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Background: Though stroke risk factors such as substance use may vary with age, less is known about trends in substance use over time or about performance of toxicology screens in young adults with stroke., Methods: Using the Greater Cincinnati Northern Kentucky Stroke Study, a population-based study in a 5-county region comprising 1.3 million people, we reported the frequency of documented substance use (cocaine/marijuana/opiates/other) obtained from electronic medical record review, overall and by race/gender subgroups among physician-adjudicated stroke events (ischemic and hemorrhagic) in adults 20 to 54 years of age. Secondary analyses included heavy alcohol use and cigarette smoking. Data were reported for 5 one-year periods spanning 22 years (1993/1994-2015), and trends over time were tested. For 2015, to evaluate factors associated with performance of toxicology screens, multiple logistic regression was performed., Results: Overall, 2152 strokes were included: 74.5% were ischemic, mean age was 45.7±7.6, 50.0% were women, and 35.9% were Black. Substance use was documented in 4.4%, 10.4%, 19.2%, 24.0%, and 28.8% of cases in 1993/1994, 1999, 2005, 2010, and 2015, respectively ( P trend <0.001). Between 1993/1994 and 2015, documented substance use increased in all demographic subgroups. Adjusting for gender, comorbidities, and National Institutes of Health Stroke Scale, predictors of toxicology screens included Black race (adjusted odds ratio, 1.58 [95% CI, 1.02-2.45]), younger age (adjusted odds ratio, 0.70 [95% CI, 0.53-0.91], per 10 years), current smoking (adjusted odds ratio, 1.62 [95% CI, 1.06-2.46]), and treatment at an academic hospital (adjusted odds ratio, 1.80 [95% CI, 1.14-2.84]). After adding chart-reported substance use to the model, only chart-reported substance abuse and age were significant., Conclusions: In a population-based study of young adults with stroke, documented substance use increased over time, and documentation of substance use was higher among Black compared with White individuals. Further work is needed to confirm race-based disparities and trends in substance use given the potential for bias in screening and documentation. Findings suggest a need for more standardized toxicology screening.

Background and Purpose- Sex differences in stroke incidence over time were previously reported from the GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study). We aimed to determine whether these differences continued through 2015 and whether they were driven by particular age groups. Methods- Within the GCNKSS population of 1.3 million, incident (first ever) strokes among residents ≥20 years of age were ascertained at all local hospitals during 5 periods: July 1993 to June 1994 and calendar years 1999, 2005, 2010, and 2015. Out-of-hospital cases were sampled. Sex-specific incidence rates per 100 000 were adjusted for age and race and standardized to the 2010 US Census. Trends over time by sex were compared (overall and age stratified). Sex-specific case fatality rates were also reported. Bonferroni corrections were applied for multiple comparisons. Results- Over the 5 study periods, there were 9733 incident strokes (56.3% women). For women, there were 229 (95% CI, 215-242) per 100 000 incident strokes in 1993/1994 and 174 (95% CI, 163-185) in 2015 ( P <0.05), compared with 282 (95% CI, 263-301) in 1993/1994 to 211 (95% CI, 198-225) in 2015 ( P <0.05) in men. Incidence rates decreased between the first and last study periods in both sexes for IS but not for intracerebral hemorrhage or subarachnoid hemorrhage. Significant decreases in stroke incidence occurred between the first and last study periods for both sexes in the 65- to 84-year age group and men only in the ≥85-year age group; stroke incidence increased for men only in the 20- to 44-year age group. Conclusions- Overall stroke incidence decreased from the early 1990s to 2015 for both sexes. Future studies should continue close surveillance of sex differences in the 20- to 44-year and ≥85-year age groups, and future stroke prevention strategies should target strokes in the young- and middle-age groups, as well as intracerebral hemorrhage.

