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Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship.In a pooled, patient-level analysis of EXTEND-IA trials and SELECT study, we employed a mediation analysis framework to quantify infarct growth and cerebral edema(midline shift) mediation effect on successful reperfusion(mTICI≥2b) association with functional outcome(mRS distribution). Further, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift.542/665(81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful vs unsuccessful reperfusion. Median(IQR) infarct growth was 12.3(1.8-48.4)ml and median(IQR) midline shift was 0(0,2.2)mm. Of 249(37%) demonstrating a midline shift of ≥1mm, median(IQR) shift was 2.75(1.89, 4.21)mm). Successful reperfusion was associated with reductions in both predefined mediators; infarct growth (β, -1.19; 95%CI, -1.51to-0.88;p0.001) and midline shift (aOR:0.36,95%CI:0.23-0.57,p0.001). Successful reperfusion association with improved functional outcome (acOR:2.68; 95%CI:1.86-3.88,p0.001), became insignificant (acOR:1.39, 95%CI:0.95-2.04,p=0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect. Analysis considering alternative hypothesis demonstrated consistent results.In this mediation analysis from a pooled, patient-level cohort, a significant proportion(~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect and identify novel therapeutic targets to further enhance reperfusion benefits. This article is protected by copyright. All rights reserved.

Objective This study was undertaken to evaluate functional and safety outcomes for endovascular thrombectomy (EVT) versus medical management (MM) in patients with large vessel occlusion (LVO) and mild neurological deficits, stratified by perfusion imaging mismatch. Methods The pooled cohort consisted of patients with National Institutes of Health Stroke Scale (NIHSS) < 6 and internal carotid artery (ICA), M1, or M2 occlusions from the Extending the Time for Thrombolysis in Emergecy Neurological Deficits - Intra-Arterial (EXTEND-IA) Trial, Tenecteplase vs Alteplase before Endovascular Thrombectomy in Ischemic Stroke (EXTEND-IA TNK) trials Part I/II and prospective data from 15 EVT centers from October 2010 to April 2020. RAPID software estimated ischemic core and mismatch. Patients receiving primary EVT (EVTpri) were compared to those who received primary MM (MMpri), including those who deteriorated and received rescue EVT, in overall and propensity score (PS)-matched cohorts. Patients were stratified by target mismatch (mismatch ratio >= 1.8 and mismatch volume >= 15ml). Primary outcome was functional independence (90-day modified Rankin Scale = 0-2). Secondary outcomes included safety (symptomatic intracerebral hemorrhage [sICH], neurological worsening, and mortality). Results Of 540 patients, 286 (53%) received EVTpri and demonstrated larger critically hypoperfused tissue (Tmax > 6 seconds) volumes (median [IQR]: 64 [26-96] ml vs MMpri: 40 [14-76] ml, p < 0.001) and higher presentation NIHSS (median [IQR]: 4 [2-5] vs MMpri: 3 [2-4], p < 0.001). Functional independence was similar (EVTpri: 77.4% vs MMpri: 75.6%, adjusted odds ratio [aOR] = 1.29, 95% confidence interval [CI] = 0.82-2.03, p = 0.27). EVT had worse safety regarding sICH (EVTpri: 16.3% vs MMpri: 1.3%, p < 0.001) and neurological worsening (EVTpri: 19.6% vs MMpri: 6.7%, p < 0.001). In 414 subjects (76.7%) with target mismatch, EVT was associated with improved functional independence (EVTpri: 77.4% vs MMpri: 72.7%, aOR = 1.68, 95% CI = 1.01-2.81, p = 0.048), whereas there was a trend toward less favorable outcomes with primary EVT (EVTpri: 77.4% vs MMpri: 83.3%, aOR = 0.39, 95% CI = 0.12-1.34, p = 0.13) without target mismatch (p(interaction) = 0.06). Similar findings were observed in a propensity score-matched subpopulation. Interpretation Overall, EVT was not associated with improved clinical outcomes in mild strokes due to LVO, and sICH was increased. However, in patients with target mismatch profile, EVT was associated with increased functional independence. Perfusion imaging may be helpful to select mild stroke patients for EVT. ANN NEUROL 2022

