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Background: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo., Methods: The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes., Results: Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes., Conclusions: Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivariable model, and the large sample size, we think this is the most definitive analysis of the predictors of preclinical stroke outcome to date. Future multicenter experimental stroke trials should standardize or at least ensure a balanced representation of the biological and procedural variables identified herein as potential confounders., Competing Interests: P.D. Lyden reports compensation from the National Institutes of Health Clinical Center for other services, and compensation from Apex Innovations and EMD Serono for consultant services. C. Ayata reports compensation from Neurelis Inc for other services.

Background: Intracranial hemorrhage (ICH) is a serious complication associated with oral anticoagulant use and is associated with significant morbidity and mortality. Although anticoagulation reversal agents are utilized as standard of care, practitioners are limited in their ability to assess degree of anticoagulation reversal for direct oral anticoagulants (DOACs). There is a clinical need identify biomarkers to assess anticoagulation status in patients with DOAC-associated ICH to ensure hemostatic efficacy of anticoagulation reversal agents in the acute setting. The purpose of this study was to assess the utility of thromboelastography (TEG) to assess the impact of anticoagulation reversal in patients presenting to the emergency department (ED) with DOAC-associated ICH., Methods: We conducted a prospective, observational cohort study in adult patients presenting to the ED with acute DOAC-associated ICH. Patients were excluded if last DOAC dose was >48 hours prior to hospital arrival, if they experienced polytrauma, were pregnant, incarcerated, had a history of hepatic failure or coagulopathy, or received anticoagulation reversal with products other than prothrombin complex concentrates (PCCs). We collected baseline TEG samples from participants prior to anticoagulation reversal, as well as 30-minutes, 12-hours, and 24-hours post-reversal. TEG samples were also collected from participants who transferred to our facility after reversal at ED presentation, as well as 12- and 24-hours post-reversal., Results: Pre-reversal TEG was collected on 10 participants prior to DOAC reversal. A significant decrease in TEG R-time was observed at 30 minutes post-reversal. R-time increased at 12- and 24-hours to baseline levels. Significant changes were not observed in K-time, clot strength, maximum amplitude, or coagulation index., Conclusions: TEG R-time may be able to detect a change in anticoagulation activity of DOACs in ICH after anticoagulation reversal. R-time decreases acutely after anticoagulation reversal and rebounds at 12- and 24-hours post-reversal.

The article summarizes the training pathways and vocational opportunities within the field of vascular neurology. It highlights the groundbreaking clinical trials that transformed acute stroke care and the resultant increased demand for readily available vascular neurology expertise. The article emphasizes the need to train a larger number of diverse physicians in the subspecialty and the role of vascular neurologists in improving outcomes across demographic and geographic lines., Competing Interests: Disclosure Dr. H.J. Roeder has no financial disclosures. Dr. E.C. Leira receives salary support from the NIH, United States-NINDS and is the vice chair of the Vascular Neurology Examination Writing Committee of the American Board of Psychiatry and Neurology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Transcarotid artery revascularization (TCAR) is an interventional therapy for symptomatic internal carotid artery disease. Currently, the utilization of TCAR is contentious due to limited evidence. In this study, we evaluate the safety and efficacy of TCAR in patients with symptomatic internal carotid artery disease compared with carotid endarterectomy (CEA) and carotid artery stenting (CAS)., Methods: A systematic review was conducted, spanning from January 2000 to February 2023, encompassing studies that used TCAR for the treatment of symptomatic internal carotid artery disease. The primary outcomes included a 30-day stroke or transient ischemic attack, myocardial infarction, and mortality. Secondary outcomes comprised cranial nerve injury and major bleeding. Pooled odds ratios (ORs) for each outcome were calculated to compare TCAR with CEA and CAS. Furthermore, subgroup analyses were performed based on age and degree of stenosis. In addition, a sensitivity analysis was conducted by excluding the vascular quality initiative registry population., Results: A total of 7 studies involving 24 246 patients were analyzed. Within this patient cohort, 4771 individuals underwent TCAR, 12 350 underwent CEA, and 7125 patients underwent CAS. Compared with CAS, TCAR was associated with a similar rate of stroke or transient ischemic attack (OR, 0.77 [95% CI, 0.33-1.82]) and myocardial infarction (OR, 1.29 [95% CI, 0.83-2.01]) but lower mortality (OR, 0.42 [95% CI, 0.22-0.81]). Compared with CEA, TCAR was associated with a higher rate of stroke or transient ischemic attack (OR, 1.26 [95% CI, 1.03-1.54]) but similar rates of myocardial infarction (OR, 0.9 [95% CI, 0.64-1.38]) and mortality (OR, 1.35 [95% CI, 0.87-2.10])., Conclusions: Although CEA has traditionally been considered superior to stenting for symptomatic carotid stenosis, TCAR may have some advantages over CAS. Prospective randomized trials comparing the 3 modalities are needed., Competing Interests: Disclosures Dr Matouk is a consultant for Silk Road Medical, MicroVention, Inc, and Penumbra, Inc. Dr Derdeyn is involved in data and safety monitoring at Penumbra (MIND and THUNDER trials), NoNO (ESCAPE NEXT and FRONTIER), and Silk Road (NITE trial); has stock options in Euphrates Vascular; and is a professor and a chair at The University of Iowa. Dr Levy is a shareholder and has ownership interest in NeXtGen Biologics, Claret Medical, Inc, Imperative Care, Inc, Rebound Therapeutics, StimMed, and Three Rivers Medical; is a consultant at Clarion, GLG Consulting, Guidepoint Global, Misionix, Mosaic, and StimMed and at Medtronic Vascular, Inc, Microvetion, and Penumbra, Inc; and has stock options in Rapid Medical Ltd. Dr de Havenon has stock options at Certus and TitinKM, received grant/contract from the National Institutes of Health, and is a consultant at Novo Nordisk. Dr Leira received a grant/contract from the American Stroke Association and is a professor of neurology, neurosurgery, and epidemiology at the University of Iowa. Dr Henninger received a grant/contract from the National Institutes of Health and the US Department of Defense and is an associate professor at the University of Massachusetts Medical School. Dr Chaturvedi received a grant/contract from Mayo Clinic. The other authors report no conflicts.

Introduction: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life., Methods: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE., Conclusion: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins., (S. Karger AG, Basel.)

