Management of Stroke in Patients With Chronic Liver Disease: A Practical Review.

Chronic liver disease (CLD) is a highly prevalent condition. There is burgeoning recognition that there are many people with subclinical liver disease that may nonetheless be clinically significant. CLD has a variety of systemic aberrations relevant to stroke, including thrombocytopenia, coagulopathy, elevated liver enzymes, and altered drug metabolism. There is a growing body of literature on the intersection of CLD and stroke. Despite this, there have been few efforts to synthesize these data, and stroke guidelines provide scant guidance on this topic. To fill this gap, this multidisciplinary review provides a contemporary overview of CLD for the vascular neurologist while appraising data regarding the impact of CLD on stroke risk, mechanisms, and outcomes. Finally, the review addresses acute and chronic treatment considerations for patients with stroke-ischemic and hemorrhagic-and CLD.

Cost-Effectiveness of Smoking Cessation Interventions in Patients With Ischemic Stroke and Transient Ischemic Attack.

BACKGROUND: Smoking cessation rates after stroke and transient ischemic attack are suboptimal, and smoking cessation interventions are underutilized. We performed a cost-effectiveness analysis of smoking cessation interventions in this population. METHODS: We constructed a decision tree and used Markov models that aimed to assess the cost-effectiveness of varenicline, any pharmacotherapy with intensive counseling, and monetary incentives, compared with brief counseling alone in the secondary stroke prevention setting. Payer and societal costs of interventions and outcomes were modeled. The outcomes were recurrent stroke, myocardial infarction, and death using a lifetime horizon. Estimates and variance for the base case (35% cessation), costs and effectiveness of interventions, and outcome rates were imputed from the stroke literature. We calculated incremental cost-effectiveness ratios and incremental net monetary benefits. An intervention was considered cost-effective if the incremental cost-effectiveness ratio was less than the willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY) or when the incremental net monetary benefit was positive. Probabilistic Monte Carlo simulations modeled the impact of parameter uncertainty. RESULTS: From the payer perspective, varenicline and pharmacotherapy with intensive counseling were associated with more QALYs (0.67 and 1.00, respectively) at less total lifetime costs compared with brief counseling alone. Monetary incentives were associated with 0.71 more QALYs at an additional cost of $120 compared with brief counseling alone, yielding an incremental cost-effectiveness ratio of $168/QALY. From the societal perspective, all 3 interventions provided more QALYs at less total costs compared with brief counseling alone. In 10 000 Monte Carlo simulations, all 3 smoking cessation interventions were cost-effective in >89% of runs. CONCLUSIONS: For secondary stroke prevention, it is cost-effective and potentially cost-saving to deliver smoking cessation therapy beyond brief counseling alone.

Prevalence of neurological complaints among emergency department patients with severe hypertension.

OBJECTIVE: Severe hypertension can accompany neurological symptoms without obvious signs of target organ damage. However, acute cerebrovascular events can also be a cause and consequence of severe hypertension. We therefore use US population-level data to determine prevalence and clinical characteristics of patients with severe hypertension and neurological complaints. METHODS: We used nationally representative data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) collected in 2016-2019 to identify adult ED patients with severely elevated blood pressure (BP) defined as systolic BP ≥ 180 mmHg and/or diastolic BP ≥120 mmHg. We used ED reason for visit data fields to define neurological complaints and used diagnosis data fields to define acute target organ damage. We applied survey visit weights to obtain national estimates. RESULTS: Based on 5083 observations, an estimated 40.4 million patients (95% CI: 37.5-43.0 million) in EDs nationwide from 2016 to 2019 had severe hypertension, equating to 6.1% (95% CI: 5.7-6.5%) of all ED visits. Only 2.8% (95% CI: 2.0-3.9%) of ED patients with severe hypertension were diagnosed with acute cerebrovascular disease; hypertensive urgency was diagnosed in 92.0% (95% CI: 90.3-93.4%). Neurological complaints were frequent in both patients with (75.6%) and without (19.9%) cerebrovascular diagnoses. Hypertensive urgency patients with neurological complaints were more often older, female, had prior stroke/TIA, and had neuroimaging than patients without these complaints. Non-migraine headache and vertigo were the most common neurological complaints recorded. CONCLUSION: In a nationally representative survey, one-in-sixteen ED patients had severely elevated BP and one-fifth of those patients had neurological complaints.

Association of liver fibrosis with cognitive test performance and brain imaging parameters in the UK Biobank study.