Background: The aim of the present study was to compare sex-specific associations between cardiovascular risk factors and diabetes mellitus (DM) among patients with acute ischemic stroke (AIS) in the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS)., Methods: The GCNKSS ascertained AIS cases in 2005 and 2010 among adult (age ≥ 20 years) residents of a biracial population of 1.3 million. Past and current stroke risk factors were compared between those with and without DM using Chi-squared tests and multiple logistic regression analysis to examine sex-specific profiles., Results: There were 3515 patients with incident AIS; 1919 (55%) were female, 697 (20%) were Black, and 1146 (33%) had DM. Among both women and men with DM, significantly more were obese and had hypertension, high cholesterol, and coronary artery disease (CAD) compared with those without DM. For women with AIS, multivariable sex-specific adjusted analyses revealed that older age was associated with decreased odds of having DM (adjusted odds ratio [aOR] 0.88, 95% confidence interval [CI] 0.80-0.98). For women with CAD, the odds of DM were increased (aOR 1.76, 95% CI 1.33-2.32). Age and CAD were not significant factors in differentiating the profiles of men with and without DM., Conclusions: Women with DM had strokes at a younger age, whereas no such age difference existed in men. Compared with men, women with DM were also more likely to have CAD than those without DM, suggesting a sex difference in the association between DM and vascular disease. These findings may suggest a need for more aggressive risk factor management in diabetic women., (© 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: We examined practice patterns of inpatient testing to identify stroke etiologies and treatable risk factors for acute ischemic stroke recurrence., Methods and Results: We identified stroke cases and related diagnostic testing from four 1-year study periods (July 1993 to June 1994, 1999, 2005, and 2010) of the Greater Cincinnati/Northern Kentucky Stroke Study. Patients aged ≥18 years were included. We focused on evaluation of extracranial arteries for carotid stenosis and assessment of atrial fibrillation because randomized controlled trials supported treatment of these conditions for stroke prevention across all 4 study periods. In each study period, we also recorded stroke etiology, as determined by diagnostic testing and physician adjudication. An increasing proportion of stroke patients received assessment of both extracranial arteries and the heart over time (50%, 58%, 74%, and 78% in the 1993-1994, 1999, 2005, and 2010 periods, respectively; P <0.0001 for trend), with the most dramatic individual increases in echocardiography (57%, 63%, 77%, and 83%, respectively). Concurrently, we observed a decrease in strokes of unknown etiology (47%, 48%, 41%, and 38%, respectively; P <0.0001 for trend). We also found a significant increase in strokes of other known causes (32%, 25%, 45% and 59%, respectively; P <0.0001 for trend)., Conclusions: Stroke workup for treatable causes of stroke are being used more frequently over time, and this is associated with a decrease in cryptogenic strokes. Future study of whether better determination of treatable stroke etiologies translates to a decrease in stroke recurrence at the population level will be essential., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background and Purpose: Acute ischemic stroke (AIS) patients may have raised serum cardiac troponin levels on admission, although it is unclear what prognostic implications this has, and whether elevated levels are associated with cardiac causes of stroke or structural cardiac disease as seen on echocardiogram. We investigated the positivity of cardiac troponin and echocardiogram testing within a large biracial AIS population and any association with poststroke mortality., Methods: Within a catchment area of 1.3 million, we screened emergency department admissions from 2010 using International Classification of Diseases, Ninth Edition , discharge codes 430 to 436 and ascertained all physician-confirmed AIS cases by retrospective chart review. Hypertroponinemia was defined as elevation in cardiac troponin above the standard 99th percentile. Multiple logistic regression was performed, controlling for stroke severity, history of cardiac disease, and all other stroke risk factors., Results: Of 1999 AIS cases, 1706 (85.3%) had a cardiac troponin drawn and 1590 (79.5%) had echocardiograms. Hypertroponinemia occurred in 353 of 1706 (20.7%) and 160 of 1590 (10.1%) had echocardiogram findings of interest. Among 1377 who had both tests performed, hypertroponinemia was independently associated with echocardiogram findings (odds ratio, 2.9; 95% confidence interval, 2-4.2). When concurrent myocardial infarctions (3.5%) were excluded, hypertroponinemia was also associated with increased mortality at 1 year (35%; odds ratio, 3.45; 95% confidence interval, 2.1-5.6) and 3 years (60%; odds ratio, 2.91; 95% confidence interval, 2.06-4.11)., Conclusions: Hypertroponinemia in the context of AIS without concurrent myocardial infarction was associated with structural cardiac disease and long-term mortality. Prospective studies are needed to determine whether further cardiac evaluation might improve the long-term mortality rates seen in this group., (© 2017 American Heart Association, Inc.)

Background and Purpose: Computed tomographic angiography and conventional angiography provide timely vascular anatomic information in patients with stroke. However, iodinated contrast dye may cause acute kidney injury (AKI). Within a large, biracial population, we examined in-hospital incidence of new or worsening kidney disease in patients with stroke and its association with administration of intravenous dye., Methods: All adult residents of the Greater Cincinnati/Northern Kentucky region with acute ischemic stroke or intracerebral hemorrhage who presented to an emergency department in 2010 were included. Prevalence of unsuspected kidney disease at the time of emergency department presentation and the incidence of AKI after admission in 2 groups of patients-those who did and those who did not receive intravenous dye-were determined., Results: In 2010, 2299 patients met inclusion criteria (89% ischemic stroke and 11% intracerebral hemorrhage); mean age 69 years (SD 15), 22% black, and 54% women. Among these patients, 37% had kidney disease at baseline, including 22% (516/2299) in whom this was unsuspected. Two percent (2%; 15/853) of patients with baseline kidney disease developed AKI during the hospital stay. Of those with no baseline kidney disease, 1% (14/14 467) developed AKI. There was no association between dye administration and new or worsening kidney disease., Conclusions: Although 22% of patients in the Greater Cincinnati/Northern Kentucky stroke population had unsuspected kidney disease, the incidence of new or worsening kidney disease was low, and AKI was not associated with dye administration. These findings confirm single-center reports that the risk of severe renal complications after contrast dye is small., (© 2017 American Heart Association, Inc.)

Background Although statin therapy is associated with reduced stroke and mortality risk, some studies report that higher lipid levels are associated with improved outcomes following ischemic stroke. Aims We examined the association of hyperlipidemia (HLD) combined with statin therapy on all-cause mortality in stroke patients. Methods All stroke patients in the Greater Cincinnati Northern Kentucky region of ∼1.3 million were identified using ICD-9 discharge codes in 2005 and 2010. Stroke patients with and without HLD were categorized based on their reported statin use at baseline or discharge into three groups: no-HLD/no-statins, HLD/no-statins, and HLD/on-statins. Cox proportional hazards model was used to estimate the risk of mortality at 30 days, 1 year, and 3 years poststroke. Results Overall, 77% (2953) of the 3813 ischemic stroke patients were diagnosed with HLD and 72% ( n = 2123) of those patients were on statin medications. The mean age was 70.0 ± 14.6 years, 56% were women, and 21% were black. In adjusted analyses, the HLD/no-statins group showed 35% (adjusted hazard ratio (aHR) = 0.65, 95% CI: 0.46-0.92), 27% (aHR = 0.73, 95% CI: 0.59-0.90), and 17% (aHR = 0.83, 95% CI: 0.70-0.97) reduced risk of mortality at 30 days, 1 year, and 3 years, respectively, poststroke, compared with no-HLD/no-statins group. The HLD/on-statins group showed an additional 17% significant survival benefit at 3 years poststroke compared with HLD/no-statins group. Conclusions A diagnosis of HLD in ischemic stroke patients is associated with reduced short- and long-term mortality, irrespective of statin use. Statin therapy is associated with significant, additional long-term survival benefit.

