Stroke Prevention in Atrial Fibrillation: Our Current Failures and Required Research.

Nonvalvular atrial fibrillation is a common rhythm disorder of middle-aged to older adults that can cause ischemic strokes and systemic embolism. Lifelong use of oral anticoagulants reduces the risk of these ischemic events but increases the risk of major and clinically relevant hemorrhages. These medications also require strict compliance for efficacy, and they have nontrivial failure rates in higher-risk patients. Left atrial appendage closure is a nonpharmacological method to prevent ischemic strokes in atrial fibrillation without the need for lifelong anticoagulant use, but this procedure has the potential for complications and residual embolic events. This workshop of the Roundtable of Academia and Industry for Stroke Prevention discussed future research needed to further decrease the ischemic and hemorrhagic risks among patients with atrial fibrillation. A direct thrombin inhibitor, factor Xa inhibitors, and left atrial appendage closure are FDA-approved approaches whereas factor XIa inhibitors are currently being studied in phase 3 randomized controlled trials for stroke prevention. The benefits, risks, and shortcomings of these treatments and future research required in different high-risk patient populations are reviewed in this consensus statement.

Association of Multiple Passes during Mechanical Thrombectomy with Incomplete Reperfusion and Lesion Growth.

INTRODUCTION: Despite complete recanalization by mechanical thrombectomy, abnormal perfusion can be detected on MRI obtained post-endovascular therapy (EVT). The presence of residual perfusion abnormalities post-EVT may be associated with blood-brain barrier breakdown in response to mechanical disruption of the endothelium from multiple-pass thrombectomy. We hypothesize that multiple-pass versus single-pass thrombectomy is associated with a higher rate of residual hypoperfusion and increased lesion growth at 24 h. MATERIALS AND METHODS: For this analysis, we included patients presenting to one of two stroke centers between January 2015 and February 2018 with an acute ischemic stroke within 12 h from symptom onset if they had a large vessel occlusion of the anterior circulation documented on magnetic resonance angiography or CTA, baseline MRI pre-EVT with imaging evidence of hypoperfusion, underwent EVT, and had a post-EVT MRI with qualitatively interpretable perfusion-weighted imaging data at 24 h. MRI Tmax maps using a time delay threshold of >6 s were used to quantitate hypoperfusion volumes. Residual hypoperfusion at 24 h was solely defined as Tmax volume >10 mL with >6 s delay. Complete recanalization was defined as modified treatment in cerebral infarction visualized on angiography at EVT completion. Hyperintense acute reperfusion injury marker was assessed on post-EVT pre-contrast fluid-attenuated inversion recovery at 24 h. Major early neurological improvement was defined as a reduction of the admission National Institutes of Health Stroke Scale by ≥8 points or a score of 0-1 at 24 h. Good functional outcome was defined as 0-2 on the modified Rankin Scale on day 30 or 90. RESULTS: Fifty-five patients were included with median age 67 years, 58% female, 45% Black/African American, 36% White/Caucasian, median admission National Institutes of Health Stroke Scale 19, large vessel occlusion locations: 71% M1, 14.5% iICA, 14.5% M2, 69% treated with intravenous recombinant tissue plasminogen activator. Of these, 58% had multiple-pass thrombectomy, 39% had residual perfusion abnormalities at 24 h, and 64% had severe hyperintense acute reperfusion injury marker at 24 h. After adjusting for complete recanalization, only multiple-pass thrombectomy (odds ratio, 4.3 95% CI, 1.07-17.2; p = 0.04) was an independent predictor of residual hypoperfusion at 24 h. Patients with residual hypoperfusion had larger lesion growth on diffusion-weighted imaging (59 mL vs. 8 mL, p < 0.001), lower rate of major early neurological improvement (24% vs. 70%, p = 0.002) at 24 h, and worse long-term outcome based on the modified Rankin Scale at 30 or 90 days, 5 versus 2 (p < 0.001). CONCLUSIONS: Our findings suggest that incomplete reperfusion on post-EVT MRI is present even in some patients with successful recanalization at the time of EVT and is associated with multiple-pass thrombectomy, lesion growth, and worse outcome. Future studies are needed to investigate whether patients with residual hypoperfusion may benefit from immediate adjunctive therapy to limit lesion growth and improve clinical outcome.

TRANSCENDS: A Career Development Program for Underrepresented in Medicine Scholars in Academic Neurology.

