Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Age, Sex, and Racial Differences in Neuroimaging Use in Acute Stroke: A Population-Based Study.

BACKGROUND AND PURPOSE: Limited information is available regarding differences in neuroimaging use for acute stroke work-up. Our objective was to assess whether race, sex, or age differences exist in neuroimaging use and whether these differences depend on the care center type in a population-based study. MATERIALS AND METHODS: Patients with stroke (ischemic and hemorrhagic) and transient ischemic attack were identified in a metropolitan, biracial population using the Greater Cincinnati/Northern Kentucky Stroke Study in 2005 and 2010. Multivariable regression was used to determine the odds of advanced imaging use (CT angiography/MR imaging/MR angiography) for race, sex, and age. RESULTS: In 2005 and 2010, there were 3471 and 3431 stroke/TIA events, respectively. If one adjusted for covariates, the odds of advanced imaging were higher for younger (55 years or younger) compared with older patients, blacks compared with whites, and patients presenting to an academic center and those seen by a stroke team or neurologist. The observed association between race and advanced imaging depended on age; in the older age group, blacks had higher odds of advanced imaging compared with whites (odds ratio, 1.34; 95% CI, 1.12-1.61; P < .01), and in the younger group, the association between race and advanced imaging was not statistically significant. Age by race interaction persisted in the academic center subgroup (P < .01), but not in the nonacademic center subgroup (P = .58). No significant association was found between sex and advanced imaging. CONCLUSIONS: Within a large, biracial stroke/TIA population, there is variation in the use of advanced neuroimaging by age and race, depending on the care center type.

Association of stroke risk biomarkers with stroke symptoms: the Reasons for Geographic and Racial Differences in Stroke cohort.

Essentials Stroke symptom history predicts future stroke and may indicate prior unrecognized stroke. We studied associations of stroke symptoms with stroke risk biomarkers. Several stroke risk biomarkers were independently associated with stroke symptom history. Findings support a hypothesis that stroke symptoms may represent unrecognized stroke. SUMMARY: Background History of stroke symptoms in the absence of prior diagnosed stroke or transient ischemic attack (TIA) is associated with future stroke risk, as are biomarkers of inflammation, cardiac function and hemostasis. Objective To better elucidate the pathobiology of stroke symptoms, we studied associations of these biomarkers with history of stroke symptoms. Methods The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 30 239 black and white Americans age 45 years and older in 2003-7. In cross-sectional analyses in a random sample of 960 participants without prior stroke or TIA, levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), fibrinogen, factor VIII (FVIII), factor XI (FXI), C-reactive protein (CRP) and D-dimer were studied in relation to self-reported history of six sudden onset stroke symptoms. Results There were 190 participants with at least one stroke symptom and 770 without. Adjusting for age, race, sex and stroke risk factors, NT-proBNP, FXI, CRP and D-dimer in the top vs. bottom quartile were associated with prevalent stroke symptoms with odds ratios 2.69 (95% confidence interval [CI], 1.45-4.98), 1.65 (95% CI, 1.00-2.73), 2.21 (95% CI, 1.32-3.71) and 2.14 (95% CI, 1.22-3.75), respectively. Conclusions Strong associations of stroke risk biomarkers with stroke symptoms in persons without a clinical history of cerebrovascular disease support a hypothesis that some of these stroke symptoms represent unrecognized cerebrovascular disease. Future work is needed to determine whether these biomarkers identify persons with stroke symptoms who have a particularly high stroke risk.

The adverse effect of spasticity on 3-month poststroke outcome using a population-based model.

Several devices and medications have been used to address poststroke spasticity. Yet, spasticity's impact on outcomes remains controversial. Using data from a cohort of 460 ischemic stroke patients, we previously published a validated multivariable regression model for predicting 3-month modified Rankin Score (mRS) as an indicator of functional outcome. Here, we tested whether including spasticity improved model fit and estimated the effect spasticity had on the outcome. Spasticity was defined by a positive response to the question "Did you have spasticity following your stroke?" on direct interview at 3 months from stroke onset. Patients who had expired by 90 days (n = 30) or did not have spasticity data available (n = 102) were excluded. Spasticity affected the 3-month functional status (ß = 0.420, 95 CI = 0.194 to 0.645) after accounting for age, diabetes, leukoaraiosis, and retrospective NIHSS. Using spasticity as a covariable, the model's R (2) changed from 0.599 to 0.622. In our model, the presence of spasticity in the cohort was associated with a worsened 3-month mRS by an average of 0.4 after adjusting for known covariables. This significant adverse effect on functional outcomes adds predictive value beyond previously established factors.

