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Purpose of Review: Many patients with ischemic stroke have a stroke syndrome and neuroimaging findings consistent with embolism, but no evidence of atrial fibrillation. Recent data suggest that the pathological atrial substrate, or atrial cardiopathy, that underlies atrial fibrillation, rather than atrial fibrillation itself, may be an important cause of unexplained strokes. This paper will review the literature on the rationale and data behind the concept of atrial cardiopathy, its pathophysiology, suggested biomarkers of atrial cardiopathy, and therapeutic implications., Recent Findings: Several lines of evidence suggest that patients can have strokes associated with disorders of the atrium, even without frank atrial fibrillation. Even in patients with paroxysmal atrial fibrillation, cardiac emboli may occur temporally disassociated from episodes of atrial fibrillation, and the left atrial appendage flow patterns associated with increased thromboembolic risk may occur even when the surface electrocardiogram demonstrates normal sinus rhythm. Biomarkers of left atrial structural and electrophysiological abnormalities have been associated with stroke risk, even in the absence of atrial fibrillation. Atrial cardiopathy, as determined by the presence of biomarkers of left atrial dysfunction, may provide a therapeutic target to reduce the risk of cardioembolic stroke in the absence of atrial fibrillation. Clinical trials are currently ongoing to test this hypothesis.

Background The American Heart Association Life's Simple 7 metric defines ideal cardiovascular health (CVH) on 7 factors: smoking, diet, physical activity, body mass index, blood sugar, blood pressure, and cholesterol. This metric has been used to define optimal brain health, but data relative to subclinical imaging biomarkers of brain aging are lacking. This study examines the association between Life's Simple 7 with white matter hyperintensity volume, silent brain infarcts, and cerebral volume. Methods and Results A subsample of stroke-free participants from the population-based Northern Manhattan Study underwent brain magnetic resonance imaging an average of 7 years after baseline. Linear and logistic regression models were constructed to estimate associations between the number of ideal CVH metrics achieved with imaging biomarkers of brain aging, adjusting for sociodemographics. Among 1031 participants (mean age at magnetic resonance imaging=72±8, 40% men, 19% black, 16% white, and 65% Hispanic), no one had ideal status in all 7 factors, 1% had ideal status in 6 factors, 18% in 4 to 5 factors, 30% in 3 factors, 33% in 2 factors, and 18% in 0 to 1 factors. The number of ideal CVH factors achieved was inversely associated with white matter hyperintensity volume (beta per factor=-0.047; P=0.04) and silent brain infarct (odds ratio per factor=0.84; 95% confidence interval=0.72-0.97) and positively associated with cerebral volume (beta per factor=0.300; P=0.002). Conclusions An increasing ideal CVH score was associated with less white matter hyperintensity volume and silent brain infarcts and greater cerebral volumes, supporting the Life's Simple 7 metric as a useful measure to quantify optimal brain health. Monitoring and promoting achievement of Life's Simple 7 ideal CVH factors may improve subclinical and clinical brain health outcomes.

Objective: We aimed to evaluate the association between cancer and cerebrovascular disease in a prospective cohort study with adjudicated cerebrovascular diagnoses., Methods: We analyzed participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who were 45 years and older and had Medicare coverage for 365 days before their baseline study visit. Participants with a history of cancer or cerebrovascular events were excluded. The time-dependent exposure was a new diagnosis of malignant cancer identified through Medicare claims algorithms. Participants were prospectively followed from their baseline study visit (2003-2007) through 2014 for the outcome of a neurologist-adjudicated cerebrovascular event defined as a composite of stroke (ischemic or hemorrhagic) or TIA. Cox regression was used to evaluate the association between a new cancer diagnosis and subsequent cerebrovascular events. Follow-up time was modeled in discrete time periods to fulfill the proportional hazard assumption., Results: Among 6,602 REGARDS participants who met eligibility criteria, 1,149 were diagnosed with cancer during follow-up. Compared to no cancer, a new cancer diagnosis was associated with subsequent cerebrovascular events in the first 30 days after diagnosis (hazard ratio 6.1, 95% confidence interval 2.7-13.7). This association persisted after adjustment for demographics, region of residence, and vascular risk factors (hazard ratio 6.6, 95% confidence interval 2.7-16.0). There was no association between cancer diagnosis and incident cerebrovascular events beyond 30 days. Cancers considered high risk for venous thromboembolism demonstrated the strongest associations with cerebrovascular event risk., Conclusion: A new diagnosis of cancer is associated with a substantially increased short-term risk of cerebrovascular events., (© 2018 American Academy of Neurology.)

Objective: We examined whether greater depressive symptoms were associated with domain-specific cognitive performance, change in cognition, and MRI markers of brain atrophy and subclinical cerebrovascular disease in a diverse sample of older adults from the Northern Manhattan Study., Methods: Data were analyzed from the Northern Manhattan Study, a prospective cohort study of mostly Caribbean Hispanic, stroke-free, older adults. A total of 1,111 participants had baseline measures of depressive symptoms, measured as the Center of Epidemiological Studies-Depression Scale, MRI markers, and cognitive function. A Center of Epidemiological Studies-Depression score ≥16 was considered indicative of greater depressive symptoms. Multivariable linear and logistic regression models were used to examine the associations of interest., Results: At baseline, 22% of participants had greater depressive symptoms. Greater depressive symptoms were significantly associated with worse baseline episodic memory in models adjusted for sociodemographic, vascular risk factor, behavioral, and antidepressive medication variables (β [95% confidence interval] = -0.21 [-0.33 to -0.10], p = 0.0003). Greater depressive symptoms were also associated with smaller cerebral parenchymal fraction (β [95% confidence interval] = -0.56 [-1.05 to -0.07], p = 0.02) and increased odds of subclinical brain infarcts (odds ratio [95% confidence interval] = 1.55 [1.00-2.42], p = 0.05), after adjustment for sociodemographic, behavioral, and vascular risk factor variables. Greater depressive symptoms were not significantly associated with white matter hyperintensity volume, hippocampal volume, or change in cognition over an average of 5 years. Results were unchanged when stabilized inverse probability weights were applied to address selective attrition during the study period., Conclusions: In this sample of mostly Caribbean Hispanic, stroke-free, older adults, greater depressive symptoms were associated with worse episodic memory, smaller cerebral volume, and silent infarcts., (© 2018 American Academy of Neurology.)

Background: The left atrial appendage (LAA) is the main source of thrombus in atrial fibrillation, and there is an association between non-chicken wing (NCW) LAA morphology and stroke. We hypothesized that the prevalence of NCW LAA morphology would be higher among patients with cardioembolic (CE) stroke and embolic stroke of undetermined source (ESUS) than among those with noncardioembolic stroke (NCS)., Methods: This multicenter retrospective pilot study included consecutive patients with ischemic stroke from 3 comprehensive stroke centers who previously underwent a qualifying chest computed tomography (CT) to assess LAA morphology. Patients underwent inpatient diagnostic evaluation for ischemic stroke, and stroke subtype was determined based on ESUS criteria. LAA morphology was determined using clinically performed contrast enhanced thin-slice chest CT by investigators blinded to stroke subtype. The primary predictor was NCW LAA morphology and the outcome was stroke subtype (CE, ESUS, NCS)., Results: We identified 172 patients with ischemic stroke who had a clinical chest CT performed. Mean age was 70.1 ± 14.3 years and 51.7% were male. Compared with patients with NCS, the prevalence of NCW LAA morphology was higher in patients with CE stroke (58.7% versus 46.3%, P = .1) and ESUS (58.8% versus 46.3%, P = .2), but this difference did not achieve statistical significance., Conclusion: The prevalence of NCW LAA morphology may be similar in patients with ESUS and CE, and may be higher than that in those with NCS. Larger studies are needed to confirm these associations., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The pathogenesis of increased stroke risk in human immunodeficiency virus (HIV) remains unclear. Our study investigated the relationship between adventitial and intimal CD3 + T cells and brain arterial remodeling that potentially contributes to HIV-related vasculopathy and stroke. Large brain arteries from 84 HIV + cases and 78 HIV - cases were analyzed to determine interadventitial and luminal diameters, intimal and wall thickness, percent stenosis, and the presence of atherosclerosis. Immunohistochemical analysis was performed to detect and visually score CD3, a pan-T-cell marker, in the intima and adventitia. Our study showed that numbers of adventitial CD3 + T cells are lower among persons with HIV than among those without HIV, especially if CD4 counts are <200, though intimal CD3 + T cell numbers did not differ by HIV status. Among those with HIV but CD4 counts of <200 at the time of death, intimal CD3 + T cells were associated with hypertrophic outward remodeling, while among those with HIV and CD4 of >200 or HIV - controls, intimal CD3 + T cells were associated with hypertrophic inward remodeling. We conclude that intimal lymphocytic inflammation is involved in brain arterial remodeling that may contribute to HIV-related cerebrovascular pathology. IMPORTANCE Although mortality from human immunodeficiency virus (HIV) has decreased with the use of combination antiretroviral therapies, there is now an increased risk of cardiovascular and cerebrovascular disease associated with HIV. Thus, there is a need to understand the pathogenesis of stroke in HIV infection. Our study examines how lymphocytic inflammation in brain arteries may contribute to increased cerebral vasculopathy. With this understanding, our study can potentially help direct future therapies to target and prevent brain arterial remodeling processes associated with HIV., (Copyright © 2018 American Society for Microbiology.)

