Konstantinos Kostulas

We expanded our genome-wide association study on atrial fibrillation (AF) in Iceland, which previously identified risk variants on 4q25, and tested the most significant associations in samples from Iceland, Norway and the United States. A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated significantly with AF (odds ratio OR = 1.21, P = 1.4 x 10(-10)). This variant also associated with ischemic stroke (OR = 1.11, P = 0.00054) and cardioembolic stroke (OR = 1.22, P = 0.00021) in a combined analysis of five stroke samples.

Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

To find sequence variants that associate with the risk for ischemic stroke (IS), we performed a genome-wide association study.We genotyped 1,661 Icelandic IS patients and 10,815 control subjects using the Infinium HumanHap300 chip (Illumina, San Diego, CA). A total of 310,881 single nucleotide polymorphisms (SNPs) were tested for association with IS, and the most significant signals were replicated in two large European IS sample sets (2,224 cases/2,583 control subjects). Two SNPs, rs2200733 and rs10033464, were tested further in additional European IS samples (2,327 patients and 16,760 control subjects).In the Icelandic samples and the two replication sets combined, rs2200733 associated significantly with cardioembolic stroke (CES) (odds ratio [OR], 1.54; p = 8.05 x 10(-9)). No other variants associated with IS or any of its subtypes. rs2200733 associated significantly with IS in all sample sets combined (OR, 1.26; p = 2.18 x 10(-10)), and both rs2200733 and its neighbour, rs10033464 associated strongly with CES (rs2200733: OR, 1.52; p = 5.8 x 10(-12); rs10033464: OR, 1.27; p = 6.1 x 10(-4)). Interestingly, rs2200733 also showed significant association to IS not classified as CES.We discovered that variants previously shown to associate with atrial fibrillation (AF), rs2200733 and rs10033464, significantly associated with IS, with the strongest risk for CES. The association with noncardiogenic stroke is intriguing and suggests that atrial fibrillation may be underdiagnosed in patients presenting with stroke. This discovery may have implications for workup and treatment of IS.

The purpose of the European Stroke Organisation–Karolinska Stroke Update Conference is to provide updates on recent stroke therapy research and to give an opportunity for the participants to discuss how these results may be implemented into clinical routine. The meeting started 22 years ago as Karolinska Stroke Update, but since 2014 it is a joint conference with European Stroke Organisation. Importantly, it provides a platform for discussion on the European Stroke Organisation guidelines process and on recommendations to the European Stroke Organisation guidelines committee on specific topics. By this, it adds a direct influence from stroke professionals otherwise not involved in committees and work groups on the guideline procedure. The discussions at the conference may also inspire new guidelines when motivated. The topics raised at the meeting are selected by the scientific programme committee mainly based on recent important scientific publications. This year’s European Stroke Organisation–Karolinska Stroke Update Meeting was held in Stockholm on 11–13 November 2018. There were 11 scientific sessions discussed in the meeting including two short sessions. Each session except the short sessions produced a consensus statement (Full version with background, issues, conclusions and references are published as web-material and at www.eso-karolinska.org and http://eso-stroke.org) and recommendations which were prepared by a writing committee consisting of session chair(s), scientific secretary and speakers. These statements were presented to the 250 participants of the meeting. In the open meeting, general participants commented on the consensus statement and recommendations and the final document were adjusted based on the discussion from the general participants Recommendations (grade of evidence) were graded according to the 1998 Karolinska Stroke Update meeting with regard to the strength of evidence. Grade A Evidence: Strong support from randomised controlled trials and statistical reviews (at least one randomised controlled trial plus one statistical review). Grade B Evidence: Support from randomised controlled trials and statistical reviews (one randomised controlled trial or one statistical review). Grade C Evidence: No reasonable support from randomised controlled trials, recommendations based on small randomised and/or non-randomised controlled trials evidence.

The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components.It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis.The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (n(e) = 4,572); venous thromboembolism (n(e) = 4,607); intracranial aneurysm (n(e) = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588).LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 × 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 × 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15).LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.

For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms.We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations.There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)).Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.