INTRODUCTION: We hypothesized that liver fibrosis is associated with worse cognitive performance and corresponding brain imaging changes. METHODS: We examined the association of liver fibrosis with cognition and brain imaging parameters in the UK Biobank study. Liver fibrosis was assessed using the Fibrosis-4 (FIB-4) score. The primary cognitive outcome was the digit symbol substitution test (DSST); secondary outcomes were additional executive function/processing speed and memory tests. Imaging outcomes were hippocampal, total brain, and white matter hyperintensity (WMH) volumes. RESULTS: We included 105,313 participants with cognitive test data, and 41,982 with magnetic resonance imaging (MRI). In adjusted models, liver fibrosis was associated with worse performance on the DSST and tests of executive function but not memory. Liver fibrosis was associated with lower hippocampal and total brain volumes, without compelling association with WMH volume. DISCUSSION: Liver fibrosis is associated with worse performance on select cognitive tests and lower hippocampal and total brain volumes. HIGHLIGHTS: It is increasingly recognized that chronic liver conditions impact brain health. We performed an analysis of data from the UK Biobank prospective cohort study. Liver fibrosis was associated with worse performance on executive function tests. Liver fibrosis was not associated with memory impairment. Liver fibrosis was associated with lower hippocampal and total brain volumes.

Fatty liver and cerebrovascular disease: plausible association and possible mechanisms.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity and has wide ranging extrahepatic manifestations, including through cardiometabolic pathways. As such, there is growing interest in the impact of NAFLD on cerebrovascular disease and brain health more broadly. In this review, we assess recent research into understanding the association between NAFLD and brain health while highlighting potential clinical implications. RECENT FINDINGS: Mechanistically, NAFLD is characterized by both a proinflammatory and proatherogenic state, which results in vascular inflammation and neurodegeneration, potentially leading to clinical and subclinical cerebrovascular disease. Mounting epidemiological evidence suggests an association between NAFLD and an increased risk and severity of stroke, independent of other vascular risk factors. Studies also implicate NAFLD in subclinical cerebrovascular disease, such as carotid atherosclerosis and microvascular disease. In contrast, there does not appear to be an independent association between NAFLD and cognitive impairment. SUMMARY: The current literature supports the formulation of NAFLD as a multisystem disease that may also have implications for cerebrovascular disease and brain health. Further prospective studies are needed to better assess a temporal relationship between the two diseases, confirm these early findings, and decipher mechanistic links.

Smoking Cessation in Stroke Survivors in the United States: A Nationwide Analysis.

BACKGROUND: Continued smoking after stroke is associated with a high risk of stroke recurrence and other cardiovascular disease. We sought to comprehensively understand the epidemiology of smoking cessation in stroke survivors in the United States. Furthermore, we compared smoking cessation in stroke and cancer survivors because cancer is another smoking-related condition in which smoking cessation is prioritized. METHODS: We performed a cross-sectional analysis of data from the Centers for Disease Control and Prevention Behavioral Risk Factor Surveillance System, an annual, nationally representative health survey. Using pooled data from 2013 to 2019, we identified stroke and cancer survivors with a history of smoking. We used survey procedures to estimate frequencies and summarize quit ratios with attention to demographic and geographic (state-wise and rural-urban) factors for stroke survivors. The quit ratio is conventionally defined as the proportion of ever smokers who have quit. Then, we used multivariable logistic regression to compare quit ratios in stroke and cancer survivors while adjusting for demographics and smoking-related comorbidities. RESULTS: Among 4 434 604 Americans with a history of stroke and smoking, the median age was 68 years (interquartile range, 59-76), and 45.4% were women. The overall quit ratio was 60.8% (95% CI, 60.1%-61.6%). Quit ratios varied by age group, sex, race and ethnicity, and several geographic factors. There was marked geographic variation in quit ratios, ranging from 48.3% in Kentucky to 71.5% in California. Furthermore, compared with cancer survivors, stroke survivors were less likely to have quit smoking (odds ratio, 0.72 [95% CI, 0.67-0.79]) after accounting for differences in demographics and smoking-related comorbidities. CONCLUSIONS: There were considerable demographic and geographic disparities in smoking quit ratios in stroke survivors, who were less likely to have quit smoking than cancer survivors. A targeted initiative is needed to improve smoking cessation for stroke survivors.