Background and Purpose: Peripartum strokes during delivery admissions are rare but have high maternal morbidity. Infections have been proposed as a possible stroke trigger. We hypothesized that women who had infections diagnosed at the time of delivery admission would have higher risk of stroke during their delivery hospitalization., Methods: We conducted a case-control study using state inpatient administrative databases for California (2007-2011), Florida (2009-2011), and New York (2009-2011). Women whose admission included a vaginal or cesarean delivery, with a new diagnosis of stroke during the admission, were considered cases and were randomly matched to 3 in-state controls by age/admission year and presence and severity of hypertensive disorders of pregnancy. The primary exposure of interest was infection of any type present on admission. Secondary exposures included race/ethnicity, payer status, delivery method, and known vascular risk factors such as chronic hypertension, diabetes mellitus, smoking, alcohol abuse, hypercoagulable states, coagulopathies, and renal disease. We used multivariable conditional logistic regression to estimate the odds ratios and 95% confidence intervals for the association of infections and known vascular risk factors with stroke risk., Results: A total of 455 cases (mean age, 29.8), of whom 195 (42.9%) had hypertensive disorders of pregnancy, were matched with 1365 controls. Infection of any type present on admission increased the odds of stroke diagnosis during the admission (adjusted odds ratio, 1.74; 95% confidence interval, 1.29-2.35). Risk was higher for genitourinary infections (adjusted odds ratio, 2.56; 95% confidence interval, 1.25-5.24) and sepsis (adjusted odds ratio, 10.4; 95% confidence interval, 2.15-20.0). The association between infection and stroke during delivery admission did not differ by the presence of hypertensive disorders of pregnancy., Conclusions: Infections present on admission increased stroke risk during delivery admissions in women with and without hypertensive disorders of pregnancy. The results were driven by genitourinary infections and sepsis. Infections may be an underrecognized precipitant of peripartum stroke., (© 2018 American Heart Association, Inc.)

Background and Purpose: Carotid plaque (CP), carotid intima media thickness (cIMT), and stiffness (STIFF) are pre-clinical markers of atherosclerosis and predictors of cerebrovascular disease (CVD). We sought to investigate whether STIFF is a significant determinant of cIMT and CP, which may provide an insight into the mechanism by which STIFF adds to the risk of CVD., Methods: We analyzed 876 stroke-free subjects from the Northern Manhattan Study with available ultrasound measures. To obtain the associations with STIFF, we performed multivariable-adjusted regression, negative binomial regression (for CP number), and multinomial logistic regression (for plaque area)., Results: The mean age was 64 ± 9 years; 63% women and 65% Caribbean Hispanics. The mean cIMT was 0.93 ± 0.9 mm, the mean diastolic diameter 6.24 ± 0.94 mm, and STIFF 8.6 ± 6.2 ln mmHg. Prevalence of CP was 57%, and the mean total plaque area was 22.6 ± 23.0 mm 2 . STIFF was positively associated with cIMT but not with CP. There was an association between diastolic diameter and thick plaque. For each millimeter increase in diastolic diameter, there was about a 20% increased risk of having thick plaque (vs. no plaque). In longitudinal analyses, each millimeter increase in diastolic diameter was associated with a 37% increased risk of incident plaque., Conclusion: Increased STIFF was associated with increased cIMT and carotid artery dilatation with greater plaque burden. Increased cIMT and plaque burden represent vascular remodeling likely resulting from the two different age-related mechanisms, one that includes diffuse wall thickening (cIMT) with STIFF and another that incorporates focal atherosclerosis (plaque) with luminal dilatation.

Background and Purpose: Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke., Methods: The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults ≥65 years of age. For this study, we excluded participants diagnosed with stroke or AF before baseline. Exposures were several markers of atrial cardiopathy: baseline P-wave terminal force in ECG lead V 1 , left atrial dimension on echocardiogram, and N terminal pro B type natriuretic peptide (NT-proBNP), as well as incident AF. Incident AF was ascertained from 12-lead electrocardiograms at annual study visits for the first decade after study enrollment and from inpatient and outpatient Medicare data throughout follow-up. The primary outcome was incident ischemic stroke. We used Cox proportional hazards models that included all 4 atrial cardiopathy markers along with adjustment for demographic characteristics and established vascular risk factors., Results: Among 3723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 participants (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When all atrial cardiopathy markers were combined in 1 Cox model, we found significant associations with stroke for P-wave terminal force in ECG lead V 1 (hazard ratio per 1000 μV*ms 1.04; 95% confidence interval, 1.001-1.08), log-transformed NT-proBNP (hazard ratio per doubling of NT-proBNP, 1.09; 95% confidence interval, 1.03-1.16), and incident AF (hazard ratio, 2.04; 95% confidence interval, 1.67-2.48) but not left atrial dimension (hazard ratio per cm, 0.96; 95% confidence interval, 0.84-1.10)., Conclusions: In addition to clinically apparent AF, other evidence of abnormal atrial substrate is associated with subsequent ischemic stroke. This finding is consistent with the hypothesis that thromboembolism from the left atrium may occur in the setting of several different manifestations of atrial disease., (© 2018 American Heart Association, Inc.)

Objectives: To test the hypothesis that brain arterial diameters are associated with cognitive performance, particularly in arteries supplying domain-specific territories., Methods: Stroke-free participants in the Northern Manhattan Study were invited to have a brain MRI from 2003-2008. The luminal diameters of 13 intracranial arterial segments were obtained using time-of-flight magnetic resonance angiogram (MRA), and then averaged and normalized into a global score and region-specific arterial diameters. Z-Scores for executive function, semantic memory, episodic memory and processing speed were obtained at MRI and during follow-up. Adjusted generalized additive models were used to assess for associations., Results: Among the 1034 participants with neurocognitive testing and brain MRI, there were non-linear relationships between left anterior (ACA) and middle cerebral artery (MCA) diameter and semantic memory Z-scores (χ2=10.00; DF=3; p=.019), and left posterior cerebral artery (PCA) and posterior communicating artery (Pcomm) mean diameter and episodic memory Z-scores (χ2=9.88; DF=3; p=.020). Among the 745 participants who returned for 2nd neuropsychological testing, on average 5.0±0.4 years after their MRI, semantic memory change was associated non-linearly with the left PCA/Pcomm mean diameter (χ2=13.09; DF=3; p=.004) and with the right MCA/ACA mean diameter (χ2=8.43; DF=3; p=.03). In both cross-sectional and longitudinal analyses, participants with the larger brain arterial diameters had more consistently lower Z-scores and greater decline than the rest of the participants., Conclusions: Brain arterial diameters may have downstream effects in brain function presenting as poorer cognition. Identifying the mechanisms and the directionality of such interactions may increase the understanding of the vascular contribution to cognitive impairment and dementia. (JINS, 2018, 24, 335-346).

Introduction: The aim of this study was to compare the risk of ischemic stroke in patients who have atrial fibrillation and patients who have atrial flutter., Methods: Using inpatient and outpatient Medicare claims data from 2008 to 2014 for a 5% sample of all beneficiaries 66 years of age or older, we identified patients diagnosed with atrial fibrillation and those diagnosed with atrial flutter. The primary outcome was ischemic stroke. In the primary analysis, patients with atrial flutter were censored upon converting to fibrillation; in a secondary analysis, they were not. Survival statistics were used to compare incidence of stroke in patients with flutter and patients with fibrillation. Cox proportional hazards analysis was used to compare the associations of flutter and fibrillation with ischemic stroke after adjustment for demographics and risk factors., Results: We identified 14,953 patients with flutter and 318,138 with fibrillation. During a mean follow-up period of 2.8 (±2.3) years, we identified 18,900 ischemic strokes. The annual incidence of ischemic stroke in patients with flutter was 1.38% (95% confidence interval [CI] 1.22%-1.57%) compared with 2.02% (95% CI 1.99%-2.05%) in patients with fibrillation. After adjustment for demographics and stroke risk factors, flutter was associated with a lower risk of stroke compared with fibrillation (hazard ratio .69; 95% CI .60-.79, P < .05). Within 1 year, 65.7% (95% CI 64.9%-66.4%) of patients with flutter converted to fibrillation but remained at a lower risk of ischemic stroke (hazard ratio .85; 95% CI .78-.92)., Conclusions: Patients with atrial flutter faced a lower risk of ischemic stroke than patients with atrial fibrillation., (Published by Elsevier Inc.)

