 2 and 6 h after permanent middle cerebral artery occlusion (pMCAO; Raw microarray CEL data files are available in the GEO database with an accession number GSE163654). Differentially expressed genes (adj. p ≤ 0.05) were organized by hierarchical clustering, correlation plots, Venn diagrams and pathway analyses in each species and at each time-point. Emphasis was placed on genes already known to be associated with stroke, including validation by RT-PCR. Gene expression patterns in the ischemic penumbra differed strikingly between the species at both 2 h and 6 h. Nearly 90% of significantly regulated genes and most pathways modulated by ischemia differed between mice and rats. These differences were evident globally, among stroke-associated genes, immediate early genes, genes implicated in stress response, inflammation, neuroprotection, ion channels, and signal transduction. The findings of this study may have significant implications for the choice of species for screening putative stroke therapies.

Neuroprotection for acute ischemic stroke is achievable with the eicosapeptide nerinetide, an inhibitor of the protein-protein interactions of the synaptic scaffolding protein PSD-95. However, nerinetide is subject to proteolytic cleavage if administered after alteplase, a standard-of-care thrombolytic agent that nullifies nerinetide's beneficial effects. Here, we showed, on the basis of pharmacokinetic data consistent between rats, primates, and humans, that in a rat model of embolic middle cerebral artery occlusion (eMCAO), nerinetide maintained its effectiveness when administered before alteplase. Because of its short plasma half-life, it can be followed by alteplase within minutes without reducing its neuroprotective effectiveness. In addition, the problem of protease sensitivity is solved by substituting cleavage-prone amino acids from their l- to their d-enantiomeric form. Treatment of rats subjected to eMCAO with such an agent, termed d-Tat-l-2B9c, eliminated protease sensitivity and maintained neuroprotective effectiveness. Our data suggest that both the clinical-stage PSD-95 inhibitor nerinetide and protease-resistant agents such as d-Tat-l-2B9c may be practically integrated into existing stroke care workflows and standards of care.

The purpose of this retrospective observational study is to investigate the long-term changes in cerebrovascular reactivity (CVR) as a measure of cerebral hemodynamics in patients with intracranial steno-occlusive disease (IC-SOD) after they have undergone an Extracranial-intracranial (EC-IC) bypass. Twenty-six patients suffering from IC-SOD were selected from our CVR database. Nineteen patients underwent unilateral and 7 underwent bilateral revascularization. CVR measurements were done using BOLD-MRI and precisely controlled CO2 and expressed as ΔBOLD (%)/Δ PETCO2 (mmHg). Trends in CVR over time were compared in both vascularized and non-vascularized hemispheres. Repeated measures analysis of variance with Greenhouse-Geisser correction was used to determine CVR changes within the grey matter MCA for longitudinal assessments. Overall, re-vascularized hemisphere showed a significant increase in CVR at the first follow-up, followed by a slight decrease at the second follow-up that significantly increased compared to the pre-bypass. However, the changes in the postoperative CVR were quite variable across the patients. Similar variability was seen in subsequent follow-ups, with a slight overall decline in the long term CVR as compared with first post-operative CVR. Our study demonstrates that EC-IC bypass has a beneficial long-term effect on cerebral hemodynamics and this effect varies between patients probably due to the variability in the underlying vascular pattern receiving the bypass. Hence, in the postoperative follow-up of patients routine functional imaging to monitor cerebral hemodynamics may be useful as the risk of stroke and cognitive decline remain present with impaired CVR.