Background: There are several situations in which magnetic resonance imaging (MRI) might impact whether an cerebrovascular event is considered a new stroke. These include clinically non-focal events with positive imaging for acute cerebral infarction, and worsening of older symptoms without evidence of new infarction on MRI. We sought to investigate the impact of MRI on stroke detection and stroke incidence, by describing agreement between a strictly clinical definition of stroke and a definition based on physician opinion, including MRI imaging findings., Methods: All hospitalized strokes that occurred in five Ohio and Northern Kentucky counties (population 1.3 million) in the calendar year of 2005 were identified using ICD-9 discharge codes 430-436. The two definitions used were: "clinical case definition" which included sudden onset focal neurologic symptoms referable to a vascular territory for >24 h, compared to the "best clinical judgment of the physician definition", which considers all relevant information, including neuroimaging findings. The 95% confidence intervals (CI) for the incidence rates were calculated assuming a Poisson distribution. Rates were standardized to the 2000 U.S. population, adjusting for age, race, and sex, and included all age groups., Results: There were 2403 ischemic stroke events in 2269 patients; 1556 (64%) had MRI performed. Of the events, 2049 (83%) were cases by both definitions, 185 (7.7%) met the clinical case definition but were non-cases in the physician's opinion and 169 (7.0%) were non-cases by clinical definition but were cases in the physician's opinion. There was no significant difference in the incidence rates of first-ever or total ischemic strokes generated by the two different definitions, or when only those with MRI imaging were included., Conclusions: We found that MRI findings do not appear to substantially change stroke incidence estimates, as the strictly clinical definition of stroke did not significantly differ from a definition that included imaging findings. Including MRI in the case definition "rules out" almost the same number of strokes as it "rules in".

Background and Purpose: The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (r-tPA; CLEAR) in Acute Ischemic Stroke (AIS) and CLEAR-Enhanced Regimen (CLEAR-ER) trials demonstrated safety of reduced dose r-tPA plus the glycoprotein 2b/3a inhibitor, eptifibatide, in AIS compared with r-tPA alone. The objective of the CLEAR-Full Dose Regimen (CLEAR-FDR) trial was to estimate the rate of symptomatic intracerebral hemorrhage (sICH) in AIS patients treated with the combination of full-dose r-tPA plus eptifibatide., Methods: CLEAR-FDR was a single-arm, prospective, open-label, multisite study. Patients aged 18 to 85 years treated with 0.9 mg/kg IV r-tPA within 3 hours of symptom onset were enrolled. After obtaining consent, eptifibatide (135 μg/kg bolus and 2-hour infusion at 0.75 μg/kg per minute) was administered. The primary end point was the proportion of patients who experienced sICH within 36 hours. An independent clinical monitor adjudicated if an sICH had occurred and an independent neuroradiologist reviewed all images. The stopping rule was 3 sICHs within the first 19 patients or 4 sICHs within 29 patients., Results: From October 2013 to December 2014, 27 patients with AIS were enrolled. Median age was 73 years (range, 34-85; interquartile range, 65-80) and median National Institute of Health stroke scale score was 12 (range, 6-26; interquartile range, 9-16). One sICH (3.7%; 95% confidence interval, 0.7%-18%) was observed., Conclusions: These results demonstrate comparable safety of full-dose r-tPA plus eptifibatide with historical rates of sICH with r-tPA alone and support proceeding with a phase 3 trial evaluating full-dose r-tPA combined with eptifibatide to improve outcomes after AIS., (© 2015 American Heart Association, Inc.)

Background and Purpose: Sex differences in recombinant tissue-type plasminogen activator (r-tPA) administration are present in some populations. It is unknown whether this is because of eligibility differences or the modifiable exclusion criterion of severe hypertension. Our aim was to investigate sex differences in r-tPA eligibility, in individual exclusion criteria, and in the modifiable exclusion criterion, hypertension., Methods: We included all ischemic stroke patients ≥18 years among residents of the Greater Cincinnati/Northern Kentucky region who presented to 16-area emergency departments in 2005. Eligibility for r-tPA and individual exclusion criteria were determined using 2013 American Heart Association (AHA) and European Cooperative Acute Stroke Study (ECASS) III guidelines., Results: Of 1837 ischemic strokes, 58% were women, 24% were black. Mean age in years was 72.2 for women and 66.1 for men. Eligibility for r-tPA was similar by sex (6.8% men and 6.1% women; P=0.55), even after adjusting for age (7.0% and 5.9%; P=0.32). Similar proportions of women and men arrived beyond 3- and 4.5-hour time windows, but more women had severe hypertension. There were no sex differences in blood pressure treatment rates among those with severe hypertension (14.6% women and 20.8% men; P=0.21). More women were >80 years and had National Institutes of Health Stroke Scale (NIHSS) >25., Conclusions: Within a large, biracial population, eligibility for r-tPA was similar by sex. Women were more likely to have the modifiable exclusion criterion of severe hypertension but were not more likely to be treated. Women were more likely to have 2 of the 5 ECASS III exclusion criteria. Undertreatment of hypertension in women is a potentially modifiable contributor to reported differences in r-tPA administration., (© 2015 American Heart Association, Inc.)

Background and Purpose: The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial demonstrated safety of recombinant tissue-type plasminogen activator (r-tPA) plus eptifibatide in acute ischemic stroke (AIS). CLEAR-ER randomized AIS patients (5:1) to 0.6 mg/kg r-tPA plus eptifibatide versus standard r-tPA (0.9 mg/kg). Interventional Management of Stroke III randomized AIS patients to r-tPA plus endovascular therapy versus standard r-tPA. Albumin in Acute Stroke Part 2 randomized patients to albumin±r-tPA versus saline±r-tPA. Our aim was to compare outcomes in CLEAR-ER combination arm patients to propensity score-matched r-tPA only subjects in Albumin in Acute Stroke Part 2 and Interventional Management of Stroke III., Methods: The primary outcome was 90-day severity-adjusted modified Rankin score (mRS) dichotomization based on baseline National Institutes of Health Stroke Scale. Secondary outcomes were 90-day mRS dichotomization as excellent (mRS, 0-1); mRS dichotomization as favorable (mRS, 0-2); and nonparametric analysis of the ordinal mRS., Results: Eighty-five combination arm CLEAR-ER subjects were matched with 169 Albumin in Acute Stroke Part 2 and Interventional Management of Stroke III trials' r-tPA only patients (controls). Median age in CLEAR-ER and control subjects was 68years; median National Institutes of Health Stroke Scale in the CLEAR-ER subjects was 11 and in control subjects 12. At 90 days, CLEAR-ER subjects had a nonsignificantly greater proportion of patients with favorable outcomes (45% versus 36%; unadjusted relative risks, 1.24; 95% confidence intervals, 0.91-1.69; P=0.18). Secondary outcomes were 52% versus 34% excellent outcomes (relative risks, 1.51; 95% confidence intervals, 1.13-2.02; P=0.007); 60% versus 53% favorable outcome (relative risks, 1.13; 95% confidence intervals, 0.90-1.41; P=0.31); and ordinal Cochran-Mantel-Haenszel P=0.10., Conclusion: r-tPA plus eptifibatide showed a favorable direction of effect that was consistent across multiple approaches for AIS outcome evaluation. A phase III trial to establish the efficacy of r-tPA plus eptifibatide for improving AIS outcomes is warranted., (© 2014 American Heart Association, Inc.)

Background: The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator (rt-PA) in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial found that intravenous rt-PA plus eptifibatide (combination arm) in acute ischemic stroke (AIS) was safe and had a direction of effect that would justify a phase III trial. CLEAR-ER had unanticipated imbalances between treatment groups. We compared the rates of symptomatic intracranial hemorrhage (sICH) and good outcomes for combination therapy patients in the CLEAR-ER trial to a matched cohort of rt-PA patients from the National Institute of Neurological Disorders and Stroke (NINDS) trial., Methods: CLEAR-ER was a multicenter, double-blind, randomized study; rt-PA-eligible AIS patients were randomized to .6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and .75mcg/kg/min two-hour infusion) versus standard rt-PA (.9 mg/kg). For this analysis, we matched 1:1 CLEAR-ER combination therapy patients with rt-PA arm NINDS trial patients. Patients were matched by age, gender, race, baseline modified Rankin Scale score, baseline National Institutes of Health Stroke Scale (NIHSS) score, and stroke onset to rt-PA time., Results: Fifty-four matches were made. One (1.8%) sICH occurred in each group (odds ratio [OR] 1.00, 95% confidence interval [CI] .01-78.50). At 90 days, 51.8% of the CLEAR-ER group had good outcomes versus 46.3% in the NINDS rt-PA group (OR 1.30, 95% CI .57-2.96). For subjects with baseline NIHSS score > 12 (CLEAR-ER median NIHSS score), 38.5% of the CLEAR-ER group had good outcomes versus 23.1% in the NINDS group (OR 2.33, 95% CI .60-9.02)., Conclusions: The safety and direction of effect of eptifibatide plus rt-PA were confirmed. A phase III trial is needed to determine the efficacy of eptifibatide plus rt-PA for improving long-term outcomes after AIS., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Little is known about the distribution of National Institutes of Health Stroke Scale (NIHSS) scores from patients with ischemic stroke sampled from population-based studies. We describe the distribution of NIHSS in ischemic stroke cases from the Cincinnati/Northern Kentucky Stroke Study., Methods: Within a biracial population of 1.3 million, all strokes among area residents in 2005 were ascertained by screening discharge records at local hospitals and outpatient clinics. A sampling scheme was developed to ascertain additional cases presenting to physician offices and nursing homes, not identified through the other sources. All confirmed ischemic stroke cases underwent chart abstraction, and a retrospective NIHSS (rNIHSS) score (range, 0-42) was generated on the basis of initial physician examination findings., Results: There were 2233 ischemic stroke cases identified during the 12-month study. The overall median rNIHSS score was 3 (interquartile range, 1-7). Median rNIHSS score was 3, 7, and 1, respectively, for stroke cases ascertained through the admitted, in-hospital, and out-of-hospital sources. Median rNIHSS was significantly higher in subjects ≥80 years compared with younger cases (4 versus 3)., Conclusions: More than half of all ischemic stroke cases have mild symptom severity on initial presentation (ie, rNIHSS≤3). Monitoring trends in NIHSS represents a legitimate target for population-based surveillance efforts.