Boosting enrolment in clinical trials: validation of a regional network model.

BACKGROUND: Clinical trials of stroke therapy have been hampered by slow rates of enrolment. PURPOSE: Our purpose is to validate a previously developed model for accelerating enrolment in clinical trials by replicating it at new locations. The model employs coordinators who travel from a host institution to enrol participants from a network of participating hospitals. Active surveillance assures identification of all eligible patients. METHODS: Among 70 U.S. investigators participating in National Institutes of Health-funded trial of stroke prevention, five investigators were invited to develop local identification and outreach networks (LIONs). Each LION comprised a LION coordinating centre servicing multiple hospitals. Hospitals provided names of patients with stroke or transient ischaemic attack to researchers at the LION coordinating centre who initiated contact; patients were offered home visits for consent and randomization. Outcomes were feasibility, enrolment, data quality, and cost. RESULTS: Five LIONs varied in size from two to eight hospitals. All 24 hospitals we approached agreed to participate. The average monthly rate of enrolment at the research sites increased from 1.4 participants to 3.5 after expanding from a single institution model to the LION format (mean change = 2.1, range 0.9-3.7). Monthly performance improved over time. Data quality was similar for LIONs and non-LION sites, except for drug adherence which was lower at LIONs. The average cost to randomize and follow one participant during the study interval was 2.4 times the cost under the per-patient, cost-reimbursement strategy at non-LION sites. The cost ratio declined from 3.4 in year one to 1.8 in year two. LIMITATIONS: The LION strategy requires unprecedented collaboration and trust among institutions. Applicability beyond stroke requires confirmation. CONCLUSION: LIONs are a practical, reproducible method to increase enrolment in trial research. Twelve months were required for the average site to reach its potential. The per-participant cost at LIONs was higher than conventional sites but declined over time.

Population-based study of wake-up strokes.

OBJECTIVE: Previous studies have estimated that wake-up strokes comprise 8%to 28% of all ischemic strokes, but these studies were either small or not population-based. We sought to establish the proportion and event rate of wake-up strokes in a large population-based study and to compare patients who awoke with stroke symptoms with those who were awake at time of onset. METHODS: First-time and recurrent ischemic strokes among residents of the Greater Cincinnati/Northern Kentucky region (population 1.3 million) in 2005 were identified using International Classification of Diseases-9 codes 430-436 and verified via study physician review. Ischemic strokes in patients aged 18 years and older presenting to an emergency department were included. Baseline characteristics were ascertained, along with discharge modified Rankin Scale scores and 90-day mortality. RESULTS: We identified 1,854 ischemic strokes presenting to an emergency department, of which 273 (14.3%) were wake-up strokes. There were no differences between wake-up strokes and all other strokes with regard to clinical features or outcomes except for minor differences in age and baseline retrospective NIH Stroke Scale score. The adjusted wake-up stroke event rate was 26.0/100,000. Of the wake-up strokes, at least 98 (35.9%) would have been eligible for thrombolysis if arrival time were not a factor. CONCLUSIONS: Within our population, approximately 14% of ischemic strokes presenting to an emergency department were wake-up strokes. Wake-up strokes cannot be distinguished from other strokes by clinical features or outcome. We estimate that approximately 58,000 patients with wake-up strokes presented to an emergency department in the United States in 2005.

Smoking and family history and risk of aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Smoking and family history of aneurysmal subarachnoid hemorrhage (aSAH) are independent risk factors for aSAH. Using a population-based case-control study of hemorrhagic stroke, we hypothesized that having both a first-degree relative with a brain aneurysm or SAH (+FH) and current smoking interact to increase the risk of aSAH. METHODS: Cases of aneurysmal SAH were prospectively recruited from all 17 hospitals in the five-county region around the University of Cincinnati. Controls were identified by random digit dialing. Controls were matched to cases of aSAH by age (+/-5 years), race, and sex. Conditional multiple logistic regression was used to identify independent risk factors. For deviation from the additive model, the interaction constant ratio test was used. RESULTS: A total of 339 cases of aSAH were matched to 1,016 controls. Compared to current nonsmokers with no first-degree relatives with aSAH (-FH), the odds ratio (OR) for aSAH for current nonsmokers with +FH was 2.5 (95% confidence interval [CI] 0.9-6.9); for current smokers with -FH, OR = 3.1 (95% CI 2.2-4.4); and for current smokers with +FH, OR = 6.4 (95% CI 3.1-13. 2). The interaction constant ratio, which measured the deviation from the additive model, was significant: 2.19 (95% CI 0.80-5.99). The lower bound of the 95% CI >0.5 signifies a departure from the additive model. CONCLUSION: Evidence of a gene-environment interaction with smoking exists for aneurysmal subarachnoid hemorrhage. This finding is important to counseling family members and for screening of intracranial aneurysm (IA) as well as the design and interpretation of genetic epidemiology of IA studies.