Understanding risk factors for intracranial aneurysm growth is important for patient management. We performed a retrospective study examining risk factors for the growth of unruptured intracranial aneurysms followed at our institution, evaluating both traditional risk factors and the PHASES (Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site) score.We retrospectively reviewed a consecutive series of unruptured intracranial aneurysms followed at our institution for a minimum of 6 months over a 15-year period. The primary outcome of this study was aneurysm growth, defined as a ≥1-mm increase in maximum diameter. Risk factors studied included PHASES score, ELAPSS (Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age, Population, Size, and Shape) score, demographics, multiple aneurysms, previous subarachnoid hemorrhage, family history of aneurysm or subarachnoid hemorrhage, smoking, hypertension, and aneurysm shape, size, and location. The χThe study cohort comprised 352 patients with a total of 431 unruptured intracranial aneurysms. The mean duration of follow-up was 4.8 years, and there was a total of 2100 aneurysm-years of follow-up. Forty aneurysms (9.3%) grew, for an annualized growth rate of 2.0% of aneurysms/year. Current smoking status was the sole modifiable risk factor associated with growth (growth rate of 5.1%/year compared with 1.5%/year for never smokers; P = 0.0004). Increasing size (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.11-1.33; P0.0001), ELAPSS score (OR, 1.10; 95% CI, 1.09-1.11; P0.0001), and PHASES score (OR, 1.24; 95% CI, 1.20-1.28; P0.0001) were associated with growth as well. Age, location, previous subarachnoid hemorrhage, and hypertension were not independently associated with aneurysm growth.Our retrospective study suggests that aneurysm size, smoking status, PHASES score, and ELAPSS score are associated with aneurysm growth.

Under physiological conditions, neurotransmitters shape neuronal networks and control several cellular and synaptic functions. In the mammalian central nervous system (CNS), excitatory and inhibitory neurotransmission are mediated in large part by glutamate and gamma-aminobutyric acid (GABA), which are excitatory and inhibitory neurotransmitters, respectively. Glutamate and GABA also play crucial roles in neurological disorders such as cerebral ischemia. Glutamate in particular causes excitotoxicity, known as one of the hallmark mechanisms in the pathophysiology of cerebral ischemic injury for more than thirty years. Excitotoxicity occurs due to excessive glutamate release leading to overactivation of postsynaptic glutamate receptors, which evokes a downstream cascade that eventually leads to neuronal dysfunction and degeneration. Also, a reduction in GABA receptor response after ischemia impedes these inhibitory effectors from attenuating excitotoxicity and thereby further enabling the excitotoxic insult. This review focuses on the mechanisms by which glutamate and GABA mediate excitotoxicity and ischemic injury. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

See related article, p 2341 Stroke risk and poststroke disability have steadily decreased in the United States over the past 2 decades because of improved prevention and access to reperfusion therapies for acute ischemic stroke, such as tPA (tissue-type plasminogen activator; alteplase) and endovascular thrombectomy. Despite the efficacy and safety of thrombolysis and thrombectomy, not all patients who receive the treatment improve to full, independent recovery, and most patients are ineligible for treatment. Additionally, there are no efficacious treatments to improve long-term outcomes for patients after the acute phase of ischemic stroke or to reduce brain injury induced by acute intracerebral hemorrhage. Therefore, development of new therapies for both acute and chronic stroke is sorely needed. Stroke occurs because of a variety of vascular pathologies and injury mechanisms, some of which are difficult to model in animals. With the exception of reperfusion therapy, preclinical research end points do not generally reflect clinical outcomes. Pharmacodynamics, pharmacokinetics, and target engagement in the human brain need to be further developed and optimized for stroke interventions so that drug level in brain tissue, time to initiation, and duration of treatment can be accurately measured in clinical trials. Many variables, such as heterogeneity of vascular pathologies, patient demographics, and a host of comorbid conditions, as well as the lack of validated biomarkers to stratify patient populations, limit the ability of typical stroke clinical trials to detect a treatment effect. To address these gaps, the National Institute of Neurological Disorders and Stroke organized and sponsored the workshop Translational Stroke Research: Vision and Opportunities, which was held in Bethesda, Maryland, on November 1 to 2, 2016. The workshop gathered over 180 registered participants from academia, industry, the Food and Drug Administration, and other public and private funding agencies. …

