Influence of Infarct Morphology and Patterns on Cognitive Outcomes After Endovascular Thrombectomy.

BACKGROUND: To assess the association of qualitative and quantitative infarct characteristics and 3 cognitive outcome tests, namely the Montreal Cognitive Assessment (MOCA) for mild cognitive impairment, the Boston Naming Test for visual confrontation naming, and the Sunnybrook Neglect Assessment Procedure for neglect, in large vessel occlusion stroke. METHODS: Secondary observational cohort study using data from the randomized-controlled ESCAPE-NA1 trial (Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke), in which patients with large vessel occlusion undergoing endovascular treatment were randomized to receive either intravenous Nerinetide or placebo. MOCA, Sunnybrook Neglect Assessment Procedure, and 15-item Boston Naming Test were obtained at 90 days. Total infarct volume, gray matter, and white matter infarct volumes were manually measured on 24-hour follow-up imaging. Infarcts were also visually classified as either involving the gray matter only or both the gray and white matter and scattered versus territorial. Associations of infarct variables and cognitive outcomes were analyzed using multivariable ordinal or binary logistic regression models. RESULTS: Of 1105 patients enrolled in ESCAPE-NA1, 1026 patients with visible infarcts on 24-hour follow-up imaging were included. MOCA and Sunnybrook Neglect Assessment Procedure were available for 706 (68.8%) patients and the 15-item Boston Naming Test was available for 682 (66.5%) patients. Total infarct volume was associated with worse MOCA scores (adjusted common odds ratio per 10 mL increase, 1.05 [95% CI, 1.04-1.06]). After adjusting for baseline variables and total infarct volume, mixed gray and white matter involvement (versus gray matter-only adjusted common odds ratio, 1.92 [95% CI, 1.37-2.69]), white matter infarct volume (adjusted common odds ratio per 10 mL increase 1.36 [95% CI, 1.18-1.58]) and territorial (versus scattered) infarct pattern (adjusted common odds ratio, 1.65 [95% CI, 1.15-2.38]) were associated with worse MOCA scores. Results for Sunnybrook Neglect Assessment Procedure and 15-item Boston Naming Test were similar, except for the territorial infarct pattern, which did not reach statistical significance in multivariable analysis. CONCLUSIONS: Besides total infarct volume, infarcts that involve the white matter and that show a territorial distribution were associated with worse cognitive outcomes, even after adjusting for total infarct volume.

Increased Risk of Recurrent Stroke in Symptomatic Large Vessel Disease With Impaired BOLD Cerebrovascular Reactivity.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) has been correlated with recurrent ischemic stroke. However, for clinical purposes, most CVR techniques are rather complex, time-consuming, and lack validation for quantitative measurements. The recent adaptation of a standardized hypercapnic stimulus in combination with a blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging signal as a surrogate for cerebral blood flow offers a potential universally comparable CVR assessment. We investigated the association between impaired BOLD-CVR and risk for recurrent ischemic events. METHODS: We conducted a retrospective analysis of patients with symptomatic cerebrovascular large vessel disease who had undergone a prospective hypercapnic-challenged BOLD-CVR protocol at a single tertiary stroke referral center between June 2014 and April 2020. These patients were followed up for recurrent acute ischemic events for up to 3 years. BOLD-CVR (%BOLD signal change per mm Hg CO2) was calculated on a voxel-by-voxel basis. Impaired BOLD-CVR of the affected (ipsilateral to the vascular pathology) hemisphere was defined as an average BOLD-CVR, falling 2 SD below the mean BOLD-CVR of the right hemisphere in a healthy age-matched reference cohort (n=20). Using a multivariate Cox proportional hazards model, the association between impaired BOLD-CVR and ischemic stroke recurrence was assessed and Kaplan-Meier survival curves to visualize the acute ischemic stroke event rate. RESULTS: Of 130 eligible patients, 28 experienced recurrent strokes (median, 85 days, interquartile range, 5-166 days). Risk factors associated with an increased recurrent stroke rate included impaired BOLD-CVR, a history of atrial fibrillation, and heart insufficiency. After adjusting for sex, age group, and atrial fibrillation, impaired BOLD-CVR exhibited a hazard ratio of 10.73 (95% CI, 4.14-27.81; P<0.001) for recurrent ischemic stroke. CONCLUSIONS: Among patients with symptomatic cerebrovascular large vessel disease, those exhibiting impaired BOLD-CVR in the affected hemisphere had a 10.7-fold higher risk of recurrent ischemic stroke events compared with individuals with nonimpaired BOLD-CVR.

