Publications by authors named "Ashkan Shoamanesh"

94 Publications

Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source: NAVIGATE ESUS Trial.

Stroke 2021 Sep 20:STROKEAHA120032976. Epub 2021 Sep 20.

Population Health Research Institute, Hamilton Health Sciences, Ontario, Canada (R.G.H., S.J.C.).

Background And Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial.

Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics.

Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26-115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack (<0.001), modified Rankin Scale score >0 (<0.001), and current tobacco use (=0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS.

Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02313909.
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http://dx.doi.org/10.1161/STROKEAHA.120.032976DOI Listing
September 2021

Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities.

Stroke 2021 Sep 14:STROKEAHA121035002. Epub 2021 Sep 14.

Department of Neurology, Stanford University (M.G.L.).

Cilostazol is a PDE3 (phosphodiesterase III) inhibitor with a long track record of safety that is Food and Drug Administration and European Medicines Agency approved for the treatment of claudication in patients with peripheral arterial disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials that have demonstrated a reduction in stroke recurrence among patients with noncardioembolic stroke. The onset of benefit appears after 60 to 90 days of treatment, which is consistent with cilostazol's pleiotropic effects on platelet aggregation, vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms, and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in a large secondary stroke prevention trial (CSPS.com [Cilostazol Stroke Prevention Study for Antiplatelet Combination]). Due to limitations of prior trials, such as open-label design, premature trial termination, large loss to follow-up, lack of functional or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol for secondary prevention in the millions of patients worldwide who have experienced a noncardioembolic ischemic stroke.
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http://dx.doi.org/10.1161/STROKEAHA.121.035002DOI Listing
September 2021

Tandem Occlusions: A Tale of Two Treatments.

Stroke 2021 Aug 10:STROKEAHA121036219. Epub 2021 Aug 10.

Department of Neurosciences, Centre Hospitalier de l'Université de Montréal (A.Y.P.).

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http://dx.doi.org/10.1161/STROKEAHA.121.036219DOI Listing
August 2021

Changes in Stroke Hospital Care During the COVID-19 Pandemic: A Systematic Review and Meta-Analysis.

Stroke 2021 Aug 4:STROKEAHA121034601. Epub 2021 Aug 4.

Second Department of Neurology, "Attikon" Hospital, School of Medicine, National and Kapodistrian University of Athens, Greece (A.H.K., L.P., G. Tsivgoulis.).

Background And Purpose: We systematically evaluated the impact of the coronavirus 2019 (COVID-19) pandemic on stroke care across the world.

Methods: Observational studies comparing characteristics, acute treatment delivery, or hospitalization outcomes between patients with stroke admitted during the COVID-19 pandemic and those admitted before the pandemic were identified by Medline, Scopus, and Embase databases search. Random-effects meta-analyses were conducted for all outcomes.

Results: We identified 46 studies including 129 491 patients. Patients admitted with stroke during the COVID-19 pandemic were found to be younger (mean difference, -1.19 [95% CI, -2.05 to -0.32]; =70%) and more frequently male (odds ratio, 1.11 [95% CI, 1.01-1.22]; =54%) compared with patients admitted with stroke in the prepandemic era. Patients admitted with stroke during the COVID-19 pandemic, also, had higher baseline National Institutes of Health Stroke Scale scores (mean difference, 0.55 [95% CI, 0.12-0.98]; =90%), higher probability for large vessel occlusion presence (odds ratio, 1.63 [95% CI, 1.07-2.48]; =49%) and higher risk for in-hospital mortality (odds ratio, 1.26 [95% CI, 1.05-1.52]; =55%). Patients with acute ischemic stroke admitted during the COVID-19 pandemic had higher probability of receiving endovascular thrombectomy treatment (odds ratio, 1.24 [95% CI, 1.05-1.47]; =40%). No difference in the rates of intravenous thrombolysis administration or difference in time metrics regarding onset to treatment time for intravenous thrombolysis and onset to groin puncture time for endovascular thrombectomy were detected.

Conclusions: The present systematic review and meta-analysis indicates an increased prevalence of younger patients, more severe strokes attributed to large vessel occlusion, and higher endovascular treatment rates during the COVID-19 pandemic. Patients admitted with stroke during the COVID-19 pandemic had higher in-hospital mortality. These findings need to be interpreted with caution in view of discrepant reports and heterogeneity being present across studies.
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http://dx.doi.org/10.1161/STROKEAHA.121.034601DOI Listing
August 2021

Prevalence, Characteristics, and Outcomes of Undetermined Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis.

Stroke 2021 Aug 4:STROKEAHA120031471. Epub 2021 Aug 4.

Second Department of Neurology, National and Kapodistrian University of Athens, "Attikon" University Hospital, Greece. (C.Z., A.T., A.H.K., K.V., G.T.).

Background And Purpose: There are scarce data regarding the prevalence, characteristics and outcomes of intracerebral hemorrhage (ICH) of undetermined (unknown or cryptogenic) etiology. We sought to determine the prevalence, radiological characteristics, and clinical outcomes of undetermined ICH.

Methods: Systematic review and meta-analysis of studies involving patients with spontaneous ICH was conducted to primarily assess the prevalence and clinical-radiological characteristics of undetermined ICH. Additionally, we assessed the rates for ICH secondary to hypertensive arteriopathy and cerebral amyloid angiopathy. Subgroup analyses were performed based on the use of (1) etiology-oriented ICH classification, (2) detailed neuroimaging, and (3) Boston criteria among patients with cerebral amyloid angiopathy related ICH. We pooled the prevalence rates using random-effects models, and assessed the heterogeneity using Cochran and statistics.

Results: We identified 24 studies comprising 15 828 spontaneous ICH patients (mean age, 64.8 years; men, 60.8%). The pooled prevalences of hypertensive arteriopathy ICH, undetermined ICH, and cerebral amyloid angiopathy ICH were 50% (95% CI, 43%-58%), 18% (95% CI, 13%-23%), and 12% (95% CI, 7%-17% [<0.001 between subgroups]). The volume of ICH was the largest in cerebral amyloid angiopathy ICH (24.7 [95% CI, 19.7-29.8] mL), followed by hypertensive arteriopathy ICH (16.2 [95% CI, 10.9-21.5] mL) and undetermined ICH (15.4 [95% CI, 6.2-24.5] mL). Among patients with undetermined ICH, the rates of short-term mortality (within 3 months) and concomitant intraventricular hemorrhage were 33% (95% CI, 25%-42%) and 38% (95% CI, 28%-48%), respectively. Subgroup analysis demonstrated a higher rate of undetermined ICH among studies that did not use an etiology-oriented classification (22% [95% CI, 15%-29%]). No difference was observed between studies based on the completion of detailed neuroimaging to assess the rates of undetermined ICH (=0.62).

Conclusions: The etiology of spontaneous ICH remains unknown or cryptogenic among 1 in 7 patients in studies using etiology-oriented classification and among 1 in 4 patients in studies that avoid using etiology-oriented classification. The short-term mortality in undetermined ICH is high despite the relatively small ICH volume.
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http://dx.doi.org/10.1161/STROKEAHA.120.031471DOI Listing
August 2021

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

Neurocrit Care 2021 Jul 22. Epub 2021 Jul 22.

Department of Neurology J. P. Kistler Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial.

Methods: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days.

Results: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions.

Conclusions: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).
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http://dx.doi.org/10.1007/s12028-021-01254-9DOI Listing
July 2021

Which older emergency patients are at risk of intracranial bleeding after a fall? A protocol to derive a clinical decision rule for the emergency department.

BMJ Open 2021 07 2;11(7):e044800. Epub 2021 Jul 2.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.

Introduction: Falling on level ground is now the most common cause of traumatic intracranial bleeding worldwide. Older adults frequently present to the emergency department (ED) after falling. It can be challenging for clinicians to determine who requires brain imaging to rule out traumatic intracranial bleeding, and often head injury decision rules do not apply to older adults who fall. The goal of our study is to derive a clinical decision rule, which will identify older adults who present to the ED after a fall who do not have clinically important intracranial bleeding.

Methods And Analysis: This is a prospective cohort study enrolling patients aged 65 years or older, who present to the ED of 11 hospitals in Canada and the USA within 48 hours of having a fall. Patients are included if they fall on level ground, off a chair, toilet seat or out of bed. The primary outcome is the diagnosis of clinically important intracranial bleeding within 42 days of the index ED visit. An independent adjudication committee will determine the primary outcome, blinded to all other data. We are collecting data on 17 potential predictor variables. The treating physician completes a study data form at the time of initial assessment, prior to brain imaging. Data extraction is supplemented by an independent, structured electronic medical record review. We will perform binary recursive partitioning using Classification and Regression Trees to derive a clinical decision rule.

Ethics And Dissemination: The study was initially approved by the Hamilton Integrated Research Ethics Committee and subsequently approved by the research ethics boards governing all participating sites. We will disseminate our results by journal publication, presentation at international meetings and social media.

Trial Registration Number: NCT03745755.
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http://dx.doi.org/10.1136/bmjopen-2020-044800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256748PMC
July 2021

Utility of Intravenous Alteplase Prior to Endovascular Stroke Treatment: A Systematic Review and Meta-analysis of RCTs.

Neurology 2021 08 18;97(8):e777-e784. Epub 2021 Jun 18.

