Risk Of Arterial Ischemic Stroke Research Articles

The relationship between thrombotic genetics markers and recurrent arterial ischemic stroke in young (S36.007)

<h3>Objective:</h3> This study aims to determine significant clinical and genetic factors of AIS recurrence. <h3>Background:</h3> The involvement of thrombotic genetic markers such methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T and A1298C), factor V Leiden (FVL), G20210A mutation of prothrombin (PT) and recurrent arterial ischemic stroke (AIS) in adults remains unclear. <h3>Design/Methods:</h3> We investigated a cohort study of AIS patients (18–50 years old) followed in the neurology department over 5 years. Traditional and genetic risk factors were carried out through a multivariable logistic regression model. <h3>Results:</h3> Two hundred and seventy patients were enrolled in our study. The risk of AIS recurrence was 36.2% within 5 years. The potential risk of recurrence of AIS increased with traditional risk factors notably hypertension, diabetes mellitus, heart failure, and family history of cerebrovascular diseases. The TT polymorphism of MTHFR 677 increased 2.4-fold the risk of AIS recurrence (OR: 2.47; 95%CI [1.35–4.53]). Both variants AC and CC of MTHFR 1298 polymorphism were associated with a second ischemic cerebral attack (OR:2.68, 95%CI [1.44–4.90], 6.89, 95%CI [2.35–20.23], respectively). The GA variation of FVL was considered a significant genetic factor increasing the risk of AIS recurrence 2.5-fold (OR: 2.54; 95% CI [1.15–5.61]). But, no significant difference was observed between the two groups concerning PT mutation. <h3>Conclusions:</h3> Our findings suggest that besides traditional risk factors, the MTHFR polymorphisms, and FVL play an important role in increasing the risk of recurrent AIS in young patients. <b>Disclosure:</b> Miss M’barek has nothing to disclose. khadija maalla has nothing to disclose. Nadia Bouattour has nothing to disclose. Sawsan Daoud has nothing to disclose. Nouha Farhat has nothing to disclose. mariem damak has nothing to disclose. Salma Sakka has nothing to disclose. Prof. Mhiri has received personal compensation for serving as an employee of Hikma. Prof. Mhiri has received personal compensation for serving as an employee of Sanofi Genzyme. Prof. Mhiri has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Prof. Mhiri has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche.

Synergistic effect of MTHFR polymorphisms in arterial ischemic stroke in young adult (P3-5.014)

<h3>Objective:</h3> Aims to evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T and A1298C) in arterial ischemic stroke (AIS) among young patients. <h3>Background:</h3> The imputability of MTHFR polymorphisms in the occurrence of AIS remains ambiguous currently. <h3>Design/Methods:</h3> Blood samples were collected from patients and healthy controls aged under 50 years from Tunisia, from January 2015 to December 2019. Statistical analysis was carried out to evaluate the relationship between MTHFR polymorphisms and AIS occurrence. <h3>Results:</h3> A total of 275 cases including 161 patients and 114 healthy controls, all matched for age and gender. The mutant genotypes of MTHFR C677T polymorphisms were found to significantly increase the risk of AIS (p&lt; 10–3). Besides, the CC genotype of MTHFR A1298C polymorphism is significantly more prevalent in the pathologic group when compared to controls (OR: 3.471; 95% CI [1.594–7.557], p &lt; 0.005). regarding the synergistic effect of both MTHFR (C667T/A1298C) polymorphisms, the TT /AA and TT/AC genotype was significantly associated with AIS (OR: 2.225; 95%CI [1.984–5.032] and 2.832 95%CI [1.613–13.091] respectively). The CC/CC genotype was not associated with stroke (p = 0.26). The compound genotype of CT/AC revealed a 4.98-fold increased risk for AIS (OR: 4.98; 95%CI [2.016–12.336]). <h3>Conclusions:</h3> Our study confirmed the involvement of MTHFR polymorphisms as AIS’s important risk factors. We assume that the synergistic effect of both MTHFR polymorphisms increases the risk of the AIS. <b>Disclosure:</b> Miss M’barek has nothing to disclose. khadija maalla has nothing to disclose. Nadia Bouattour has nothing to disclose. Sawsan Daoud has nothing to disclose. Nouha Farhat has nothing to disclose. mariem damak has nothing to disclose. Salma Sakka has nothing to disclose. Prof. Mhiri has received personal compensation for serving as an employee of Hikma. Prof. Mhiri has received personal compensation for serving as an employee of Sanofi Genzyme. Prof. Mhiri has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Prof. Mhiri has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche.