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

Background: In clinical practice, some investigations can have low diagnostic yield or little impact on treatment. Objectives: This article reviews the impact of asymptomatic carotid artery stenosis on management of syncope, and the role of carotid Doppler ultrasound in carotid sinus syndrome and in syncope. Unclear concepts in syncope workup and management are identified. Methods: We conducted a clinical survey of 206 internal medicine providers, to explore how many would consider unilateral carotid revascularization to treat isolated syncope, and how many would consider carotid ultrasound in evaluating carotid sinus syndrome. We searched the literature to identify cases in which carotid revascularization improved syncope, and whether or not carotid ultrasound was used to evaluate carotid sinus syndrome. Literature was reviewed for carotid ultrasound use in syncope. Results: 34% of medical providers surveyed considered carotid endarterectomy for isolated syncope treatment for unilateral high-grade carotid stenosis and 45% of surveyed providers considered carotid ultrasound in evaluating carotid sinus syndrome. The literature revealed older studies of syncope resolution following carotid endarterectomy in patients with specific characteristics; their detailed features are identified here, and revealed that evaluation of carotid sinus syndrome did not require carotid ultrasound. Conclusions: Carotid revascularization is not recommended for unilateral asymptomatic carotid artery stenosis to treat isolated syncope, and carotid ultrasound is not needed in the evaluation of carotid sinus syndrome and rates of neurological complications following carotid sinus massage were low.

IMPORTANCE: A direct to angiography (DTA) treatment paradigm without repeated imaging for transferred patients with large vessel occlusion (LVO) may reduce time to endovascular thrombectomy (EVT). Whether DTA is safe and associated with better outcomes in the late (>6 hours) window is unknown. Also, DTA feasibility and effectiveness in reducing time to EVT during on-call vs regular-work hours and the association of interfacility transfer times with DTA outcomes have not been established. OBJECTIVE: To evaluate the functional and safety outcomes of DTA vs repeated imaging in the different treatment windows and on-call hours vs regular hours. DESIGN, SETTING, AND PARTICIPANTS: This pooled retrospective cohort study at 6 US and European comprehensive stroke centers enrolled adults (aged ≥18 years) with anterior circulation LVO (internal cerebral artery or middle cerebral artery subdivisions M1/M2) and transferred for EVT within 24 hours of the last-known-well time from January 1, 2014, to February 29, 2020. EXPOSURES: Repeated imaging (computed tomography with or without computed tomographic angiography or computed tomography perfusion) before EVT vs DTA. MAIN OUTCOMES AND MEASURES: Functional independence (90-day modified Rankin Scale score, 0-2) was the primary outcome. Symptomatic intracerebral hemorrhage, mortality, and time metrics were also compared between the DTA and repeated imaging groups. RESULTS: A total of 1140 patients with LVO received EVT after transfer, including 327 (28.7%) in the DTA group and 813 (71.3%) in the repeated imaging group. The median age was 69 (interquartile range [IQR], 59-78) years; 529 were female (46.4%) and 609 (53.4%) were male. Patients undergoing DTA had greater use of intravenous alteplase (200 of 327 [61.2%] vs 412 of 808 [51.0%]; P = .002), but otherwise groups were similar. Median time from EVT center arrival to groin puncture was faster with DTA (34 [IQR, 20-62] vs 60 [IQR, 37-95] minutes; P 6 to 24 hours; P = .88 for interaction). Three-month mortality was lower with DTA (53 of 312 [17.0%] vs 186 of 763 [24.4%]; P = .008). A 10-minute increase in EVT-center arrival to groin puncture in the repeated imaging group correlated with 5% reduction in the functional independence odds (aOR, 0.95 [95% CI, 0.91-0.99]; P = .01). The rates of modified Rankin Scale score of 0 to 2 decreased with interfacility transfer times of greater than 3 hours in the DTA group (96 of 161 [59.6%] vs 15 of 42 [35.7%]; P = .006), but not in the repeated imaging group (75 of 208 [36.1%] vs 71 of 192 [37.0%]; P = .85). CONCLUSIONS AND RELEVANCE: The DTA approach may be associated with faster treatment and better functional outcomes during all hours and treatment windows, and repeated imaging may be reasonable with prolonged transfer times. Optimal EVT workflow in transfers may be associated with faster, safe reperfusion with improved outcomes.

