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ObjectiveTo conduct a meta-analysis to evaluate the effect of endovascular therapy (EVT) in mild acute ischemic stroke (AIS) due to proximal versus distal occlusions.MethodsWe searched PubMed, Embase, the Cochrane Library, and clinicaltrials.gov from January 2000 to September 2021 to identify studies comparing EVT versus best medical management (BMM) in AIS with National Institutes of Health Stroke Scale (NIHSS) scores ≤5 due to proximal internal carotid artery (ICA) or M1 versus distal M2 occlusions. We included studies that reported the number of patients with proximal or distal occlusions separately and reported the number of patients with freedom of disability (modified Rankin Scale (mRS) score 0-1) or functional independence (mRS score 0-2) at 90 days in proximal or M2 occlusions, respectively. OR with 95% CI was used.ResultsWe identified six studies with 653 proximal ICA and M1 occlusion patients and 666 distal M2 occlusion patients. Pooled results showed EVT versus BMM was associated with a higher rate of being disability-free in patients with proximal occlusions (OR 1.58, 95% CI 1.09 to 2.30), but was associated with a lower rate of being disability-free in patients with M2 occlusions (OR 0.70, 95% CI 0.49 to 0.99). Effect of EVT in proximal versus distal occlusions was substantially different (P for interaction=0.002). A similar pattern was seen for functional independence (P for interaction=0.05).ConclusionsFor patients with mild AIS, observational data suggest that EVT may be beneficial for proximal ICA or M1 but not for distal M2 occlusions. Randomized trials are needed to confirm these findings.Prospero registration numberCRD42021281034.

BackgroundIntracerebral hemorrhage (ICH) is the deadliest form of stroke. In observational studies, lower serum magnesium has been linked to more hematoma expansion (HE) and intracranial hemorrhage, implying that supplemental magnesium sulfate is a potential acute treatment for patients with ICH and could reduce HE. FAST-MAG (Field Administration of Stroke Therapy - Magnesium) was a clinical trial of magnesium sulfate started prehospital in patients with acute stroke within 2 hours of last known well enrolled. CT was not required prior to enrollment, and several hundred patients with acute ICH were enrolled. In this ancillary analysis, we assessed the effect of magnesium sulfate treatment upon HE in patients with acute ICH.MethodsWe retrospectively analyzed data that were prospectively collected in the FAST-MAG study. Patients received intravenous magnesium sulfate or matched placebo within 2 hours of onset. We compared HE among patients allocated to intravenous magnesium sulfate or placebo with a Mann-Whitney U. We used the same method to compare neurological deficit severity (National Institutes of Health Stroke Scale) and global disability (modified Rankin Scale) at 3 months.ResultsAmong 268 patients with ICH meeting study entry criteria, mean 65.4±13/4 years, 33% were female, and 211 (79%) had a history of hypertension. Initial deficit severities were median (interquartile range) of 4 (3-5) on the Los Angeles Motor Scale in the field and National Institutes of Health Stroke Scale score of 16 (9.5-25.5) early after hospital arrival. Follow-up brain imaging was performed a median of 17.1 (11.3-22.7) hours after first scan. The magnesium and placebo groups did not statistically differ in hematoma volume on arrival, 10.1 (5.6-28.7) versus 12.4 (5.6-28.7) mL (P=0.6), or HE, 2.0 (0.1-7.4) versus 1.5 (-0.2 to 8) mL (P=0.5). There was no difference in functional outcomes (modified Rankin Scale score of 3-6), 59% versus 50% (P=0.5).ConclusionsMagnesium sulfate did not reduce HE or improve functional outcomes at 90 days. A benefit for patients with initial hypomagnesemia was not addressed.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT00059332.

The objective of this study is to quantify the increase in brain-under-protection time that may be achieved with pre-hospital compared with the post-arrival start of neuroprotective therapy among patients undergoing endovascular thrombectomy. In order to do this, a comparative analysis was performed of two randomized trials of neuroprotective agents: (1) pre-hospital strategy: Field administration of stroke therapy-magnesium (FAST-MAG) Trial; (2) in-hospital strategy: Efficacy and safety of nerinetide for the treatment of acute ischemic stroke (ESCAPE-NA1) Trial. In the FAST-MAG trial, among 1,041 acute ischemic stroke patients, 44 were treated with endovascular reperfusion therapy (ERT), including 32 treated with both intravenous thrombolysis and ERT and 12 treated with ERT alone. In the ESCAPE-NA1 trial, among 1,105 acute ischemic stroke patients, 659 were treated with both intravenous thrombolysis and ERT, and 446 were treated with ERT alone. The start of the neuroprotective agent was sooner after onset with pre-hospital vs. in-hospital start: 45 m (IQR 38-56) vs. 122 m. The neuroprotective agent in FAST-MAG was started 8 min prior to ED arrival compared with 64 min after arrival in ESCAPE-NA1. Projecting modern endovascular workflows to FAST-MAG, the total time of "brain under protection" (neuroprotective agent start to reperfusion) was greater with pre-hospital than in-hospital start: 94 m (IQR 90-98) vs. 22 m. Initiating a neuroprotective agent in the pre-hospital setting enables a faster treatment start, yielding 72 min additional brain protection time for patients with acute ischemic stroke. These findings provide support for the increased performance of ambulance-based, pre-hospital treatment trials in the development of neuroprotective stroke therapies.

BackgroundThere is little information regarding the safety of intravenous tissue plasminogen activator (IV-tPA) in patients with stroke and COVID-19.MethodsThis multicenter study included consecutive stroke patients with and without COVID-19 treated with IV-tPA between February 18, 2019, to December 31, 2020, at 9 centers participating in the CASCADE initiative. Clinical outcomes included modified Rankin Scale (mRS) at hospital discharge, in-hospital mortality, the rate of hemorrhagic transformation. Using Bayesian multiple regression and after adjusting for variables with significant value in univariable analysis, we reported the posterior adjusted odds ratio (OR, with 95% Credible Intervals [CrI]) of the main outcomes.ResultsA total of 545 stroke patients, including 101 patients with COVID-19 were evaluated. Patients with COVID-19 had a more severe stroke at admission. In the study cohort, 85 (15.9%) patients had a hemorrhagic transformation, and 72 (13.1%) died in the hospital. After adjustment for confounding variables, discharge mRS score ≥2 (OR: 0.73, 95% CrI: 0.16, 3.05), in-hospital mortality (OR: 2.06, 95% CrI: 0.76, 5.53), and hemorrhagic transformation (OR: 1.514, 95% CrI: 0.66, 3.31) were similar in COVID-19 and non COVID-19 patients. High-sensitivity C reactive protein level was a predictor of hemorrhagic transformation in all cases (OR:1.01, 95%CI: 1.0026, 1.018), including those with COVID-19 (OR:1.024, 95%CI:1.002, 1.054).ConclusionIV-tPA treatment in patients with acute ischemic stroke and COVID-19 was not associated with an increased risk of disability, mortality, and hemorrhagic transformation compared to those without COVID-19. IV-tPA should continue to be considered as the standard of care in patients with hyper acute stroke and COVID-19.

