Brown, Robert D.

Background: Current guidelines recommend that initial management of patients with an intracerebral hemorrhage (ICH) occur in a neuroscience intensive care unit (ICU). However, some patients can be safely managed without ICU care. We evaluated factors that may predict the need for ICU level of care. Methods: We reviewed the medical records of all adult patients with supratentorial ICH presenting within 72 hours of symptom onset seen from 2009-2012. Patients admitted for palliative care or ICH due to a known structural lesion were excluded. Criteria defining need for ICU level of care were: need for intubation/mechanical ventilation, hyperosmolar therapy, neurosurgical procedure, prolonged ICU admission, or significant clinical deterioration. A univariate and multivariable logistic regression analysis was performed on patient demographics, medical comorbidities, time to presentation, vital signs, GCS/FOUR score, medications, laboratory studies, and imaging to identify independent predictors of the need for ICU admission. Results: 229 patients met inclusion criteria. Based on our triage criteria, 128 patients (56%) required ICU level of care. Multivariable analysis identified five factors that best predicted the need for ICU admission: younger age, shorter time to presentation, lower FOUR score, larger hemorrhage volume, and use of anticoagulants at presentation (table). Intraventricular hemorrhage and GCS score were not significant predictors on the multivariable analysis. Conclusion: Age, time to presentation, FOUR score, hemorrhage volume, and use of anticoagulants predict the need for ICU care after ICH. These variables will be used to develop a formula to aid clinicians in appropriate initial triage of patients with ICH.

Introduction: Intracranial aneurysm (IA) and abdominal aortic aneurysm (AAA) rupture carry high mortality (40% and 75% respectively) and substantial morbidity in survivors. Recent research suggests that IA and AAA share genetic risk in addition to environmental factors. Retrospective data from our institution identified a population harboring both IA and AAA and showed a high rupture rate for IA (44.2%). We previously demonstrated that screening for AAA in patients with IA is cost-effective based on estimated and published data. We hypothesize that screening for IA in patients with AAA is also cost-effective. Method: We developed a decision-making model using TreeAge Pro 2013 software assuming a hypothetical population with known AAA and truncated screening versus no screening for IA using magnetic resonance angiography. Based on IA size and location, patients were either treated endovascularly or placed on surveillance. Proportions, risks, utilities, and costs for each decision arm were derived from literature. Results: At a given rupture rate, incremental effectiveness varied linearly with coprevalence of AAA and IA. For an assumed rupture rate of 5%/year, screening was effective for coprevalence >6.8% (top graph) and was cost-effective for coprevalence >7.7%. The incremental cost-effectiveness ratio (ICER) favored screening (ICER=$54,193/QALY) at a 7.8% coprevalence and dropped to $27,841.50/QALY at 8.8% coprevalence. Our model was sensitive to IA rupture rate as well as coprevalence (bottom graph). Conclusion: Our model suggests the cost-effectiveness of screening for IA in patients with AAA, below the accepted societal threshold of an ICER $60,000/QALY at a coprevalence ≥7.8% and IA rupture rate ≥5%. These are plausible assumptions for this genetically high-risk population. Further prospective study is warranted to establish coprevalence of AAA and IA, rupture rates, and determine the benefit of dedicated screening.

Background: The heterogeneity of ischemic stroke has relevance for determination of risk for recurrence, prediction of outcomes, and identification of genetic risk factors. Among the many systems created for classifying patients into subtypes of stroke, the Trial of Org10172 Acute Stroke Trial (TOAST) and Causative Classification of Stroke (CCS) systems are among the most commonly used. Both systems generate similar subtype diagnoses although the two systems use different criteria for subtype assignment. The purpose of this study was to assess the level of agreement between subtype classification made using these two systems. Methods: Study subjects included 14,106 adult men and women accrued in the NINDS Stroke Genetics Network (SiGN) across 21 centers in the US and Europe classified independently using both with TOAST and CCS. Kappa statistics were calculated for the five major ischemic stroke subtypes common to both systems. Results: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; kappa = 0.60, 95% confidence interval [CI], 0.59 to 0.61). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large artery atherosclerosis (kappa, 0.71; 95% CI, 0.70 to 0.73) and lowest for small artery occlusion (kappa = 0.56, 95%CI, 0.54 to 0.58). Conclusion: Agreement between TOAST and CCS diagnoses was only moderate. Caution is warranted when comparing or combining results based upon the two systems. Re-phenotyping using one system should be encouraged when possible to ensure valid results. Table: Cross-classification of stroke subtypes by TOAST and CCS