From the Division of Neurology (A.H.K., A.S.), McMaster University/Population Health Research Institute, Hamilton, Ontario, Canada; Department of Neurology (G. Turc), GHU Paris Psychiatrie et Neurosciences, Hôpital Sainte-Anne; Université de Paris (G. Turc); INSERM U1266 (G. Turc); FHU Neurovasc (G. Turc), Paris, France; Department of Neuroradiology (M.P.), Clinic for Radiology and Nuclear Medicine, University Hospital Basel; Department of Diagnostic and Interventional Neuroradiology and Department of Diagnostic, Interventional and Pediatric Radiology (J.K., J.G.), Inselspital University Hospital Bern, Switzerland; Second Department of Neurology (L.P., M.I.S., G. Tsivgoulis), Attikon Hospital, School of Medicine, National and Kapodistrian University of Athens; Stroke Unit (G.M.), Metropolitan Hospital, Piraeus; Department of Neurosurgery (M.T.), Pediatric Hospital of Athens, Agia Sophia, Greece; Neuroscience Section (S.S.), Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, Italy; Department of Diagnostic and Interventional Neuroradiology (J.F.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Neurological Research Unit (D.S.), Department of Neurology, Neurocenter, Helsinki University Hospital, Finland; Department of Neurology (A.V.A., G. Tsivgoulis), University of Tennessee Health Science Center, Memphis; and Department of Neurology (U.F.), University Hospital Bern, Inselspital, University of Bern, Switzerland.

Objective: To provide a critical appraisal on the evidence from randomized controlled clinical trials (RCTs) on the utility of direct endovascular treatment (dEVT) compared to the combination of endovascular treatment preceded by IV thrombolysis (bridging therapy [BT]) for patients with acute large vessel occlusion (LVO).

Methods: Eligible RCTs were identified by searching Medline and Scopus. We calculated the corresponding odds ratios (ORs) and 95% confidence intervals (CIs) and pooled estimates using random-effects models. The primary outcome was the probability of modified Rankin scale (mRS) score of 0 to 2 at 3 months.

Results: We included 3 studies comprising 1,092 patients. No difference between the dEVT and BT groups was detected for the outcomes of mRS score of 0 to 2 (OR 1.08, 95% CI 0.85-1.38; adjusted OR 1.11, 95% CI 0.76-1.63), mRS score of 0 to 1 (OR 1.10, 95% CI 0.84-1.43; adjusted OR 1.16, 95% CI 0.84-1.61), and functional improvement at 3 months (common OR 1.08, 95% CI 0.88-1.34; adjusted common OR 1.09, 95% CI 0.86-1.37). Patients receiving dEVT had significantly lower likelihood of successful recanalization before the endovascular procedure compared to those receiving BT (OR 0.37, 95% CI 0.18-0.77). Patients receiving dEVT had lower intracranial bleeding rates compared to those receiving BT (OR 0.67, 95% CI 0.49-0.92) but without a significant difference in the probability of symptomatic intracranial hemorrhage. No differences in all-cause mortality, serious adverse events, or procedural complications between the 2 groups were uncovered.

Conclusions: We detected no differences in functional outcomes of IV thrombolysis-eligible patients with an acute LVO receiving dEVT compared to BT. Because uncertainty for most endpoints remains large and the available data are not able to exclude the possibility of overall benefit or harm, further RCTs are needed.
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http://dx.doi.org/10.1212/WNL.0000000000012390DOI Listing
August 2021

Antiplatelet Therapy in Patients with Atrial Fibrillation: A Systematic Review and Metaanalysis of Randomized Trials.

Eur Heart J Cardiovasc Pharmacother 2021 Jun 17. Epub 2021 Jun 17.

Population Health Research Institute, McMaster University, Hamilton, Canada.

Aims: To systematically assess the effects of antiplatelets on clinical outcomes in patients with atrial fibrillation (AF), treated and not treated with oral anticoagulation.

Methods And Results: We searched MEDLINE, Embase and CENTRAL from inception until September 2020. From 5,446 citations, we selected randomized trials allocating patients with AF to antiplatelet therapy vs. control. We applied random-effects models for meta-analysis and assessed potential effect modification with background anticoagulation use. Eighteen trials including 21,518 participants met our prespecified eligibility criteria. In 10 studies without background anticoagulation, antiplatelets reduced all-cause stroke (486/6,165 [events/patients] vs. 621/6,061; risk ratio [RR] 0.77, 95% confidence interval [CI] 0.69-0.86, I2=0%). In 8 studies with background anticoagulation, there was a signal for an increase in all-cause stroke with antiplatelets (97/4,608 vs. 72/4,684; RR 1.33, 95% CI 0.98-1.79, I2=0%), p-value for interaction < 0.001. A similar pattern emerged for ischaemic stroke. Irrespective of background anticoagulation use, antiplatelets increased major bleeding (509/10,402 vs. 328/10,496; RR 1.54, 95% CI 1.35-1.77, I2=0%) and intracranial Haemorrhage (107/10,221 vs. 65/10,232; RR 1.64, 95% CI 1.20-2.24, I2=0%), and reduced myocardial infarction (201/9,679 vs. 260/9,751; RR 0.79, 95% CI 0.65-0.94, I2=0%), all p-values for interaction ≥ 0.36. Antiplatelets did not affect mortality (1,221/10,299 vs. 1,211/10,287; RR 1.02, 95% CI 0.89-1.17, I2=29%), p-value for interaction = 0.23.

Conclusions: In patients with AF not receiving oral anticoagulation, antiplatelet therapy modestly reduced stroke. There was a corresponding signal for harm when used on top of anticoagulation. Irrespective of background anticoagulation use, antiplatelet therapy significantly increased bleeding, moderately reduced myocardial infarction and did not affect mortality.
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http://dx.doi.org/10.1093/ehjcvp/pvab044DOI Listing
June 2021

Global Impact of COVID-19 on Stroke Care and IV Thrombolysis.

Neurology 2021 06 25;96(23):e2824-e2838. Epub 2021 Mar 25.