Background and purposeWhether reperfusion into infarcted tissue exacerbates cerebral edema has treatment implications in patients presenting with extensive irreversible injury. We investigated the effects of endovascular thrombectomy and reperfusion on cerebral edema in patients presenting with radiological evidence of large hemispheric infarction at baseline.MethodsIn a systematic review and individual patient-level meta-analysis of 7 randomized controlled trials comparing thrombectomy versus medical therapy in anterior circulation ischemic stroke published between January 1, 2010, and May 31, 2017 (Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration), we analyzed the association between thrombectomy and reperfusion with maximal midline shift (MLS) on follow-up imaging as a measure of the space-occupying effect of cerebral edema in patients with large hemispheric infarction on pretreatment imaging, defined as diffusion-magnetic resonance imaging or computed tomography (CT)-perfusion ischemic core 80 to 300 mL or noncontrast CT-Alberta Stroke Program Early CT Score ≤5. Risk of bias was assessed using the Cochrane tool.ResultsAmong 1764 patients, 177 presented with large hemispheric infarction. Thrombectomy and reperfusion were associated with functional improvement (thrombectomy common odds ratio =2.30 [95% CI, 1.32–4.00]; reperfusion common odds ratio =4.73 [95% CI, 1.66–13.52]) but not MLS (thrombectomy β=−0.27 [95% CI, −1.52 to 0.98]; reperfusion β=−0.78 [95% CI, −3.07 to 1.50]) when adjusting for age, National Institutes of Health Stroke Score, glucose, and time-to-follow-up imaging. In an exploratory analysis of patients presenting with core volume >130 mL or CT-Alberta Stroke Program Early CT Score ≤3 (n=76), thrombectomy was associated with greater MLS after adjusting for age and National Institutes of Health Stroke Score (β=2.76 [95% CI, 0.33–5.20]) but not functional improvement (odds ratio, 1.71 [95% CI, 0.24–12.08]).ConclusionsIn patients presenting with large hemispheric infarction, thrombectomy and reperfusion were not associated with MLS, except in the subgroup with very large core volume (>130 mL) in whom thrombectomy was associated with increased MLS due to space-occupying ischemic edema. Mitigating cerebral edema-mediated secondary injury in patients with very large infarcts may further improve outcomes after reperfusion therapies.

Background and purposeThe Stroke Treatment Academic Industry Roundtable (STAIR) sponsored an imaging session and workshop during the Stroke Treatment Academic Industry Roundtable XI via webinar on October 1 to 2, 2020, to develop consensus recommendations, particularly regarding optimal imaging at primary stroke centers.MethodsThis forum brought together stroke neurologists, neuroradiologists, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke, industry representatives, and members of the US Food and Drug Administration to discuss imaging priorities in the light of developments in reperfusion therapies, particularly in an extended time window, and reinvigorated interest in brain cytoprotection trials.ResultsThe imaging session summarized and compared the imaging components of recent acute stroke trials and debated the optimal imaging strategy at primary stroke centers. The imaging workshop developed consensus recommendations for optimizing the acquisition, analysis, and interpretation of computed tomography and magnetic resonance acute stroke imaging, and also recommendations on imaging strategies for primary stroke centers.ConclusionsRecent positive acute stroke clinical trials have extended the treatment window for reperfusion therapies using imaging selection. Achieving rapid and high-quality stroke imaging is therefore critical at both primary and comprehensive stroke centers. Recommendations for enhancing stroke imaging research are provided.

Cerebrovascular events have emerged as a central feature of the clinical syndrome associated with Sars-CoV-2 infection. This increase in infection-related strokes is marked by atypical presentations including stroke in younger patients and a high rate of hemorrhagic transformation after ischemia. A variety of pathogenic mechanisms may underlie this connection. Efforts to identify synergism in the pathophysiology underlying stroke and Sars-CoV-2 infection can inform the understanding of both conditions in novel ways. In this review, the molecular cascades connected to Sars-CoV-2 infection are placed in the context of the cerebral vasculature and in relationship to pathways known to be associated with stroke. Cytokine-mediated promotion of systemic hypercoagulability is suggested while direct Sars-CoV-2 infection of cerebral endothelial cells may also contribute. Endotheliopathy resulting from direct Sars-CoV-2 infection of the cerebral vasculature can modulate ACE2/AT1R/MasR signaling pathways, trigger direct viral activation of the complement cascade, and activate feed-forward cytokine cascades that impact the blood-brain barrier. All of these pathways are already implicated as independent mechanisms driving stroke and cerebrovascular injury irrespective of Sars-CoV-2. Recognizing the overlap of molecular pathways triggered by Sars-CoV-2 infection with those implicated in the pathogenesis of stroke provides an opportunity to identify future therapeutics targeting both Sars-CoV-2 and stroke thereby reducing the impact of the global pandemic.

BackgroundIntracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke with a high risk of clinical stroke recurrence. Multiple mechanisms may underlie cerebral ischemia in this condition. The study's objective is to discern the mechanisms of recurrent ischemia in ICAD through imaging biomarkers of impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, and artery-to-artery embolism.MethodsThis prospective multicenter observational study enrolled patients with recent (≤21 days) ischemic stroke or transient ischemic attack (TIA) caused by ICAD with 50-99% stenosis treated medically. We obtained baseline quantitative MRA (QMRA), perfusion MRI (PWI), transcranial Doppler vasoreactivity (VMR), and emboli detection studies (EDS). The primary outcome was ischemic stroke in the territory of the stenotic artery within 1 year of follow-up; secondary outcomes were TIA at 1 year and new infarcts in the territory on MRI at 6-8 weeks.ResultsAmongst 102 of 105 participants with clinical follow-up (mean 253±131 days), the primary outcome occurred in 8.8% (12.7/100 patient-years), while 5.9% (8.5/100 patient-years) had a TIA. A new infarct in the territory of the symptomatic artery was noted in 24.7% at 6-8 weeks. A low flow state on QMRA was noted in 25.5%, poor distal perfusion on PWI in 43.5%, impaired vasoreactivity on VMR in 67.5%, and microemboli on EDS in 39.0%. No significant association was identified between these imaging biomarkers and primary or secondary outcomes.ConclusionsDespite intensive medical management in ICAD, there is a high risk of clinical cerebrovascular events at 1 year and an even higher risk of new imaging-evident infarcts in the subacute period after index stroke. Hemodynamic and plaque instability biomarkers did not identify a higher risk group. Further work is needed to identify mechanisms of ischemic stroke and infarct recurrence and their consequence on long-term physical and cognitive outcomes.Trial registrationClinicalTrials.gov: NCT02121028.

Background and purposeSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with an increased rate of cerebrovascular events including ischemic stroke and intracerebral hemorrhage. The mechanisms underlying cerebral endothelial susceptibility and response to SARS-CoV-2 are unknown yet critical to understanding the association of SARS-CoV-2 infection with cerebrovascular events.MethodsEndothelial cells were isolated from human brain and analyzed by RNA sequencing. Human umbilical vein and human brain microvascular cells were used in both monolayer culture and endothelialized within a 3-dimensional printed vascular model of the middle cerebral artery. Gene expression levels were measured by quantitative polymerase chain reaction and direct RNA hybridization. Recombinant SARS-CoV-2 S protein and S protein-containing liposomes were used to measure endothelial binding by immunocytochemistry.ResultsACE2 (angiotensin-converting enzyme-2) mRNA levels were low in human brain and monolayer endothelial cell culture. Within the 3-dimensional printed vascular model, ACE2 gene expression and protein levels were progressively increased by vessel size and flow rates. SARS-CoV-2 S protein-containing liposomes were detected in human umbilical vein endothelial cells and human brain microvascular endothelial cells in 3-dimensional middle cerebral artery models but not in monolayer culture consistent with flow dependency of ACE2 expression. Binding of SARS-CoV-2 S protein triggered 83 unique genes in human brain endothelial cells including upregulation of complement component C3.ConclusionsBrain endothelial cells are susceptible to direct SARS-CoV-2 infection through flow-dependent expression of ACE2. Viral S protein binding triggers a unique gene expression profile in brain endothelia that may explain the association of SARS-CoV-2 infection with cerebrovascular events.