Although there is increasing evidence for microglial activation after an ischaemic stroke in the infarct core and the peri-infarct region, the “evolution” of the process in stroke patients is poorly known. Using PET and [11C]vinpocetine, we measured the regional changes of TSPO in the brain of nine ischaemic stroke patients up to 14 weeks after the insult. Already a week after stroke there was an increased radioligand uptake, indicating the up-regulation of TSPO and the presence of activated microglia, in both the ischaemic core and the peri-infarct zone. This increased activation showed a steady decrease with post stroke time. The proportion between %SUV values in the peri-infarct zone and the ischaemic core increased with time. There were no time-dependent TSPO activity changes in other regions, not affected directly by the stroke. The present observations demonstrate that increased regional microglia activation, as a consequence of stroke, can be visualised with PET, using the TSPO molecular imaging biomarker [11C]vinpocetine. The evolution of this microglial activation shows a time dependent decrease the gradient of which is different between the peri-infarct zone and the ischaemic core. The findings indicate an increased microglial activation in the peri-stroke region for several weeks after the insult.

Background Prior statin treatment and high admission cholesterol have been associated with favorable outcome after ischemic stroke (IS), a paradox not completely explained. The aim of this study was to investigate the effect of admission cholesterol levels and the impact of statin treatment on short- and long-term survival after IS. Methods Consecutive patients admitted in 2006 and 2010 were included in the study. Total cholesterol of 4.6 mmol/L or more was defined as high. Logistic regression analysis was performed to assess predictors of 1-month mortality, and Cox proportional hazard regression analysis was applied to investigate predictors of long-term mortality. Results Of 190 patients included in the final analysis, 21 (11%) died within 1 month and 61 (32%) died during 7 years of observation. Low cholesterol was associated with older age, lower blood pressure (BP), presence of angina, and higher risk of death. Three-month, 1-year, and 5-year survival rates were 100%, 98%, and 84%, respectively, in high cholesterol patients, compared with 92%, 87%, and 57% in low cholesterol group (P = .0001 with the log-rank test). Mortality risk was increased for patients with low cholesterol (hazard ratio: 1.97; 95% confidence interval [CI]: 1.05-3.69), after adjustment for age and admission National Institutes of Health Stroke Scale score. After further adjustment for angina and admission BP, the effect of cholesterol on mortality risk was still obvious, yet attenuated (hazard ratio: 1.87; 95% CI: .94-3.32). Conclusions High admission cholesterol may be associated with increased long-term survival after IS. Future studies on the temporal profile of cholesterol levels and stroke outcome would be of interest. Prior statin treatment and high admission cholesterol have been associated with favorable outcome after ischemic stroke (IS), a paradox not completely explained. The aim of this study was to investigate the effect of admission cholesterol levels and the impact of statin treatment on short- and long-term survival after IS. Consecutive patients admitted in 2006 and 2010 were included in the study. Total cholesterol of 4.6 mmol/L or more was defined as high. Logistic regression analysis was performed to assess predictors of 1-month mortality, and Cox proportional hazard regression analysis was applied to investigate predictors of long-term mortality. Of 190 patients included in the final analysis, 21 (11%) died within 1 month and 61 (32%) died during 7 years of observation. Low cholesterol was associated with older age, lower blood pressure (BP), presence of angina, and higher risk of death. Three-month, 1-year, and 5-year survival rates were 100%, 98%, and 84%, respectively, in high cholesterol patients, compared with 92%, 87%, and 57% in low cholesterol group (P = .0001 with the log-rank test). Mortality risk was increased for patients with low cholesterol (hazard ratio: 1.97; 95% confidence interval [CI]: 1.05-3.69), after adjustment for age and admission National Institutes of Health Stroke Scale score. After further adjustment for angina and admission BP, the effect of cholesterol on mortality risk was still obvious, yet attenuated (hazard ratio: 1.87; 95% CI: .94-3.32). High admission cholesterol may be associated with increased long-term survival after IS. Future studies on the temporal profile of cholesterol levels and stroke outcome would be of interest.

