Brown, Robert D.

Background: Considerable disagreement exists among experts regarding the appropriate extent of diagnostic testing after ischemic stroke (IS). Evidence-based data guiding stroke evaluation for individual patients according to the underlying phenotype are unknown. We sought to determine the yield of cardiac and arterial evaluations for identifying an alternative major stroke etiology in patients with a given phenotype in the NINDS Stroke Genetics Network (SiGN). Methods: SiGN is a consortium of IS studies at 22 US and European sites aiming to identify stroke susceptibility genes. Adjudicators certified in Causative Classification of Stroke (CCS) system determined major etiologic stroke phenotypes based on chart review. All diagnostic data entered into the CCS software were stored in a confidential database. We determined the probability of identifying an alternative major abnormality based on cardiac (history, EKG, echocardiography) and arterial [intracranial (IC), extracranial (EC)] evaluations in 3 stroke phenotypes: lacunar infarct (LI), large artery atherosclerosis (LAA), and cardiac embolism (CE). Proportions of alternative major etiologies were calculated in patients with complete evaluations in each phenotype. Results: The analyses included 15720 patients. Among these, 2299 had phenotypic subtype of LI (1660 with cardiac and 1691 with arterial evaluations); 4228 had CE (2451 with arterial evaluation); and 2613 had LAA (2047 with cardiac evaluation). Cardiac evaluation revealed a major cardiac source of embolism in 12.3% of patients with LI and 20.3% with LAA. Echocardiography demonstrated an additional major structural cardiac source not seen by history/examination/EKG in 1.9% and 1.6% in LI and LAA respectively. Arterial evaluation led to the identification of ≥50%ipsilateral stenosis in 13.5% (IC: 8.9%, EC: 5.8%) of patients with LI and 17% (IC: 8.1%, EC: 11.3%) of those with CE. In LI patients with complete cardiac and vascular evaluations, 24.1% had an alternative major stroke etiology. Conclusions: A considerable proportion of IS patients with LI, LAA, and CE harbor an alternative major etiology. In the future, these results can be used to generate evidence-based and cost-effective evaluation and management strategies.

Background & Purpose: Seizures are a recognized complication of stroke. However, available data are conflicting in terms of incidence, risk factors for occurrence, and impact on functional outcome and mortality. The aim of this study was to assess the incidence and characteristics of seizures following ischemic stroke in a well-defined population, and their effect on long-term patient outcome. Methodology: Utilizing the Rochester Epidemiology Project medical record linkage system, we identified all incident cases of ischemic stroke (IS) that occurred between January 1, 1990, and December 31, 1994. We identified all patients who developed seizures following first IS. Detailed data regarding stroke (including TOAST subtype, anatomic location, functional outcome), seizures (date, type, functional outcome, recurrence, presence of status epilepticus, complications, treatment, EEG findings), and patient status at the last follow-up were recorded and analyzed. Results: We identified 490 patients with first IS. Mean follow-up was 6.5 years (range 0.0 - 23.8). Of these, 35 (7.1%) developed seizures. Early seizures (occurring within 14 days of stroke) were present in 13 (37.1%), of which 9 (69.2%) had their seizure within the first 24 hours. Partial seizures were the most common type (23 patients, 65.7%). Status epilepticus occurred in two cases (5.7%). Tongue biting was the most common complication of poststroke seizures (4 patients, 11.4%). Treatment with antiepileptic drugs (AEDs) was initiated in 32 cases (91.4%). Only one drug was necessary for seizure control in all treated patients. The mean modified Rankin Scale score was 2.9 (SD 1.48) after the first IS, and worsened to 3.3 (SD 1.43) after the first seizure. Mortality at the last follow-up was higher in the seizure group compared to the non-seizure group, even after adjusting for TOAST subtype (HR 1.52; 95% CI 1.07 - 2.16; P = 0.02). Conclusion: Seizures are mostly a late complication of IS. They do not bear a high risk of life-threatening complications and are readily controllable by a single AED. However, patients who developed poststroke seizures tended to have a worse functional outcome and an increased mortality.