Background: Cerebral white matter hyperintensities (WMHs) on MRI are common and associated with vascular and functional outcomes. However, the relationship between WMHs and longitudinal trajectories of functional status is not well characterized. We hypothesized that whole brain WMHs are associated with functional decline independently of intervening clinical vascular events and other vascular risk factors., Methods and Findings: In the Northern Manhattan Study (NOMAS), a population-based racially/ethnically diverse prospective cohort study, 1,290 stroke-free individuals underwent brain MRI and were followed afterwards for a mean 7.3 years with annual functional assessments using the Barthel index (BI) (range 0-100) and vascular event surveillance. Whole brain white matter hyperintensity volume (WMHV) (as percentage of total cranial volume [TCV]) was standardized and treated continuously. Generalized estimating equation (GEE) models tested associations between whole brain WMHV and baseline BI and change in BI, adjusting for sociodemographic, vascular, and cognitive risk factors, as well as stroke and myocardial infarction (MI) occurring during follow-up. Mean age was 70.6 (standard deviation [SD] 9.0) years, 40% of participants were male, 66% Hispanic; mean whole brain WMHV was 0.68% (SD 0.84). In fully adjusted models, annual functional change was -1.04 BI points (-1.20, -0.88), with -0.74 additional points annually per SD whole brain WMHV increase from the mean (-0.99, -0.49). Whole brain WMHV was not associated with baseline BI, and results were similar for mobility and non-mobility BI domains and among those with baseline BI 95-100. A limitation of the study is the possibility of a healthy survivor bias, which would likely have underestimated the associations we found., Conclusions: In this large population-based study, greater whole brain WMHV was associated with steeper annual decline in functional status over the long term, independently of risk factors, vascular events, and baseline functional status. Subclinical brain ischemic changes may be an independent marker of long-term functional decline.

Objective: We hypothesized that ILI is associated with risk of incident stroke, and that the risk would be highest closest in time to the event., Methods: This case-crossover analysis utilized data obtained from the California State Inpatient Database of the Healthcare Cost and Utilization Project (HCUP). The outcome of interest was ischemic stroke. Exposure was defined as a visit to the emergency department or hospitalization for influenza-like illness (ILI) 365, 180, 90, 30, or 15 days before stroke (risk period) or similar time intervals exactly 1 or 2 years before stroke (control period). Conditional logistic regression was used to calculate the odds ratio and 95% confidence interval (OR, 95% CI)., Results: In 2009, 36,975 hospitalized ischemic strokes met inclusion criteria, and of these strokes, 554 (1.5%) had at least 1 episode of ILI in the 365-day risk period prior to their stroke. Using non-overlapping time intervals from ILI to stroke, the odds of ischemic stroke was greatest in the first 15 days post ILI (OR: 2.88, 95% CI: 1.86-4.47). The strength of the relationship decreased as the time from ILI increased, and was no longer significant after 60 days. There was a significant interaction ( P = 0.017) with age and ILI; the odds of stroke associated increased 7% with each 10-year decrease in age (OR per 10-year age decrease 1.07, 95% CI: 1.03-1.35)., Interpretation: We found that ILI increases short-term risk of stroke, particularly in people under the age of 45, and therefore may be considered to act as a trigger for stroke.

Background: Apolipoprotein E (APOE) polymorphism has previously been associated with carotid intima-media thickness (cIMT) in predominantly Caucasian populations. We sought to test the strength of the relationship between APOE-ε4 carrier status and subclinical atherosclerosis in a tri-ethnic population with a large Hispanic representation., Methods: We assessed the association between APOE polymorphism and cIMT and plaque burden among 1243 stroke-free individuals (mean age 69 years, 65% Hispanic, 18% black, 17% white) using a sequence of multivariable regression models., Results: After adjusting for demographics, vascular risk factors and plasma low-density lipoprotein (LDL) levels, APOE-ε4 carrier status was positively associated with cIMT (mean difference, .013 mm; 95% confidence interval, .003-.023 mm). The APOE-ε4 association with cIMT appeared to be segment-specific with greater differences in IMT between APOE-ε4 carriers and noncarriers in the common carotid artery (CCA, .014 mm) and bifurcation (.017 mm) than in the internal carotid artery (ICA) IMT (.007 mm). This relationship was not modified by race-ethnicity. Presence of diabetes modified the ε4-cIMT relationship in CCA (P = .045) and ICA (P = .046). APOE-ε4 carrier status was not associated with plaque presence or plaque area., Conclusions: APOE-ε4 carriers had elevated cIMT independent of demographics and vascular risk factors including LDL levels. Diabetes was an effect modifier of the relationship between APOE-ε4 and IMT, such that ε4 carriers with diabetes had greater IMT in the CCA and ICA than those without diabetes. The APOE-IMT relationship was not modified by race-ethnicity., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Cognition and education influence functional trajectories, but whether associations differ with subclinical brain infarcts (SBI) or white matter hyperintensity volume (WMHV) is unknown. We hypothesized that SBI and WMHV moderated relationships between cognitive performance and education and functional trajectories., Methods: A total of 1290 stroke-free individuals underwent brain magnetic resonance imaging and were followed for 7.3 years (mean) with annual functional assessments with the Barthel index (range, 0-100). Magnetic resonance imaging measurements included pathology-informed SBI (PI-SBI) and WMHV (% total cranial volume). Generalized estimating equation models tested associations between magnetic resonance imaging variables and baseline Barthel index and change in Barthel index, adjusting for demographic, vascular, cognitive, and social risk factors, and stroke and myocardial infarction during follow-up. We tested interactions among education level, baseline cognitive performance (Mini-Mental State score), and functional trajectories and ran models stratified by levels of magnetic resonance imaging variables., Results: Mean age was 70.6 (SD, 9.0) years; 19% had PI-SBI, and mean WMHV was 0.68%. Education did not modify associations between cognition and functional trajectories. PI-SBI modified associations between cognition and functional trajectories ( P =0.04) with a significant protective effect of better cognition on functional decline seen only in those without PI-SBI. There was no significant interaction for WMHV ( P =0.8). PI-SBI, and greater WMHV, were associated with 2- to 3-fold steeper functional decline, holding cognition constant., Conclusions: PI-SBI moderated the association between cognition and functional trajectories, with 3-fold greater decline among those with PI-SBI (compared with no PI-SBI) and normal baseline cognition. This highlights the strong and independent association between subclinical markers and patient-centered trajectories over time., (© 2018 American Heart Association, Inc.)

Objective: Rebleeding remains a frequent and catastrophic event leading to poor outcome after subarachnoid hemorrhage (SAH). Reduced platelet function after the initial bleed is associated with higher risk of early rebleeding. Desmopressin (DDAVP) is a well-known hemostatic agent, and recent guidelines already suggest its use in individuals exposed to antiplatelet drugs. The authors hypothesized that DDAVP administration in patients with SAH at admission would be associated with lower risks of rebleeding., Methods: The authors performed an observational cohort study of patients enrolled in the Columbia University SAH Outcome Project between August 1996 and July 2015. The authors compared the rate of rebleeding between patients who were and those who were not treated with DDAVP. After adjustment for known predictors, logistic regression was used to measure the association between treatment with DDAVP and risks of rebleeding., Results: Among 1639 patients with SAH, 12% were treated with DDAVP. The main indication for treatment was suspected exposure to an antiplatelet agent. The overall incidence of rebleeding was 9% (1% among patients treated with DDAVP compared with 8% among those not treated). After adjustment for antiplatelet use and known predictors, treatment with DDAVP was associated with a 45% reduction in the risks of rebleeding (adjusted OR 0.55, 95% CI 0.27-0.97). DDAVP was associated with a higher incidence of hyponatremia but not with thrombotic events or delayed cerebral ischemia., Conclusions: Treatment with DDAVP was associated with a lower risk of rebleeding among patients with SAH. These findings support further study of DDAVP as first-line therapy for medical hemostasis in patients with SAH.

Epidemiologic studies assessing the relationship between blood pressure (BP), body mass, and cardiovascular events have primarily been based on office BP measurements, and few data are available in the elderly. The aim of the present study was to evaluate the relationship between body mass index (BMI) and BP values obtained by ambulatory blood pressure monitoring (ABPM) as compared to office BP measurements, and the effect of anti-hypertensive treatment on the relationship. The study population consisted of 813 subjects participating in the cardiovascular abnormalities and brain lesions (CABL) study who underwent 24-h ABPM. Office BP (mean of two measurements) was found to be associated with increasing BMI, for both SBP (p ≤ 0.05) and DBP (p ≤ 0.001). In contrast, there was no association seen of increasing BMI with ABPM parameters in the overall cohort, even after adjusting for age and gender. However, among subjects not on anti-hypertensive treatment, office SBP and DBP measurements were significantly correlated with increasing BMI (p ≤ 0.01) as were daytime SBP and 24-h SBP, although with a smaller spread across BMI subgroups compared with office readings. In treated hypertensives, there was only a trend toward increasing office DBP and increasing DBP variability with higher BMI. Our results suggest that body mass may have a less significant influence on BP values in the elderly when ABPM rather than office measurements are considered, particularly in patients receiving anti-hypertensive treatment.

Background and Purpose: Although increased heart rate (HR) is a predictor of cardiovascular events and mortality, its possible association with subclinical cerebrovascular disease, which is prevalent in the elderly, has not been evaluated. This study aimed to investigate the association of daytime, nighttime, 24-hour HR, and HR variability with subclinical cerebrovascular disease in an elderly cohort without history of stroke., Methods: The study cohort consisted of 680 participants (mean age, 73±7 years; 42% men) in sinus rhythm who underwent 24-hour ambulatory blood pressure and HR monitoring, 2-dimensional echocardiography, and brain magnetic resonance imaging as part of the CABL study (Cardiac Abnormalities and Brain Lesion). Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume (WMHV). The relationship of HR measures with the presence of silent brain infarct and upper quartile of log WMHV (log WMHV4) was analyzed., Results: Presence of silent brain infarct was detected in 93 participants (13.7%); mean log WMHV was -0.92±0.93 (median, -1.05; min, -5.88; max, 1.74). Multivariate analysis showed that only nighttime HR (adjusted odds ratio, 1.29 per 10 bpm; 95% confidence interval, 1.03-1.61; P =0.026) was significantly associated with log WMHV4, independent of traditional cardiovascular risk factors, ambulatory systolic blood pressure, and echocardiographic parameters. No similar association was observed for daytime HR and HR variability. There was no significant association between all HR measures and silent brain infarct., Conclusions: In a predominantly elderly cohort, elevated nighttime HR was associated with WMHV, suggesting an independent role of HR in subclinical cerebrovascular disease., (© 2017 American Heart Association, Inc.)