Background: Intravenous thrombolysis (IVT) is an effective stroke therapy that remains underused. Currently, the use of IVT in patients with recent direct oral anticoagulant (DOAC) intake is not recommended. In this study we aim to investigate the safety and efficacy of IVT in patients with acute ischemic stroke and recent DOAC use., Methods and Results: A systematic review and meta-analysis of proportions evaluating IVT with recent DOAC use was conducted. Outcomes included symptomatic intracranial hemorrhage, any intracranial hemorrhage, serious systemic bleeding, and 90-day functional independence (modified Rankin scale score 0-2). Additionally, rates were compared between patients receiving IVT using DOAC and non-DOAC by a random effect meta-analysis to calculate pooled odds ratios (OR) for each outcome. Finally, sensitivity analysis for idarucizumab, National Institutes of Health Stroke Scale, and timing of DOAC administration was completed. Fourteen studies with 247 079 patients were included (3610 in DOAC and 243 469 in non-DOAC). The rates of IVT complications in the DOAC group were 3% (95% CI, 3-4) symptomatic intracranial hemorrhage, 12% (95% CI, 7-19) any ICH, and 0.7% (95%CI, 0-1) serious systemic bleeding, and 90-day functional independence was achieved in 57% (95% CI, 43-70). The rates of symptomatic intracranial hemorrhage (3.4 versus 3.5%; OR, 0.95 [95% CI, 0.67-1.36]), any intracranial hemorrhage (17.7 versus 17.3%; OR, 1.23 [95% CI, 0.61-2.48]), serious systemic bleeding (0.7 versus 0.6%; OR, 1.27 [95% CI, 0.79-2.02]), and 90-day modified Rankin scale score 0-2 (46.4 versus 56.8%; OR, 1.21 [95% CI, 0.400-3.67]) did not differ between DOAC and non-DOAC groups. There was no difference in symptomatic intracranial hemorrhage rate based on idarucizumab administration., Conclusions: Patients with acute ischemic stroke treated with IVT in recent DOAC versus non-DOAC use have similar rates of hemorrhagic complications and functional independence. Further prospective randomized trials are warranted.

Uric acid (UA) is a strong endogenous antioxidant that neutralizes the toxicity of peroxynitrite and other reactive species on the neurovascular unit generated during and after acute brain ischemia. The realization that a rapid reduction of UA levels during an acute ischemic stroke was associated with a worse stroke outcome paved the way to investigate the value of exogenous UA supplementation to counteract the progression of redox-mediated ischemic brain damage. The long translational journey for UA supplementation recently reached a critical milestone when the results of the multicenter NIH stroke preclinical assessment network (SPAN) were reported. In a novel preclinical paradigm, 6 treatment candidates including UA supplementation were selected and tested in 6 independent laboratories following predefined criteria and strict methodological rigor. UA supplementation was the only intervention in SPAN that exceeded the prespecified efficacy boundary with male and female animals, young mice, young rats, aging mice, obese mice, and spontaneously hypertensive rats. This unprecedented achievement will allow UA to undergo clinical testing in a pivotal clinical trial through a NIH StrokeNet thrombectomy endovascular platform created to assess new treatment strategies in patients treated with mechanical thrombectomy. UA is a particularly appealing adjuvant intervention for mechanical thrombectomy because it targets the microcirculatory hypoperfusion and oxidative stress that limits the efficacy of this therapy. This descriptive review aims to summarize the translational development of UA supplementation, highlighting those aspects that likely contributed to its success. It includes having a well-defined target and mechanism of action, and an approach that simultaneously integrated rigorous preclinical assessment, with epidemiologic and preliminary human intervention studies. Validation of the clinical value of UA supplementation in a pivotal trial would confirm the translational value of the SPAN paradigm in preclinical research., (© 2023 American Academy of Neurology.)

Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.

Background: Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin α9β1 is expressed on neutrophils and stabilizes adhesion to the endothelium via ligands, including Fn-EDA (fibronectin containing extra domain A) and tenascin C. Although myeloid deletion of α9 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived α9. We determined the role of neutrophil-specific α9 in stroke outcomes in a mice model with obesity-induced hyperglycemia., Methods: α9 Neu-KO (α9 fl/fl MRP8Cre + ) and littermate control α9 WT (α9 fl/fl MRP8Cre - ) mice were fed on a 60% high-fat diet for 20 weeks to induce obesity-induced hyperglycemia. Functional outcomes were evaluated up to 28 days after stroke onset in mice of both sexes using a transient (30 minutes) middle cerebral artery ischemia. Infarct volume (magnetic resonance imaging) and postreperfusion thrombo-inflammation (thrombi, fibrin, neutrophil, phospho-nuclear factor kappa B [p-NFκB], TNF [tumor necrosis factor]-α, and IL [interleukin]-1β levels, markers of neutrophil extracellular traps) were measured post 6 or 48 hours of reperfusion. In addition, functional outcomes (modified Neurological Severity Score, rota-rod, corner, and wire-hanging test) were measured for up to 4 weeks., Results: Stroke upregulated neutrophil α9 expression more in obese mice ( P <0.05 versus lean mice). Irrespective of sex, deletion of neutrophil α9 improved functional outcomes up to 4 weeks, concomitant with reduced infarct, improved cerebral blood flow, decreased postreperfusion thrombo-inflammation, and neutrophil extracellular traps formation (NETosis) ( P <0.05 versus α9 WT obese mice). Obese α9 Neu-KO mice were less susceptible to thrombosis in FeCl 3 injury-induced carotid thrombosis model. Mechanistically, we found that α9/cellular fibronectin axis contributes to NETosis via ERK (extracellular signal-regulated kinase) and PAD4 (peptidyl arginine deiminase 4), and neutrophil α9 worsens stroke outcomes via cellular fibronectin-EDA but not tenascin C. Obese wild-type mice infused with anti-integrin α9 exhibited improved functional outcomes up to 4 weeks ( P <0.05 versus vehicle)., Conclusions: Genetic ablation of neutrophil-specific α9 or pharmacological inhibition improves long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation., Competing Interests: Disclosures None.

