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Background: We studied the evolution over time of diffusion weighted imaging (DWI) lesion volume and the factors involved on early and late infarct growth (EIG and LIG) in stroke patients undergoing endovascular treatment (EVT) according to the final revascularization grade. Methods: This is a prospective cohort of patients with anterior large artery occlusion undergoing EVT arriving at 1 comprehensive stroke center. Magnetic resonance imaging was performed on arrival (pre-EVT), Results: We included 98 patients (mean age 70, median National Institutes of Health Stroke Scale score 17, final mTICI≥2b 86%). Median EIG and LIG were 48 and 63.3 mL in patients with final mTICIρ =0.667; P ρ =0.614; P Conclusions: Infarct grows during and after EVT, especially in nonrecanalizers but also to a lesser extent in recanalizers. In recanalizers, number of passes and DWI volume influence EIG, while number of passes, DWI, and hypoperfused volume after the procedure determine LIG.

Introduction: After achieving successful reperfusion some acute stroke patients still exhibit persistent perfusion deficits. These deficits have been defined in a heterogeneous manner by using CBF, CBV or Tmax maps as a perfusion deficit in the previous ischemic penumbra (impaired microcirculation perfusion-IMP) or inside the infarcted tissue (no reflow-NR). The significance, frequency and pathophysiology of this phenomenon are so far unknown. Methods: Prospective cohort of patients with isolated anterior intracranial occlusion undergoing endovascular treatment (EVT) and achieving complete recanalization (final mTICI≥2B). Brain MRI was performed on arrival (pre-EVT) and &lt2h after EVT (post-EVT). Infarcted tissue was segmented on DWI pre-EVT. Pre and post-EVT perfusion maps were obtained with Olea software. NR was defined in the post-EVT perfusion maps as the region inside the infarcted tissue which showed a CBV&lt15% compared to the contralateral side, while IMP was the equivalent area inside the previous tissue in penumbra. We evaluated the association between both NR and IMP and NIHSS at 24h, NIHSS at discharge and modified Rankin score (mRS) at three months adjusting by baseline NIHSS and final mTICI. Results: Thirty-five patients were included. All of them had IMP areas and 25 (71%) had NR areas. The median volume of NR and IMP was 3.43ml [IQR 1.43-8.81], corresponding to 17.9% of the infarcted tissue [IQR 4.2-50.3] and 33.9ml [IQR 14.0-69.3] (27.7% [IQR 8.2-51.2] of the penumbra) respectively. Patients with NR areas had higher NIHSS at 24 h and at discharge and higher mRS at 3 months. Volume of NR was independently associated with higher NIHSS at 24 h and at discharge. No independent association was found with IMP volume. Neither NR nor IMP were associated with hemorrhagic transformation. Patients receiving rTPA previous to EVT showed higher perfusion values inside the infarct than patients with primary EVT (2.31 mL/100g [1.48-2.43] vs 0.92 [0.7-1.47] p=0.02), although NR areas appeared in the same proportion in both groups. Conclusions: No reflow phenomenon can be a marker of poor outcome in the early evaluation of successfully recanalized stroke patients especially when the persistent perfusion deficit is located inside the infarcted tissue.

Funding: This work was supported by grants from the Emergency Medicine Foundation Career Development Grant; AHA Mentored Clinical & Population Research Award (14CRP18860027); NIH/NINDS-R01-NS085419 (C.C., J.M.L.); NIH/NINDS-R37-NS107230, NIH/NINDS U24-NS107230 (J.M.L.); NIH/NINDS-K23-NS099487 (L.H.); NIH/NIA-K99-AG062723 (L.I.); Barnes-Jewish Hospital Foundation (J.M.L.); Biogen (C.C., J.M.L.); Bright Focus Foundation, US Department of Defense, Helsinki University Central Hospital; Finnish Medical Foundation; Finland government subsidiary funds; Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (grants ‘Registro BASICMAR’ Funding for Research in Health (PI051737), ‘GWALA project’ from Fondos de Investigación Sanitaria ISC III (PI10/02064, PI12/01238 and PI15/00451), JR18/00004); Fondos FEDER/EDRF Red de Investigación Cardiovascular (RD12/0042/0020); Fundació la Marató TV3; Genestroke Consortium (76/C/2011); Recercaixa’13 (JJ086116). Tomás Sobrino (CPII17/00027), Francisco Campos (CPII19/00020) and Israel Fernandez are supported by Miguel Servet II Program from Instituto de Salud Carlos III and Fondos FEDER. I.F. is also supported by Maestro project (PI18/01338) and Pre-test project (PMP15/00022) from Instituto de Salud Carlos III and Fondos Feder, Agaur; and Epigenesis project from Marató TV3 Foundation. J.C., J.M., A.D., J.M.-F., J.A. and I.F. are supported by Invictus plus Network (RD16/0019) from Instituto de Salud Carlos III and Fondos Feder. Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-2013/07559-3) (I.L.-C.), Sigrid Juselius Foundation. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. B.S., B.A. and F.S. are supported by NIH awards NS097000, NS101718, NS075035, NS079153 and NS106950. During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6h of stroke onset and NIHSS at 24h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Postprint