Department of Neurology (R.G.N., M.H.M., M.Frankel, D.C.H.), Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine, Atlanta; Department of Radiology (M.M.Q., M.A., T.N.N., A.K.) and Radiation Oncology (M.M.Q.), Boston Medical Center, Boston University School of Medicine, Massachusetts; Department of Neurology (S.O.M.), Federal University of Rio Grande do Sul, Porto Alegre; Hospital de Clínicas de Porto Alegre (S.O.M.), Brazil; Department of Stroke Neurology (H. Yamagami), National Hospital Organization, Osaka National Hospital, Japan; Department of Neurology (Z.Q.), Xinqiao Hospital of the Army Medical University, Chongqing, China; Department of Neurology (O.Y.M.), Stroke and Neurointervention Division, Alexandria University Hospital, Alexandria University, Egypt; Boston University School of Medicine (A.S.), Massachusetts; 2nd Department of Neurology (A.C.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (G.T., L.P.), National & Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Athens, Greece; Faculdade de Medicina (D.A.d.S.), Universidade de Lisboa, Lisbon, Portugal; Department of Neurology (J.D., R.L.), Leuven University Hospital, Belgium; International Clinical Research Center and Department of Neurology (R.M.), St. Anne´s University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic; Department of Neurology (P.V.), Groeninge Hospital, Kortrijk; Department of Neurology (P.V.), University Hospitals Antwerp; Department of Translational Neuroscience (P.V.), University of Antwerp, Belgium; Department of Neurology (J.E.S., T.G.J.), Cooper Neurological Institute, Cooper University Hospital, Camden, New Jersey; Department of Neurology and Neurosurgery (J. Kõrv), University of Tartu, Estonia; Department of Neurology (J.B., R.V.,S.R.), Loyola University Chicago Stritch School of Medicine, Illinois; Department of Neurosurgery (C.W.L.), Kaiser Permanente Fontana Medical Center; Department of Neurology (N.S.S.), Kaiser Permanente Los Angeles Medical Center; Department of Neurology (A.M.Z., S.A.S.), UT Health McGovern Medical School, Houston, Texas; Department of Neurology (A.L.Z.), Medical University of South Carolina, Charleston; Department of Internal Medicine (G.N.), School of Health Sciences, University of Thessaly, Larissa, Greece; Department of Neurology (K.M., A.T.), Allegheny Health Network, Pittsburgh, Pennsylvania; Department of Neurology (A.L.), Ohio Health Riverside Methodist Hospital Columbus; Department of Medicine and Neurology (A.R.), University of Otago and Wellington Hospital, New Zealand; Department of Neurology (E.A.M.), Vanderbilt University Medical Center, Nashville, Tennessee; Department of Neurology (A.W.A., D. Alsbrook), University of Tennessee Health Center, Memphis; Department of Neurology (D.Y.H.), University of North Carolina at Chapel Hill; Departments of Neurology (S.Y.) and Radiology (E.R.), New York University Grossman School of Medicine; Douala Gynaeco-Obstetric and Pediatric Hospital (E.G.B.L.), University of Douala, Faculty of Medicine and Pharmaceutical Science, Cameroon; Ain Shams University Specialized Hospital (H.M.A., H.M.S., A.E., T.R.); Cairo University Affiliated MOH Network (F.H.); Department of Neurology (TM.), Nasser Institute for Research and Treatment, Cairo; Mansoura University Affiliated Private Hospitals Network (W.M.), Egypt; Kwame Nkrumah University of Science and Technology (F.S.S.), Kumasi, Ghana; Stroke Unit (T.O.A., K.W.), University of Ilorin Teaching Hospital; Neurology Unit (B.A.), Department of Medicine, Lagos State University Teaching Hospital; Department of Medicine (E.O.N.), Federal Medical Centre Owerri, Imo State, Nigeria; Neurology Unit (T.A.S.), Department of Medicine, Federal Medical Centre, Owo, Ondo State, Nigeria; University College Hospital (J.Y.), Ibadan, Nigeria; The National Ribat University Affiliated Hospitals (H.H.M.), Khartoum, Sudan; Neurology Section (P.B.A.), Department of Internal Medicine, Aga-Khan University, Medical College East Africa, Dar es Salaam, Tanzania; Tunis El Manar University (A.D.R.), Military Hospital of Tunis; Department of Neurology (S.B.S.), Mongi Ben Hmida National Institute of Neurology, Faculty of Medicine of Tunis, University Tunis El Manar, Tunisia; Department of Physiology (L.G.), Parirenyatwa Hospital, and Departments of Physiology and Medicine (G.W.N.), University of Zimbabwe, Harare; Department of Cerebrovascular/Endovascular Neurosurgery Division (D.S.), Erebouni Medical Center, Yerevan, Armenia; Department of Neurology (A.R.), Sir Salimulah College, Dhaka, Bangladesh; Department of Neurology (Z.A.), Taihe Hospital of Shiyan City, Hubei; Department of Neurology (F.B.), Nanyang Central Hospital, Henan; Department of Neurology (Z.D.), Wuhan No. 1 Hospital, Hubei, China; Department of Neurology (Y. Hao.), Sir Run Run Shaw Hospital, Zhejiang University School of Medicine; Department of Neurology (W.H.), Traditional Chinese Medicine Hospital of Maoming, Guangdong; Department of Neurology (G.Li.), Affiliated Hospital of Qingdao University, Shandong; Department of Neurology (W.L), The First Affiliated Hospital of Hainan Medical College; Department of Neurology (G.Liu.), Wuhan Central Hospital, Hubei; Department of Neurology (J.L.), Mianyang 404th Hospital, Sichuan; Department of Neurology (X.S.), Yijishan Hospital of Wannan Medical College, Anhui; Department of Neurology and Neuroscience (Y.S.), Shenyang Brain Institute, Shenyang First People's Hospital, Shenyang Medical College Affiliated Brain Hospital; Department of Neurology (L.T.), Affiliated Yantai Yuhuangding Hospital of Qingdao University, Shandong; Department of Neurology (H.W.), Xiangyang Central Hospital, Hubei; Department of Neurology (B.W., Y.Yan), West China Hospital, Sichuan University, Chengdu; Department of Neurology (Z.Y.), Affiliated Hospital of Southwest Medical University, Sichuan; Department of Neurology (H.Z.), Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine; Department of Neurology (J.Z.), The First Affiliated Hospital of Shandong First Medical University; Department of Neurology (W.Z.), First Affiliated Hospital of Fujian Medical University, China; Acute Stroke Unit (T.W.L.), The Prince of Wales Hospital, Kwok Tak Seng Centre for Stroke Research and Intervention, The Chinese University of Hong Kong; Interventional Neurology (C.C.), MAX Superspecialty Hospital, Saket, New Delhi; NH Institute of Neurosciences (V.H.), NH Mazumdar Shaw Medical Center, Bangalore; Department of Neurology (B.M.), Apollo Speciality Hospitals Nellore; Department of Neurology (J.D.P.), Christian Medical College, Ludhiana, Punjab; Sree Chitra Tirunal Institute for Medical Sciences and Technology (P.N.S.), Kerala, India; Stroke Unit (F.S.U.), Pelni Hospital, Jakarta, Indonesia; Neurosciences Research Center (M. Farhoudi, E.S.H.), Tabriz University of Medical Sciences, Tabriz, Iran; Beer Sheva Hospital (A.H.); Department of Interventional Neuroradiology, Rambam Healthcare Campus, Haifa, Israel (A.R., R.S.H.); Departments of Neurology (N.O.) and Neurosurgery (N.S.), Kobe City Medical Center General Hospital, Kobe; Department of Stroke and Neurovascular Surgery (D.W.), IMS Tokyo-Katsushika General Hospital; Yokohama Brain and Spine Center (R.Y.); Iwate Prefectural Central (R.D.); Department of Neurology and Stroke Treatment (N.T.), Japanese Red Cross Kyoto Daiichi Hospital; Department of Neurology (T.Y.), Kyoto Second Red Cross Hospital; Department of Neurology (T.T.), Japanese Red Cross Kumamoto Hospital; Department of Stroke Neurology (Y. Yazawa), Kohnan Hospital, Sendai; Department of Cerebrovascular Medicine (T.U.), Saga-Ken Medical Centre; Department of Neurology (T.D.), Saitama Medical Center, Kawagoe; Department of Neurology (H.S.), Nara City Hospital; Department of Neurology (Y.S.), Toyonaka Municipal Hospital, Osaka; Department of Neurology (F. Miyashita), Kagoshima City Hospital; Department of Neurology (H.F.), Japanese Red Cross Matsue Hospital, Shimane; Department of Neurology (K.M.), Shiroyama Hospital, Osaka; Department of Cerebrovascular Medicine (J.E.S.), Niigata City General Hospital; Department of Neurology (Y.S.), Sugimura Hospital, Kumamoto; Stroke Medicine (Y. Yagita), Kawasaki Medical School, Okayama; Department of Neurology (Y.T.), Osaka Red Cross Hospital; Department of Stroke Prevention and Treatment (Y.M.), Department of Neurosurgery, University of Tsukuba, Ibaraki; Department of Neurology (S.Y.), Stroke Center and Neuroendovascular Therapy, Saiseikai Central Hospital, Tokyo; Department of Neurology (R.K.), Kin-ikyo Chuo Hospital, Hokkaido; Department of Cerebrovascular Medicine (T.K.), NTT Medical Center Tokyo; Department of Neurology and Neuroendovascular Treatment (H. Yamazaki), Yokohama Shintoshi Neurosurgical Hospital; Department of Neurology (M.S.), Osaka General Medical Center; Department of Neurology (K.T.), Osaka University Hospital; Department of Advanced Brain Research (N.Y.), Tokushima University Hospital Tokushima; Department of Neurology (K.S.), Saiseikai Fukuoka General Hospital, Fukuoka; Department of Neurology (T.Y.), Tane General Hospital, Osaka; Division of Stroke (H.H.), Department of Internal Medicine, Osaka Rosai Hospital; Department of Comprehensive Stroke (I.N.), Fujita Health University School of Medicine, Toyoake, Japan; Department of Neurology (A.K.), Asfendiyarov Kazakh National Medical University; Republican Center for eHealth (K.F.), Ministry of Health of the Republic of Kazakhstan; Department of Medicine (S.K.), Al-Farabi Kazakh National University; Kazakh-Russian Medical University (M.Z.), Kazakhstan; Department of Neurology (J.