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The objective of this study was to investigate the cross-sectional associations of atrial fibrillation with neuroimaging measures of cerebrovascular disease and Alzheimer’s disease-related pathology, and their interaction with cognitive impairment. MRI scans of non-demented individuals (n=1044) from the population-based Mayo Clinic Study of Aging were analyzed for infarctions, total grey matter, hippocampal and white matter hyperintensity volumes. A subset of 496 individuals underwent FDG and C-11 Pittsburgh compound B (PiB) PET scans. We assessed the associations of atrial fibrillation with i) categorical MRI measures (cortical and subcortical infarctions) using multivariable logistic regression models, and with ii) continuous MRI measures ( hippocampal, total grey matter, and white matter hyperintensity volumes) and FDG-PET and PiB-PET measures using multivariable linear regression models, and adjusting for confounders. Among participants who underwent MRI (median age, 77.8, 51.6% male), 13.5% had atrial fibrillation. Presence of atrial fibrillation was associated with subcortical infarctions (odds ratio [OR], 1.83; p=0.002), cortical infarctions (OR, 1.91; p=0.03), total grey matter volume (Beta [β], -.025, p<.0001) after controlling for age, education, gender, APOE e4 carrier status, coronary artery disease, diabetes, history of clinical stroke, and hypertension. However, atrial fibrillation was not associated with white matter hyperintensity volume, hippocampal volume, Alzheimer’s pattern of FDG hypometabolism or PiB uptake. There was a significant interaction of cortical infarction (p for interaction=0.004) and subcortical infarction (p for interaction =0.015) with atrial fibrillation with regards to odds of mild cognitive impairment (MCI). Using subjects with no atrial fibrillation and no infarction as the reference, the OR (95% confidence intervals [CI]) for MCI was 2.98 (1.66, 5.35;p = 0.0002) among participants with atrial fibrillation and any infarction, 0.69 (0.36, 1.33;p= 0.27) for atrial fibrillation and no infarction, and 1.50 (0.96, 2.32;p = 0.07) for no atrial fibrillation and any infarction. These data highlight that atrial fibrillation is associated with MCI in the presence of infarctions.

Background: Fever has been associated with worse clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH). However, the impact of the cause, severity, and duration of fever is not clear. We conducted this study to evaluate the impact of fever and subfebrile load and fever characteristics on functional outcome. Methods: We collected detailed information on fever onset, cause, severity, and duration during the ICU stay in a cohort of 586 consecutive patients with aSAH. Fever was defined as core body temperature ≥ 38.3°C. Subfebrile measurements were those between 37 and 38.2°C. Febrile and subfrebile loads were defined as number of hours with fever or subfebrile measurements. Poor outcome was defined as modified Rankin score (mRS) > 2. Univariate and multivariate logistic regression models were developed to define predictors of outcome using various categorizations of fever cause, severity, and duration. Results: 532/586 patients (90.9%) had fever for a mean of 2.1±3.0 days. Fever started within 24 hours in 69 (11.8%) and within 72 hours in 110 (18.8%). Poor outcome occurred in 175 patients (29.9%). On univariate analysis, days of fever, febrile load, fever onset within 24 hours, and fever onset within 72 hours were associated with poor outcome (all p<0.001), but subfebrile load was not (p=0.58). On multivariate model constructed with all variables associated with outcome on univariate analyses (including age, WFNS grade, modified Fisher grade) days of fever remained independently associated with poor outcome (OR 1.14 of poor outcome per day of fever, 95% CI 1.06-1.22; p=0.0006) displacing all other fever measures from the final model. Conclusions: The great majority of patients with aSAH are febrile during their ICU stay. Early onset of fever, number of hours with fever, and especially days of fever are associated with poor functional outcome. Conversely, the number of hours with elevated but subfebrile temperature does not influence clinical outcome. These data suggest that prolonged fever should be avoided, but subfebrile temperatures do not justify intervention.