Warfarin use leads to larger intracerebral hematomas.

BACKGROUND: Among patients with intracerebral hemorrhage (ICH), warfarin use before onset leads to greater mortality. In a retrospective study, we sought to determine whether warfarin use is associated with larger initial hematoma volume, one determinant of mortality after ICH. METHODS: We identified all patients hospitalized with ICH in the Greater Cincinnati region from January through December 2005. ICH volumes were measured on the first available brain scan by using the abc/2 method. Univariable analyses and a multivariable generalized linear model were used to determine whether international normalized ratio (INR) influenced initial ICH volume after adjusting for other factors, including age, race, sex, antiplatelet use, hemorrhage location, and time from stroke onset to scan. RESULTS: There were 258 patients with ICH, including 51 patients taking warfarin. In univariable comparison, when INR was stratified, there was a trend toward a difference in hematoma volume by INR category (INR <1.2, 13.4 mL; INR 1.2-2.0, 9.3 mL; INR 2.1-3.0, 14.0 mL; INR >3.0, 33.2 mL; p = 0.10). In the model, compared with patients with INR <1.2, there was no difference in hematoma size for patients with INR 1.2-2.0 (p = 0.25) or INR 2.1-3.0 (p = 0.36), but patients with INR >3.0 had greater hematoma volume (p = 0.02). Other predictors of larger hematoma size were ICH location (lobar compared with deep cerebral, p = 0.02) and shorter time from stroke onset to scan (p < 0.001). CONCLUSION: Warfarin use was associated with larger initial intracerebral hemorrhage (ICH) volume, but this effect was only observed for INR values >3.0. Larger ICH volume among warfarin users likely accounts for part of the excess mortality in this group.

How important is surrogate consent for stroke research?

BACKGROUND: Patients with stroke may have cognitive deficits that impact their capacity to provide informed consent for research. Some institutional review boards restrict surrogate consent to persons who have specific legal authority to provide it. We examined the importance of surrogate consent in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial, the study that led to the only US Food and Drug Administration-approved treatment for acute ischemic stroke. METHODS: The NINDS rt-PA Stroke Trial randomized subjects with ischemic stroke to treatment with recombinant tissue plasminogen activator (rt-PA) or placebo. We compared the baseline characteristics and clinical outcomes of subjects enrolled by self-consent with those of subjects enrolled by surrogate consent. RESULTS: Surrogate consent was used to enroll 439 of 624 (70%) subjects. Subjects enrolled by surrogate consent were older (68.5 vs 63.4 years, p < 0.001), had more severe strokes (median NIH Stroke Scale score 17 vs 9, p < 0.001), and were less likely to make a good recovery (p < 0.001 for all measures) than patients who provided their own consent. There was no interaction between method of consent and response to rt-PA. If the trial had used the same sample size and recruited at the same rate but excluded patients who could not provide their own consent, it would have taken 12.5 years to complete. CONCLUSIONS: The National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) Stroke Trial would not have been completed in a timely fashion without subjects enrolled by surrogate consent. Furthermore, exclusion of subjects who could not provide their own consent would have severely limited the generalizability and value of trial results.

The increasing incidence of anticoagulant-associated intracerebral hemorrhage.