-H.B.), Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology (Y. Hwang), Kyungpook National University Hospital, School of Medicine, Kyungpook National University; Ajou University Hospital (J.S.L.); Department of Neurology (S.B.L.), Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea; Department of Neurology (J.M.), National Medical Center, Seoul; Department of Neurology (H.P., S.I.S.), Keimyung University School of Medicine, Dongsan Medical Center, Daegu; Department of Neurology (J.H.S.), Busan Paik Hospital, School of Medicine, Inje University, Busan; Department of Neurology (K.-D.S.), National Health Insurance Service Ilsan Hospital, Goyang; Asan Medical Center (C.J.Y.), Seoul, South Korea; Department of Neurology (R.A.), LAU Medical Center-Rizk Hospital, Beirut, Lebanon; Department of Medicine (W.A.W.Z., N.W.Y.), Pusat Perubatan Universiti Kebangsaan Malaysia, Kuala Lumpur; Sultanah Nur Zahirah (Z.A.A., K.A.I.), Kuala Terengganu; University Putra Malaysia (H.b.B.); Sarawak General Hospital, Kuching (L.W.C.); Hospital Sultan Abdul Halim (A.B.I.), Sungai Petani Kedah; Hospital Seberang Jaya (I.L.), Pulau Pinang; Thomson Hospital Kota Damansara (W.Y.T.), Malaysia; "Nicolae Testemitanu" State University of Medicine and Pharmacy (S.G., P.L.), and Department of Neurology, Emergency Medicine Institute, Chisinau, Republic of Moldova; Department of Stroke Unit (A.M.A.H.), Royal Hospital Muscat, Oman; Neuroscience Institute (Y.Z.I., N.A.), Hamad Medical Corporation, Doha, Qatar; St. Luke's Medical Center-Institute of Neurosciences (M.C.P.-F., C.O.C.), Quezon City, Philippines; Endovascular Neurosurgery (D.K.), Saint-Petersburg Dzhanelidze Research Institute of Emergency Medicine, St. Petersburg, Russia; Department of Neurology (A.A.), Stroke Unit, King Saud University, College of Medicine, Riyadh; Department of Neurosurgery (H.A.-J.), Interventional Radiology, and Critical Care Medicine, King Fahad Hospital of the University, Imam Abdulrahman bin Faisal University, Saudi Arabia; Singapore National Neuroscience Institute (C.H.T.); Changi General Hospital (M.J.M.), Singapore; Neuroscience Center, Raffles Hospital (N.V.), Singapore; Department of Neurology (C.-H.C., S.-C.T.), National Taiwan University Hospital; Department of Radiology (A.C.), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Dicle University Medical School and Hospital (E.A.), Diyarbakir; Stroke and Neurointervention Unit (O.A., A.O.O.), Eskisehir Osmangazi University; Gaziantep University Faculty of Medicine (S.G.), Turkey; Department of Neurology (S.I.H., S.J.), Neurological Institute at Cleveland Clinic Abu Dhabi, United Arab Emirates; Stroke Center (H.L.V., A.D.C.), Hue Central Hospital, Hue, Vietnam; Stroke Department (H.H.N., T.N.P.), Da Nang Hospital, Da Nang City; 115 People's Hospital (T.H.N., T.Q.N.), Ho Chi Minh City, Vietnam; Department of Neurology (T.G., C.E.), Medical University of Graz; Department of Neurology (M. K.-O.), Research Institute of Neurointervention, University Hospital Salzburg/Paracelsus Medical University, Austria; Department of Neurology (F.B., A.D.), Centre Hospitalier Universitaire de Charleroi, Belgium; Department of Neurology (S.D.B., G.V.), Sint Jan Hospital, Bruges; Department of Neurology (S.D.R.), Brussels University Hospital (UZ Brussel); Department of Neurology (N.L.), ULB Erasme Hospitals Brussels; Department of Neurology (M.P.R.), Europe Hospitals Brussels; Department of Neurology (L.Y.), Antwerp University Hospital, Belgium; Neurology Clinic (F.A., T.S.), St. Anna University Hospital, Sofia, Bulgaria; Department of Neurology (M.R.B.), Sestre Milosrdnice University Hospital, Zagreb; Department of Neurology (H.B.), Sveti Duh University Hospital, Zagreb; Department of Neurology (I.C.), General Hospital Virovitica; Department of Neurology (Z.H.), General Hospital Zabok; Department of Radiology (F. Pfeifer), University Hospital Centre Zagreb, Croatia; Regional Hospital Karlovy Vary (I.K.); Masaryk Hospital Usti nad Labem (D.C.); Military University Hospital Praha (M. Sramek); Oblastní Nemocnice Náchod (M. Skoda); Regional Hospital Pribram (H.H.); Municipal Hospital Ostrava (L.K.); Hospital Mlada Boleslav (M. Koutny); Hospital Vitkovice (D.V.); Hospital Jihlava (O.S.); General University Hospital Praha (J.F.); Hospital Litomysl (K.H.); Hospital České Budejovice (M.N.); Hospital Pisek (R.R.); Hospital Uherske Hradiste (P.P.); Hospital Prostejov (G.K.); Regional Hospital Chomutov (J.N.); Hospital Teplice (M.V.); Mining Hospital Karvina (H.B.); Thomayer Hospital Praha (D.H.); Hospital Blansko (D.T.); University Hospital Brno (R.J.); Regional Hospital Liberec (L.J.); Hospital Ceska Lipa (J.N.); Hospital Sokolov (A.N.); Regional Hospital Kolin (Z.T.); Hospital Trutnov (P. Fibrich); Hospital Trinec (H.S.); Department of Neurology (O.V.), University Hospital Ostrava, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Bispebjerg Hospital (H.K.C.), University of Copenhagen; Stroke Center (H.K.I., T.C.T.), Rigshospitalet, University of Copenhagen; Aarhus University Hospital (C.Z.S.), Aarhus; Neurovascular Center, Zealand University Hospital, University of Copenhagen (T.W.), Roskilde, Denmark; Department of Neurology and Neurosurgery (R.V.), University of Tartu, Estonia; Neurology Clinic (K.G.-P.), West Tallinn Central Hospital; Center of Neurology (T.T.), East Tallinn Central Hospital, School of Natural Sciences and Health, Tallinn University; Internal Medicine Clinic (K.A.), Pärnu Hospital, Estonia; Université Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition (C.C., F.C.); Centre Hospitalier d'Arcachon (M.D.), Gujan-Mestras; Centre Hospitalier d'Agen (J.-M.F.); Neurologie Vasculaire (L.M.) and Neuroradiologie (O.E.), Hospices Civils de Lyon, Hôpital Pierre Wertheimer, Bron; Centre Hospitalier et Universitaire de Bordeaux (E.L., F.R.); Centre Hospitalier de Mont de Marsan (B.O.); Neurologie (R.P.), Fondation Ophtalmologique Adolphe de Rothschild; Versailles Saint-Quentin-en-Yvelines University (F. Pico); Neuroradiologie Interventionelle (M.P.), Fondation Ophtalmologique Adolphe de Rothschild; Neuroradiologie Interventionelle (R.P.), Hôpitaux Universitaires de Strasbourg, France; K. Eristavi National Center of Experimental and Clinical Surgery (T.G.), Tbilisi; Department of Neurosurgery (M. Khinikadze), New Vision University Hospital, Tbilisi; Vivamedi Medical Center (M. Khinikadze), Tbilisi; Pineo Medical Ecosystem (N.L.), Tbilisi; Ivane Javakhishvili Tbilisi State University (A.T.), Tbilisi, Georgia; Department of Neurology (S.N., P.A.R.), University Hospital Heidelberg; Department of Neurology (M. Rosenkranz), Albertinen Krankenhaus, Hamburg; Department of Neurology (H.S.), Elbe Klinken Stade, University Medical Center Göttingen; Department of Neurology (T.S.), University Hospital Carl Gustav Carus, Dresden; Kristina Szabo (K.S.), Department of Neurology, Medical Faculty Mannheim, University Heidelberg, Mannheim; Klinik und Poliklinik für Neurologie (G.T.), Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Germany; Department of Internal Medicine (D.S.), School of Health Sciences, University of Thessaly, Larissa; Second Department of Neurology (O.K.), Stroke Unit, Metropolitan Hospital, Piraeus, Greece; University of Szeged (P.K.), Szeged; University of Pecs (L.S., G.T.), Hungary; Stroke Center (A.A.), IRCCS Istituto di Ricovero e Cura a Carattere Scientifico, Negrar, Verona; Department of Neurology (F.B.), Ospedale San Paolo, Savona,; Institute of Neurology (P.C., G.F.), Fondazione Policlinico Universitario Agostino Gemelli, Rome; Interventional Neurovascular Unit (L.R.), Careggi University Hospital, Florence; Stroke Unit (D.S.), Azienda Socio Sanitaria Territoriale (ASST) di Lecco, Italy; Maastricht University Medical Center; Department of Neurology (M.U.), Radiology, University Medical Center Groningen; Department of Neurology (I.v.d.W.), Haaglanden Medical Center, the Hague, the Netherlands; Department of Neurology (E.S.K.), Akershus University Hospital, Lørenskog, General Practice, HELSAM, University of Oslo, Norway; Neurological Ward with Stroke Unit (W.B.), Specialist Hospital in Konskie, Gimnazjalna, Poland and Collegium Medicum, Jan Kochanowski University, Kielce, Poland; Neurological Ward with Stroke Unit (M.F.), District Hospital in Skarzysko-Kamienna; Department of Neurology (E.H.L.), Szpitala im T. Marciniaka in Wroclaw; 2nd Department of Neurology (M. Karlinski), Institute of Psychiatry and Neurology, Warsaw; Department of Neurology and Cerebrovascular Disorders (R.K., P.K.), Poznan University of Medical Sciences; 107th Military Hospital with Polyclinic (M.R.), Walcz; Department of Neurology (R.K.), St. Queen Jadwiga, Clinical Regional Hospital No. 2, Rzeszow; Department of Neurology (P.L.), Medical University of Lublin; 1st Department of Neurology (H.S.-J.), Institute of Psychiatry and Neurology, Warsaw; Department of Neurology and Stroke Unit (P.S.), Holy Spirit Specialist Hospital in Sandomierz, Collegium Medicum Jan Kochanowski University in Kielce; Copernicus PL (W.F.), Neurology and Stroke Department, Hospital M. Kopernik, Gdansk; Stroke Unit (M.W.), Neurological Department, Stanislaw Staszic University of Applied Sciences, Pila, Poland; Hospital São José (Patricia Ferreira), Centro Hospitalar Universitário de Lisboa Central, Lisbon; Stroke Unit (Paulo Ferreira, V.T.C.), Hospital Pedro Hispano, Matosinhos; Stroke Unit, Internal Medicine Department (L.F.), Neuroradiology Department, Centro Hospitalar Universitário de São João, Porto; Department of Neurology (J.P.M.), Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal; Department of Neurosciences (T.P.e.M.), Hospital de Santa Maria-CHLN, North Lisbon University Hospital; Hospital São José (A.P.N.), Centro Hospitalar Universitário de Lisboa Central, Lisbon; Department of Neurology (M. Rodrigues), Hospital Garcia de Orta, Portugal; Department of Neurology (C.F.