Prevalence of "Ghost Infarct Core" after Endovascular Thrombectomy.

BACKGROUND AND PURPOSE: Baseline CTP sometimes overestimates the size of the infarct core ("ghost core" phenomenon). We investigated how often CTP overestimates infarct core compared with 24-hour imaging, and aimed to characterize the patient subgroup in whom a ghost core is most likely to occur. MATERIALS AND METHODS: Data are from the randomized controlled ESCAPE-NA1 trial, in which patients with acute ischemic stroke undergoing endovascular treatment were randomized to intravenous nerinetide or placebo. Patients with available baseline CTP and 24-hour follow-up imaging were included in the analysis. Ghost infarct core was defined as CTP core volume minus 24-hour infarct volume > 10 mL). Clinical characteristics of patients with versus without ghost core were compared. Associations of ghost core and clinical characteristics were assessed by using multivariable logistic regression. RESULTS: A total of 421 of 1105 patients (38.1%) were included in the analysis. Forty-seven (11.2%) had a ghost core > 10 mL, with a median ghost infarct volume of 13.4 mL (interquartile range 7.6-26.8). Young patient age, complete recanalization, short last known well to CT times, and possibly male sex were associated with ghost infarct core. CONCLUSIONS: CTP ghost core occurred in ∼1 of 10 patients, indicating that CTP frequently overestimates the infarct core size at baseline, particularly in young patients with complete recanalization and short ischemia duration.

Mediation of Age and Thrombectomy Outcome by Neuroimaging Markers of Frailty in Patients With Stroke.

Importance: Age is a leading predictor of poor outcomes after brain injuries like stroke. The extent to which age is associated with preexisting burdens of brain changes, visible on neuroimaging but rarely considered in acute decision-making or trials, is unknown. Objectives: To explore the mediation of age on functional outcome by neuroimaging markers of frailty (hereinafter neuroimaging frailty) in patients with acute ischemic stroke receiving endovascular thrombectomy (EVT). Design, Setting, and Participants: This cohort study was a post hoc analysis of the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, which investigated intravenous (IV) nerinetide in patients who underwent EVT within a 12-hour treatment window. Patients from 48 acute care hospitals in 8 countries (Canada, US, Germany, Korea, Australia, Ireland, UK, and Sweden) were enrolled between March 1, 2017, and August 12, 2019. Markers of brain frailty (brain atrophy [subcortical or cortical], white matter disease [periventricular or deep], and the number of lacunes and chronic infarctions) were retrospectively assessed while reviewers were blinded to other imaging (eg, computed tomography angiography, computed tomography perfusion) or outcome variables. All analyses were done between December 1, 2022, and January 31, 2023. Exposures: All patients received EVT and were randomized to IV nerinetide (2.6 mg/kg of body weight) and alteplase (if indicated) treatment vs best medical management. Main Outcome and Measures: The primary outcome was the proportion of the total effect of age on 90-day outcome, mediated by neuroimaging frailty. A combined mediation was also examined by clinical features associated with frailty and neuroimaging markers (total frailty). Structural equation modeling was used to create latent variables as potential mediators, adjusting for baseline, early ischemic changes; stroke severity; onset-to-puncture time; nerinetide treatment; and alteplase treatment. Results: Among a total of 1105 patients enrolled in the study, 1102 (median age, 71 years [IQR, 61-80 years]; 554 [50.3%] male) had interpretable imaging at baseline. Of these participants, 549 (49.8%) were treated with IV nerinetide. The indirect effect of age on 90-day outcome, mediated by neuroimaging frailty, was associated with 85.1% of the total effect (ß coefficient, 0.04 per year [95% CI, 0.02-0.06 per year]; P < .001). When including both frailty constructs, the indirect pathway was associated with essentially 100% of the total effect (ß coefficient, 0.07 per year [95% CI, 0.03-0.10 per year]; P = .001). Conclusions and Relevance: In this cohort study, a secondary analysis of the ESCAPE-NA1 trial, most of the association between age and 90-day outcome was mediated by neuroimaging frailty, underscoring the importance of features like brain atrophy and small vessel disease, as opposed to chronological age alone, in predicting poststroke outcomes. Future trials could include such frailty features to stratify randomization or improve adjustment in outcome analyses.

