Risk Of Arterial Ischemic Stroke Research Articles

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.

Preventable Pediatric Stroke via Vaccination?

Investigators from the Vascular Effects of Infection in Pediatric Stroke (VIPS) group studied the risk of arterial ischemic stroke (AIS) associated with minor infection and routine childhood vaccinations.

Risk of Recurrent Arterial Ischemic Stroke in Childhood: A Prospective International Study.

Published cohorts of children with arterial ischemic stroke (AIS) in the 1990s to early 2000s reported 5-year cumulative recurrence rates approaching 20%. Since then, utilization of antithrombotic agents for secondary stroke prevention in children has increased. We sought to determine rates and predictors of recurrent stroke in the current era. The Vascular Effects of Infection in Pediatric Stroke (VIPS) study enrolled 355 children with AIS at 37 international centers from 2009 to 2014 and followed them prospectively for recurrent stroke. Index and recurrent strokes underwent central review and confirmation, as well as central classification of causes of stroke, including arteriopathies. Other predictors were measured via parental interview or chart review. Of the 355 children, 354 survived their acute index stroke, and 308 (87%) were treated with an antithrombotic medication. During a median follow-up of 2.0 years (interquartile range, 1.0-3.0), 40 children had a recurrent AIS, and none had a hemorrhagic stroke. The cumulative stroke recurrence rate was 6.8% (95% confidence interval, 4.6%-10%) at 1 month and 12% (8.5%-15%) at 1 year. The sole predictor of recurrence was the presence of an arteriopathy, which increased the risk of recurrence 5-fold when compared with an idiopathic AIS (hazard ratio, 5.0; 95% confidence interval, 1.8-14). The 1-year recurrence rate was 32% (95% confidence interval, 18%-51%) for moyamoya, 25% (12%-48%) for transient cerebral arteriopathy, and 19% (8.5%-40%) for arterial dissection. Children with AIS, particularly those with arteriopathy, remain at high risk for recurrent AIS despite increased utilization of antithrombotic agents. Therapies directed at the arteriopathies themselves are needed.

Abstract T MP114: Hyperlipidemia and Statin Use: Is There an Effect on Mortality Following an Ischemic Stroke?

Background: Prior treatment with stain use is associated with reduced risk of arterial ischemic stroke (AIS) occurrence and recurrence. Recent studies report elevated lipid levels are associated with improved survival in AIS patients. We investigated the association of hyperlipidemia and statin use on all-cause mortality in AIS patients. Methods: All AIS patients, age ≥ 20 years (n=3898) residing within the Greater Cincinnati/Northern Kentucky region in 2005 and 2010 were included in the analysis. Based on prior medical history of hyperlipidemia or elevated fasting LDL levels during hospitalization (HLD) and statin use at baseline and/or discharge, patients were categorized as follows. Group1: no HLD and no statin use, Group2: HLD and no statin use, Group3: HLD and statin use. Covariates included age, BMI, baseline stroke severity (NIHSS), history of: hypertension, heart disease, diabetes, end-stage renal disease, dementia, prior stroke, and smoking. Multivariable logistic regression was used to estimate the odds of mortality, at 30- and 90-days and 1-, 2- and 3-years post stroke. Results: There were 22%, 21%, and 56% patients in groups 1, 2, and 3 respectively. Those in groups 2 and 3 were significantly younger, heavier, more likely to be male and have hypertension, diabetes, heart disease, and severe stroke, but less likely to have atrial fibrillation, dementia, and prestroke disability compared to patients in group 1. In unadjusted and adjusted analyses, patients in group 3 showed lower odds of mortality at all the time points compared to patients in groups 1 and 2. Patients in group 2 also showed lower odds of mortality at all the time points compared to patients in group 1 (Table). Conclusions: A pre-morbid diagnosis of HLD is associated with lower mortality in AIS patients, irrespective of statin use. Statin use appears to be associated with additional improved survival.

Timing and number of minor infections as risk factors for childhood arterial ischemic stroke.