With the main objective of comparing the prospective diagnostic power of two 11C-labelled molecular imaging biomarkers with affinity for TSPO and used for the visualisation of activated microglia after a stroke, we measured with positron emission tomography (PET) in four post-stroke patients the regional brain uptake and binding potential of [11C]vinpocetine and [11C]PK11195. Percentage standard uptake values (%SUV) and binding potential (BPND) were used as outcome measures. The total peak brain uptake value and average global brain uptake value were higher for [11C]vinpocetine than for [11C]PK11195. The regional %SUV values were significantly higher for [11C]vinpocetine than for [11C]PK11195 in the hemispheres as well as in almost all standard brain regions. The %SUV values of [11C]vinpocetine were higher in the peri-infarct zone than in the ischaemic core, however, the difference did not prove to be significant. There was basically no difference in %SUV values between the ischaemic core and the peri-infarct zone for [11C]PK11195. The BPND values for [11C]vinpocetine were higher in all standard regions than those for [11C]PK11195, but the difference was not significant between them. The BPND values of [11C]vinpocetine were higher in the peri-infarct zone than in the ischaemic core, however, the difference did not prove to be significant. A comparative analysis of the two ligands indicates that [11C]vinpocetine shows a number of favourable characteristics over [11C]PK11195, but to demonstrate that it may serve as a prospective molecular imaging biomarker of microglia activation in post-stroke patients, further studies are required. Keywords: (PBR)18 kD translocator protein (TSPO), molecular imaging biomarker, peripheral benzodiazepine receptor, [11C]PK11195, microglia, [11C]vipocetine, radioligand, Positron emission tomography (PET), stroke, peripheral benzodiazepine receptor (PBR)

The etiology of small fiber neuropathy (SFN) often remains unclear. Since SFN may be the only symptom of late-onset Fabry disease, it may be underdiagnosed in patients with idiopathic polyneuropathy. We aimed to uncover the etiological causes of seemingly idiopathic SFN by applying a focused investigatory procedure, to describe the clinical phenotype of true idiopathic SFN, and to elucidate the possible prevalence of late-onset Fabry disease in these patients.Forty-seven adults younger than 60 years with seemingly idiopathic pure or predominantly small fiber sensory neuropathy underwent a standardized focused etiological and clinical investigation. The patients deemed to have true idiopathic SFN underwent genetic analysis of the alpha-galactosidase A gene (GLA) that encodes the enzyme alpha-galactosidase A (Fabry disease).The following etiologies were identified in 12 patients: impaired glucose tolerance (58.3%), diabetes mellitus (16.6%), alcohol abuse (8.3%), mitochondrial disease (8.3%), and hereditary neuropathy (8.3%). Genetic alterations of unknown clinical significance in GLA were detected in 6 of the 29 patients with true idiopathic SFN, but this rate did not differ significantly from that in healthy controls (n=203). None of the patients with genetic alterations in GLA had significant biochemical abnormalities simultaneously in blood, urine, and skin tissue.A focused investigation may aid in uncovering further etiological factors in patients with seemingly idiopathic SFN, such as impaired glucose tolerance. However, idiopathic SFN in young to middle-aged Swedish patients does not seem to be due to late-onset Fabry disease.

Background Genetic variants in Phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP) have been shown to confer risk of Ischemic Cerebrovascular Disease (ICVD) in Iceland. We investigated whether these variants associate with ICVD in Sweden. Methods Previously published PDE4D and ALOX5AP gene variants were genotyped for cases (685) and controls (751). In PDE4D this consisted of SNP41, SNP45 and microsatellite AC008818-1 and in ALOX5AP four SNPs that define the HapA haplotype. Results The PDE4D SNPs, showed a non-significant risk in the ICVD group which increased for the Large Artery Atherosclerosis subtype (SNP45: RR=1.43, P=0.063, SNP41: RR=1.57, P=0.018). The SNP haplotype GA (SNP45, SNP41) showed an increased risk for LAA (RR=1.58, P=0.016) and the combined LAA and Cardioembolism (CE) (RR=1.34, P=0.031) subgroups. As the SNPs are in strong LD, this haplotype corresponds to the complement of the protective haplotype in the Icelandic study. No allele of the microsatellite marker, showed association to stroke or any subtype and nor did the Icelandic PDE4D at-risk haplotype (GA0). We did not confirm the association between ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the LAA subtype. Conclusion Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, are consistent with the association observed in the original study, with a trend observed in the whole ICVD group, which was strengthened in the stroke subtype LAA and the combined group of LAA and CE stroke. This supports the notion that PDE4D contributes to the risk of developing stroke.