OBJECTIVE: To define temporal trends in the incidence of anticoagulant-associated intracerebral hemorrhage (AAICH) during the 1990s and relate them to rates of cardioembolic ischemic stroke. METHODS: We identified all patients hospitalized with first-ever intracerebral hemorrhage (ICH) in greater Cincinnati during 1988, from July 1993 through June 1994, and during 1999. AAICH was defined as ICH in patients receiving warfarin or heparin. Patients from the same region hospitalized with first-ever ischemic stroke of cardioembolic mechanism were identified during 1993/1994 and 1999. Incidence rates were calculated and adjusted to the 2000 US population. Estimates of warfarin distribution in the United States were obtained for the years 1988 through 2004. RESULTS: AAICH occurred in 9 of 184 ICH cases (5%) in 1988, 23 of 267 cases (9%) in 1993/1994, and 54 of 311 cases (17%) in 1999 (p < 0.001). The annual incidence of AAICH per 100,000 persons was 0.8 (95% CI 0.3 to 1.3) in 1988, 1.9 (1.1 to 2.7) in 1993/1994, and 4.4 (3.2 to 5.5) in 1999 (p < 0.001 for trend). Among persons aged > or =80, the AAICH rate increased from 2.5 (0 to 7.4) in 1988 to 45.9 (25.6 to 66.2) in 1999 (p < 0.001 for trend). Incidence rates of cardioembolic ischemic stroke were similar in 1993/1994 and 1999 (31.1 vs 30.4, p = 0.65). Warfarin distribution in the United States quadrupled on a per-capita basis between 1988 and 1999. CONCLUSIONS: The incidence of anticoagulant-associated intracerebral hemorrhage quintupled in our population during the 1990s. The majority of this change can be explained by increasing warfarin use. Anticoagulant-associated intracerebral hemorrhage now occurs at a frequency comparable to subarachnoid hemorrhage.

Long-term mortality after intracerebral hemorrhage.

OBJECTIVE: To characterize long-term mortality following intracerebral hemorrhage (ICH) in two large population-based cohorts assembled more than a decade apart. METHODS: All patients age > or = 18 hospitalized with nontraumatic ICH in the Greater Cincinnati/Northern Kentucky area were identified during 1988 (Cohort 1) and from May 1998 to July 2001 and August 2002 to April 2003 (Cohort 2). Mortality was tabulated using actuarial methods and compared with a log-rank test. RESULTS: There were 183 patients with ICH in Cohort 1 and 1,041 patients in Cohort 2. Patients in Cohort 1 were more likely to be white (p = 0.024) and undergo operation for their ICH (p = 0.002), whereas patients in Cohort 2 were more commonly on anticoagulants (p < 0.001). Among patients in Cohort 1, mortality at 7 days, 1 year, and 10 years was 31, 59, and 82%. Among patients in Cohort 2, mortality at 7 days and 1 year was 34 and 53%. Mortality rates did not differ between cohorts by log-rank test (p = 0.259). CONCLUSIONS: Intracerebral hemorrhage (ICH) mortality did not improve significantly between study periods. Operation for ICH became less frequent, whereas anticoagulant-associated ICH became more common.

Cognitive scores in carriers of Huntington's disease gene compared to noncarriers.

Huntington's disease (HD) is a progressive neurodegenerative disorder recently shown to be due to an excess number of CAG trinucleotide repeats in the 5' translated region of chromosome 4. One of the cardinal features of HD is cognitive decline. While mental deterioration is obvious later in the disease course, the time of its onset is difficult to determine precisely. A sample of at-risk individuals without signs or symptoms of HD by self-report was studied. The Wechsler Adult Intelligence Test--Revised and a neurological rating scale were administered. The genotypes of 394 individuals were then determined by polymerase chain reaction testing. On all portions of the WAIS-R test, the mean score of the HD gene carriers was lower than that of the noncarriers. Scores on two of the performance subtests, the digit symbol and the picture arrangement, were significantly different in the two groups, even after the scores from all gene carriers who were diagnosed as affected based on their neurological motor examination were removed. The scores for the gene carriers on the various subtests were negatively correlated with the number of CAG repeats in the expanded HD allele. Such a relationship was not seen with the normal alleles of the noncarriers. Taken together, our results suggest that a deficit in cognitive function is an early finding of HD and that in this patient population, the degree of cognitive deficit is proportional to the number of CAG repeats in the HD allele.

In-frame deletion in the proteolipid protein gene of a family with Pelizaeus-Merzbacher disease.

We describe an in-frame deletion of parts of exons 3 and 4 of the proteolipid protein gene (PLP), with all of the intervening sequence, in a 3-generation family with Pelizaeus-Merzbacher disease. The mutation removes 49 amino acids of the PLP.