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Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

BACKGROUND: Dysphagia following stroke is prevalent, however dysphagia treatment is often applied haphazardly and outcomes unclear. Neuromuscular Electrical stimulation (NMES) has received increased attention as a treatment for post stroke dysphagia; but application data remain conflicted. OBJECTIVE: This study investigated effectiveness and safety of an exercised-based swallowing therapy (McNeill Dysphagia Therapy: MDTP) +NMES for dysphagia rehabilitation following stroke. METHODS: Stroke patients (n=53, [Formula: see text] age: 66 [13.2], 47.2% male) with dysphagia admitted to sub-acute rehabilitation hospital were randomized to MDTP+NMES [NMES], MDTP+ sham NMES [MDTP] or usual care [UC] swallowing therapy groups. Patients were treated for one hour per day for 3 weeks and monitored to 3-months by a blinded evaluator. Outcomes included clinical swallowing ability, oral intake, weight, patient perception of swallow, and occurrence of dysphagia–related complications. RESULTS: Post treatment dysphagia severity and treatment response were significantly different between groups (p ≤0.0001). MDTP demonstrated greater positive change than either NMES or UC arms, including increase in oral intake (χ(2)=5, p ≤ 0.022) and improved functional outcome by 3-months post stroke (RR = 1.72, 1.04–2.84). Exploratory Cox regression revealed the MDTP group conferred the greatest benefit in time to “return to pre-stroke diet” of 4.317 [95% CI: 1.08–17.2, p< .03]. CONCLUSION: Greater benefit (e.g. reduction in dysphagia severity, improved oral intake, and earlier return to pre-stroke diet) resulted from a program of MDTP alone vs. NMES or UC.

Introduction: Risk of lobar and non-lobar intracerebral hemorrhage (ICH) varies among blacks, whites and Hispanics. We sought to determine whether these differences could be due to variability in the effects of Apolipoprotein E (APOE) epsilon (ε) alleles, the most potent genetic risk factor for ICH. Methods: Primary ICH cases and controls were collected from US and European sites contributing to the International Stroke Genetic Consortium (ISGC). We meta-analyzed the effects of APOE allele status on ICH risk applying a two-stage clustering approach based on race/ethnicity and the contributing study. Models were adjusted for age, sex, history of hypertension, hypercholesterolemia, warfarin, statin and antiplatelet use, smoking and alcohol use. A propensity score analysis was used to model the influence of APOE against the burden of hypertension across races/ethnicities. Results: 13,124 subjects (54.5% male, median age 66 years) were included. In whites, APOE ε2 (odds ratio (OR)=1.85, 95% confidence interval (CI)=1.27-2.69, p Conclusion: APOE ε4 and ε2 alleles affect lobar ICH risk variably by race and ethnicity. Associations are confirmed in whites but can be shown in Hispanics only when the excess burden of hypertension is propensity score-matched. Further studies are needed to explore interactions between APOE alleles and environmental exposures that vary by race and ethnicity in representative populations at risk for ICH.

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using ‘Multi-Trait Analysis of GWAS’ (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10(−8)] at 1q22; rs72932727 (P = 1.7 × 10(−8)) at 2q33; and rs9515201 (P = 5.3 × 10(−10)) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10(−4) in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10(−7) in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10(−7)) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.

Background and Purpose— Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. Methods— We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P − 8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0–2 versus 3–6) modified Rankin Scale using ordinal and logistic regression, respectively. Results— The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P =4.4×10 −8 ) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P =4.3×10 −8 ) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 ( P =0.04; meta-analysis P =2.5×10 −9 ; heterogeneity, P =0.16) but not for 22q13 ( P =0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P =0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P =0.045). Conclusions— We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry./n© 2015 American Academy of Neurology. Kristiina Rannikmäe is supported by the Edinburgh and Lothians Health Foundation REMIND Fund and Stroke Research and Amenities Endowments Fund; Cathie Sudlow is supported by the Scottish Funding Council; Gail Davies is supported by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1), BBSRC and Medical Research Council (MSRC). Tom Van Agtmael is supported by the Kidney Research UK project grant RP19/2012. Details of funding for the studies contributing to the ICH GWAS can be found in: Woo D, Falcone GJ, Devan WJ, et al. Meta-analysis of genome-wide association studies identifies 1q22 as a novel susceptibility locus for intracerebral hemorrhage. American Journal of Human Genetics 2014;pii: S0002-9297(14)00070-6. doi:10.1016/j.ajhg.2014.02.012. [Epub ahead of print]. Details of funding for the studies contributing to the ischaemic stroke GWAS can be found in: Traylor M, Farrall M, Holliday EG, et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurology 2012;11:951-962. Details of funding for the studies contributing to the WMH in ischaemic stroke GWAS can be found in: Adib-Samii P, Rost N, Traylor M, et al. 17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischaemic Stroke, But Not With Lacunar Stroke Status. Stroke 2013;44:1609-1615. Details of funding for the studies contributing to the WMH in population GWAS can be found in: Fornage M, Debette S, Bis JC, et al. Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium. Annals of Neurology 2011;69:928-939. Martin Dichgans is supported by the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain); Guido J Falcone is supported by the NIH / NINDS grant P50NS061343; Chistopher D Anderson is supported by the American Brain Foundation Clinical Research Training Fellowship, NIH-NINDS K23NS086873, Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care SPARK award; Jonathan Rosand is supported by the NIH / NINDS grant R01NS059727.