Background: There are limited data regarding the best management and outcomes of acute stroke during pregnancy and the puerperium., Methods: Pregnancy-related hospitalizations with age > 18 years were identified from the Nationwide Readmissions Database 2016-2018. The study cohort consisted of all patients with acute stroke and a 5% random sample of the remaining non-stroke hospitalizations. Logistic regression and survival analyses were used to compare the in-hospital outcomes and readmissions in patients with and without acute stroke., Results: There were 11,829,044 pregnancy-related hospitalizations, of which 4057 had acute stroke. The mean ± SD age of the study cohort was 29.0 ± 5.7 years. Among patients with acute ischemic stroke, 60 (3.7%) patients received intravenous thrombolysis and 112 (6.8%) patients underwent endovascular thrombectomy. Among patients with intracranial hemorrhage, 205 (10.5%) patients underwent ventriculostomy and 18 (0.9%) patients underwent decompressive craniotomy. Patients with stroke had longer length of stay (mean: 10.7 vs 2.7 days), higher in-hospital mortality (4.6% vs 0.0001%) and were less likely to discharge home (73.0% vs 98.6%). Non-elective readmission within 90 days of discharge occurred in 14.8% of patients with stroke versus in 3.9% of patients without stroke. Readmissions due to cerebrovascular events occurred in 2.3% of patients with stroke versus in 0.007% of patients without stroke within 1 year of discharge, with mean ± SD time to readmission 66.2 ± 78.0 days., Conclusion: Stroke is a serious complication of pregnancy, associated with high morbidity and mortality. Recurrence of stroke occurs in a small proportion of patients, and the risk is highest during the initial 3 months.

Background: Current imaging modalities underestimate the severity of intracranial atherosclerotic disease (ICAD). High resolution vessel wall imaging (HR-VWI) MRI is a powerful tool in characterizing plaques. We aim to show that HR-VWI MRI is more accurate at detecting and characterizing intracranial plaques compared to digital subtraction angiography (DSA), time-of-flight (TOF) MRA, and computed tomography angiogram (CTA)., Methods: Patients with symptomatic ICAD prospectively underwent 7T HR-VWI. We calculated: degree of stenosis, plaque burden (PB), and remodeling index (RI). The sensitivity of detecting a culprit plaque for each modality as well as the correlations between different variables were analyzed. Interobserver agreement on the determination of a culprit plaque on every imaging modality was evaluated., Results: A total of 44 patients underwent HR-VWI. Thirty-four patients had CTA, 18 TOF-MRA, and 18 DSA. The sensitivity of plaque detection was 88% for DSA, 78% for TOF-MRA, and 76% for CTA. There's significant positive correlation between PB and degree of stenosis on HR-VWI MRI (p < 0.001), but not between PB and degree of stenosis in DSA (p = 0.168), TOF-MRA (p = 0.144), and CTA (p = 0.253). RI had a significant negative correlation with degree of stenosis on HR-VWI MRI (p = 0.003), but not on DSA (p = 0.783), TOF-MRA (p = 0.405), or CTA (p = 0.751). The best inter-rater agreement for culprit plaque detection was with HR-VWI (p = 0.001)., Conclusions: The degree of stenosis measured by intra-luminal techniques does not fully reflect the true extent of ICAD. HR-VWI is a more accurate tool in characterizing atherosclerotic plaques and may be the default imaging modality in clinical practice.

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues-such as incomplete mechanistic knowledge and faulty clinical trial design-a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.