Background and Purpose: In a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial., Methods: CLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score ≤1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression., Results: Of 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01-1.40; P=0.053). At 90 days, 49.5% of the combination group had mRS ≤1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70-4.31; P=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51-3.76; P=0.52)., Conclusions: The combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00894803.

Background and Purpose: Initial National Institutes of Health Stroke Scale (NIHSS) score is highly predictive of outcome after ischemic stroke. We examined whether grouping strokes by presence of individual NIHSS symptoms could provide prognostic information additional or alternative to the NIHSS total score., Methods: Ischemic strokes from the Greater Cincinnati Northern Kentucky Stroke Study in 2005 were used to develop the model. Latent class analysis was implemented to form groups of patients with similar retrospective NIHSS (rNIHSS) item responses. Profile group was then used as an independent predictor of discharge modified Rankin and mortality, using logistic regression and Cox proportional hazards model., Results: A total of 2112 stroke patients were identified in 2005. Six distinct profiles were characterized. Consistent with the profile patterns, the median rNIHSS total score decreased from profile A "most severe" (median [interquartile range], 20 [15-25]) to profile F "mild" (1[1-2]). Two profiles falling between these extremes, C and D, both had median rNIHSS total score of 5, but different survival rates. Compared with A, C was associated with 59% risk reduction for death, whereas D with 70%. C patients were more likely to have decreased level of consciousness and abnormal language, whereas D patients were more likely to have abnormal right arm and right leg motor function., Conclusions: Six rNIHSS profiles were identifiable using latent class analysis. In particular, 2 symptom profiles with identical median rNIHSSS were observed with widely disparate outcomes, which may prove useful both clinically and for research studies as an enhancement to the overall NIHSS score.

Objective: Hemorrhagic transformation (HT) is a major complication of ischemic stroke that worsens outcomes and increases mortality. Disruption of the blood-brain barrier is a central feature of HT pathogenesis, and leukocytes may contribute to this process. We sought to determine whether ischemic strokes that develop HT have differences in RNA expression in blood within 3 hours of stroke onset prior to treatment with thrombolytic therapy., Methods: Stroke patient blood samples were obtained prior to treatment with thrombolysis, and leukocyte RNA was assessed by microarray analysis. Strokes that developed HT (n = 11) were compared to strokes without HT (n = 33) and controls (n = 14). Genes were identified (corrected p < 0.05, fold change ≥|1.2|), and functional analysis was performed. RNA prediction of HT in stroke was evaluated using cross-validation, and in a second stroke cohort (n = 52)., Results: Ischemic strokes that developed HT had differential expression of 29 genes in circulating leukocytes prior to treatment with thrombolytic therapy. A panel of 6 genes could predict strokes that later developed HT with 80% sensitivity and 70.2% specificity. Key pathways involved in HT of human stroke are described, including amphiregulin, a growth factor that regulates matrix metalloproteinase-9; a shift in transforming growth factor-β signaling involving SMAD4, INPP5D, and IRAK3; and a disruption of coagulation factors V and VIII., Interpretation: Identified genes correspond to differences in inflammation and coagulation that may predispose to HT in ischemic stroke. Given the adverse impact of HT on stroke outcomes, further evaluation of the identified genes and pathways is warranted to determine their potential as therapeutic targets to reduce HT and as markers of HT risk., (© 2013 American Neurological Association.)

Background and Purpose: Approximately 5% of strokes occur in adults aged 18 to 44 years. Substance abuse is a prevalent risk factor for stroke in young adults. We sought to identify trends in substance abuse detection among stroke patients., Methods: Using a population-based design, we sought to identify all patients aged 18 to 54 years experiencing a stroke (ischemic or hemorrhagic) in the Greater Cincinnati and Northern Kentucky Study region during 1993 to 1994, 1999, and 2005. Demographic and clinical characteristics and substance use data were obtained retrospectively from chart review and adjudicated by physicians., Results: The number of young patients identified with a stroke increased from 1993 to 1994 (297) to 2005 (501). Blacks (61% vs 51%; P<0.02) and men (61% vs 47%; P<0.002) reported substance abuse (current smoking, alcohol, or illegal drug use) more frequently than did whites and women. Overall use of substances increased across study periods, 45% in 1993 versus 62% in 2005 (P=0.003). The trend was significant for illegal drug use (3.8% in 1993 vs 19.8% in 2005) and ever smoking (49% in 1993 vs 66% in 2005). Documentation of both cocaine and marijuana use increased over time. In 2005, half of young adults with a stroke were current smokers, and 1 in 5 abused illegal drugs., Conclusions: Substance abuse is common in young adults experiencing a stroke. The observed increase in substance abuse is contributing to the increased incidence of stroke in young adults. Patients aged younger than 55 years who experience a stroke should be routinely screened and counseled regarding substance abuse.