While non-contrast head computed tomography is effective in detecting blood, it is not sensitive in diagnosing hyperacute ischemic stroke. One neuroradiologic marker for early thromboembolic occlusion of the distal middle cerebral artery is the middle cerebral artery “dot” sign. The “dot” seen on the typical axial plane represents a hyperdensity of the middle cerebral artery in the Sylvian fissure. A review of medical literature was conducted via PubMed utilizing search phrases “MCA,” “dot,” and “sign.” The review was limited to the intravenous tissue-type plasminogen activator era, 1996 and on. Articles were analyzed to determine the use of the sagittal plane of non-contrast head computed tomography to locate the middle cerebral artery “dot” sign. The search terms yielded 11 results which revealed that computed tomography reconstruction and sagittal planes were not used for detection of the middle cerebral artery “dot” signs. Our patient had no known past medical history. The initial non-contrast head computed tomography was read as having a hypodensity in the right insular region and a middle cerebral artery “dot” sign. Multiplanar reconstruction of the computed tomography demonstrated a hyperdense sagittal string-like appearance of the middle cerebral artery along the Sylvian fissure. Computed tomography angiography confirmed the M2 occlusion. This is the first report of using the head computed tomography sagittal plane for diagnosis of the middle cerebral artery “dot” sign. Incorporating multiplanar reconstruction and producing the sagittal plane may lead to a higher sensitivity of the middle cerebral artery “dot” sign. Further studies incorporating a patient cohort will be needed to determine how much the sagittal plane view augments predictive value of the middle cerebral artery “dot” sign.

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Objective: We aimed to assess the effect of APOE e variants on warfarin-related intracerebral hemorrhage (wICH), evaluated their predictive power, and tested for interaction with warfarin in causing wICH. Methods: This was a prospective, 2-stage (discovery and replication), case-control study. wICH was classified as lobar or nonlobar based on the location of the hematoma. Controls were sampled from ambulatory clinics (discovery) and random digit dialing (replication). APOE e variants were directly genotyped. A case-control design and logistic regression analysis were utilized to test for association between APOE e and wICH. A case-only design and logistic regression analysis were utilized to test for interaction between APOE e and warfarin. Receiver operating characteristic curves were implemented to evaluate predictive power. Results: The discovery stage included 319 wICHs (44% lobar) and 355 controls. APOE e2 was associated with lobar (odds ratio [OR] 2.46; p p = 0.04), whereas e4 was associated with lobar (OR 2.09; p p = 0.35). The replication stage (63 wICHs and 1,030 controls) confirmed the association with e2 ( p = 0.03) and e4 ( p = 0.003) for lobar but not for nonlobar wICH ( p > 0.20). Genotyping information on APOE e variants significantly improved case/control discrimination of lobar wICH (C statistic 0.80). No statistical interaction between warfarin and APOE was found ( p > 0.20). Conclusions: APOE e variants constitute strong risk factors for lobar wICH. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary. Evaluation of the predictive ability of APOE in cohort studies is warranted.

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

Background and Purpose— Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage. Methods— A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed. Results— No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE , and APOC1 , met genome-wide significance ( P APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome-wide significance level in gene-based association testing. Conclusions— Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for sufficient power except for loci with large effects.