Ethnic-Associated Phenotype Variations in Moyamoya Cerebrovascular Outcomes

Introduction: Moyamoya has been extensively described in East Asian populations, and despite its accepted clinical presentation and course, it is fundamental to describe major cerebrovascular complications in other ethnically diverse samples. Hence, we sought to determine if distinct ethnic groups are at higher risk of developing stroke using the National Inpatient Sample (NIS) database. Methods: We included all moyamoya patients admitted from January 2013 until December 2018 in the NIS database. Multivariate regression analysis was used to determine the risk of developing stroke and poor outcomes in different races compared to white patients. Results: Out of the 6093 admissions with diagnosis of moyamoya disease that were captured, 2,520 were white (41.6%), 2,078 were African American (AA) (34.1%), 721 were Hispanic (11.8%), and 496 were Asian (8.14%). For arterial ischemic stroke (AIS), we found that AA race had a significantly reduced risk of AIS compared to white patients (odds ratio = 0.8, 95% confidence interval: 0.7–0.9, p = 0.031). While being Hispanic or Asian significantly increased 1.5 and 2-fold the risk of hemorrhagic stroke. Conclusion: This study highlights the unique features and phenotypes of moyamoya cases among different ethnicities. While possibly AA are protected from developing AIS due to underlying causes of moyamoya such as sickle cell disease, Asians seems to be more susceptible to hemorrhagic stroke.

Acute Arterial Ischemic Stroke Following COVID-19 Vaccination: A Systematic Review and Meta-analysis.

Acute arterial ischemic stroke (AIS) has been reported as a rare adverse event following coronavirus disease 2019 (COVID-19) vaccination with messenger RNA (mRNA) or viral vector vaccines. However, data are sparse regarding the risk of postvaccination AIS and its potential association with thrombotic-thrombocytopenia syndrome (TTS). A systematic review and meta-analysis of randomized controlled clinical trials (RCTs), pharmacovigilance registries, registry-based studies, observational cohorts, and case-series was performed with the aim to calculate the following: (1) the pooled proportion of patients presenting with AIS following COVID-19 vaccination; (2) the prevalence of AIS after mRNA and vector-based vaccination; and (3) the proportion of TTS among postvaccination AIS cases. Patient characteristics were assessed as secondary outcomes. Two RCTs, 3 cohort studies, and 11 registry-based studies comprising 17,481 AIS cases among 782,989,363 COVID-19 vaccinations were included in the meta-analysis. The pooled proportion of AIS following exposure to any COVID-19 vaccine type was 4.7 cases per 100,000 vaccinations (95% CI 2.2-8.1; I 2 = 99.9%). The pooled proportion of AIS following mRNA vaccination (9.2 cases per 100,000 vaccinations; 95% CI 2.5-19.3; I 2 = 99.9%) did not differ compared with adenovirus-based vaccination (2.9 cases per 100,000 vaccinations; 95% CI 0.3-7.8; I 2 = 99.9%). No differences regarding demographics were disclosed between patients with AIS following mRNA-based or vector-based vaccination. The pooled proportion of TTS among postvaccination AIS cases was 3.1% (95% CI 0.7%-7.2%; I 2 = 78.8%). The pooled proportion of AIS following COVID-19 vaccination is comparable with the prevalence of AIS in the general population and much lower than the AIS prevalence among severe acute respiratory syndrome coronavirus 2-infected patients. TTS is very uncommonly reported in patients with AIS following COVID-19 vaccination.