The goal of any clinical trial is to operationalize a paradigm in which the study enrolls the greatest proportion of responders in a setting that maximizes that study intervention’s treatment effect. Such a trial would have the most power to detect the therapeutic benefit it seeks to evaluate. Importantly, the trial should be grounded in—and consistent with—the pre-clinical science of the test intervention. Based on this, an acute ischemic stroke (AIS) trial must overcome the following 4 challenges: to have a design that conforms to that of animal studies that support the intervention, to minimize subject heterogeneity, to ensure that the treatment effect size is maximized, and to enroll subjects in the correct therapeutic window. Recent trials of endovascular thrombectomy (EVT)1–5 have decisively risen to this challenge for each of these aforementioned criteria: EVT recapitulates a wealth of animal studies demonstrating that stroke outcomes from temporary ischemia (eg, temporary middle cerebral artery occlusion [MCAO]) are better than in analogous animal models in which the MCAO is permanent. Subject heterogeneity in the recent EVT trials was reduced by selecting only those subjects who, on medical imaging, exhibit a large vessel occlusion (LVO). Selecting subjects with LVO also maximized the treatment effect size because untreated patients with LVO have a poorer prognosis even with tissue-type plasminogen activator (tPA) therapy,6–8 thus expanding the opportunity for EVT to provide a clinical benefit. Enrollment in the correct therapeutic window was achieved by optimizing the speed from diagnosis to reperfusion9 and, in some instances,1–3 by imaging criteria ensuring that enrolled patients still exhibited a penumbra. The success of recent EVT trials teaches that studies designed with the deliberate strategy of meeting these criteria may provide a better opportunity to demonstrate a clinical benefit than those that …

Background Lateral approaches to treat anterior cranial fossa lesions have evolved since the first frontotemporal approach described by Dandy in 1918. We describe a less invasive approach to perform extradural anterior clinoidectomy through a lateral supraorbital (LSO) approach for anterior circulation aneurysms and anterolateral skull base lesions. Methods The extended LSO approach involves performing a standard lateral supraorbital craniotomy followed by drilling of the sphenoid wing and lateral wall of the orbit through the frontal bony opening of the LSO approach, without any temporal extension of the craniotomy. This creates a frontopterio-orbital window exposing the periorbita; superior, medial, and anterior aspect of the temporal dura mater; and superior orbital fissure. After unroofing the superior orbital fissure, the meningo-orbital fold is cut, and the temporal dura mater is peeled from the lateral wall of the cavernous sinus to expose the anterior clinoid process allowing a standard opening of the optic canal and anterior clinoidectomy. Results The extended LSO approach and extradural anterior clinoidectomy allowed access to 4 sphenoid wing/anterior clinoidal meningiomas, 5 anterior circulation aneurysms, 2 temporomesial lesions, and 1 orbital/cavernous sinus abscess. Postoperatively, 2 patients had transient hemiparesis, 2 patients had transient third nerve palsy, and 1 patient had minimal visual field deterioration. All patients had a modified Rankin Scale score ≤1 at 8-week follow-up. Conclusion The extended LSO approach opens a new route (frontopterio-orbital window) to perform extradural anterior clinoidectomy safely and increases surgical exposure, angles, and operability of a less invasive keyhole craniotomy (LSO approach) to treat anterior cranial fossa lesions.