Background and Purpose: Brain white matter hyperintensities (WMH) have been associated with increased risk of stroke, cognitive decline, and dementia. WMH can be a manifestation of small vessel disease, although the total microvascular contribution to multifactorial WMH pathophysiology remains unknown. We hypothesized a possible relationship between carotid intima-media thickness (cIMT), an ultrasound imaging marker of subclinical vascular disease, and brain WMH in a multiethnic, elderly stroke-free community-based cohort., Methods: We evaluated the relationship between cIMT and WMH in the population-based Northern Manhattan Study, among individuals free of stroke. We used linear regression to examine the association of continuous measures of cIMT with quantitatively derived WMH volume, as a proportion of cranial volume, measured from fluid-attenuaded inversion recovery magnetic resonance imaging while adjusting for sociodemographics, lifestyle, and vascular risk factors., Results: In a cohort of 1229 participants (mean age, 71±9 years; 60% women, 15% White; 18% Black; 65% Hispanics), the mean cIMT was 0.71±0.08 mm and the median log-transformed WMH volume was 0.36 (interquartile range, 0.21-0.76). In a multivariable model, larger cIMT was significantly associated with greater WMH volume (β=0.046 per SD cIMT; P =0.04). Age and race/ethnicity were significant modifiers ( P for age, 0.02; and P for race/ethnicity, 0.04). cIMT was associated with WMH volume in participants 70 years or older (β=0.088 per SD cIMT; P =0.01) and among Hispanics (β=0.084 per SD cIMT; P =0.003)., Conclusions: Larger cIMT was associated with greater burden of cerebral WM lesions independently of demographics and traditional vascular risk factors, particularly among elderly and Hispanic participants, who are at high risk for stroke and cognitive decline., (© 2017 American Heart Association, Inc.)

Background: Artificially (diet) and sugar-sweetened (regular) soda consumption have been associated with an increased risk of diabetes, but the literature on diet soda is inconsistent and the mechanisms unclear., Objective: We examined the relation between diet soda and regular soda consumption with the risk of incident diabetes in a longitudinal multiethnic population-based cohort., Methods: The study population included 2019 participants (mean ± SD age:  69 ± 10 y; 64% women; 23% white, 22% black, 53% Hispanic) in the Northern Manhattan Study who were free of diabetes and stroke at baseline. Soda consumption was assessed by a food-frequency questionnaire at baseline and examined continuously and categorically (<1/mo: sugar-sweetened = 908, diet = 1615; 1/mo-6/wk: sugar-sweetened = 830, diet = 298; daily: sugar-sweetened = 281, diet = 106). Weibull regression models were used to estimate the associations between soda consumption and incident diabetes, adjusting for demographics and vascular risk factors including body mass index (BMI) and calorie consumption., Results: During a mean ± SD follow-up of 11 ± 5 y, 368 participants developed diabetes. Sugar-sweetened soda was positively associated with incident diabetes (per soda per day HR = 1.15, 95% CI:  1.02, 1.31). The observed association between diet soda and elevated risk of diabetes was largely explained by BMI at the time of diet assessment, though the association remained strong and independent of BMI among those who were overweight or obese (daily compared to <1/mo: HR = 1.63, 95% CI:  1.04, 2.55)., Conclusions: This study supports the importance of sugar-sweetened beverage consumption in the diabetes epidemic. However, the results support previous studies suggesting that switching to artificially sweetened diet beverages may not lower the risk of diabetes, as diet soda consumption cannot be ruled out as an independent diabetes risk factor.

Background/objectives: We previously showed that global brain white matter hyperintensity volume (WMHV) was associated with accelerated long-term functional decline. The objective of the current study was to determine whether WMHV in particular brain regions is more predictive of functional decline., Design: Prospective population-based study., Setting: Northern Manhattan magnetic resonance imaging (MRI) study., Participants: Individuals free of stroke at baseline (N = 1,195; mean age 71 ± 9; n = 460 (39%) male)., Measurements: Participants had brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences. Volumetric WMHV distribution across 14 brain regions (brainstem; cerebellum; bilateral frontal, occipital, temporal, and parietal lobes; and bilateral anterior and posterior periventricular white matter (PVWM)) was determined using a combination of bimodal image intensity distribution and atlas-based methods. Participants had annual functional assessments using the Barthel Index (BI) (range 0-100) over a mean of 7.3 years and were followed for stroke, myocardial infarction (MI), and mortality. Because there were multiple collinear variables, least absolute shrinkage and selection operator (LASSO) regression-selected regional WMHV variables most associated with outcomes and adjusted generalized estimating equations models were used to estimate associations with baseline BI and change over time., Results: Using LASSO regularization, only right anterior PVWM was found to meet criteria for selection, and each standard deviation greater WMHV was associated with accelerated functional decline of 0.95 additional BI points per year (95% confidence interval (CI) = -1.20 to -0.70) in an unadjusted model, -0.92 points per year (95% CI = -1.18 to -0.67) with baseline covariate adjustment, and -0.87 points per year (95% CI = -1.12 to -0.62) after adjusting for incident stroke and MI., Conclusion: In this large population-based study with long-term repeated measures of function, periventricular WMHV was particularly associated with accelerated functional decline., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Background and Purpose: Elevated cardiac troponin is a marker of cardiac disease and has been recently shown to be associated with embolic stroke risk. We hypothesize that early elevated troponin levels in the acute stroke setting are more prevalent in patients with embolic stroke subtypes (cardioembolic and embolic stroke of unknown source) as opposed to noncardioembolic subtypes (large-vessel disease, small-vessel disease, and other)., Methods: We abstracted data from our prospective ischemic stroke database and included all patients with ischemic stroke during an 18-month period. Per our laboratory, we defined positive troponin as ≥0.1 ng/mL and intermediate as ≥0.06 ng/mL and <0.1 ng/mL. Unadjusted and adjusted regression models were built to determine the association between stroke subtype (embolic stroke of unknown source and cardioembolic subtypes) and positive and intermediate troponin levels, adjusting for key confounders, including demographics (age and sex), clinical characteristics (hypertension, hyperlipidemia, diabetes mellitus, renal function, coronary heart disease, congestive heart failure, current smoking, and National Institutes of Health Stroke Scale score), cardiac variables (left atrial diameter, wall-motion abnormalities, ejection fraction, and PR interval on ECG), and insular involvement of infarct., Results: We identified 1234 patients, of whom 1129 had admission troponin levels available; 10.0% (113/1129) of these had a positive troponin. In fully adjusted models, there was an association between troponin positivity and embolic stroke of unknown source subtype (adjusted odds ratio, 4.46; 95% confidence interval, 1.03-7.97; P =0.003) and cardioembolic stroke subtype (odds ratio, 5.00; 95% confidence interval, 1.83-13.63; P =0.002)., Conclusions: We found that early positive troponin after ischemic stroke may be independently associated with a cardiac embolic source. Future studies are needed to confirm our findings using high-sensitivity troponin assays and to test optimal secondary prevention strategies in patients with embolic stroke of unknown source and positive troponin., (© 2017 American Heart Association, Inc.)

Background: Despite anticoagulation therapy, ischemic stroke risk in atrial fibrillation (AF) remains substantial. We hypothesize that left atrial enlargement (LAE) is more prevalent in AF patients admitted with ischemic stroke who are therapeutic, as opposed to nontherapeutic, on anticoagulation., Methods: We included consecutive patients with AF admitted with ischemic stroke between April 1, 2015, and December 31, 2016. Patients were divided into two groups based on whether they were therapeutic (warfarin with an international normalized ratio ≥ 2.0 or non-vitamin K oral anticoagulant with uninterrupted use in the prior 2 weeks) versus nontherapeutic on anticoagulation. Univariable and multivariable models were used to estimate associations between therapeutic anticoagulation and clinical factors, including CHADS2 score and LAE (none/mild versus moderate/severe)., Results: We identified 225 patients during the study period; 52 (23.1%) were therapeutic on anticoagulation. Patients therapeutic on anticoagulation were more likely to have a larger left atrial diameter in millimeters (45.6 ± 9.2 versus 42.3 ± 8.6, P = .032) and a higher CHADS2 score (2.9 ± 1.1 versus 2.4 ± 1.1, P = .03). After adjusting for the CHADS2 score, patients who had a stroke despite therapeutic anticoagulation were more likely to have moderate to severe LAE (odds ratio, 2.05; 95% confidence interval, 1.01-4.16)., Conclusion: LAE is associated with anticoagulation failure in AF patients admitted with an ischemic stroke. This provides indirect evidence that LAE may portend failure of anticoagulation therapy in patients with AF; further studies are needed to delineate the significance of this association and improve stroke prevention strategies., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Introduction: White matter hyperintensity volume (WMHV) and subclinical brain infarcts (SBI) are associated with impaired mobility, but less is known about the association of WMHV in specific brain regions. We hypothesized that anterior WMHV would be associated with lower scores on the Short Physical Performance Battery (SPPB), a well-validated mobility scale., Methods: The SPPB was measured a median of 5 years after enrollment into the Northern Manhattan MRI sub study. Volumetric distributions for WMHV in 14 brain regions as a proportion of total cranial volume were determined. Multi-variable linear regression was performed to examine the association of SBI and regional log-WMHV with the SPPB score., Results: Among 668 participants with SPPB measurements (mean 74 ± 9 years, 37% male and 70% Hispanic), the mean SPPB score was 8.2 ± 2.9. Total (beta = -0.3 per SD, p = 0.001), anterior periventricular (beta = -0.4 per SD, p = 0.001), parietal (beta = -0.2 per SD, p = 0.02) and frontal (beta = -0.3 per SD, p = 0.002) WMHVs were associated with SPPB; other WMHV and SBI were not associated with the SPPB., Conclusions: WMHV, especially in the anterior -cerebral regions, is associated with a lower SPPB. Prevention of subclinical cerebrovascular disease is a potential target to prevent physical decline in the elderly., (© 2018 S. Karger AG, Basel.)