Introduction: In observational studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of spontaneous intracerebral hemorrhage (ICH). Common DNA sequence variants within the cholesteryl ester transfer protein ( CETP ) gene decrease CETP protein activity and increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development to combat coronary artery disease. Hypothesis: Common CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed a two-stage case-control genetic association study in Caucasians. The discovery phase utilized data on 12 independent loci within CETP (+/- 50 kilobases) from 3 genome-wide association studies of ICH. Replication involved direct genotyping in 5 additional studies. We also constructed a genetic risk score with 7 independent CETP variants and tested it for association with HDL-C and ICH risk. We used principal component analysis to account for population structure and a Bonferroni-adjusted p Results: The discovery phase included 1149 ICH cases (43% lobar hemorrhages) and 1238 controls. Twelve variants were nominally associated (p-4 ) and no heterogeneity across studies (I 2 =0%). This association was replicated in 1625 cases (43% lobar hemorrhages) and 1845 controls (OR 1.12, 95%CI 1.02-1.24; p=0.03). A genetic score of independent CETP variants known to increase HDL-C by ~2.85 mg/dL was strongly associated with ICH risk (OR 1.86, 95%CI 1.44-2.40; p=1.4x10 -6 ). Conclusion: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes is warranted.

Cerebrovascular complications of endocarditis occur in 25-70% of patients with infective endocarditis. The cornerstone of treatment is early initiation of antibiotic treatment, which significantly reduces the risk of embolization after 1 week of treatment. In general, thrombolysis and anticoagulation of these patients should be avoided, while antiplatelet therapy may be considered in those with other indications. Endovascular treatment of acute septic emboli is uncertain, but a few case reports have demonstrated benefit. Other complications of infective endocarditis include intracerebral hemorrhage, which may be predicted by the presence of two or more cerebral microbleeds on gradient echo sequences. Intracranial mycotic aneurysms can often be managed with serial imaging and coiled if there is evidence of failure to reduce in size, or enlargement.

Objective: Prior studies investigating the association between APOE alleles epsilon 2/epsilon 4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for epsilon 2 and epsilon 4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results: Alleles epsilon 2 and epsilon 4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 x 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 x 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele epsilon 4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 x 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation: APOE epsilon 2 and epsilon 4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE epsilon 4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010;68:934-943

Background and Purpose— The extent of potential consent bias in observational studies elucidating genetic and environmental contributions to ischemic stroke is largely unknown. The purpose of this study was to assess differences in stroke cohort characteristics between those who provided informed consent and those whose enrollment was authorized by surrogate decision makers. Methods— The Ischemic Stroke Genetics Study (ISGS) is a prospective, 5-center, case-control study of first-ever ischemic stroke. Demographic, clinical, and stroke characteristics were compared between cases enrolled by self versus by surrogate. Data from one site that limits enrollment only to those able to self-consent were also analyzed to compare those who enrolled with those not able to consent. Results— Overall, 10% (54 of 517) were enrolled using surrogate authorization. Self-consented and surrogate-authorized cases did not differ significantly in age, sex, or conventional risk factors. Surrogate-authorized cases had significantly more severe stroke deficits, larger infarcts, and infarcts localizing to left supratentorial regions. Similarly, at the site restricting enrollment, stroke severity and characteristics differed between self-consented individuals and those otherwise eligible but unable to provide consent. Conclusions— Failure to permit surrogate authorization in genetic studies of ischemic stroke may skew enrollment toward less severe strokes caused by smaller infarcts. This potential consent bias may undermine the ability to identify genetic determinants of risk and severity and suggests that surrogate enrollment in these studies can be ethically justifiable.

Technological advances in molecular genetics allow rapid and sensitive identification of genomic copy number variants (CNVs). This, in turn, has sparked interest in the function such variation may play in disease. While a role for copy number mutations as a cause of Mendelian disorders is well established, it is unclear whether CNVs may affect risk for common complex disorders. We sought to investigate whether CNVs may modulate risk for ischemic stroke (IS) and to provide a catalog of CNVs in patients with this disorder by analyzing copy number metrics produced as a part of our previous genome-wide single-nucleotide polymorphism (SNP)-based association study of ischemic stroke in a North American white population. We examined CNVs in 263 patients with ischemic stroke (IS). Each identified CNV was compared with changes identified in 275 neurologically normal controls. Our analysis identified 247 CNVs, corresponding to 187 insertions (76%; 135 heterozygous; 25 homozygous duplications or triplications; 2 heterosomic) and 60 deletions (24%; 40 heterozygous deletions; 3 homozygous deletions; 14 heterosomic deletions). Most alterations (81%) were the same as, or overlapped with, previously reported CNVs. We report here the first genome-wide analysis of CNVs in IS patients. In summary, our study did not detect any common genomic structural variation unequivocally linked to IS, although we cannot exclude that smaller CNVs or CNVs in genomic regions poorly covered by this methodology may confer risk for IS. The application of genome-wide SNP arrays now facilitates the evaluation of structural changes through the entire genome as part of a genome-wide genetic association study.