Arterial Ischemic Stroke in Moyamoya Patients Who Underwent Vaginal Delivery and Cesarean Section

Moyamoya disease (MMD) is characterized by stenosis, occlusion, and formation of aberrant collaterals of brain vessels. This derangement in the brain vessels in conditions associated with changes in intracranial pressure can lead to arterial ischemic stroke (AIS). A major challenge for stroke physicians is to recommend the safest method of delivery for pregnant patients with MMD. Using a large national database, our objective in this study was to analyze the risk of AIS in patients with MMD who underwent vaginal delivery (VD) and cesarean section (C-section). We used the National Inpatient Sample database for the years 2013-2018 to identify patients with a diagnosis of MMD who underwent VD or C-section. Multiple logistic regression was performed to assess the risk of AIS in VD versus C-section. Of 2166 female patients with MMD, 97 underwent VD or C-section: 49 (50.51%) underwent VD, and 48 (49.48%) underwent C-section. The analysis of outcomes between VD and C-section showed a higher prevalence of AIS after VD compared with C-section (8.2% vs 6.3%, P= 0.716). The multivariate analysis for AIS showed that VD is not an independent risk factor compared with C-section (odds ratio= 2.1, 95% CI= 0.3-13.3, P= 0.417). Our data did not find evidence that VD and C-section are risk factors for AIS in pregnant patients with MMD.

Synergic effect of MTHFR and FVL polymorphisms increased risk of arterial ischemic stroke in Tunisia (4159)

Synergic effect of MTHFR and FVL polymorphisms increased risk of arterial ischemic stroke in Tunisia (4159)

АРТЕРИАЛЬНЫЙ ИШЕМИЧЕСКИЙ ИНСУЛЬТ РАННЕГО ВОЗРАСТА, АССОЦИРОВАННЫЙ С МИНЕРАЛИЗУЮЩЕЙ ЛЕНТИКУЛОСТРИАРНОЙ АНГИОПАТИЕЙ И ЛЕГКОЙ ЧЕРЕПНО-МОЗГОВОЙ ТРАВМОЙ

Study aims: 1) to evaluate the significance of mineralizing angiopathy of lenticulostriate arteries (MALA) in the development of arterial ischemic stroke (AIS) in children; 2) to study clinical and neuroimaging signs of AIS that develops after a head injury and does not meet the criteria of known disease types. Material and methods: to achieve the first aim, groups were formed: 1) the main group – patients with AI, n=86, Me 2,9 years; control – healthy children, n=131, Me 3,2 years. In the compared groups, neurosonography (NSG) protocols were studied for MALA. For the second aim, anamnesis and data from a clinical neuroimaging examination of 106 patients with AIS (Me 2,9 years) were analyzed. Stroke type was identified by the Childhood Arterial Ischemic Stroke Standardized Classification and Diagnostic Evaluation (CASCADE). Results: MALA increases the risk of AIS (ОR 16,15 [95% CI 5,43–48,1]). Stroke that does not meet the criteria of 1–5 types according to CASCADE is often associated with MALA. Clinical of AIS in patients with MALA are early age and mild head trauma (F=6,9, R=0,73, p&lt;0,0001); the onset is marked by the absence of fever, vomiting, seizures, Glasgow coma scale 13, improvement in the first week (F=8,49, R=0,546, p&lt;0,0001). Neuroimaging signs are the basal ganglia lacunar infarct and the absence of cerebral arteriopathy according to magnetic resonance angiography (F=52,8, R=0,402, p&lt;0,0001). The percentage of this type stroke in children with AIS is 26,4%. Conclusion: MALA is a risk factor of AIS in children. AIS in infants which is associated with mineralizing angiopathy of lenticulostriate arteries and mild head trauma is an independent type of stroke. For its verification, computed tomography or NSG are needed.

MTHFR (C677T, A1298C), FV Leiden polymorphisms, and the prothrombin G20210A mutation in arterial ischemic stroke among young tunisian adults.

Arterial ischemic stroke (AIS) in young adults is less common in older adults, but the underlying pathogenesis and risk factors are more multi-faceted. The role of inherited thrombophilia such as 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, (C677T and A1298C), factor V of Leiden (FVL) polymorphism, and the prothrombin G20210A mutations remains unclear. This study aims to evaluate the role of prothrombin genetic factor in AIS among young adults in Tunisia and to assess the synergistic effect between thrombogenic mutations in the pathogenesis of AIS. In this case-control study, blood samples were collected from patients and healthy controls, all matched for age and gender. The difference between them is evaluated by using the chi-square test. The odds ratio (OR) was carried out to evaluate the associations between each polymorphism and AIS risk using a binary logistic regression model. Values were considered statistically significant when p < 0.05. Patients carrying simultaneously the MTHFR polymorphisms (677T and 1298C) have a higher risk to develop AIS compared to controls. The heterozygous variants FVL increased the risk of AIS only when it is associated with MTHFR C677T or MTHFR A1298C polymorphisms. In conclusion, our study confirmed the involvement of MTHFR polymorphisms as AIS's important risk factors. The existence of FVL polymorphism or prothrombin G20210A mutation alone doesn't correlate with the occurrence of stroke. We assume that the presence of both MTHFR and FVL polymorphisms has a synergistic effect and increased the risk of the AIS.