-P.), Transilvania University, Brasov, Romania; Department of Neurology (G.K., M. Mako), Faculty Hospital Trnava, Slovakia; Department of Neurology and Stroke Center (M.A.d.L., E.D.T.), Hospital Universitario La Paz, Madrid; Department of Neurology (J.F.A.), Hospital Clínico Universitario, Universidad de Valladolid; Department of Neurology (O.A.-M.), Complejo Hospitalario Universitario de Albacete; Department of Neurology (A.C.C.), Unidad de Ictus, Hospital Universitario Ramon y Cajal, Madrid; Department of Neurology (S.P.-S), Hospital Universitario Virgen Macarena & Neurovascular Research Laboratory (J.M.), Instituto de Biomedicina de Sevilla-IbiS; Rio Hortega University Hospital (M.A.T.A.), University of Valladolid; Cerebrovascular Diseases (A.R.V.), Hospital Clinic of Barcelona, Spain; Department of Neurology (M. Mazya), Karolinska University Hospital and Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Department of Interventional Neuroradiology (G.B.), University Hospitals of Geneva; Department of Interventional and Diagnostic Neuroradiology (A.B., M.-N.P.), Radiology and Nuclear Medicine, University Hospital Basel; Department of Neurology (U.F.), University of Bern; Department of Neuroradiology (J.G.), University of Bern; Department of Neuroscience (P.L.M., D.S.), Lausanne University Hospital, Switzerland; Department of Stroke Medicine (S.B., J. Kwan), Imperial College Healthcare NHS Trust, Charing Cross Hospital, London; Department of Neurology (K.K.), Queen's Medical Centre, Nottingham University Hospitals NHS Trust, United Kingdom; Department of Neurology (A.B., A. Shuaib), University of Alberta, Edmonton; Department of Neurology (L.C., A. Shoamanesh), McMaster University, Hamilton; Department of Clinical Neurosciences and Hotchkiss Brain Institute (A.M.D., M.D.H.), University of Calgary; Department of Neurology (T.F., S.Y.), University of British Columbia, Vancouver; Mackenzie Health (J.H., C.A.S.) Richmond Hill, Ontario; Department of Neurology (H.K.), Sunnybrook Health Sciences Centre, University of Toronto; Department of Neurology (A. Mackey), Hopital Enfant Jesus, Centre Hospitalier de l'Universite Laval, Quebec City; Department of Neurology (A.P.), University of Toronto; Medicine (G.S.), St. Michael's Hospital, University of Toronto, Canada; Department of Neurosciences (M.A.B.), Hospital Dr. Rafael A. Calderon Guardia, CCSS. San Jose, Costa Rica; Neurovascular Service (J.D.B.), Hospital General San Juan de Dios, Guatemala City; Department of Neurología (L.I.P.R.), Hospital General de Enfermedades, Instituto Guatemalteco de Seguridad Social, Guatemala City, Guatemala; Department of Neurology (F.G.-R.), University Hospital Jose Eleuterio Gonzalez, Universidad Autonoma de Nuevo Leon, Mexico; Pacífica Salud-Hospital Punta Pacífica (N.N.-E., A.B., R.K.), Panama; Department of Neurology, Radiology (M.A.), University of Kansas Medical Center; Department of Neurointerventional Neurosurgery (D. Altschul), The Valley Baptist Hospital, Ridgewood, New Jersey; Palmetto General Hospital (A.J.A.-O.), Tenet, Florida; Neurology (I.B., P.K.), University Hospital Newark, New Jersey Medical School, Rutgers, Newark, New Jersey; Community Healthcare System (A.B.), Munster, Indiana; Department of Neurology (N.B., C.B.N.), California Pacific Medical Center, San Francisco; Department of Neurology (C.B.), Mount Sinai South Nassau, New York; University of Toledo (A.C.), Ohio; Department of Neurology (S.C.), University of Maryland School of Medicine, Baltimore, Maryland; Neuroscience (S.A.C.), Inova Fairfax Hospital, Virginia; Department of Neurology (H.C.), Abington Jefferson Hospital, Pennsylvania; Department of Neurology (J.H.C.), Mount Sinai South Nassau, New York; Baptist Health Medical Center (S.D.), Little Rock, Arkansas; Department of Neurology (K.D.), HCA Houston Healthcare Clearlake, Texas; Department of Neurology (T.G.D., R.S.), Erlanger, Tennessee; Wilmington North Carolina (V.T.D.); Department of Vascular and Neurointerventional Services (R.E.), St. Louis University, Missouri; Department of Neurology (M.E.), Massachusetts General Hospital, Boston; Department of Neurology, Neurosurgery, and Radiology (M.F., S.O.-G., N.R.), University of Iowa Hospitals and Clinics, Iowa City; Department of Radiology (D.F.), Swedish Medical Center, Englewood, Colorado; Department of Radiology (D.G.), Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland; Adventist Health Glendale Comprehensive Stroke Center (M.G.), Los Angeles, California; Wellstar Neuroscience Institute (R.G.), Marietta, Georgia; Department of Neurology (A.E.H.), University of Texas Rio Grande Valley-Valley Baptist Medical Center, Texas; Department of Neurology (J.H., B.V.), Lahey Hospital & Medical Center, Beth Israel Lahey Health, Burlington, Massachusetts; Department of Neurology (A.M.K.), Wayne State, Detroit, Michigan; HSHS St. John's Hospital (N.N.K.), Southern Illinois University School of Medicine, Springfield; Virginia Hospital Center (B.S.K.), Arlington; Department of Neurology, University of Michigan, Ann Arbor; Weill-Cornell Medical College (D.O.K.), New York-Presbyterian Queens; Department of Neurology (V.H.L.), Ohio State University, Columbus; Department of Neurology (L.Y.L.), Tufts Medical Center, Boston, Massachusetts; Vascular and Neurointerventional Services (G.L.), St. Louis University, Missouri; Miami Cardiac & Vascular Institute (I.L., A.K.S.), Florida; Department of Neurology (H.L.L.), Oregon Health & Science University, Portland; Department of Emergency Medicine (L.M., M.S.), Steward Holy Family Hospital, Methuen, MA; Vidant Medical Center (S.M.), Greenville, North Carolina; Department of Neurology (A.M.M., D.R.Y.) and Neurosurgery (D.R.Y.), University of Miami Miller School of Medicine, Florida; Department of Neurology (H.M.), SUNY Upstate New York, Syracuse; Memorial Neuroscience Institute (B.P.M.), Pembroke Pines, Florida; Neurosciences (J.M., J.P.T.), Spectrum Health, Michigan State University College of Medicine, Grand Rapids, Michigan; Sutter Health (M.M.), Sacramento, California; Department of Neurology (J.G.M.), Maine Medical Center, Portland; Department of Neurology (S.S.M.), Bayhealth, Dover, Delaware; Department of Neurology and Pediatrics (F.N.), Emory University, Atlanta, Georgia; Department of Neurology (K.N.), University of Arkansas for Medical Sciences, Little Rock; Department of Radiology and Neurology (R.N.-W.), UT Southwestern Medical Center, Dallas, Texas; Ascension St. John Medical Center (R.H.R.), Tulsa, Oklahoma; Riverside Regional Medical Center (P.R.), Newport, Virginia; Department of Neurology (J.R.R., T.N.N.), Boston University School of Medicine, MA; Department of Neurology (A.R.), Hospital of the University of Pennsylvania, Philadelphia; Department of Neurology (M.S.), University of Washington School Medicine, Seattle; Department of Neurology (B.S.), University of Massachusetts Medical Center, Worcester; Department of Neurology (A.S.), CHI-Immanuel Neurological Institute, Creighton University, Omaha, Nebraska; Holy Cross Hospital (S.L.S.), Fort Lauderdale, Florida; Department of Neurology (V.S.), Interventional Neuroradiology, University of California in Los Angeles; Banner Desert Medical Center (M.T.), Mesa, Arizona; Hospital de Agudos Dr. Ignacio Privano (O.B., A.L.), Argentina; Institute for Neurological Research, FLENI (V.A.P.L.), Buenos Aires, Argentina; Hospital das Clinicas/São Paulo University (M.S.A., A.C.); Sumare State Hospital (F.B.C., L.V.), São Paulo; Hospital Vera Cruz (L.D.D.S.), Deus Campinas; Irmanandade Santa Casa de Porto Alegre (L.V.G.); Stroke Unit (F.O.L., F. Mont'alverne), Hospital Geral de Fortaleza; Stroke Unit (A.L.L., P.S.C.M.), Hospital Sao Jose, Joinville, Santa Catarina; Stroke Unit (R.T.M.), Neurology, Nossa Senhora da Conceição Hospital, Porto Alegre; Department of Neurology (D.L.M.C.), Hospital Moinhos de Vento, Porto Alegre; Department of Neurology (L.C.R.), Hospital de Base do Distrito Federal; Hospital Ana (V.F.C.), Hospital Juliane, Federal University of Parana, Curitiba, Brazil; Vascular Neurology Unit (P.M.L., V.V.O.), Neurology Service, Department of Neurology and Psychiatry, Clínica Alemana, Universidad del Desarrollo, Santiago; Hospital Padre Hurtado (V.N., J.M.A.T.) Santiago, Chile; Fundación Valle del Lili (P.F.R.A.), Cali; Stroke Center (H.B.), Fundación Santa Fe de Bogotá; Department of Neurology (A.B.C.-Q.), Hospital Departamental Universitario del Quindio San Juan de Dios, Armenia; Clinica Universitaria Colombia (C.E.R.O.), Bogotá; University Hospital of San Vicente Foundation (D.K.M.B.), Medellin; Barranquilla, Colombia (O.L.); Hospital Infantil Universitario de San Jose (M.R.P.), Bogota; Stroke Unit (L.F.D.-E.), Hospital de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Asunción; Neurology Service (D.E.D.M.F., A.C.V.), Hospital Central del Instituto de Prevision Social, Paraguay; Internal Medicine Service (A.J.Z.Z.), Hospital Central de Policia "Rigoberto Caballero", Paraguay; National Institute of Neurological Sciences of Lima Peru (D.M.B.I.); Hospital Edgardo Rebagliati Martins Lima-Peru (L.R.K.); Department of Neurology (B.C.), Royal Melbourne Hospital; Department of Neurology (G.J.H.), Sir Charles Gairdner Hospital and Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth; University of Melbourne (C.H., R.S.), Ballarat Health Service, Australia University of Melbourne; Department of Neurology (T.K.), Royal Adelaide Hospital; Department of Neurosurgery (A. Ma), Royal North Shore Hospital, Sydney; Department of Neurology (R.T.M.), Mater Hospital, Brisbane; Department of Neurology (R.S.), Austin Health, Victoria; Florey Institute of Neuroscience and Mental Health (R.S.), Parkville, Melbourne, Australia; Greymouth Base Hospital (D.S.), New Zealand; Department of Neurology (T.Y.-H.W.), Christchurch Hospital, New Zealand; Department of Neurology (D.L.), University of California in Los Angeles; and Department of Neurology (O.O.Z.), Mercy Health Neurosciences, Toledo, Ohio.