Risk of Stroke After Posterior Reversible Encephalopathy Syndrome.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) can cause short-term cerebrovascular complications, such as brain infarction and hemorrhage. We hypothesized that PRES is also associated with an increased long-term risk of stroke. METHODS: We performed a retrospective cohort study in the United States using statewide all-payer claims data from 2016 to 2018 on all admissions to nonfederal hospitals in 11 states. Adults with PRES were compared with adults with renal colic (negative control) and transient ischemic attack (TIA; positive control). Any stroke and the secondary outcomes of ischemic and hemorrhagic stroke were ascertained using International Classification of Diseases, Tenth Revision, Clinical Modification codes. We excluded prevalent stroke. We used time-to-event statistics to calculate incidence rates and Cox proportional hazards analyses to evaluate the association between PRES and stroke, adjusting for demographics and stroke risk factors. In a sensitivity analysis, outcomes within 2 weeks of index admission were excluded. RESULTS: We identified 1606 patients with PRES, 1192 with renal colic, and 38 216 with TIA. Patients with PRES had a mean age of 56±17 years; 72% were women. Over a median follow-up of 0.9 years, the stroke incidence per 100 person-years was 6.1 (95% CI, 5.0-7.4) after PRES, 1.0 (95% CI, 0.62-1.8) after renal colic, and 9.7 (95% CI, 9.4-10.0) after TIA. After statistical adjustment for patient characteristics and risk factors, patients with PRES had an elevated risk of stroke compared with renal colic (hazard ratio [HR], 2.3 [95% CI, 1.7-3.0]), but lower risk than patients with TIA (HR, 0.67 [95% CI, 0.54-0.82]). In secondary analyses, compared with TIA, PRES was associated with hemorrhagic stroke (HR, 2.0 [95% CI, 1.4-2.9]). PRES was associated with ischemic stroke when compared with renal colic (HR, 1.9 [95% CI, 1.4-2.7]) but not when compared with TIA (HR, 0.49 [95% CI, 0.38-0.63]). Results were similar with 2-week washout. CONCLUSIONS: Patients with PRES had an elevated risk of incident stroke.

Association between liver fibrosis and incident dementia in the UK Biobank study.

BACKGROUND AND PURPOSE: There is growing recognition that chronic liver conditions influence brain health. The impact of liver fibrosis on dementia risk was unclear. We evaluated the association between liver fibrosis and incident dementia in a cohort study. METHODS: We performed a cohort analysis using data from the UK Biobank study, which prospectively enrolled adults starting in 2007, and continues to follow them. People with a Fibrosis-4 (FIB-4) liver fibrosis score >2.67 were categorized as at high risk of advanced fibrosis. The primary outcome was incident dementia, ascertained using a validated approach. We excluded participants with prevalent dementia at baseline. We used Cox proportional hazards models to evaluate the association between liver fibrosis and dementia while adjusting for potential confounders. RESULTS: Among 455,226 participants included in this analysis, the mean age was 56.5 years and 54% were women. Approximately 2.17% (95% confidence interval [CI] 2.13%-2.22%) had liver fibrosis. The rate of dementia per 1000 person-years was 1.76 (95% CI 1.50-2.07) in participants with liver fibrosis and 0.52 (95% CI 0.50-0.54) in those without. After adjusting for demographics, socioeconomic deprivation, educational attainment, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with an increased risk of dementia (hazard ratio 1.52, 95% CI 1.22-1.90). Results were robust to sensitivity analyses. Effect modification by sex, metabolic syndrome, and apolipoprotein E4 carrier status was not observed. CONCLUSION: Liver fibrosis in middle age was associated with an increased risk of incident dementia, independent of shared risk factors. Liver fibrosis may be an underrecognized risk factor for dementia.

Long-Term Risk of Ischemic Stroke among Elderly Survivors of Non-Traumatic Subarachnoid Hemorrhage.