Polymorphisms variants of the MTHFR C677T and PAI-1 5G/4G genes and their combinations in the group of children with arterial ischemic stroke

Introduction. Arterial ischemic stroke (AIS) in childhood is a disorder associated with different predisposing factors, thrombophilia is one of them. We present the study of the MTHFR C677T and PAI-1 5G/4G gene polymorphisms as a possible risk factor for the development of AIS in the group of Ukrainian children. Materials and methods. 77 children from 29 days to 15 years of age were involved in this study: study group - 44 children with AIS, and 33 in a control group. Children enrolled to both groups were at similar age. Results. In the study group there was an increase in the frequency of genotypes 677CT (OR = 2.69) and 677TT, CT + TT genotypes (OR = 3.67) of the MTHFR gene, increased frequency of the 677T allele (OR = 2.57). In the study group detection of 5G/5G + 5G/4G genotypes was higher (OR = 2.82) with statistically predominance of the 5G allele (OR = 2.26) of the gene PAI -1. Higher frequency of the combination of genotypes genes 677CT + 5G/5G was found in the main group. The model of interpreting interactions was built, it allows to predict indirectly the potential intergenic interactions. Conclusions. We conclude that risk of AIS is higher in children with polymorphic variants 677CT and 677TT for the MTHFR gene; the association of polymorphic variants 5G/4G and 5G/5G for the PAI-1 gene with a decrease in the risk of developing AIS; direct interaction with the MTHFR was found for PAI-1, but of weak strength

Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis

It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)Rx] directed to apo(a) (n = 7) or placebo (n = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a)Rx and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a)Rx was -69.3 ± 12.2% versus -5.4 ± 6.9% placebo (P < 0.0010) at day 85/92/99 and -15.6 ± 8.9% versus 3.2 ± 12.2% (P = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a)Rx and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study.

Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis.

BackgroundInherited thrombophilias are well‐established predisposing factors for venous thromboembolism, but their role in arterial thrombosis, such as arterial ischemic stroke, remains uncertain. We aimed to evaluate the association between inherited thrombophilia (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency) and risk of arterial ischemic stroke in adults.Methods and ResultsWe searched PubMed, EMBASE, and Cochrane Library Databases from inception to December 31, 2018. We included case‐control or cohort studies of adults reporting the prevalence of inherited thrombophilias in those with arterial ischemic stroke and subjects without arterial ischemic stroke. Two reviewers (T.C., E.D.) independently searched the literature and extracted data. Pooled odds ratios (ORs) and 95% CIs were calculated using random‐effects model. We identified 68 eligible studies, which collectively enrolled 11 916 stroke patients and 96 057 controls. The number of studies reporting factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency were 56, 45, 15, 17, and 12, respectively. Compared with controls, patients with arterial ischemic stroke were significantly more likely to have the following inherited thrombophilias: factor V Leiden (OR, 1.25; 95% CI, 1.08–1.44; I2=0%), prothrombin G20210A mutation (OR, 1.48; 95% CI, 1.22–1.80; I2=0%), protein C deficiency (OR, 2.13; 95% CI, 1.16–3.90; I2=0%), and protein S deficiency (OR, 2.26; 95% CI, 1.34–3.80; I2=8.8%). Statistical significance was not reached for antithrombin deficiency (OR, 1.25; 95% CI, 0.58–2.67; I2=8.8%).ConclusionsInherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, and protein S deficiency) are associated with an increased risk of arterial ischemic stroke in adults. The implications of these findings with respect to clinical management of patients with ischemic stroke require further investigation.