Background and Purpose— Although current guidelines state that carotid endarterectomy is probably recommended before or concomitant to coronary artery bypass grafting (CABG) in patients with carotid stenosis, s ignificant controversies to this recommendation still persist. Carotid artery stenting has been recently introduced as an alternative revascularization modality in high-risk patients. The aim of this study was to define, based on the published information, if carotid artery stenting is beneficial in this setting. Methods— A search of MEDLINE and a manual search of the literature from selected articles were performed. A total of 6 studies with 277 patients reporting carotid stenting followed by staged CABG were available for this clinical outcome analysis. All were retrospective and single-center studies. Results— The mean age was 69 years; 78% were males. Asymptomatic carotid stenosis was present in 76% of patients. The mean time to CABG was 32 days. The incidence of stroke and death associated with the stent procedure was 4.7%. Only 6 patients (2.2%) developed stroke associated with CABG. The overall combined 30-day event rate after CABG, including all events during carotid artery stenting, were as follows: minor stroke, 2.9%; major stroke, 3.2%; mortality, 7.6%; and combined death and any stroke, 12.3%. Conclusions— In this pooled analysis, the combined incidence of death and stroke in patients undergoing carotid artery stenting and staged CABG remains elevated. These results confirm that the presence of carotid stenosis is per se a marker of risk that might persists independent of its treatment. A systematic or randomized evaluation appears warranted.

Background: Epidemiologic studies suggest sex differences in evaluation of patients presenting with ischemic stroke. Sex differences in stroke evaluation could lead to sex differences in the validity of diagnosing ischemic stroke subtypes. This study assessed sex differences in the Ischemic Stroke Genetics Study (ISGS). Methods: The ISGS is a prospective case-control genetic association study of patients with first-ever ischemic stroke at 5 US tertiary stroke centers. The diagnostic tests performed as part of medical care were recorded for each enrolled patient. Results: A total of 505 patients were enrolled; 45% (229 of 505) were women and 55% (276 of 505) were men. Mean age at time of stroke was greater for women (66.6 v 61.9 years; P = .001). Frequency of brain computed tomography was 92% (254 of 276) for men and 90% (206 of 229) for women ( P = .42). Magnetic resonance imaging was completed in 84% (232 of 276) of men and 83% (191 of 229) of women ( P = .91). Frequency of electrocardiography was 91% (252 of 276) for men and 90% (206 of 229) for women ( P = .60). Echocardiography was done in 74% (203 of 276) of men and 79% (180 of 229) of women ( P = .19). Cervical arterial imaging occurred in 91% (208 of 229) of women and 86% (237 of 276) of men ( P = .09). Intracranial vascular imaging was performed in 75% (207 of 276) of men and 79% (181 of 229) of women ( P = .28). Conclusions: Our findings suggest no significant sex differences in the extent to which major diagnostic tests were performed in patients in ISGS. Dedicated tertiary stroke centers may reduce the sex bias in stroke evaluation that has been identified by previous studies.

Acute stroke patients with dysphagia are at increased risk for poor hydration. Dysphagia management practices may directly impact hydration status. This study examined clinical factors that might impact hydration status in acute ischemic stroke patients with dysphagia. A retrospective chart review was completed on 67 ischemic stroke patients who participated in a prior study of nutrition and hydration status during acute care. Prior results indicated that patients with dysphagia demonstrated elevated BUN/Cr compared to non-dysphagia cases during acute care and that BUN/Cr increased selectively in dysphagic patients. This chart review evaluated clinical variables potentially impacting hydration status: diuretics, parenteral fluids, tube feeding, oral diet, and nonoral (NPO) status. Exposure to any variable and number of days of exposure to each variable were examined. Dysphagia cases demonstrated significantly more NPO days, tube fed days, and parenteral fluid days, but not oral fed days, or days on diuretics. BUN/Cr values at discharge were not associated with NPO days, parenteral fluid days, oral fed days, or days on diuretics. Patients on modified solid diets had significantly higher mean BUN/Cr values at discharge (27.12 vs. 17.23) as did tube fed patients (28.94 vs. 18.66). No difference was noted between these subgroups at baseline (regular diet vs. modified solids diets). Any modification of solid diets (31.11 vs. 17.23) or thickened liquids (28.50 vs. 17.81) resulted in significantly elevated BUN/Cr values at discharge. Liquid or diet modifications prescribed for acute stroke patients with dysphagia may impair hydration status in these patients.