In a population-based case-control study, we examined whether the timing and number of minor infections increased risk of childhood arterial ischemic stroke (AIS). Among 102 children with AIS and 306 age-matched controls identified from a cohort of 2.5 million children in a large integrated health care plan (1993-2007), we abstracted data on all medical visits for minor infection within the 2 years prior to AIS or index date for pairwise age-matched controls. We excluded cases of AIS with severe infection (e.g., sepsis, meningitis). Using conditional logistic regression, we examined the effect of timing and total number of minor infections on stroke risk. After adjusting for known pediatric stroke risk factors, the strongest association between infection and AIS was observed for infectious visits ≤3 days prior to stroke (odds ratio [OR] 12.1, 95% confidence interval [CI] 2.5, 57, p = 0.002). Respiratory infections represented 80% of case infections in that time period. Cases had more infectious visits, but not significantly so, for all time periods ≥4 days prior to the stroke. A greater cumulative number of infectious visits over 2 years did not increase risk of AIS. Minor infections appear to have a strong but short-lived effect on pediatric stroke risk, while cumulative burden of infection had no effect. Proposed mechanisms for the link between minor infection and stroke in adults include an inflammatory-mediated prothrombotic state and chronic endothelial injury. The transient effect of infection in children may suggest a greater role for a prothrombotic mechanism.

Abstract 39: Infection, Vaccination, and Childhood Stroke: Preliminary Results of the Vascular Effects of Infection in Pediatric Stroke (VIPS) Study

Background: Acute minor infection was associated with childhood arterial ischemic stroke (AIS) in a retrospective study. In a prospective study, we tested the hypothesis that acute infection increases stroke risk, while vaccination against infection is protective. Methods: VIPS is an international multi-center prospective case-control study with a target enrollment of 350 cases of AIS (28 days-18 years old); parental interviews were conducted within 3 weeks of stroke occurrence in cases. Unmatched controls were identified and interviewed within 3 weeks of routine clinic visits for annual check-ups, migraine, or developmental delay, or urgent visits for trauma. Data were collected on recent infections and routine childhood vaccines. We explored attitudes toward vaccination by asking if the child had received all, most, some, few, or none of the routine vaccines expected for his/her age. Results: Data were available for 310 cases and 289 controls. Median (IQR) age was 7.5 (2.8, 14.2) and 8.2 (3.3, 12.8) years respectively (p=0.96). Infection ≤1week prior to stroke/interview date conferred a 6.5-fold risk of AIS (p<0.0001); the most common type of infection reported in this time period was upper respiratory (75% of controls and 50% of cases). In general, cases were under-vaccinated compared to controls (Table). Children reported to have had some/few/no routine vaccinations were at higher risk of AIS than those receiving all or most (OR 6.72, 95% CI 2.30, 19.6, p<0.0001). In logistic regression adjusted for age, ever having received an MMR, polio, or pneumococcus vaccine were each significantly protective against stroke. Conclusions: Recent infection confers an increased risk of childhood AIS, while routine vaccinations appear protective. This finding has positive implications for both primary and secondary stroke prevention.

Childhood arterial ischaemic stroke incidence, presenting features, and risk factors: a prospective population-based study

Arterial ischaemic stroke is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood arterial ischaemic stroke have been undertaken. We aimed to investigate the epidemiology and clinical features of childhood arterial ischaemic stroke in a population-based cohort. Children aged 29 days to less than 16 years with radiologically confirmed arterial ischaemic stroke occurring over a 1-year period (July 1, 2008, to June 30, 2009) residing in southern England (population denominator 5·99 million children) were eligible for inclusion. Cases were identified using several sources (paediatric neurologists and trainees, the British Paediatric Neurology Surveillance Unit, paediatricians, radiologists, physiotherapists, neurosurgeons, parents, and the Paediatric Intensive Care Audit Network). Cases were confirmed by personal examination of cases and case notes. Details of presenting features, risk factors, and investigations for risk factors were recorded by analysis of case notes. Capture-recapture analysis was used to estimate completeness of ascertainment. We identified 96 cases of arterial ischaemic stroke. The crude incidence of childhood arterial ischaemic stroke was 1·60 per 100 000 per year (95% CI 1·30-1·96). Capture-recapture analysis suggested that case ascertainment was 89% (95% CI 77-97) complete. The incidence of arterial ischaemic stroke was highest in children aged under 1 year (4·14 per 100 000 per year, 95% CI 2·36-6·72). There was no difference in the risk of arterial ischaemic stroke between sexes (crude incidence 1·60 per 100 000 per year [95% CI 1·18-2·12] for boys and 1·61 per 100 000 per year [1·18-2·14] for girls). Asian (relative risk 2·14, 95% CI 1·11-3·85; p=0·017) and black (2·28, 1·00-4·60; p=0·034) children were at higher risk of arterial ischaemic stroke than were white children. 82 (85%) children had focal features (most commonly hemiparesis) at presentation. Seizures were more common in younger children (≤1 year) and headache was more common in older children (>5 years; p<0·0001). At least one risk factor for childhood arterial ischaemic stroke was identified in 80 (83%) cases. Age and racial group, but not sex, affected the risk of arterial ischaemic stroke in children. Investigation of such differences might provide causative insights. The Stroke Association, UK.