Arterial Ischemic Stroke Secondary to Cardiac Disease in Neonates and Children

ObjectiveWe describe the risk factors for peri-procedural and spontaneous arterial ischemic stroke (AIS) in children with cardiac disease. MethodsWe identified children with cardiac causes of AIS enrolled in the International Pediatric Stroke Study registry from January 2003 to July 2014. Isolated patent foramen ovale was excluded. Peri-procedural AIS (those occurring during or within 72 hours of cardiac surgery, cardiac catheterization, or mechanical circulatory support) and spontaneous AIS that occurred outside of these time periods were compared. ResultsWe identified 672 patients with congenital or acquired cardiac disease as the primary risk factor for AIS. Among these, 177 patients (26%) had peri-procedural AIS and 495 patients (74%) had spontaneous AIS. Among non-neonates, spontaneous AIS occurred at older ages (median 4.2 years, interquartile range 0.97 to 12.4) compared with peri-procedural AIS (median 2.4 years, interquartile range 0.35 to 6.1, P < 0.001). About a third of patients in both groups had a systemic illness at the time of AIS. Patients who had spontaneous AIS were more likely to have a preceding thrombotic event (16 % versus 9 %, P = 0.02) and to have a moderate or severe neurological deficit at discharge (67% versus 33%, P = 0.01) compared to those with peri-procedural AIS. ConclusionsChildren with cardiac disease are at risk for AIS at the time of cardiac procedures but also outside of the immediate 72 hours after procedures. Many have acute systemic illness or thrombotic event preceding AIS, suggesting that inflammatory or prothrombotic conditions could act as a stroke trigger in this susceptible population.

Abnormal red blood cell indices increase the risk of arterial ischemic stroke in children

A high red cell distribution width (RDW) and low hemoglobin level increase the risk of arterial ischemic stroke (AIS), mostly in adults. The mechanisms related to AIS remain unknown. A total of 233 subjects (90 patients and 143 healthy controls [HC]) were enrolled. The mean(SD) age in patients and HC was 9.5(3.8) and 11.4(1.8) years, respectively. We found increased odds ratios (ORs) for large vessel and small vessel subtypes in patients without underlying diseases with a mean corpuscular volume (MCV) <80 fL (OR: 5.4, 95%CI 1.8–16.3 and 2.8, 95%CI 1.2–7.2), mean corpuscular hemoglobin levels <27 pg (OR: 2.9, 95%CI 1.0–6.7 and 2.6, 95%CI 1.0–6.7), and RDW >15% (OR: 5.5, 95%CI 1.3–24.5 and 2.7, 95%CI 1.0–7.3). RBC indices showed significant correlations with TM levels. Therefore, low MCV and MCH levels, and a high RDW were risk factors for AIS and associated with TM levels in this population.

Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis

Introduction:The inherited thrombophilias Factor V Leiden (FVL), the Prothrombin G20210A mutation (PTM), Protein C deficiency (PCD), Protein S deficiency (PSD), and Antithrombin deficiency (ATD) are well-established predisposing factors for venous thromboembolism, but their role in arterial thrombosis such as arterial ischemic stroke remains uncertain. The 2018 American Heart Association/American Stroke Association clinical practice guideline recommends against thrombophilia testing in patients with ischemic stroke, though such testing remains common in clinical practice. We conducted a systematic review and meta-analysis to evaluate the association of inherited thrombophilias and risk of arterial ischemic stroke in adults.Methods:A systematic literature search was performed using MEDLINE, EMBASE, and Cochrane Library Databases from inception to December 31, 2017 without language restrictions. Manual reviews of conference abstracts and bibliographies of included studies were performed to identify additional eligible studies. We included case-control studies of adults age ≥15 years that reported the prevalence of at least one of the inherited thrombophilias of interest (FVL, PTM, PCD, PSD, ATD) in both subjects with a history of arterial ischemic stroke (cases) and subjects without arterial ischemic stroke (controls). Studies were required to have ≥10 subjects in each group. Studies that enrolled patients with transient ischemic attack, hemorrhagic stroke, cerebral venous sinus thrombosis, and other arterial thromboses were excluded. Two reviewers (T.C. and E.D.) independently searched the literature and extracted data from eligible studies. Disagreements were resolved by consensus or a third reviewer (A.C.) when necessary. Methodological quality of included studies was appraised using the NIH Quality Assessment of Case-Control Studies assessment tool. Data analysis was performed using R version 3.4.4. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Inter-study heterogeneity was evaluated using Cochran's Q test and I2statistics. Prespecified subgroup analyses were performed in young patients (<65 years), patients with a patent foramen ovale (PFO), and patients with cryptogenic stroke. Funnel plots and Egger's test were used to assess for the presence of publication bias. The study protocol is available on PROSPERO (CRD42018090020).Results:A total of 1,730 records were retrieved from the literature search. After screening by title and abstract, 1527 records were excluded. The remaining 203 references underwent full text review, 71 of which met eligibility criteria and were included in the analysis. These 71 studies collectively enrolled 13,347 stroke patients and 31,676 controls. The number of studies that reported on FVL, PTM, PCD, PSD, and ATD were 59, 47, 14, 15, and 11, respectively. Heterogeneity among studies was low. Compared with controls, inherited thrombophilia was significantly more common in patients with arterial ischemic stroke for the following defects: homozygous FVL (OR 2.24; 95%CI, 1.24-4.07; I2=0%), heterozygous FVL (OR 1.32; 95%CI, 1.11-1.57; I2=33%), homozygous PTM (OR 7.19; 95%CI 2.47-20.95; I2=0%), heterozygous PTM (OR 1.53; 95%CI, 1.27-1.84; I2=2%), PCD (OR 2.70; 95%CI, 1.44-5.04; I2=0%), and PSD (OR 2.75; 95%CI, 1.56-4.85; I2=34%) (Figure 1). Statistical significance was not reached for ATD (OR 1.84; 95%CI, 0.92-3.71; I2=11%). Subgroup analyses showed a higher magnitude of stroke risk in young patients across all thrombophilias. The associations were non-significant for patients with PFO and cryptogenic stroke (Table 1). Funnel plots were symmetrical and Egger's test was non-significant (p>0.05), suggesting absence of publication bias, for all thrombophilias except heterozygous FVL (p=0.003).Conclusions: Our results suggest that inherited thrombophilias including FVL, PTM, PCD, and PSD are associated with an increased risk of arterial ischemic stroke, particularly in young patients. The association with FVL and PTM is stronger in the homozygous than in the heterozygous state, suggesting a potential dose-response relationship and causal role for inherited thrombophilias. The implications of these findings with respect to the evaluation and management of patients with ischemic stroke require further investigation. [Display omitted] DisclosuresCrowther:Alnylam: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shinogi: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Speakers Bureau. Garcia:Bristol Meyers Squibb: Consultancy; Daiichi Sankyo: Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Portola: Research Funding; Incyte: Research Funding; Retham Technologies LLC: Consultancy; Shingoi: Consultancy; Boehringer Ingelheim: Consultancy. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Research Funding; Synergy: Consultancy; Genzyme: Consultancy.

Is varicella vaccination associated with pediatric arterial ischemic stroke? A population-based cohort study

Background and purpose: Varicella disease is a risk factor for pediatric Arterial Ischemic Stroke (AIS). Isolated case reports have emerged suggesting that varicella vaccination may also pose a risk for AIS. Methods: This retrospective population-based cohort study assessed the risk of AIS in children who received a varicella-containing vaccine, as compared to those who did not. The study cohort consisted of children born between January 1, 2006 and December 31, 2013, in the Canadian province of Alberta, where all routine childhood vaccinations are publicly-funded, and recorded in a central immunization repository. These data were linked with hospital discharge abstract data to identify children diagnosed with AIS. A Cox proportional hazard model assessed the risk of AIS in the 12 months following vaccination for children receiving a varicella vaccine between 11 and 23 months of age, as compared to non-vaccinated children. Results: Of the 368,992 children in the cohort, 325,729 were vaccinated with a varicella-containing vaccine between 11 and 23 months of age. The rate of AIS was 7.8 (95% CI 4.8–10.9) per 100,000 person years at risk in the 12 months following varicella vaccination, as compared to 6.8 (95% CI 1.3–12.2) for children who did not receive a varicella vaccine. The adjusted Hazard Ratio for the risk of AIS, controlling for other AIS risk factors, in vaccinated children as compared to non-vaccinated children was 1.6 (95% CI 0.7–3.7) in the 12 months following vaccination and 1.7 (95% CI 0.5–4.9) in the 30 days following vaccination. Conclusions: Our study found no evidence of an increased risk of AIS following varicella vaccination. This population-based cohort study provides reassurance to parents and clinicians regarding the safety of varicella vaccination.

Post-varicella Arterial Ischemic Stroke in Denmark 2010 to 2016

BackgroundVaricella, most often a benign disease of childhood, is associated with an increased risk of arterial ischemic stroke in children. The aim of the present study was to estimate the incidence of post-varicella arterial ischemic stroke in the Danish child population and describe clinical characteristics of children admitted with post-varicella arterial ischemic stroke. MethodsIn the Danish National Patient Register, we identified inpatients 28 days to 16 years of age with a discharge diagnosis of stroke or cerebrovascular disease from 2010 to 2016. Medical files were reviewed, and children with arterial ischemic stroke and varicella infection less than 12 months before onset of symptoms were included. ResultsWe identified 15 children with arterial ischemic stroke and varicella less than 12 months before. In nine children, the diagnosis was confirmed by detection of varicella zoster virus DNA or varicella zoster virus immunoglobulin G in the cerebrospinal fluid. All children were previously healthy, the mean age was four years, and 67% were male. The median time from varicella rash to arterial ischemic stroke was 4.6 months. The most common location of arterial ischemic stroke was the basal ganglia, and affected vessels were most often in the anterior circulation. Fifty-three percent experienced neurological sequelae of varying degree. ConclusionsIn Denmark, where varicella vaccination is not part of the childhood vaccination program, the estimated risk of post-varicella arterial ischemic stroke was one case (including possible cases) per 26,000 children with varicella.

The rs10757278 Polymorphism of the 9p21.3 Locus in Children with Arterial Ischemic Stroke: A Family-Based and Case-Control Study

The association of 9p21.3 locus single nucleotide polymorphisms with arterial ischemic stroke in adults was demonstrated in many studies, but there are no studies in pediatric arterial ischemic stroke patients. We investigated whether the 9p21.3 locus polymorphism, namely rs10757278, is associated with the arterial ischemic stroke risk in children. The study group consisted of 335 individuals: 80 children with arterial ischemic stroke, their biological parents (n = 122), and 133 children (age and sex matched) without any symptoms of arterial ischemic stroke as a control group. The rs10757278 polymorphism was genotyped using the TaqMan® Pre-designed SNP Genotyping Assay (Applied Biosystems). Two different study design models were used: family-based association test (transmission-disequilibrium test) and case-control model. There were no statistically significant differences in the distribution of genotypes and alleles of the rs10757278 polymorphism between groups of children with arterial ischemic stroke and controls. The frequency of both transmitted alleles in transmission-disequilibrium test analysis was identical (50%). The A allele carrier state (AA+AG genotype) was more frequent in arterial ischemic stroke children with hemiparesis than in patients without this symptom (94.5% versus 68.0%, P = .004). There is no evidence to consider the 9p21.3 locus polymorphism as a risk factor for childhood arterial ischemic stroke.

P.054 Bone marrow transplant restores Cerebrovascular Reactivity (CVR) in Sickle Cell Disease (SCD): a case presentation

Background: A diagnosis of SCD in childhood confers a 200-fold increase in the risk of arterial ischemic stroke. Blood flow velocity measures provide better identification of ischemic risk compared to angiography. This indicates that steno-occlusive arteriopathy is not the singular causative factor. Cerebrovascular reactivity allows for augmentation of cerebral blood flow when needed. Kosinski et al in 2016 demonstrated a direct correlation between CVR and hematocrit levels in SCD. We report a case where CVR persistently normalized in an SCD patient following bone marrow transplant therapy (BMT). Methods: A nine-month-old SCD patient presented with right AIS. Angiography revealed a bilateral Moya-Moya like arteriopathy. A TCD study was normal while a CVR-MRI study revealed markedly impaired reactivity in the entire anterior circulation. Haemaglobin-S at that time was 20.2 %. BMT was performed at age four due to frequent sickle cell crises. Results: One year post-transplant, CVR had dramatically improved in areas previously shown to have impairment (haemoglobin-S 0%). Neuroimaging five years post-transplant showed no further arteriopathy and persistently normalized CVR. Conclusions: BMT therapy resulted in the arrest of progressive intracranial arteriopathy and persistently restored vascular reserve. SCD might not only produce global hematological effects but also triggers local processes such as endothelial dysfunction and vascular inflammation that impair cerebrovascular function.