Objective: To measure the global impact of COVID-19 pandemic on volumes of IV thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with 2 control 4-month periods.

Methods: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases.

Results: There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95% confidence interval [CI] -11.7 to -11.3, < 0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95% CI -13.8 to -12.7, < 0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95% CI -13.7 to -10.3, = 0.001). Recovery of stroke hospitalization volume (9.5%, 95% CI 9.2-9.8, < 0.0001) was noted over the 2 later (May, June) vs the 2 earlier (March, April) pandemic months. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was noted in 3.3% (1,722/52,026) of all stroke admissions.

Conclusions: The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID-19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months.
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http://dx.doi.org/10.1212/WNL.0000000000011885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205458PMC
June 2021

Combatting Secondary Injury From Intracerebral Hemorrhage With Supplemental Antioxidant Therapy.

Stroke 2021 Apr 25;52(4):1182-1184. Epub 2021 Feb 25.

Division of Neurology, Population Health Research Institute, McMaster University, Hamilton, ON, Canada.

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http://dx.doi.org/10.1161/STROKEAHA.121.033849DOI Listing
April 2021

Cerebral microbleeds: from depiction to interpretation.

J Neurol Neurosurg Psychiatry 2021 Feb 9. Epub 2021 Feb 9.

Department of Neurology, U1172 - LilNCog - Lille Neuroscience & Cognition, Univ. Lille, Inserm, CHU Lille, F-59000 Lille, France

Cerebral microbleeds (CMBs) are defined as hypointense foci visible on T2*-weighted and susceptible-weighted MRI sequences. CMBs are increasingly recognised with the widespread use of MRI in healthy individuals as well as in the context of cerebrovascular disease or dementia. They can also be encountered in major critical medical conditions such as in patients requiring extracorporeal mechanical oxygenation. The advent of MRI-guided postmortem neuropathological examinations confirmed that, in the context of cerebrovascular disease, the vast majority of CMBs correspond to recent or old microhaemorrhages. Detection of CMBs is highly influenced by MRI parameters, in particular field strength, postprocessing methods used to enhance T2* contrast and three dimensional sequences. Despite recent progress, harmonising imaging parameters across research studies remains necessary to improve cross-study comparisons. CMBs are helpful markers to identify the nature and the severity of the underlying chronic small vessel disease. In daily clinical practice, presence and numbers of CMBs often trigger uncertainty for clinicians especially when antithrombotic treatments and acute reperfusion therapies are discussed. In the present review, we discuss those clinical dilemmas and address the value of CMBs as diagnostic and prognostic markers for future vascular events.
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February 2021

Cortical superficial siderosis in the general population: The Framingham Heart and Rotterdam studies.

Int J Stroke 2021 01 21:1747493020984559. Epub 2021 Jan 21.

Erasmus MC, Rotterdam, The Netherlands.

Objective: We aimed to characterize cortical superficial siderosis, its determinants and sequel, in community-dwelling older adults.

Methods: The sample consisted of Framingham ( = 1724; 2000-2009) and Rotterdam ( = 4325; 2005-2013) study participants who underwent brain MRI. In pooled individual-level analysis, we compared baseline characteristics in patients with cortical superficial siderosis to two reference groups: (i) persons without hemorrhagic MRI markers of cerebral amyloid angiopathy (no cortical superficial siderosis and no microbleeds) and (ii) those with presumed cerebral amyloid angiopathy based on the presence of strictly lobar microbleeds but without cortical superficial siderosis.

Results: Among a total of 6049 participants, 4846 did not have any microbleeds or cortical superficial siderosis (80%), 401 had deep/mixed microbleeds (6.6%), 776 had strictly lobar microbleeds without cortical superficial siderosis (12.8%) and 26 had cortical superficial siderosis with/without microbleeds (0.43%). In comparison to participants without microbleeds or cortical superficial siderosis and to those with strictly lobar microbleeds but without cortical superficial siderosis, participants with cortical superficial siderosis were older (OR 1.09 per year, 95% CI 1.05, 1.14;  < 0.001 and 1.04, 95% CI 1.00, 1.09;  = 0.058, respectively), had overrepresentation of the APOE ɛ4 allele (5.19, 2.04, 13.25;  = 0.001 and 3.47, 1.35, 8.92;  = 0.01), and greater prevalence of intracerebral hemorrhage (72.57, 9.12, 577.49;  < 0.001 and 81.49, 3.40, >999.99;  = 0.006). During a mean follow-up of 5.6 years, 42.4% participants with cortical superficial siderosis had a stroke (five intracerebral hemorrhage, two ischemic strokes and four undetermined strokes), 19.2% had transient neurological deficits and 3.8% developed incident dementia.

Conclusion: Our study adds supporting evidence to the association between cortical superficial siderosis and cerebral amyloid angiopathy within the general population. Community-dwelling persons with cortical superficial siderosis may be at high risk for intracerebral hemorrhage and future neurological events.
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January 2021

Global impact of COVID-19 on stroke care.

Int J Stroke 2021 07 29;16(5):573-584. Epub 2021 Mar 29.

Neurology, Grady Memorial Hospital, Emory University, Atlanta, Georgia, USA.

Background: The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide.

Aims: We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March-31 May 2020) compared with two control three-month periods (immediately preceding and one year prior).

Methods: Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers.

Results: The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, -19.7 to -18.7), 11.5% (95%CI, -12.6 to -10.6), and 12.7% (95%CI, -13.6 to -11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers. High-volume COVID-19 centers (-20.5%) had greater declines in mechanical thrombectomy volumes than mid- (-10.1%) and low-volume (-8.7%) centers (p < 0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions.

Conclusion: The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.
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http://dx.doi.org/10.1177/1747493021991652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010375PMC
July 2021

COVID-19 and cerebrovascular diseases: a comprehensive overview.

Ther Adv Neurol Disord 2020 8;13:1756286420978004. Epub 2020 Dec 8.

Fourth Department of Internal Medicine, 'Attikon' University Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Neurological manifestations are not uncommon during infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A clear association has been reported between cerebrovascular disease and coronavirus disease 2019 (COVID-19). However, whether this association is causal or incidental is still unknown. In this narrative review, we sought to present the possible pathophysiological mechanisms linking COVID-19 and cerebrovascular disease, describe the stroke syndromes and their prognosis and discuss several clinical, radiological, and laboratory characteristics that may aid in the prompt recognition of cerebrovascular disease during COVID-19. A systematic literature search was conducted, and relevant information was abstracted. Angiotensin-converting enzyme-2 receptor dysregulation, uncontrollable immune reaction and inflammation, coagulopathy, COVID-19-associated cardiac injury with subsequent cardio-embolism, complications due to critical illness and prolonged hospitalization can all contribute as potential etiopathogenic mechanisms leading to diverse cerebrovascular clinical manifestations. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been described in case reports and cohorts of COVID-19 patients with a prevalence ranging between 0.5% and 5%. SARS-CoV-2-positive stroke patients have higher mortality rates, worse functional outcomes at discharge and longer duration of hospitalization as compared with SARS-CoV-2-negative stroke patients in different cohort studies. Specific demographic, clinical, laboratory and radiological characteristics may be used as 'red flags' to alarm clinicians in recognizing COVID-19-related stroke.
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http://dx.doi.org/10.1177/1756286420978004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727052PMC
December 2020

Intravenous Thrombolysis With Tenecteplase in Patients With Large Vessel Occlusions: Systematic Review and Meta-Analysis.

Stroke 2021 01 4;52(1):308-312. Epub 2020 Dec 4.

Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Greece (A. Safouris, G.T.).

Background And Purpose: Accumulating evidence from randomized controlled clinical trials suggests that tenecteplase may represent an effective treatment alternative to alteplase for acute ischemic stroke. In the present systematic review and meta-analysis, we sought to compare the efficacy and safety outcomes of intravenous tenecteplase to intravenous alteplase administration for acute ischemic stroke patients with large vessel occlusions (LVOs).

Methods: We searched MEDLINE (Medical Literature Analysis and Retrieval System Online) and Scopus for published randomized controlled clinical trials providing outcomes of acute ischemic stroke with confirmed LVO receiving intravenous thrombolysis with either tenecteplase at different doses or alteplase at a standard dose of 0.9 mg/kg. The primary outcome was the odds of modified Rankin Scale score of 0 to 2 at 3 months.

Results: We included 4 randomized controlled clinical trials including a total of 433 patients. Patients with confirmed LVO receiving tenecteplase had higher odds of modified Rankin Scale scores of 0 to 2 (odds ratio, 2.06 [95% CI, 1.15-3.69]), successful recanalization (odds ratio, 3.05 [95% CI, 1.73-5.40]), and functional improvement defined as 1-point decrease across all modified Rankin Scale grades (common odds ratio, 1.84 [95% CI, 1.18-2.87]) at 3 months compared with patients with confirmed LVO receiving alteplase. There was little or no heterogeneity between the results provided from included studies regarding the aforementioned outcomes (I≤20%). No difference in the outcomes of early neurological improvement, symptomatic intracranial hemorrhage, any intracranial hemorrhage, and the rates of modified Rankin Scale score 0 to 1 or all-cause mortality at 3 months was detected between patients with LVO receiving intravenous thrombolysis with either tenecteplase or alteplase.

Conclusions: Acute ischemic stroke patients with LVO receiving intravenous thrombolysis with tenecteplase have significantly better recanalization and clinical outcomes compared with patients receiving intravenous alteplase.
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http://dx.doi.org/10.1161/STROKEAHA.120.030220DOI Listing
January 2021

The Impact of SARS-CoV-2 on Stroke Epidemiology and Care: A Meta-Analysis.

Ann Neurol 2021 02 9;89(2):380-388. Epub 2020 Dec 9.

Second Department of Neurology, Attikon Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Objective: Emerging data indicate an increased risk of cerebrovascular events with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and highlight the potential impact of coronavirus disease (COVID-19) on the management and outcomes of acute stroke. We conducted a systematic review and meta-analysis to evaluate the aforementioned considerations.

Methods: We performed a meta-analysis of observational cohort studies reporting on the occurrence and/or outcomes of patients with cerebrovascular events in association with their SARS-CoV-2 infection status. We used a random-effects model. Summary estimates were reported as odds ratios (ORs) and corresponding 95% confidence intervals (CIs).