BACKGROUND: The Training in Research for Academic Neurologists to Sustain Careers and Enhance the Numbers of Diverse Scholars (TRANSCENDS) program is a career advancement opportunity for individuals underrepresented in biomedical research, funded by the National Institute and Neurological Disorders and Stroke; and American Academy of Neurology (AAN). OBJECTIVE: To report on qualitative and quantitative outcomes in TRANSCENDS. DESIGN: Early career individuals (neurology fellows and junior faculty) from groups underrepresented in medicine were competitively selected from a national pool of applicants (2016-2019). TRANSCENDS activities comprised an online Clinical Research degree program, monthly webinars, AAN meeting activities, and mentoring. Participants were surveyed during and after completion of TRANSCENDS to evaluate program components. OUTCOMES: Of 23 accepted scholars (comprising four successive cohorts), 56% were women; 61% Hispanic/Latinx, 30% Black/African American, 30% assistant professors. To date, 48% have graduated the TRANSCENDS program and participants have published 180 peer-reviewed articles. Mentees' feedback noted that professional skills development (i.e., manuscript and grant writing), networking opportunities, and mentoring were the most beneficial elements of the program. Stated opportunities for improvement included: incorporating a mentor-the-mentor workshop, providing more transitional support for mentees in the next stage of their careers, and requiring mentees to provide quarterly reports. CONCLUSIONS: TRANSCENDS is a feasible program for supporting underrepresented in medicine neurologists towards careers in research and faculty academic appointments attained thus far have been sustained. While longer term outcomes and process enhancements are warranted, programs like this may help increase the numbers of diverse academic neurologists, and further drive neurological innovation.

Sickle Cell Trait and Risk of Ischemic Stroke in Young Adults.

BACKGROUND AND PURPOSE: Approximately 8% of Blacks have sickle cell trait (SCT), and there are conflicting reports from recent cohort studies on the association of SCT with ischemic stroke (IS). Most prior studies focused on older populations, with few data available in young adults. METHODS: A population-based case-control study of early-onset IS was conducted in the Baltimore-Washington region between 1992 and 2007. From this study, 342 Black IS cases, ages 15 to 49, and 333 controls without IS were used to examine the association between SCT and IS. Each participant's SCT status was established by genotyping and imputation. For analysis, χ2 tests and logistic regression models were performed with adjustment for potential confounding variables. RESULTS: Participants with SCT (n=55) did not differ from those without SCT (n=620) in prevalence of hypertension, previous myocardial infarction, diabetes mellitus, and current smoking status. Stroke cases had increased prevalence in these risk factors compared with controls. We did not find an association between SCT and early-onset IS in our overall population (odds ratio=0.9 [95% CI, 0.5-1.7]) or stratified by sex in males (odds ratio=1.26 [95% CI, 0.56-2.80]) and females (odds ratio=0.67 [95% CI, 0.28-1.69]). CONCLUSIONS: Our data did not find evidence of increased risk of early-onset stroke with SCT.

Reversible diffusion-weighted imaging lesions in acute ischemic stroke: A systematic review.

OBJECTIVES: To systematically review the literature for reversible diffusion-weighted imaging (DWIR) lesions and to describe its prevalence, predictors, and clinical significance. METHODS: Studies were included if the first DWI MRI was performed within 24 hours of stroke onset and follow-up DWI or fluid-attenuated inversion recovery (FLAIR)/T2 was performed within 7 or 90 days, respectively, to measure DWIR. We abstracted clinical, imaging, and outcomes data. RESULTS: Twenty-three studies met the study criteria. The prevalence of DWIR was 26.5% in DWI-based studies and 6% in FLAIR/T2-based studies. DWIR was associated with recanalization or reperfusion of the ischemic tissue with or without the use of tissue plasminogen activator (t-PA) or endovascular therapy, earlier treatment with t-PA, shorter time to endovascular therapy after MRI, and absent or less severe perfusion deficit within the DWI lesion. DWIR was associated with early neurologic improvement in 5 of 6 studies (defined as improvement in the NIH Stroke Scale (NIHSS) score by 4 or 8 points from baseline or NIHSS score 0 to 2 at 24 hours after treatment or at discharge or median NIHSS score at 7 days) and long-term outcome in 6 of 7 studies (defined as NIHSS score ≤1, improvement in the NIHSS score ≥8 points, or modified Rankin Scale score up to ≤2 at 30 or 90 days) likely due to reperfusion. CONCLUSIONS: DWIR is seen in up to a quarter of patients with acute ischemic stroke, and it is associated with good clinical outcome following reperfusion. Our findings highlight the pitfalls of DWI to define ischemic core in the early hours of stroke.