INTRODUCTION: Non-traumatic subarachnoid hemorrhage (SAH) is associated with poor long-term functional outcomes, but the risk of ischemic stroke among SAH survivors is poorly understood. OBJECTIVES: The aim of this study was to evaluate the risk of ischemic stroke among survivors of SAH. METHODS: We performed a retrospective cohort study using claims data from Medicare beneficiaries from 2008 to 2015. The exposure was a diagnosis of SAH, while the outcome was an acute ischemic stroke, both identified using previously validated ICD-9-CM diagnosis codes. We used Cox regression analysis adjusting for demographics and stroke risk factors to evaluate the association between SAH and long-term risk of ischemic stroke. RESULTS: Among 1.7 million Medicare beneficiaries, 912 were hospitalized with non-traumatic SAH. During a median follow-up of 5.2 years (IQR, 2.7-6.7), the cumulative incidence of ischemic stroke was 22 per 1,000 patients per year among patients with SAH, and 7 per 1,000 patients per year in those without SAH. In adjusted Cox models, SAH was associated with an increased risk of ischemic stroke (HR, 2.0; 95% confidence interval, 1.4-2.8) as compared to beneficiaries without SAH. Similar results were obtained in sensitivity analyses, when treating death as a competing risk (sub HR, 3.0; 95% CI, 2.8-3.3) and after excluding ischemic stroke within 30 days of SAH discharge (HR, 1.5; 95% CI, 1.1-2.3). CONCLUSIONS: In a large, heterogeneous national cohort of elderly patients, survivors of SAH had double the long-term risk of ischemic stroke. SAH survivors should be closely monitored and risk stratified for ischemic stroke.

Short-term stroke risk after emergency department treat-and-release headache visit.

OBJECTIVE: To evaluate whether patients discharged to home after an emergency department (ED) visit for headache face a heightened short-term risk of stroke. BACKGROUND: Stroke hospitalizations that occur soon after ED visits for headache complaints may reflect diagnostic error. METHODS: We conducted a retrospective cohort study using statewide administrative claims data for all ED visits and admissions at nonfederal hospitals in Florida 2005-2018 and New York 2005-2016. Using standard International Classification of Diseases (ICD) codes, we identified adult patients discharged to home from the ED (treat-and-release visit) with a benign headache diagnosis (cohort of interest) as well as those with a diagnosis of renal colic or back pain (negative controls). The primary study outcome was hospitalization within 30 days for stroke (ischemic or hemorrhagic) defined using validated ICD codes. We assess the relationship between index ED visit discharge diagnosis and stroke hospitalization adjusting for patient demographics and vascular comorbidities. RESULTS: We identified 1,502,831 patients with an ED treat-and-release headache visit; mean age was 41 (standard deviation: 17) years and 1,044,520 (70%) were female. A total of 2150 (0.14%) patients with headache were hospitalized for stroke within 30 days. In adjusted analysis, stroke risk was higher after headache compared to renal colic (hazard ratio [HR]: 2.69; 95% confidence interval [CI]: 2.29-3.16) or back pain (HR: 4.0; 95% CI: 3.74-4.3). In the subgroup of 26,714 (1.78%) patients with headache who received brain magnetic resonance imaging at index ED visit, stroke risk was only slightly elevated compared to renal colic (HR: 1.47; 95% CI: 1.22-1.78) or back pain (HR: 1.49; 95% CI: 1.24-1.80). CONCLUSION: Approximately 1 in 700 patients discharged to home from the ED with a headache diagnosis had a stroke in the following month. Stroke risk was three to four times higher after an ED visit for headache compared to renal colic or back pain.

Recent Advances in the Impact of Infection and Inflammation on Stroke Risk and Outcomes.

PURPOSE OF THE REVIEW: Inflammation is a key component in the pathogenesis of cerebrovascular diseases. In the past few years, the role of systemic infection and gut dysbiosis in modulating inflammation and stroke risk has been increasingly acknowledged. In this review, we synthesize contemporary literature on the effects of infection and inflammation on stroke risk and outcomes, with a focus on periodontal disease, COVID-19 infection, and gut dysbiosis. RECENT FINDINGS: Chronic and acute infections such as periodontitis and COVID-19 induce systemic inflammation that cause atherogenesis and increase cardiac injury and arrhythmias. These infections also directly injure the endothelium leading to worsened secondary inflammation after stroke. Gut dysbiosis engenders a pro-inflammatory state by modulating intestinal lymphocyte populations that can traffic directly to the brain. Additionally, post-stroke immune dysregulation creates a compounding feedback loop of further infections and gut dysbiosis that worsen outcomes. Recent advances in understanding the pathophysiology of how infection and dysbiosis affect the progression of stroke, as well as long-term recovery, have revealed tantalizing glimpses at potential therapeutic targets. We discuss the multidirectional relationship between stroke, infection, and gut dysbiosis, and identify areas for future research to further explore therapeutic opportunities.

Access to Mechanical Thrombectomy for Ischemic Stroke in the United States.