Background Ischaemic cerebrovascular disease (ICVD) is a heterogeneous syndrome to which different genetic factors may contribute. We have investigated the distribution of alleles of the angiotensin‐converting enzyme (ACE) gene, which has been suggested to be of possible importance in ischaemic stroke or cardiovascular disease, in groups of patients with ischaemic stroke and carotid artery stenosis (CS). Materials and methods One hundred and thirty patients with ischaemic stroke and 68 patients with more than 50% stenosis of the internal carotid artery were investigated and compared with age‐ and sex‐matched healthy control subjects. Alleles of an insertion/deletion polymorphism of the ACE gene were determined by one‐stage polymerase chain reaction and visualized on agarose gels. Results There was a significant difference ( P &lt; 0.05) in the distribution of ACE alleles, homozygosity for the presumed susceptibility deletion allele being more common in patients with CS than in healthy control subjects. There was also a significant difference ( P &lt; 0.05) in patients with CS in comparison with matched ICVD patients without CS, both in allelic frequencies and in homozygosity for the deletion allele. Conclusions Our results indicate that the ACE gene polymorphism may be a risk factor for the development of CS. The observed difference in ACE allele distribution may be seen as evidence for a genetic distinction between ICVD and CS, two clinically related conditions, which further supports the hypothesis that genetic factors are of importance for this group of diseases.

Background Patent foramen ovale (PFO) is considered to be a risk factor for ischemic cerebrovascular disease (ICVD), especially in young people. However, the potential pathophysiological relevance in ischemic stroke is controversial and in need of further investigation. In this study, we examined the conventional risk factors and the distribution of 100 polymorphisms in 47 suspected susceptibility genes for ICVD in stroke patients with or without a PFO. Methods In the South Stockholm Ischemic Stroke Study, 928 ICVD patients and 602 controls were genotyped for 100 different gene polymorphisms. The stroke patients also underwent relevant investigation and standardized blood tests. Patients who underwent transeosophageal echocardiography as part of their investigation were divided into groups that either had or did not have a PFO. Results There were no significant differences in the 2 groups with regard to conventional risk factors or blood analyses. Three different polymorphisms located in the prothrombin, F2 (20210G/A), and apolipoprotein-C3 (−641A/C and −455T/A) genes were significantly associated with ICVD and PFO. The strongest association was found for F2 (P = .0049; odds ratio 26.4). Conclusions We found that F2, which previously has been described as being a possible link between PFO and ICVD, was significantly associated with ICVD and PFO. There was also a trend toward an association between 2 other polymorphisms in the APO-CIII gene and PFO and ICVD. Patent foramen ovale (PFO) is considered to be a risk factor for ischemic cerebrovascular disease (ICVD), especially in young people. However, the potential pathophysiological relevance in ischemic stroke is controversial and in need of further investigation. In this study, we examined the conventional risk factors and the distribution of 100 polymorphisms in 47 suspected susceptibility genes for ICVD in stroke patients with or without a PFO. In the South Stockholm Ischemic Stroke Study, 928 ICVD patients and 602 controls were genotyped for 100 different gene polymorphisms. The stroke patients also underwent relevant investigation and standardized blood tests. Patients who underwent transeosophageal echocardiography as part of their investigation were divided into groups that either had or did not have a PFO. There were no significant differences in the 2 groups with regard to conventional risk factors or blood analyses. Three different polymorphisms located in the prothrombin, F2 (20210G/A), and apolipoprotein-C3 (−641A/C and −455T/A) genes were significantly associated with ICVD and PFO. The strongest association was found for F2 (P = .0049; odds ratio 26.4). We found that F2, which previously has been described as being a possible link between PFO and ICVD, was significantly associated with ICVD and PFO. There was also a trend toward an association between 2 other polymorphisms in the APO-CIII gene and PFO and ICVD.