RationaleIntracranial atherosclerotic disease (ICAD) is the most common cause of ischemic stroke with the highest rate of recurrence, despite aggressive medical management. Diverse mechanisms may be responsible for ICAD-related cerebral ischemia, with potential therapeutic implications. Here we present the rationale, design and methods of the Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease (MyRIAD) study. The aim of MyRIAD is to determine the mechanisms of stroke in ICAD through physiologic imaging biomarkers that evaluate impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, artery to artery embolism, and their interaction.Methods and designThis is a prospective observational study of patients with recently symptomatic (

Background and purposeThe novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), now named coronavirus disease 2019 (COVID-19), may change the risk of stroke through an enhanced systemic inflammatory response, hypercoagulable state, and endothelial damage in the cerebrovascular system. Moreover, due to the current pandemic, some countries have prioritized health resources towards COVID-19 management, making it more challenging to appropriately care for other potentially disabling and fatal diseases such as stroke. The aim of this study is to identify and describe changes in stroke epidemiological trends before, during, and after the COVID-19 pandemic.MethodsThis is an international, multicenter, hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. We will describe patterns in stroke management, stroke hospitalization rate, and stroke severity, subtype (ischemic/hemorrhagic), and outcomes (including in-hospital mortality) in 2020 during COVID-19 pandemic, comparing them with the corresponding data from 2018 and 2019, and subsequently 2021. We will also use an interrupted time series (ITS) analysis to assess the change in stroke hospitalization rates before, during, and after COVID-19, in each participating center.ConclusionThe proposed study will potentially enable us to better understand the changes in stroke care protocols, differential hospitalization rate, and severity of stroke, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that management of cerebrovascular comorbidity is appropriately prioritized during the global crisis. It will also guide public health guidelines for at-risk populations to reduce risks of complications from such comorbidities.

ImportanceRecent epidemiologic and therapeutic advances have transformed understanding of the role of and therapeutic approach to patent foramen ovale (PFO) in ischemic stroke. Patent foramen ovale is likely responsible for approximately 5% of all ischemic strokes and 10% of those occurring in young and middle-aged adults.ObservationsRandomized clinical trials have demonstrated that, to prevent recurrent ischemic stroke in patients with PFO and an otherwise-cryptogenic index ischemic stroke, PFO closure is superior to antiplatelet medical therapy alone; these trials have provided some evidence that, among medical therapy options, anticoagulants may be more effective than antiplatelet agents.Conclusions and relevanceThese new data indicate a need to update classification schemes of causative mechanisms in stroke, developed in an era in which an association between PFO and stroke was viewed as uncertain. We propose a revised general nomenclature and classification framework for PFO-associated stroke and detailed revisions for the 3 major stroke subtyping algorithms in wide use.

Background and Purpose- We determined the effect of sex on outcome after endovascular stroke thrombectomy in acute ischemic stroke, including lifelong disability outcomes. Methods- We analyzed patients treated with the Solitaire stent retriever in the combined SWIFT (Solitaire FR With the Intention for Thrombectomy), STAR (Solitaire FR Thrombectomy for Acute Revascularization), and SWIFT PRIME (Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment) cohorts. Ordinal and logistic regression were used to examine known factors influencing outcome after endovascular stroke thrombectomy and study the effect of sex on the association between these factors and outcomes, including age and time to reperfusion. Years of optimal life after thrombectomy were defined as disability-adjusted life years and calculated by projecting disability through adjusted poststroke life expectancy by sex. Results- Among 389 patients treated with endovascular stroke thrombectomy, 55% were females, and median National Institutes of Health Stroke Scale was 17 (interquartile range, 8-28). There were no differences between females versus males in presenting deficit severity (National Institutes of Health Stroke Scale score, 17 versus 17, P=0.21), occlusion location (69% versus 64% M1, P=0.62), presenting infarct extent (Alberta Stroke Program Early CT Score 8 versus 8, P=0.24), rate of substantial reperfusion (Thrombolysis in Cerebral Infarction 2b/3, 87% versus 83%, P=0.37), onset to reperfusion time (294 versus 302 minutes, P=0.46). Despite older ages (69 versus 64, P

Cerebrovascular disease (CVD) remains a leading cause of death and the leading cause of adult disability in most developed countries. This work summarizes state-of-the-art, and possible future, diagnostic and evaluation approaches in multiple stages of CVD, including (i) visualization of sub-clinical disease processes, (ii) acute stroke theranostics, and (iii) characterization of post-stroke recovery mechanisms. Underlying pathophysiology as it relates to large vessel steno-occlusive disease and the impact of this macrovascular disease on tissue-level viability, hemodynamics (cerebral blood flow, cerebral blood volume, and mean transit time), and metabolism (cerebral metabolic rate of oxygen consumption and pH) are also discussed in the context of emerging neuroimaging protocols with sensitivity to these factors. The overall purpose is to highlight advancements in stroke care and diagnostics and to provide a general overview of emerging research topics that have potential for reducing morbidity in multiple areas of CVD.

BackgroundWe examined neurologic consultations for altered mental status in perioperative liver transplant patients to determine the overall incidence, to assess the presumed etiology and the data reviewed to determine that etiology, and to assess outcomes.MethodsRetrospective chart review conducted for all 728 adult patients receiving orthotopic liver transplantation (OLT) between January 01, 2010, to June 30, 2014, with identification of 218 receiving neurology consults between 30 days pre-OLT and 90 days post-OLT, with review of all records necessary to determine initial findings and follow-up examination.ResultsSeventy-three consults for 69 patients were identified, with 27 felt to be altered since a procedure, 20 with sudden-onset altered mentation, and 26 with gradual or waxing-waning course. A single underlying etiology was identified in only 19 cases, with multiple factors involved in all others, with metabolic, toxic, infectious, and structural etiologies most often implicated. There was no statistically significant difference in outcome for those with altered mental status consults versus the total OLT population, though the sudden-onset presentation group did show significantly increased mortality rates.ConclusionsThis systematic study illustrates the variety of potential causes of altered mentation within the perioperative setting of liver transplantation. Workup including neuroimaging (preferably magnetic resonance imaging), infectious cultures, and expanded metabolic laboratory tests should be undertaken.

BACKGROUND AND PURPOSE:Individuals with migraine are at higher risk for stroke, but the mechanism has not been established. On the basis of the association between migraine and intracardiac right-to-left shunt, it has been proposed that stroke in migraineurs could be caused by a paradoxical embolus passing through a patent foramen ovale (PFO) or pulmonary arteriovenous malformation. The aim of this study was to determine the prevalence of PFO with right-to-left shunt in patients who presented with cryptogenic stroke and had a history of migraine. METHODS:Patients between 18 and 60 years old who presented with an ischemic stroke were characterized based on ASCOD phenotyping (atherosclerosis; small-vessel disease; cardiac pathology; other causes; dissection). A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study with either transcranial Doppler, transthoracic, or transesophageal echocardiography. RESULTS:Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history. The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%). Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%). In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%. Only 5 patients (4%) had a history compatible with migrainous infarction. CONCLUSIONS:In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of PFO with right-to-left shunt. The timing of the stroke in migraineurs is usually not related to a migraine attack. These observations are consistent with the hypothesis that the mechanism of stroke in migraineurs is most likely because of a paradoxical embolus. Future cryptogenic stroke classification schemes should consider including PFO as a separate etiologic category.

Background and purposePrehospital scales have been developed to identify patients with acute cerebral ischemia (ACI) because of large vessel occlusion (LVO) for direct routing to Comprehensive Stroke Centers (CSCs), but few have been validated in the prehospital setting, and their impact on routing of patients with intracranial hemorrhage has not been delineated. The purpose of this study was to validate the Los Angeles Motor Scale (LAMS) for LVO and CSC-appropriate (LVO ACI and intracranial hemorrhage patients) recognition and compare the LAMS to other scales.MethodsThe performance of the LAMS, administered prehospital by paramedics to consecutive ambulance trial patients, was assessed in identifying (1) LVOs among all patients with ACI and (2) CSC-appropriate patients among all suspected strokes. Additionally, the LAMS administered postarrival was compared concurrently with 6 other scales proposed for paramedic use and the full National Institutes of Health Stroke Scale.ResultsAmong 94 patients, age was 70 (±13) and 49% female. Final diagnoses were ACI in 76% (because of LVO in 48% and non-LVO in 28%), intracranial hemorrhage in 19%, and neurovascular mimic in 5%. The LAMS administered by paramedics in the field performed moderately well in identifying LVO among patients with ACI (C statistic, 0.79; accuracy, 0.72) and CSC-appropriate among all suspected stroke transports (C statistic, 0.80; accuracy, 0.72). When concurrently performed in the emergency department postarrival, the LAMS showed comparable or better accuracy versus the 7 comparator scales, for LVO among ACI (accuracies LAMS, 0.70; other scales, 0.62-0.68) and CSC-appropriate (accuracies LAMS, 0.73; other scales, 0.56-0.73).ConclusionsThe LAMS performed in the field by paramedics identifies LVO and CSC-appropriate patients with good accuracy. The LAMS performs comparably or better than more extended prehospital scales and the full National Institutes of Health Stroke Scale.