Association of Polymorphisms in Coagulation Factor Genes and Enzymes of Homocysteine Metabolism With Arterial Ischemic Stroke in Children.

Despite the identification of a wide range of inherited and acquired risk factors for arterial ischemic stroke (AIS) in children, genetic risk factors are incompletely characterized and may vary among different populations. We investigated the role of individual and combined inherited prothrombotic and intermediate-risk factors in 73 children with perinatal (n = 35) and childhood AIS (n = 38) and 100 age- and sex-matched controls. Ten polymorphisms in 8 candidate genes encoding coagulation and fibrinolytic proteins (factor V [FV] Leiden, FV HR2, factor II [FII] G20210A, β-fibrinogen [β-FBG]-455G>A, factor XIII [FXIII]-A p.Val34Leu, plasminogen activator inhibitor 1 4G/5G), homocysteine metabolism (methylenetetrahydrofolate reductase [MTHFR] C677T, MTHFR A1298C), and intermediate-risk factors (angiotensin-converting enzyme I/D, apoE ∊2-4) were detected using a multilocus genotyping assay. Allele-specific polymerase chain reaction was used for the determination of human platelet alloantigens (HPA-1, HPA-2, HPA-3, and HPA-5). Factor V Leiden was associated with an increased risk of AIS (odds ratio [OR]: 4.72, 95% confidence interval [CI]: 1.22-18.27) and perinatal AIS (OR: 8.29, 95% CI: 1.95-35.24). Human platelet antigen-3b allele carriers had a 2-fold lower risk of AIS (OR: 0.51, 95% CI: 0.26-0.98) and perinatal AIS (OR: 0.40, 95% CI: 0.18-0.92). A 2.21-fold increased risk of childhood AIS (95% CI: 1.03-4.73) was identified in FXIII-A Leu34 allele carriers. Combined FV Leiden/FV HR2, FV Leiden/MTHFR A1298C, FV Leiden/MTHFR C677T/MTHFR A1298C, and FV Leiden/FV HR2/MTHFR A1298C heterozygosity was identified in children with AIS but not in controls, which revealed a statistically significant difference. This case-control study shows that besides already documented association between FV Leiden and AIS, other previously unreported polymorphisms (FXIII-A p.Val34Leu, HPA-3) and several genotype combinations that always include heterozygous FV Leiden can be related to AIS in Croatian population.

Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study.

Epidemiological studies demonstrate that childhood infections, including varicella zoster virus, are associated with an increased risk of arterial ischemic stroke (AIS). Other herpesviruses have been linked to childhood AIS in case reports. We sought to determine whether herpesvirus infections, which are potentially treatable, increase the risk of childhood AIS. We enrolled 326 centrally confirmed cases of AIS and 115 stroke-free controls with trauma (29 days to 18 years of age) with acute blood samples (≤3 weeks after stroke/trauma); cases had convalescent samples (7-28 days later) when feasible. Samples were tested by commercial enzyme-linked immunosorbent assay kits for immunoglobulin M/immunoglobulin G antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. An algorithm developed a priori classified serological evidence of past and acute herpesvirus infection as dichotomous variables. The median (quartiles) age was 7.7 (3.1-14.3) years for cases and 10.7 (6.9-13.2) years for controls (P=0.03). Serological evidence of past infection did not differ between cases and controls. However, serological evidence of acute herpesvirus infection doubled the odds of childhood AIS, even after adjusting for age, race, and socioeconomic status (odds ratio, 2.2; 95% confidence interval, 1.2-4.0; P=0.007). Among 187 cases with acute and convalescent blood samples, 85 (45%) showed evidence of acute herpesvirus infection; herpes simplex virus 1 was found most often. Most infections were asymptomatic. Herpesviruses may act as a trigger for childhood AIS, even if the infection is subclinical. Antivirals like acyclovir might have a role in the prevention of recurrent stroke if further studies confirm a causal relationship.