Background: The reliability of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system of stroke in siblings of stroke-affected probands has not been tested. Similarly, the reliability of using clinical medical records to classify ischemic stroke has not been assessed. The purpose of this study was to establish the interrater reliability of sibling stroke subtyping by applying the TOAST criteria to retrospectively obtained medical records. Methods: Thirty medical records were randomly sampled from among the records of all siblings previously classified as stroke affected by the Siblings with Ischemic Stroke Study (SWISS) Stroke Verification Committee. Blinded medical records for these individuals were sent to 6 physician reviewers who independently classified TOAST stroke subtype on the basis of record review. Results: Using the κ statistic to assess interrater reliability, the overall reliability (SE) for assigning a TOAST subtype of stroke was 0.54 (0.03). Pair-wise comparisons between the original SWISS Stroke Verification Committee diagnoses and the diagnoses made by other reviewers exhibited moderate reliability (κ range 0.41-0.56). The κ statistics for common stroke subtypes were large vessel, 0.80 (0.06); cardioembolic, 0.80 (0.06); small vessel, 0.53 (0.06); and unknown cause, 0.40 (0.06). Conclusion We conclude that TOAST subtyping had moderate interrater reliability. Large-artery and cardioembolic subtype diagnoses seemed most reliable.

Background and Purpose— Giving stroke victims who reside outside communities with hospitals that can administer tissue plasminogen activator (rtPA) access to thrombolytic therapy is a challenge. Helicopter transport to a stroke center is a potential way to make rtPA available to these communities. We examined the experience of the Shands-Jacksonville Acute Stroke Transport Program, a field-to-stroke center helicopter transport program that serves rural counties in the northeastern Florida/southeastern Georgia region. Methods— Prospectively collected data of 111 consecutive helicopter transports to Shands-Jacksonville, from an 11-county region, over a 3-year period were reviewed. Results— Eighty-five patients (76%) had a cerebrovascular event. Forty-seven patients (42%) had an ischemic stroke, 19 (17%) had a transient ischemic attack, and 19 (17%) had a hemorrhagic stroke. Thrombolytic therapy was administered to 18 ischemic stroke patients (38%), with 15 being treated intravenously. Three patients who arrived beyond the 3-hour window were treated intra-arterially. Average field-to-hospital distance for all patients was 29.4 miles (range, 11 to 90 miles). Most patients (n=65) arrived within 135 minutes from symptom onset. Conclusions— A helicopter-based transport system can link a rural region to a stroke center and promote access to thrombolytic therapy.

Introduction: Nurses who provide inpatient care to acute ischemic stroke (AIS) patients routinely perform neurologic assessments that are intended to monitor the stability of neurological deficit. A variety of assessment tools are used, however none of these tools have been validated as a stroke specific assessment tool for nurses. The purpose of this study was to evaluate the validity of a novel nurse performed stroke assessment tool, the Post Stroke Assessment Tool (PSAT). Methods: An interdisciplinary team, from a single certified primary stroke center devised the PSAT. The PSAT encompasses evaluation of 4 components of neurologic function (level of consciousness, cranial nerves, limb strength, and limb coordination). PSAT scores range from 0 (no deficits) to 63. A Clinical Nurse Educator trained neurology nurses on PSAT performance prior to study initiation. A nurse performed the PSAT on patients with AIS. A physician performed the National Institutes of Health Stroke Scale (NIHSS) within 30 minutes of PSAT completion. General linear regression and Pearson correlation was used to evaluate the relationship between scores. All analysis was done in SAS® Version 9.3 for Windows. Results: A total of 26 nurses conducted a PSAT on 46 patients. Mean NIHSS was 6.1 (S.D. +/- 6.9) and mean PSAT score was 10.2 (S.D. +/- 11.8). The r 2 was 0.8349. Overall, the model was significant (p-value < 0.0001). Both the regression model and Pearson correlation showed a significant relationship between PSAT and NIHSS (p Conclusions: In this exploratory study, the PSAT appears to be a reliable nursing assessment tool to monitor post stroke neurologic deficit. Total and categorical PSAT scores highly correlated with total and categorical NIHSS scores. No attempt to compare inter-rater reliability from one nurse to another was included in this study. Future research concerning the reliability of the PSAT will be necessary before this tool can become a standard nursing assessment for patients following AIS.