Background We sought to determine the occurrence of major bleeding events in a population-based cohort of stroke patients with atrial fibrillation in a population-based cohort who were risk-stratified at baseline, one and five years, following initiation of warfarin treatment. Methods The resources of the Rochester Epidemiology Project Medical Linkage System were used to identify acute ischemic stroke patients with atrial fibrillation undergoing warfarin treatment for secondary stroke prevention from 1980 to 1995. These patients were risk-stratified according to the HAS-BLED and HEMORRHAGES scores prior to warfarin initiation following stroke onset; these scores were reassessed one and five years later. Major bleeding was considered in patients with fatal or clinically overt bleeding associated with either transfusion of >2 units of blood or >2 g/dl decrease in hemoglobin. Results One hundred patients (mean age, 79.3 years; 68% women) were studied. Median duration of warfarin treatment was 2.4 years (interquartile range, 0.4-6.6) and duration from stroke onset to death was 3.7 years (1.1-8.8). Major bleeding events occurred in 41 patients at a median duration of 19 months (5-58) following warfarin initiation. Sixteen events occurred within a year of treatment, 25 events from years 1-5, and 14 events in patients treated for >5 years. Patients with baseline HAS-BLED scores ≥2 had higher life-time risks of major bleeding events compared with those ≤1 (95% vs 5%, p=0.002), while those with HEMORRHAGES score ≥2 had higher life-time risks of major bleeding events compared with those ≤1 (90% vs 10%, p=0.030). Periodic reassessments of these risks were associated with a higher detection of major bleeding events. Patients with an increase in the HAS-BLED scores had a higher subsequent risk of major bleeding events compared with those with no change (year one, 64% vs 34%, p=0.043; year five, 75% vs 29%, p=0.018). Similarly, patients with an increase in the HEMORRHAGES scores had a higher risks of major bleeding events compared to those with no change (year one, 57% vs 33%, p=0.063; year five, 71% vs 10%, p<0.001). Conclusions Periodic assessments of bleeding risks using prognostic scales are associated with a higher detection of major bleeding events. These scales should be periodically reassessed in the years following warfarin initiation to determine if the benefit of ongoing use outweighs the bleeding risk.

Background and Purpose- It is important to know the costs for hospitalization for endovascular embolectomy patients so that comparisons can be made to payments to hospitals. Methods- Using the National Inpatient Sample, we evaluated the costs for hospitalization for patients treated with endovascular embolectomy in the United States from 2006-2008. The primary endpoint examined in this study was total hospital costs, and these were correlated with clinical outcome. Hospitalization costs were then compared with Medicare payments for their respective outcomes. MS-DRG 24 was the diagnostic related group code (DRG) for mechanical embolectomy with good outcome and MS-DRG 23 was the DRG code for mechanical embolectomy with major complications. Medicare payments were available at http://www.cms.hhs.gov . Results- A total of 3864 patients received endovascular embolectomy. 1649 patients were <65 years old and 2205 patients were ≥65 years old. Median hospital costs in 2008 dollars were $36,999 (IQR $26,662-$56,405) for patients with good outcome, $50,628 (IQR $33,135-$76,063) for patients with severe disability, and $35,109 (IQR $25,053-$62,621) for patients with mortality. Reimbursement in the year 2008 for DRG 24 (good outcome) was $22075 and reimbursement for DRG 23 (major complications) was $26639. Conclusions- Our study of the NIS shows that hospitalization costs in the United States for ischemic stroke patients treated with endovascular embolectomy are rather high, probably due to the serious nature of their illness. Medicare payments have not been adequate in reimbursing these hospitalizations. Further work is needed to ensure the future reconciliation of costs with payments.

Background: Symptomatic intracranial hemorrhage (SICH) is the most feared complication of intravenous recombinant tissue plasminogen activator (rtPA). Differences exist in the criteria used to define neurologic decline, cerebral hemorrhage and interval between rtPA treatment and onset of cerebral hemorrhage. Methods: We performed a systematic review to investigate SICH rates following rtPA treatment and assess their consistency with respect to mortality rates reported in the literature. Studies were identified from the PubMed and EMBASE databases from January 1994 to June 2011 by cross-referencing the following MeSH terms: “thrombolysis”, “recombinant tissue plasminogen activator”, “rtPA”, “TPA”, “Alteplase”, “thrombolytics”, “cerebral ischemia” and “stroke”. We restricted our selection to stroke registries and larger cohort studies that comprised consecutively recruited stroke patients with an operational cutoff of >200 subjects. Studies that (1) involve endovascular-treated patients, (2) applied pre-selection criteria (e.g. the presence of demonstrable arterial occlusion and pretreatment MRI), and (3) did not report both SICH and mortality rates, were excluded. We calculated the age, baseline NIHSS scores, time from stroke onset to rtPA treatment, SICH and mortality rates using published data from these studies. Results: The initial search identified 3538 studies which were reduced to 211 potentially eligible studies that were relevant to our investigation. After application of exclusion criteria, 7 clinical trials, 7 stroke registries and 10 cohort studies (4 multi-center and 6 single-center) were included in this analysis. The mean (SD) age of these patients is 68.8 years (2.9), of whom 56.3% (4.5%) were men. These patients presented with mean baseline NIHSS 12.5 (1.4) and received intravenous rtPA 175 (62) minutes from stroke onset. The mean SICH and mortality rates were 5.6% (2.3%) and 14.7% (4.8%) respectively. Higher SICH rates were reported in randomized controlled trials (mean, 7.45%) compared with those in stroke registries (mean, 3.50%). Studies that defined SICH as parenchymal hemorrhage with neurologic decline NIHSS≥4 occurring within 36 hours of rtPA treatment have a higher consistency between SICH and mortality rates (correlation coefficient, 0.631). Conclusion: We highlight several inconsistencies in the criteria used to define the neurologic decline, neuroimaging classification and interval between rtPA treatment and cerebral hemorrhage. These discrepancies may, in part, explain the rather striking disparities between SICH and mortality rates reported in randomized controlled trials, stroke registries and cohort studies.

Background and Objective The Alberta Stroke Program Early CT Score (ASPECTS) is a validated grading system to assess ischemic changes on CT in acute ischemic stroke. Magnetic resonance imaging with diffusion weighted imaging (DWI) sequence is commonly used to identify the final ischemic changes. We examined the difference between the relationship of NIHSS at admission and ASPECT score calculated using CT scan versus MRI DWI sequence. Methods We conducted a retrospective analysis of prospectively collected data from 99 cases of acute ischemic stroke treated with IV rt-PA by time criteria, admitted to Mayo Clinic from March, 2002 through June, 2011. CT head at 24 hours and MRI DWI sequence were used to assign ASPECT score. We dichotomized ASPECTS (categorized as 0 to 7 versus 8 to 10) and favorable patient outcome at 3 month (modified Rankin score less than equal to 2 and more than 2). Univariate analysis including t-test, Chi-square, and Fisher Exact test was used when appropriate. Results Mean age was 70±14 years. Mean admission NIHSS score was 8±4. DWI ASPECTS (p<0.001) and CT ASPECTS (p=0.127) were inversely associated with admission NIHSS. Higher (8-10) CT ASPECTS (p=0.001) or DWI ASPECTS (p=0.002) were associated with good outcome (mRS ≤2) at 3 months. Sensitivity, specificity, positive predictive value and negative predictive value for good outcome identified by CT ASPECTS versus DWI ASPECTS were 81% vs 52%, 54% vs 54%, 83% vs 59% and 50% vs 47% respectively. Conclusion CT and MRI DWI are comparably useful to calculate the ASPECTS for estimation of functional outcome, but CT scan at 24 hours may be more sensitive for the prediction of good recovery.