Background and Purpose: Mechanical thrombectomy helps prevent disability in patients with acute ischemic stroke involving occlusion of a large cerebral vessel. Thrombectomy requires procedural expertise and not all hospitals have the staff to perform this intervention. Few population-wide data exist regarding access to mechanical thrombectomy. Methods: We examined access to thrombectomy for ischemic stroke using discharge data from calendar years 2016 to 2018 from all nonfederal emergency departments and acute care hospitals across 11 US states encompassing 80 million residents. Facilities were classified as hubs if they performed mechanical thrombectomy, gateways if they transferred patients who ultimately underwent mechanical thrombectomy, and gaps otherwise. We used standard descriptive statistics and unadjusted logistic regression models in our primary analyses. Results: Among 205 681 patients with ischemic stroke, 100 139 (48.7% [95% CI, 48.5%­48.9%]) initially received care at a thrombectomy hub, 72 534 (35.3% [95% CI, 35.1%­35.5%]) at a thrombectomy gateway, and 33 008 (16.0% [95% CI, 15.9%­16.2%]) at a thrombectomy gap. Patients who initially received care at thrombectomy gateways were substantially less likely to ultimately undergo thrombectomy than patients who initially received care at thrombectomy hubs (odds ratio, 0.27 [95% CI, 0.25­0.28]). Rural patients had particularly limited access: 27.7% (95% CI, 26.9%­28.6%) of such patients initially received care at hubs versus 69.5% (95% CI, 69.1%­69.9%) of urban patients. For 93.8% (95% CI, 93.6%­94.0%) of patients with stroke at gateways, their initial facility was capable of delivering intravenous thrombolysis, compared with 76.3% (95% CI, 75.8%­76.7%) of patients at gaps. Our findings were unchanged in models adjusted for demographics and comorbidities and persisted across multiple sensitivity analyses, including analyses adjusting for estimated stroke severity. Conclusions: We found that a substantial proportion of patients with ischemic stroke across the United States lacked access to thrombectomy even after accounting for interhospital transfers. US systems of stroke care require further development to optimize thrombectomy access.

Association between Pregnancy and Cervical Artery Dissection.

OBJECTIVE: We wanted to determine whether pregnancy is associated with cervical artery dissection. METHODS: We performed a case-control study using claims data from all nonfederal emergency departments and acute care hospitals in New York and Florida between 2005 and 2015. Cases were women 12-42 years of age hospitalized with cervical artery dissection, defined using validated diagnosis codes for carotid/vertebral artery dissection. Controls were women 12-42 years of age with a primary diagnosis of renal colic. Cases and controls were matched 1:1 on age, race, insurance, income, state, and visit year. The exposure variable was pregnancy, defined as labor and delivery within 90 days before or 6 months after the index visit. Logistic regression was used to compare the odds of pregnancy between cases and controls. We performed a secondary cohort-crossover study comparing the risk of cervical artery dissection during pregnancy versus the same time period 1 year later. RESULTS: Pregnancy was twice as common among 826 women with cervical artery dissection compared with the 826 matched controls with renal colic (odds ratio, 2.5; 95% confidence interval [CI], 1.3-4.7). In our secondary analysis, pregnancy was associated with a higher risk of cervical artery dissection (incidence rate ratio [IRR], 2.2; 95% CI, 1.3-3.5), with the heightened risk limited to the postpartum period (IRR, 5.5; 95% CI, 2.6-11.7). INTERPRETATION: Pregnancy, specifically the postpartum period, was associated with hospitalization for cervical artery dissection. Although these findings might in part reflect ascertainment bias, our results suggest that arterial dissection is one mechanism by which pregnancy can lead to stroke. ANN NEUROL 2020;88:596-602.

Liver Fibrosis and Perihematomal Edema Growth in Primary Intracerebral Hemorrhage.

