Arterial Ischemic Stroke In Adults Research Articles

Reperfusion Therapies for Children With Arterial Ischemic Stroke.

Modern hyperacute reperfusion therapies including intravenous thrombolysis and mechanical thrombectomy have transformed the management of arterial ischemic stroke (AIS) in adults. Multiple randomized clinical trials have demonstrated that these therapies enable remarkable improvements in clinical outcome for properly selected patients with AIS. Because pediatric patients were excluded from predicate clinical trials, there is a conspicuous lack of data to guide selection of therapies and inform age-adjusted and pathology-oriented treatment modifications for children. Specifically, technical guidance concerning treatment eligibility, drug dosing, and device implementation is lacking. This review aims to outline important features that differentiate pediatric AIS from adult AIS and provide practical strategies that will assist the stroke specialist with therapeutic decision making.

Initial Diagnostic Evaluation of the Child With Suspected Arterial Ischemic Stroke.

Numerous factors make the initial diagnostic evaluation of children with suspected arterial ischemic stroke (AIS) a relatively unsettling challenge, even for the experienced stroke specialist. The low frequency of pediatric AIS, diversity of unique age-oriented stroke phenotypes, and unconventional approaches required for diagnosis and treatment all contribute difficulty to the process. This review aims to outline important features that differentiate pediatric AIS from adult AIS and provide practical strategies that will assist the stroke specialist with diagnostic decision making in the initial phase of care.

Definitive Diagnostic Evaluation of the Child With Arterial Ischemic Stroke and Approaches to Secondary Stroke Prevention.

In children with arterial ischemic stroke (AIS), the definitive diagnosis of stroke subtype and confirmation of stroke etiology is necessary to mitigate stroke morbidity and prevent recurrent stroke. The common causes of AIS in children are sharply differentiated from the common causes of adult AIS. A comprehensive, structured diagnostic approach will identify the etiology of stroke in most children. Adequate diagnostic evaluation relies on advanced brain imaging and vascular imaging studies. A variety of medical and surgical secondary stroke prevention strategies directed at the underlying cause of stroke are available. This review aims to outline strategies for definitive diagnosis and secondary stroke prevention in children with AIS, emphasizing the critical role of neuroimaging.

The Impact of Sex on Arterial Ischemic Stroke in Young Patients: From Stroke Occurrence to Poststroke Consequences.

The male sex has been suggested to predominate in paediatric patients with arterial ischemic stroke (AIS), especially in newborns. The explanation for this phenomenon remains unsatisfactory since it focuses on the analysis of the potential relationship with trauma and arterial dissection. In turn, in some populations of young adults, men suffer from AIS more frequently than women, which may be related to the protective role of oestrogen. On the other hand, certain data indicate that women dominate over men. Some of the disparities in the frequencies of particular symptoms of AIS and poststroke consequences in both children and young adults have been suggested; however, data are scarce. Unfortunately, the low number of studies on the subject does not allow certain conclusions to be drawn. For adults, more data are available for patients aged over 60 years, the results of which are more obvious. The present literature review aimed to discuss available data on the prevalence of AIS, its clinical presentations, and poststroke consequences in regard to the sex of young patients. We considered young patients to be children from birth up to the age of 19 years of life and young adults to be individuals up to the age of 55 years. The role of sex hormones in AIS and possible gender differences in genetic risk factors for AIS were also discussed briefly.

Risk Factors for Recurrent Arterial Ischemic Stroke in Children and Young Adults.

Arterial ischemic stroke (AIS) experienced at a young age is undoubtedly a serious medical problem. AIS very rarely occurs at a developmental age, whereas in young adults, it occurs with a higher frequency. The etiologic mechanisms of AIS occurring in childhood and adulthood differ. However, for both age populations, neurological consequences of AIS, including post-stroke seizures, motor disability, and recurrence of the disease, are connected to many years of care, rehabilitation, and treatment. Recurrent stroke was observed to increase the risk of patients’ mortality. One of the confirmed risk factors for recurrent stroke in children is the presence of vasculopathies, especially Moyamoya disease and syndrome, and focal cerebral arteriopathy of childhood (FCA). FCA causes a 5-fold increase in the risk of recurrent stroke in comparison with idiopathic AIS. In turn, young adults with recurrent stroke were found to more often suffer from hypertension, diabetes mellitus, or peripheral artery disease than young patients with first-ever stroke. Some reports also indicate relationships between specific genetic polymorphisms and AIS recurrence in both age groups. The aim of the present literature review was to discuss available data regarding the risk factors for recurrent AIS in children and young adults.

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.

Abstract 52: Inflammatory Biomarkers Correlate With Etiology in Childhood Arterial Ischemic Stroke

Introduction: Etiologies of childhood arterial ischemic stroke (AIS) are heterogeneous, yet most cases fall into one of three subtypes: arteriopathic, cardioembolic, or idiopathic. Circulating inflammatory mediators could play a role in the pathogenesis of each subtype, whether through inflammatory injury to arterial or cardiac endothelium, or by promoting thrombosis. Hypothesis: Patterns of post-stroke serum inflammation in children will differ by etiologic subtype. Methods: From the “Vascular effects of Infection in Pediatric Stoke” (VIPS) study cohort (355 cases of AIS, ages 29 days through 18 years), we selected cases centrally classified as arteriopathic (N=119), spontaneous cardioembolic (N=58; excluding peri-procedural cardioembolic AIS), or idiopathic (N=82). We used Luminex assays to measure serum concentrations (pg/mL) of 20 inflammatory biomarkers selected for their correlation with adult AIS or arteriopathy in other settings. We compared analyte concentrations across the three etiologic subtypes in unadjusted and adjusted analyses. Results: Serum samples were collected at a median of 5.5 days post-stroke (IQR 3, 10 days). Compared to children with idiopathic AIS, those with cardioembolic AIS had higher levels of four analytes (IL-6, IL-8, IL-10, IP-10), even after adjustment for age, sex, infarct volume, and other potential confounders (Table). Children with arteriopathic AIS, on the other hand, had higher levels of two analytes (IL-10, IP-10), and lower levels of another two (fractalkine, MCP-1). Conclusion: Patterns of post-AIS serum inflammation differ by stroke subtype in children, and may provide clues to stroke pathogenesis. We will perform network analyses using unsupervised machine learning approaches to elucidate these patterns further.

Research progress of arterial ischemic stroke in children

Stroke is among the top 10 causes of death and a leading cause of childhood disability.Pediatric arterial ischemic stroke (AIS) differs from adult AIS in several ways.There are many risk factors among which non-atherosclerotic arterial disease and heart disease are the most frequently identified risk factors of AIS in children.Clinical manifestations do vary with age.The clinical manifestations are extremely atypical in neonates and infants.The treatment and prognosis are obviously different from that of adults.This review will discuss important developments in childhood arterial ischemic stroke, focus on improved understanding of the risk factors, clinical manifestations, consequences and targets for intervention. Key words: Arterial ischemic stroke; Risk factors; Children,

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.028 Incidence and management of seizures and epilepsy after ischemic stroke: a systematic review

Background: Seizures and epilepsy are well-recognized complications after stroke. However, the reported incidence varies and so does their management. Methods: We conducted a systematic review and sought observational studies that reported incidence of seizures and/or epilepsy following arterial ischemic stroke in adults, and those that reported the management of epilepsy, specifically the use of EEG to determine the diagnosis, timing of initiation of anti-epileptic drug (AED), and the treatment response to AEDs. We systematically searched in Medline including Pre-Medline and EMBASE databases from their inception to October 1, 2015. First the titles and then the articles were reviewed and rated by two independent reviewers, and disagreements were resolved by consultation with a third reviewer. A pre-set data abstraction form was used for extracting the information of interest. Results: A total of 11,815 titles were found from the initial search strategy across all databases following de-duplication. Of these 130 studies are included for full text review. The adjudication process is underway and the reviewers are sifting through these studies to select the studies that will be included in the final review. Conclusions: Understanding incidence and management of post-stroke epilepsy is important to improve the quality of life of stroke survivors.

Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study.

Minor infection can trigger adult arterial ischemic stroke (AIS) and is common in childhood. We tested the hypotheses that infection transiently increases risk of AIS in children, regardless of stroke subtype, while vaccination against infection is protective. The Vascular Effects of Infection in Pediatric Stroke study is an international case-control study that prospectively enrolled 355 centrally confirmed cases of AIS (29 days-18 years old) and 354 stroke-free controls. To determine prior exposure to infections and vaccines, we conducted parental interviews and chart review. Median (interquartile range) age was 7.6 years for cases and 9.3 for controls (p = 0.44). Infection in the week prior to stroke, or interview date for controls, was reported in 18% of cases, vs 3% of controls, conferring a 6.3-fold increased risk of AIS (p < 0.0001); upper respiratory infections were most common. Prevalence of preceding infection was similar across stroke subtypes: arteriopathic, cardioembolic, and idiopathic. Use of vasoactive cold medications was similarly low in both groups. Children with some/few/no routine vaccinations were at higher stroke risk than those receiving all or most (odds ratio [OR] 7.3, p = 0.0002). In an age-adjusted multivariate logistic regression model, independent risk factors for AIS included infection in the prior week (OR 6.3, p < 0.0001), undervaccination (OR 8.2, p = 0.0004), black race (compared to white; OR 1.9, p = 0.009), and rural residence (compared to urban; OR 3.0, p = 0.0003). Infection may act as a trigger for childhood AIS, while routine vaccinations appear protective. Hence, efforts to reduce the spread of common infections might help prevent stroke in children.

Etiology and treatment of arterial ischemic stroke in children and young adults.

Stroke is the second leading cause of death worldwide (Go et al. Circulation 129:e28-292, 2014) and is a major cause of morbidity and mortality. Compared with older adults, arterial ischemic stroke (AIS) is relatively uncommon in children and young adults, comprising 5-10% of all stroke (Biller Nat Rev Cardiol 6:395-97, 2009), but is associated with significant cost. In contrast to the declining overall incidence of stroke, some early studies suggest that the rate of stroke hospitalizations in children and young adults is rising (George et al. Ann Neurol 70:713-21, 2011; Kissela et al. Stroke 41:e224, 2010; Nguyen-Huynh et al. Stroke 43, 2012), emphasizing the importance of understanding the similarities and differences in etiology and treatment of AIS across the age spectrum. Among the most common causes of AIS in children are cardioembolism (often related to congenital heart disease), cervicocephalic arterial dissections, focal arteriopathy of childhood and several genetic and metabolic disorders, such as sickle cell disease (SCD). AIS in young adults is less well understood, but likely overlaps in etiology with both children and older adults. Young adults with AIS often have classic atherosclerotic risk factors similar to older adults, but are also more likely to have thrombophilias, cervicocephalic arterial dissections and cardioembolism, similar to children with AIS. Since little evidence exists regarding both acute treatment and secondary prevention after AIS in children and young adults, standard treatment practices are mainly extrapolated from research done in older adults. In most cases we recommend treating young adults per the guidelines published by the American Heart Association for adults with stroke (Jauch et al. Stroke 44:870-947, 2013; Kernan et al. Stroke 45:2160-2236, 2014) and children per the equivalent guidelines regarding pediatric stroke (Roach et al. Stroke 39:2644-91, 2008). It is also important in children and young adults to consider less common structural, metabolic and genetic risk factors for stroke, which may require more specific treatment. Other standard risk factors for stroke, including hypertension, hyperlipidemia and diabetes mellitus should also be addressed, but are less likely in children and young adults. Given the lack of data and possibility of rare underlying etiologies such as Antiphospholipid Antibody Syndrome or Ehlers-Danlos syndrome, we recommend including multiple specialists in the care of these patients, such as hematologists and vascular neurologists.

Towards a Consensus-Based Classification of Childhood Arterial Ischemic Stroke

The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS. Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinician's current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted κ-statistic. In Group 1 (with training), IRR was improved using CASCADE criteria (κ=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (κ=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (κ=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (κ=0.23, 95% CI=[0.03, 0.36]). A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.