Electrical Bioimpedance Cerebral Monitoring is assessment in real time of health of brain tissue through study of passive dielectric properties of brain. During the last two decades theory and technology have been developed in parallel with animal experiments aiming to confirm feasibility of using bioimpedance-based technology for prompt detection of brain damage. Here, for the first time, we show that electrical bioimpedance measurements for left and right hemispheres are significantly different in acute cases of unilateral stroke within 24 hours from onset.Electrical BIS measurements have been taken in healthy volunteers and patients suffering from acute stroke within 24 hours of onset. BIS measurements have been obtained using SFB7 bioimpedance spectrometer manufactured by Impedimed ltd. and 4-electrode method. Measurement electrodes, current, and voltage have been placed according to 10-20 EEG system obtaining mutual BIS measurements from 4 different channels situated in pairs symmetrically from the midsagittal line. Obtained BIS data has been analyzed, assessing for symmetries and differences regarding healthy control data.7 out of 10 patients for Side-2-Side comparisons and 8 out 10 for central/lateral comparison presented values outside the range defined by healthy control group. When combined only 1 of 10 patients exhibited values within the healthy range.If these initial observations are confirmed with more patients, we can foresee emerging of noninvasive monitoring technology for brain damage with the potential to lead to paradigm shift in treatment of brain stroke and traumatic brain damage.

Ischaemic stroke is pathogenetically heterogeneous, but there is strong evidence that genetic as well as environment factors contribute to the risk of the individual. Here we report the similar distribution of polymorphic markers of the lipoprotein lipase (LPL) gene in 128 patients with ischaemic stroke, 56 patients with carotid artery stenosis and 95 healthy control subjects, in spite of a significant influence of the Asn291-->Ser mutation on serum levels of triglycerides. We conclude that these LPL polymorphisms do not contribute greatly to the overall risk of ischaemic stroke in the general population.

Carotid artery stenosis (CS) is a major risk factor for ischemic cerebrovascular disease (ICVD) and is therefore of interest in genetic investigating. Here we report the distribution of 100 polymorphisms in 47 suspected susceptibility genes for ICVD and its risk factors.Previously published markers in suspected susceptibility genes were genotyped in ICVD patients and controls (928/602). Genotyping was performed using multiplex polymerase chain reaction (PCR) and linear immobilized probe array assays. ICVD cases were subtyped according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) or subdivided into CS and non-CS patients by ultrasonography in a separate analysis.Three polymorphisms located in the lipoprotein lipase (LPL), angiotensinogen (AGT) and guanine nucleotide-binding protein beta-3 (GNB3) genes were significantly associated with ICVD after correction for age and gender. The strongest association was found for the protective LPL Ser447Term polymorphism. All the significant markers showed varying frequencies in different subphenotypes of ICVD. Factor VII, apolipoprotein E and two renin polymorphisms were differentially frequent in patients with evidence of CS compared with non-CS patients.We have found that some previously described susceptibility polymorphisms are weakly associated with ICVD and that subdivision of patients into CS and non-CS groups may help to identify new candidate polymorphisms.

The objective of this study was to estimate the level of health outcomes and resource use at a hospital level during the first year after a stroke, and to identify any potential differences between hospitals after adjusting for patient characteristics (case mix).Data from several registries were linked on individual level: seven regional patient administrative systems, Swedish Stroke Register, Statistics Sweden, National Board of Health and Welfare and Swedish Social Insurance Agency. The study population consisted of 14 125 patients presenting with a stroke during 2010. Case-mix adjusted analysis of hospital differences was made on five aspects of health outcomes and resource use, 1 year post-stroke.The results indicated that 26% of patients had died within a year of their stroke. Among those who survived, almost 5% had a recurrent stroke and 40% were left with a disability. On average, the patients had 22 inpatient days and 23 outpatient visits, and 13% had moved into special housing. There were significant variations between hospitals in levels of health outcomes achieved and resources used after adjusting for case mix.Differences in health outcomes and resource use between hospitals were substantial and not entirely explained by differences in patient mix, indicating tendencies of unequal stroke care in Sweden. Healthcare organisation of regions and other structural features could potentially explain parts of the differences identified.