BACKGROUND: Liver disease is associated with altered serum osmolality, increased thrombin generation, and systemic inflammation, all of which may contribute to perihematomal edema (PHE) after intracerebral hemorrhage (ICH). We evaluated the association between a validated liver fibrosis index and PHE growth in a cohort of patients with primary ICH. METHODS: We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive-ICH. We included adult patients with primary ICH presenting within 6 h of symptom onset. The exposure of interest was the Fibrosis-4 (FIB-4) score, a validated liver fibrosis index; this was modeled as a continuous variable. The primary outcome was absolute PHE growth over 96 h. Secondary outcomes were absolute admission and 96-h PHE volumes. We used multiple linear regression models adjusted for established determinants of PHE. In a secondary analysis, the FIB-4 score was modeled as a categorical variable to compare patients with versus without liver fibrosis. RESULTS: Among 354 patients with ICH, 8% had evidence of liver fibrosis based on a validated cutoff. The FIB-4 score was not associated with PHE growth in unadjusted (ß, 0.03; 95% CI, - 0.01 to 0.12) or adjusted models (ß, 0.04; 95% CI, - 0.03 to 0.13). In a secondary analysis treating FIB-4 as a categorical variable, patients with liver fibrosis did not have greater PHE growth than those without liver fibrosis. FIB-4 score was also not associated with absolute admission or 96-h PHE volumes. CONCLUSIONS: In a multicenter cohort of patients with primary intracerebral hemorrhage, a liver fibrosis score was not associated with PHE volume or growth.

Liver Fibrosis is Associated with Ischemic Stroke Risk in Women but not Men: The REGARDS Study.

BACKGROUND: Nonalcoholic fatty liver disease is inconsistently associated with ischemic stroke, with one study suggesting an association in women and not men. The relative importance of liver fibrosis, as opposed to fatty liver, for cardiovascular risk is increasingly appreciated. We hypothesized that advanced liver fibrosis is associated with incident ischemic stroke risk, and especially in women. METHODS: We performed a case-cohort study in the REasons for Geographic and Racial Differences in Stroke cohort. Black and white individuals aged 45 and older were recruited between 2003 and 2007 and followed for ischemic stroke. The Fibrosis-4 (FIB-4) score and Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS) were calculated using baseline data for stroke cases and a cohort random sample; advanced liver fibrosis was classified using validated cutoffs. Cox proportional hazards models were used to estimate hazard ratios (HR) of stroke after adjusting for potential confounders. Sex differences were assessed. RESULTS: There were 572 incident ischemic strokes (285 in women) over 5.4 (SD, 2.2) years. Advanced liver fibrosis was not significantly associated with ischemic stroke overall using the FIB-4 (HR 1.44; 95% CI 0.49-4.28) or NFS (HR 1.76; 95% CI 0.67-4.61). However, liver fibrosis was associated with stroke in women (HR 3.51; 95% CI 1.00-12.34) but not men (HR 0.70, 95% CI 0.16-3.16) (P = 0.098 for interaction) when using FIB-4. A similar but non-significant sex difference was seen for NFS. CONCLUSION: Advanced liver fibrosis may be associated with a higher risk of ischemic stroke in women but not men.

Trends in Active Cigarette Smoking Among Stroke Survivors in the United States, 1999 to 2018.

Background and Purpose- Patients who continue to smoke after a stroke face a higher risk of recurrent stroke. While several effective drugs for smoking cessation became available over the past 2 decades, whether active smoking has decreased among stroke survivors is unknown. We, therefore, evaluated trends in active smoking among stroke survivors during this period. Methods- We performed trends analyses using cross-sectional data collected every 1 to 2 years from 2 US health surveys spanning 1999 to 2018. In the National Health and Nutrition Examination Survey (NHANES) and the Behavioral Risk Factor Surveillance System (BRFSS) survey, participants were asked about prior stroke and active tobacco smoking. In NHANES, serum cotinine levels were available as a secondary measure of active smoking. We used multivariable logistic regression models for survey data to assess trends in active smoking among participants with and without prior stroke. Results- Among 49 375 participants in NHANES during 1999 to 2016 and 3 621 741 participants in BRFSS during 2011 to 2018, the prevalence of stroke was ≈3%. The overall prevalence of active smoking among stroke survivors was 24% in NHANES and 23% in BRFSS. Among individuals without prior stroke, the odds of smoking decreased over time in both NHANES (odds ratio, 0.95 per 2 years [95% CI, 0.93-0.96]) and BRFSS (odds ratio, 0.96 per year [95% CI, 0.96-0.96]). In contrast, there was no decrease in smoking among stroke survivors in NHANES (odds ratio, 1.00 [95% CI, 0.93-1.07]) or BRFSS (odds ratio, 0.99 [95% CI, 0.98-1.004]). Results were consistent in secondary analysis using biochemical ascertainment of active smoking in NHANES and in sensitivity analyses accounting for potential demographic changes in stroke epidemiology. Conclusions- In contrast to the general population, the prevalence of active smoking among stroke survivors has not decreased during the past 2 decades.

Reclassification of Ischemic Stroke Etiological Subtypes on the Basis of High-Risk Nonstenosing Carotid Plaque.