The purpose of this study was to develop and evaluate a scoring system for assessing reperfusion status based on arterial spin labeled (ASL) perfusion MRI in acute ischemic stroke (AIS) patients receiving thrombolysis and/or endovascular treatment. Pseudo-continuous ASL with background suppressed 3D GRASE was acquired along with DWI in 90 patients within 24 h post-treatment. An automatic reperfusion scoring system (auto-RPS) was devised based on the Alberta Stroke Program Early CT Score (ASPECTS) template, and compared with manual RPS and DWI-ASPECTS. TICI (thrombolysis in cerebral infarction) scores were graded in 48 patients who received endovascular treatment. Favorable outcomes were defined by a modified Rankin Scale score of 0-2 at three months. Auto-RPS was positively correlated with DWI-ASPECTS (ρ = 0.6, P

Background and purposeThe relative contribution of each Alberta Stroke Program Early CT Score (ASPECTS) region to poststroke disability likely varies across regions. Determining the relative weights of each ASPECTS region may improve patient selection for endovascular stroke therapy (EST).MethodsIn the combined Solitaire Flow Restoration with the Intention for Thrombectomy (SWIFT), Solitaire Flow Restoration Thrombectomy for Acute Revascularization (STAR), and Solitaire Flow Restoration with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) databases, we identified patients treated with the Solitaire stent retriever. Using 24-h CT scan, a multivariate ordinal regression was used to determine the relative contribution of each ASPECTS region to clinical outcome separately in each hemisphere. The coefficients from the regression were used to create a weighted ASPECTS (wASPECTS), which was compared with the original ASPECTS to predict 90-day modified Rankin Scale disability outcomes in an independent validation cohort.ResultsAmong 342 patients treated with EST, the average age was 67 years, 57% were female, and the median National Institutes of Health Stroke Scale (NIHSS) score was 17 (IQR 13-20). The median ASPECTS at presentation was 8 (IQR 7-10). The most commonly involved ASPECTS regions on 24-h CT were the lentiform nuclei (70%), insula (55%), and caudate (52%). In multivariate analysis, preservation of M6 (β = 9.7) and M4 (β = 4.4) regions in the right hemisphere was most strongly predictive of good outcome. For the left hemisphere, M6 (β = 5.5), M5 (β = 4.1), and M3 (β = 3.1) generated the greatest parameter estimates, though they did not reach statistical significance. A wASPECTS incorporating all 20 parameter estimates resulted in improved discrimination against the original ASPECTS in the independent cohort (C-statistic 0.78 vs. 0.67, right hemisphere).ConclusionsFor both right and left hemisphere, preservation of the high cortical regions was more strongly associated with improved outcomes compared to the deep regions. Our findings support taking into consideration the location and relative weightings of the involved ASPECTS regions when evaluating a patient for EST.

Background and aims:Assessment of ischemic lesions on computed tomography or MRI diffusion-weighted imaging (DWI) using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used to guide acute stroke treatment. However, it has never been defined how many voxels need to be affected to label a DWI-ASPECTS region ischemic. We aimed to assess the effect of various lesion load thresholds on DWI-ASPECTS and compare this automated analysis with visual rating. Materials and methods:We analyzed overlap of individual DWI lesions of 315 patients from the previously published predictive value of fluid-attenuated inversion recovery study with a probabilistic ASPECTS template derived from 221 CT images. We applied multiple lesion load thresholds per DWI-ASPECTS region (>0, >1, >10, and >20% in each DWI-ASPECTS region) to compute DWI-ASPECTS for each patient and compared the results to visual reading by an experienced stroke neurologist. Results:By visual rating, median ASPECTS was 9, 84 patients had a DWI-ASPECTS score ≤7. Mean DWI lesion volume was 22.1 (±35) ml. In contrast, by use of >0, >1-, >10-, and >20%-thresholds, median DWI-ASPECTS was 1, 5, 8, and 10; 97.1% (306), 72.7% (229), 41% (129), and 25.7% (81) had DWI-ASPECTS ≤7, respectively. Overall agreement between automated assessment and visual rating was low for every threshold used (>0%: κw = 0.020 1%: κw = 0.151; 10%: κw = 0.386; 20% κw = 0.381). Agreement for dichotomized DWI-ASPECTS ranged from fair to substantial (≤7: >10% κ = 0.48; >20% κ = 0.45; ≤5: >10% κ = 0.528; and >20% κ = 0.695). Conclusion:Overall agreement between automated and the standard used visual scoring is low regardless of the lesion load threshold used. However, dichotomized scoring achieved more comparable results. Varying lesion load thresholds had a critical impact on patient selection by ASPECTS. Of note, the relatively low lesion volume and lack of patients with large artery occlusion in our cohort may limit generalizability of these findings.

BackgroundEndovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation.MethodsSTRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass.ResultsA total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients (P

Recirculation, from arterial inflow routes through venous outflow pathways, was conceptualized in stroke research 50 years ago. As new technologies were developed, blocked arteries could be reopened, capillaries could be reperfused, and the use of recanalization and reperfusion grew to dominate therapeutic strategies. These approaches overwhelmingly focused on restoration of arterial and capillary inflow, but not on veins even though venous disorders may initiate or exacerbate brain injury. In this commentary, we advance the term "recirculation" after "recanalization" and "reperfusion" as a primary concept of stroke pathophysiology that targets the restoration of both the arterial and venous cerebral circulations.

Acute ischemic stroke affects over 800,000 US adults annually, with hundreds of thousands more experiencing a transient ischemic attack. Emergent evaluation, prompt acute treatment, and identification of stroke or TIA (transient ischemic attack) etiology for specific secondary prevention are critical for decreasing further morbidity and mortality of cerebrovascular disease. The Biomarkers of Acute Stroke Etiology (BASE) study is a multicenter observational study to identify serum markers defining the etiology of acute ischemic stroke. Observational trial of patients presenting to the hospital within 24 h of stroke onset. Blood samples are collected at arrival, 24, and 48 h later, and RNA gene expression is utilized to identify stroke etiology marker candidates. The BASE study began January 2014. At the time of writing, there are 22 recruiting sites. Enrollment is ongoing, expected to hit 1000 patients by March 2017. The BASE study could potentially aid in focusing the initial diagnostic evaluation to determine stroke etiology, with more rapidly initiated targeted evaluations and secondary prevention strategies.Clinical Trial Registration Clinicaltrials.gov NCT02014896 https://clinicaltrials.gov/ct2/show/NCT02014896?term=biomarkers+of+acute+stroke+etiology&rank=1.

Background and purposePatients with acute ischemic stroke are at increased risk of developing parenchymal hemorrhage (PH), particularly in the setting of reperfusion therapies. We have developed a predictive model to examine the risk of PH using combined magnetic resonance perfusion and diffusion parameters, including cerebral blood volume (CBV), apparent diffusion coefficient, and microvascular permeability (K2).MethodsVoxel-based values of CBV, K2, and apparent diffusion coefficient from the ischemic core were obtained using pretreatment magnetic resonance imaging data from patients enrolled in the MR RESCUE clinical trial (Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy). The associations between PH and extreme values of imaging parameters were assessed in univariate and multivariate analyses. Receiver-operating characteristic curve analysis was performed to determine the optimal parameter(s) and threshold for predicting PH.ResultsIn 83 patients included in this analysis, 20 developed PH. Univariate analysis showed significantly lower 10th percentile CBV and 10th percentile apparent diffusion coefficient values and significantly higher 90th percentile K2 values within the infarction core of patients with PH. Using classification tree analysis, the 10th percentile CBV at threshold of 0.47 and 90th percentile K2 at threshold of 0.28 resulted in overall predictive accuracy of 88.7%, sensitivity of 90.0%, and specificity of 87.3%, which was superior to any individual or combination of other classifiers.ConclusionsOur results suggest that combined 10th percentile CBV and 90th percentile K2 is an independent predictor of PH in patients with acute ischemic stroke with diagnostic accuracy superior to individual classifiers alone. This approach may allow risk stratification for patients undergoing reperfusion therapies.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00389467.