There is a critical need for cerebro-protective interventions to improve the suboptimal outcomes of patients with ischemic stroke who have been treated with reperfusion strategies. We found that nuclear pyruvate kinase muscle 2 (PKM2), a modulator of systemic inflammation, was upregulated in neutrophils after the onset of ischemic stroke in both humans and mice. Therefore, we determined the role of PKM2 in stroke pathogenesis by using murine models with preexisting comorbidities. We generated novel myeloid cell-specific PKM2-/- mice on wild-type (PKM2fl/flLysMCre+) and hyperlipidemic background (PKM2fl/flLysMCre+Apoe-/-). Controls were littermate PKM2fl/flLysMCre- or PKM2fl/flLysMCre-Apoe-/- mice. Genetic deletion of PKM2 in myeloid cells limited inflammatory response in peripheral neutrophils and reduced neutrophil extracellular traps after cerebral ischemia and reperfusion, suggesting that PKM2 promotes neutrophil hyperactivation in the setting of stroke. In the filament and autologous clot and recombinant tissue plasminogen activator stroke models, irrespective of sex, deletion of PKM2 in myeloid cells in either wild-type or hyperlipidemic mice reduced infarcts and enhanced long-term sensorimotor recovery. Laser speckle imaging revealed improved regional cerebral blood flow in myeloid cell-specific PKM2-deficient mice that was concomitant with reduced post-ischemic cerebral thrombo-inflammation (intracerebral fibrinogen, platelet [CD41+] deposition, neutrophil infiltration, and inflammatory cytokines). Mechanistically, PKM2 regulates post-ischemic inflammation in peripheral neutrophils by promoting STAT3 phosphorylation. To enhance the translational significance, we inhibited PKM2 nuclear translocation using a small molecule and found significantly reduced neutrophil hyperactivation and improved short-term and long-term functional outcomes after stroke. Collectively, these findings identify PKM2 as a novel therapeutic target to improve brain salvage and recovery after reperfusion., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Since 2013, the U.S. Food and Drug administration (FDA) has required that intravenous immune globulin (IGIV) products carry a boxed warning concerning the risk of thromboembolic events (TEEs). This study assessed the incidence of TEEs attributable to IGIV in a large population-based cohort. A self-controlled risk interval design was used to quantify the transient increase in TEE risk during the risk interval (days 0-2 and 0-13 following IGIV for arterial and venous TEEs, respectively) relative to a later control interval (days 14-27 following IGIV). Potential IGIV-exposed TEE cases from 2006 to 2012 were identified from the FDA-sponsored Sentinel Distributed Database and confirmed through medical record review. Inpatient IGIV exposures were not included in the venous TEE analysis due to concerns about time-varying confounding. 19,069 new users of IGIV who received 93,555 treatment episodes were included. Charts were retrieved for 62% and 70% of potential venous and arterial cases, respectively. There was a transient increase in the risk of arterial TEEs during days 0-2 following IGIV treatment (RR = 4.69; 95% CI 1.87, 11.90; absolute increase in risk = 8.86 events per 10,000 patients, 95% CI 3.25, 14.6), but no significant increase in venous TEE risk during days 0-13 following outpatient IGIV treatments (RR = 1.07, 95% CI 0.34, 3.48). Our results suggest there is a small increase in the absolute risk of arterial TEEs following IGIV. However, lower-than-expected chart retrieval rates and the possibility of time-varying confounding mean that our results should be interpreted cautiously. Continued pharmacovigilance efforts are warranted., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The mechanism of increased risk of venous thromboembolism (VTE) after acute ischemic stroke (AIS) is unclear. In this study, we aimed to evaluate the risk of VTE in hospitalizations due to AIS as compared to those due to non-vascular neurological conditions. We also aimed to assess any potential association between VTE risk and the use of intravenous thrombolysis (rtPA) among hospitalizations with AIS., Materials and Methods: In this case-control study, data were obtained from the Nationwide Inpatient Sample 2016-2018. Propensity score matching was used to adjust for the baseline differences between the groups. Logistic regression analysis was used to compare the risk of VTE., Results: We identified 1,541,685 hospitalizations due to AIS and 1,453,520 hospitalizations due to non-vascular neurological diagnoses that served as controls. After propensity score matching, 640,560 cases with AIS and corresponding well-matched controls were obtained. Hospitalizations due to AIS had higher odds of VTE as compared to the controls [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.40-1.60, P<0.001]. Among hospitalizations with AIS, 184,065 (11.9%) got rtPA. The odds of VTE were lower among the AIS hospitalizations that received rtPA as compared to those that did not (OR 0.89, 95% CI 0.79-0.99, P0.035)., Conclusion: Hospitalizations due to AIS have a higher risk of VTE as compared to the non-vascular neurological controls. Among AIS cases, the risk of VTE is lower among patients treated with rtPA. These epidemiological findings support the hypothesis that the risk of VTE after AIS might be partly mediated by an intrinsic pro-coagulant state., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To determine whether the intracerebral hemorrhage (ICH) score is accurate in predicting 30-day mortality in young adults, we calculated the ICH score for 156 young adults (aged 18-45) with primary spontaneous ICH and compared predicted to observed 30-day mortality rates., Methods: We retrospectively reviewed all patients aged 18-45 consecutively presenting to the University of Iowa from 2009 to 2019 with ICH. We calculated the ICH score and recorded its individual subcomponents for each patient. Poisson regression was used to test the association of ICH score components with 30-day mortality., Results: We identified 156 patients who met the inclusion criteria; mean± standard deviation (SD) age was 35±8 years. The 30-day mortality rate was 15% (n=24). The ICH score was predictive of 30-day mortality for each unit increase (p= 0.04 for trend), but the observed mortality rates for each ICH score varied considerably from the original ICH score predictions. Most notably, the 30-day mortality rates for ICH scores of 1, 2, and 3 are predicted to be 13%, 26%, and 72% respectively, but were observed in our population to be 0%, 3%, and 41%. An ICH volume of >30cc [relative risk (RR) 28, 95% confidence intervals (CI) 3-315, p=0.01] and a GCS score of <5 (RR 13, 95% CI 0.1-1176, p=0.01) were independently associated with 30-day mortality., Conclusions: The ICH score tends to overestimate mortality in young adults. ICH volume and GCS score are the most relevant items in predicting mortality at 30 days in young adults., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Data regarding the risk of cerebrovascular events following transient global amnesia (TGA) remain controversial. While some neuroradiological studies suggest an underlying cerebrovascular etiology, results from the clinical studies have been largely conflicting. We, therefore, aimed to evaluate the risk of ischemic stroke in a large, nationally representative sample of patients with TGA., Methods: We utilized the Nationwide Readmissions Database 2010-2015 to identify all hospitalizations with the primary discharge diagnosis of TGA. We selected a 2% random sample of all elective admissions to be included as controls. A propensity score-matched analysis was performed to match patients with TGA and the controls. The primary outcome was readmission due to ischemic stroke up to 1 year following discharge from the index hospitalization, assessed using the Kaplan-Meier survival analysis in the propensity-matched groups., Results: There were 24,803 weighted hospitalizations due to TGA (mean ± SD age: 65.6 ± 10.4 years, female: 54.9%) and 699,644 corresponding controls. At baseline, patients with TGA were significantly older, more likely to be male, and had a higher prevalence of hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, and migraine, as compared to the controls. However, after propensity score matching, we obtained 21,202 cases and 21,293 well-matched corresponding controls, and the risk of readmission due to ischemic stroke in patients with TGA was not different compared to the control group (HR: 1.13, 95% CI 0.62-2.05, P 0.686) during the mean (SD) follow-up period of 192.2 (102.4) days., Conclusions: After adjustment for demographics and cerebrovascular risk factors, TGA is not associated with an increased risk of subsequent ischemic stroke., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Purpose of Review: The menstrual cycle involves recurrent fluctuations in hormone levels and temperature via neuroendocrine feedback loops. This paper reviews the impact of the menstrual cycle on several common neurological conditions, including migraine, seizures, multiple sclerosis, stroke, and Parkinson's disease., Recent Findings: The ovarian steroid hormones, estrogen and progesterone, have protean effects on central nervous system functioning that can impact the likelihood, severity, and presentation of many neurological diseases. Hormonal therapies have been explored as a potential treatment for many neurological diseases with varying degrees of evidence and success. Neurological conditions also impact women's reproductive health, and the cessation of ovarian function with menopause may also alter the course of neurological diseases. Medication selection must consider hormonal effects on metabolism and the potential for adverse drug reactions related to menstruation, fertility, and pregnancy outcomes. Novel medications with selective affinity for hormonal receptors are desirable. Neurologists and gynecologists must collaborate to provide optimal care for women with neurological disorders.

Background: Unlike warfarin direct oral anticoagulants (DOACs) are administered in fixed doses, which raises concerns of its effectiveness on larger patients. Data from randomized trials are limited on the safety and efficacy of DOACs in morbidly obese individuals with atrial fibrillation (AF)., Methods: We analyzed a cohort of obese (≥ 120 kg) and morbidly obese (BMI > 40 kg/m 2 ) patients from the Veterans Health Administration system with AF who initiated apixaban, rivaroxaban, dabigatran, or warfarin between years 2012 and 2018. We used inverse probability of treatment weighting (IPTW) and Cox proportional hazards regression models to evaluate the relative hazard of death, myocardial infarction (MI), ischemic stroke, heart failure (HF), and bleeding events between oral anticoagulant (OAC) groups while censoring for medication cessation., Results: We identified 6052 obese patients on apixaban, 4233 on dabigatran, 4309 on rivaroxaban, and 13,417 on warfarin (mean age 66.7 years, 91% males, 80.4% whites). At baseline patients on apixaban had the lowest glomerular filtration rate and highest rates of previous stroke and MI compared to other OACs. Among patients with weight ≥ 120 kg and those with BMI > 40 kg/m 2 , all DOACs were associated with lower risk of any hemorrhage, hemorrhagic stroke, and gastrointestinal (GI) bleeding. Patients with BMI > 40 kg/m 2 treated with DOACs had similar ischemic stroke risk with those on warfarin., Conclusions: In this large cohort of obese Veterans Health Administration system patients, the use of DOACs resulted in lower hemorrhagic complications than warfarin while maintaining efficacy on ischemic stroke prevention.