Introduction Current recommendations for regional stroke destination suggest that patients with severe acute stroke in non-urban areas should be triaged based on the estimated transport time to a referral thrombectomy-capable center. Methods We performed a post hoc analysis to evaluate the association of pre-hospital workflow times with neurological outcomes in patients included in the RACECAT trial. Workflow times evaluated were known or could be estimated before transport allocation. Primary outcome was the shift analysis on the modified Rankin score at 90 days. Results Among the 1,369 patients included, the median time from onset to emergency medical service (EMS) evaluation, the estimated transport time to a thrombectomy-capable center and local stroke center, and the estimated transfer time between centers were 65 minutes (interquartile ratio [IQR] = 43-138), 61 minutes (IQR = 36-80), 17 minutes (IQR = 9-27), and 62 minutes (IQR = 36-73), respectively. Longer time intervals from stroke onset to EMS evaluation were associated with higher odds of disability at 90 days in the local stroke center group (adjusted common odds ratio (acOR) for each 30-minute increment = 1.03, 95% confidence interval [CI] = 1.01-1.06), with no association in the thrombectomy-capable center group (acOR for each 30-minute increment = 1.01, 95% CI = 0.98-1.01, p(interaction) = 0.021). No significant interaction was found for other pre-hospital workflow times. In patients evaluated by EMS later than 120 minutes after stroke onset, direct transport to a thrombectomy-capable center was associated with better disability outcomes (acOR = 1.49, 95% CI = 1.03-2.17). Conclusion We found a significant heterogeneity in the association between initial transport destination and neurological outcomes according to the elapse of time between the stroke onset and the EMS evaluation (: NCT02795962). ANN NEUROL 2022

Background and Purpose- We report the relation of onset-to-treatment time and door-to-needle time with functional outcomes and mortality among patients with ischemic stroke with imaging-proven large vessel occlusion treated with intravenous alteplase. Methods- Individual patient-level data from the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration were pooled from 7 trials that randomized patients to mechanical thrombectomy added to best medical therapy versus best medical therapy alone. Analysis was restricted to patients who received alteplase directly at the endovascular hospital. The primary outcome was disability defined on the modified Rankin Scale at 3 months. Results- Among 601 patients, mean age was 66.0 years (SD, 13.9), 50% were women, and median National Institutes of Health Stroke Scale score was 17. Onset-to-treatment time was median 125 minutes (interquartile range, 90-170). Door-to-treatment time was median 38 minutes (interquartile range, 26-55). Each 60-minute onset-to-treatment time delay was associated with greater disability at 90 days; the odds of functional independence (modified Rankin Scale, 0-2) at 90 days was 0.82 (95% CI, 0.66-1.03). With each 60-minute delay in door-to-needle time; the odds of functional independence was 0.55 (95% CI, 0.37-0.81) at 90 days. The absolute decline in the rate of excellent outcome (modified Rankin Scale, 0-1 at 90 days) was 20.3 per 1000 patients treated per 15-minute delay in door-to-needle time. The adjusted absolute risk difference for a door-to-needle time30 minutes versus 30 to 60 minutes was 19.3% for independent outcome (number-needed-to-treat ≈5 to gain 1 additional good outcome). Symptomatic intracranial hemorrhage occurred in 3.4% of patients, without a significant time dependency: odds ratio, 0.74 (95% CI, 0.43-1.28). Conclusions- Faster intravenous thrombolysis delivery is associated with less disability at 3 months among patients with large vessel occlusion.

Introduction: Mechanical thrombectomy (MT) improves clinical outcome of patients with acute ischemic stroke (AIS) and a large vessel occlusion. Approximately 90% of patients in the recent MT trials received intravenous thrombolysis (IVT) prior to MT. Aim: To determine if IVT in combination with MT is superior to MT alone in patients with AIS and a large vessel occlusion. Methods: A patient-level pooled analysis of the STAR and SWIFT studies, two large multicenter prospective studies on MT for AIS was utilized. Using multivariate logistic regression analysis, we compared mRS at follow-up, reperfusion rates, and complication rates (intracerebral hemorrhage and emboli to uninvolved territories) between patients who underwent MT following IVT, to those who underwent only MT. An independent core laboratory scored all radiological outcomes. Results: Of 291 included patients, 160 (55%) underwent MT following IVT, and 131 (45%) underwent only MT. Of the patients treated with IVT, 116 were IVT failures (full tpa dose) and 44 received bridging therapy (mean tpa dose 0.62 mg/kg). Patients who received IVT less often had atrial fibrillation (33 vs. 47 %, p=0.016) and diabetes (14 vs. 24%, p=0.023), and had a lower mean ASPECTS (8.1 vs. 8.5, p=0.031) compared to thos who underwent only MT. There was no difference in baseline NIHSS (both median 17) or location of the occlusion between groups. We did not find a statistically significant association between use of IVT in addition to MT vs. MT alone for any of the outcomes. There were trends towards a lower risk of symptomatic intracerebral hemorrhage (adjusted OR 0.12, 95% CI 0.01-1.13), a higher risk of vasospasm (adjusted OR 1.81, 95% CI 0.86-3.80), and a higher chance of mRS 0-2 (adjusted OR 1.60, 95% CI 0.86-3.80) in patients who received MT following IVT, compared to MT alone. Conclusions: We observed no statistically significant benefit or harm for the use of IVT in addition to MT in patients with AIS and a large vessel occlusion.