Several hereditary disorders induce angiopathy in the intracranial cerebrovasculature and thus cause ischemic strokes. MELAS is a maternally inherited mitochondrial disorder that produces stroke-like events. Sickle cell disease, which is the result of a single base pair substitution, is a major cause of strokes in children. Homocystinuria, an autosomal recessive syndrome, produces premature atherosclerosis. Hereditary cerebroretinal vasculopathy is an autosomal dominant disorder that causes retinal and brain infarctions. Fabry disease is an x-linked disorder that can cause stroke in adults. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is an autosomal dominant syndrome that is associated with ischemic stroke and migraine-like headaches. The clinical presentation, stroke pathophysiology, and gene defects associated with these heritable disorders are reviewed.

Introduction Inadequate health literacy is a pervasive problem with major implications for reduced health status and health disparities. Despite the role of focused education in both primary and secondary prevention of stroke, the effect of health literacy on stroke education retention has not been reported. We examined the relationship of health literacy to the retention of knowledge after recommended stroke education. Methods This prospective cross-sectional study was conducted at an urban safety-net hospital. Study subjects were patients older than 18 admitted to the hospital stroke unit with a diagnosis of acute ischemic stroke who were able to provide informed consent to participate (N = 100). Health literacy levels were measured by using the short form of Test of Functional Health Literacy in Adults. Patient education was provided to patients at an inpatient stroke unit by using standardized protocols, in compliance with Joint Commission specifications. The education outcomes for poststroke care education, knowledge retention, was assessed for each subject. The effect of health literacy on the Stroke Patient Education Retention scores was assessed by using univariate and multivariate analyses. Results Of the 100 participating patients, 59% had inadequate to marginal health literacy. Stroke patients who had marginal health literacy (mean score, 7.45; standard deviation [SD], 1.9) or adequate health literacy (mean score, 7.31; SD, 1.76) had statistically higher education outcome scores than those identified as having inadequate health literacy (mean score, 5.58; SD, 2.06). Results from multivariate analysis indicated that adequate health literacy was most predictive of education outcome retention. Conclusions This study demonstrated a clear relationship between health literacy and stroke education outcomes. Studies are needed to better understand the relationship of health literacy to key educational outcomes for primary or secondary prevention of stroke and to refine stroke education for literacy levels of high-risk populations.

Introduction: The National Institutes of Health Stroke Scale (NIHSS) quantifies physical impairment caused by stroke. Emergency Medicine (EM) physicians must be competent to perform the NIHSS as scale cut points are utilized to identify patients with acute ischemic stroke who may be candidates for thrombolytic therapy. Simulation is a teaching method that integrates imitation of real life scenarios into educational exercises. This study discerned if standardized patient simulation can be adopted into an educational exercise aimed at training EM residents to adequately perform the NIHSS. Methods: This preliminary study was completed with EM residents, in various years of training, from a single academic center. All residents attended a lecture on performance of the NIHSS. Each resident then performed the NIHSS on 2 patients with chronic, fixed neurological deficits. Residents were observed by a NIHSS certified healthcare professional who gave immediate feedback on examination technique. Data was analyzed with basic statistics using means and standard deviations (± SD). Results: Twenty eight EM residents, 7 NIHSS certified healthcare professionals (1 Neurologist, 5 Neurology residents, 1 nurse), and 7 patients participated in the trial. Mean certifier NIHSS score of patients was 2.7 (SD ±1.6). Resident score exactly correlated with certifier score in 11/56 examinations (20%), was within ±2 points of the certifier score in 28 examinations (50%), and within ±3 or 4 in 17 examinations (30%). Average time to complete one patient examination was 5 minutes 36 seconds (SD ±1 min 3 sec). In a post exercise survey, all residents rated this training experience as being beneficial to their medical training. Conclusions: An educational format incorporating didactic and return demonstration aimed at training a large group of EM residents to competently perform the NIHSS is practical. Immediate feedback on examination technique and a relatively short time to complete the educational exercise are advantages of this format compared to on-line training modules often used to educate physicians. Further refinement of this exercise is necessary before it can be used for the purpose of NIHSS certification.