Neuroimaging evolution of ischemia in men and women: an observational study.

Objective: We present an exploratory study for identification of sex differences in imaging biomarkers that could further refine selection of patients for acute reperfusion therapy and trials based on sex and imaging targets. Methods: The Lesion Evolution in Stroke and Ischemia On Neuroimaging (LESION) study included consecutive acute stroke patients who underwent MRI within 24 h of time from last known well and prior to therapy. Those demonstrating a potential therapeutic target on imaging were identified by presence of: (1) arterial occlusion on angiography, (2) focal ischemic region on perfusion maps, or (3) a mismatch of perfusion versus diffusion imaging lesion size. The prevalence of imaging targets within clinically relevant time intervals was calculated for each patient and examined. The relationship of time from stroke onset to probability of detection of imaging targets was evaluated. Results: Of 7007 patients screened, of which 86.7% were scanned with MRI, 1092 patients (477/615 men/women) were included in LESION. The probability of imaging target detection was significantly different between men and women, with women more likely to present with all assessed imaging targets, odds ratios between 1.36 and 1.59, P < 0.02, adjusted for NIHSS, age, and time from last known well to MRI scan. This trend held for the entire 24-h studied. Interpretation: Women present more often with treatable ischemic stroke than men. The greater probability of potentially viable and/or treatable imaging targets in women at all time points suggests that tissue injury is slower to evolve in women.

Functional Independence After Stroke Thrombectomy Using Thrombolysis In Cerebral Infarction Grade 2c: A New Aim of Successful Revascularization.

BACKGROUND: Within the Thrombolysis In Cerebral Infarction (TICI) classification, TICI 2b has been historically considered successful recanalization. However, TICI 2b may result in worse functional outcomes compared with TICI 3 or a proposed TICI 2c revascularization grade. The aim of this study was to evaluate differences in functional independence at 90 days between TICI 2b, 2c, and 3 grades. METHODS: A retrospective review of 185 consecutive patients with anterior cerebral circulation occlusions was performed; 33 patients who were treated >8 hours after onset were excluded. Patient angiograms were graded by 2 experienced neurointerventional physicians. Baseline demographics and functional independence at 90 days were compared. RESULTS: Of 152 patients included in the study, 113 patients achieved TICI grade 2b (n = 37), 2c (n = 34), or 3 (n = 42). A significant difference in functional independence at 90 days was observed between TICI 2b and 2c/3 (P = 0.0008), between 2b and 2c (P = 0.0005), and between 2b and 3 (P = 0.01). There was no significant difference in functional independence between 2c and 3 (P = 0.24). CONCLUSIONS: TICI 2c revascularization is associated with significantly improved outcomes compared with TICI 2b revascularization and similar outcomes compared with TICI 3 revascularization. Using a TICI grading system that includes an additional TICI 2c grade or expands the current definition of TICI 3 allows for refined prediction of functional independence. Achieving TICI 2c/3 reperfusion should be considered during stroke thrombectomy.

Smoking and Risk of Ischemic Stroke in Young Men.

BACKGROUND AND PURPOSE: There is a strong dose-response relationship between smoking and risk of ischemic stroke in young women, but there are few data examining this association in young men. We examined the dose-response relationship between the quantity of cigarettes smoked and the odds of developing an ischemic stroke in men under age 50 years. METHODS: The Stroke Prevention in Young Men Study is a population-based case-control study of risk factors for ischemic stroke in men ages 15 to 49 years. The χ2 test was used to test categorical comparisons. Logistic regression models were used to calculate the odds ratio for ischemic stroke occurrence comparing current and former smokers to never smokers. In the first model, we adjusted solely for age. In the second model, we adjusted for potential confounding factors, including age, race, education, hypertension, myocardial infarction, angina, diabetes mellitus, and body mass index. RESULTS: The study population consisted of 615 cases and 530 controls. The odds ratio for the current smoking group compared with never smokers was 1.88. Furthermore, when the current smoking group was stratified by number of cigarettes smoked, there was a dose-response relationship for the odds ratio, ranging from 1.46 for those smoking <11 cigarettes per day to 5.66 for those smoking 40+ cigarettes per day. CONCLUSIONS: We found a strong dose-response relationship between the number of cigarettes smoked daily and ischemic stroke among young men. Although complete smoking cessation is the goal, even smoking fewer cigarettes may reduce the risk of ischemic stroke in young men.