Background: Mobile stroke units (MSUs) reduce time to thrombolytic therapy in acute ischemic stroke. These units are widely used, but the clinical information systems underlying MSU operations are understudied., Objective: The first MSU on the East Coast of the United States was established at New York Presbyterian Hospital (NYP) in October 2016. We describe our program's 7-month pilot, focusing on the integration of our hospital's clinical information systems into our MSU to support patient care and research efforts., Methods: NYP's MSU was staffed by two paramedics, one radiology technologist, and a vascular neurologist. The unit was equipped with four laptop computers and networking infrastructure enabling all staff to access the hospital intranet and clinical applications during operating hours. A telephone-based registration procedure registered patients from the field into our admit/discharge/transfer system, which interfaced with the institutional electronic health record (EHR). We developed and implemented a computerized physician order entry set in our EHR with prefilled values to permit quick ordering of medications, imaging, and laboratory testing. We also developed and implemented a structured clinician note to facilitate care documentation and clinical data extraction., Results: Our MSU began operating on October 3, 2016. As of April 27, 2017, the MSU transported 49 patients, of whom 16 received tissue plasminogen activator (t-PA). Zero technical problems impacting patient care were reported around registration, order entry, or intranet access. Two onboard network failures occurred, resulting in computed tomography scanner malfunctions, although no patients became ineligible for time-sensitive treatment as a result. Thirteen (26.5%) clinical notes contained at least one incomplete time field., Conclusion: The main technical challenges encountered during the integration of our hospital's clinical information systems into our MSU were onboard network failures and incomplete clinical documentation. Future studies are necessary to determine whether such integrative efforts improve MSU care quality, and which enhancements to information systems will optimize clinical care and research efforts., Competing Interests: None., (Schattauer GmbH Stuttgart.)

Background: Risk factors for pediatric stroke are poorly understood and require study to improve prevention. Total cholesterol and triglyceride values peak to near-adult levels before puberty, a period of increased stroke incidence. The role of lipids in childhood arterial ischemic stroke has been minimally investigated., Methods: We performed a cross-sectional analysis of lipid and Lp(a) concentrations in children with arterial ischemic stroke in the International Pediatric Stroke Study to compare the prevalence of dyslipidemia and high- or low-ranking lipid values in our dataset with reported population values. We analyzed sex, body mass index, race, ethnicity, family history, and stroke risk factors for associations with dyslipidemia, high non-high-density lipoprotein cholesterol, and hypertriglyceridemia., Results: Compared with the National Health and Nutrition Examination Survey, a higher proportion of children ≥5 years with arterial ischemic stroke had dyslipidemia (38.4% versus 21%), high total cholesterol (10.6% versus 7.4%), high non-high-density lipoprotein cholesterol (23.1% versus 8.4%), and low high-density lipoprotein cholesterol (39.8% versus 13.4%). The lipid values that corresponded to one standard deviation above the mean (84th percentile) in multiple published national studies generally corresponded to a lower ranking percentile in children aged five years or older with arterial ischemic stroke. Dyslipidemia was more likely associated with an underweight, overweight, or obese body mass index compared with a healthy weight. Ethnic background and an acute systemic illness were also associated with abnormal lipids., Conclusions: Dyslipidemia and hypertriglyceridemia may be more prevalent in children with arterial ischemic stroke compared with stroke-free children., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Systemic inflammatory response syndrome (SIRS) may be related to poor outcomes after intracerebral hemorrhage (ICH)., Methods: The Ethnic/Racial Variations of Intracerebral Hemorrhage study is an observational study of ICH in whites, blacks, and Hispanics throughout the United Sates. SIRS was defined by standard criteria as 2 or more of the following on admission: (1) body temperature <36°C or >38°C, (2) heart rate >90 beats per minute, (3) respiratory rate >20 breaths per minute, or (4) white blood cell count <4,000/mm 3 or >12,000/mm 3 . The relationship among SIRS, infection, and poor outcome (modified Rankin Scale [mRS] 3-6) at discharge and 3 months was assessed., Results: Of 2,441 patients included, 343 (14%) met SIRS criteria at admission. Patients with SIRS were younger (58.2 vs 62.7 years; p < 0.0001) and more likely to have intraventricular hemorrhage (IVH; 53.6% vs 36.7%; p < 0.0001), higher admission hematoma volume (25.4 vs 17.5 mL; p < 0.0001), and lower admission Glasgow Coma Scale (GCS; 10.7 vs 13.1; p < 0.0001). SIRS on admission was significantly related to infections during hospitalization (adjusted odds ratio [OR] 1.36, 95% confidence interval [CI] 1.04-1.78). In unadjusted analyses, SIRS was associated with poor outcomes at discharge (OR 1.96, 95% CI 1.42-2.70) and 3 months (OR 1.75, 95% CI 1.35-2.33) after ICH. In analyses adjusted for infection, age, IVH, hematoma location, admission GCS, and premorbid mRS, SIRS was no longer associated with poor outcomes., Conclusions: SIRS on admission is associated with ICH score on admission and infection, but it was not an independent predictor of poor functional outcomes after ICH.

Importance: Ischemic strokes may accelerate long-term functional decline apart from their acute effects on neurologic function., Objective: To test whether the increase in long-term disability is steeper after than before the event for ischemic stroke but not myocardial infarction (MI)., Design, Settings, and Participants: In the population-based, prospective cohort Cardiovascular Health Study (1989-2013), longitudinal follow-up was conducted for a mean (SD) of 13 (6.2) years. Follow-up data were used until September 1, 2013; data analysis was performed from August 1, 2013, to June 1, 2016. Models based on generalized estimating equations adjusted for baseline covariates and included a test for different slopes of disability before and after the event. Participants included 5888 Medicare-eligible individuals 65 years or older who were not institutionalized, expected to reside in the area for 3 or more years, and able to provide informed consent. Exclusions were needing a wheelchair, receiving hospice care, and undergoing radiotherapy or chemotherapy., Exposures: Ischemic stroke and MI., Main Outcomes and Measures: Annual assessments with a disability scale (measuring activities of daily living [ADLs] and instrumental ADLs). The number of ADLs and instrumental ADLs (range, 0-12) that the participant could not perform was analyzed continuously., Results: The mean (SD) age of the entire cohort (n = 5888) was 72.8 (5.6) years; 2495 (42.4%) were male. During follow-up, 382 (6.5%) participants had ischemic stroke and 395 (6.7%) had MI with 1 or more disability assessment after the event. There was a mean of 3.7 (2.4) visits before stroke and 3.7 (2.3) visits after stroke; there was a mean of 3.8 (2.5) visits before MI and 3.8 (2.4) visits after MI. The increase in disability near the time of the event was greater for stroke (0.88 points on the disability scale; 95% CI, 0.57 to 1.20; P < .001) than MI (0.20 points on the disability scale; 95% CI, 0.06 to 0.35; P = .006). The annual increase in disability before stroke (0.06 points per year; 95% CI, 0.002 to 0.12; P = .04) more than tripled after stroke (0.15 additional points per year; 95% CI, 0.004 to 0.30; P = .04). The annual increase in disability before MI (0.04 points per year; 95% CI, 0.004 to 0.08; P = .03) did not change significantly after MI (0.02 additional points per year; 95% CI, -0.07 to 0.11; P = .69)., Conclusions and Relevance: In this large, population-based study, a trajectory of increasing disability became significantly steeper after stroke but not after MI. Thus, in addition to the acute brain injury and consequent impairment, ischemic stroke may also be associated with potentially treatable long-term adverse effects on the brain that lead to accelerated functional decline.