Isolated observations suggest a role for genetic risk factors in intracerebral hemorrhage (ICH). However, no systematic evaluation on the role of DNA variation in ICH has been attempted to date. We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls. We included 1104 ICH cases attributable to cerebral amyloid angiopathy (CAA-ICH) and 1085 hypertensive ICH cases (H-ICH). Recently developed methods were used to determine heritability from unrelated ICH cases and controls. We also analyzed clinical ICH phenotypes: …

Background and Purpose— Intracerebral hemorrhage (ICH) is the acute manifestation of a progressive disease of the cerebral small vessels. The severity of this disease seems to influence not only risk of ICH but also the size of the hematoma. As the burden of high blood pressure–related alleles is associated with both hypertension-related end-organ damage and risk of ICH, we sought to determine whether this burden influences ICH baseline hematoma volume. Methods— Prospective study in subjects of European descent with supratentorial ICH who underwent genome-wide genotyping. Forty-two single nucleotide polymorphisms associated with high blood pressure were identified from a publicly available database. A genetic risk score was constructed based on these single nucleotide polymorphisms. The score was used as the independent variable in univariate and multivariate regression models for admission ICH volume and poor clinical outcome (modified Rankin Scale, 3–6). Results— A total of 323 ICH cases were enrolled in the study (135 deep and 188 lobar intracranial hematomas). The blood pressure–based genetic risk score was associated with both baseline hematoma volume and poor clinical outcome specifically in deep ICH. In multivariate regression analyses, each additional SD of the score increased mean deep ICH volume by 28% (or 2.7 mL increase; β=0.28; SE=0.11; P =0.009) and risk of poor clinical outcome by 71% (odds ratio, 1.71; 95% confidence interval, 1.05–2.80; P =0.03). Conclusions— Increasing numbers of high blood pressure–related alleles are associated with mean baseline hematoma volume and poor clinical outcome in ICH. These findings suggest that the small vessel vasculopathy responsible for the occurrence of the hemorrhage also influences its volume.

To date there is only one single-center study that has exclusively reported characteristics, location, and outcomes of spontaneous intracerebral hemorrhages (ICH) among cocaine users. We aimed to describe the radiological location and characteristics along with clinical outcomes of spontaneous ICH in a similar population. We conducted a retrospective chart review of consecutive patients admitted to a tertiary care hospital, with a spontaneous ICH, who had a urine drug screen performed within 48 hours of admission. Exposure to cocaine was defined by a positive urine drug screen within 48 hours of hospital admission. Demographics, radiographic features of ICH, and short-term clinical outcomes of patients with a positive urine drug screen were analyzed and compared with the cocaine negative group. Among the 102 patients analyzed, 20 (19.6%) had documented exposure to cocaine. There was a predominance of males in both groups with significantly more Blacks in the cocaine positive group (P = 0.0246). A statistically significant number of patients with cocaine use had ICH in a subcortical location (P = 0.0224) when compared to cocaine negative patients. There was no difference in GCS, ICH volume, intraventricular extension, ICU days, hospital days, hospital cost, mortality, and ICH score. ICH in cocaine use is more frequently seen in the subcortical location.

Background and Purpose— Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. Methods— We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality. Results— ICH risk heritability was estimated at 29% (SE, 11%) for non- APOE loci and at 15% (SE, 10%) for APOE . Heritability for 90-day ICH mortality was 41% for non- APOE loci and 10% (SE, 9%) for APOE . Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non- APOE loci and at 12% (SE, 4%) for APOE . Conclusions— Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.

Background Patients with Cogan syndrome typically present with nonsyphilitic interstitial keratitis and acute onset of sensorineural hearing loss. Neurological manifestations have been reported, but various frequencies and mechanisms have been proposed. Review summary We critically reviewed the English literature of Cogan syndrome to determine the nature, frequency, and most likely mechanisms of its neurological manifestations. Conclusions On the basis of our review, we believe that Cogan syndrome can be associated with neurological manifestations. Our conclusion is based on reported tissue evidence of vasculitis involving the dura, brain, optic nerve, cochleovestibular nerve, and muscle, in patients with referable symptoms. However, we believe that the frequency of neurological manifestations may have been over reported due to lack of confirmatory testing in many of these cases.

