Transcarotid Arterial Revascularization of Symptomatic Internal Carotid Artery Disease: A Systematic Review and Study-Level Meta-Analysis.

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.

PKM2 promotes neutrophil activation and cerebral thromboinflammation: therapeutic implications for ischemic stroke.

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.

Rationale and Design of the Statins Use in Intracerebral Hemorrhage Patients (SATURN) Trial.

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.

Targeting Neutrophil α9 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia.

BACKGROUND: Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin α9ß1 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: α9Neu-KO (α9fl/flMRP8Cre+) and littermate control α9WT (α9fl/flMRP8Cre-) 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]-1ß 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 α9WT obese mice). Obese α9Neu-KO mice were less susceptible to thrombosis in FeCl3 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.

The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results.

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.

Self-controlled assessment of thromboembolic event (TEE) risk following intravenous immune globulin (IGIV) in the U.S. (2006-2012).

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.

Impact of Intracerebral Hematoma Evacuation During Decompressive Hemicraniectomy on Functional Outcomes.

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.

Risk of Ischemic Stroke after an Inpatient Hospitalization for Transient Ischemic Attack in the United States.

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.

Effects of the Menstrual Cycle on Neurological Disorders.

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.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Obese Patients with Atrial Fibrillation.

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/m2) 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/m2, all DOACs were associated with lower risk of any hemorrhage, hemorrhagic stroke, and gastrointestinal (GI) bleeding. Patients with BMI > 40 kg/m2 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.

The Intracerebral Hemorrhage Score Overestimates Mortality in Young Adults.

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.

Risk of Venous Thromboembolism in Hospitalized Patients with Acute Ischemic Stroke Versus Other Neurological Conditions.

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.

Detection and Quantification of Symptomatic Atherosclerotic Plaques With High-Resolution Imaging in Cryptogenic Stroke.

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.

Low-Frequency Vibrations Enhance Thrombolytic Therapy and Improve Stroke Outcomes.

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 mm3; 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 mm3; 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 mm3; 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.

Differential Risk Factors and Outcomes of Ischemic Stroke due to Cervical Artery Dissection in Young Adults.

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.

Characteristics and outcomes in patients with atrial fibrillation receiving direct oral anticoagulants in off-label doses.

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.

Secular Trends for Etiologies of Acute Ischemic Stroke in Young Adults.

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.

Management of Ischemic Stroke Following Left Ventricular Assist Device.

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.

Neurological Complications in Patients with Systemic Lupus Erythematosus.

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.

Neurological Complications of Cardiological Interventions.

PURPOSE OF REVIEW: Neurological complications are common during cardiac procedures. The type of procedure influences the profile of neurological complications and their management. In this article, we review the different neurological complications encountered following cardiac procedures, and treatment strategies for managing those complications. RECENT FINDINGS: Recent clinical trials have expanded the time window of eligibility for mechanical thrombectomy and intravenous thrombolysis. As a result, more options are now available for the treatment of periprocedural strokes. Early recognition of neurological complications, particularly stroke, will allow more patients to be treated effectively. The expanded window for intravenous thrombolysis and mechanical thrombectomy using advanced neuroimaging for selection provides more opportunities for treatment of periprocedural stroke. There is a paucity of data on the management of cerebrovascular complications, such as ischemic and hemorrhagic strokes, in the setting of left ventricular assist device or mechanical valve.