Rabinstein, Alejandro A.

Introduction: Pulmonary embolism (PE) is an uncommon medical complication after stroke. Predisposing factors include deep vein thrombosis (DVT) in patients with hemiplegia or an underlying hypercoagulable state. However, little information is known regarding PE in stroke patients. Objective: We evaluated clinical characteristics, predisposing factors, and outcomes in stroke patients who developed PE. Methods: We included patients with an acute ischemic stroke (AIS) admitted to the participating institutions in the Registry of the Canadian Stroke Network between 2003 to 2008. Pulmonary embolism was diagnosed by nuclear imaging within 30 days of the stroke case index. Demographic data and clinical variables were collected. Logistic regression and survival analyses were completed to determine the association of risk factors with the outcomes of interest. Outcome Measures: primary outcome was death or disability at discharge defined as the modified Rankin scale >3. Secondary outcomes include admission to the Intensive Care Unit, disposition, and length of hospital stay, death at 3 months and at 1 year. Results: Among 11,287 patients with AIS, PE was found in 89 (0.78%) of patients. The development of PE was associated with higher risk of death in 30 days (25.8%vs 13.6%;p <0.001) and 1 year, (47.2% vs 24.6%;p <0.001). Disability was also more common in stroke patients with PE (85.4% vs 63.6% without PE; p <0.001). Mean length of stay was longer in stroke patients with PE (36 vs 16 days; p<0.001). Past medical history of cancer or deep vein thrombosis, history of cardiac arrest or deep vein thrombosis during admission were associated with PE. After adjustment, PE was associated with lower survival at 30 days (p value = 0.0012) and 1 year (p value < 0.0001) (Figures 1 & 2 represent survival function). Conclusions: In this large study, PE occurs in approximately 1% of AIS patients. PE was associated with higher disability, longer length of stay and lower short and long-term survival.

Objective: To determine the effect of Selective Serotonin Reuptake Inhibitor (SSRI)/Selective Norepinephrine Reuptake Inhibitor (SNRI) use prior to or during admission for aneurysmal subarachnoid hemorrhage (aSAH) on the risk of symptomatic vasospasm and diffuse cerebral ischemia (DCI). Methods: Review of electronic records at Mayo Clinic, Rochester from Jan. 2001 to Dec. 2013 of consecutive patients with aSAH. The variables collected and analyzed were: age, sex, active smoking, transfusion, modified Fisher score, WFNS grade, and outcome at discharge. Multivariate logistic regression analysis was used to evaluate factors associated with DCI, symptomatic vasospasm, and poor outcome (modified Rankin score 3-6) within 1 year. Results: 583 [females 367 (63%)] patients with a median age of 55 (47-65) years were admitted with aSAH during the study period. WFNS at nadir was IV-V in 243 (41.6%) and modified Fisher score was 3-4 in 438 (75.2%). Eighty one (14.6%) patients were taking SSRI or SNRI prior to admission and these medications were continued in all of them. Symptomatic vasospasm was present in 154 (27.7%), radiological infarction in 172(29.5%), and DCI in 250(42.9%) patients. SSRI/SNRI use was not associated with the occurrence of DCI (p=0.458), symptomatic vasospasm (p=0.097), radiological infarction (p=0.972), or poor functional outcome (p=0.376). Conclusions: The use of SSRI/SNRI prior to admission and/or during hospitalization in patients with aSAH was not associated with symptomatic vasospasm or DCI.

Background and Purpose: Ultrasound is the most commonly used imaging modality for assessment of carotid artery stenosis. A number of studies have demonstrated that surface irregularities, heterogeneous echotexture and hypoechoic plaques are risk factors for acute ischemic stroke. We performed a systematic review and meta-analysis of the literature to better define the risk of stroke based off of the sonographic characteristics of carotid plaques. Materials and Methods: We performed a comprehensive literature search evaluating the association of carotid plaque characteristics on ultrasound with ischemic outcomes. We included both case-control and cohort studies examining the relationship between complex plaque and acute ischemic stroke. Complex plaque was defined as plaque that had any of the following characteristics: heterogeneous plaque echogenicity, hypoechoic plaque, plaque neovascularization, plaque surface irregularity, plaque ulceration, and intraplaque motion. Meta-analyses using the random-effects model were performed for complex plaque and each of the individual complex plaque characteristics. Results: A total of 1013 articles were screened and 30 studies with 11528 patients (3054 symptomatic and 8474 asymptomatic) were included. The odds ratios for the association between complex plaque and ischemic symptoms was 5.18 (95%CI=4.63-5.79). Heterogeneous echotexture (OR=11.72, 95%CI=9.82-13.98), intraplaque motion (OR=1.57, 95%CI=1.02-2.41), plaque echolucency (OR=3.23, 95%CI=2.72-3.84), plaque neovascularity (OR=5.66, 95%CI=3.15-10.16) and plaque ulceration (OR=2.65, 95%CI=1.89-3.73) were all associated with ischemic symptoms. Surface irregularity without frank ulceration was not associated with ischemic symptoms (OR=1.35, 95%CI=0.98-1.86). Conclusions: Complex plaque, heterogeneous plaque echogenicity, hypoechoic plaque, plaque neovascularization, plaque ulceration and intraplaque motion are associated with ischemic symptoms. Assessment of carotid plaque on ultrasound provides stroke risk information beyond measurement of luminal stenosis.