Background and purposeMulti-delay arterial spin-labeling (ASL) perfusion imaging has been used as a promising modality to evaluate cerebral perfusion. Our aim was to assess the association of leptomeningeal collateral perfusion scores based on ASL parameters with outcome of endovascular treatment in patients with acute ischemic stroke (AIS) in the middle cerebral artery (MCA) territory.Materials and methodsASL data at 4 post-labeling delay (PLD) times (PLD = 1.5, 2, 2.5, 3 s) were acquired during routine clinical magnetic resonance examination on AIS patients prior to endovascular treatment. A 3-point scale of leptomeningeal collateral perfusion grade on 10 anatomic regions was determined based on arterial transit times (ATT), cerebral blood flow (CBF), and arterial cerebral blood volume (CBV), estimated by the multi-delay ASL protocol. Based on a 90-day modified Rankin Scale (mRS), the patients were dichotomized to moderate/good (mRS 0-3) and poor outcome (mRS 4-6) and the regional collateral flow scores were compared.ResultsFifty-five AIS patients with unilateral MCA stroke (mean 73.95±14.82 years) including 23 males were enrolled. Compared with poor outcome patients, patients with moderate to good outcomes had a significantly higher leptomeningeal collateral perfusion scores on CBV (3.01±2.11 vs. 1.82±1.51, p=0.024) but no differences on scores on CBF (2.31±1.61 vs. 1.66±1.32, p=0.231) and ATT (2.67±2.33 vs. 3.42±3.37, p=0.593).ConclusionsHigher leptomeningeal collateral perfusion scores on CBV images by ASL may be a specific marker of clinical outcome after endovascular treatment in patients with acute MCA ischemic stroke. Further study with larger sample size is warranted.

BackgroundAdvances in diagnostic imaging of stroke include multimodal techniques such as noninvasive angiography and perfusion imaging. We aimed to characterize trends in neuroimaging utilization among acute stroke patients. Utilization of multimodal imaging for acute stroke in the community has remained largely uncharacterized despite its increased adoption at academic medical centers.MethodsWe quantified neuroimaging utilization in the emergency department (ED) for 1,700 hyperacute stroke patients presenting

BackgroundA common dilemma in acute ischemic stroke management is whether to pursue recanalization therapy in patients with large vessel occlusions but minimal neurologic deficits. We describe and report preliminary experience with a provocative maneuver, i.e. 90-degree elevation of the head of bed for 30 min, which stresses collaterals and facilitates decision-making.MethodsA prospective cohort study of

IntroductionThe specific protein composition of stroke-causing emboli is unknown. Because ischemic stroke has a varied etiology, it is possible that the composition of the thrombus from which an embolus originated will have distinctive molecular characteristics reflective of the underlying pathophysiology. We used mass spectrometry to evaluate the protein composition of retrieved emboli from patients with differing stroke etiologies and correlated the protein levels to serum predictors of atherosclerosis.MethodsEmboli from 20 consecutive acute stroke patients were retrieved by thrombectomy during routine stroke care. Thrombus proteins were extracted, digested, and multidimensional fractionation of peptides was performed. Fractionated peptides underwent nano-liquid chromatography with tandem mass spectrometry. Spectra were searched using Mascot software in which results with p

Background and purposeIn acute arterial occlusion, fluid-attenuated inversion recovery vascular hyperintensity (FVH) has been linked to slow flow in leptomeningeal collaterals and cerebral hypoperfusion, but the impact on clinical outcome is still controversial. In this study, we aimed to investigate the association between FVH topography or FVH-Alberta Stroke Program Early CT Score (ASPECTS) pattern and outcome in acute M1-middle cerebral artery occlusion patients with endovascular treatment.MethodsWe included acute M1-middle cerebral artery occlusion patients treated with endovascular therapy (ET). All patients had diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery before ET. Distal FVH-ASPECTS was evaluated according to distal middle cerebral artery-ASPECT area (M1-M6) and acute DWI lesion was also reviewed. The presence of FVH inside and outside DWI-positive lesions was separately analyzed. Clinical outcome after ET was analyzed with respect to different distal FVH-ASPECTS topography.ResultsAmong 101 patients who met inclusion criteria for the study, mean age was 66.2±17.8 years and median National Institutes of Health Stroke Scale was 17.0 (interquartile range, 12.0-21.0). FVH-ASPECTS measured outside of the DWI lesion was significantly higher in patients with good outcome (modified Rankin Scale [mRS] score of 0-2; 8.0 versus 4.0, P

BackgroundThe influence of cerebral microbleeds (CMBs) on post-thrombolytic hemorrhagic transformation (HT) in patients with acute ischemic stroke remains controversial.ObjectiveTo investigate the association of CMBs with HT and clinical outcomes among patients with large-vessel occlusion strokes treated with mechanical thrombectomy.MethodsWe analyzed patients with acute stroke treated with Merci Retriever, Penumbra system or stent-retriever devices. CMBs were identified on pretreatment T2-weighted, gradient-recall echo MRI. We analyzed the association of the presence, burden, and distribution of CMBs with HT, procedural complications, in-hospital mortality, and clinical outcome.ResultsCMBs were detected in 37 (18.0%) of 206 patients. Seventy-three foci of microbleeds were identified. Fourteen patients (6.8%) had ≥2 CMBs, only 1 patient had ≥5 CMBs. Strictly lobar CMBs were found in 12 patients, strictly deep CMBs in 12 patients, strictly infratentorial CMBs in 2 patients, and mixed CMBs in 11 patients. There were no significant differences between patients with CMBs and those without CMBs in the rates of overall HT (37.8% vs 45.6%), parenchymal hematoma (16.2% vs 19.5%), procedure-related vessel perforation (5.4% vs 7.1%), in-hospital mortality (16.2% vs 18.3%), and modified Rankin Scale score 0-3 at discharge. CMBs were not independently associated with HT or in-hospital mortality in patients treated with either thrombectomy or intravenous thrombolysis followed by thrombectomy.ConclusionsPatients with CMBs are not at increased risk for HT and mortality following mechanical thrombectomy for acute stroke. Excluding such patients from mechanical thrombectomy is unwarranted. The risk of HT in patients with ≥5 CMBs requires further study.

BackgroundSelection bias may have affected enrollment in first generation endovascular stroke trials. We investigate, evaluate, and quantify such bias for these trials at our institution.MethodsDemographic, clinical, imaging, and angiographic data were prospectively collected on a consecutive cohort of patients with acute ischemic stroke who were enrolled in formal trials of endovascular stroke therapy (EST) or received EST in clinical practice outside of a randomized trial for acute cerebral ischemia at a single tertiary referral center from September 2004 to December 2012.ResultsAmong patients considered appropriate for EST in practice, 47% were eligible for trials, with rates for individual trials ranging from 17% to 70%. Compared with trial ineligible patients treated with EST, trial eligible patients were younger (67 vs. 74 years; p

ObjectiveTo assess whether the association between reperfusion and improved clinical outcomes after stroke differs depending on the site of the arterial occlusive lesion (AOL).MethodsWe pooled data from Solitaire With the Intention for Thrombectomy (SWIFT), Solitaire FR Thrombectomy for Acute Revascularisation (STAR), Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2), and Interventional Management of Stroke Trial (IMS III) to compare the strength of the associations between reperfusion and clinical outcomes in patients with internal carotid artery (ICA), proximal middle cerebral artery (MCA) (M1), and distal MCA (M2/3/4) occlusions.ResultsAmong 710 included patients, the site of the AOL was the ICA in 161, the proximal MCA in 389, and the distal MCA in 160 patients (M2 = 131, M3 = 23, and M4 = 6). Reperfusion was associated with an increase in the rate of good functional outcome (modified Rankin Scale [mRS] score 0-2) in patients with ICA (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.7-7.2) and proximal MCA occlusions (OR 6.2, 95% CI 3.8-10.2), but not in patients with distal MCA occlusions (OR 1.4, 95% CI 0.8-2.6). Among patients with M2 occlusions, a subset of the distal MCA cohort, reperfusion was associated with excellent functional outcome (mRS 0-1; OR 2.2, 95% CI 1.0-4.7).ConclusionsThe association between endovascular reperfusion and better clinical outcomes is more profound in patients with ICA and proximal MCA occlusions compared to patients with distal MCA occlusions. Because there are limited data from randomized controlled trials on the effect of endovascular therapy in patients with distal MCA occlusions, these results underscore the need for inclusion of this subgroup in future endovascular therapy trials.

ImportanceAtherosclerotic vertebrobasilar (VB) occlusive disease is a significant etiology of posterior circulation stroke, with regional hypoperfusion as an important potential contributor to stroke risk.ObjectiveTo test the hypothesis that, among patients with symptomatic VB stenosis or occlusion, those with distal blood flow compromise as measured by large-vessel quantitative magnetic resonance angiography (QMRA) are at higher risk of subsequent posterior circulation stroke.Design, setting, and participantsA prospective, blinded, longitudinal cohort study was conducted at 5 academic hospital-based centers in the United States and Canada; 82 patients from inpatient and outpatient settings were enrolled. Participants with recent VB transient ischemic attack or stroke and 50% or more atherosclerotic stenosis or occlusion in vertebral and/or basilar arteries underwent large-vessel flow measurement in the VB territory using QMRA. Physicians performing follow-up assessments were blinded to QMRA flow status. Follow-up included monthly telephone calls for 12 months and biannual clinical visits (for a minimum of 12 months, and up to 24 months or the final visit). Enrollment took place from July 1, 2008, to July 31, 2013, with study completion on June 30, 2014; data analysis was performed from October 1, 2014, to April 10, 2015.ExposureStandard medical management of stroke risk factors.Main outcomes and measuresThe primary outcome was VB-territory stroke.ResultsOf the 82 enrolled patients, 72 remained eligible after central review of their angiograms. Sixty-nine of 72 patients completed the minimum 12-month follow-up; median follow-up was 23 (interquartile range, 14-25) months. Distal flow status was low in 18 of the 72 participants (25%) included in the analysis and was significantly associated with risk for a subsequent VB stroke (P = .04), with 12- and 24-month event-free survival rates of 78% and 70%, respectively, in the low-flow group vs 96% and 87%, respectively, in the normal-flow group. The hazard ratio, adjusted for age and stroke risk factors, in the low distal flow status group was 11.55 (95% CI, 1.88-71.00; P = .008). Medical risk factor management at 6-month intervals was similar between patients with low and normal distal flow. Distal flow status remained significantly associated with risk even when controlling for the degree of stenosis and location.Conclusions and relevanceDistal flow status determined using a noninvasive and practical imaging tool is robustly associated with risk for subsequent stroke in patients with symptomatic atherosclerotic VB occlusive disease. Identification of high-risk patients has important implications for future investigation of more aggressive interventional or medical therapies.

Imaging of stroke and neurovascular disorders has profoundly enhanced clinical practice and related research during the last 40 years since the introduction of computed tomography (CT) and magnetic resonance imaging (MRI) enabled mapping of the brain. We highlight recent advances in neurovascular imaging. We describe how the convergence of readily available data and new clinical trial paradigms will recast our methods for studying the neurovascular patient. The application of a precision medicine approach to the collaterome, a comprehensive synthesis of neurovascular pathophysiology, will entail novel methods for clinical trial randomization, collection of routine and clinical trial imaging results, data archiving, and analysis.

Background and purposeCollateral flow can determine ischemic core and tissue at risk. Using the Interventional Management of Stroke (IMS) III trial data, we explored the relationship between computed tomography angiogram (CTA) collateral status and CT perfusion (CTP) parameters.MethodsBaseline CTA collaterals were trichotomized as good, intermediate, and poor, and CTP studies were analyzed to quantify ischemic core, tissue at risk, and mismatch ratios. Kruskal-Wallis and Spearman tests were used to measure the strength of association and correlation between CTA collaterals and CTP parameters.ResultsA total of 95 patients had diagnostic CTP studies in the IMS III trial. Of these, 53 patients had M1/M2 middle cerebral artery±intracranial internal carotid artery occlusion, where baseline CTA collateral grading was performed. CTA collaterals were associated with smaller CTP measured ischemic core volume (P=0.0078) and higher mismatch (P=0.0004). There was moderate negative correlation between collaterals and core (rs=-0.45; 95% confidence interval, -0.64 to -0.20) and moderate positive correlation between collaterals and mismatch (rs=0.53; 95% confidence interval, 0.29-0.71).ConclusionBetter collaterals were associated with smaller ischemic core and higher mismatch in the IMS III trial. Collateral assessment and perfusion imaging identify the same biological construct about ischemic tissue sustenance.

Background and purposeThree-dimensional pseudocontinuous arterial spin labeling with multiple postlabeling delays has been used to assess cerebral blood flow (CBF). We used this modality to estimate antegrade and collateral flow in patients with unilateral middle cerebral artery stenosis.MethodsConsecutive patients with unilateral middle cerebral artery 50% to 99% stenosis at 2 centers underwent pseudocontinuous arterial spin labeling with a postlabeling delays of 1.5 and 2.5 s. Mean CBF of bilateral middle cerebral artery territory at the postlabeling delays 1.5 and 2.5 s was measured. Early-arriving flow proportion was defined as (CBF 1.5 s at lesion side/CBF 2.5 s at normal side)×100%. Late-arriving retrograde flow proportion was defined as ([CBF 2.5 s-CBF 1.5 s] at lesion side-[CBF 2.5 s-CBF 1.5 s] at normal side)/CBF 2.5 s at normal side×100%. Antegrade and collateral scales were evaluated in patients with conventional angiography. Spearman correlation coefficients were calculated between early-arriving flow and late-arriving retrograde flow proportions on arterial spin labeling and antegrade and collateral scales on conventional angiography, respectively.ResultsForty-one patients (46.0±12.0 years) were enrolled. The mean early-arriving flow proportion was 78.3±14.9%. The mean late-arriving retrograde flow proportion was 16.1±10.2%. In 21 patients with conventional angiography, Spearman correlation coefficient was 0.53 (95% confidence interval, 0.11-0.79) between antegrade grade and early-arriving flow proportion (P=0.01) and 0.81 (95% confidence interval, 0.56-0.92) between collateral grade and late-arriving retrograde flow proportion (P

Background and purposeThe enrollment yield and reasons for screen failure in prehospital stroke trials have not been well delineated.MethodsThe Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial identified patients for enrollment using a 2 stage screening process-paramedics in person followed by physician-investigators by cell phone. Outcomes of consecutive screening calls from paramedics to enrolling physician-investigators were prospectively recorded.ResultsFrom 2005 to 2012, 4458 phone calls were made by paramedics to physician-investigators, an average of 1 call per vehicle every 135.7 days. A total of 1700 (38.1%) calls resulted in enrollments. The rate of enrollment of stroke mimics was 3.9%. Among the 2758 patients not enrolled, 3140 reasons for screen failure were documented. The most common reasons for nonenrollment were >2 hours from last known well (17.2%), having a prestroke condition causing disability (16.1%), and absence of a consent provider (9.5%). Novel barriers for phone informed consent specific to the prehospital setting were infrequent, but included: cell phone connection difficulties (3.2%), patient being hard of hearing (1.4%), insufficient time to complete consent (1.3%), or severely dysarthric (1.3%).ConclusionsIn this large, multicenter prehospital trial, nearly 40% of every calls from the field to physician-investigators resulted in trial enrollments. The most common reasons for nonenrollment were out of window last known well time, prestroke confounding medical condition, and absence of a consent provider.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