Infarct Evolution on MR-DWI After Thrombectomy in Acute Stroke Patients Randomized to Nerinetide or Placebo: The REPERFUSE-NA1 Study

BACKGROUND AND OBJECTIVES: The neuroprotectant nerinetide has shown promise in reducing infarct volumes in primate models of ischemia reperfusion. We hypothesized that early secondary infarct growth after endovascular therapy (EVT) (1) may be a suitable surrogate biomarker for testing neuroprotective compounds, (2) is feasible to assess in the acute setting using sequential MRI, and (3) can be modified by treatment with nerinetide. METHODS: REPERFUSE-NA1 was a prospective, multisite MRI substudy of the randomized controlled trial ESCAPE-NA1 (ClinicalTrials.gov NCT02930018) that involved patients with acute disabling large vessel occlusive stroke undergoing EVT within 12 hours of onset who were randomized to receive intravenous nerinetide or placebo. Patients enrolled in REPERFUSE-NA1 underwent sequential MRI <5 hours post-EVT (day 1) and at 24 hours (day 2). The primary outcome was total diffusion-weighted MRI infarct growth early after EVT, defined as the lesion volume difference between day 2 and day 1. The secondary outcome was region-specific infarct growth in different brain tissue compartments. Statistical analyses were performed using the Mann-Whitney U test and multiple linear regression. RESULTS: Sixty-seven of 71 patients included had MRI of sufficient quality. The median infarct volume post-EVT was 12.98 mL (IQR, 5.93-28.08) in the nerinetide group and 10.80 mL (IQR, 3.11-24.45) in the control group (p = 0.59). Patients receiving nerinetide showed a median early secondary infarct growth of 5.92 mL (IQR, 1.09-21.30) compared with 10.80 mL (interquartile range [IQR], 2.54-21.81) in patients with placebo (p = 0.30). Intravenous alteplase modified the effect of nerinetide on region-specific infarct growth in white matter and basal ganglia compartments. In patients with no alteplase, the infarct growth rate was reduced by 120% (standard error [SE], 60%) in the white matter (p = 0.03) and by 340% (SE, 140%) in the basal ganglia (p = 0.02) in the nerinetide group compared with placebo after adjusting for confounders. DISCUSSION: This study highlights the potential of using MR imaging as a biomarker to estimate the effect of a neuroprotective agent in acute stroke treatment. Patients with acute large vessel occlusive stroke exhibited appreciable early infarct growth both in the gray matter and the white matter after undergoing EVT. Acknowledging relatively small overall infarct volumes in this study, treatment with nerinetide was associated with slightly reduced percentage infarct growth in the white matter and basal ganglia compared with placebo in patients not receiving intravenous alteplase and had no effect on the total early secondary infarct growth. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT02930018. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute large vessel ischemic stroke undergoing EVT, nerinetide did not significantly decrease early post-EVT infarct growth compared with placebo.

Brain Stress Test for Assessing Risk for Hemodynamic Stroke.

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.

Symptomatic Non-stenotic Carotid Disease in Embolic Stroke of Undetermined Source : Analysis of the ESCAPE-NA1 Trial.

