Background and Purpose— There are few studies analyzing stroke in women, taking into account the vascular risk factors, cause of stroke, clinical picture, and outcome. The purpose of this study was to analyze possible sex differences in patients suffering first-ever acute stroke. Methods— From December 1995 to January 2002, 1581 patients with first-ever acute stroke were analyzed, taking into account sex, age, risk factors, clinical presentation, stroke subtype, treatment, and outcome data. Results— Mean age was higher in women than in men ( P <0.001). Hypertension ( P =0.0027) and cardioembolic disease ( P =0.0035) were independent factors related to women. Alcohol overuse ( P <0.001), smoking ( P <0.001), and vascular peripheral disease ( P =0.031) were related to the male sex. Women more often suffered aphasic disorders ( P <0.001), visual field disturbances ( P <0.05), and dysphagia ( P <0.01) than men. There were no differences in hemorrhagic and ischemic strokes according to sex. Women suffered more cardioembolic strokes ( P <0.001); men suffered more atherothrombotic ( P <0.001) and lacunar strokes ( P <0.05). Women who survived remained more disabled than men ( P <0.001). Conclusions— Sex determines some clear differences in patients suffering a first-ever stroke. Women were, on average, 6 years older than men and had a different profile of vascular risk factors and a different distribution of stroke subtypes. Women had a longer hospital stay and remained more disabled than men. The amelioration of hypertension control and increase in anticoagulant treatment in patients with atrial fibrillation would be the best options for preventing stroke, especially in women.

The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10-8; joint OR 1·19, 1·12-1·26, p=1·30 × 10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10-19; joint OR 1·37, 1·30-1·45, p=2·79 × 10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10-7; joint OR 1·17, 1·11-1·23, p=2·29 × 10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10-8; joint OR 1·24, 1·15-1·33, p=4·52 × 10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10-8; joint OR 1·17, 1·11-1·23, p=2·92 × 10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed. Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. US National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual complication characterized by a decreasing level of consciousness, focal neurological deficits, cognitive slowing, vomiting, drowsiness, and lethargy. We have thoroughly reviewed the predisposing factors and their screening, the biochemical and physiopathological mechanisms involved, the different treatments described, and those that are being investigated. Etiopathogenesis is not completely understood, although hyperammonemia has been postulated as the main cause of the clinical syndrome. The increase in serum ammonium level is due to several mechanisms, the most important one appearing to be the inhibition of carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Polytherapy with several drugs, such as phenobarbital and topiramate, seems to contribute to hyperammonemia. Hyperammonemia leads to an increase in the glutamine level in the brain, which produces astrocyte swelling and cerebral edema. There are several studies that suggest that treatment with supplements of carnitine can lead to an early favorable clinical response due to the probable carnitine deficiency induced by a valproate (VPA) treatment. Development of the progressive confusional syndrome, associated with an increase in seizure frequency after VPA treatment onset, obliges us to rule out VHE by screening for blood ammonium levels and the existence of urea cycle enzyme deficiency, such as ornithine carbamoyltransferase deficiency. Electroencephalography (EEG) is characterized by signs of severe encephalopathy with continuous generalized slowing, a predominance of theta and delta activity, occasional bursts of frontal intermittent rhythmic delta activity, and triphasic waves. These EEG findings, as well as clinical manifestations and hyperammonemia, tend to normalize after VPA withdrawal.

Type 2 diabetes mellitus (DM) is an established risk factor for a wide range of vascular diseases, including ischemic stroke (IS). Glycated hemoglobin A1c (HbA1c), a marker for average blood glucose levels over the previous 12 weeks, is used as a measure of glycemic control and also as a diagnostic criterion for diabetes (HbA1c levels ≥ 6.5%). Epigenetic mechanisms, such as DNA methylation, may be associated with aging processes and with modulation of the risk of various pathologies, such as DM. Specifically, DNA methylation could be one of the mechanisms mediating the relation between DM and environmental exposures. Our goal was to identify new CpG methylation sites associated with DM. We performed a genome-wide methylation study in whole-blood DNA from an IS patient cohorts. Illumina HumanMethylation450 BeadChip array was used to measure DNA methylation in CpG sites. All statistical analyses were adjusted for sex, age, hyperlipidemia, body mass index (BMI), smoking habit and cell count. Findings were replicated in two independent cohorts, an IS cohort and a population-based cohort, using the same array. In the discovery phase (N = 355), we identified a CpG site, cg19693031 (located in the TXNIP gene) that was associated with DM (P = 1.17 × 10⁻¹²); this CpG was replicated in two independent cohorts (N = 167 and N = 645). Methylation of TXNIP was inversely and intensely associated with HbA1c levels (P = 7.3 × 10⁻¹⁶), specifically related to diabetic patients with poor control of glucose levels. We identified an association between the TXNIP gene and DM through epigenetic mechanisms, related to sustained hyperglycemia levels (HbA1c ≥ 7%).

Background and Purpose— The aim of our study was to identify factors associated with stroke recurrence after an initial minor stroke or transient ischemic attack (TIA) in a prospective hospital-series. Methods— Included in the series were 689 patients with NIHSS lower than 4 at hospital admission. The end point was a new neurological event (worsening ≥4 points in the initial NIHSS was considered as recurrence) at 90 days (and additionally at 7 days). Factors based on two previous reported scores (ABCD and SPI-II) were analyzed in relation with stroke recurrence: age, duration of symptoms >1 hour, weakness, speech impairment, initial hypertension, hypertension, diabetes, coronary disease, minor stroke versus TIA, prior stroke, and heart failure. We also analyzed: gender, hyperlipidemia, severe alcohol intake (>60gr/d), current smoking habits, peripheral arterial disease, atrial fibrillation, acute lesion in initial head computed tomography, severe symptomatic extra or intracranial arterial disease (SSAD; arterial stenosis ≥70%), previous TIA, and vertebrobasilar event. Patients were also analyzed separately according to diagnosis of TIA or minor stroke. Results— 90-day recurrence occurred in 111 patients (16.1%), whereas 62 patients had 7-day recurrence (9%). The independent variables associated with 90-day recurrence were: SSAD (OR=4.97), weakness (OR=3.25), speech impairment (OR=1.96), severe alcohol intake (OR=4.18), heart failure (OR=2.41), previous TIA (OR=4.62), and vertebrobasilar events (OR=2.87). SSAD was independently associated with 7-day recurrence (OR=7.73) and also for TIA (OR=3.45) and minor stroke (OR=5.15) patients. Conclusions— An arterial study to discard SSAD would be necessary, in combination with clinical factors, to improve the identification of patients with a higher risk of 90-day recurrence after an initial minor stroke or TIA.