Background and Purpose: Decompressive hemicraniectomy has been used to treat spontaneous intracerebral hemorrhage, but the benefit of evacuating the hematoma during the procedure is unclear. We aim to evaluate the utility of performing clot evacuation during hemicraniectomy for spontaneous intracerebral hemorrhage., Methods: Retrospective cohort of consecutive patients (2010-2019) treated with decompressive hemicraniectomy for a spontaneous supratentorial intracerebral hemorrhage at the University of Iowa. We compared hemicraniectomy alone to hemicraniectomy plus hematoma evacuation. We analyzed clinical features and hematoma characteristics. The outcomes at 6 months were dichotomized into unfavorable (Glasgow Outcome Scale score 1-3) and favorable (Glasgow Outcome Scale score 4-5)., Results: Eighty-three patients underwent decompressive hemicraniectomy for spontaneous intracerebral hemorrhage, 52 with hematoma evacuation, and 31 without hematoma evacuation. There were no statistically significant differences in clinical and radiographic characteristics between the 2 groups. Evacuating the hematoma in addition to hemicraniectomy did not change the odds of favorable outcome at 6 months ( P =0.806)., Conclusions: In this retrospective study, the performance of hematoma evacuation during decompressive hemicraniectomy for spontaneous intracerebral hemorrhage may not change functional outcomes over performing the hemicraniectomy alone.

Rationale: The potential value of rescue intraarterial thrombolysis in patients with large vessel occlusion stroke treated with mechanical thrombectomy has not been assessed in randomized trials., Aim: The CHemical OptImization of Cerebral Embolectomy trial aims to establish whether rescue intraarterial thrombolysis is more effective than placebo in improving suboptimal reperfusion scores in patients with large vessel occlusion stroke treated with mechanical thrombectomy., Sample Size Estimates: A sample size of 200 patients allocated 1:1 to intraarterial thrombolysis or intraarterial placebo will have >95% statistical power for achieving the primary outcome (5% in the control versus 60% in the treatment group) for a two-sided (5% alpha, and 5% lost to follow-up)., Methods and Design: We conducted a multicenter, randomized, placebo-controlled, double blind, phase 2b trial. Eligible patients are 18 or older with symptomatic large vessel occlusion treated with mechanical thrombectomy resulting in a modified treatment in cerebral ischemia score 2b at end of the procedure. Patients will receive 20-30 min intraarterial infusion of recombinant tissue plasminogen activator or placebo (0.5 mg/ml, maximum dose limit 22.5 mg)., Study Outcome(s): The primary outcome is the proportion of patients with an improved modified treatment in cerebral ischemia score 10 min after the end of the study treatment. Secondary outcomes include the shift analysis of the modified Rankin Scale, the infarct expansion ratio, the proportion of excellent outcome (modified Rankin Scale 0-1), the proportion of infarct expansion, and the infarction volume. Mortality and symptomatic intracerebral bleeding will be assessed., Discussion: The study will provide evidence whether rescue intraarterial thrombolysis improves brain reperfusion in patients with large vessel occlusion stroke and incomplete reperfusion (modified treatment in cerebral ischemia 2b) at the end of mechanical thrombectomy.

Cardiac surgeries are commonly associated with neurologic complications. The type and complexity of the surgery, as well as patients' comorbidities, determine the risk for these complications. Awareness and swift recognition of these complications may have significant implications on management and prognosis. Recent trials resulted in an expansion of the time window to treat patients with acute ischemic stroke with intravenous thrombolysis and/or mechanical thrombectomy using advanced neuroimaging for screening. The expanded time window increases the reperfusion treatment options for patients that suffer a periprocedural ischemic stroke. Moreover, there is now limited data available to help guide management of intracerebral hemorrhage in patients undergoing treatment with anticoagulation for highly thrombogenic conditions, such as left ventricular assist devices and mechanical valves. In addition to cerebrovascular complications patients undergoing heart surgery are at increased risk for seizures, contrast toxicity, cognitive changes, psychological complications, and peripheral nerve injuries. We review the neurological complications associated with the most common cardiac surgeries and discuss clinical presentation, diagnosis and management strategies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: A diagnosis of transient ischemic attack (TIA) must be followed by prompt investigation and rapid initiation of measures to prevent stroke. Prior studies evaluating the risk of stroke after TIA were conducted in the emergency room or clinic settings. Experience of patients admitted to the hospital after a TIA is not well known. We sought to assess the early risk of ischemic stroke after inpatient hospitalization for TIA., Methods: We used the 2010-2015 Nationwide Readmissions Database to identify all hospitalizations with the primary discharge diagnosis of TIA and investigated the incidence of ischemic stroke readmissions within 90 days of discharge from the index hospitalization., Results: Of 639,569 index TIA admissions discharged alive (mean ± SD age 70.4 ± 14.4 years, 58.7% female), 9,131 (1.4%) were readmitted due to ischemic stroke within 90 days. Male sex, head/neck vessel atherosclerosis, hypertension, diabetes, atrial flutter/fibrillation, previous history of TIA/stroke, illicit drug use, and higher Charlson Comorbidity Index score were independently associated with readmissions due to ischemic stroke. Ischemic stroke readmissions were associated with excess mortality, discharge disposition other than to home, and elevated cost., Conclusions: Patients hospitalized for TIA have a lower risk of ischemic stroke compared to that reported in the studies based on the emergency room and/or outpatient clinic evaluation. Among these patients, those with cardiovascular comorbidities remain at a higher risk of readmission due to ischemic stroke despite undergoing an inpatient evaluation and should therefore be the target for future preventive strategies., (© 2020 S. Karger AG, Basel.)

Background: Ischemic stroke is not rare among young adults. Understanding secular trends in the mechanism of ischemic stroke in young adults may help guide evaluation and secondary prevention. This study compares the mechanism of ischemic stroke and diagnostic studies in two groups of young adults treated at the University of Iowa 20 years apart., Methods: We retrospectively reviewed all patients aged 15-45 who presented to the University of Iowa Hospitals between 1/2010-11/2016 with ischemic stroke confirmed by imaging. Diagnostic studies and stroke etiologies for each patient using the TOAST criteria were reviewed and compared to a historic sample of young patients of the same age who presented to our center in 1977-1993., Results: We identified 322 young adults, 165 (51.2%) were women. The mean age was 36.3 ± 7.2 years. Vessel imaging was performed in 317 (95.2%) cases vs. 68.9% in the historic sample. Of these, 259 (80.4%) had magnetic resonance angiography (MRA), while diagnostic angiogram was the sole modality used for vessel imaging in the historic sample. Transthoracic echocardiography (TTE) was performed in 101 (31.4%) and transesophageal echocardiography (TEE) was performed in 169 (52.5%) cases compared to 67.1% who underwent TTE in the historic sample. In comparison with the historic sample, there was a significant decline in strokes due to small vessel disease [odds ratio (OR) 0.49, 95% confidence intervals (CI) 0.25-0.97]. The most common etiology of stroke in our sample was cervical artery dissection in 79 (24.5%) patients, whereas this was found in only 6.0% of patients in the historic sample [OR 5.0 and CI (2.99-8.44)., Conclusions: Using the TOAST classification, cryptogenic stroke remained the most common subtype in young adults. While the most common cause for ischemic stroke was cervical artery dissection., Disclosures: Enrique Leira receive salary support from the National Institute of Health., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Acute ischemic stroke is a common complication and an important source of morbidity and mortality in patients with left ventricular assist devices. There are no standardized protocols to guide management of ischemic stroke among patients with left ventricular assist device. We evaluated our experience treating patients who had an acute ischemic stroke following left ventricular assist device placement., Methods: We retrospectively reviewed all patients who underwent left ventricular assist device placement from 2010-2019 and identified patients who had acute ischemic stroke following left ventricular assist device placement., Results: Of 216 patients having left ventricular assist device placement (mean±SD age 52.9±16.2 years, women 26.9%), 19 (8.8%) had acute ischemic stroke (mean±SD age 55.8±12.0 years, women 36.8%). Median (interquartile range) time to ischemic stroke following left ventricular assist device placement was 96 (29-461) days. At the time of the ischemic stroke, 16/19 (84.2%) patients were taking both antiplatelet and anticoagulation therapy, 1/19 (5.3%) patient was receiving only anticoagulants, 1/19 (5.3%) patient was taking aspirin and dipyridamole, and 1/19 (5.3%) patient was not taking antithrombic agents. INR was subtherapeutic (INR<2.0) in 7/17 (41.2%) patients. No patient was eligible to receive thrombolytic therapy, while 5/19 (26.3%) underwent mechanical thrombectomy. Anticoagulation was continued in the acute stroke phase in 11/19 (57.9%) patients and temporarily held in 8/19 (42.1%) patients. Hemorrhagic transformation of the ischemic stroke occurred in 6/19 (31.6%) patients. Anticoagulation therapy was continued following ischemic stroke in 4/6 (66.7%) patients with hemorrhagic transformation., Conclusions: While thrombolytic therapy is frequently contraindicated in the management of acute ischemic stroke following left ventricular assist device, mechanical thrombectomy remains a valid option in eligible patients. Anticoagulation is often continued through the acute phase of ischemic stroke secondary to concerns for LVAD thrombosis. The risks and benefits of continuing anticoagulation must be weighed carefully, especially in patients with large infarct volume, as hemorrhagic transformation remains a common complication., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: High-resolution vessel wall imaging (HR-VWI) is a powerful tool in diagnosing intracranial vasculopathies not detected on routine imaging. We hypothesized that 7T HR-VWI may detect the presence of atherosclerotic plaques in patients with intracranial atherosclerosis disease initially misdiagnosed as cryptogenic strokes., Methods: Patients diagnosed as cryptogenic stroke but suspected of having an intracranial arteriopathy by routine imaging were prospectively imaged with HR-VWI. If intracranial atherosclerotic plaques were identified, they were classified as culprit or nonculprit based on the likelihood of causing the index stroke. Plaque characteristics, such as contrast enhancement, degree of stenosis, and morphology, were analyzed. Contrast enhancement was determined objectively after normalization with the pituitary stalk. A cutoff value for plaque-to-pituitary stalk contrast enhancement ratio (CR) was determined for optimal prediction of the presence of a culprit plaque. A revised stroke cause was adjudicated based on clinical and HR-VWI findings., Results: A total of 344 cryptogenic strokes were analyzed, and 38 eligible patients were imaged with 7T HR-VWI. Intracranial atherosclerosis disease was adjudicated as the final stroke cause in 25 patients. A total of 153 intracranial plaques in 374 arterial segments were identified. Culprit plaques (n=36) had higher CR and had concentric morphology when compared with nonculprit plaques ( P ≤0.001). CR ≥53 had 78% sensitivity for detecting culprit plaques and a 90% negative predictive value. CR ≥53 ( P =0.008), stenosis ≥50% ( P <0.001), and concentric morphology ( P =0.030) were independent predictors of culprit plaques., Conclusions: 7T HR-VWI allows identification of underlying intracranial atherosclerosis disease in a subset of stroke patients with suspected underlying vasculopathy but otherwise classified as cryptogenic. Plaque analysis in this population demonstrated that culprit plaques had more contrast enhancement (CR ≥53), caused a higher degree of stenosis, and had a concentric morphology.

Background and Purpose: There is mounting evidence supporting the benefit of intra-arterial administration of vasodilators in diagnosing reversible cerebral vasoconstriction syndrome. We prospectively quantified the degree of luminal diameter dilation after intra-arterial administration of verapamil and its accuracy in diagnosing reversible cerebral vasoconstriction syndrome., Materials and Methods: Patients suspected of having intracranial arteriopathy on noninvasive imaging and referred for digital subtraction angiography were enrolled in a prospective registry. Intra-arterial verapamil was administered in vascular territories with segmental irregularities. The caliber difference (Caliber post - Caliber pre ) and the proportion of caliber change ([(Caliber post - Caliber pre )/Caliber pre ] × 100%) were used to determine the response to verapamil. The diagnosis of reversible cerebral vasoconstriction syndrome was made on the basis of clinical and imaging features at a follow-up appointment, independent of the reversibility of verapamil. Receiver operating characteristic curve analysis was performed to determine the best threshold., Results: Twenty-six patients were included, and 9 (34.6%) were diagnosed with reversible cerebral vasoconstriction syndrome. A total of 213 vascular segments were assessed on diagnostic angiography. Every patient with a final diagnosis of reversible cerebral vasoconstriction syndrome responded to intra-arterial verapamil. The maximal proportion of change ( P  < .001), mean proportion of change ( P  = .002), maximal caliber difference ( P  = .004), and mean caliber difference ( P  = .001) were statistically different between patients with reversible cerebral vasoconstriction syndrome and other vasculopathies. A maximal proportion of change  ≥32% showed a sensitivity of 100% and a specificity of 88.2% to detect reversible cerebral vasoconstriction syndrome (area under the curve = 0.951). The Reversible Cerebral Vasoconstriction Syndrome-2 score of  ≥5 points achieved a lower area under the curve (0.908), with a sensitivity of 77.8% and a specificity of 94.1%., Conclusions: Objective measurement of the change in the arterial calibers after intra-arterial verapamil is accurate in distinguishing reversible cerebral vasoconstriction syndrome from other vasculopathies. A proportion of change  ≥32% has the best diagnostic performance., (© 2020 by American Journal of Neuroradiology.)