Objectives: Genetic and environmental influences contribute to differences in ischemic stroke phenotype across race-ethnic groups. The Causative Classification System (CSS) is an ischemic stroke phenotype characterization tool developed for etiological and causative classification. The CCS phenotypes across ethnic groups were analyzed and compared. Methods: The NINDS S troke G enetics N etwork (SiGN) is a large consortium aimed at identifying subtype-specific ischemic stroke susceptibility genes. Over 12,000 subjects at 22 sites across US and Europe were enrolled, with CSS locally adjudicated. Central CCS quality control was performed on all participants. Analysis was performed on 7,674 patients with complete workups. Findings: Significant ethnic differences were found in stroke etiology across ethnic groups (p <0.0001) with large artery atherosclerosis present most commonly in Asians, cardioembolic sources among Caucasian Europeans, and lacunar strokes among African Americans. African Americans were the youngest ethnic cohort analyzed (see Table 1). Conclusion: Significant differences in stroke subtypes are present across ethnic groups. Future genetic analyses may contribute to our understanding of these differences.

Introduction: The long term effectiveness of preventive intracranial treatment of unruptured aneurysms for hemorrhage and aneurysm-related morbidity and mortality has been hypothesized. No randomized trial has been done. Propensity adjusted comparison within The International Study of Unruptured Intracranial Aneurysms was undertaken to compare long-term effectiveness. Hypothesis: The purpose of this analysis was to compare the long-term outcome in the treatment cohorts (surgery and endovascular) with those of the untreated subgroup. Methods: Patients were subdivided into the initial treatment and untreated cohorts based upon observation or treatment practices in 61 centers from 1991-1998. 1691 patients were in the observational cohort, 471 were in the endovascular cohort and 1917 patients were in the surgical cohort. The cohorts were followed for a median follow-up of 9.2 years. Outcomes were determined prospectively and with central review. The data were grouped together and analyzed to determine treatment decisions. Comparison of outcomes was done using covariate adjustment and using propensity analysis where equivalent probability groups were constructed. Similar main predictors of treatment and outcome were observed. Analysis of hemorrhage, mortality and short-term and long-term morbidity and mortality were assessed. Risk-benefit ratios were also calculated. Results: Significant differences in baseline variables between treatment and observed patients were aneurysm size, symptoms, age, prior SAH or not group, geographical region, family history, hypertension and myocardial infarction history. The results show comparability of groups using the patient propensity-based score subset. Using the propensity score method, the results showed a benefit in prevention of hemorrhage by surgery and endovascular treatment versus observation (p<.01). No difference was found between endovascular versus surgery. However when procedure-related outcomes are included, no significant difference at 1 year, 5 years or 10 years in the combined aneurysm or procedure related endpoint was evident between cohorts. Conclusions: Propensity score matching to achieve comparability resulted in balanced groups. Comparison of long-term results showed that intervention demonstrated a benefit in reducing hemorrhage risk. However, peri-procedural risk negates any short-term benefit for 10 years.

Background Meeting Recruitment goals in a research study can be challenging. Recruitment for pedigree-based research, in which data and DNA are collected from genetically important family members, is especially difficult. The Familial Intracranial Aneurysm (FIA) study is a multicenter international study whose goal is to identify genetic and other risk factors for the formation and rupture of intracranial aneurysms (IAs). The chosen sites for the study are major referral centers for the diagnosis and treatment of IAs. In this analysis, we sought to determine what factors caused a recruited family to be incomplete, and what impact the methods used in identifying families had on the successful completion of family enrollment. Methods Three recruitment strategies were utilized to identify and enroll families: prospective monitoring of every new case of IA, subarachnoid hemorrhage, or intracranial hemorrhage; retrospective review of IA cases; and advertisement on the Internet, in scientific journals, and at professional meetings. An unexpected additional source of recruitment was exposure to the study through the news media. To help with public accessibility to the study, a web site and toll free number were established. Families were eligible for the study if they fit one of 4 patterns: [1] ≥2 living siblings affected with IA; [2] ≥2 affected siblings, 1 living and 1 genotype reconstructed from living spouse and children; [3] ≥3 affected members, 2 living and 1 reconstructed; [4] ≥ 3 affected members, 1 living, ≥1 reconstructed, and ≥1 living connecting relative. Exclusion criteria included fusiform-shaped IA; IA part of an AVM; family history of polycystic kidney disease; Ehlers-Danlos, Marfan, or moyamoya syndrome; fibromuscular dysplasia; or failure to obtain informed consent. Results Between 8/2002 and 10/2007, 3771 IA patients were screened for family history, and 681 potential families were identified, of which 441 successfully completed enrollment. There were 240 families which did not complete enrollment, due to refusal to participate (97), inability to locate needed relatives (87), exclusion criteria (50), no reason documented (5), and duplication (1 recruited at two sites). Completion of study enrollment was not significantly different by recruitment category (p=.17): 191 of 311 prospectively-recruited (61%), 66 of 89 retrospective (74%), 95 of 145 advertisement (66%), and 89 of 136 methods not documented (65%) families successfully completed enrollment. Conclusion In our study, the major reason for family exclusion was the inability to enroll needed family members, through refusal or failure to locate. All three methods used to identify potential families were successful in completing eligible families. The combination of recruitment strategies can be effectively implemented in future studies.