Elevated lipoprotein (a), small apolipoprotein (a), and the risk of arterial ischemic stroke in North American children

Lipoprotein (a) is a risk factor for adult cardiovascular events, in which the apolipoprotein (a) component is thought to promote atherogenesis and impair fibrinolysis. We investigated whether elevated plasma lipoprotein (a) concentration and small predominant apolipoprotein (a) isoform size (number of kringle-4 domains) are risk factors for childhood arterial ischemic stroke and correlate with plasma fibrinolytic function. Patients who had had an arterial ischemic stroke in childhood (29 days - <21 years at onset; n=43) and healthy controls (n=127) were recruited for plasma sampling and laboratory determinations. Cases were followed for recurrence in a prospective cohort study. The median lipoprotein (a) concentration did not differ between groups [cases: median 18.0 nmol/L (7.5 mg/dL) and observed range 0.9-259 nmol/L (0.38-108.0 mg/dL), controls: 20.4 nmol/L (8.5 mg/dL) and 0.2-282 nmol/L (0.08-117.5 mg/dL); P=0.62]. While odds of incident stroke were not significantly increased, risks of recurrent arterial ischemic stroke were each more than ten-times increased for lipoprotein(a) >90(th) percentile of race-specific reference values and apolipoprotein (a) <10(th) percentiles [odds ratio=14.0 (95% confidence interval: 1.0-184), P=0.05 and odds ratio=12.8 (1.61-101), P=0.02]. Statistically significant but weak correlations were observed between euglobulin lysis time and both lipoprotein (a) level (r=0.18, P=0.03) and apolipoprotein (a) size (r= -0.26, P=0.002). In conclusion, elevated lipoprotein (a) and small apolipoprotein (a) potently increase the risk of recurrent arterial ischemic stroke in children, with a mechanism only partially attributable to impaired fibrinolysis. Collaborative studies are warranted to investigate these findings further and, more broadly, to establish key risk factors for incident and recurrent arterial ischemic stroke in children.

Stroke in Children With Posterior Fossa Brain Malformations, Hemangiomas, Arterial Anomalies, Coarctation of the Aorta and Cardiac Defects, and Eye Abnormalities (PHACE) Syndrome

PHACE is an acronym for posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Several case reports of arterial ischemic stroke (AIS) in individuals with PHACE have been published, but risk factors for AIS in PHACE have not been clearly defined. The objective of this article is to review all cases of stroke in PHACE in children and describe clinical characteristics that may be associated with an increased risk of AIS. A literature and registry search was conducted to identify patients with PHACE who had experienced AIS. Data were analyzed to determine age of onset, presenting signs and symptoms, and clinical features among this cohort compared with PHACE without AIS. Twenty-two individuals with PHACE and AIS were identified. Imaging of the arteries of the head and neck was reported in 20 of 22. Narrowing or nonvisualization of at least 1 great cerebral vessel was present in 19 of 20 and of those, 15 had ≥ 2 vessels involved. Aortic arch anomalies were reported in 13 of 22 individuals. Aplasia, hypoplasia, or occlusion of a major cerebral artery appears to be a significant risk factor for AIS in children with PHACE, especially when >1 vessel is involved or if there is coarctation of the aorta.

Infant, obstetrical and maternal characteristics associated with thromboembolism in infancy: a nationwide population-based case-control study

ObjectivesTo identify infant, obstetrical and maternal characteristics associated with arterial ischaemic stroke (AIS) and venous thromboembolism (VTE) in infancy (<1 year).DesignNationwide, population-based nested case-control study. All infants with a verified...