Background and Purpose: The Joint Commission mandates that certified Primary Stroke Centers provide patient education addressing stroke warning signs, use of 911 for access to emergent care, personal risk factors, medications prescribed, and follow-up after discharge. The patient’s retention of this information is imperative for reducing secondary stroke occurrence and morbidity. This study evaluated the Acute Ischemic Stroke (AIS) patient’s ability to retain the stroke education information provided near the time of hospital discharge. Methods: A prospective hospital-based cohort study was comprised of AIS patients who were admitted to the stroke unit at an urban core hospital located in Jacksonville, Florida. Diagnosis of AIS was confirmed by a Neurologist and by a CT or MRI. All participants received Joint Commission mandated stroke education administered by a nurse during their hospitalization. The patient education included verbal instructions with the use of illustrative handouts. Stroke education retention was evaluated near the time of hospital discharge using a five-question survey. The level of health literacy was assessed by the Short Version-Test of Functional Health Literacy in Adults (S-TOFLHA). Results: Of 189 consecutive patients screened between October 2009 and June 2010, 100 (53%) consented to participate. Seventy patients were excluded due to severe cognitive impairment, and 18 eligible patients refused to participate. The average age was 60 years old, 57% were male, 56% African American, 43% resided within the urban core, and 75% earned less than $25,000 per year. A total of 59% of patients had low to marginal health literacy. Retention of stroke knowledge was lacking even with standard stroke post education; 12% could name all 5 warning signs, 43% knew their personal risk factors, 85% knew to call 911 for warning signs of stroke, 76% knew their medications prescribed for stroke prevention, and 53% knew their type of stroke. Conclusion: Current methods of educating hospitalized AIS patients may not adequately prepare the hospitalized stroke survivor with basic knowledge on stroke prevention. Alternative methods of education will need to be developed for AIS patients in urban core hospitals. By using the Patient-Centered Care model and principles of adult learning, this study has the potential to lead to changes in educational interventions, nursing practices, and communication.

Objective: Accumulated evidence suggests that a variant within the CR1 gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences β-amyloid (Aβ) deposition in brain tissue. Given the biologic overlap between AD and cerebral amyloid angiopathy (CAA), a leading cause of intracerebral hemorrhage (ICH) in elderly individuals, we investigated whether rs6656401 increases the risk of CAA-related ICH and influences vascular Aβ deposition. Methods: We performed a case-control genetic association study of 89 individuals with CAA-related ICH and 280 individuals with ICH unrelated to CAA and compared them with 324 ICH-free control subjects. We also investigated the effect of rs6656401 on risk of recurrent CAA-ICH in a prospective longitudinal cohort of ICH survivors. Finally, association with severity of histopathologic CAA was investigated in 544 autopsy specimens from 2 longitudinal studies of aging. Results: rs6656401 was associated with CAA-ICH (odds ratio [OR] = 1.61, 95% confidence interval [CI] 1.19–2.17, p = 8.0 × 10 −4 ) as well as with risk of recurrent CAA-ICH (hazard ratio = 1.35, 95% CI 1.04–1.76, p = 0.024). Genotype at rs6656401 was also associated with severity of CAA pathology at autopsy (OR = 1.34, 95% CI 1.05–1.71, p = 0.009). Adjustment for parenchymal amyloid burden did not cancel this effect, suggesting that, despite the correlation between parenchymal and vascular amyloid pathology, CR1 acts independently on both processes, thus increasing risk of both AD and CAA. Conclusion: The CR1 variant rs6656401 influences risk and recurrence of CAA-ICH, as well as the severity of vascular amyloid deposition.

Dysphagia may predispose stroke patients toward undernutrition and hydration. These comorbidities increase patient risks for reduced functional outcome and short-term mortality. Despite this impact, available information on relationships among dysphagia, nutrition, and hydration status in acute stroke is limited and conflicted. This study evaluated nutrition and hydration status in ischemic stroke patients with versus without clinically significant dysphagia at admission and at discharge from acute care. Sixty-seven patients admitted to the stroke unit in a tertiary-care hospital provided data for this study. On the day of hospital admission and upon discharge or at 7 days post admission, serum biochemical measures were obtained for nutrition (prealbumin) and hydration status (BUN/Cr). Clinical evaluation for dysphagia, nutrition status, and stroke severity were completed an average of 1.4 days following hospital admission. Dysphagia was identified in 37 % of the cohort. At admission 32 % of patients demonstrated malnutrition based on prealbumin levels and 53 % demonstrated evidence of dehydration based on BUN/Cr levels. No differences in nutrition status were attributed to dysphagia. Patients with dysphagia demonstrated significantly higher BUN/Cr levels (greater dehydration) than patients without dysphagia at admission and at discharge. Dehydration at both admission and discharge was associated with dysphagia, clinical nutrition status, and stroke severity. Results of this study support prior results indicating that dysphagia is not associated with poor nutrition status during the first week post stroke. Dehydration status is associated with dysphagia during this period. The results have implications for future confirmatory research and for clinical management of dysphagia in the acute stroke period.

Background and Purpose— Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods— We conducted a prospective multicenter case–control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results— No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02–1.21; P =0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07–1.30; P =0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04–1.31; P =0.009) and ICH cases (OR, 1.15; 95% CI, 1.01–1.31; P =0.04). Similar results were obtained when using a weighted score. Conclusion— Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN.