Publications by authors named "Scott E Kasner"

235 Publications

Patent Foramen Ovale Closure Decreases the Incidence but Not the Size of New Brain Infarction on Magnetic Resonance Imaging: An Analysis of the REDUCE Trial.

Stroke 2021 Aug 30:STROKEAHA121034451. Epub 2021 Aug 30.

Department of Neurology, University of Pennsylvania, Philadelphia. (S.R.M., S.E.K.).

Background And Purpose: Randomized patent foramen ovale closure trials have used open-label end point ascertainment which increases the risk of bias and undermines confidence in the conclusions. The Gore REDUCE trial prospectively performed baseline and follow-up magnetic resonance imaging (MRIs) for all subjects providing an objective measure of the effectiveness of closure.

Methods: We performed blinded evaluations of the presence, location, and volume of new infarct on diffusion-weighted imaging of recurrent clinical stroke or new infarct (>3 mm) on T2/fluid attenuated inversion recovery from baseline to follow-up MRI at 2 years, comparing closure to medical therapy alone. We also examined the effect of shunt size and the development of atrial fibrillation on infarct burden at follow-up.

Results: At follow-up, new clinical stroke or silent MRI infarct occurred in 18/383 (4.7%) patients who underwent closure and 19/177 (10.7%) medication-only patients (relative risk, 0.44 [95% CI, 0.24-0.81], =0.02). Clinical strokes were less common in closure patients compared with medically treated patients, 5 (1.3%) versus 12 (6.8%), =0.001, while silent MRI infarcts were similar, 13 (3.4%) versus 7 (4.0%), =0.81. There were no differences in number, volumes, and distribution of new infarct comparing closure patients to those treated with medication alone. There were also no differences of number, volumes, and distribution comparing silent infarcts to clinical strokes. Infarct burden was also similar for patients who developed atrial fibrillation and for those with large shunts.

Conclusions: The REDUCE trial demonstrates that patent foramen ovale closure prevents recurrent brain infarction based on the objective outcome of new infarcts on MRI. Only clinical strokes were reduced by closure while silent infarctions were similar between study arms, and there were no differences in infarct volume or location comparing silent infarcts to clinical strokes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00738894.
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http://dx.doi.org/10.1161/STROKEAHA.121.034451DOI Listing
August 2021

Statins for the Prevention of Post-Stroke Seizure and Epilepsy Development: A Systematic Review and Meta-Analysis.

J Stroke Cerebrovasc Dis 2021 Aug 23;30(10):106024. Epub 2021 Aug 23.

Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States.

Objectives: Cerebrovascular disease is the leading cause of seizures and incident epilepsy of known etiology in older adults. Statins have increasingly garnered attention as a potential preventive strategy due to their pleiotropic effects beyond lipid-lowering, which may include neuroprotective and anti-epileptogenic properties. We aim to assess the evidence on statin use for prevention of post-stroke early-onset seizures and post-stroke epilepsy.

Materials And Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines, which was prospectively registered with PROSPERO (CRD42019144916). PubMed and Embase were searched from database inception to 05/2020 for English-language, full-text studies examining the association between statin use in adults and development of early-onset seizures (≤7 days post-stroke) or post-stroke epilepsy. Pooled analyses were based on random-effects models using the inverse-variance method.

Results: Of 182 citations identified, 175 were excluded due to duplication or ineligibility. The 7 eligible publications were all cohort studies from East Asia or South America, with a total of 53,579 patients. Pre-stroke statin use was not associated with post-stroke epilepsy (3 studies pooled: OR 1.14, CI 0.91-1.42). However, post-stroke statin use was associated with lower risk of both early-onset seizures (3 studies pooled: OR 0.36, CI 0.25-0.53), and post-stroke epilepsy (6 studies pooled: OR 0.64, CI 0.46-0.88).

Conclusions: Review of 7 cohort studies suggested post-stroke, but not pre-stroke, statin use may be associated with reduced risk of early-onset seizures and post-stroke epilepsy. Further research is warranted to validate these findings in broader populations and better parse the temporal components of the associations.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106024DOI Listing
August 2021

Primary Care of Adult Patients After Stroke: A Scientific Statement From the American Heart Association/American Stroke Association.

Stroke 2021 Aug 15;52(9):e558-e571. Epub 2021 Jul 15.

Primary care teams provide the majority of poststroke care. When optimally configured, these teams provide patient-centered care to prevent recurrent stroke, maximize function, prevent late complications, and optimize quality of life. Patient-centered primary care after stroke begins with establishing the foundation for poststroke management while engaging caregivers and family members in support of the patient. Screening for complications (eg, depression, cognitive impairment, and fall risk) and unmet needs is both a short-term and long-term component of poststroke care. Patients with ongoing functional impairments may benefit from referral to appropriate services. Ongoing care consists of managing risk factors such as high blood pressure, atrial fibrillation, diabetes, carotid stenosis, and dyslipidemia. Recommendations to reduce risk of recurrent stroke also include lifestyle modifications such as healthy diet and exercise. At the system level, primary care practices can use quality improvement strategies and available resources to enhance the delivery of evidence-based care and optimize outcomes.
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http://dx.doi.org/10.1161/STR.0000000000000382DOI Listing
August 2021

Encephalopathy at admission predicts adverse outcomes in patients with SARS-CoV-2 infection.

CNS Neurosci Ther 2021 Oct 16;27(10):1127-1135. Epub 2021 Jun 16.

Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, China.

Aims: To determine if neurologic symptoms at admission can predict adverse outcomes in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: Electronic medical records of 1053 consecutively hospitalized patients with laboratory-confirmed infection of SARS-CoV-2 from one large medical center in the USA were retrospectively analyzed. Univariable and multivariable Cox regression analyses were performed with the calculation of areas under the curve (AUC) and concordance index (C-index). Patients were stratified into subgroups based on the presence of encephalopathy and its severity using survival statistics. In sensitivity analyses, patients with mild/moderate and severe encephalopathy (defined as coma) were separately considered.

Results: Of 1053 patients (mean age 52.4 years, 48.0% men [n = 505]), 35.1% (n = 370) had neurologic manifestations at admission, including 10.3% (n = 108) with encephalopathy. Encephalopathy was an independent predictor for death (hazard ratio [HR] 2.617, 95% confidence interval [CI] 1.481-4.625) in multivariable Cox regression. The addition of encephalopathy to multivariable models comprising other predictors for adverse outcomes increased AUCs (mortality: 0.84-0.86, ventilation/ intensive care unit [ICU]: 0.76-0.78) and C-index (mortality: 0.78 to 0.81, ventilation/ICU: 0.85-0.86). In sensitivity analyses, risk stratification survival curves for mortality and ventilation/ICU based on severe encephalopathy (n = 15) versus mild/moderate encephalopathy (n = 93) versus no encephalopathy (n = 945) at admission were discriminative (p < 0.001).

Conclusions: Encephalopathy at admission predicts later progression to death in SARS-CoV-2 infection, which may have important implications for risk stratification in clinical practice.
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http://dx.doi.org/10.1111/cns.13687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444722PMC
October 2021

Blood flow response to orthostatic challenge identifies signatures of the failure of static cerebral autoregulation in patients with cerebrovascular disease.

BMC Neurol 2021 Apr 9;21(1):154. Epub 2021 Apr 9.

Department of Neurology (Stroke Unit). Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.

Background: The cortical microvascular cerebral blood flow response (CBF) to different changes in head-of-bed (HOB) position has been shown to be altered in acute ischemic stroke (AIS) by diffuse correlation spectroscopy (DCS) technique. However, the relationship between these relative ΔCBF changes and associated systemic blood pressure changes has not been studied, even though blood pressure is a major driver of cerebral blood flow.

Methods: Transcranial DCS data from four studies measuring bilateral frontal microvascular cerebral blood flow in healthy controls (n = 15), patients with asymptomatic severe internal carotid artery stenosis (ICA, n = 27), and patients with acute ischemic stroke (AIS, n = 72) were aggregated. DCS-measured CBF was measured in response to a short head-of-bed (HOB) position manipulation protocol (supine/elevated/supine, 5 min at each position). In a sub-group (AIS, n = 26; ICA, n = 14; control, n = 15), mean arterial pressure (MAP) was measured dynamically during the protocol.

Results: After elevated positioning, DCS CBF returned to baseline supine values in controls (p = 0.890) but not in patients with AIS (9.6% [6.0,13.3], mean 95% CI, p < 0.001) or ICA stenosis (8.6% [3.1,14.0], p = 0.003)). MAP in AIS patients did not return to baseline values (2.6 mmHg [0.5, 4.7], p = 0.018), but in ICA stenosis patients and controls did. Instead ipsilesional but not contralesional CBF was correlated with MAP (AIS 6.0%/mmHg [- 2.4,14.3], p = 0.038; ICA stenosis 11.0%/mmHg [2.4,19.5], p < 0.001).

Conclusions: The observed associations between ipsilateral CBF and MAP suggest that short HOB position changes may elicit deficits in cerebral autoregulation in cerebrovascular disorders. Additional research is required to further characterize this phenomenon.
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http://dx.doi.org/10.1186/s12883-021-02179-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033703PMC
April 2021

An assessment of annual procedure volumes and therapy adoption of transcatheter closure of patent foramen ovale in four European countries.

Eur Stroke J 2021 Mar 24;6(1):72-80. Epub 2020 Sep 24.

Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.

Introduction: Patent foramen ovale closure reduces recurrence of cryptogenic ischaemic stroke compared to anti-platelet therapy. Our goal was to determine procedure volumes and closure utilisation as a proportion of candidates in four large European countries.

Patients And Methods: National statistics were obtained for Germany, England, France, and Italy for the last available five years (2014-2018). Eligibility was aligned to the enrolment criteria of pivotal trials and current consensus documents. Stroke and transient ischaemic attack incidences were obtained from epidemiological registries and claims data. The eligible candidate pool for analysis included current year candidates plus untreated patients from the prior two years. Absolute strokes avoided assumed the hazard ratio for ischaemic stroke recurrence from a recent meta-analysis.

Results: In 2018, closure incidence rates were 5.64, 0.53, 2.94 and 5.26 per 100,000 in Germany, England, France and Italy, respectively. This reflects five-year increases of 128% in Germany, 462% in France and 36% in Italy ( < 0.05 for all), and a decline of 37% in England. The proportions of treated patients versus candidates for the combined stroke and transient ischaemic attack pool were 55%, 30%, 80%, and 6%, respectively.

Discussion: Patent foramen ovale closure volumes increased after the 2017 announcement of positive trial results but still differ substantially across large European countries. If all closure candidates in 2018 with prior ischaemic stroke were treated, the resulting absolute reduction of recurrent ischaemic strokes, compared to anti-platelet therapy alone, would be between 782 and 2295 across the four countries over five years.

Conclusion: Many eligible patients at risk for a recurrent cryptogenic event might remain untreated due to regional practice variations.
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http://dx.doi.org/10.1177/2396987320939804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995320PMC
March 2021

Antithrombotic therapy for cervical arterial dissection.

Authors:
Scott E Kasner

Lancet Neurol 2021 05 23;20(5):328-329. Epub 2021 Mar 23.

Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(21)00073-9DOI Listing
May 2021

Stroke, Timing of Atrial Fibrillation Diagnosis, and Risk of Death.

Neurology 2021 03 3;96(12):e1655-e1662. Epub 2021 Feb 3.

From the Division of Cardiovascular Medicine, Department of Medicine (A.B., Y.B., M.C.H., J.A., D.J.C., N.C., S.D., A.E.E., D.S.F., F.C.G., R.K., J.J.L., D.L., S.N., M.P.R., P.S., R.D.S., G.E.S., F.M., R.D.), and Department of Neurology (S.R.M., S.E.K.), Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia; Department of Biostatistics (R.K.), University of Washington, Seattle; and Division of Cardiology (P.J.P.), St. Vincent Medical Group, Indianapolis, IN.

Objective: To evaluate the prognosis of patients with ischemic stroke according to the timing of an atrial fibrillation (AF) diagnosis, we created an inception cohort of incident stroke events and compared the risk of death between patients with stroke with (1) sinus rhythm, (2) known AF (KAF), and (3) AF diagnosed after stroke (AFDAS).

Methods: We used the Penn AF Free study to create an inception cohort of patients with incident stroke. Mortality events were identified after linkage with the National Death Index through June 30, 2017. We also evaluated initiation of anticoagulants and antiplatelets across the study duration. Cox proportional hazards models evaluated associations between stroke subtypes and death.

Results: We identified 1,489 individuals who developed an incident ischemic stroke event: 985 did not develop AF at any point during the study period, 215 had KAF before stroke, 160 had AF detected ≤6 months after stroke, and 129 had AF detected >6 months after stroke. After a median follow-up of 4.9 years (interquartile range 1.9-6.8), 686 deaths occurred. The annualized mortality rate was 8.8% in the stroke, no AF group; 12.2% in the KAF group; 15.8% in the AFDAS ≤6 months group; and 12.7% in the AFDAS >6 months group. Patients in the AFDAS ≤6 months group had the highest independent risk of all-cause mortality even after multivariable adjustment for demographics, clinical risk factors, and the use of antithrombotic therapies (hazard ratio 1.62 [1.22-2.14]). Compared to the stroke, no AF group, those with KAF had a higher mortality risk that was rendered nonsignificant after adjustment.

Conclusions: The AFDAS group had the highest risk of death, which was not explained by comorbidities or use of antithrombotic therapies.
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http://dx.doi.org/10.1212/WNL.0000000000011633DOI Listing
March 2021

European position paper on the management of patients with patent foramen ovale. Part II - Decompression sickness, migraine, arterial deoxygenation syndromes and select high-risk clinical conditions.

Eur Heart J 2021 04;42(16):1545-1553

Ospedale San Giovanni Bosco, Turin, Italy.

Patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions but to date only one official position paper related to left circulation thromboembolism has been published. This interdisciplinary paper, prepared with the involvement of eight European scientific societies, reviews the available evidence and proposes a rationale for decision making for other PFO-related clinical conditions. In order to guarantee a strict evidence-based process, we used a modified grading of recommendations, assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements were weighed and graded according to predefined scales. Despite being based on limited and observational or low-certainty randomised data, a number of position statements were made to frame PFO management in different clinical settings, along with suggestions for new research avenues. This interdisciplinary position paper, recognising the low or very low certainty of existing evidence, provides the first approach to several PFO-related clinical scenarios beyond left circulation thromboembolism and strongly stresses the need for fresh high-quality evidence on these topics.
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http://dx.doi.org/10.1093/eurheartj/ehaa1070DOI Listing
April 2021

Cancer and Embolic Stroke of Undetermined Source.

Stroke 2021 Mar 28;52(3):1121-1130. Epub 2021 Jan 28.

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY (B.B.N., L.M.D.).

One-quarter to one-third of ischemic strokes have no established mechanism after standard diagnostic evaluation and are classified as embolic stroke of undetermined source (ESUS). Failure of randomized trials to demonstrate a benefit of direct oral anticoagulants over aspirin for the treatment of ESUS as a single homogeneous entity has led to renewed interest by stroke experts to divide ESUS into subgroups. Emerging data suggest that active cancer, which is present in 5% to 10% of patients with ESUS, is a distinct and important subgroup of ESUS with unique clinical characteristics, underlying pathophysiologies, and treatment and prognostic considerations. Furthermore, the prevalence of cancer-related ESUS is expected to increase as patients with cancer, even those with distant metastases, survive longer due to improvements in cancer treatments. In this topical review, we examine the epidemiological link between ESUS and cancer, the clinical features and potential mechanistic underpinnings of ESUS with cancer (with a focus on novel biomarkers and their relationship to recurrent stroke and other thromboembolic events), and the potential treatment strategies for cancer-related ESUS. We include a critical appraisal of existing data and ongoing or planned clinical trials of different antithrombotic approaches. As cancer-related ESUS is a dynamic disease with variable course, we recommend close collaboration between neurologists and oncologists to develop individualized management plans.
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http://dx.doi.org/10.1161/STROKEAHA.120.032002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902455PMC
March 2021

Vessel Wall Magnetic Resonance Imaging Biomarkers of Symptomatic Intracranial Atherosclerosis: A Meta-Analysis.

Stroke 2021 01 2;52(1):193-202. Epub 2020 Dec 2.