Abstract 39: Timing Of Infection And Risk Of Arterial Ischemic Stroke In Children

Background. Minor acute infections have been associated with arterial ischemic stroke (AIS) in both adults and children, and exposure to multiple infections over time is thought to contribute to atherosclerosis in adults. Our goal was to examine the association between infection and stroke, and assess whether timing or burden of infection is a stronger predictor of childhood AIS. Methods. We performed a case-control study nested in a cohort of 2.5 million children (&lt;20y) enrolled in a large integrated health care plan (1993-2007). Non-neonatal AIS cases were identified from searches of diagnostic and radiology databases, and confirmed through independent chart review; 3 controls per case were randomly selected from the cohort, matched by age and primary care facility. A medical records analyst abstracted data on all out-patient visits for infection during the 2 years prior to the stroke, or index date in controls (stroke date for the paired case). The proportion of subjects who had an infectious visit in each period: from 0-2 days, 3-7 days, 8-28 days, 1-3 months, 3-6 months, 6-12 months, and 12-24 months prior to stroke was determined. Cases were compared to controls using conditional logistic regression and the Kaplan-Meier method. Results. We identified 126 cases (median age 10.5 years) and 378 controls. Infectious visits within the prior 2 years were documented in 79% of cases and 62% of controls. A striking disparity in number of cases and controls with an infectious visit was observed in the first 2 days prior to stroke: 29% of cases vs. 1% of controls (p&lt;0.0001). From 3-7 days prior, 13% of cases and 2% of controls had a visit for infection (p&lt;0.0001). Analysis with Kaplan-Meier methods, defining time-to-event as days prior to stroke/index date of most proximate infection, yielded a significant difference between survival functions for cases vs. controls (p&lt;0.0001). In conditional logistic regression adjusted for gender, and hematologic, autoimmune, and cardiac disease, a visit with infection in the 2 days prior to stroke was associated with a relative hazard of 182 (p&lt;0.0001), which dropped to 10 (p&lt;0.0001) and 2 (p=0.046) for periods of 3-7 and 8-28 days prior. Conclusions. The risk of stroke is substantially elevated among children in the week after a visit for infection. The risk was greatest in the first 2 days after infection but remained elevated for the first month, even after adjustment for the presence of chronic disease. After the first month, infectious burden was not significantly different between cases and controls, and does not appear to be associated with an increased risk of childhood AIS.

Limb-shaking transient ischemic attacks in an adult PHACE syndrome: a case report and review of the literature

PHACE syndrome is a neuro-cutaneous syndrome characterized by malformations of the Posterior fossa, facial Hemangiomas, Arterial anomalies, Cardiac anomalies, and abnormalities of the Eye. The arterial abnormalities usually involve the cervical and cerebral vasculature and include congenital abnormalities and progressive cerebral vasculopathy. The progressive cerebral vasculopathy leads to increased risk for arterial ischemic stroke (AIS) in patients with PHACE syndrome. Here we described the clinical neurological sequelae, the malformation of brain, the cervical and cerebral vasculopathy in a 23-year-old female of PHACE syndrome. Besides, she presented AIS with limb-shaking transient ischemic attack, a rare clinical presentation of AIS in patients of PHACE syndrome.

Failure to Impact Prevalence of Arterial Ischemic Stroke in Pediatric Cardiac Patients over Three Decades

Over the past three decades, significant advances in treatment have improved the mortality of children with cardiac disease. The effect of these advances on the prevalence of arterial ischemic stroke (AIS) is unknown. We describe AIS in children with cardiac disease in the modern era. The prospectively enrolled Intermountain Pediatric Stroke Database (including Utah, Wyoming, Idaho, and Nevada) was queried for all patients less than 18 years old with new-onset AIS between January 1, 2003 and August 31, 2009. Medical records of patients with AIS and cardiac disease were reviewed for cardiac diagnosis, age at AIS, anticoagulant therapy, diuretics, hematocrit, bolus fluids, and ongoing morbidity. Data were analyzed using chi-square test and a mixed-effects Poisson regression growth curve model. AIS incidence in our catchment area was 0.01% (10.7/100,000; N = 97). The incidence of AIS in patients with cardiac disease was higher compared with AIS in the total population (incidence 0.13% [132/100,000], odds ratio [OR] 16.1, 95% confidence interval [CI; 9.7--25.9], P < 0.001). Of the 97 patients with AIS, 24 had cardiac disease (25%). The most common cardiac diagnosis was single ventricle (SV; 8/24, 33%). The incidence of AIS in patients with SV cardiac disease was higher compared with those with other cardiac diagnoses (incidence 1.38% [1380/100,000], OR 15.3, 95% CI [5.7--38.2], P < 0.001). Modeling the prevalence estimates reported since 1978, the prevalence of cardiac disease in AIS patients has remained unchanged across time (prevalence increase per each additional year, 0.5%, 95% CI [--2.1%, 3.1%], P = 0.71). Children with cardiac disease (particularly those with SV) have increased risk for AIS. The prevalence is unchanged from reports over previous decades. AIS occurred in SV patients despite compliance with current anticoagulation recommendations. Future efforts should focus on best practices to prevent AIS in cardiac patients.