BACKGROUND: Recent genome-wide association studies (GWAS) have identified a number of novel SNPs associated with blood pressure and hypertension-related traits although studies were very large (approaching 80K participants) and effect sizes were modest with per allele effect sizes as small variants as a single millimeter of mercury difference in blood pressure. However, because hypertension is the most potent modifiable risk factor for ischemic stroke, lowering blood pressure by a few mm Hg can translate into measurable decrease in stroke risk. METHODS: We investigated 22 hypertension (HTN) associated SNPs in a case-control analysis of ischemic stroke in multiple stroke studies including the Siblings With Ischemic Stroke Study (SWISS), the Ischemic Stroke Genetics Study (ISGS), the Bio-Repository of DNA in Stroke (BRAINS), the Vitamin Intervention for Stroke Prevention (VISP) trial, and the Women's Health Initiative (WHI). SWISS/ISGS/BRAINS were analyzed together and included subtype information. Genotyping was funded through the individual studies, the Genomics and Randomized Trials Network (GARNET) consortium, and the SHARe (SNP Health Association Resource). All studies had both raw and imputed GWAS data. Analyses included the following phenotypes: all ischemic stroke, stroke subtypes, and age-at-stroke-onset and were stratified by race. Analyses were minimally adjusted for age, sex and principal components 1 & 2. Alpha was set at 0.05. RESULTS: Eleven of the SNPs from the HTN GWAS were associated with ischemic stroke in European ancestry from one or more of the study populations. Two SNPs on chromosome 12 and one on chromosome 21 were associated in multiple European ancestry cohorts. No SNP was associated in all studies. A SNP previously associated with HTN in African ancestry populations was associated with stroke in African-Americans. Analysis of subtypes found associations with small vessel disease and cardioembolic stroke but not large artery disease. The case-only age-at-stroke-onset analysis also found associations for the two SNPs on chromosome 12. CONCLUSION: These data suggest that candidate SNPs from a HTN GWAS may be associated with ischemic stroke and warrant further investigation. Racial differences were observed. Replication in populations from the other SiGN (Stroke Genetics Network), GENEVA (Gene Environment Association Studies) consortium, and the ISGC (International Stroke Genetics Consortium) studies are underway.

Introduction: The risk of stroke or transient ischemic attack (TIA) remains increased after transcatheter aortic valve replacement (TAVR), especially in the first 30 days. Limited data is available regarding the impact of procedural characteristics on risk of stroke/TIA. Hypothesis: Post deployment balloon dilatation (PD) and total number of balloon dilatations (pre, valve and post insertion) may be associated with increased risk of stroke/TIA in patients undergoing TAVR. Methods: We included consecutive patients who underwent balloon-expandable TAVR until June 2014 at Mayo Clinic, Rochester. Patients who died in the operating room, converted to open surgery, or had valve-in-valve, or underwent self-expanding TAVR were excluded. Primary end-point was stroke or TIA at 30 days. Results: Mean age was 80.9±8 y, mean STS score was 8.3±5 and 50% underwent transfemoral access. The overall incidence of PD was 14% (n=53). Total number of dilations ranged from 2-7, with 5% (n=19) getting ≥ 4 total dilatations. Out of the 370 patients, 13 patients (3.5%) suffered stroke/TIA (9.4% in PD group vs. 2.2% in non-PD group) in the first 30 days after TAVR. Cox-proportional hazards regression analysis indicated that PD during TAVR was associated with a significantly increased risk of 30-day stroke/TIA (HR, 3.8; 95% CI, 1.2-11.6; p=0.02). There was a trend towards increased stroke/TIA with total number of dilations (HR, 1.5; 95% CI, 0.87-2.6; p=0.14), longer procedural time (HR per 30 minutes, 1.3; 95% CI, 0.96-1.7; p=0.09) and severity of atherosclerosis (moderate-severe - HR, 1.9; 95% CI 0.95- 3.8; p=0.07). PD was not significantly associated with the risk of 30 day death (HR, 1.1; 95% CI, 0.24-4.85; p=0.93). Conclusions: In patients undergoing PD after balloon-expandable TAVR, 9.4% suffered a stroke or TIA in the first 30 days. PD was associated with a four-fold increase in 30 day risk of stroke or TIA.