PURPOSE: Non-stenotic (< 50%) carotid disease may play an important etiological role in ischemic stroke classified as embolic stroke of undetermined source (ESUS). We aimed to assess the prevalence of non-stenotic carotid disease and its association with ipsilateral ischemic stroke. METHODS: Data are from ESCAPE-NA1, a randomized controlled trial investigating the neuroprotectant nerinetide in patients with acute ischemic stroke and large vessel occlusion (LVO). The degree of stenosis of the extracranial internal carotid artery (ICA) and high-risk plaque features were assessed on baseline computed tomography (CT) angiography. We evaluated the association of non-stenotic carotid disease and ipsilateral stroke by age-adjusted and sex-adjusted logistic regression and calculated the attributable risk of ipsilateral stroke caused by non-stenotic carotid disease. RESULTS: After excluding patients with non-assessable imaging, symptomatic > 50% carotid stenosis and extracranial dissection, 799/1105 (72.1%) patients enrolled in ESCAPE-NA1 remained for this analysis. Of these, 127 (15.9%) were classified as ESUS. Non-stenotic carotid disease occurred in 34/127 ESUS patients (26.8%) and was associated with the presence of ipsilateral ischemic stroke (odds ratio, OR 1.6, 95% confidence interval, CI 1.0-2.6, p = 0.049). The risk of ipsilateral ischemic stroke attributable to non-stenotic carotid disease in ESUS was estimated to be 19.7% (95% CI -5.7% to 39%), the population attributable risk was calculated as 4.3%. Imaging features such as plaque thickness, plaque irregularity or plaque ulceration were not different between non-stenotic carotids with vs. without ipsilateral stroke. CONCLUSION: Non-stenotic carotid disease frequently occurs in patients classified as ESUS and is associated with ipsilateral ischemic stroke. Our findings support the role of non-stenotic carotid disease as stroke etiology in ESUS, but further prospective research is needed to prove a causal relationship.

Predicting outcome in acute stroke with large vessel occlusion-application and validation of MR PREDICTS in the ESCAPE-NA1 population.

BACKGROUND: Predicting outcome after endovascular treatment for acute ischemic stroke is challenging. We aim to investigate differences between predicted and observed outcomes in patients with acute ischemic stroke treated with endovascular treatment and to evaluate the performance of a validated outcome prediction score. PATIENTS AND METHODS: MR PREDICTS is an outcome prediction tool based on a logistic regression model designed to predict the treatment benefit of endovascular treatment based on the MR CLEAN and HERMES populations. ESCAPE-NA1 is a randomized trial of nerinetide vs. placebo in patients with acute stroke and large vessel occlusion. We applied MR PREDICTS to patients in the control arm of ESCAPE-NA1. Model performance was assessed by calculating its discriminative ability and calibration. RESULTS: Overall, 556/1105 patients (50.3%) in the ESCAPE-NA1-trial were randomized to the control arm, 435/556 (78.2%) were treated within 6 h of symptom onset. Good outcome (modified Rankin scale 0-2) at 3 months was achieved in 275/435 patients (63.2%), the predicted probability of good outcome was 52.5%. Baseline characteristics were similar in the study and model derivation cohort except for age (ESCAPE-NA1: mean: 70 y vs. HERMES: 66 y), hypertension (72% vs. 57%), and collaterals (good collaterals, 15% vs. 44%). Compared to HERMES we observed higher rates of successful reperfusion (TICI 2b-3, ESCAPE-NA1: 87% vs. HERMES: 71%) and faster times from symptom onset to reperfusion (median: 201 min vs. 286 min). Model performance was good, indicated by a c-statistic of 0.76 (95%confidence interval: 0.71-0.81). CONCLUSION: Outcome-prediction using models created from HERMES data, based on information available in the emergency department underestimated the actual outcome in patients with acute ischemic stroke and large vessel occlusion receiving endovascular treatment despite overall good model performance, which might be explained by differences in quality of and time to reperfusion. These findings underline the importance of timely and successful reperfusion for functional outcomes in acute stroke patients.

Health economic impact of Nerinetide in addition to mechanical thrombectomy without concurrent alteplase.