Objective: To evaluate the long-term functional outcome of interhospital transfer of patients with stroke with suspected large vessel occlusion (LVO) using Helicopter Emergency Medical Services (HEMS)., Methods: Records of consecutive patients evaluated through 2 telestroke networks and transferred to thrombectomy-capable stroke centers between March 2017 and March 2018 were reviewed. Inverse probability of treatment weighting (IPTW) using the propensity score was performed to address confounding factors. Multivariate logistic regression analysis with IPTW was used to determine whether HEMS were associated with good long-term functional outcome (modified Rankin scale score ≤ 2)., Results: A total of 199 patients were included; median age was 67 years (interquartile range [IQR] 55-79 years), 90 (45.2%) were female, 120 (60.3%) were white, and 100 (50.3%) were transferred by HEMS. No significant differences between the 2 groups were found in mean age, sex, race, IV tissue plasminogen activator (tPA) receipt, and thrombectomy receipt. The median baseline NIH Stroke Scale score was 14 (IQR 9-18) in the helicopter group vs 11 (IQR 6-18) for patients transferred by ground ( p = 0.039). The median transportation time was 60 minutes (IQR 49-70 minutes) by HEMS and 84 minutes (IQR 25-102 minutes) by ground ( p < 0.001). After weighting baseline characteristics, the use of HEMS was associated with higher odds of good long-term outcome (OR 4.738, 95% CI 2.15-10.444, p < 0.001) controlling for transportation time, door-in-door-out time, and thrombectomy and tPA receipt. The magnitude of the HEMS effect was larger in thrombectomy patients who had successful recanalization (OR 1.758, 95% CI 1.178-2.512, p = 0.027)., Conclusions: HEMS use was associated with better long-term functional outcome in patients with suspected LVO, independently of transportation time., (© 2019 American Academy of Neurology.)

The coronavirus 2019 (COVID-19) pandemic requires drastic changes in allocation of resources, which can affect the delivery of stroke care, and many providers are seeking guidance. As caregivers, we are guided by 3 distinct principles that will occasionally conflict during the pandemic: (1) we must ensure the best care for those stricken with COVID-19, (2) we must provide excellent care and advocacy for patients with cerebrovascular disease and their families, and (3) we must advocate for the safety of health care personnel managing patients with stroke, with particular attention to those most vulnerable, including trainees. This descriptive review by a diverse group of experts in stroke care aims to provide advice by specifically addressing the potential impact of this pandemic on (1) the quality of the stroke care delivered, (2) ethical considerations in stroke care, (3) safety and logistic issues for providers of patients with stroke, and (4) stroke research. Our recommendations on these issues represent our best opinions given the available information, but are subject to revision as the situation related to the COVID-19 pandemic continues to evolve. We expect that ongoing emergent research will offer additional insights that will provide evidence that could prompt the modification or removal of some of these recommendations., (© 2020 American Academy of Neurology.)

Background and Purpose- We aim to determine the potential impact on stroke thrombolysis of drip-and-ship helicopter flights and specifically of their low-frequency vibrations (LFVs). Methods- Mice with a middle cerebral artery autologous thromboembolic occlusion were randomized to receive rtPA (recombinant tissue-type plasminogen activator; or saline) 90 minutes later in 3 different settings: (1) a motion platform simulator that reproduced the LFV signature of the helicopter, (2) a standardized actual helicopter flight, and (3) a ground control. Results- Mice assigned to the LFV simulation while receiving tPA had smaller infarctions (31.6 versus 54.9 mm 3 ; P =0.007) and increased favorable neurological outcomes (86% versus 28%; P =0.0001) when compared with ground controls. Surprisingly, mice receiving tPA in the helicopter did not exhibit smaller infarctions (47.8 versus 54.9 mm 3 ; P =0.58) nor improved neurological outcomes (37% versus 28%; P =0.71). This could be due to a causative effect of the 20- to 30-Hz band, which was inadvertently attenuated during actual flights. Mice using saline showed no differences between the LFV simulator and controls with respect to infarct size (80.9 versus 95.3; P =0.81) or neurological outcomes (25% versus 11%; P =0.24), ruling out an effect of LFV alone. There were no differences in blood-brain barrier permeability between LFV simulator or helicopter, compared with controls (2.45-3.02 versus 4.82 mm 3 ; P =0.14). Conclusions- Vibration in the low-frequency range (0.5-120 Hz) is synergistic with rtPA, significantly improving the effectiveness of thrombolysis without impairing blood-brain barrier permeability. Our findings reveal LFV as a novel, safe, and simple-to-deliver intervention that could improve the outcomes of patients. Visual Overview- An online visual overview is available for this article.