Neurology (S.E.K., S.R.M.), Hospital of the University of Pennsylvania, Philadelphia.

Background And Purpose: Intracranial atherosclerotic disease is a common cause of stroke worldwide. Intracranial vessel wall magnetic resonance imaging may be able to identify imaging biomarkers of symptomatic plaque. We performed a meta-analysis to evaluate the strength of association of imaging features of symptomatic plaque leading to downstream ischemic events. Effects on the strength of association were also assessed accounting for possible sources of bias and variability related to study design and magnetic resonance parameters.

Methods: PubMed, Scopus, Web of Science, EMBASE, and Cochrane databases were searched up to October 2019. Two independent reviewers extracted data on study design, vessel wall magnetic resonance imaging techniques, and imaging end points. Per-lesion odds ratios (OR) were calculated and pooled using a bivariate random-effects model. Subgroup analyses, sensitivity analysis, and evaluation of publication bias were also performed.

Results: Twenty-one articles met inclusion criteria (1750 lesions; 1542 subjects). Plaque enhancement (OR, 7.42 [95% CI, 3.35-16.43]), positive remodeling (OR, 5.60 [95% CI, 2.23-14.03]), T1 hyperintensity (OR, 2.05 [95% CI, 1.27-3.32]), and surface irregularity (OR, 4.50 [95% CI, 1.39-8.57]) were significantly associated with downstream ischemic events. T2 signal intensity was not significant (=0.59). Plaque enhancement was significantly associated with downstream ischemic events in all subgroup analyses and showed stronger associations when measured in retrospectively designed studies (=0.02), by a radiologist as a rater (<0.001), and on lower vessel wall magnetic resonance imaging spatial resolution sequences (=0.02).

Conclusions: Plaque enhancement, positive remodeling, T1 hyperintensity, and surface irregularity emerged as strong imaging biomarkers of symptomatic plaque in patients with ischemic events. Plaque enhancement remained significant accounting for sources of bias and variability in both study design and instrument. Future studies evaluating plaque enhancement as a predictive marker for stroke recurrence with larger sample sizes would be valuable.
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http://dx.doi.org/10.1161/STROKEAHA.120.031480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773134PMC
January 2021

Trends in oral anticoagulant co-prescription with antiepileptic drugs among adults with epilepsy, 2010-2018.

Epilepsy Behav 2020 12 24;113:107550. Epub 2020 Nov 24.

Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Department of Neurology, Translational Center of Excellence for Neuroepidemiology and Neurology Outcomes Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.

Treatment considerations for epilepsy patients requiring anticoagulation are changing, and actual prescribing practices have not been characterized. We used the 2010-2018 Optum Clinformatics® Data Mart Database to estimate the annual prevalence and distinguish the patterns of oral anticoagulants (OACs) co-dispensed with antiepileptic drugs (AEDs) among adults with epilepsy. Monotonic trends were assessed using the Spearman rank correlation coefficient (ρ). Multivariable logistic regression models were built to evaluate the associations of sociodemographic characteristics. Among 345,892 adults with epilepsy (56.5% female; median age 61, IQR 46-74) on studied AEDs, the prevalence per thousand of concurrent OACs increased from 58.4 in 2010 to 92.0 in 2018 (OR 1.63, CI 1.58-1.69). Direct-acting oral anticoagulant (DOAC) use rapidly increased from 2010 to 2018 (ρ = 1.00; P < 0.001), with a corresponding decrease in warfarin use (ρ = -0.97; P < 0.001). Among OAC/AED dispensings in 2018, warfarin was more likely to be co-dispensed with potentially interacting, enzyme-inducing antiepileptic drugs (EI-AEDs) versus presumably non-interacting, non-enzyme inducing antiepileptic drugs (OR 1.48, CI 1.38-1.59). Characteristics independently associated with concurrent OAC/EI-AED use included younger age, female sex, white race, net worth <$250 K, and lower education levels. Our findings demonstrate the expanding use and evolving patterns of OAC/AED co-dispensing, and ensuing critical need to further understanding regarding postulated interactions.
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http://dx.doi.org/10.1016/j.yebeh.2020.107550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780425PMC
December 2020

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

Impact of carotid tortuosity on outcome after endovascular thrombectomy.

Neurol Sci 2021 Jun 12;42(6):2347-2351. Epub 2020 Oct 12.

Department of Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Background And Objectives: Endovascular thrombectomy (EVT) is efficacious in patients with large vessel occlusion stroke (LVO). We explored whether internal carotid (ICA) tortuosity increases the technical difficulty of EVT thereby lowering the chances of successful recanalization and favorable outcomes.

Patients And Methods: Consecutive patients with LVO and patent ICAs who underwent EVT were included. Carotid tortuosity was determined on pre-EVT CTA and classified by raters blinded to outcomes into: type 1-straight ICA trunk and type 2-severe tortuosity potentially impeding adequate catheter placement. Thrombolysis in cerebral infarction (TICI) 2b-3 was considered successful recanalization, and 90-day-modified Rankin Scale ≤ 2 was considered favorable functional outcome.

Results: Among 302 patients (mean age 70 ± 15, median NIHSS 17), 53% had type 1, and 47% type 2 tortuosity. Overall, 85% had successful recanalization. Patients with type 2 tortuosity were significantly older (p < 0.0001) and less frequently achieved successful recanalization (80% vs. 90%; p = 0.019) but had similar outcomes compared with those without tortuosity. On regression analysis, marked tortuosity was associated with lower chances of successful recanalization (OR 0.43 95% CI 0.20-0.92) but had no effect on clinical outcomes.