BACKGROUND AND PURPOSE: The ESCAPE-NA1 trial has shown that intravenous Nerinetide improves clinical outcomes in acute ischemic stroke patients with large vessel occlusion undergoing endovascular treatment without concurrent intravenous alteplase. We assessed the health economic impact of intravenous Nerinetide as an adjunctive treatment in endovascular treatment patients who do not receive concurrent intravenous alteplase. METHODS: Data are from the ESCAPE-NA1 trial, in which acute ischemic stroke with large vessel occlusion endovascular treatment patients were randomized to receive intravenous Nerinetide or placebo. Only those patients not treated with concurrent intravenous alteplase were included in this analysis. We used a Markov state transition model (12 months cycle length) to estimate expected lifetime costs and outcomes, assuming Nerinetide cost being zero for the purpose of this analysis. We calculated incremental cost-effectiveness ratios and derived mean net monetary benefits with 95% prediction intervals from a probabilistic sensitivity analysis. Upper, middle, and lower willingness-to-pay thresholds were set at $50,000,$100,000, and $150,000. RESULTS: The incremental cost-effectiveness ratio for Nerinetide in addition to endovascular treatment was $13,721/quality-adjusted life year (healthcare perspective) and $14,453/quality-adjusted life year (societal perspective). At the upper willingness-to-pay threshold, Nerinetide in addition to endovascular treatment resulted in a higher mean net monetary benefit compared to endovascular treatment alone, both from a healthcare perspective (449,526 [95% prediction interval: 448,627-450,425] vs. 382,584 [381,781-383,386]) and a societal perspective (350,750 [349,842-351,658] vs. 282,896 [282,068-283,725]). Mean net monetary benefits were also higher for Nerinetide in addition to endovascular treatment at the middle and lower willingness-to-pay thresholds. CONCLUSION: Treating patients with a cerebroprotectant, such as Nerinetide, in addition to endovascular treatmentl in patients who cannot receive intravenous alteplase may be beneficial from a health-economic standpoint.

Association of Brain Atrophy With Functional Outcome and Recovery Trajectories After Thrombectomy: Post Hoc Analysis of the ESCAPE-NA1 Trial.

BACKGROUND AND OBJECTIVES: Brain frailty may impair the ability of acute stroke patients to cope with the injury, irrespective of their chronologic age, resulting in impaired recovery. We aim to investigate the impact of brain atrophy on functional outcome assessed at different time points after endovascular thrombectomy (EVT). METHODS: In this retrospective post hoc analysis of the ESCAPE-NA1 trial, we analyzed CT imaging data for cortical atrophy by using the GCA scale, including region-specific scales, and subcortical atrophy by using the intercaudate distance to inner table width (CC/IT) ratio. The primary outcome was 90-day mRS (ordinal shift analysis), and the secondary outcome was the mRS score over time. Adjustments were made for age, sex, baseline NIHSS, final infarct volume, stroke laterality, total Fazekas score, and nerinetide-alteplase interaction. Sensitivity analyses were additionally performed in only those patients for whom MRI data were available. RESULTS: Of 1,102 participants (mean age of 69.5 ± 13.7 years; 554 men), 818 (74%) had GCA = 0, 220 (20%) had GCA = 1, and 64 (6%) had GCA = 2/3. The median CC/IT ratio was 0.12 (IQR0.10-0.15). Cortical atrophy (GCA ≥ 1 vs GCA 0) was associated with worse 90-day mRS (acOR = 1.62 [95% CI 1.22-2.16]; p = 0.001), lower rates of 90-day mRS0-2 (aOR = 0.65 [95% CI 0.45-0.94]; p = 0.022), and higher mortality (aOR = 2.12 [95% CI 1.28-3.5]; p = 0.003), regardless of the region assessed. Subcortical atrophy was associated with worse 90-day mRS (acOR [per 0.01 increase in CC/IT ratio] = 1.07 [95% CI 1.04-1.11]; p < 0.001) and lower rates of 90-day mRS0-2 (aOR = 0.92 [95% CI 0.88-0.97]; p = 0.001). Furthermore, with various degrees of atrophy, we observed heterogeneity in mRS measurements during follow-up: worse mRS scores for higher atrophy grades (p < 0.001). Compared with participants with GCA = 0, the mRS for participants with GCA = 1 was higher at 30 days (adjusted difference = 0.41 [95% CI 0.18-0.65]) and remained worse at 90 days (adjusted difference = 0.72 [95% CI 0.49-0.95]). Similar effects were seen for participants with worse cortical atrophy, regardless of the region assessed, and worse subcortical atrophy. Furthermore, 26/63(41%) and 124/274(45%) patients with severe cortical/subcortical atrophy (GCA 2/3 and highest CC/IT ratio quartile, respectively) achieved good functional outcome (mRS0-2), compared with 539/812(66.4%) with no cortical atrophy and 209/274(76%) in the lowest CC/IT ratio quartile. DISCUSSION: In this large RCT-derived population, participants with brain atrophy, as visually assessed on acute noncontrast computed tomography imaging, showed less favorable stroke recovery after EVT and worse 90-day functional outcomes compared with participants without brain atrophy. This may support physicians with recovery expectations when planning post-EVT care with patients and their families.