Background and Purpose- Carotid artery plaque with <50% luminal stenosis may be an underappreciated stroke mechanism. We assessed how many stroke causes might be reclassified after accounting for nonstenosing plaques with high-risk features. Methods- We included patients enrolled in the Cornell Acute Stroke Academic Registry from 2011 to 2015 who had anterior circulation infarction, magnetic resonance imaging of the brain, and magnetic resonance angiography of the neck. High-risk plaque was identified by intraplaque hemorrhage ascertained from routine neck magnetic resonance angiography studies using validated methods. Infarct location was determined from diffusion-weighted imaging. Intraplaque hemorrhage and infarct location were assessed separately in a blinded fashion by a neuroradiologist. We used the McNemar test for matched data to compare the prevalence of intraplaque hemorrhage ipsilateral versus contralateral to brain infarction. We reclassified stroke subtypes by including large-artery atherosclerosis as a cause if there was intraplaque hemorrhage ipsilateral to brain infarction, regardless of the degree of stenosis. Results- Among the 1721 acute ischemic stroke patients registered in the Cornell Acute Stroke Academic Registry from 2011 to 2015, 579 were eligible for this analysis. High-risk plaque was more common ipsilateral versus contralateral to brain infarction in large-artery atherosclerotic (risk ratio [RR], 3.7 [95% CI, 2.2-6.1]), cryptogenic (RR, 2.1 [95% CI, 1.4-3.1]), and cardioembolic strokes (RR, 1.7 [95% CI, 1.1-2.4]). There were nonsignificant ipsilateral-contralateral differences in high-risk plaque among lacunar strokes (RR, 1.2 [95% CI, 0.4-3.5]) and strokes of other determined cause (RR, 1.5 [95% CI, 0.7-3.3]). After accounting for ipsilateral high-risk plaque, 88 (15.2%) patients were reclassified: 38 (22.6%) cardioembolic to multiple potential etiologies, 6 (8.5%) lacunar to multiple, 3 (15.8%) other determined cause to multiple, and 41 (20.8%) cryptogenic to large-artery atherosclerosis. Conclusions- High-risk carotid plaque was more prevalent ipsilateral to brain infarction across several ischemic stroke subtypes. Accounting for such plaques may reclassify the etiologies of up to 15% of cases in our sample.

Machine Learning Prediction of Stroke Mechanism in Embolic Strokes of Undetermined Source.

BACKGROUND AND PURPOSE: One-fifth of ischemic strokes are embolic strokes of undetermined source (ESUS). Their theoretical causes can be classified as cardioembolic versus noncardioembolic. This distinction has important implications, but the categories' proportions are unknown. METHODS: Using data from the Cornell Acute Stroke Academic Registry, we trained a machine-learning algorithm to distinguish cardioembolic versus non-cardioembolic strokes, then applied the algorithm to ESUS cases to determine the predicted proportion with an occult cardioembolic source. A panel of neurologists adjudicated stroke etiologies using standard criteria. We trained a machine learning classifier using data on demographics, comorbidities, vitals, laboratory results, and echocardiograms. An ensemble predictive method including L1 regularization, gradient-boosted decision tree ensemble (XGBoost), random forests, and multivariate adaptive splines was used. Random search and cross-validation were used to tune hyperparameters. Model performance was assessed using cross-validation among cases of known etiology. We applied the final algorithm to an independent set of ESUS cases to determine the predicted mechanism (cardioembolic or not). To assess our classifier's validity, we correlated the predicted probability of a cardioembolic source with the eventual post-ESUS diagnosis of atrial fibrillation. RESULTS: Among 1083 strokes with known etiologies, our classifier distinguished cardioembolic versus noncardioembolic cases with excellent accuracy (area under the curve, 0.85). Applied to 580 ESUS cases, the classifier predicted that 44% (95% credibility interval, 39%-49%) resulted from cardiac embolism. Individual ESUS patients' predicted likelihood of cardiac embolism was associated with eventual atrial fibrillation detection (OR per 10% increase, 1.27 [95% CI, 1.03-1.57]; c-statistic, 0.68 [95% CI, 0.58-0.78]). ESUS patients with high predicted probability of cardiac embolism were older and had more coronary and peripheral vascular disease, lower ejection fractions, larger left atria, lower blood pressures, and higher creatinine levels. CONCLUSIONS: A machine learning estimator that distinguished known cardioembolic versus noncardioembolic strokes indirectly estimated that 44% of ESUS cases were cardioembolic.