Conclusions: Carotid tortuosity does not appear to impact the likelihood of favorable functional outcome but may influence recanalization.
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http://dx.doi.org/10.1007/s10072-020-04813-8DOI Listing
June 2021

Natural History of Hemodynamics in Vertebrobasilar Disease: Temporal Changes in the VERiTAS Study Cohort.

Stroke 2020 11 9;51(11):3295-3301. Epub 2020 Oct 9.

Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City (C.P.D.).

Background And Purpose: The role of regional hypoperfusion as a contributor to stroke risk in atherosclerotic vertebrobasilar disease has recently been confirmed by the observational VERiTAS (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke) Study. We examined the stability of hemodynamic status over time and its relationship to stroke risk in patients from this prospective cohort.

Methods: VERiTAS enrolled patients with recently symptomatic ≥50% atherosclerotic stenosis/occlusion of vertebral and/or basilar arteries. Large vessel flow in the vertebrobasilar territory was assessed using quantitative magnetic resonance angiography, and patients were designated as low or normal flow based on distal territory regional flow, incorporating collateral capacity. Patients underwent standard medical management and follow-up for primary outcome event of vertebrobasilar territory stroke. Quantitative magnetic resonance angiography imaging was repeated at 6, 12, and 24 months. Flow status over time was examined relative to baseline and relative to subsequent stroke risk using a cause-specific proportional hazard model, with flow status treated as a time-varying covariate. Mean blood pressure was examined to assess for association with changes in flow status.

Results: Over 19±8 months of follow-up, 132 follow-up quantitative magnetic resonance angiography studies were performed in 58 of the 72 enrolled patients. Of the 13 patients with serial imaging who had low flow at baseline, 7 (54%) had improvement to normal flow at the last follow-up. Of the 45 patients who had normal flow at baseline, 3 (7%) converted to low flow at the last follow-up. The mean blood pressure did not differ in patients with or without changes in flow status. The time-varying flow status remained a strong predictor of subsequent stroke (hazard ratio, 10.3 [95% CI, 2.2-48.7]).

Conclusions: There is potential both for improvement and worsening of hemodynamics in patients with atherosclerotic vertebrobasilar disease. Flow status, both at baseline and over time, is a risk factor for subsequent stroke, thus serving as an important prognostic marker. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00590980.
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http://dx.doi.org/10.1161/STROKEAHA.120.029909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606530PMC
November 2020

Imaging endpoints of intracranial atherosclerosis using vessel wall MR imaging: a systematic review.

Neuroradiology 2021 Jun 7;63(6):847-856. Epub 2020 Oct 7.

Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Purpose: The vessel wall MR imaging (VWI) literature was systematically reviewed to assess the criteria and measurement methods of VWI-related imaging endpoints for symptomatic intracranial plaque in patients with ischemic events.

Methods: PubMed, Scopus, Web of Science, EMBASE, and Cochrane databases were searched up to October 2019. Two independent reviewers extracted data from 47 studies. A modified Guideline for Reporting Reliability and Agreement Studies was used to assess completeness of reporting.

Results: The specific VWI-pulse sequence used to identify plaque was reported in 51% of studies. A VWI-based criterion to define plaque was reported in 38% of studies. A definition for culprit plaque was reported in 40% of studies. Frequently scored qualitative imaging endpoints were plaque quadrant (21%) and enhancement (21%). Frequently measured quantitative imaging endpoints were stenosis (19%), lumen area (15%), and remodeling index (14%). Reproducibility for all endpoints ranged from good to excellent (range: ICC = 0.451 to ICC = 0.983). However, rater specialty and years of experience varied among studies.

Conclusions: Investigators are using different criteria to identify and measure VWI-imaging endpoints for culprit intracranial plaque. Early awareness of these differences to address methods of acquisition and measurement will help focus research resources and efforts in technique optimization and measurement reproducibility. Consensual definitions to detect plaque will be important to develop automatic lesion detection tools particularly in the era of radiomics.
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http://dx.doi.org/10.1007/s00234-020-02575-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024415PMC
June 2021

Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices.

Hypertension 2020 11 28;76(5):1350-1367. Epub 2020 Sep 28.

Division of Nephrology and Hypertension (K.A.N., V.D.G.), Mayo Clinic College of Medicine, Rochester, MN.

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685174PMC
November 2020

Anticoagulation Choice and Timing in Stroke Due to Atrial Fibrillation: A Survey of US Stroke Specialists (ACT-SAFe).

J Stroke Cerebrovasc Dis 2020 Oct 31;29(10):105169. Epub 2020 Jul 31.

University of Pennsylvania, Philadelphia, PA, USA.

Objective: Risk of early recurrent ischemic stroke in patients with atrial fibrillation may be high. ASA/AHA guidelines provide imprecise recommendations on the timing and anticoagulant choice for this indication. We assessed current opinions of stroke neurologists.

Methods: Case scenarios describing patients with acute ischemic stroke (AIS) due to paroxysmal atrial fibrillation (AF) were presented to US board-certified stroke neurologists in an internet-based questionnaire. Questions assessed timing and choice of anticoagulation for secondary stroke prevention, factors prompting earlier anticoagulation, reasons for specific anticoagulant choice, and alternatives to anticoagulation in ineligible patients. Open-ended comments were also solicited.