Background and Purpose— In animal models of acute ischemic stroke (AIS), the free radical–trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS. Methods— Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome. Results— An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (n=2438) compared with the placebo group (n=2456): odds ratio for limiting disability=1.02; 95% CI, 0.92 to 1.13 ( P =0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome. Conclusions— NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage.

Background: Laterality of the posterior cerebral artery (LPCA) in acute stroke has been related with a better leptomeningeal collateral circulation and with improved functional outcome at 6 months in patients treated with IV tPA. We aim to study the association between LPCA and the amount of brain tissue at risk of infarction in patients with anterior circulation arterial occlusion. Methods: From our prospective database of ischemic stroke we selected patients with anterior circulation arterial occlusion who underwent multimodal MRI < 12h of symptom onset. We considered LPCA when the following criteria were accomplished: a) ipsilateral PCA to the occlusion site was extended in 1 or more segments compared to the contralateral PCA and b) ipsilateral P4 segment was visible on axial TOF images. Two independent readers blinded to clinical data retrospectively assessed the presence of LPCA (k=0.65). We analyzed the association between LPCA and the volume of ischemic penumbra at baseline (Tmax>6s) and the final infarct volume (CT 24h). Good outcome was defined as mRS ≤ 2 at 90 days. Results: Seventy-two patients were included in the study (mean age 67y, 45% male). LPCA was present in 39 (54.1%). There were no differences between groups with or without LPCA, except a lower baseline NIHSS in the LPCA group (15 vs 19; p=0.003). Proportion of patients treated with reperfusion therapies was similar between groups. Patients with LPCA had a smaller lesion in Tmax>6s (54 vs 79cc; p=0.02), smaller final infarct volume (47 vs 111cc; p=0.013), and higher proportion of good outcome (52.8% vs 27.3%; p=0.03). In a multivariate analysis, LPCA was independently associated with smaller lesion volume on Tmax>6s (B -18, IC95% [-36,-0.3]), smaller final infarct volume (B -64.8, IC95% [-100,-29]) and better clinical outcome (OR 4.66, IC95% [1.04,20.8]). Conclusion: LPCA sign in patients with anterior circulation arterial occlusion is associated with smaller volume of brain tissue at risk resulting in smaller infarct volume and better clinical outcome. These findings suggest favorable leptomeningeal collaterals.

Background: The angiographic visualization of arteriovenous shunting (AVS) in large vessel occlusion strokes (LVOS) is thought to be a consequence of microcirculatory collapse in the setting of irreversible tissue injury and therefore may represent an ominous prognostic sign. We sought to establish the relationship between the presence of AVS on CT imaging characteristics and clinical outcomes in the Solitaire Flow Restoration Thrombectomy for Acute Revascularization (STAR) trial. Methods: STAR Trial patients with complete angiographic images were categorized according to the presence (AVS+) or absence (AVS-) of AVS at the end of the thrombectomy procedure. Baseline variables were compared to assess for any significant differences amongst the two groups. The impact of AVS on pre- and post-treatment CT imaging and in the rates of revascularization (TICI 2b-3), symptomatic intracranial hemorrhage (sICH), good functional outcomes (90-day mRS≤2), and 90-day mortality was subsequently analyzed. Results: There was no significant differences in terms of age, baseline NIHSS, gender, time to treatment, or glucose levels between the AVS+ (n=52) and the AVS- (n=116) patients (Table 1). AVS+ patients had a non-significant trend towards more proximal occlusions. The presence of AVS did not have any significant impact on the rates of favorable CT imaging on either pre-treatment (AVS- vs. AVS+ ASPECTS>7: 65.5 vs. 72%;p=0.47) or post-treatment (ASPECTS>7:45.6 vs. 51%;p=0.61) scans. Similarly, AVS was not associated with any significant differences in the rates of good outcome (58.6 vs. 65.4%;p=0.49), mortality (8.6 vs. 3.8%;p=0.35), sICH (1.7 vs. 1.9%;p=0.92), or recanalization (89.7 vs. 92.3%;p=0.78). Conclusions: In contrast to the current belief, the angiographic visualization of AVS in LVOS patients does not appear to have any meaningful consequences in terms of infarct size or clinical outcomes and therefore should not influence treatment decisions.