Cortical and Subcortical Brain Atrophy Assessment Using Simple Measures on NCCT Compared with MRI in Acute Stroke.

BACKGROUND AND PURPOSE: Brain atrophy is an important surrogate for brain reserve, the capacity of the brain to cope with acquired injuries such as acute stroke. It is unclear how well atrophy measurements on MR imaging can be reproduced using NCCT imaging. We aimed to compare pragmatic atrophy measures on NCCT with MR imaging in patients with acute ischemic stroke. MATERIALS AND METHODS: This is a post hoc analysis, including baseline NCCT and 24-hour follow-up MR imaging data from the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial. Cortical atrophy was measured using the global cortical atrophy scale, and subcortical atrophy was measured using the intercaudate distance-to-inner-table width (CC/IT) ratio. Agreement and correlation between these measures on NCCT and MR imaging were calculated using the Gwet agreement coefficient 1 and Pearson correlation coefficients, respectively. RESULTS: Among 1105 participants in the ESCAPE-NA1 trial, interpretable NCCT and 24-hour MR imaging were available in 558 (50.5%) patients (mean age, 67.2 [SD, 13.7] years; 282 women). Cortical atrophy assessments performed on NCCT underestimated atrophy severity compared with MR imaging (eg, patients with global cortical atrophy of ≥1 assessed on NCCT = 133/558 [23.8%] and on MR imaging = 247/558 [44.3%]; a 20.5% difference). Overall, cortical (ie, global cortical atrophy) atrophy assessments on NCCT had substantial or better agreement with MR imaging (Gwet agreement coefficient 1 of > 0.784; P < .001). Subcortical atrophy measures (CC/IT ratio) showed strong correlations between NCCT and MR imaging (Pearson correlation = 0.746, P < .001). CONCLUSIONS: Brain atrophy can be evaluated using simple measures in emergently acquired NCCT. Subcortical atrophy assessments on NCCT show strong correlations with MR imaging. Although cortical atrophy assessments on NCCT are strongly correlated with MR imaging ratings, there is a general underestimation of atrophy severity on NCCT.

A dual-center validation of the PIRAMD scoring system for assessing the severity of ischemic Moyamoya disease.

Background: Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD) is a recently proposed imaging-based scoring system that incorporates the severity of disease and its impact on parenchymal hemodynamics in order to better support clinical management and evaluate response to intervention. In particular, PIRAMD may have merit in identifying symptomatic patients that may benefit most from revascularization. Our aim was to validate the PIRAMD scoring system. Methods: Patients with ischemic Moyamoya disease, who underwent catheter angiographic [modified Suzuki Score (mSS) and collateralization status], morphological MRI and a parenchymal hemodynamic evaluation with blood oxygenation-level dependent cerebrovascular reactivity (BOLD-CVR) at two transatlantic centers, were retrospectively included. The primary outcome was the presence of neurological symptoms. The diagnostic capacity of each PIRAMD feature alone was evaluated, as well as combined and the inter-institutional differences of each parameter were evaluated. Results: Seventy-two hemispheres of 38 patients were considered for analysis, of which 39 (54%) were classified as symptomatic. The presence of a prior infarct had the highest odds ratio [odds ratio (OR) =24; 95% CI: 6.7-87.2] for having neurological symptoms, followed by impaired CVR (OR =17; 95% CI: 5-62). No inter-institutional differences in the odds ratios or area under the curve (AUC) were found for any study parameter. The PIRAMD score had an AUC of 0.88 (95% CI: 0.80-0.96) with a similar AUC for the PIRAMD grading score. Conclusions: Our multicentric validation of the recently published PIRAMD scoring system was highly effective in rating the severity of ischemic Moyamoya disease with excellent inter-institutional agreement. Future studies should investigate the prognostic value of this novel imaging-based score in symptomatic patients with Moyamoya disease.