Background: Patients with cerebral or spinal cavernous malformations (CM) and a primary headache disorder are often limited in medication options due to concern for bleeding risk. Methods: From a prospective cohort of CM patients (2015–2020), demographics, mode of clinical presentation, and radiographic data were collected. Follow up of patients was performed with electronic medical record review, in person visits and/or written surveys. Select medication use was ascertained from the time of the CM diagnosis to a censor date of first prospective symptomatic hemorrhage, complete surgical excision of sporadic form CM, or death. The influence of non-aspirin NSAID (NA-NSAID), triptan, or OnabotulinumtoxinA on prospective hemorrhage risk was assessed. Results: As of August 20, 2020, 329 patients with spinal or cerebral CM (58% female; 20.1% familial; 42.2% initial presentation due to hemorrhage; 27.4% brainstem) were included. During a follow-up of 1799.9 patient years, 92 prospective hemorrhages occurred. Use of NA-NSAIDs, triptans, and OnabotulinumtoxinA after the diagnosis of CM was unassociated with an increased risk of prospective hemorrhage. Conclusions: Use of triptans and NA-NSAIDs, does not precipitate CM hemorrhage. Similarly, we did not find that OnabotulinumtoxinA precipitated CM hemorrhage in a limited number of patients at doses <200 units per session.

Introduction: Small case series have suggested that cerebral amyloid angiopathy (CAA) and reversible cerebral vasoconstriction syndrome (RCVS) are the most common causes of non-traumatic convexal SAH (cSAH). Our objective was to describe the spectrum of clinical and imaging features in a large series of non-traumatic cSAH patients. Methods: A retrospective observational study of consecutive patients with non-traumatic cSAH was performed. The Mayo Clinic Medical Records Linkage system was used to identify all patients evaluated at Mayo Clinic in Rochester with potential non-traumatic cSAH between January 1, 1996 and October 1, 2014. Clinical and radiologic data were abstracted from the comprehensive medical record. Results: We identified 88 patients [median age, 64 years (range: 25-85)] with non-traumatic cSAH. The most common causes were reversible cerebral vasoconstriction syndrome (26, 29.5%), cerebral amyloid angiopathy (23, 26.1%), indeterminate (14, 15.9%), and endocarditis (9, 10.2%). Other causes include posterior reversible encephalopathy syndrome, cerebral vein thrombosis, vasculitis, carotid occlusive disease, thrombosed developmental venous anomaly, and hyperperfusion syndrome after carotid revascularization. CAA patients commonly presented at an older age than RCVS patients (75 years vs 51 years, p<0.0001). The most common clinical presentation for CAA was sensorimotor dysfunction while thunderclap headache was the most common presentation of RCVS. Thirteen patients (14.7%) had recurrent cSAH and twelve patients (13.6%) had a subsequent intracerebral hemorrhage over a median follow up of 16 months. The risk was high among CAA patients, with subsequent lobar ICH occurring in 43.5% of cases, superficial siderosis in 95%, and recurrent cSAH in 39.1%, compared to 3.8%, 28.5% and 7.7% respectively in RCVS. Conclusions: Our study demonstrates the clinical diversity of cSAH. Older age, sensorimotor dysfunctions suggest CAA as the underlying cause. Younger age and thunderclap headache predict RCVS. Various other causes also need to be considered in the differential diagnosis. CAA patients have high rates of subsequent lobar ICH, development of superficial siderosis, and recurrent cSAH.