Genes Associated With Adult Cerebral Venous Thrombosis

Quantitative predictions of the risk of cerebral venous thrombosis (CVT) conferred by certain genotypes have yet to be reliably established. We conducted a comprehensive meta-analysis of all candidate genes studied to assess their genetic contribution to the etiology of CVT. We compared our findings against equivalent analyses for pediatric CVT and adult ischemic stroke. Databases were searched to August 2010 for all genes investigated in adult CVT, and odds ratios (ORs) for each gene-disease association were calculated. A mendelian randomization strategy was also undertaken to determine whether a causal relation to one gene could be ascertained. We identified 26 case-control studies investigating 6 polymorphisms in 6 genes and included 1183 CVT cases and 5189 controls. Statistically significant associations with CVT were found for factor V Leiden/G1691A (OR=2.40; 95% CI, 1.75 to 3.30; P<0.00001) and prothrombin/G20210A (OR=5.48; 95% CI, 3.88 to 7.74; P<0.00001). After iterative analysis controlling for interstudy heterogeneity, methylene tetrahydrofolate reductase/C677T was also found to be significantly associated (OR=2.30; 95% CI, 1.20 to 4.42; P=0.02). Variants in the remaining 3 genes (Janus kinase-2, plasminogen activator inhibitor-1, and protein Z) were not significantly associated. Pooled ORs for CVT risk in adults for factor V Leiden and prothrombin were significantly greater when compared against childhood CVT and adult arterial ischemic stroke. A causal relation with methylene tetrahydrofolate reductase may exist. CVT has a genetic basis. Genes involved in the clotting cascade provide a greater level of thrombosis risk in the cerebral venous circulation compared with its arterial circulation, and a greater level of risk exists for adults compared with children.

Treatment of childhood arterial ischemic stroke

Traditional risk factors associated with adult arterial ischemic stroke (AIS; ie, hypertension, hyperlipidemia, diabetes, smoking, and atherosclerosis) are relatively rare in children. Childhood AIS is instead associated with a variety of conditions including cerebral arteriopathies, congenital heart disease, infection, head and neck trauma, sickle cell anemia, and prothrombotic abnormalities. Although the pathophysiology and outcomes of adult AIS differ significantly from those in childhood AIS, therapeutic management remains similar, largely because of the paucity of evidence from devoted pediatric observational studies and clinical trials. The purpose of this article is to review the current guidelines and evidence in the treatment of childhood AIS, within the context of that which exists in adult AIS. Medical management of hypoxia, hyperglycemia, fever, blood pressure, and increased intracranial pressure has been insufficiently investigated in childhood stroke, resulting in a lack of guidance in these areas. Although acute antithrombotic management in childhood AIS has received relatively greater attention in published recommendations, it is based almost exclusively on consensus and expert opinion, and differs considerably among existing pediatric guidelines. Rehabilitation therapy in childhood AIS has great potential for meaningful improvements in long-term outcomes, especially given the plasticity of the young brain; however, little guidance for rehabilitative measures is provided by published recommendations. Ongoing and future multicenter cohort study efforts, and ultimately devoted pediatric clinical trials, will be essential to establish comprehensive evidence-based guidelines for the treatment of childhood AIS.

Promoter Polymorphisms in the Plasma Glutathione Peroxidase ( GPx-3 ) Gene

Background and Purpose— Plasma glutathione peroxidase ( GPx-3 )–deficiency increases extracellular oxidant stress, decreases bioavailable nitric oxide, and promotes platelet activation. The aim of this study is to identify polymorphisms in the GPx-3 gene, examine their relationship to arterial ischemic stroke (AIS) in a large series of children and young adults, and determine their functional molecular consequences. Methods— We studied the GPx-3 gene promoter from 123 young adults with idiopathic AIS and 123 age- and gender-matched controls by single-stranded conformational polymorphism and sequencing analysis. A second, independent population with childhood stroke was used for a replication study. We identified 8 novel, strongly linked polymorphisms in the GPx-3 gene promoter that formed 2 main haplotypes (H1 and H2). The transcriptional activity of the 2 most prevalent haplotypes was studied with luciferase reporter gene constructs. Results— The H2 haplotype was over-represented in both patient populations and associated with an independent increase in the risk of AIS in young adults (odds ratio=2.07, 95% CI=1.03 to 4.47; P =0.034) and children (odds ratio=2.13, 95% CI=1.23 to 4.90; P =0.027). In adults simultaneously exposed to vascular risk factors, the risk of AIS approximately doubled (odds ratio=5.18, 95% CI=1.82 to 15.03; P &lt;0.001). Transcriptional activity of the H2 haplotype was lower than that of the H1 haplotype, especially after upregulation by hypoxia (normalized relative luminescence: 3.54±0.32 versus 2.47±0.26; P =0.0083). Conclusion— These findings indicate that a novel GPx-3 promoter haplotype is an independent risk factor for AIS in children and young adults. This haplotype reduces the gene’s transcriptional activity, thereby compromising gene expression and plasma antioxidant and antithrombotic activities.