Cerebral venous thrombosis (CVT) usually accounts for

Background Opsoclonus-myoclonus syndrome (OMS) is a rare neuroimmunologic disorder characterized by opsoclonus, myoclonic jerks mostly in the face and limbs, cerebellar ataxia, tremors, and encephalopathy. OMS is rare in adults and exceedingly rarer in pregnancy, as only a few cases in pregnancy have been reported. We present what we understand is the first case of postpartum OMS. Methods and results We report and discuss a challenging case of OMS which started 6 weeks postpartum. Despite extensive infectious and malignancy evaluation, an underlying etiology was not readily apparent thus we treated her with high dose intravenous steroids and intravenous immunoglobulin (IVIG) for presumed idiopathic autoimmune OMS. She relapsed and additional workup identified new enhancing lesion on MRI brain, positive MOG-IgG, and CSF negative for oligoclonal bands. She was transitioned to maintenance IVIG and ultimately to rituximab with better results. At 2 year follow up her exam was improved and without objective evidence of abnormal movement or opsoclonus on maintenance Rituximab infusion 1,000 mg every 6 months. Conclusion In OMS, an autoimmune response is usually thought to occur by molecular mimicry with neuronal cell surface antigens in association with infections. Since a preceding infection was absent in this case, we propose that the immune response here was initiated due to immunological changes in pregnancy and postpartum period possibly due to fetal tissue exposure (fetal microchimerism). The presence of the MOG antibody raises the possibility that OMS is another clinical manifestation of MOG-associated disease (MOG-AD), which in our case is supported by characteristic CSF and radiographic findings of MOG-AD.

BACKGROUND AND PURPOSE A standardized and validated method to measure brain shifts in malignant middle cerebral artery (MCA) stroke with decompressive hemicraniectomy (DHC) could facilitate clinical decision making, prognostication, and comparison of results between studies. METHODS We tested for reliability simplified methods to measure transcalvarial herniation, midline brain shift, and the contralateral cerebral ventricular atrium in malignant MCA stroke after DHC. Multiple raters measured brain shifts on post-DHC computed tomography (CT) scans with aligned and unaligned slice orientations in 25 patients. We compared the simplified measurements to previously reported more meticulous measurements. RESULTS The simplified measurements correlate well with the more meticulous measurements on both aligned and unaligned CTs (intraclass correlation coefficients .72-.89). CONCLUSIONS These simplified and expedient methods of measuring brain shifts in malignant MCA stroke after DHC correlate well with the more meticulous methods.

Cell therapies have attracted significant attention in treating multiple neurological disorders including stroke. The preclinical studies have paved the road in understanding the potential clinical applications of cell therapies in stroke recovery. Cells can be obtained from multiple sources and transplanted through different routes. Animal and human studies suggest that cell therapies exert their effect via paracrine and immunomodulatory effects rather than physically replacing the damaged cells. Clinical studies are still in the early phases but show safety and feasibility and some hints at efficacy.

A standardized and validated method to measure brain shifts in malignant middle cerebral artery (MCA) stroke with decompressive hemicraniectomy (DHC) could facilitate clinical decision making, prognostication, and comparison of results between studies.We tested for reliability simplified methods to measure transcalvarial herniation, midline brain shift, and the contralateral cerebral ventricular atrium in malignant MCA stroke after DHC. Multiple raters measured brain shifts on post-DHC computed tomography (CT) scans with aligned and unaligned slice orientations in 25 patients. We compared the simplified measurements to previously reported more meticulous measurements.The simplified measurements correlate well with the more meticulous measurements on both aligned and unaligned CTs (intraclass correlation coefficients .72-.89).These simplified and expedient methods of measuring brain shifts in malignant MCA stroke after DHC correlate well with the more meticulous methods.