Background and Purpose— Mechanical thrombectomy using stent retriever devices have been advocated to increase revascularization in intracranial vessel occlusion. We present the results of a large prospective study on the use of the Solitaire Flow Restoration in patients with acute ischemic stroke. Methods— Solitaire Flow Restoration Thrombectomy for Acute Revascularization was an international, multicenter, prospective, single-arm study of Solitaire Flow Restoration thrombectomy in patients with large vessel anterior circulation strokes treated within 8 hours of symptom onset. Strict criteria for site selection were applied. The primary end point was the revascularization rate (thrombolysis in cerebral infarction ≥2b) of the occluded vessel as determined by an independent core laboratory. The secondary end point was the rate of good functional outcome (defined as 90-day modified Rankin scale, 0–2). Results— A total of 202 patients were enrolled across 14 comprehensive stroke centers in Europe, Canada, and Australia. The median age was 72 years, 60% were female patients. The median National Institute of Health Stroke Scale was 17. Most proximal intracranial occlusion was the internal carotid artery in 18%, and the middle cerebral artery in 82%. Successful revascularization was achieved in 79.2% of patients. Device and procedure-related severe adverse events were found in 7.4%. Favorable neurological outcome was found in 57.9%. The mortality rate was 6.9%. Any intracranial hemorrhagic transformation was found in 18.8% of patients, 1.5% were symptomatic. Conclusions— In this single-arm study, treatment with the Solitaire Flow Restoration device in intracranial anterior circulation occlusions results in high rates of revascularization, low risk of clinically relevant procedural complications, and good clinical outcomes in combination with low mortality at 90 days. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01327989.

Objective: To study clinical and biological factors associated with the different cervicocephalic location of atherosclerosis in Caucasian stroke-free individuals. Methods: Carotid and intracranial atherosclerosis were assessed in the same lab by ECO-Doppler in a random sample population of 933 Caucasian subjects older than 50, with a moderate-high vascular risk and without history of stroke (64% males, mean age 66 years). Hypertension, dyslipemia, diabetes and smoking habit were defined based on clinical history and/or current medications. The following inflammatory and endothelial dysfunction biomarkers were determined at baseline and considered as continuous variables for the analyses: C-reactive protein (CRP), plasminogen activator inhibitor (PAI-1), resistin and asymmetric dimethylarginine (ADMA). Results: Subjects were classified according to the cervicocephalic location of atherosclerotic lesions: 449 (48.1%) had no lesions (reference group), 404 (43.3%) had isolated carotid extracranial lesions (EC), 57 (6.1%) had isolated intracranial lesions (IC) and 23 (2.5%) had combined extra-intracranial lesions (C). After multinomial regression analyses, factors independently associated with each location of atherosclerosis compared to the reference group were: with EC, age (OR 1.06[1.04-1.09]p Conclusions: Our findings show distinct clinical and biological signatures of the cervico-cephalic location of subclinical atherosclerosis.

We describe a case of acute alcoholic myopathy evaluated by computed tomography. Computed tomography showed a low-density, delimited area in the semimembranous muscle and edema of the subcutaneous cell tissue, permitting determination of the extent of the disease and its localization for purposes of biopsy and fasciotomy of the affected muscle.

P178 The ethics of randomising a patient to the placebo group in acute stroke clinical trials has been called into question in one study as these patients may be deprived of routinely applied therapies. No other study has previously analysed this hypothesis. Objective: To compare the prognosis at day 90 of patients included in clinical trials of acute stroke and randomised to the placebo group with patients not included in any clinical trial. Material and Methods: 50 patients consecutively included in the placebo group (CLASS, ECASS-II, Trafermin, GAIN), and 50 patients not included in any clinical trial randomly selected from those sharing similar characteristics (age, sex, stroke severity and stroke subtype using the TOAST criteria) and hospitalised during the same period. Results: No differences were found in neurological attention delay, Canadian scale at admission, final infarct volume and length of hospital stay. The placebo group had a lower proportion of progressing stroke than the control group (14% vs. 25%). Infectious and cardiovascular complications were more frequent in the placebo group (12% vs. 6% and 15% vs. 8%, respectively). However, the placebo group displayed a more favourable outcome at day 90 (Figure). Conclusions: Inclusion in a placebo group in acute stroke clinical trials results in a significant benefit. This advantage may be explained by a more active intervention over progressing stroke, resulting from a higher rate of detection and control of the related factors.