Migraine, especially with aura, is a risk factor for ischemic stroke. In this study, we investigated descriptive data and prevalence of migraine in an in-patient stroke population.Patients with acute cerebrovascular disease (CVD) admitted to the stroke unit during a 6-month period were recruited. Prevalence of migraine was assessed using a structured questionnaire. Additional clinical data regarding risk factors for CVD were evaluated for all responding patients.A total of 229 patients received a questionnaire and 175 answers were collected (response frequency of 76.4%). Responders matched the initial cohort regarding distribution of age, sex, and type of stroke. Thirty-six cases (20.6%) fulfilled the criteria for migraine or probable migraine according to the 2nd edition of the International Headache Classification (ICHD-2). Sixty percent of migraine patients had migraine with aura. Stroke patients with migraine were younger (P = 0.007), the presence of patent foramen ovale (PFO) was significantly increased (P = 0.008), and atrial fibrillation was less common (P = 0.048). There were no other differences between patients with and without migraine headache regarding conventional risk factors.The prevalence of migraine in this hospital-based stroke cohort was comparable to the estimated prevalence of migraine usually described in population studies. In our study population, the prevalence of migraine with aura was higher than expected. The increased prevalence of PFO in patients with migraine headache corresponds well to previous population studies.

Neuropathology and Applied NeurobiologyVolume 32, Issue 4 p. 455-458 Scientific correspondence Q. Miao, Q. Miao Department of Pathology, Turku University Hospital andUniversity of Turku, Turku, Finland, Search for more papers by this authorH. Kalimo, H. Kalimo Department of Pathology, Turku University Hospital andUniversity of Turku, Turku, Finland, Department of Pathology, HelsinkiUniversity and University Hospital, Helsinki, Finland, and Department of Pathology, Uppsala University and AcademicHospital, Uppsala, Sweden, Search for more papers by this authorN. Bogdanovic, N. Bogdanovic Neurotec Department,Karolinska Institutet and Karolinska University HospitalHuddinge, Stockholm, Sweden, Search for more papers by this authorK. Kostulas, K. Kostulas Neurotec Department,Karolinska Institutet and Karolinska University HospitalHuddinge, Stockholm, Sweden, Search for more papers by this authorA. Börjesson-Hanson, A. Börjesson-Hanson Psychiatry Section, SahlgrenskaAcademy at Gothenburg University, Gothenburg, Sweden, Search for more papers by this authorM. Viitanen, M. Viitanen Neurotec Department,Karolinska Institutet and Karolinska University HospitalHuddinge, Stockholm, Sweden, Department of Geriatric Medicine, University of Turku andTurku City Hospital, Turku, FinlandSearch for more papers by this author Q. Miao, Q. Miao Department of Pathology, Turku University Hospital andUniversity of Turku, Turku, Finland, Search for more papers by this authorH. Kalimo, H. Kalimo Department of Pathology, Turku University Hospital andUniversity of Turku, Turku, Finland, Department of Pathology, HelsinkiUniversity and University Hospital, Helsinki, Finland, and Department of Pathology, Uppsala University and AcademicHospital, Uppsala, Sweden, Search for more papers by this authorN. Bogdanovic, N. Bogdanovic Neurotec Department,Karolinska Institutet and Karolinska University HospitalHuddinge, Stockholm, Sweden, Search for more papers by this authorK. Kostulas, K. Kostulas Neurotec Department,Karolinska Institutet and Karolinska University HospitalHuddinge, Stockholm, Sweden, Search for more papers by this authorA. Börjesson-Hanson, A. Börjesson-Hanson Psychiatry Section, SahlgrenskaAcademy at Gothenburg University, Gothenburg, Sweden, Search for more papers by this authorM. Viitanen, M. Viitanen Neurotec Department,Karolinska Institutet and Karolinska University HospitalHuddinge, Stockholm, Sweden, Department of Geriatric Medicine, University of Turku andTurku City Hospital, Turku, FinlandSearch for more papers by this author First published: 07 July 2006 https://doi.org/10.1111/j.1365-2990.2006.00746.xCitations: 8Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume32, Issue4August 2006Pages 455-458 RelatedInformation