Background: Recruitment and phenotyping constitute major costs in stroke genetics research. Clinical trial datasets that include biological samples provide an opportunity to leverage richly phenotyped cases for genomic research. However, the heterogeneity of stroke and methodological differences across studies present challenges. We developed and validated a systematic method of mapping data abstracted from a multicenter randomized clinical trial to the inputs of the CCS stroke subtyping system for the SiGN study. Methods: The SiGN Phenotype Committee and the Secondary Prevention of Small Subcortical Strokes (SPS3) research team systematically reviewed SPS3 case report forms (CRF) to identify key elements required to generate CCS subtyping, and drafted and refined mapping rules using a derivation set of 30 charts. The resultant algorithm was compared to manual entry of clinical information into the CCS in a test set of 30 randomly selected charts. This identified problems due to multiple versions of CRFs (up to 7 versions) and prompted revision of the mapping rules. We assessed the revised algorithm in an independent test set. Results: None of the subtype classifications agreed in the initial testing prompting revision to allow capture information from different versions of the CRFs. The revised mapping algorithm applied to the same test set performed well; 29/30 agreed - 20 small artery occlusion (SAO) evident, 4 SAO possible, 2 SAO probable and 3 supra-aortic large artery atherosclerosis evident). The one chart that disagreed was classified as SAO evident by manual entry but as undetermined by the data mapping rules. In the 2nd independent test set, 30/30 agreed: 22 SAO evident, 4 SAO possible, 3 supra-aortic large artery atherosclerosis evident and 1 undetermined unknown - incomplete evaluation. Conclusions: We created mapping rules using CRFs from a clinical trial to allow reliable subtype classification using the CCS. Issues related to multiple iterations of CRFs presented challenges. Highly phenotyped stroke cases from clinical trials represent a cost-effective opportunity for genomic research.

Background and Purpose: NINDS Stroke Genetics Network (SiGN) is an international consortium of ischemic stroke studies that aims to generate high quality phenotype data to identify the genetic basis of ischemic stroke subtypes. The goal of this analysis is to characterize the etiopathogenetic basis of ischemic stroke in the consortium. Methods: This analysis included 16,954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries. 52 trained and certified adjudicators used the web-based Causative Classification of Stroke System for etiologic stroke classification through chart reviews to determine both phenotypic (abnormal test findings categorized in major etiologic groups without weighting towards the most likely cause in the presence of multiple etiologies) and causative subtypes in each subject. Classification reliability was assessed with blinded re-adjudication of 1509 randomly selected cases. Findings: The figure shows the distribution of etiologic categories. Overall, only 40% to 54% of cases with a given major ischemic stroke etiology (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0·72, 95%CI:0·69-0·75) and phenotypic classifications (kappa 0·73, 95%CI:0·70-0·75). Conclusions: This study provides high quality data on etiologic stroke subtypes and demonstrates that etiologic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes suggests that the presence of an abnormality in a stroke patient does not necessarily mean that it is the cause of stroke.

Introduction: Giant intracranial aneurysms are uncommon, have a high risk for rupture and are difficult to treat. The International Study of Unruptured Intracranial Aneurysms (ISUIA) prospective cohort included 187 patients with maximal diameter of 25 mm or greater. This analysis was to determine the long-term prognosis of these aneurysms both treated and untreated. Methods: Patients were enrolled into ISUIA at 61 centers from 1991-1998. A prospective cohort included the managed with observation, surgery or endovascular treatment. Patients were followed for a median of 9.2 years. Aneurysms were measured using a central reading of bi-planar cerebral angiography. Outcomes were determined prospectively and with central review. Results: 187 patients with a maximum diameter of 25 mm were followed. The mean size was 30.3 mm, ranging from 25 to 63 mm. 39% of the aneurysms were surgically treated at baseline, 27% were endovascularly treated, and 32% were managed conservatively;3% had subsequent endovascular treatment and 5% surgical treatment. Patients with giant aneurysms were predominantly women (83%), had a baseline Rankin Score of in 93%, were located predominantly in the anterior circulation (internal carotid 44%, cavernous ICA 28%, middle cerebral 12%). 80% of the patients were symptomatic with cranial nerve deficit in 47% (III and VI nerves), mass effect in 16%, headaches in 44%, orbital pain in 21%, and vision loss in 25%. Smoking history was present in 67%, hypertension in 44%, vascular headaches in 29% and family history in 10%. 70 patients (39%) died during follow-up however 59% were still Rankin 1 or 2. Both surgical and endovascular treated patients had 60-64% good outcome and 34-36% mortality. Untreated patients had a 57% mortality. Subarachnoid hemorrhage occurred in 11 untreated patients and 12 treated patients with most occurring in the first year. Conclusions: Giant intracranial aneurysms are typically symptomatic, and have a high risk of rupture early after diagnosis. Outcome was similar with surgical and endovascular treatment but post-procedure hemorrhage did occur.