Background and Purpose— The management of unruptured brain arteriovenous malformations (ubAVMs) remains controversial despite ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation), a controlled trial that suggested superiority of conservative management over intervention. However, microsurgery occurred in only 14.9% of ARUBA intervention cases, raising concerns about the study’s generalizability. Our purpose was to evaluate whether, in a larger ARUBA-eligible ubAVM population, microsurgery produces acceptable outcomes. Methods— Demographic data, AVM characteristics, and treatment outcomes were evaluated in 155 ARUBA-eligible bAVMs treated with microsurgery between 1994 and 2014. Outcomes were rates of early disabling deficits and permanent disabling deficits with modified Rankin Scale score ≥3 or any permanent neurological deficits with modified Rankin Scale score ≥1. Covariates associated with outcomes were determined by regression analysis. Results— Of 977 AVM patients, 155 ARUBA-eligible patients had microsurgical resection (71.6% surgery only and 25.2% with preoperative embolization). Mean follow-up was 36.1 months. Complete obliteration was achieved in 94.2% after initial surgery and 98.1% on final angiography. Early disabling deficits and permanent disabling deficits occurred in 12.3% and 4.5%, respectively, whereas any permanent neurological deficit (modified Rankin Scale score ≥1) occurred in 16.1%. Among ubAVM of Spetzler–Martin grades 1 and 2, complete obliteration occurred in 99.2%, with early disabling deficits and permanent disabling deficits occurring in 9.3% and 3.4%, respectively. Major bleeding was the only significant predictor of early disabling deficits on multivariate analysis ( P Conclusions— Microsurgery in this cohort produced less disabling deficits than ARUBA with similar morbidity and AVM obliteration as other cohort series. This disparity between our results and ARUBA suggests that future controlled trials should focus on the safety and efficacy of microsurgery with or without adjunctive embolization in carefully selected ubAVM patients.

Background Intracranial dural arteriovenous fistulae (DAVF) may present a treatment challenge. Endovascular embolization is in most cases the first line of treatment but does not always achieve cure. Gamma Knife (GK) radiosurgery represents an alternative treatment option, and the purpose of this study was to further evaluate its utility. Methods We reviewed all cases of DAVF treated between 2009 and 2016 at our institution with GK radiosurgery independently, or following failed/refused endovascular or surgical management. Patients’ clinical files, radiological images, catheter angiograms, and surgical DAVF disconnection reports were retrospectively reviewed. Results Sixteen DAVF (14 patients) treated by GK radiosurgery were identified. Eleven fistulae were aggressive and five were benign. Marginal doses ranged from 15 to 25 Gy. Target volumes ranged from 0.04 to 4.47 cm3. In all symptomatic patients, GK treatment resulted in symptom palliation. In 13/15 lesions, cure of symptoms (86.0%) was reported. One lesion was asymptomatic. Angiographic cure was achieved in eight cases (50%), small residual DAVF occurred in four, and four were unchanged. One patient developed headache that resolved at one year. No hemorrhage occurred during the follow-up period. There was no significant association between Borden type and cure rate. Prior failed endovascular treatment and small target volume were associated with lower rates of cure. Conclusions Stereotactic radiosurgery is viable treatment for DAVF. It is very effective in palliating symptoms as a de novo approach or adjunctive to endovascular therapy. In our experience it is only somewhat effective in achieving complete angiographic cure.

Background Both conventional bypass utilizing temporary recipient vessel occlusion and the excimer laser-assisted nonocclusive anastomosis (ELANA) bypass technique are possible strategies in the treatment of giant aneurysms. These treatments have only been studied in single institutional retrospective studies. The potential advantage of the ELANA technique is the absence of temporary occlusion of major arteries, decreasing the risk of intraoperative ischemia. Objective To investigate the risks and potential benefits of high-flow bypass surgery for giant and complex aneurysms of the anterior cerebral circulation. In addition, the effectiveness of the ELANA bypass procedure in the treatment of these aneurysms is determined. Methods A total of 37 patients were included in 8 vascular neurosurgical centers in the United States, Canada, and Europe. A 30-d postoperative bypass follow-up was studied by using digital subtraction angiography and/or magnetic resonance angiography and computed tomography angiography to assess patency as well as by clinical monitoring in all patients. Results In 35 patients, an ELANA high-flow bypass was performed and the aneurysm treated. Four patients had remaining neurological deficits after 30 d caused by stroke (11.4%). These strokes were not related to the ELANA anastomosis device. Conclusion This study does not prove that the ELANA technique has an advantage over conventional bypass techniques, but it appears to be an acceptable alternative to conventional transplanted high-flow bypass in this very-difficult-to-treat patient group, especially in select patients whom cannot be bypassed using conventional means in which temporary occlusion is considered to be not recommended.