Ischemic stroke is a leading cause of death worldwide, despite preventive and therapeutic advances during the last twenty years. Blood-borne biomarkers have been studied in association to short- and long-term outcome, in order to investigate possible modifiable predictors of disability and death. Increased homocysteine has been associated with increased vascular risk and unfavorable outcome, but homocysteine lowering treatment has not consistently been successful in risk reduction. The aim of this study was to investigate homocysteine levels upon acute ischemic stroke in association to long-term mortality.Of 622 patients included in our hospital-based registry, 331 survived the first month after admission, and had a diagnosis of ischemic stroke and available homocysteine values. All-cause and vascular mortality were investigated based on the national patient- and cause of death-registries. Survival analysis and Cox proportional hazard models were used to investigate time to death and predictors of outcome.Of 331 patients, 148 (45%) had low homocysteine (<13 micromol/L) and 183 (55%) had high homocysteine (> = 13 micromol/L). During 10 years of follow-up (median 5.5 years), 47 patients (32%) with low homocysteine and 94 (51%) with high homocysteine died (p<0.0001). Estimated median survival was not reached for the low homocysteine group, and was 80 months in the high homocysteine group (p with log-rank test 0.002). High homocysteine was not independently associated with increased risk for death after adjustment for age, sex, comorbidities, and eGFR (HR 1.29, 95% CI 0.86-1.93; p = 0.2). Subgroup analysis by sex showed that high homocysteine was an independent predictor of mortality in women after adjustment for age and vascular comorbidities (HR 1.85; 95% CI 1.03-3.31; p = 0.04), but not in men (HR 0.87; 95% CI 0.52-1.43; p = 0.6).Increased plasma homocysteine (> = 13 micromol/L) upon acute ischemic stroke was not independently associated with mortality in our study. In the subgroup of women, high homocysteine was associated with increased five-year risk of death. Our study's retrospective design and the exploratory nature of subgroup analysis, prevent robust conclusions based on that observation. Future studies on homocysteine levels before as well as upon stroke will shed further light on a possible causal association.

Nat. Genet. 40, 886–891 (2008); published online 18 May 2008; corrected after print 29 July 2008 In the version of this article initially published, there were two errors in the numbers reported in the abstract. The correct odds ratio for the association of the ASIP haplotype with risk of basal cellcarcinoma is 1.

Migraine, especially migraine with aura, has been described to be associated with an increased risk for ischemic stroke. An increased incidence of silent lesions in the posterior circulation has also been described.Six cases with migraine and stroke in close relation over time were retrospectively reviewed.All patients had previously known MA or MO and suffered from a stroke within the first 24-hour period after an acute migraine attack. None of the patients fulfilled the IHS criteria for migrainous infarction. Four out of these six patients had a patent foramen ovale (PFO) or an atrial septal defect (ASD).None of these cases can be categorized as migrainous infarctions according to IHS. However, the migraine attack might have been involved in the mechanisms for the development of the infarctions.

Patent foramen ovale (PFO) is associated with cryptogenic stroke (CS) and migraine with aura (MA). Endothelial dysfunction (ED) is a risk factor for development of cardiovascular disease, but might also be involved in migraine pathophysiology. Short-term worsening of migraine has been described after closure of PFO. We evaluated endothelial function in patients with CS and PFO, before and after closure of PFO, and in patients with migraine, whether changes in endothelial function was related to a change in migraine frequency.Patients with CS and PFO were included; 20 with planned closure of PFO and seven controls on medical treatment only. Endothelial function was assessed by peripheral arterial tonometry (EndoPatR ) and biomarkers of endothelial activation. Patients were followed longitudinally at baseline, day 1, 1 month, and 6 months. A headache diary was used to assess migraine frequency.Mean age of the cohort was 45.4 years, and migraine prevalence was 50% whereof 84.6% had MA. Median EndoPatR index (RHI) at baseline was 1.60 (IQR 1.41-2.00). There was no change in RHI over time, either in closure patients (P = 0.66), nor in controls (P = 0.31), and there was no change in biomarkers of endothelial activation. Three migraine patients experienced worsening of migraine frequency directly after closure.Endothelial function did not change after closure of PFO. Although patients were lacking cardiovascular risk factors, a high proportion had impaired endothelial function. Whether ED can have predictive value, identifying PFO at higher risk for recurrent stroke warrants further investigations.

Stroke Pathogenesis Alters Dielectric Properties of Brain Tissue Supporting Electrical Bioimpedance Technology as a tool for Cerebral Monitoring