Rabinstein, Alejandro A.

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.

Introduction: Cortical superficial siderosis (cSS) refers to deposition of blood breakdown products along the cerebral cortex, causing characteristic staining patterns seen with iron-sensitive MRI techniques. Cortical superficial siderosis is a relatively rare disorder, but has been linked to cerebral amyloid angiopathy and Alzheimer’s disease. The objective of this study was to determine the frequency and natural history of cSS in the general elderly population. Methods: MRI scans from the Mayo Clinic Study of Aging (MCSA), an ongoing population-based study of elderly residents in Olmsted County, Minnesota, were reviewed by neuroradiologists. Participants with cSS were identified based on linear pattern of hypointensity on gradient recalled echo imaging consistent with cSS. Exclusion criteria were: 1) MRI findings not consistent with cSS or 2) alternative explanation for MRI findings (such as aneurysmal subarachnoid hemorrhage, intracranial surgery, or trauma). Additional data abstracted included extent of cSS, presence of cerebral microbleeds, and clinical outcome. Results: Eleven out of 1,441 participants had MRI scans showing cSS (0.8%). When stratified by age, the frequency was 0.4% in those 50 to 70 years old and 1.1% in those over 70 years old. Six participants had only focal involvement of cSS (restricted to three or fewer sulci) and five had disseminated involvement (affecting more than three sulci). Microbleeds were seen in four of five (80%) participants with disseminated cSS, but none with focal cSS. Five participants (2 focal, 3 disseminated cSS) had follow up MRI scans, with an average follow up of 25 months. There was no further hemorrhage in those with focal cSS. However, all three participants with disseminated cSS experienced additional hemorrhage: one with new microbleeds, one with new microbleeds and lobar hemorrhage, and one with sulcal subarachnoid hemorrhage and lobar hemorrhage. Conclusion: Although rare, cSS may be encountered in the general elderly population. Extent of involvement of cSS and concomitant microbleeds may be important risk factors for progression of disease and intracerebral hemorrhage. The clinical significance of focal cSS occurring in the absence of microbleeds requires further investigation.

Introduction: Acute stroke pre-arrival notification by emergency medical services (EMS) allows hospital personnel to mobilize resources in advance, thereby improving treatment times and outcomes. However, criteria for pre-arrival notification vary by institution. In developing our own pre-arrival notification system, we aimed to determine whether objective measures, EMS clinical impression, or a combination of both best predicted accurate stroke team activation. Methods: Retrospective review of consecutive patients presenting to our institution via EMS with suspicion of acute stroke from 2014-2015. Data recorded included age, gender, time of symptom onset, glucose, Cincinnati Prehospital Stroke Scale (CPSS), Glasgow Coma Scale (GCS), and EMS impression. Univariate logistic regression was performed with acute stroke team activation in the emergency department (ED) as the endpoint. Results: 130 patients met inclusion criteria. Of these, 88 prompted the ED provider to activate the acute stroke team. Of variables analyzed, CPSS was clinically and statistically significant (OR. 1.7, 95% CI 1.2-2.5, p=0.0035) on univariate analysis, with arm weakness being the most predictive component (OR 2.9, 95% CI 1.04-8.1, p=0.04). EMS impression was not statistically significant (p>0.05). We then performed sensitivity and specificity analyses of CPSS, EMS impression, and CPSS combined with EMS impression (Table). A CPSS score of 3 had the highest specificity, and CPSS score of 1 combined with EMS impression the highest sensitivity. Conclusion: CPSS was the key significant predictor of ED acute stroke team activation, and more specific than EMS clinical impression. By combining CPSS and EMS impression, sensitivity improved, but at the expense of specificity. This suggests that reproducible measurements and scores, such as CPSS, should be the main driver for stroke pre-notification systems and should be integrated systematically into EMS education programs.

Background: Spontaneous spinal subarachnoid hemorrhage (SSAH) is a rare but serious condition that can lead to a variety of medical complications. Methods: Using the Mayo Clinic Rochester database, patients admitted to the Mayo Clinic Rochester, MN hospital with spontaneous SSAH (not iatrogenic or traumatic) between January 2000 and December 2015 were retrospectively reviewed. Demographic and clinical data and functional outcomes as described by the modified Rankin Scale (mRS) score at the time of discharge and at post-admission follow-up were assessed. Results: Eight consecutive patients (median age 70 years, range 51-87) were identified. Seven patients presented with acute onset back pain or headache. Seven patients had poorly controlled chronic hypertension. Two patients had vasculitis, and one had an arteriovenous malformation (AVM). An increase in blood pressure was observed in all patients during their acute presentation as compared to their baseline outpatient readings. Complications included cord compression (n = 4), hyponatremia (n = 5), sulcal subarachnoid hemorrhage (n = 2), chronic arachnoiditis (n=1), vasospasm (n=1), and late cord ischemia (n = 1). All eight patients were managed medically including blood pressure control and repeat imaging. One patient had an aneurysm which was embolized, and two received steroids for vasculitis. One patient died during hospitalization, one died within a week of discharge, five had improved mRS score at post-hospitalization follow-up and had unchanged mRS of 1 at discharge and follow-up. Conclusions: To our knowledge this is the first compilation of cases of spontaneous SSAH. Risk factors for spontaneous SSAH are hypertension, AVM, vasculitis, coarctation of the aorta, and malignancy. Symptomatic cord compression is not uncommon, but can be managed conservatively.