Objectives: To evaluate cross-sectional and prospective associations between short and long sleep duration and depressive symptoms in older adults (aged >65 years)., Methods: The data from a subsample of the racially/ethnically diverse Northern Manhattan Study were analyzed. Depressive symptoms were assessed twice with the Center for Epidemiologic Studies Depression Scale (CES-D), approximately 5 years apart. The presence of depressive symptoms was defined as a CES-D score ≥16 or use of antidepressants. Self-reports of short (<6 h), intermediate (6-8 h) and long (≥9 h) sleep were assessed prior to the initial CES-D. Logistic regression was used to evaluate the cross-sectional associations between short and long sleep durations with depressive symptoms, using intermediate sleep as the reference. The prospective association between sleep duration and depression in a sample of participants without depressive symptoms at first CES-D was also analyzed. All models were adjusted for demographic, behavioral, and vascular risk factors., Results: The initial sample consisted of 1110 participants: 62% women, 69% Hispanic, 17% black, 14% white. Short sleep was reported by 25%, intermediate sleep by 65%, and long sleep by 9%. Depressive symptoms were described in 25% of the initial sample. Short sleep, but not long sleep, was associated with depressive symptoms at baseline (adjusted OR 1.8, 95% CI 1.3-2.6), and at follow-up (adjusted OR 1.9, 95% CI 1.1-3.5; median follow-up = 5.1 years)., Conclusion: Short sleep duration had a cross-sectional and prospective association with depressive symptoms in an urban multi-ethnic cohort of older adults., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: There is growing evidence that increased dietary sodium (Na) intake increases the risk of vascular diseases, including stroke, at least in part via an increase in blood pressure. Higher dietary potassium (K), seen with increased intake of fruits and vegetables, is associated with lower blood pressure. The goal of this study was to determine the association of a dietary Na:K with risk of stroke in a multiethnic urban population., Methods: Stroke-free participants from the Northern Manhattan Study, a population-based cohort study of stroke incidence, were followed-up for incident stroke. Baseline food frequency questionnaires were analyzed for Na and K intake. We estimated the hazard ratios and 95% confidence intervals for the association of Na:K with incident total stroke using multivariable Cox proportional hazards models., Results: Among 2570 participants with dietary data (mean age, 69±10 years; 64% women; 21% white; 55% Hispanic; 24% black), the mean Na:K ratio was 1.22±0.43. Over a mean follow-up of 12 years, there were 274 strokes. In adjusted models, a higher Na:K ratio was associated with increased risk for stroke (hazard ratio, 1.6; 95% confidence interval, 1.2-2.1) and specifically ischemic stroke (hazard ratio, 1.6; 95% confidence interval, 1.2-2.1)., Conclusions: Na:K intake is an independent predictor of stroke risk. Further studies are required to understand the joint effect of Na and K intake on risk of cardiovascular disease., (© 2017 American Heart Association, Inc.)

Background and Purpose: Case-control studies suggest that acute infection transiently increases the risk of childhood arterial ischemic stroke. We hypothesized that an unbiased pathogen discovery approach utilizing MassTag-polymerase chain reaction would identify pathogens in the blood of childhood arterial ischemic stroke cases., Methods: The multicenter international VIPS study (Vascular Effects of Infection in Pediatric Stroke) enrolled arterial ischemic stroke cases, and stroke-free controls, aged 29 days through 18 years. Parental interview included questions on recent infections. In this pilot study, we used MassTag-polymerase chain reaction to test the plasma of the first 161 cases and 34 controls enrolled for a panel of 28 common bacterial and viral pathogens., Results: Pathogen DNA was detected in no controls and 14 cases (8.7%): parvovirus B19 (n=10), herpesvirus 6 (n=2), adenovirus (n=1), and rhinovirus 6C (n=1). Parvovirus B19 infection was confirmed by serologies in all 10; infection was subclinical in 8. Four cases with parvovirus B19 had underlying congenital heart disease, whereas another 5 had a distinct arteriopathy involving a long-segment stenosis of the distal internal carotid and proximal middle cerebral arteries., Conclusions: Using MassTag-polymerase chain reaction, we detected parvovirus B19-a virus known to infect erythrocytes and endothelial cells-in some cases of childhood arterial ischemic stroke. This approach can generate new, testable hypotheses about childhood stroke pathogenesis., (© 2017 American Heart Association, Inc.)

Background and Purpose: Sex and race disparities in recombinant tissue plasminogen activator (rt-PA) use have been reported. We sought to explore sex and race differences in the utilization of rt-PA at primary stroke centers (PSCs) compared to non-PSCs across the US., Methods: Data from the National (Nationwide) Inpatient Sample (NIS) 2004-2010 was utilized to assess sex differences in treatment for ischemic stroke in PSCs compared to non-PSCs., Results: There were 304,152 hospitalizations with a primary diagnosis of ischemic stroke between 2004 and 2010 in the analysis: 75,160 (24.7%) patients were evaluated at a PSC. A little over half of the patients evaluated at PSCs were female (53.8%). A lower proportion of women than men received rt-PA at both PSCs (6.8 vs. 7.5%, p  < 0.001) and non-PSCs (2.3 vs. 2.8%, p  < 0.001). After adjustment for potential confounders the odds of being treated with rt-PA remained lower for women regardless of presentation to a PSC (OR 0.87, 95% CI 0.81-0.94) or non-PSC (OR 0.88, 95% CI 0.82-0.94). After stratifying by sex and race, the lowest absolute treatment rates were observed in black women (4.4% at PSC, 1.9% at non-PSC). The odds of treatment, relative to white men, was however lowest for white women (PSC OR = 0.85, 95% CI 0.78-0.93; non-PSC OR = 0.80, 95% CI 0.75-0.85). In the multivariable model, sex did not modify the effect of PSC certification on rt-PA utilization ( p -value for interaction = 0.58)., Conclusion: Women are less likely to receive rt-PA than men at both PSCs and non-PSCs. Absolute treatment rates are lowest in black women, although the relative difference in men and women was greatest for white women.

Asymmetry of brain dysfunction may disrupt brain network efficiency. We hypothesized that greater left-right white matter hyperintensity volume (WMHV) asymmetry was associated with functional trajectories. Methods: In the Northern Manhattan Study, participants underwent brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences, with baseline interview and examination. Volumetric WMHV distribution across 14 brain regions was determined separately by combining bimodal image intensity distribution and atlas based methods. Participants had annual functional assessments with the Barthel index (BI, range 0-100) over a mean of 7.3 years. Generalized estimating equations (GEE) models estimated associations of regional WMHV and regional left-right asymmetry with baseline BI and change over time, adjusted for baseline medical risk factors, sociodemographics, and cognition, and stroke and myocardial infarction during follow-up. Results: Among 1,195 participants, greater WMHV asymmetry in the parietal lobes (-8.46 BI points per unit greater WMHV on the right compared to left, 95% CI -3.07, -13.86) and temporal lobes (-2.48 BI points, 95% CI -1.04, -3.93) was associated with lower overall function. Greater WMHV asymmetry in the parietal lobes (-1.09 additional BI points per year per unit greater WMHV on the left compared to right, 95% CI -1.89, -0.28) was independently associated with accelerated functional decline. Conclusions: In this large population-based study with long-term repeated measures of function, greater regional WMHV asymmetry was associated with lower function and functional decline. In addition to global WMHV, WHMV asymmetry may be an important predictor of long-term functional status.