Results: Responses were available from 238/1239 stroke neurologists surveyed. In patients with small AIS without hemorrhagic transformation (HT), 51% elected to start anticoagulation within 96 hours. With increased stroke severity and asymptomatic HT, only 29% and 26% respectively chose to anticoagulate within 7 days. Few requested stability imaging before starting anticoagulation. With symptomatic HT the majority (79%) waited >14 days. 93% would anticoagulate earlier if left atrium/left atrial appendage or acute left ventricular thrombi, or mechanical heart valve were present. Direct oral anticoagulants (DOACs) were the preferred anticoagulation strategy (64%), and the remaining 38% preferred Warfarin. Aspirin was preferred by 57% in anticoagulation ineligible.

Conclusion: Apart from AIS with symptomatic HT, there is a remarkable lack of consensus among stroke neurologists regarding the timing of anticoagulation for secondary stroke prevention in patients with AIS due to PAF. DOACs are the preferred anticoagulation strategy. More studies are required to clarify anticoagulant management in this patient population.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105169DOI Listing
October 2020

Intracranial and systemic atherosclerosis in the NAVIGATE ESUS trial: Recurrent stroke risk and response to antithrombotic therapy.

J Stroke Cerebrovasc Dis 2020 Aug 8;29(8):104936. Epub 2020 Jun 8.

Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.

Background: Non-stenotic intracranial and systemic atherosclerosis are associated with ischemic stroke. We report frequency and response to anticoagulant vs. antiplatelet prophylaxis of patients with embolic stroke of undetermined source (ESUS) who have non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis.

Methods: Exploratory analysis of the international NAVIGATE ESUS randomized trial comparing rivaroxaban 15mg daily with aspirin 100mg daily in 7213 patients with recent ESUS. Among participants with results of intracranial arterial imaging with either computed tomographic angiography (CTA) or magnetic resonance angiography (MRA), the frequency and predictors of non-stenotic intracranial and systemic atherosclerosis and responses to antithrombotic therapy were assessed.

Results: Among 4723 participants with available intracranial CTA or MRA results (65% of the trial cohort), the prevalence of intracranial atherosclerosis was 16% (n=739). Patient features independently associated with intracranial atherosclerosis included East Asian region (odds ratio 2.7, 95%CI 2.2,3.3) and cervical carotid plaque (odds ratio 2.3, 95%CI 1.9,2.7), among others. The rate of recurrent ischemic stroke averaged 4.8%/year among those with intracranial atherosclerosis vs. 5.0.%/year for those without (HR 0.95, 95%CI 0.65, 1.4). Among those with intracranial atherosclerosis, the recurrent ischemic stroke rate was higher if assigned to rivaroxaban (5.8%/year) vs. aspirin (3.7%/year), but the difference was not statistically significant (HR 1.6, 95%CI 0.78, 3.3). There was trend for the effect of antithrombotic treatments to be different according to the presence or absence of intracranial atherosclerosis (p=0.09). Among participants with evidence of systemic atherosclerosis by either history or imaging (n=3820), recurrent ischemic stroke rates were similar among those assigned to rivaroxaban (5.5%/year) vs. aspirin (4.9%/year)(HR 1.1, 95%CI 0.84, 1.5).

Conclusions: East Asia region was the strongest factor associated with intracranial atherosclerosis. There were no statistically significant differences between rivaroxaban and aspirin prophylaxis for recurrent ischemic stroke in patients with non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104936DOI Listing
August 2020

A double-blind, randomized, controlled study of two dose strengths of dalfampridine extended release on walking deficits in ischemic stroke.

Restor Neurol Neurosci 2020 ;38(4):301-309

Acorda Therapeutics, Inc., Ardsley, NY, USA.

Background: Stroke-induced ischemia affects both cortex and underlying white matter. Dalfampridine extended release tablets (D-ER) enhance action potential conduction in demyelinated axons, which may positively affect post-stroke recovery.

Objective: Based on promising preliminary data, we compared efficacy of D-ER administered at 7.5 mg or 10 mg with placebo on post-stroke ambulation. Primary study outcome (response) was a ≥20% increase on the 2-minute walk test (2 MinWT) at 12 weeks after first drug administration.

Methods: This was a multicenter, randomized, placebo-controlled, 3-arm, parallel-group, safety and efficacy trial. After obtaining baseline measures of 2 MinWT, Walk-12, and Timed Up and Go, subjects entered a 2-week, single-blind placebo run-in period and were randomized 1:1:1 to receive 7.5 mg D-ER, 10 mg D-ER, or placebo, dosed twice-daily for 12 weeks. Follow-up evaluations occurred at weeks 14 and 16 when subjects were off study drug.

Results: The study was terminated early with 377 of planned 540 patients enrolled, due to no treatment effect. At week 12, mean increase in distances walked in 2 minutes were similar among the 3 study groups (14.9±40.0 feet; 19.4±39.6 feet; and 20.4±38.3 feet for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively). The proportion of subjects who showed ≥20% improvement on 2 MinWT at week 12 was 13.5%, 14.0%, and 19.0%, for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively; these were nonsignificant changes from baseline for all groups.

Conclusions: D-ER at either a 7.5-mg or 10-mg dose did not significantly increase performance on the 2 MinWT in stroke survivors with gait impairment, although this study was terminated early before full enrollment. (Clinical Trial # NCT02271217).
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http://dx.doi.org/10.3233/RNN-201009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592666PMC
July 2021

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

Outcomes Following Ischemic Stroke in Older Patients With CKD Stages 4 and 5: A Retrospective Cohort Study.

Am J Kidney Dis 2020 12 28;76(6):784-793. Epub 2020 May 28.

Department of Neurology, University of Pennsylvania, Philadelphia, PA.