BackgroundEndovascular reperfusion techniques are a promising intervention for acute ischemic stroke (AIS). Prior studies have identified markers of initial injury (arrival NIH stroke scale (NIHSS) or infarct volume) as predictive of outcome after these procedures. We sought to define the role of collateral flow at the time of presentation in determining the extent of initial ischemic injury and its influence on final outcome.MethodsDemographic, clinical, laboratory, and radiographic data were prospectively collected on a consecutive cohort of patients who received endovascular therapy for acute cerebral ischemia at a single tertiary referral center from September 2004 to August 2010.ResultsHigher collateral grade as assessed by the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading scheme on angiography at the time of presentation was associated with improved reperfusion rates after endovascular intervention, decreased post-procedural hemorrhage, smaller infarcts on presentation and discharge, as well as improved neurological function on arrival to the hospital, discharge, and 90 days later. Patients matched by vessel occlusion, age, and time of onset demonstrated smaller strokes on presentation and better functional and radiographic outcome if found to have superior collateral flow. In multivariate analysis, lower collateral grade independently predicted higher NIHSS on arrival.ConclusionsImproved collateral flow in patients with AIS undergoing endovascular therapy was associated with improved radiographic and clinical outcomes. Independent of age, vessel occlusion and time, in patients with comparable ischemic burdens, changes in collateral grade alone led to significant differences in initial stroke severity as well as ultimate clinical outcome.

ImportanceTreatments for symptomatic intracerebral hemorrhage (sICH) are based on expert opinion, with limited data available on efficacy.ObjectiveTo better understand the natural history of thrombolysis-related sICH, with a focus on the efficacy of various treatments used.Design, setting, and participantsMulticenter retrospective study between January 1, 2009, and April 30, 2014, at 10 primary and comprehensive stroke centers across the United States. Participants were all patients with sICH, using the definition by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), which included a parenchymal hematoma type 2 and at least a 4-point increase in the National Institutes of Health Stroke Scale score.Main outcomes and measuresThe primary outcome was in-hospital mortality, and the secondary outcome was hematoma expansion, defined as a 33% increase in the hematoma volume on follow-up imaging.ResultsOf 3894 patients treated with intravenous recombinant tissue plasminogen activator (rtPA) within 4½ hours after symptom onset of ischemic stroke, 128 (3.3%) had sICH. The median time from initiation of rtPA therapy to sICH diagnosis was 470 minutes (range, 30-2572 minutes), and the median time from diagnosis to treatment of sICH was 112 minutes (range, 12-628 minutes). The in-hospital mortality rate was 52.3% (67 of 128), and 26.8% (22 of 82) had hematoma expansion. In the multivariable models, code status change to comfort measures after sICH diagnosis was the sole factor associated with increased in-hospital mortality (odds ratio, 3.6; 95% CI, 1.2-10.6). Severe hypofibrinogenemia (fibrinogen level,

BackgroundExternal counterpulsation (ECP) increases perfusion to a variety of organs and may be helpful for acute stroke.MethodsWe conducted a single-blinded, prospective, randomized controlled feasibility and safety trial of ECP for acute middle cerebral artery (MCA) ischemic stroke. Twenty-three patients presenting within 48 hours of symptom onset were randomized into one of two groups. One group was treated with ECP for 1 hour at a pressure of up to 300 mmHg ("full pressure"). During the procedure, we also determined the highest possible pressure that would augment MCA mean flow velocity (MFV) by 15%. The other group was treated with ECP at 75 mmHg ("sham pressure"). Transcranial Doppler MCA flow velocities and National Institutes of Health Stroke Scale (NIHSS) scores of both groups were checked before, during, and after ECP. Outcomes were assessed at 30 days after randomization.ResultsAlthough the procedures were feasible to implement, there was a frequent inability to augment MFV by 15% despite maximal pressures in full-pressure patients. In sham-pressure patients, however, MFV frequently increased as shown by increases in peak systolic velocity and end diastolic velocity. In both groups, starting ECP was often associated with contemporaneous improvements in NIHSS stroke scores. There were no between-group differences in NIHSS, modified Rankin Scale Scores, and Barthel Indices, and no device or treatment-related serious adverse events, deaths, intracerebral hemorrhages, or episodes of acute neuro-worsening.ConclusionsECP was safe and feasible to use in patients with acute ischemic stroke. It was associated with unexpected effects on flow velocity, and contemporaneous improvements in NIHSS score regardless of pressure used, with a possibility that even very low ECP pressures had an effect. Further study is warranted.

The interval appearance of cerebral microbleeds (CMBs) after endovascular treatment has never been described. We investigated the frequency and predictors of new CMBs that developed shortly after mechanical thrombectomy for acute ischemic stroke, and its impact on clinical outcome.We retrospectively analyzed patients with large-vessel occlusion strokes treated with Merci Retriever, Penumbra System, or stent-retriever devices. Serial T2*-weighted gradient-recall echo (GRE) magnetic resonance imaging (MRI) before and 48 h after endovascular thrombectomy were assessed to identify new CMBs. We examined independent factors associated with new CMBs after mechanical thrombectomy. We analyzed the association of the presence, burden, and distribution of new CMBs with clinical outcome.A total of 187 consecutive patients with serial GRE were enrolled in this study. CMBs were evident in 36 (19.3%) patients before mechanical thrombectomy. New CMBs occurred in 41 (21.9%) patients after mechanical thrombectomy. Of the 68 new CMBs, 45 appeared in the lobar location, 18 in the deep location and 5 in the infratentorial location. The presence of baseline CMBs was associated with new CMBs after mechanical thrombectomy (OR 5.38; 95% CI 2.13-13.59; P < 0.001), no matter whether the patients were treated primarily with mechanical thrombectomy or with intravenous thrombolysis followed by mechanical thrombectomy. Patients with new CMBs did not have increased rates of hemorrhagic transformation, in-hospital mortality, and modified Rankin Scale score 4 to 6 at discharge.New CMBs are common after mechanical thrombectomy in one-fifth of patients with acute ischemic stroke. Baseline CMBs before mechanical thrombectomy predicts the development of new CMBs. New CMBs after mechanical thrombectomy do not influence clinical outcome.

Background and purposeEmergency medical services routing of patients with acute stroke to designated centers may increase the proportion of patients receiving care at facilities meeting national standards and augment recruitment for prehospital stroke research.MethodsWe analyzed consecutive patients enrolled within 2 hours of symptom onset in a prehospital stroke trial, before and after regional Los Angeles County Emergency Medical Services implementation of preferentially routing patients with acute stroke to approved stroke centers (ASCs). From January 2005 to mid-November 2009, patients were transported to the nearest emergency department, whereas from mid-November 2009 to December 2012, patients were preferentially transported to first 9, and eventually 29, ASCs.ResultsThere were 863 subjects enrolled before and 764 after emergency medical service preferential routing, with implementation leading to an increase in the proportion cared for at an ASC from 10% to 91% (P9 in 10, with no clinically significant increase in prehospital care times and enhanced recruitment of patients into a prehospital treatment trial.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

Despite significant quality improvement efforts to streamline in-hospital acute stroke care in the conventional model, there remain inherent layers of treatment delays, which could be eliminated with prehospital diagnostics and therapeutics administered in a mobile stroke unit. Early diagnosis using telestroke and neuroimaging while in the ambulance may enable targeted routing to hospitals with specialized care, which will likely improve patient outcomes. Key clinical trials in telestroke, mobile stroke units with prehospital neuroimaging capability, prehospital ultrasound and co-administration of various classes of neuroprotectives, antiplatelets and antithrombin agents with intravenous thrombolysis are discussed in this article.

