Consensus statements and recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 11-13 November 2018

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 and ) 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.Peer reviewe

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Genetic analysis of ischemic stroke and predisposing carotid artery stenosis : A stroke carol

Ischemic cerebrovascular disease (ICVD), consisting of ischemic stroke and transient ischemic attacks (TIA), is a complex disease where contribution from both the environment and genes promote pathogenesis of the disease-complex. Carotid stenosis is sometimes a predisposing factor or cause for ICVD and a complex disease in itself. Studies of adoptees and twins support the idea that genes are of importance in ICVD and family studies in CS. Two different strategies have been applied to search the genome for ICVD genes, a candidate genome approach and a genome-wide search in familial disease. During the last two decades different candidate genes coding for coagulation-proteins, lipoproteins, renin-angiotensin-aldosterone system and different inflammatory genes have been investigated with different results. Successful examples of the genome-wide search are the phosphodiesterase 4D (PDE4D) gene and the 5- lipoxygenase activating protein (ALOX5AP) gene found in an Icelandic population. These genes have later been studied as a candidate gene in different populations. The South Stockholm Ischemic Stroke Study (SSISS) was started in 1996 to study genetic associations of ICVD and predisposing carotid stenosis (CS), the hypothesis being that genetic factors could be used to find more coherent pathogenetical subgroups to the ischemic cerebrovascular disease complex to facilitate a more individual treatment and prophylaxis. During the first phase of the project three suspected susceptibility genes were examined in a smaller cohort (<200) of patients, namely lipoprotein lipase (LPL), methylene-tetrahydrofolate reductase (MTHFR) and angiotensin-converting enzyme (ACE). We concluded that LPL and MTHFR polymorphisms did not contribute greatly to the overall risk of ICVD or CS. In the examination of ACE we found a significant difference for the presumed susceptibility allele in patients with CS compared to healthy controls and age-matched non-CS ICVD patients. We concluded that the ACE gene polymorphism is a risk factor for the development of CS. In the last phase of the project we expanded the material to more than 1000 patients with ICVD and phenotyped the subjects in detail including subtyping by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. We went on to examine PDE4D and ALOX5AP, genes discovered by linkage analysis on Iceland. We were not able confirm the association between the ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the large artery atherosclerosis (LAA) TOAST subtype. Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, were consistent with the original Icelandic association, with a trend in the whole ICVD group, strengthened in LAA and the combined group of LAA and cardio embolic (CE) subtypes. In the last study we examined 100 polymorphisms in 47 suspected susceptibility genes and found three polymorphisms to be weakly associated with ICVD after correction for age and gender (LPL, angiotensinogen and guanine nucleotide-binding protein beta-3). These markers were differently prevalent in the subtypes examined. Factor VII, apolipoprotein E and two renin polymorphisms were significantly more frequent in patients with evidence of CS compared to non-CS patients. In conclusion we have found weak associations to some candidate genes and by subdividing ICVD patients by presence of CS the patterns of association change. We therefore conclude that larger well phenotyped ICVD cohorts are needed

Elevated plasma homocysteine upon ischemic stroke is associated with increased long-term mortality in women.

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). During 10 years of follow-up (median 5.5 years), 47 patients (32%) with low homocysteine and 94 (51%) with high homocysteine died (p = 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

Idiopathic Small Fiber Neuropathy : Phenotype, Etiologies, and the Search for Fabry Disease

Background and Purpose 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. Methods 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). Results 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. Conclusions 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

Kaplan-Meier survival curves for 10-year observation of 1-month survivors by tHcy status.

<p>The analyses were performed for all patients (a), for women (b), and men (c).</p

Baseline characteristics of study participants according to plasma homocysteine levels.

<p>Baseline characteristics of study participants according to plasma homocysteine levels.</p

Hospital comparison of stroke care in Sweden : a register-based study

Background and purpose 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). Method 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. Results 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. Conclusion 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

To Alfred Deakin

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldOBJECTIVE: To find sequence variants that associate with the risk for ischemic stroke (IS), we performed a genome-wide association study. METHODS: 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). RESULTS: 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. INTERPRETATION: 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