Results: We identified 18 cohort studies including 67,845 patients. Among patients with SARS-CoV-2, 1.3% (95% CI = 0.9-1.6%, I = 87%) were hospitalized for cerebrovascular events, 1.1% (95% CI = 0.8-1.3%, I = 85%) for ischemic stroke, and 0.2% (95% CI = 0.1-0.3%, I = 64%) for hemorrhagic stroke. Compared to noninfected contemporary or historical controls, patients with SARS-CoV-2 infection had increased odds of ischemic stroke (OR = 3.58, 95% CI = 1.43-8.92, I = 43%) and cryptogenic stroke (OR = 3.98, 95% CI = 1.62-9.77, I = 0%). Diabetes mellitus was found to be more prevalent among SARS-CoV-2 stroke patients compared to noninfected historical controls (OR = 1.39, 95% CI = 1.00-1.94, I = 0%). SARS-CoV-2 infection status was not associated with the likelihood of receiving intravenous thrombolysis (OR = 1.42, 95% CI = 0.65-3.10, I = 0%) or endovascular thrombectomy (OR = 0.78, 95% CI = 0.35-1.74, I = 0%) among hospitalized ischemic stroke patients during the COVID-19 pandemic. Odds of in-hospital mortality were higher among SARS-CoV-2 stroke patients compared to noninfected contemporary or historical stroke patients (OR = 5.60, 95% CI = 3.19-9.80, I = 45%).

Interpretation: SARS-CoV-2 appears to be associated with an increased risk of ischemic stroke, and potentially cryptogenic stroke in particular. It may also be related to an increased mortality risk. ANN NEUROL 2021;89:380-388.
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http://dx.doi.org/10.1002/ana.25967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753413PMC
February 2021

Statin treatment and cerebral microbleeds: A systematic review and meta-analysis.

J Neurol Sci 2021 01 8;420:117224. Epub 2020 Nov 8.

Division of Neurology, McMaster University / Population Health Research Institute, Hamilton, ON, Canada.

Although statins have been associated with increased risk of spontaneous intracerebral hemorrhage, their relationship with cerebral microbleeds (CMBs) formation is poorly understood. We systematically reviewed previously published studies reporting on the association between CMBs presence and current statin use. We performed a systematic search in MEDLINE and SCOPUS databases on October 24, 2019 to identify all cohorts from randomized-controlled clinical trials or observational studies reporting on CMB prevalence and statin use. We extracted cross-sectional data on CMBs presence, as provided by each study, in association to the history of current statin use. Random effects model was used to calculate the pooled estimates. We included 7 studies (n = 3734 participants): unselected general population [n = 1965], ischemic stroke [n = 849], hemorrhagic stroke [n = 252] and patients with hypertension over the age of 60 [n = 668]. Statin use was not associated with CMBs presence in either unadjusted (OR = 1.15, 95%CI: 0.76-1.74) or adjusted analyses (OR = 1.09, 95%CI: 0.64-1.86). Statin use was more strongly related to lobar CMB presence (OR = 2.01, 95%CI: 1.48-2.72) in unadjusted analysis. The effect size of this association was consistent, but no longer statistically significant in adjusted analysis that was confined to two eligible studies (OR = 2.26, 95%CI: 0.86-5.91). Except for the analysis on the unadjusted probability of lobar CMBs presence, considerable heterogeneity was present in all other analyses (I > 60%). Our findings suggest that statin treatment seems not to be associated with CMBs overall, but may increase the risk of lobar CMB formation. This hypothesis deserves further investigation within magnetic resonance imaging ancillary studies of randomized trials.
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http://dx.doi.org/10.1016/j.jns.2020.117224DOI Listing
January 2021

Canadian stroke best practice recommendations: , 7th Edition Update 2020.

Int J Stroke 2021 04 11;16(3):321-341. Epub 2020 Nov 11.

Department of Neurology, Universite de Montreal, Montreal, Canada.

Spontaneous intracerebral hemorrhage is a particularly devastating type of stroke with greater morbidity and mortality compared with ischemic stroke and can account for half or more of all deaths from stroke. The seventh update of the includes a new stand-alone module on intracerebral hemorrhage, with a focus on elements of care that are unique or affect persons disproportionately relative to ischemic stroke. Prior to this edition, intracerebral hemorrhage was included in the Acute Stroke Management module and was limited to its management during the first 12 h. With the growing evidence on intracerebral hemorrhage, a separate module focused on this topic across the care continuum was added. In addition to topics related to initial clinical management, neuroimaging, blood pressure management, and surgical management, new sections have been introduced addressing topics surrounding inpatient complications such as venous thromboembolism, seizure management, and increased intracranial pressure, rehabilitation as well as issues related to secondary management including lifestyle management, maintaining a normal blood pressure and antithrombotic therapy, are addressed. The () are intended to provide up-to-date evidence-based guidelines for the prevention and management of stroke and to promote optimal recovery and reintegration for people who have experienced stroke, including patients, families, and informal caregivers.
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http://dx.doi.org/10.1177/1747493020968424DOI Listing
April 2021

Microbleeds and the Effect of Anticoagulation in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

JAMA Neurol 2021 01;78(1):11-20

Division of Neurology, McMaster University / Population Health Research Institute, Hamilton, Ontario, Canada.

Importance: The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging.

Objective: To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy.

Design, Setting, And Participants: Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial.

Interventions: Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily.

Main Outcomes And Measures: The primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality.

Results: Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI, 1.54-3.15), multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97).

Conclusions And Relevance: Microbleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical outcomes.

Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.
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http://dx.doi.org/10.1001/jamaneurol.2020.3836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573796PMC
January 2021

In-Hospital Delays for Acute Stroke Treatment Delivery During the COVID-19 Pandemic.

Can J Neurol Sci 2021 Jan 3;48(1):59-65. Epub 2020 Aug 3.

Division of Neurology, Hamilton General Hospital-Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.

Background: We investigated the impact of regionally imposed social and healthcare restrictions due to coronavirus disease 2019 (COVID-19) to the time metrics in the management of acute ischemic stroke patients admitted at the regional stroke referral site for Central South Ontario, Canada.

Methods: We compared relevant time metrics between patients with acute ischemic stroke receiving intravenous tissue plasminogen activator (tPA) and/or endovascular thrombectomy (EVT) before and after the declared restrictions and state of emergency imposed in our region (March 17, 2020).

Results: We identified a significant increase in the median door-to-CT times for patients receiving intravenous tPA (19 min, interquartile range (IQR): 14-27 min vs. 13 min, IQR: 9-17 min, p = 0.008) and/or EVT (20 min, IQR: 15-33 min vs. 11 min, IQR: 5-20 min, p = 0.035) after the start of social and healthcare restrictions in our region compared to the previous 12 months. For patients receiving intravenous tPA treatment, we also found a significant increase (p = 0.005) in the median door-to-needle time (61 min, IQR: 46-72 min vs. 37 min, IQR: 30-50 min). No delays in the time from symptom onset to hospital presentation were uncovered for patients receiving tPA and/or endovascular reperfusion treatments in the first 1.5 months after the establishment of regional and institutional restrictions due to the COVID-19 pandemic.

Conclusion: We detected an increase in our institutional time to treatment metrics for acute ischemic stroke patients receiving tPA and/or endovascular reperfusion therapies, related to delays from hospital presentation to the acquisition of cranial CT imaging for both tPA- and EVT-treated patients, and an added delay to treatment with tPA.
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http://dx.doi.org/10.1017/cjn.2020.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533482PMC
January 2021

A Pooled Analysis of Diffusion-Weighted Imaging Lesions in Patients With Acute Intracerebral Hemorrhage.

JAMA Neurol 2020 11;77(11):1390-1397

Division of Neurosciences Critical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: The etiology and significance of diffusion-weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear.

Objective: To evaluate which factors are associated with DWI lesions, whether associated factors differ by ICH location, and whether DWI lesions are associated with functional outcomes.

Design, Setting, And Participants: This analysis pooled individual patient data from 3 randomized clinical trials (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, and Intracerebral Hemorrhage Deferoxamine phase 2 trial) and 1 multicenter prospective study (Ethnic/Racial Variations of Intracerebral Hemorrhage). Patients were enrolled from August 1, 2010, to September 30, 2018. Of the 4782 patients, 1788 who underwent magnetic resonance imaging scans of the brain were included. Data were analyzed from July 1 to December 31, 2019.

Main Outcomes And Measures: The primary outcome consisted of factors associated with DWI lesions. Secondary outcomes were poor functional outcome, defined as a modified Rankin score (mRS) of 4 to 6, and mortality, both assessed at 3 months. Mixed-effects logistic regression was used to evaluate the association between exposures and outcomes. Subgroup analyses stratified by hematoma location were performed.

Results: After exclusion of 36 patients with missing data on DWI lesions, 1752 patients were included in the analysis (1019 men [58.2%]; mean [SD] age, 60.8 [13.3] years). Diffusion-weighted imaging lesions occurred in 549 patients (31.3%). In mixed-effects regression models, factors associated with DWI lesions included younger age (odds ratio [OR] per year, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.64; 95% CI, 1.17-2.30), admission systolic blood pressure (OR per 10-mm Hg increase, 1.13; 95% CI, 1.08-1.18), baseline hematoma volume (OR per 10-mL increase, 1.12; 95% CI, 1.02-1.22), cerebral microbleeds (OR, 1.85; 95% CI, 1.39-2.46), and leukoaraiosis (OR, 1.59; 95% CI, 1.67-2.17). Diffusion-weighted imaging lesions were independently associated with poor mRS (OR, 1.50; 95% CI, 1.13-2.00), but not with mortality (OR, 1.11; 95% CI, 0.72-1.71). In subgroup analyses, similar factors were associated with DWI lesions in lobar and deep ICH. Diffusion-weighted imaging lesions were associated with poor mRS in deep but not lobar ICH.

Conclusions And Relevance: In a large, heterogeneous cohort of prospectively identified patients with ICH, results were consistent with the hypothesis that DWI lesions represent acute sequelae of chronic cerebral small vessel disease, particularly hypertensive vasculopathy. Diffusion-weighted imaging lesions portend a worse prognosis after ICH, mainly deep hemorrhages.
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http://dx.doi.org/10.1001/jamaneurol.2020.2349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372494PMC
November 2020

Oral factor Xa inhibitors and risk of subdural hematoma: COMPASS trial results and meta-analysis.