Objectives: We describe temporal trends in stroke incidence stratified by age from our population-based stroke epidemiology study. We hypothesized that stroke incidence in younger adults (age 20-54) increased over time, most notably between 1999 and 2005., Methods: The Greater Cincinnati/Northern Kentucky region includes an estimated population of 1.3 million. Strokes were ascertained in the population between July 1, 1993, and June 30, 1994, and in calendar years 1999 and 2005. Age-, race-, and gender-specific incidence rates with 95 confidence intervals were calculated assuming a Poisson distribution. We tested for differences in age trends over time using a mixed-model approach, with appropriate link functions., Results: The mean age at stroke significantly decreased from 71.2 years in 1993/1994 to 69.2 years in 2005 (p < 0.0001). The proportion of all strokes under age 55 increased from 12.9% in 1993/1994 to 18.6% in 2005. Regression modeling showed a significant change over time (p = 0.002), characterized as a shift to younger strokes in 2005 compared with earlier study periods. Stroke incidence rates in those 20-54 years of age were significantly increased in both black and white patients in 2005 compared to earlier periods., Conclusions: We found trends toward increasing stroke incidence at younger ages. This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable.

Background and Purpose: The publication of the European Cooperative Acute Stroke Study (ECASS III) expanded the treatment time to thrombolysis for acute ischemic stroke from 3 to 4.5 hours from symptom onset. The impact of the expanded time window on treatment rates has not been comprehensively evaluated in a population-based study., Methods: All patients with an ischemic stroke presenting to an emergency department during calendar year 2005 in the 17 hospitals that compromise the large 1.3 million Greater Cincinnati/Northern Kentucky population were included in the analysis. Criteria for exclusion from thrombolytic therapy are analyzed retrospectively for both the standard and expanded timeframes with varying door-to-needle times., Results: During the study period, 1838 ischemic strokes presenting to an emergency department were identified. A small proportion of them arrived in the expanded time window (3.4%) compared with the standard time window (22%). Only 0.5% of those who arrived in this timeframe met eligibility criteria for thrombolysis compared with 5.9% using standard eligibility criteria in the standard timeframe. These results did not vary significantly by repeated analysis varying the door-to-needle time or the expanded time window's exclusion criteria., Conclusions: In reality, the expanded time window for thrombolysis in acute ischemic stroke benefits few patients. If we are to improve recombinant tissue-type plasminogen activator administration rates, our focus should be on improving stroke awareness, transport to facilities with ability to administer thrombolysis, and familiarity of physicians with acute stroke treatment guidelines.

This study examined the effects of gender on RNA expression after ischemic stroke (IS). RNA obtained from blood of IS patients (n=51; 153 samples at < or =3, 5, and 24 hours) and from matched controls (n=52) were processed on Affymetrix microarrays. Analyses of covariance for stroke versus control samples were performed separately for both genders and the regulated genes for females compared with males. In all, 242, 227, and 338 male-specific genes were regulated at < or =3, 5, and 24 hours after IS, respectively, of which 59 were regulated at all time points. Overall, 774, 3,437, and 571 female-specific stroke genes were regulated at < or =3, 5, and 24 hours, respectively, of which 152 were regulated at all time points. Male-specific stroke genes were associated with integrin, integrin-liked kinase, actin, tight junction, Wnt/β-catenin, RhoA, fibroblast growth factors (FGF), granzyme, and tumor necrosis factor receptor (TNFR)2 signaling. Female-specific stroke genes were associated with p53, high-mobility group box-1, hypoxia inducible factor (HIF)1α, interleukin (IL)1, IL6, IL12, IL18, acute-phase response, T-helper, macrophage, and estrogen signaling. Cell death signaling was overrepresented in both genders, although the molecules and pathways differed. Gender affects gene expression in the blood of IS patients, which likely implies gender differences in immune, inflammatory, and cell death responses to stroke.

Background and Purpose: Malignant middle cerebral artery infarction is estimated to occur in 10% of ischemic strokes, but few patients undergo decompressive hemicraniectomy, a proven therapy. We determined the proportion of patients with ischemic stroke without significant baseline disability with large middle cerebral artery infarction who would have been potentially eligible for hemicraniectomy in an era before publication of recent hemicraniectomy trials., Methods: Ischemic stroke cases that occurred in 2005 among residents of the 5-county Greater Cincinnati/Northern Kentucky area were ascertained. Two study physicians reviewed all clinical and neuroimaging data for patients with baseline modified Rankin Scale score < 2, age ≥ 18 years with National Institutes of Health Stroke Scale score ≥ 10. Large middle cerebral artery infarction was defined as >50% of the middle cerebral artery territory or >145 mL on diffusion-weighted MRI. Other eligibility criteria for hemicraniectomy, based on the pooled analysis of recent clinical trials, were age 18 to 60 years and National Institutes of Health Stroke Scale score > 15., Results: Of 2227 ischemic strokes, 39 (1.8%) with baseline modified Rankin Scale score < 2 had large middle cerebral artery infarction. None underwent hemicraniectomy, and 16 (41.0%) died within 30 days. Six patients (0.3% of all ischemic strokes) were potentially eligible for hemicraniectomy; 1 died within 30 days., Conclusions: Based on criteria from clinical trials, only 0.3% of cases were eligible for hemicraniectomy. Given the survival and functional outcome benefit in treated patients, future studies should determine whether additional subgroups of patients with ischemic stroke may benefit from hemicraniectomy.

Background and Purpose: Antithrombotic medications (anticoagulants and antiplatelets) are often withheld in the periprocedural period and after bleeding complications to limit the risk of new or recurrent bleeding. These medications are also stopped by patients for various reasons such as cost, side effects, or unwillingness to take medication., Methods: Patient records from the population-based Greater Cincinnati/Northern Kentucky Stroke Study were reviewed to identify cases of ischemic stroke in 2005 and determine the temporal association of strokes with withdrawal of antithrombotic medication. Ischemic strokes and reasons for medication withdrawal were identified by study nurses for subsequent physician review., Results: In 2005, 2197 cases of ischemic stroke among residents of the region were identified through hospital discharge records. Of the 2197 ischemic strokes, 114 (5.2%) occurred within 60 days of an antithrombotic medication withdrawal, 61 (53.5%) of these after stoppage of warfarin and the remainder after stoppage of an antiplatelet medication. Of the strokes after withdrawal, 71 (62.3%) were first-ever and 43 (37.7%) were recurrent; 54 (47.4%) occurred after withdrawal of medication by a physician in the periprocedural period., Conclusions: The withdrawal of antiplatelet and antithrombotic medications in the 60 days preceding an acute ischemic stroke was associated with 5.2% of ischemic strokes in our study population. This finding emphasizes the need for thoughtful decision-making concerning antithrombotic medication use in the periprocedural period and efforts to improve patient compliance.

Objective: The cause of stroke remains unknown or cryptogenic in many patients. We sought to determine whether gene expression signatures in blood can distinguish between cardioembolic and large-vessel causes of stroke, and whether these profiles can predict stroke etiology in the cryptogenic group., Methods: A total of 194 samples from 76 acute ischemic stroke patients were analyzed. RNA was isolated from blood and run on Affymetrix U133 Plus2.0 microarrays. Genes that distinguish large-vessel from cardioembolic stroke were determined at 3, 5, and 24 hours following stroke onset. Predictors were evaluated using cross-validation and a separate set of patients with known stroke subtype. The cause of cryptogenic stroke was predicted based on a model developed from strokes of known cause and identified predictors., Results: A 40-gene profile differentiated cardioembolic stroke from large-vessel stroke with >95% sensitivity and specificity. A separate 37-gene profile differentiated cardioembolic stroke due to atrial fibrillation from nonatrial fibrillation causes with >90% sensitivity and specificity. The identified genes elucidate differences in inflammation between stroke subtypes. When applied to patients with cryptogenic stroke, 17% are predicted to be large-vessel and 41% to be cardioembolic stroke. Of the cryptogenic strokes predicted to be cardioembolic, 27% were predicted to have atrial fibrillation., Interpretation: Gene expression signatures distinguish cardioembolic from large-vessel causes of ischemic stroke. These gene profiles may add valuable diagnostic information in the management of patients with stroke of unknown etiology though they need to be validated in future independent, large studies.

Background and Purpose: A blood-based biomarker of acute ischemic stroke would be of significant value in clinical practice. This study aimed to (1) replicate in a larger cohort our previous study using gene expression profiling to predict ischemic stroke; and (2) refine prediction of ischemic stroke by including control groups relevant to ischemic stroke., Methods: Patients with ischemic stroke (n=70, 199 samples) were compared with control subjects who were healthy (n=38), had vascular risk factors (n=52), and who had myocardial infarction (n=17). Whole blood was drawn ≤3 hours, 5 hours, and 24 hours after stroke onset and from control subjects. RNA was processed on whole genome microarrays. Genes differentially expressed in ischemic stroke were identified and analyzed for predictive ability to discriminate stroke from control subjects., Results: The 29 probe sets previously reported predicted a new set of ischemic strokes with 93.5% sensitivity and 89.5% specificity. Sixty- and 46-probe sets differentiated control groups from 3-hour and 24-hour ischemic stroke samples, respectively. A 97-probe set correctly classified 86% of ischemic strokes (3 hour+24 hour), 84% of healthy subjects, 96% of vascular risk factor subjects, and 75% with myocardial infarction., Conclusions: This study replicated our previously reported gene expression profile in a larger cohort and identified additional genes that discriminate ischemic stroke from relevant control groups. This multigene approach shows potential for a point-of-care test in acute ischemic stroke.

Background and Purpose: Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination., Methods: The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke-funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 microg/kg bolus followed by 0.75 microg/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy., Results: Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 (P=0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 (P=0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA-only arm (P=0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate outcome of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group., Conclusions: The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.

Background: The stroke volume among black ischemic stroke patients in phase I of the population-based Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) was smaller than reported among acute stroke studies, with a median stroke volume of 2.5 cm. However, it is not known if stroke volume was similar between black and white patients within the same study population., Methods: Phase II of the GCNKSS identified all ischemic strokes between July 1993 and June 1994. The stroke volume was estimated by study physicians using the modified ellipsoid method. Analysis of stroke volume by race, sex and age was performed for strokes with a measurable lesion of >or=0.5 cm(3)., Results: Among verified cases of ischemic stroke, 334 patients were eligible for this analysis. There were 191 whites (57%) and 143 blacks (43%). The mean age was 69.4 years. The median stroke volume for all patients was 8.8 cm(3) (range 0.5-540), with a mean of 36.4 cm(3). Stroke volume was not different between men and women, and it tended to increase with age. Although stroke volume was significantly higher among whites, age was a confounding factor. Subsequent analysis of stroke volume stratified by age showed no difference between blacks and whites in any age group., Conclusions: Our data show that most ischemic stroke lesions, regardless of the race, are of small size, and this may be an important reason for the low percentage of strokes treated currently with tissue-type plasminogen activator. The association of age with stroke volume requires further study., (Copyright 2008 S. Karger AG, Basel.)

Introduction: Only 8% of ischemic stroke (IS) patients are eligible for rt-PA, and the largest exclusion criterion is delayed time of presentation to the ED. We sought to investigate whether patients are arriving to the ED more quickly in 1999 than in 1993/94 within our large biracial population of 1.3 million., Methods: Using ICD-9 codes 430-436, we ascertained all stroke events that presented to a local ED within our population in 7/93-6/94 and again in 1999. Times were recorded as documented in the medical record., Results: There were 1,792 IS patients that presented to an ED in 1993/94 and 1,973 in 1999. The percentage of patients with documented times arriving in under 3 h improved slightly in 1999 (26% vs. 23% in 93/94, P = 0.03), however, the percentage arriving in under 2 h did not. Blacks significantly improved in arrivals under 3 h: 26% in 1999 compared to 17% in 1993/94 (P = 0.01), while whites did not (26% vs. 25%, P = 0.29). In 1999, only 9% of patients arrived from 3-8 h after symptom onset, the large majority of times were either estimated, unknown, or >8 h., Discussion: We found only marginal improvement in arrival times during the 1990s. In our population, blacks improved in early arrival after symptom onset, while whites did not. Very few patients arrive 3-8 h after onset; therefore expansion of the acute treatment time window to 8 h is unlikely to dramatically affect acute treatment of ischemic stroke.

Ischemic brain and peripheral white blood cells release cytokines, chemokines and other molecules that activate the peripheral white blood cells after stroke. To assess gene expression in these peripheral white blood cells, whole blood was examined using oligonucleotide microarrays in 15 patients at 2.4+/-0.5, 5 and 24 h after onset of ischemic stroke and compared with control blood samples. The 2.4-h blood samples were drawn before patients were treated either with tissue-type plasminogen activator (tPA) alone or with tPA plus Eptifibatide (the Combination approach to Lysis utilizing Eptifibatide And Recombinant tPA trial). Most genes induced in whole blood at 2 to 3 h were also induced at 5 and 24 h. Separate studies showed that the genes induced at 2 to 24 h after stroke were expressed mainly by polymorphonuclear leukocytes and to a lesser degree by monocytes. These genes included: matrix metalloproteinase 9; S100 calcium-binding proteins P, A12 and A9; coagulation factor V; arginase I; carbonic anhydrase IV; lymphocyte antigen 96 (cluster of differentiation (CD)96); monocarboxylic acid transporter (6); ets-2 (erythroblastosis virus E26 oncogene homolog 2); homeobox gene Hox 1.11; cytoskeleton-associated protein 4; N-formylpeptide receptor; ribonuclease-2; N-acetylneuraminate pyruvate lyase; BCL6; glycogen phosphorylase. The fold change of these genes varied from 1.6 to 6.8 and these 18 genes correctly classified 10/15 patients at 2.4 h, 13/15 patients at 5 h and 15/15 patients at 24 h after stroke. These data provide insights into the inflammatory responses after stroke in humans, and should be helpful in diagnosis, understanding etiology and pathogenesis, and guiding acute treatment and development of new treatments for stroke.

Objective: Diabetes is a well known risk factor for stroke, but the impact of diabetes on stroke incidence rates is not known. This study uses a population-based study to describe the epidemiology of ischemic stroke in diabetic patients., Research Design and Methods: Hospitalized cases were ascertained by ICD-9 discharge codes, prospective screening of emergency department admission logs, and review of coroner's cases. A sampling scheme was used to ascertain cases in the out-of-hospital setting. All potential cases underwent detailed chart abstraction by study nurses followed by physician review. Diabetes-specific incidence rates, case fatality rates, and population-attributable risks were estimated., Results: Ischemic stroke patients with diabetes are younger, more likely to be African American, and more likely to have hypertension, myocardial infarction, and high cholesterol than nondiabetic patients. Age-specific incidence rates and rate ratios show that diabetes increases ischemic stroke incidence at all ages, but this risk is most prominent before age 55 in African Americans and before age 65 in whites. One-year case fatality rates after ischemic stroke are not different between those patients with and without diabetes., Conclusions: Given the "epidemic" of diabetes, with substantially increasing diabetes prevalence each year across all age- and race/ethnicity groups, the significance of diabetes as a risk factor for stroke is becoming more evident. Diabetes is clearly one of the most important risk factors for ischemic stroke, especially in those patients less than 65 years of age. We estimate that 37-42% of all ischemic strokes in both African Americans and whites are attributable to the effects of diabetes alone or in combination with hypertension.

Background and Purpose: Acute ischemic stroke patients are infrequently treated with recombinant tissue plasminogen activator (rtPA). We present unique population-based data regarding the eligibility of ischemic stroke patients for rtPA treatment., Methods: All ischemic strokes presenting to an emergency department (ED) within a biracial population of 1.3 million were identified. The patient was considered eligible for rtPA on the basis of exclusion criteria from the National Institute of Neurological Disorders and Stroke rtPA trial., Results: Of 2308 ischemic strokes, 1849 presented to an ED. Only 22% of all ischemic strokes in the population arrived in the ED in <3 hours from symptom onset; of these, 209 (51%) were ineligible for rtPA on the basis of mild stroke severity, medical and surgical history, or blood tests., Conclusions: In our population in 1993 to 1994, 8% of all ischemic stroke patients presented to an ED within 3 hours and met other eligibility criteria for rtPA. Even if time were not an exclusion for rtPA, only 29% of all ischemic strokes in our population would have otherwise been eligible for rtPA.