ObjectEncephaloduroarteriosynangiosis (EDAS) is a form of revascularization that has shown promising early results in the treatment of adult patients with moyamoya disease (MMD) and more recently in patients with intracranial atherosclerotic steno-occlusive disease (ICASD). Herein the authors present the long-term results of a single-center experience with EDAS for adult MMD and ICASD.MethodsPatients with ischemic symptoms despite intensive medical therapy were considered for EDAS. All patients undergoing EDAS were included. Clinical data, including recurrence of transient ischemic attack (TIA) and/or stroke, functional status, and death, were collected from a retrospective data set and a prospective cohort. Perren revascularization and American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral grades were recorded from angiograms.ResultsA total of 107 EDAS procedures were performed in 82 adults (36 with ICASD and 46 with MMD). During a median follow-up of 22 months, 2 (2.4%) patients had strokes; both patients were in the ICASD group. TIA-free survival and stroke-free survival analyses were performed using the product limit estimator (Kaplan-Meier) method. The probability of stroke-free survival at 2 years in the ICASD group was 94.3% (95% CI 80%-98.6%). No patient in the MMD group suffered a stroke. The probability of TIA-free survival at 2 years was 89.4% (95% CI 74.7%-96%) in ICASD and 99.7% (95% CI 87.5%-99.9%) in MMD. There were no hemorrhages or stroke-related deaths. Angiograms in 85.7% of ICASD and 92% of MMD patients demonstrated Perren Grade 3 and improvement in ASITN/SIR grade in all cases.ConclusionsEDAS is well tolerated in adults with MMD and ICASD and improves collateral circulation to territories at risk. The rates of stroke after EDAS are lower than those reported with other treatments, including intensive medical therapy in patients with ICASD.

BackgroundTo assess the differences across continental regions in terms of stroke imaging obtained for making acute revascularization therapy decisions, and to identify obstacles to participating in randomized trials involving multimodal imaging.MethodsSTroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-Imaging circulated an online survey through its website, through the websites of national professional societies from multiple countries as well as through email distribution lists from STIR and the above mentioned societies.ResultsWe received responses from 223 centers (2 from Africa, 38 from Asia, 10 from Australia, 101 from Europe, 4 from Middle East, 55 from North America, 13 from South America). In combination, the sites surveyed administered acute revascularization therapy to a total of 25,326 acute stroke patients in 2012. Seventy-three percent of these patients received intravenous (i.v.) tissue plasminogen activator (tPA), and 27%, endovascular therapy. Vascular imaging was routinely obtained in 79% (152/193) of sites for endovascular therapy decisions, and also as part of standard IV tPA treatment decisions at 46% (92/198) of sites. Modality, availability and use of acute vascular and perfusion imaging before revascularization varied substantially between geographical areas. The main obstacles to participate in randomized trials involving multimodal imaging included: mainly insufficient research support and staff (50%, 79/158) and infrequent use of multimodal imaging (27%, 43/158) .ConclusionThere were significant variations among sites and geographical areas in terms of stroke imaging work-up used tomake decisions both for intravenous and endovascular revascularization. Clinical trials using advanced imaging as a selection tool for acute revascularization therapy should address the need for additional resources and technical support, and take into consideration the lack of routine use of such techniques in trial planning.

The recent culmination of imaging-endowed endovascular stroke trials has decisively proven the utility of clinically relevant neuroimaging in improving the outcome of patients with potentially debilitating neurological disorders. These large multicenter trials conducted across several continents notably utilized a variety of multimodal CT/MRI modalities to rapidly identify a favorable collateral profile that presages clinically beneficial revascularization. The modern clinical neuroimager may accelerate complex decision-making through the rational use of a variety of imaging modalities and an active feedback loop of imaging at the bedside. The modern clinical neuroimager is often the initial care provider for a wide range or type of stroke patients from hemorrhage to ischemia, armed with the incredibly important aspects of clinical history and examination findings and best poised to utilize imaging to guide therapy from acute stroke to recovery and prevention. The next generation in stroke should not exclusively focus on whether to order a CT or MRI counting minutes at the bedside, but actively and efficiently integrate the vast wealth of information available when imaging is used in the proper clinical context. The novel endovascular era in stroke provides an ideal venue for the synergistic goals of translating research advances, improving patient outcomes and ongoing education as a modern neuroimager.

Ischemic stroke remains a leading cause of death and disability worldwide. Various endovascular trials have addressed clinical outcomes without elucidating the impact of imaging studies in patient selection. The success of recent endovascular trials was bolstered by the use of advanced imaging techniques for optimal selection of reperfusion candidates. This seminal juncture in the history of stroke trials warrants further consideration on the use of imaging to guide future refinements in the treatment of acute stroke. In this article, we systematically review the imaging methodology and key facets used in all published endovascular stroke trials to date, discuss the success of recent trials using latest advanced imaging techniques and focus on the importance of imaging studies for future patient selection.

We aim to investigate whether the phenomenon of "sudden drop" in blood pressure (BP) within the first 2 hours is associated with vessel recanalization.We retrospectively examined clinical and imaging data from a consecutive series of patients with stroke with large vessel occlusion treated with intravenous thrombolysis (IVT). BP was monitored every 15 minutes during the first 2 hours, then every 30 minutes for 6 hours, and then every hour for 16 hours.We observed the phenomenon of "sudden drop" in systolic BP (≥20 mm Hg) in 82 (50.9%) patients in the first 2 hours and vessel recanalization in 87 (54.0%) patients 24 hours after treatment. This phenomenon was independently associated with recanalization (odds ratio 2.100; 95% confidence interval: 1.085-4.062; P = 0.028) after adjusting for the history of atrial fibrillation, coronary heart disease, and hypertension.The phenomenon of "sudden drop" in systolic BP with 20 mm Hg or greater between 2 continuous measurements within the first 2 hours is associated with recanalization after IVT in patients with large vessel occlusion, especially for middle cerebral artery occlusion.

BackgroundThe ideal population of patients for endovascular therapy (ET) in acute ischemic stroke remains undefined. Recent ET trials have moved towards selecting patients with proximal middle cerebral artery (MCA) or internal carotid artery occlusions, which will likely leave a gap in our understanding of the treatment outcomes of M2 occlusions.Objective and methodsTo examine the presentation, treatment, and outcomes of M2 compared with M1 MCA occlusions in patients undergoing ET by assessing comprehensive MRI, angiography, and clinical data.ResultsWe found that M2 occlusions can lead to massive strokes defined by hypoperfused and infarcted volumes as well as death or moderate to severe disability in nearly 50% of patients at discharge. Compared with M1 occlusions, M2 occlusions achieved similar Thrombolysis in Cerebral Infarction (TICI) 2b/3 recanalization rates, with significantly less hemorrhage. M2 occlusions presented with smaller infarct and hypoperfused volumes and had smaller final infarct volumes regardless of recanalization. TICI 2b/3 recanalization of M2 occlusions was associated with smaller infarct volumes compared with TICI 0-2a recanalization, as well as less infarct expansion, in patients who received IV tissue plasminogen activator as well as those that did not. Successful reperfusion of M2 occlusions was associated with improved discharge modified Rankin scale.ConclusionsIf suitable as targets of ET, M2 occlusions should be given the same consideration as M1 occlusions.

Background and purposeUntil recently, acute ischemic stroke (AIS) trials have failed to show a benefit of endovascular therapy compared with standard therapy, leading some authors to recommend decreasing the time from ictus to revascularization to improve outcomes. We hypothesize that improving patient selection using the capillary index score (CIS) may also be a useful strategy.MethodsCIS was calculated, blinded to outcome, from pretreatment diagnostic cerebral angiograms for 78 subjects in the Interventional Management of Stroke III database with internal carotid artery and middle cerebral artery trunk occlusion. The CIS was dichotomized into favorable (fCIS=2 or 3) and poor (pCIS=0 or 1). Outcomes were categorized based on the modified Rankin Scale score at 90 days (0-2 considered a good outcome). Modified thrombolysis in cerebral infarction score 2b or 3 was considered good revascularization. Multivariable logistic regression was performed to relate CIS, time from ictus to revascularization, modified thrombolysis in cerebral infarction score, and National Institue of Health Stroke Scale score to good outcomes.ResultsOnly CIS and modified thrombolysis in cerebral infarction scores were correlated with good outcomes (P