Neurology 2020 08 10;95(5):e480-e487. Epub 2020 Jul 10.

From the Department of Medicine (Neurology) (L.C., K.N., S.N., K.S.P., A.S., M.S., R.G.H.), Department of Medicine (Division of Hematology & Thromboembolism) (J.W.E.), and School of Rehabilitation Science (J.B.), McMaster University/Hamilton Health Sciences/Population Health Research Institute (O.S.), Hamilton, Canada.

Objective: Subdural hematomas (SDHs) are an uncommon, but important, complication of anticoagulation therapy. We hypothesized that the risks of SDH would be similar during treatment with oral factor Xa inhibitors compared with aspirin.

Methods: We assessed the frequency and the effects of antithrombotic treatments on SDHs in the recent international Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial comparing aspirin 100 mg daily, rivaroxaban 5 mg twice daily, and rivaroxaban 2.5 mg twice daily plus aspirin. A systematic review/meta-analysis of randomized trials comparing oral factor Xa inhibitors vs aspirin on SDH risk was undertaken.

Results: Among 27,395 COMPASS participants, 28 patients with SDHs were identified (mean age 72 years). SDH-associated mortality was 7%. Incidence was 0.06 per 100 patient-years (11 SDH/17,492 years observation) during the mean 23-month follow-up among aspirin-assigned patients and did not differ significantly between treatments. Three additional randomized controlled trials including 16,177 participants reported a total of 14 SDHs with an incidence ranging from 0.06 to 0.1 per 100 patient-years. Factor Xa inhibitor use was not associated with an increased risk of SDH compared to aspirin (odds ratio, 0.97; 95% confidence interval, 0.52-1.81; I = 0%).

Conclusion: The frequency of SDH was similar in all 3 treatment arms of the COMPASS trial. The COMPASS trial results markedly increase the available evidence from randomized comparisons of oral factor Xa inhibitors with aspirin regarding SDH. From available, albeit limited, evidence from 4 randomized trials, therapeutic dosages of factor Xa inhibitors do not appear to increase the risk of SDH compared with aspirin.

Clinical Trial Identifier Number: NCT01776424.
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http://dx.doi.org/10.1212/WNL.0000000000009826DOI Listing
August 2020

High-Sensitivity Cardiac Troponin T for Risk Stratification in Patients With Embolic Stroke of Undetermined Source.

Stroke 2020 08 9;51(8):2386-2394. Epub 2020 Jul 9.

Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Germany (J.F.S., C.H.N., M.E.).

Background And Purpose: Optimal secondary prevention for patients with embolic stroke of undetermined source (ESUS) remains unknown. We aimed to assess whether high-sensitivity cardiac troponin T (hs-cTnT) levels are associated with major vascular events and whether hs-cTnT may identify patients who benefit from anticoagulation following ESUS.

Methods: Data were obtained from the biomarker substudy of the NAVIGATE ESUS trial, a randomized controlled trial testing the efficacy of rivaroxaban versus aspirin for secondary stroke prevention in ESUS. Patients were dichotomized at the hs-cTnT upper reference limit (14 ng/L, Gen V, Roche Diagnostics). Cox proportional hazard models were computed to explore the association between hs-cTnT, the combined cardiovascular end point (recurrent stroke, myocardial infarction, systemic embolism, cardiovascular death), and recurrent ischemic stroke.

Results: Among 1337 patients enrolled at 111 participating centers in 18 countries (mean age 67±9 years, 61% male), hs-cTnT was detectable in 95% and at/above the upper reference limit in 21%. During a median follow-up of 11 months, the combined cardiovascular end point occurred in 68 patients (5.0%/y, rivaroxaban 28 events, aspirin 40 events; hazard ratio, 0.67 [95% CI, 0.41-1.1]), and recurrent ischemic stroke occurred in 50 patients (4.0%/y, rivaroxaban 16 events, aspirin 34 events, hazard ratio 0.45 [95% CI, 0.25-0.81]). Annualized combined cardiovascular end point rates were 8.2% (9.5% rivaroxaban, 7.0% aspirin) for those above hs-cTnT upper reference limit and 4.8% (3.1% rivaroxaban, 6.6% aspirin) below with a significant treatment modification (=0.04). Annualized ischemic stroke rates were 4.7% above hs-cTnT upper reference limit and 3.9% below, with no suggestion of an interaction between hs-cTnT and treatment (=0.3).

Conclusions: In patients with ESUS, hs-cTnT was associated with increased cardiovascular event rates. While fewer recurrent strokes occurred in patients receiving rivaroxaban, outcomes were not stratified by hs-cTn results. Our findings support using hs-cTnT for cardiovascular risk stratification but not for decision-making regarding anticoagulation therapy in patients with ESUS. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.
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http://dx.doi.org/10.1161/STROKEAHA.120.029628DOI Listing
August 2020

Characteristics of Recurrent Ischemic Stroke After Embolic Stroke of Undetermined Source: Secondary Analysis of a Randomized Clinical Trial.

JAMA Neurol 2020 10;77(10):1233-1240

Population Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Importance: The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS.

Objective: To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke.

Design, Setting, And Participants: The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019.

Interventions: Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d.

Main Outcomes And Measures: Association of recurrent ESUS with stroke characteristics.

Results: A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively).

Conclusions And Relevance: In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy.

Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.
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http://dx.doi.org/10.1001/jamaneurol.2020.1995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550970PMC
October 2020

Frequency and Predictors of Major Bleeding in Patients With Embolic Strokes of Undetermined Source: NAVIGATE-ESUS Trial.

Stroke 2020 07 10;51(7):2139-2147. Epub 2020 Jun 10.

McMaster University/Population Health Research Institute, Hamilton Health Sciences, ON, Canada (A.S., S.J.C., R.G.H.).

Background And Purpose: Risks, sites, and predictors of major bleeding during antithrombotic therapies have not been well defined for patients with recent embolic stroke of undetermined source.

Methods: Exploratory analysis of major bleeds defined by International Society of Thrombosis and Hemostasis criteria occurring among 7213 participants in international NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial) embolic stroke of undetermined source randomized trial comparing rivaroxaban 15 mg daily with aspirin 100 mg daily.

Results: During a median follow-up of 11 months, 85 major bleeds occurred. The most frequent site was gastrointestinal (38%), followed by intracranial (29%). Assignment to rivaroxaban (hazard ratio [HR], 2.7 [95% CI, 1.7-4.3]), East Asia region (HR, 2.5 [95% CI, 1.6-3.9]), systolic blood pressure ≥160 mm Hg (HR, 2.2 [95% CI, 1.2-3.8]), and reduced estimated glomerular filtration rate (HR, 1.2 per 10 mL/min per 1.73 m decrease, [95% CI, 1.0-1.3]) were independently associated with presence of major bleeds. Five (6%) were fatal. Among 15 patients with intracerebral hemorrhage, 2 (13%) were fatal. There was no evidence of an early high-risk period following initiation of rivaroxaban. The annualized rate of intracerebral hemorrhage was 6-fold higher among East Asian participants (0.67%) versus all other regions (0.11%; HR, 6.3 [95% CI, 2.2-18.0]). Distribution of bleeding sites was similar for rivaroxaban and aspirin.

Conclusions: Among embolic stroke of undetermined source patients participating in an international randomized trial, independent predictors of major bleeding were assignment to rivaroxaban, East Asia region, increased systolic blood pressure, and impaired renal function. East Asia as a region was strongly associated with risk of intracerebral hemorrhage. Estimated glomerular filtration rate should be a consideration for stratifying bleeding risk. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.
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http://dx.doi.org/10.1161/STROKEAHA.119.027995DOI Listing
July 2020

Ultra-Early Blood Pressure Reduction Attenuates Hematoma Growth and Improves Outcome in Intracerebral Hemorrhage.

Ann Neurol 2020 08 1;88(2):388-395. Epub 2020 Jul 1.

Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Objective: The aim was to investigate whether intensive blood pressure treatment is associated with less hematoma growth and better outcome in intracerebral hemorrhage (ICH) patients who received intravenous nicardipine treatment ≤2 hours after onset of symptoms.

Methods: A post-hoc exploratory analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial was performed. This was a multicenter, international, open-label, randomized clinical trial, in which patients with primary ICH were allocated to intensive versus standard blood pressure treatment with nicardipine ≤4.5 hours after onset of symptoms. We have included 913 patients with complete imaging and follow-up data in the present analysis.

Results: Among the 913 included patients, 354 (38.7%) had intravenous nicardipine treatment initiated within 2 hours. In this subgroup of patients treated within 2 hours, the frequency of ICH expansion was significantly lower in the intensive blood pressure reduction group compared with the standard treatment group (p = 0.02). Multivariable analysis showed that ultra-early intensive blood pressure treatment was associated with a decreased risk of hematoma growth (odds ratio, 0.56; 95% confidence interval [CI], 0.34-0.92; p = 0.02), higher rate of functional independence (odds ratio, 2.17; 95% CI, 1.28-3.68; p = 0.004), and good outcome (odds ratio, 1.68; 95% CI, 1.01-2.83; p = 0.048) at 90 days. Ultra-early intensive blood pressure reduction was associated with a favorable shift in modified Rankin Scale score distribution at 3 months (p = 0.04).

Interpretation: In a subgroup of ICH patients with elevated blood pressure given intravenous nicardipine ≤2 hours after onset of symptoms, intensive blood pressure reduction was associated with reduced hematoma growth and improved functional outcome. ANN NEUROL 2020;88:388-395.
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http://dx.doi.org/10.1002/ana.25793DOI Listing
August 2020

Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children.

Can J Cardiol 2020 05;36(5):596-624

Service de néphrologie, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Quebec, Canada.

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.
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http://dx.doi.org/10.1016/j.cjca.2020.02.086DOI Listing
May 2020
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