Objective: Because age affects hormonal production differently in women compared with men, we sought to define sex and age interactions across a multiracial/ethnic population after intracerebral hemorrhage (ICH) to uncover evidence that loss of gonadal hormone production would result in loss of the known neuroprotective effects of gonadal hormones., Methods: Clinical and radiographic data from participants in the Ethnic/Racial Variations of Intracerebral Hemorrhage study and the Genetic and Environmental Risk Factors for Hemorrhagic Stroke study prior to December 2013 were used. Relationships among sex, age, and outcome after ICH in 616 non-Hispanic black, 590 Hispanic, and 868 non-Hispanic white participants were evaluated using multivariable logistic regression analysis. Poor outcome was defined as modified Rankin Scale score ≥3 at 90 days after ICH., Results: Sex differences were found in multiple variables among the racial/ethnic groups, including age at onset, premorbid neurologic status, and neurologic outcome after ICH. Overall, no sex-age interaction effect was found for mortality ( p = 0.183) or modified Rankin Scale score ( p = 0.378) at 90 days after ICH. In racial/ethnic subgroups, only the non-Hispanic black cohort provided possible evidence of a sex-age interaction on 90-day modified Rankin Scale score ( p = 0.003)., Conclusion: Unlike in ischemic stroke, there was no evidence that patient sex modified the effect of age on 90-day outcomes after ICH in a large multiracial/ethnic population. Future studies should evaluate biological reasons for these differences between stroke subtypes., Clinicaltrialsgov Identifier: NCT01202864., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: This study sought to assess the prevalence and prognostic value of abnormalities in left atrial (LA) phasic volumes and reservoir function in a community cohort., Background: LA enlargement is associated with adverse cardiovascular outcomes. Real-time 3-dimensional (RT3D) echocardiography allows assessment of LA phasic volumes and reservoir function. However, there is a paucity of data regarding normal values, clinical correlates, and prognostic value of RT3D echocardiography-derived LA phasic volumes and reservoir function, especially in the elderly, a subgroup at high risk for cardiovascular events., Methods: Left atrial maximum volume (LAVi max ), minimum volume (LAVi min ), and reservoir function assessed as emptying volume (LAEV), emptying fraction (LAEF), and expansion index (LAEI), were measured by RT3D echocardiography in participants from a community-based cohort study. Cut-off values for LA phasic volumes were derived from a healthy subgroup of participants free of cardiovascular disease and risk factors (n = 142; 66 ± 9 years of age; 55% women). Annual follow-up examinations were performed for cardiovascular outcomes (myocardial infarction, ischemic stroke, and vascular death)., Results: The cohort included 706 participants (71 ± 9 years of age; 59% women). LAVi max and LAVi min were not associated with age in the healthy subgroup but progressively increased with age in the entire cohort (p < 0.001). During a median follow-up of 7 years (minimum 0.06, maximum 9.5 years), 78 cardiovascular events occurred. In univariate analysis, LAVi max , LAVi min , and reservoir function parameters were significantly associated with outcome. In multivariate analysis, LAVi min  ≥20.5 ml/m 2 (adjusted hazard ratio [aHR]: 1.79; 95% confidence interval [CI]:1.02 to 3.16) and LAEV ≤5.7 ml/m 2 (aHR: 1.98; 95% CI: 1.02 to 3.85) remained significantly associated with events. LAVi min and LA reservoir function showed incremental prognostic value over that of LAVi max ., Conclusions: LA phasic volumes and reservoir functions assessed by RT3D echocardiography were strong independent predictors of cardiovascular events in a community-based elderly cohort. LAVi min and reservoir function assessment may improve cardiovascular outcome prediction over LAVi max ., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Whether changes in leisure-time physical activity (LTPA) over time are associated with lower risk of stroke is not well established. We examined the association between changes in self-reported LTPA 10 years apart, with risk of incident stroke in the CTS (California Teachers Study). We hypothesized that the risk of stroke would be lowest among those who remained active., Methods: Sixty-one thousand two hundred and fifty-six CTS participants reported LTPA at 2 intensity levels (moderate and strenuous activity) at 2 time points (baseline 1995-96; 10-year follow-up 2005-2006). LTPA at each intensity level was categorized based on American Heart Association (AHA) recommendations (moderate, >150 minutes/week; strenuous, >75 minutes/week). Changes in LTPA were summarized as follows: (1) not meeting recommendations at both time points; (2) meeting recommendations only at follow-up; (3) meeting recommendations only at baseline; and (4) meeting recommendations at both time points. Incident strokes were identified through California state hospitalization records. Using multivariable Cox models, we examined the associations between changes in LTPA with incident stroke., Results: Nine hundred and eighty-seven women were diagnosed with stroke who completed both questionnaires. Meeting AHA recommendations at both the time points was associated with a lower risk of all stroke (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72-0.98). The protective effects for stroke were driven by meeting AHA recommendations for moderate activity and largely observed for ischemic strokes (adjusted hazard ratio, 0.70; 95% confidence interval, 0.55-0.88)., Conclusions: Meeting AHA recommendations for moderate activity had a protective effect for reducing ischemic stroke risk. Participants who met AHA recommendations at baseline but not at follow-up, however, were not afforded reduced stroke risk., (© 2017 American Heart Association, Inc.)

Background: The effects of white matter hyperintensity volume and subclinical brain infarcts on the risk of incident stroke, its ischemic subtypes, and mortality require further study in diverse samples., Methods and Results: Stroke-free participants in the Northern Manhattan Study underwent magnetic resonance imaging (N=1287; mean age 71±9 years, 60% women, 15% non-Hispanic white, 17% non-Hispanic black, 68% Hispanic) and were followed for a median of 8 years (interquartile range: 6-9 years). Cox models estimated proportional hazards of incident stroke of all types, ischemic stroke (and its subtypes), and mortality and stratified by race/ethnicity. In total 72 participants (6%) had incident strokes and 244 died (19%). In fully adjusted models, those with larger white matter hyperintensity volume had greater risk of all stroke types (hazard ratio [HR]: 1.4; 95% CI, 1.1-1.9), ischemic stroke (HR: 1.3; 95% CI, 1.0-1.8), and cryptogenic stroke (HR: 2.2; 95% CI, 1.1-4.4). White and black but not Hispanic participants had increased stroke risk ( P <0.05 for heterogeneity for all and ischemic stroke). Those with subclinical brain infarct had greater risk for all stroke types (HR: 1.9; 95% CI, 1.1-3.3), ischemic stroke (HR: 2.2; 95% CI, 1.3-3.8), lacunar (HR: 4.0; 95% CI, 1.3-12.3), and cryptogenic stroke (HR: 3.6; 95% CI, 1.0-12.7), without significant heterogeneity across race/ethnic groups. Greater white matter hyperintensity volume increased both vascular (HR: 1.3; 95% CI, 1.1-1.7) and nonvascular (HR: 1.2; 95% CI, 1.0-1.5) mortality among Hispanic and white but not black participants ( P =0.040 for heterogeneity). Subclinical brain infarct was associated with increased vascular mortality among Hispanic participants only (HR: 2.9; 95% CI, 1.4-5.8)., Conclusions: In this urban US sample, subclinical cerebrovascular lesions increased the risk of clinical stroke and vascular mortality and varied by race/ethnicity and lesion type., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The risk of arterial thromboembolism in patients with cancer is incompletely understood., Objectives: The authors aimed to better define this epidemiological relationship, including the effects of cancer stage., Methods: Using the Surveillance Epidemiology and End Results-Medicare linked database, the authors identified patients with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, pancreatic, or gastric cancer or non-Hodgkin lymphoma from 2002 to 2011. They were individually matched by demographics and comorbidities to a Medicare enrollee without cancer, and each pair was followed through 2012. Validated diagnosis codes were used to identify arterial thromboembolism, defined as myocardial infarction or ischemic stroke. Cumulative incidence rates were calculated using competing risk survival statistics. Cox hazards analysis was used to compare rates between groups at discrete time points., Results: The authors identified 279,719 pairs of patients with cancer and matched control patients. The 6-month cumulative incidence of arterial thromboembolism was 4.7% (95% confidence interval [CI]: 4.6% to 4.8%) in patients with cancer compared with 2.2% (95% CI: 2.1% to 2.2%) in control patients (hazard ratio [HR]: 2.2; 95% CI: 2.1 to 2.3). The 6-month cumulative incidence of myocardial infarction was 2.0% (95% CI: 1.9% to 2.0%) in patients with cancer compared with 0.7% (95% CI: 0.6% to 0.7%) in control patients (HR: 2.9; 95% CI: 2.8 to 3.1). The 6-month cumulative incidence of ischemic stroke was 3.0% (95% CI: 2.9% to 3.1%) in patients with cancer compared with 1.6% (95% CI: 1.6% to 1.7%) in control patients (HR: 1.9; 95% CI: 1.8 to 2.0). Excess risk varied by cancer type (greatest for lung), correlated with cancer stage, and generally had resolved by 1 year., Conclusions: Patients with incident cancer face a substantially increased short-term risk of arterial thromboembolism., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Traditional predictors of neurological prognosis after cardiac arrest are unreliable after targeted temperature management. Absence of pupillary reflexes remains a reliable predictor of poor outcome. Diffusion-weighted imaging has emerged as a potential predictor of recovery, and here we compare imaging characteristics to pupillary exam., Methods: We identified 69 patients who had MRIs within seven days of arrest and used a semi-automated algorithm to perform quantitative volumetric analysis of apparent diffusion coefficient (ADC) sequences at various thresholds. Area under receiver operating characteristic curves (ROC-AUC) were estimated to compare predictive values of quantitative MRI with pupillary exam at days 3, 5 and 7 post-arrest, for persistence of coma and functional outcomes at discharge. Cerebral Performance Category scores of 3-4 were considered poor outcome., Results: Excluding patients where life support was withdrawn, ≥2.8% diffusion restriction of the entire brain at an ADC of ≤650×10 -6 m 2 /s was 100% specific and 68% sensitive for failure to wake up from coma before discharge. The ROC-AUC of ADC changes at ≤450×10 -6 mm 2 /s and ≤650×10 -6 mm 2 /s were significantly superior in predicting failure to wake up from coma compared to bilateral absence of pupillary reflexes. Among survivors, >0.01% of diffusion restriction of the entire brain at an ADC ≤450×10 -6 m 2 /s was 100% specific and 46% sensitive for poor functional outcome at discharge. The ROC curve predicting poor functional outcome at ADC ≤450×10 -6 mm 2 /s had an AUC of 0.737 (0.574-0.899, p=0.04)., Conclusion: Post-anoxic diffusion changes using quantitative brain MRI may aid in predicting persistent coma and poor functional outcomes at hospital discharge., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Cryptogenic stroke accounts for approximately 30% of all ischemic strokes. Recently, atrial cardiopathy diagnosed by the presence of one of its serum, imaging, or electrocardiogram biomarkers has been shown to be associated with ischemic stroke, particularly of embolic subtypes. Areas covered: This paper aims to summarize data on occult atrial fibrillation and stroke, provide an overview on mechanisms, such as inflammation and fibrosis, of stroke in atrial cardiopathy, critically review data on biomarkers of atrial cardiopathy and their association with stroke, and suggest therapeutic implications, including directions for future research. Expert commentary: Atrial cardiopathy may constitute one of the mechanisms in cryptogenic stroke, and patients with evidence of atrial cardiopathy constitute a group of patients in whom clinical trials are warranted to test anticoagulation versus antiplatelet therapy to reduce stroke recurrence risk. In addition, more studies are needed to determine the degree of overlap between these atrial cardiopathy biomarkers and which one is more useful in predicting the risk of stroke and response to anticoagulation therapy.