Background: The Stroke Genetics Network (SiGN) funded by the NINDS aims to identify genetic risk factors in ischemic stroke using whole-genome association studies (GWAS). High quality phenotyping is crucial to successful application of GWAS. As a heterogenous disorder, stroke poses specific challenges. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification is a broadly used, but its validity is challenged especially when performed by multiple investigators with differing interpretations of the system. The Causative Classification System for Ischemic Stroke (CCS) system is a new, web-based, and computerized algorithm that integrates clinical, diagnostic, and etiologic stroke characteristics in an evidence-based manner ( ccs.mgh.harvard.edu ) to generate subtypes. Methods: In planning the SiGN proposal, a sample of 20 coded charts were collected from a subset of participating studies to assess feasibility of central adjudication and comparability to study-specific TOAST. Two central adjudicators reviewed all records and generated TOAST and CCS subtypes. These were compared to study-specific TOAST subtype and the CCS phenotype generated for SiGN by local trained adjudicators. CCS data is now available for 7134 included cases using both a 5 and a 7 category system as defined in the table . Results: All 4 phenotypes were available for 115 ischemic stroke cases from 6 studies in SiGN. Basic demographics were 54% women, 63% white, and median age between 65-74. Table 1 provides the agreement between the various subtypes. Table 2 describes the types of disagreement. Conclusions: Central adjudication with only two adjudicators and curated medical records yielded more consistent subtyping independent of phenotyping system. The agreement for TOAST was higher than published rates by independent groups (∼0.50). In contrast, the agreement for CCS was lower than previously published (0.85-0.95). Site adjudicators' familiarity with TOAST and inexperience with CCS may contribute. Although CCS is an automated algorithm and has a number of user friendly features, our findings suggest that formal training and certification process before starting to use CCS may be worthwhile to achieve optimal benefit from the system.

INTRODUCTION After aneurysm treatment, patients with subarachnoid hemorrhage (SAH) are typically kept in the intensive care unit (ICU) to be monitored for signs of delayed cerebral ischemia (DCI). Identifying patients at very low risk of developing this complication who could be safely transferred out of the ICU early could have a very positive financial impact. METHOD We analyzed 307 consecutive patients admitted to the intensive care unit from October 2001 to June 2011. Demographic, clinical and neuroimaging data were recorded. The relationship between these variables and absent DCI was analyzed using univariate and multivariate logistic regression models. RESULTS DCI did not develop in 169 patients (57.9%). Among factors at admission, age ≥ 68 years (p=0.0003; OR 3.16, 95% CI 1.67-6.39), WFNS I-III at presentation (p= 0.0003;OR 2.73, 95% CI 1.57-4.79), WFNS I-III at worst (p= 0.0003; OR 2.39, 95% CI 1.48-3.87), WFNS I-III post resuscitation (p= 0.0006; OR 2.85 95% 1.56-5.32), modified Fisher grade 1-2 (p= 0.0021; OR 2.43, 95% CI 1.37-4.47), absence of intracranial hematoma (p= 0.0042; OR 2.26, 95% CI 1.29-4.01), absence of intraventricular hematoma (p=0.045; OR 1.61, 95% CI 1.01-2.58), absence of cerebrospinal fluid diversion (p= 0.0002; OR 2.54, 95% CI 1.56-4.20) and aneurysm in the posterior circulation (p=0.0253; OR 1.74, 95% CI 1.07-2.87) were associated with absence of DCI. On multivariate analysis, a model including age ≥ 68 years (p= 0.0003; OR 3.23, 95% CI 1.68-6.62), WFNS at presentation I-III (p= 0.0092; OR 2.18, 95% CI 1.21-3.99) and modified Fisher grade 1-2 (p=0.02; OR 2.04, 95% CI 1.11-3.89) was independently uniformly predictive of the absence of DCI (specificity and positive predictive value of 100%; p<0.0001). CONCLUSION We propose a new model that can reliably identify a group of patients with aneurysmal SAH who have very low risk of developing DCI. These patients could be candidates for early transfer to the general ward after treatment of the ruptured aneurysm.

Background: The influence of high body mass index (BMI) in acute stroke patients treated with intravenous thrombolysis has not been extensively studied. Previous studies have observed an “obesity paradox” among stroke patients, where better outcomes were observed among overweight and obese patients. The purpose of this study is to determine the influence of obesity and risk components of metabolic syndrome to stroke recovery in patients undergoing intravenous recombinant tissue plasminogen activator (rtPA) treatment. Methods: Patients with acute ischemic stroke who received intravenous rtPA within three-hour from symptom onset at St. Marys Hospital, Mayo Clinic, Rochester, between April 2006 and January 2011, were included in this study. Information on vascular risk factors, stroke severity, and baseline hemodynamic and laboratory indices, were collected. Study outcomes, consisting symptomatic intracerebral hemorrhage (sICH) and poor functional recovery (modified Rankin scale >2), were compared between obese (body mass index, BMI >30 kg/m 2 ), overweight (BMI 25-30 kg/m 2 ) and normal weight (BMI <25 kg/m 2 ) patients. The association between BMI, risk components of the metabolic syndrome and dose of rtPA per kg body weight to stroke outcomes were assessed in a multivariable model. Results: A total of 158 patients (mean age, 75 years; baseline NIHSS, 11), frequency-matched by age and baseline stroke severity, were included in this study. No differences in the frequency of SICH and poor functional recovery were observed among obese, overweight and normal weight patients, before and after adjusting for their baseline characteristics. A linear trend towards worse stroke recovery was observed in patients with a greater number of metabolic risk components (p-trend=0.043). By contrast, there were no significant associations between the number of risk components of metabolic syndrome with respect to sICH. Using stepwise regression analyses, age, baseline stroke severity and the number of risk components of the metabolic syndrome accounted for 52% variation in functional recovery following rtPA treatment. Conclusions: Acute stroke outcomes do not differ between obese and overweight patients. The presence of metabolic risk factors contributes significantly to functional outcomes following rtPA treatment. These results suggest that decreasing the prevalence of metabolic syndrome in the community could reduce the societal burden of stroke-related disability.

Background and Purpose: Leukoaraiosis is a poor prognostic marker for patients with acute ischemic stroke (AIS). This study sought to assess if severity of leukoaraiosis is associated with outcome in patients with AIS following endovascular thrombectomy, and to propose a leukoaraiosis-related modification to the ASPECTS score to improve its predictive value for good outcome. Methods: We analyzed consecutive patients with AIS that underwent mechanical thrombectomy for anterior circulation large vessel occlusion at our comprehensive stroke center. Leukoaraiosis burden was graded using the Fazekas scale (combined scores from two locations categorically divided into no leukoaraiosis (score = 0), mild (1-2), moderate (3-4) and severe (5-6)). The primary outcome measure was 90-day mRS. A proposed Leukoaraiosis-ASPECTS (“L-ASPECTS”) was calculated by subtracting values from the traditional ASPECT based on leukoaraiosis severity (1 point subtracted if mild, 2 if moderate, 3 if severe). Results: Of 174 included patients, 89 (51.2%) were female; average age was 68.0±9.1. 28 (16.1%) had no leukoaraiosis, 66 (37.9%) had mild, 62 (35.6%) had moderate, and 18 (10.3%) had severe. Leukoaraiosis severity was associated with worse 90-day mRS among all patients (p=0.0005) as well as those that were successfully revascularized (p=0.0002). A multivariate analysis confirmed that leukoaraiosis burden was associated with worse 90-day mRS among all patients (mild: p=0.006; moderate: p=0.002; severe: p=0.03), as well as those that underwent successful thrombectomies (p=0.005). Both L-ASPECTS and ASPECTS were associated with poor outcomes, but the association was stronger with L-ASPECTS (p<0.0001 and AUC=0.7 for L-ASPECTS; p=0.04 and AUC=0.59 for ASPECTS). Conclusion: Leukoaraiosis severity on pre-mechanical thrombectomy NCCT is associated with worse 90-day outcome in patients with AIS following endovascular recanalization, and is an independent risk factor for worse outcomes. A proposed L-ASPECTS score had stronger association with outcome than the traditional ASPECTS score.