Liver Fibrosis Indices and Outcomes After Primary Intracerebral Hemorrhage.

Background and Purpose- Cirrhosis-clinically overt, advanced liver disease-is associated with an increased risk of hemorrhagic stroke and poor stroke outcomes. We sought to investigate whether subclinical liver disease, specifically liver fibrosis, is associated with clinical and radiological outcomes in patients with primary intracerebral hemorrhage. Methods- We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive-Intracerebral Hemorrhage. We included adult patients with primary intracerebral hemorrhage presenting within 6 hours of symptom onset. We calculated 3 validated fibrosis indices-Aspartate Aminotransferase-Platelet Ratio Index, Fibrosis-4 score, and Nonalcoholic Fatty Liver Disease Fibrosis Score-and modeled them as continuous exposure variables. Primary outcomes were admission hematoma volume and hematoma expansion. Secondary outcomes were mortality, and the composite of major disability or death, at 90 days. We used linear and logistic regression models adjusted for previously established risk factors. Results- Among 432 patients with intracerebral hemorrhage, the mean Aspartate Aminotransferase-Platelet Ratio Index, Fibrosis-4, and Nonalcoholic Fatty Liver Disease Fibrosis Score values on admission reflected intermediate probabilities of fibrosis, whereas standard hepatic assays and coagulation parameters were largely normal. After adjusting for potential confounders, Aspartate Aminotransferase-Platelet Ratio Index was associated with hematoma volume (ß, 0.20 [95% CI, 0.04-0.36]), hematoma expansion (odds ratio, 1.6 [95% CI, 1.1-2.3]), and mortality (odds ratio, 1.8 [95% CI, 1.1-2.7]). Fibrosis-4 was also associated with hematoma volume (ß, 0.27 [95% CI, 0.07-0.47]), hematoma expansion (odds ratio, 1.9 [95% CI, 1.2-3.0]), and mortality (odds ratio, 2.0 [95% CI, 1.1-3.6]). Nonalcoholic Fatty Liver Disease Fibrosis Score was not associated with any outcome. Indices were not associated with the composite of major disability or death. Conclusions- In patients with largely normal liver chemistries, 2 liver fibrosis indices were associated with admission hematoma volume, hematoma expansion, and mortality after intracerebral hemorrhage.

Non-Traumatic Subdural Hemorrhage and Risk of Arterial Ischemic Events.

Background and Purpose- The risk of arterial ischemic events after subdural hemorrhage (SDH) is poorly understood. This study aimed to evaluate the risk of acute ischemic stroke and myocardial infarction among patients with and without nontraumatic SDH. Methods- We performed a retrospective cohort study using claims data from 2008 through 2014 from a nationally representative sample of Medicare beneficiaries. The exposure was nontraumatic SDH. Our primary outcome was an arterial ischemic event, a composite of acute ischemic stroke and acute myocardial infarction. Secondary outcomes were ischemic stroke alone and myocardial infarction alone. We used validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes to identify our predictor and outcomes. Using Cox regression and corresponding survival probabilities, adjusted for demographics and vascular comorbidities, we computed the hazard ratio in 4-week intervals after SDH discharge. We performed secondary analyses stratified by strong indications for antithrombotic therapy (composite of atrial fibrillation, peripheral vascular disease, valvular heart disease, and venous thromboembolism). Results- Among 1.7 million Medicare beneficiaries, 2939 were diagnosed with SDH. In the 4 weeks after SDH, patients' risk of an arterial ischemic event was substantially increased (hazard ratio, 3.6 [95% CI, 1.9-5.5]). There was no association between SDH diagnosis and arterial ischemic events beyond 4 weeks. In secondary analysis, during the 4 weeks after SDH, patients' risk of ischemic stroke was increased (hazard ratio, 4.2 [95% CI, 2.1-7.3]) but their risk of myocardial infarction was not (hazard ratio, 0.8 [95% CI, 0.2-1.7]). Patients with strong indications for antithrombotic therapy had increased risks for arterial ischemic events similar to patients in the primary analysis, but those without such indications did not demonstrate an increased risk for arterial ischemic events. Conclusions- Among Medicare beneficiaries, we found a heightened risk of arterial ischemic events driven by an increased risk of ischemic stroke, in the 4 weeks after nontraumatic SDH. This increased risk may be due to interruption of antithrombotic therapy after SDH diagnosis.