INTRODUCTION: Studies suggest 8%-28% of ischemic strokes present as wake-up strokes (WUS). The unknown time of symptom onset precludes these patients from approved treatments for acute ischemic stroke, but a substantial proportion of patients may be deemed candidates for treatment if other factors are considered. The aim of this study was to identify characteristics associated with clinical outcomes of WUS patients. METHODS: We retrospectively reviewed the medical record of patients with ischemic stroke admitted to a large academic medical center between January 2011 and May 2012. We identified patients with stroke symptoms upon awakening or those who were found with stroke symptoms with an unknown time of onset. Baseline demographics, stroke mechanism, presenting NIHSS, Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and modified Rankin Scale (mRS) scores on discharge and at 3-month follow-up were obtained. A good outcome was defined as mRS 0-2. RESULTS: WUS patients comprised 22% (162/731) of all patients with ischemic stroke at our institution during this time period. Median age was 74 years (range 15-100), median presenting NIHSS was 5 (range 0-28), and median initial ASPECTS 10 (range 0-10). A cardioembolic mechanism was identified in 68 patients (42%). Predictors of good outcome at hospital discharge were lower initial NIHSS (3.5 versus 12.0, p<0.0001) and higher ASPECTS (9.8 versus 8.1, p=0.0002). The predictors of good outcomes at 3 months were younger age (69.1 versus 75.8, p=0.009), lower initial NIHSS (5.0 versus 12.6, p<0.0001), and higher ASPECTS (9.5 versus 8.1, p=0.0006). One hundred and eleven patients (68.5%) had initial ASPECTS of 10. Of those, 19 had NIHSS≥10 and 7 were treated with acute recanalization therapies. Four of the 7 treated patients had good outcomes, and 2 of the 12 untreated patients had good outcomes. CONCLUSIONS: Few patients with strokes of unknown onset and severe deficits have good outcomes without acute stroke treatment. Patients with NIHSS≥10 and ASPECTS 10 may be candidates for acute recanalization therapy.

Background: Given the uncertainty regarding clinical applicability of early treatment trials and lack of data on long-term disease progression, we evaluated the progression of stenosis and development of symptoms on patients with asymptomatic carotid artery stenosis (ACAS) treated with contemporary medical therapy over a prolonged follow up. Methods: Retrospective review of bilateral carotid arteries from consecutive patients diagnosed with moderate or severe ACAS, at our institution between 2000 and 2001. Patient vascular risk factors and treatments, cerebrovascular imaging, ipsilateral symptoms, and revascularization were recorded. Progression of stenosis was defined by change category of stenosis. Factors associated with symptomatic carotid disease were sought using univariate and multivariate logistic regression analysis. Results: We identified 214 patients (58.8% men; median age 70 years) and collected data on 349 vessels. Severe stenosis (>70%) upon diagnosis was present in 92(26.4%) vessels. All patients were on antithrombotics, 97% on antihypertensives, and 95% on statins. Median length of follow up was 13 years (range 5-14) and the mean number of time points with follow-up imaging was 8.1±3.9. Progression of stenosis was observed in 237(67.9%) vessels. 72(20.6%) patients developed symptomatic carotid stenosis (TIA in 14.4%, non-disabling stroke in 4%, and disabling stroke in 2.2%). Median time to appearance of first symptom was 6 years (range 1-13). Revascularization procedures were performed in 118(33.8%) vessels, including 73(61.9%) vessels which had become symptomatic. On multivariate analysis, baseline stenosis (OR 1.65, 95%CI 1.12-2.44), intracranial stenosis > 50% (OR 2.87, 95%CI 1.46-5.62), plaque ulceration (OR 3.41, 95%CI 1.34-8.69), silent infarction (OR 4.25, 95%CI 2.30-7.83), and previous history of TIA/stroke (OR 2.73, 95%CI 1.14-6.54) were associated with development of TIA/stroke ipsilateral to the carotid stenosis. Conclusions: There is a substantial rate of progression of stenosis in patients with asymptomatic carotid atherosclerosis over time despite adequate medical therapy. Over long-term follow up, one in five patients with ACAS developed ipsilateral TIA/stroke.

Background and Purpose: Although IV tissue plasminogen activator (tPA) is standard care for acute ischemic strokes (AIS), its administration continues to be a topic of controversy among patients with dementia. This study compared in-hospital outcomes for dementia versus non-dementia patients treated with IV tPA for acute ischemic strokes. Materials and Methods: Using the Nationwide Inpatient Sample (NIS) from 2001-2010, patients with the primary diagnosis of ischemic stroke were identified. We studied outcomes of IV-tPA treatment for acute ischemic stroke in patients with dementia versus a non-dementia control group. Using a 1:2 matched propensity score analysis we controlled for demographic factors, cardiovascular comorbidities and Charlson comorbidity index between groups. Outcomes studied included in-hospital mortality, hospital discharge status and intracranial hemorrhage (ICH). Results: A total of 24,904 patients with acute ischemic strokes who underwent IV tPA therapy for AIS were included in this study. 659 of which had a diagnosis of dementia. After 1:2 matching based off of age, gender, cardiovascular risk factors and Charlson comorbidity index there were a total of 657 patients in the dementia group and 1314 patients in the non-dementia group. Patient outcomes after propensity core analysis showed no difference with in-hospital mortality in the dementia group vs. control (13% vs 14%, p=0.67), discharge to long-term care facilities (63% vs 59%, p=0.08) and ICH (7.9% vs. 9.1%, p=0.86). Conclusions: There was no statistically significant difference in in-hospital mortality, discharge status or ICH rates in patients with AIS and dementia who received IV tPA compared to those without dementia. These results suggest that dementia is not a predictor of poor in-hospital outcome following IV tPA administration for AIS. Further longitudinal studies are needed to determine if IV tPA therapy would improve long-term outcomes for dementia patients with AIS.

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.