Background and Purpose: It is uncertain whether previous ischemic stroke within 3 months of receiving intravenous thrombolysis (tPA [tissue-type plasminogen activator]) for acute ischemic stroke (AIS) is associated with an increased risk of adverse outcomes., Methods: Using administrative claims data, we identified adults with AIS who received intravenous tPA at California, New York, and Florida hospitals from 2005 to 2013. Our primary outcome was intracerebral hemorrhage, and our secondary outcomes were unfavorable discharge disposition and inpatient mortality. We used logistic regression to compare rates of outcomes in patients with and without previous ischemic stroke within 3 months of intravenous tPA for AIS., Results: We identified 36 599 AIS patients treated with intravenous tPA, of whom 568 (1.6%) had a previous ischemic stroke in the past 3 months. Of all patients who received intravenous tPA, the rate of intracerebral hemorrhage was 4.9% (95% confidence interval [CI], 4.7%-5.1%), and death occurred in 10.7% (95% CI, 10.4%-11.0%). After adjusting for demographics, vascular risk factors, and the Elixhauser Comorbidity Index, previous ischemic stroke within 3 months of thrombolysis for AIS was not associated with an increased risk of intracerebral hemorrhage (odds ratio, 0.9; 95% CI, 0.6-1.4; P =0.62), but was associated with an increased risk of death (odds ratio, 1.5; 95% CI, 1.2-1.9; P =0.001) and unfavorable discharge disposition (odds ratio, 1.3; 95% CI, 1.0-1.7; P =0.04)., Conclusions: Among patients who receive intravenous tPA for AIS, recent ischemic stroke is not associated with an increased risk of intracerebral hemorrhage but is associated with a higher risk of death and unfavorable discharge disposition., (© 2017 American Heart Association, Inc.)

Purpose: Cardiovascular disease is a major contributor to morbidity and mortality, and prevention relies on accurate identification of those at risk. Studies of the association between quality of life (QOL) and mortality and vascular events incompletely accounted for depression, cognitive status, social support, and functional status, all of which have an impact on vascular outcomes. We hypothesized that baseline QOL is independently associated with long-term mortality in a large, multi-ethnic urban cohort., Methods: In the prospective, population-based Northern Manhattan Study, Spitzer QOL index (SQI, range 0-10, with ten signifying the highest QOL) was assessed at baseline. Participants were followed over a median 11 years for stroke, myocardial infarction (MI), and vascular and non-vascular death. Multivariable Cox proportional hazards regression estimated hazard ratio and 95% confidence interval (HR, 95% CI) for each outcome, with SQI as the main predictor, dichotomized at 10, adjusting for baseline demographics, vascular risk factors, history of cancer, social support, cognitive status, depression, and functional status., Results: Among 3298 participants, mean age was 69.7 + 10.3 years; 1795 (54.5%) had SQI of 10. In fully adjusted models, SQI of 10 (compared to SQI <10) was associated with reduced risk of all-cause mortality (HR 0.80, 95% CI 0.72-0.90), vascular death (0.81, 0.69-0.97), non-vascular death (0.78, 0.67-0.91), and stroke or MI or death (0.82, 0.74-0.91). In fully adjusted competing risk models, there was no association with stroke (0.93, 0.74-1.17), MI (0.98, 0.75-1.28), and stroke or MI (1.03, 0.86-1.24). Results were consistent when SQI was analyzed continuously., Conclusion: In this large population-based cohort, highest QOL was inversely associated with long-term mortality, vascular and non-vascular, independently of baseline primary vascular risk factors, social support, cognition, depression, and functional status. QOL was not associated with non-fatal vascular events.

Background: Left ventricular (LV) hypertrophy and subclinical cerebrovascular disease are early manifestations of cardiac and brain target organ damage caused by hypertension. This study aimed to investigate whether intensive office systolic blood pressure (SBP) control has beneficial effects on LV morphology and function and subclinical cerebrovascular disease in elderly patients with hypertension., Methods and Results: We examined 420 patients treated for hypertension without history of heart failure and stroke from the CABL (Cardiovascular Abnormalities and Brain Lesions) study. All patients underwent 2-dimensional echocardiographic examination and brain magnetic resonance imaging. Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume. Patients were divided into 3 groups: SBP <120 mm Hg (intensive control); SBP 120 to 139 mm Hg (less intensive control); and SBP ≥140 mm Hg (uncontrolled). Prevalence of LV hypertrophy and diastolic dysfunction were lowest in the intensive control, intermediate in the less intensive control, and highest in the uncontrolled groups (12.8%, 31.8%, and 44.7%, respectively [ P <0.001], for LV hypertrophy; 46.8%, 61.7%, and 72.6%, respectively [ P =0.003], for diastolic dysfunction). Patients with less intensive SBP control had greater risk of LV hypertrophy than those with intensive control (adjusted odds ratio, 3.26; P =0.013). A similar trend was observed for LV diastolic dysfunction but did not reach statistical significance (adjusted odds ratio, 1.65; P =0.144). Conversely, intensive SBP control was not significantly associated with reduced risk of silent brain infarcts and white matter hyperintensity volume compared with less intensive control., Conclusions: Compared with less intensive control, intensive SBP control may have a stronger beneficial effect on cardiac than cerebral subclinical disease., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

We hypothesized that tumor necrosis factor receptor 1 (TNFR1) levels are associated with long-term trajectories of functional status independently of vascular risk factors and the occurrence of stroke and myocardial infarction (MI) during follow-up. In the Northern Manhattan Study, stroke-free persons aged ≥40 years in northern Manhattan (New York, New York) had annual assessments with the Barthel index (BI) for a median of 13 years (1993-2015). Assessment of baseline demographic factors, risk factors, and laboratory studies included measurement of TNFR1 (n = 1,863). Generalized estimating equations models were used to estimate standardized associations between TNFR1 and 1) baseline functional status and 2) change in function over time, adjusting for demographic factors, vascular risk factors, social variables, cognition, and depression, as well as stroke and MI occurrence during follow-up. The mean age of participants was 70 (standard deviation (SD), 10) years; 66% were women, and 55% were Hispanic. The mean TNFR1 level was 2.57 mg/L. TNFR1 was associated with baseline BI (-0.93 BI points per SD increment in TNFR1; 95% confidence interval: -1.59, -0.26) and change over time (-0.36 BI points per year per SD increment in TNFR1; 95% confidence interval: -0.69, -0.03). In this large population-based study, higher TNFR1 levels were associated with greater baseline disability and disability over time, even with adjustment for baseline covariates and stroke and MI occurrence during follow-up., (© The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Recent evidence suggests that psychological distress, including the symptoms of psychiatric illness, may acutely increase the risk of stroke. However, existing studies are limited by small sample sizes, inherent recall bias, and poorly defined criteria for what constitutes psychological distress., Methods: We analyzed administrative data from the Healthcare Cost and Utilization Project for the state of California from 2007 to 2009 using a case-crossover design. Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for combined hemorrhagic and ischemic stroke risk occurring within 15, 30, 90, 180, and 365 days of a hospitalization for a psychiatric diagnosis (as defined by International Classification of Diseases, Ninth Revision , code) among adults., Results: Psychiatric hospitalizations within 1 year before stroke were found in 2585 (5.3%) of 48 558 stroke patients. Hospitalization for a psychiatric condition was associated with increased risk of stroke within all 5 time periods, with the highest odds of stroke occurring within 15 days (0-15 days: OR, 3.5; 95% confidence interval [CI], 2.6-4.8; 0-30 days: OR, 3.0; 95% CI, 2.4-3.8; 0-90 days: OR, 2.3; 95% CI, 2.0-2.7; 0-180 days: OR, 2.2; 95% CI, 2.0-2.5; and 0-365 days: OR, 2.6; 95% CI, 2.4-2.8)., Conclusions: Psychiatric hospitalization increases the short-term risk of stroke, particularly within the 15-day period after hospitalization., (© 2017 American Heart Association, Inc.)

Background and Purpose: Thrombolysis rates among minor stroke (MS) patients are increasing because of increased recognition of disability in this group and guideline changes regarding treatment indications. We examined the association of delays in door-to-needle (DTN) time with stroke severity., Methods: We performed a retrospective analysis of all stroke patients who received intravenous tissue-type plasminogen activator in our emergency department between July 1, 2011, and February 29, 2016. Baseline characteristics and DTN were compared between MS (National Institutes of Health Stroke Scale score ≤5) and nonminor strokes (National Institutes of Health Stroke Scale score >5). We applied causal inference methodology to estimate the magnitude and mechanisms of the causal effect of stroke severity on DTN., Results: Of 315 patients, 133 patients (42.2%) had National Institutes of Health Stroke Scale score ≤5. Median DTN was longer in MS than nonminor strokes (58 versus 53 minutes; P =0.01); fewer MS patients had DTN ≤45 minutes (19.5% versus 32.4%; P =0.01). MS patients were less likely to use emergency medical services (EMS; 62.6% versus 89.6%, P <0.01) and to receive EMS prenotification (43.9% versus 72.4%; P <0.01). Causal analyses estimated MS increased average DTN by 6 minutes, partly through mode of arrival. EMS prenotification decreased average DTN by 10 minutes in MS patients., Conclusions: MS had longer DTN times, an effect partly explained by patterns of EMS prenotification. Interventions to improve EMS recognition of MS may accelerate care., (© 2017 American Heart Association, Inc.)