Objectives: Identification of gene variants of stroke subtypes is important for the development of tailored ischemic stroke therapies among various ethnic groups. Valid and reliable determination of ischemic stroke subtype is essential for achieving this goal and to standardize a classification scheme across multi-center studies and different populations. Causative Classification System for Ischemic Stroke (CCS) is a novel computerized subclassification tool developed to improve reliability and accuracy of classifying stroke types. The CCS algorithm relies on both phenotypic and causative stroke variables. A Hispanic subset of the SiGN, an important and distinct target population with greater risk of certain stroke subtypes, was evaluated with Trial of Org 10172 in Acute Stroke Treatment (TOAST) and CCS and the agreement between the two classification systems was analyzed. Methods: Over 6000 subjects at 15 sites across US and Europe were enrolled, with TOAST and CCS locally adjudicated. Blood collection and central data quality control (10% central readjudication) were performed on all participants. A subset of Hispanics was analyzed for the purpose of this study and the agreement between the TOAST and CCS were assessed by kappa statistic. Findings: Hispanics (n=595, 10.9%) compared to non-Hispanics (n=5457) were more likely to be younger (63.7 vs. 64.0), male (55% vs. 46%) and have fewer of the traditional stroke risk factors HTN (54% vs. 64%), Afib (11% vs. 14%), DM(23% vs. 25%), CAD(16% vs. 20%) and smoking(19% vs. 22%). While the TOAST showed no differences between stroke subtypes for Hispanic vs. non-Hispanics, in CCS, Hispanics were classified with more of large vessel (22% vs. 20%), cardioembolic (37% vs. 30%) and small vessel strokes (13% vs. 9%) and fewer with undetermined etiology (28% vs. 40%) as compared to non-Hispanics. TOAST and CCS offered moderate correlation across all stroke types in Hispanics: kappa of 0.66 for large artery atherosclerosis, 0.58 for cardioembolic, and 0.58 for small artery occlusion. Conclusion: CCS offers a more sensitive and accurate system for subphenotyping of strokes in Hispanics who tended to have relatively fewer risk factors and unclassified strokes. Further studies correlating the two classification systems and their relation to genotyping data are warranted.

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: 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.

Background: Identification of clinical and imaging characteristics of ischemic stroke that can predict the underlying etiology is critical for accurate stroke subtyping. We sought to investigate the relationship between stroke characteristics and stroke etiology in 7,591 patients in the NINDS Stroke Genetics Network Study. Methods: We determined the probability of having a major etiology in the presence of certain stroke characteristics that were previously linked to specific stroke mechanisms. We excluded patients with multiple competing major etiologies. All patients had brain imaging, intra- and extra-cranial vascular imaging, and complete cardiac assessment. We defined major etiologies according to the Causative Classification of Stroke System Criteria without reference to the stroke characteristics under study. Results: History of 1 ipsilateral ischemic events within the last month, the presence of internal watershed infarcts or multiple, ipsilateral, unilateral, and temporally separate infarcts were associated with large artery atherosclerosis (Table). Multiple acute infarcts in different cerebral circulations were more common in patients with major cardiac source of embolism as well as in those with uncommon/cryptogenic causes. Stereotypic lacunar TIAs within the last week and lacunar syndrome were associated with lacunar infarction Discussion: Clinical and imaging stroke characteristics appear to predict stroke etiologies. This information may find utility in developing algorithms for a guided stroke evaluation as well as help identify the most likely causative etiology in the presence of multiple competing etiologies.

Introduction: Patients with intracerebral cavernous malformations (ICMs) may present with or later develop seizures. There are limited data regarding the clinical demographics of these patients, predictors of medically treatable versus medically refractory seizures, and long term seizure outcome. Objective: We aimed to characterize the clinical and radiographic features of supratentorial ICMs that present with seizures and describe their response to medical treatment. Methods: Patients with supratentorial ICMs were identified from a radiographic database for cases seen between 1989 and 1999. Clinical and radiographic information was abstracted and prospective follow up was obtained. Medically refractory seizures were defined as patients who were not seizure-free at last follow up, or who underwent surgery for refractory seizures. Results: A total of 206 patients were identified with a radiographic diagnosis of supratentorial ICM, 103 (50%) of whom presented with seizures and 7 (3%) who later developed seizures. Compared to those with seizures, patients without seizures were more likely to have a subcortical supratentorial ICM and to be on an antithrombotic agent. Intracerebral hemorrhage (ICH) at diagnosis did not predict presentation with seizure at diagnosis. Among the 59 patients treated with antiepileptics only, 16 (27%) were seizure-free at last follow up, 7 of whom no longer required medication and 8 of whom were controlled on a single agent. In the remainder of patients who were not seizure-free, seizure frequency was reduced in 37%, unchanged in 12%, increased in 5%, and unknown in 19%. Of the total 110 patients with seizures, 46 (42%) underwent at least one surgical removal of an ICM for medically refractory seizures. Conclusions: To date this study is one of the largest cohorts of ICM patients with seizures. Seizure is a common presentation in patients with cortical supratentorial ICMs. The presence of ICH at ICM diagnosis is not related to an increased occurrence of seizures at presentation. One-fourth of patients treated with antiepileptics alone eventually become seizure-free, almost half of which do not require medication at follow-up, suggesting that some non-surgical patients may not require life-long antiepileptic therapy.