Introduction: Stroke trial subjects sustain numerous adverse events (AE’s) which may be related to the disease under study or to the therapeutic intervention. In studies involving pharmacovigilance of multiple AE’s, ongoing oversight of AEs by investigators and trial sponsors is critical to ensure the safety and well being of trial subjects. Static cluster heatmaps are used extensively in the field of gene expression studies and text analytics are used widely to monitor text on social media sites such as Twitter. Here we present novel dynamic tools using static cluster heatmaps and text analytics to aid with the visualization of AEs and of clinical site performance in AE reporting in the ESCAPE-NA-1 trial (Clinicaltrials.gov NCT 02930018). Methodology: In an interactive cluster heatmap display, the frequency of AEs is color coded in cells, with the rows corresponding to either sites or patients and columns correspond to unique AEs. Clustering is visualized on a heatmap by addition of row and column dendrograms. Quantification of AEs in the clinical trial is performed through text analytics and the results are visualized using a word cloud. Difference of AE across sites is visualized using a comparison cloud, a cloud that compares frequencies across sites. A cluster heatmap and word cloud are made interactive by formatting into HTML. Results: The main results obtained from interactive AE cluster heatmaps are patient ,site and AE clusters (Figure 1). The results obtained from text analytics are word clouds that convey overall AEs frequency and AEs frequency across sites (Figure 1). Due to active status of the trial, we will share the methodology of constructing interactive AE cluster heatmaps and word clouds and broad visual results without providing specifics of sites or AEs. Conclusion: Interactive cluster heatmaps and word clouds constructed via text analytics are a novel way of visualizing complex multidimensional AE data from clinical trials.

Introduction: According to the World Health Organization (WHO), stroke remains a leading cause of mortality and neurological disability globally. To date, there is no effective pharmacological treatment to promote recovery from stroke. Promoting regenerative repair may improve recovery and it is known that N-methyl-D- aspartate receptors (NMDARs) play important roles in neural circuit rebuilding. Therefore, an appealing strategy to promote stroke recovery is to selectively inhibit cell death mechanisms while promoting pro-survival processes mediated by NMDARs. A promising agent for this purpose is Tat-NR2B9c (NA-1), a clinical-stage agent being tested in Phase 3 trials for acute ischemic stroke. Tat-NR2B9c promotes the activation of pro-survival signaling and is a potent neuroprotector against excitotoxicity. Here we sought to determine whether treatment with Tat-NR2B9c promotes functional recovery in rats subjected to ischemic brain damage during the subacute recovery phase. Methods: Stroke was induced by Pial Vessel Disruption (PVD) in Sprague Dawley rats. Permanent devascularisation was induced by removing all the pia and the attached blood vessels of the left motor cortex. Experimental groups were: PVD + Tat-NR2B9c (n = 12); PVD + Vehicle (n = 11); Sham + Tat-NR2B9c (n = 8); Sham + Vehicle (n = 8). Tat-NR2B9c was injected intravenously (IV) beginning 3 days after stroke and was administered daily for 7 days. A behavioral battery of tests followed, composed of neurological score, cylinder test, horizontal ladder and adhesive removal tests. Brains were stained with H&E and the infarct size was analyzed by ImageJ. Results: Repeated IV injections of Tat-NR2B9c led to a significant improvement in all motor tasks: decreased number in foot slips by 3.6-fold in horizontal ladder (P < 0.0001); improved neurological score by 4.7-fold compared to control (P < 0.0001); improved use of affected limb by 58% in cylinder test (P = 0.0006); reduced adhesive removal test time by 81% (P < 0.0001). There was no difference in infarct sizes between the groups. Conclusion: Treatment with Tat-NR2B9c post stroke improved functional outcome in rats subjected to PVD. Current studies are ongoing to assess the mechanism of action underlying the observed recovery.