Rationale & Objective: The associations between ischemic stroke and time to dialysis initiation and/or death in adults with late-stage chronic kidney disease (CKD) have not been explored. We sought to measure the rate and factors associated with stroke in CKD stages 4 and 5 (CKD4-5) and assess the association of stroke with initiation of dialysis and death.

Study Design: Retrospective cohort.

Setting & Participants: Patients with CKD4-5 in Medicare 2007 to 2014.

Exposure Or Predictor: Ischemic stroke in CKD4-5.

Outcomes: Initiation of maintenance dialysis or death.

Analytical Approach: Cox proportional hazard modeling assessed factors associated with ischemic stroke. A matched analysis (stroke/no stroke) estimated the cumulative incidence of incident kidney failure and death, treated as competing events. Simulations using a state transition model determined differences in expected time to kidney failure or death and death alone for patients with and without stroke with CKD5.

Results: 123,251 patients with CKD4 and 22,054 with CKD5 were identified. Mean ages were 81.0 and 79.2 years, respectively. Female sex (HRs of 1.21 [95% CI, 1.12-1.31] and 1.39 [95% CI, 1.04-1.86] for CKD4 and CKD5, respectively) and black race (HRs of 1.25 [95% CI, 1.12-1.39] and 1.12 [95% CI, 0.80-1.58] for CKD4 and CKD5, respectively) were factors associated with ischemic stroke. Rates for 30-day mortality were 13.3% and 18.8%, and for 1-year mortality, 40.0% and 38.2%. For patients with CKD5, kidney failure or death occurred an average of 3.6 months sooner for patients with an ischemic stroke, and death (irrespective of kidney failure), a mean of 24.3 months sooner.

Limitations: Study design cannot determine causality; lack of data for stroke severity.

Conclusions: Female sex and black race were associated with increased risk for stroke in CKD4 and CKD5. In CKD5, stroke was associated with a shorter time to kidney failure or death by nearly 4 months, and to death, by more than 2 years.
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http://dx.doi.org/10.1053/j.ajkd.2020.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218249PMC
December 2020

MR Intracranial Vessel Wall Imaging: A Systematic Review.

J Neuroimaging 2020 07 11;30(4):428-442. Epub 2020 May 11.

Department of Biomedical Sciences, Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

The purpose of this systematic review is to identify trends and extent of variability in intracranial vessel wall MR imaging (VWI) techniques and protocols. Although variability in selection of protocol design and pulse sequence type is known, data on what and how protocols vary are unknown. Three databases were searched to identify publications using intracranial VWI. Publications were screened by predetermined inclusion/exclusion criteria. Technical development publications were scored for completeness of reporting using a modified Nature Reporting Summary Guideline to assess reproducibility. From 2,431 articles, 122 met the inclusion criteria. Trends over the last 23 years (1995-2018) show increased use of 3-Tesla MR (P < .001) and 3D volumetric T1-weighted acquisitions (P < .001). Most (65%) clinical VWI publications report achieving a noninterpolated in-plane spatial resolution of ≤.55 mm. In the last decade, an increasing number of technical development (n = 20) and 7 Tesla (n = 12) publications have been published, focused on pulse sequence development, improving cerebrospinal fluid suppression, scan efficiency, and imaging ex vivo specimen for histologic validation. Mean Reporting Summary Score for the technical development publications was high (.87, range: .63-1.0) indicating strong scientific technical reproducibility. Innovative work continues to emerge to address implementation challenges. Gradual adoption into the research and scientific community was suggested by a shift in the name in the literature from "high-resolution MR" to "vessel wall imaging," specifying diagnostic intent. Insight into current practices and identifying the extent of technical variability in the literature will help to direct future clinical and technical efforts to address needs for implementation.
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http://dx.doi.org/10.1111/jon.12719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946440PMC
July 2020

Practice advisory update summary: Patent foramen ovale and secondary stroke prevention: Report of the Guideline Subcommittee of the American Academy of Neurology.

Neurology 2020 05 29;94(20):876-885. Epub 2020 Apr 29.

From the Department of Neurology (S.R.M., S.E.K.), University of Pennsylvania School of Medicine, Philadelphia; Department of Neurology (G.S.G., L.R.), University of Kansas Medical Center, MO; Institute for Clinical Research and Health Policy Studies (D.M.K.), Tufts University School of Medicine, Boston, MA; Cardiology Section (J.R.K.), San Francisco Veterans Affairs Health Care System, and Departments of Medicine, and Epidemiology and Biostatistics (J.R.K.), University of California San Francisco; Division of Cardiology (S.H.), Columbia University Medical Center, New York; Department of Medicine (Cardiology) (J.D.C.), University of Colorado School of Medicine, Aurora; Department of Neurology (K.I.), New York University; and Department of Neurology (N.S.), Kaiser Permanente, Los Angeles, CA.

Objective: To update the 2016 American Academy of Neurology (AAN) practice advisory for patients with stroke and patent foramen ovale (PFO).

Methods: The guideline panel followed the AAN 2017 guideline development process to systematically review studies published through December 2017 and formulate recommendations.

Major Recommendations: In patients being considered for PFO closure, clinicians should ensure that an appropriately thorough evaluation has been performed to rule out alternative mechanisms of stroke (level B). In patients with a higher risk alternative mechanism of stroke identified, clinicians should not routinely recommend PFO closure (level B). Clinicians should counsel patients that having a PFO is common; that it occurs in about 1 in 4 adults in the general population; that it is difficult to determine with certainty whether their PFO caused their stroke; and that PFO closure probably reduces recurrent stroke risk in select patients (level B). In patients younger than 60 years with a PFO and embolic-appearing infarct and no other mechanism of stroke identified, clinicians may recommend closure following a discussion of potential benefits (absolute recurrent stroke risk reduction of 3.4% at 5 years) and risks (periprocedural complication rate of 3.9% and increased absolute rate of non-periprocedural atrial fibrillation of 0.33% per year) (level C). In patients who opt to receive medical therapy alone without PFO closure, clinicians may recommend an antiplatelet medication such as aspirin or anticoagulation (level C).
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http://dx.doi.org/10.1212/WNL.0000000000009443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526671PMC
May 2020

Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial.