Effect of incomplete reperfusion patterns on clinical outcome: insights from the ESCAPE-NA1 trial.

BACKGROUND: Incomplete reperfusion (IR) after mechanical thrombectomy (MT) can be a consequence of residual occlusion, no-reflow phenomenon, or collateral counterpressure. Data on the impact of these phenomena on clinical outcome are limited. METHODS: Patients from the ESCAPE-NA1 trial with IR (expanded Thrombolysis In Cerebral Infarction (eTICI) 2b) were compared with those with complete or near-complete reperfusion (eTICI 2c-3) on the final angiography run. Final runs were assessed for (a) an MT-accessible occlusion, or (b) a non-MT-accessible occlusion pattern. The primary clinical outcome was modified Rankin Scale (mRS) 0-2 at 90 days. Our imaging outcome was infarction in IR territory on follow-up imaging. Unadjusted and adjusted incidence rate ratios (aIRR) with 95% confidence intervals (95% CI) were obtained. RESULTS: Of 1105 patients, 443 (40.1%) with IR and 506 (46.1%) with complete or near-complete reperfusion were included. An MT-accessible occlusion was identified in 147/443 patients (33.2%) and a non-MT-accessible occlusion in 296/443 (66.8%). As compared with patients with near-complete/complete reperfusion, patients with IR had significantly lower chances of achieving mRS 0-2 at 90 days (aIRR 0.82, 95% CI 0.74 to 0.91). Rates of mRS 0-2 were lower in the MT-accessible occlusion group as compared with the non-MT-accessible occlusion pattern group (aIRR 0.71, 95% CI 0.60 to 0.83, and aIRR 0.89, 95% CI 0.81 to 0.98, respectively). More patients with MT-accessible occlusion patterns developed infarcts in the non-reperfused territory as compared with patients with non-MT occlusion patterns (68.7% vs 46.3%). CONCLUSION: IR was associated with worse clinical outcomes than near-complete/complete reperfusion. Two-thirds of our patients with IR had non-MT-accessible occlusion patterns which were associated with better clinical and imaging outcomes compared with those with MT-accessible occlusion patterns.

Management of Adult Unruptured Brain Arteriovenous Malformations: An Updated Network Meta-Analysis.

The management of unruptured brain arteriovenous malformations (ubAVMs) is a complex challenge to neurovascular practitioners. This meta-analysis aimed to identify the optimal management of ubAVMs comparing conservative management, embolization, radiosurgery, microsurgical resection, and multimodality. The search strategy was developed a priori according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the Ovid Medline, Embase, Web of Science, and Cochrane Library databases to identify relevant papers. Using R version 4.1.1., a frequentist network meta-analysis was conducted to compare different management modalities for the ubAVMs. Overall, the conservative group had the lowest risk of rupture (P-score=0.77), and the lowest rate of complications was found in the conservative group (P-score=1). Among different interventions, the multimodality group had the highest rupture risk (P-score=0.34), the lowest overall complications (P-score=0.75), the best functional improvement (P-score=0.65), and the lowest overall mortality (P-score=0.8). However, multimodality treatment showed a significantly higher risk of rupture (odds ratio [OR]=2.13; 95% confidence interval [95% CI]=1.18-3.86) and overall complication rate (OR=5.56; 95% CI=3.37-9.15) compared to conservative management; nevertheless, there were no significant differences in overall mortality or functional independence when considered independently. Conservative management is associated with the lowest rupture risk and complication rate overall. A multimodal approach is the best option when considering mortality rates and functional improvement in the context of existing morbidity/symptoms. Microsurgery, embolization, and radiosurgery alone are similar to the natural history in terms of functional improvement and mortality, but have higher complication rates.