Background: We evaluated adherence to dosing criteria for patients with atrial fibrillation (AF) taking dabigatran or rivaroxaban and the impact of off-label dosing on thromboembolic and bleeding risk., Methods: We used data for a retrospective cohort from a large U.S. health plan for Medicare beneficiaries age > =65 years with AF who initiated dabigatran or rivaroxaban during 2010-2016. Stroke and major bleeding were quantified in patients who were eligible for low dose but received standard dose, and in patients who were eligible for standard dose but received low dose., Results: We identified 8035 and 19,712 patients who initiated dabigatran or rivaroxaban, respectively. Overall, 1401 (17.4%) and 7820 (39.7%) patients who received dabigatran and rivaroxaban met criteria for low dose, respectively. Of those, 959 (68.5%) and 3904 (49.9%) received standard dose. In contrast, 1013 (15.3%) and 2551 (21.5%) of patients eligible for standard dose dabigatran and rivaroxaban received low dose. Mean follow-up for patients eligible for low and standard dose dabigatran and rivaroxaban were 13.9, 15.1, 10.1, and 12.3 months, respectively. In unadjusted analyses, patients eligible for low or standard dose dabigatran and rivaroxaban but receiving off-label dose, had no differences in the rates of ischemic stroke. Among patients who met criteria for standard dose direct oral anticoagulants (DOAC), use of low dose was associated with significantly higher risk of any major bleeding (Dabigatran: HR = 1.44; 95% CI 1.14-1.8, P = 0.002, Rivaroxaban HR 1.34, 95% CI 1.11-1.6, P = 0.002) and gastrointestinal bleeding (Dabigatran: HR = 1.48; 95% CI 1.08-2, P = 0.016). In patients who met criteria for low dose DOACs, there was lower risk of major bleeding (Dabigatran: HR = 0.59; 95% CI 0.43-0.8, P < 0.001), gastrointestinal (Rivaroxaban: HR 0.79; 95% CI 0.64-0.98, P = 0.03) and intracranial bleeding (Dabigatran: HR = 0.33; 95% CI 0.12-0.9, P = 0.001) with standard dosing. After propensity matching, use of off-label doses was not associated with stroke, major, gastrointestinal or intracranial bleeding for either dabigatran or rivaroxaban., Conclusions: While a significant number of patients receive higher or lower dose of dabigatran and rivaroxaban than recommended, we found no evidence of significant impact on thromboembolic or hemorrhagic outcomes.

Introduction: Cervical artery dissection (CeAD) is a major cause of ischemic stroke in young adults. Our understanding of the specific risk factors and clinical course of CeAD is still evolving. In this study, we evaluated the differential risk factors and outcomes of CeAD-related strokes among young adults., Methods: The study population consisted of young patients 15-45 years of age consecutively admitted with acute ischemic stroke to our comprehensive stroke center between January 1, 2010, and November 30, 2016. Diagnosis of CeAD was based on clinical and radiological findings. Univariate and multivariable logistic regression analyses were used to assess the risk factors and clinical outcomes associated with CeAD-related strokes., Results: Of the total 333 patients with acute ischemic stroke included in the study (mean ± SD age: 36.4 ± 7.1 years; women 50.8%), CeAD was identified in 79 (23.7%) patients. As compared to stroke due to other etiologies, patients with CeAD were younger in age, more likely to have history of migraine and recent neck manipulation and were less likely to have hypertension, diabetes, and previous history of stroke. Clinical outcomes of CeAD were comparable to strokes due to other etiologies. Within the CeAD group, higher initial stroke severity and history of tobacco use were associated with higher modified Rankin Scale score at follow-up., Conclusions: While history of migraine and neck manipulation are significantly associated with CeAD, most of the traditional vascular risk factors for stroke are less prevalent in this group when compared to strokes due to other etiologies. For CeAD-related strokes, higher initial stroke severity and history of tobacco use may be associated with higher stroke-related disability, but overall, patients with CeAD have similar outcomes as compared to strokes due to other etiologies., (© 2020 S. Karger AG, Basel.)

Purpose of Review: Systemic lupus erythematosus (SLE) is commonly associated with neurological manifestations. Rapid recognition and treatment of these complications may improve outcomes. In this article, we review the neurological conditions associated with SLE, their diagnosis and management strategies., Recent Findings: Recent meta-analysis showed that patients with neuropsychiatric manifestations of SLE were more likely to have positive antiphospholipid, antiribosomal P, and antineuronal antibodies. Another meta-analysis showed an association between SLE and antiphospholipid antibodies with cognitive impairment. Two large retrospective studies have shown that the peripheral nervous system is commonly involved in SLE frequently alongside the central nervous system. Neurological manifestations occur in most of SLE patients. Antiphospholipid antibodies are common in patients with SLE and increase the odds of neurological complications. Management typically involved a combination of treatments directed toward the neurological complication and therapies directed toward SLE itself. The efficacy of these treatment protocols, however, has not been rigorously studied and deserves further investigation.

Importance: Understanding of the epidemiology, outcomes, and management of spontaneous subarachnoid hemorrhage (sSAH) during pregnancy is limited. Small, single center series suggest a slight increase in morbidity and mortality., Objective: To determine if incidence of sSAH in pregnancy is increasing nationally and also to study the outcomes for this patient population., Design, Setting, and Participants: A retrospective analysis was performed utilizing the Nationwide Inpatient Sample (NIS) and Healthcare Cost and Utilization Project for the years 2002-2014 for sSAH hospitalizations. The NIS is a large administrative database designed to produce nationally weighted estimates. Female patients age 15-49 with sSAH were identified using the International Classification of Diseases, 9th Revision, Clinical Modification code 430. Pregnancy and maternal diagnosis were identified using pregnancy related ICD codes validated by previous studies. The Cochran-Armitage trend test and parametric tests were utilized to analyze temporal trends and group comparisons. Main Outcomes and Measures: National trend for incidence of sSAH in pregnancy, age, and race/ethnicity as well as associated risk factors and outcomes., Results: During the time period, there were 73,692 admissions for sSAH in women age 15-49 years, of which 3978 (5.4%) occurred during pregnancy. The proportion of sSAH during pregnancy hospitalizations increased from 4.16 % to 6.33% (P- T rend < .001) during the 12 years of the study. African-American women (8.19%) and Hispanic (7.11%) had higher rates of sSAH during pregnancy than whites (3.83%). In the NIS data, the incidence of sSAH increased from 5.4/100,000 deliveries (2002) to 8.5/100,000 deliveries (2014; P- Trend < .0001). The greatest increase in sSAH was noted to be among pregnant African-American women from (13.4 [2002]) to (16.39 [2014]/100,000 births). Mortality was lower in pregnant women (7.69% versus 17.37%, P < .0001). Pregnant women had a higher likelihood of being discharged to home (69.78% versus 53.66%, P < .0001) and lower likelihood of discharge to long term facility (22.4% versus 28.7%, P < .0001) than nonpregnant women after sSAH hospitalization., Conclusions and Relevance: There is an upward trend in the incidence of sSAH occurring during pregnancy. There was disproportionate increase in incidence of sSAH in the African American and younger mothers. Outcomes were better for both pregnant and nonpregnant women treated at teaching hospitals and in pregnant women in general as compared to nonpregnant women., (Copyright © 2019 Elsevier Inc. All rights reserved.)