Stroke 2020 06 16;51(6):1797-1804. Epub 2020 Apr 16.

Population Health Research Institute, Hamilton Health Sciences, ON, Canada (M.S., R.G.H.).

Background and Purpose- Emboli in embolic stroke of undetermined source (ESUS) may originate from various potential embolic sources (PES), some of which may respond better to anticoagulation, whereas others to antiplatelets. We analyzed whether rivaroxaban is associated with reduction of recurrent stroke compared with aspirin in patients with ESUS across different PES and by number of PES. Methods- We assessed the presence/absence of each PES (atrial cardiopathy, atrial fibrillation, arterial atherosclerosis, left ventricular dysfunction, cardiac valvulopathy, patent foramen ovale, cancer) in NAVIGATE-ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) participants. Prevalence of each PES, as well as treatment effect and risk of event for each PES were determined. Results by number of PES were also determined. The outcomes were ischemic stroke, all-cause mortality, cardiovascular mortality, and myocardial infarction. Results- In 7213 patients (38% women, mean age 67years) followed for a median of 11 months, the 3 most prevalent PES were atrial cardiopathy (37%), left ventricular disease (36%), and arterial atherosclerosis (29%). Forty-one percent of all patients had multiple PES, with 15% having ≥3 PES. None or a single PES was present in 23% and 36%, respectively. Recurrent ischemic stroke risk was similar for rivaroxaban- and aspirin-assigned patients for each PES, except for those with cardiac valvular disease which was marginally higher in rivaroxaban-assigned patients (hazard ratio, 1.8 [95% CI, 1.0-3.0]). All-cause mortality risks were similar across treatment groups for each PES while too few myocardial infarctions and cardiovascular deaths occurred for meaningful assessment. Increasing number of PES was not associated with increased stroke recurrence nor all-cause mortality, and outcomes did not vary between rivaroxaban- and aspirin-assigned patients by number of PES. Conclusions- A large proportion of patients with ESUS had multiple PES which could explain the neutral results of NAVIGATE-ESUS. Recurrence rates between rivaroxaban- and aspirin-assigned patients were similar across the spectrum of PES. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02313909.
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http://dx.doi.org/10.1161/STROKEAHA.119.028669DOI Listing
June 2020

Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale-Associated Stroke.

JAMA Neurol 2020 07;77(7):878-886

Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.

Importance: Recent epidemiologic and therapeutic advances have transformed understanding of the role of and therapeutic approach to patent foramen ovale (PFO) in ischemic stroke. Patent foramen ovale is likely responsible for approximately 5% of all ischemic strokes and 10% of those occurring in young and middle-aged adults.

Observations: Randomized clinical trials have demonstrated that, to prevent recurrent ischemic stroke in patients with PFO and an otherwise-cryptogenic index ischemic stroke, PFO closure is superior to antiplatelet medical therapy alone; these trials have provided some evidence that, among medical therapy options, anticoagulants may be more effective than antiplatelet agents.

Conclusions And Relevance: These new data indicate a need to update classification schemes of causative mechanisms in stroke, developed in an era in which an association between PFO and stroke was viewed as uncertain. We propose a revised general nomenclature and classification framework for PFO-associated stroke and detailed revisions for the 3 major stroke subtyping algorithms in wide use.
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http://dx.doi.org/10.1001/jamaneurol.2020.0458DOI Listing
July 2020

Stroke and HIV in Botswana: A prospective study of risk factors and outcomes.

J Neurol Sci 2020 06 26;413:116806. Epub 2020 Mar 26.

Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.

Objective: HIV is associated with an increased risk of stroke, but there are sparse data on risk factors for stroke in people living with HIV in Sub-Saharan African. The goal of this study was to identify HIV-specific stroke characteristics and risk factors among adults in Botswana.

Methods: We conducted a prospective cohort study in Gaborone, Botswana from June 2015 to June 2017 comparing risk factors and outcomes among adults with and without HIV admitted for acute stroke. In addition, we conducted a case-control study comparing patients with HIV and stroke to outpatients with HIV and no history of stroke.

Results: A total of 52 patients with imaging-confirmed acute stroke were enrolled. Stroke patients with HIV were younger than those without HIV (median age 40 vs 54, p = .005). Hypertension was the most common risk factor identified in both HIV+ and HIV- groups, but was more common in patients without HIV (81% vs. 55%, p = .04). Patients with HIV were significantly more likely to have a small-vessel lacunar syndrome compared to patients without HIV (67% vs. 29%, p = .02). In the case-control analysis, patients with HIV and stroke were more likely to have hypertension than stroke-free controls (53% vs. 16%; OR 7.2, 95% CI 1.5-33.8, p = .01), and were more likely to drink alcohol (53% vs. 21%, OR 3.7, 95% CI 1.1-12.1, p = .03).

Conclusions: Individuals with HIV present with strokes at younger ages than individuals without HIV. Among those with HIV, hypertension and alcohol use are significant risk factors for stroke.
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http://dx.doi.org/10.1016/j.jns.2020.116806DOI Listing
June 2020
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