Infarcts in a New Territory: Insights From the ESCAPE-NA1 Trial.

BACKGROUND: Infarct in a new territory (INT) is a known complication of endovascular stroke therapy. We assessed the incidence of INT, outcomes after INT, and the impact of concurrent treatments with intravenous thrombolysis and nerinetide. METHODS: Data are from ESCAPE-NA1 trial (Safety and Efficacy of Nerinetide [NA-1] in Subjects Undergoing Endovascular Thrombectomy for Stroke), a multicenter, international randomized study that assessed the efficacy of intravenous nerinetide in subjects with acute ischemic stroke who underwent endovascular thrombectomy within 12 hours from onset. Concurrent treatment and outcomes were collected as part of the trial protocol. INTs were identified on core lab imaging review of follow-up brain imaging and defined by the presence of infarct in a new vascular territory, outside the baseline target occlusion(s) on follow-up brain imaging (computed tomography or magnetic resonance imaging). INTs were classified by maximum diameter (<2, 2-20, and >20 mm), number, and location. The association between INT and clinical outcomes (modified Rankin Scale and death) was assessed using standard descriptive techniques and adjusted estimates of effect were derived from Poisson regression models. RESULTS: Among 1092 patients, 103 had INT (9.3%, median age 69.5 years, 49.5% females). There were no differences in baseline characteristics between those with versus without INT. Most INTs (91/103, 88.3%) were not associated with visible occlusions on angiography and 39 out of 103 (37.8%) were >20 mm in maximal diameter. The most common INT territory was the anterior cerebral artery (27.8%). Almost half of the INTs were multiple (46 subjects, 43.5%, range, 2-12). INT was associated with poorer outcomes as compared to no INT on the primary outcome of modified Rankin Scale score of 0 to 2 at 90 days (adjusted risk ratio, 0.71 [95% CI, 0.57-0.89]). Infarct volume in those with INT was greater by a median of 21 cc compared with those without, and there was a greater risk of death as compared to patients with no INT (adjusted risk ratio, 2.15 [95% CI, 1.48-3.13]). CONCLUSIONS: Infarcts in a new territory are common in individuals undergoing endovascular thrombectomy for acute ischemic stroke and are associated with poorer outcomes. Optimal therapeutic approaches, including technical strategies, to reduce INT represent a new target for incremental quality improvement of endovascular thrombectomy. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02930018.

Minimally Invasive and Outpatient Aneurysm Surgery: New Concepts.

Anterior circulation aneurysms have classically been treated using the pterional (PT) craniotomy. Minimally invasive alternatives to the PT craniotomy have been successfully used to treat vascular pathologies of the anterior circulation. These approaches offer smaller incisions and reduced tissue dissection, resulting in shorter hospital stay, improved cosmetic results, and comparable outcomes for aneurysm treatment compared with classic open approaches. The supraorbital, lateral supraorbital (LSO), mini-PT, minimal interhemispheric, and endoscopic transpterional port approach (ETPA) are each best suited for different aneurysm targets. Outpatient aneurysm surgery has been possible with the use of minimally invasive approaches.

Association of Iatrogenic Infarcts With Clinical and Cognitive Outcomes in the Evaluating Neuroprotection in Aneurysm Coiling Therapy Trial.

BACKGROUND AND OBJECTIVES: Small 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. METHODS: In 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 a z score-derived composite outcome score using quantile regression. RESULTS: Among 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). DISCUSSION: Iatrogenic 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 INFORMATION: Clinical trials registration NCT00728182.

Association of Stent-Retriever Characteristics in Establishing Successful Reperfusion During Mechanical Thrombectomy : Results from the ESCAPE-NA1 Trial.

BACKGROUND: Successful reperfusion determines the treatment effect of endovascular thrombectomy. We evaluated stent-retriever characteristics and their relation to reperfusion in the ESCAPE-NA1 trial. METHODS: 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. RESULTS: 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). CONCLUSION: The presence of bypass effect and thrombus positioning within the proximal and middle third of the stent-retriever were strongly associated with successful reperfusion.