Background A standardized, reliable, and practical method for measuring decompressive hemicraniectomy (DHC) defects and brain shifts in malignant middle cerebral artery (MCA) territory infarction is needed for reliable comparisons between computed tomography (CT) scans. Such a method could facilitate further studies on the effects of DHC. New method We describe and apply a method for measuring DHC defects and brain shifts on CT scans in 25 patients with malignant MCA territory infarction. Craniectomy area is adjusted for variations in head size, CT slice orientation is standardized, and the site of each measurement is defined. This method uses standard radiology platforms and volume-acquired helical CT scans. Results The measurements include a DHC size index (adjusted for variations in head size), midline brain shift (subfalcine), outward brain herniation (transcalvarial), and the diameter of the contralateral atrium of the lateral ventricle. Inter-rater agreement for these measurements in a sample of 15 subjects is excellent (correlation coefficients 0.90–0.98). Comparison with existing methods In contrast to previously reported methods, this method is tested in acute stroke patients, compensates for variability in head size, and includes a midline brain shift (subfalcine) and brain ventricular system measurements. Conclusions A practical method for measuring DHC size and brain shifts designed to be consistent between scans is proposed. This method should facilitate comparisons of measurements between serial scans, between patients, and perhaps between studies. This method could be useful in medical and surgical studies of brain herniations in malignant MCA territory infarction, and possibly other conditions.

Background: Enlarged perivascular spaces (PVS) in the brain are common but their etiology and specificity are unclear. Multiple studies have shown a correlation between enlarged PVS and white matter hyperintensities (WMHs), but the relationship with vascular disease is uncertain. We used albumin CSF to blood ratio as a method to measure permeability of the blood-brain barrier (BBB) in patients with vascular cognitive impairment (VCI). It is possible that the enlarged PVS are associated with an increase in BBB permeability, which could interfere with perivascular fluid flow. Therefore, we hypothesized that enlarged PVS correlate with CSF markers of increased BBB permeability and neuroinflammation. Methods: We prospectively recruited 107 VCI patients with white matter disease. At entry, they had brain MRIs with standardized ranking for enlarged PVS. Sixty-one had lumbar puncture to obtain CSF for analysis of albumin ratio, matrix metalloproteinases-2 (MMP-2) index, and amyloid-beta1-42 (Abeta42). The data was analyzed statistically with nonparametric correlation methods. Results: Enlarged PVS had a positive correlation with CSF albumin ratio, which is a biomarker for increased BBB permeability ( p p p Conclusion: Our results suggest an association between PVS, MMP-mediated increased BBB permeability, and clearance of Abeta42. The role of perivascular fluid movement and its relationship with CSF biomarkers will require further investigation.

Background: Malignant MCA infarction is a devastating disease associated with up to 80% mortality due to edema and herniation. Evidence from three European randomized trials show that decompressive hemicraniectomy (DHC) may improve functional outcomes in select patients. Adjacent cerebral territorial infarction often coincides with malignant MCA infarcts. This study compares the effects of isolated malignant MCA infarcts versus combined malignant MCA plus ipsilateral (ACA or PCA) infarcts on functional outcomes in patients surviving one or more years following DHC. We hypothesized that patients with no additional territorial involvement would have a better functional outcome. Methods: Retrospective analysis was performed on patients who underwent DHC for malignant MCA infarction from 03/2006 to 03/2012. Inclusion criteria include: Age 18-60, clinical and radiographical diagnosis of acute unilateral MCA stroke involving at least 50% of MCA territory, and DHC performed primarily to treat space occupying edema . Exclusion criteria include: Prestroke mRs of >2, life expectancy < 3 years, and death < 1 year after DHC. Patients were divided into two groups: (a) those with isolated MCA infarcts and (b) those with MCA combined with significant adjacent ipsilateral ACA or PCA involvement. Functional outcomes were calculated using the modified Rankin scale (mRs). The mean mRs was calculated for each group and the Wilcoxon-Mann-Whitney two tailed test was used to calculate statistical significance. Alpha level was set at p< 0.05. Results: A total of 26 patients met criteria. 20 patients had isolated MCA infarcts while 6 had combined MCA plus ACA or PCA infarcts. No statistical difference in functional outcome was observed between the isolated MCA group (x - =3.6) and the combined MCA group (x - =3.83) (p value=0.614). Conclusion: In this retrospective study, patients surviving one year after their DHC did not demonstrate a worse functional outcome due to additional cerebral territorial co-infarction. These findings argue against a major negative influence of combined infarctions on functional outcome compared to previous limited studies. Larger studies are needed to verify these results and to better assess criteria for ideal patient selection for DHC.