Impact of Thrombophilia on Risk of Arterial Ischemic Stroke or Cerebral Sinovenous Thrombosis in Neonates and Children

The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99). The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.

Pearls: Stroke

The diagnosis of ischemic stroke continues to be a clinical one, although advances in neuroimaging have expanded our understanding of the correlation between clinical symptoms and neuroanatomical localization. Careful neurologic examination allows localization in both neuroanatomical and vascular space. Findings on neuroimaging are then correlated to assess their clinical relevance. Transient ischemic attack is recognized as a warning sign for impending vascular disease, but even less specific transient neurologic symptoms are associated with increased risk. Stroke can occur at any age. For women, the postpartum period is a time of elevated risk for arterial ischemic stroke.

Inherited Prothrombotic Risk Factors in Children With Stroke, Transient Ischemic Attack, or Migraine

The aim of this study was to investigate the prevalence and possible association of inherited prothrombotic risk factors in children with stroke, transient ischemic attack, or migraine. We performed genotypic analysis for factor V G1691A, factor II G20210A, methylenetetrahydrofolate reductase C677T, and 4 common platelet glycoprotein polymorphisms (human platelet alloantigen-1, -2, -3, and -5) in 150 children <18 years of age with established diagnoses of stroke, transient ischemic attack, or migraine. Children were classified into 5 groups, namely, childhood arterial ischemic stroke (N = 33), perinatal arterial ischemic stroke (N = 26), hemorrhagic stroke (N = 20), transient ischemic attack (N = 36), and migraine (N = 35). The control group consisted of 112 children < or =18 years of age from the same geographical region who had no history of neurologic or thromboembolic diseases. Heterozygosity for factor V G1691A was associated with approximately sevenfold increased risk for arterial ischemic stroke, perinatal arterial ischemic stroke, and transient ischemic attack. Increased risk for transient ischemic attack was found in carriers of the human platelet alloantigen-2b allele, human platelet alloantigen-5a/b genotype, and combined human platelet alloantigen-2b and human platelet alloantigen-5b genotype. The presence of the human platelet alloantigen-2b allele was associated with a 2.23-fold increased risk for migraine, whereas carriers of the human platelet alloantigen-3b allele had a lower risk for arterial ischemic stroke than did carriers of the human platelet alloantigen-3a allele. Factor V G1691A has an important role in susceptibility to arterial ischemic stroke, both in the perinatal/neonatal period and in childhood, as well as transient ischemic attacks. A minor impact of human platelet alloantigen polymorphisms suggests that platelet glycoprotein polymorphisms may increase the risk of transient ischemic attacks and migraine, but this should be confirmed in larger studies.

Role of Promoter Polymorphisms in the Plasma Glutathione Peroxidase ( GPx-3 ) Gene as a Risk Factor for Cerebral Venous Thrombosis

Plasma glutathione peroxidase (GPx-3) is a major antioxidant enzyme in plasma and the extracellular space that scavenges reactive oxygen species produced during normal metabolism or after oxidative insult. A deficiency of this enzyme increases extracellular oxidant stress, promotes platelet activation, and may promote oxidative posttranslational modification of fibrinogen. We recently identified a haplotype (H(2)) in the GPx-3 gene promoter that increases the risk of arterial ischemic stroke among children and young adults. The aim of this study is to identify possible relationships between promoter haplotypes in the GPx-3 gene and cerebral venous thrombosis (CVT). We studied the GPx-3 gene promoter from 23 patients with CVT and 123 young controls (18 to 45 years) by single-stranded conformational polymorphism and sequencing analysis. Over half of CVT patients (52.1%) were heterozygous (H(1)H(2)) or homozygous (H(2)H(2)) carriers of the H(2) haplotype compared with 12.2% of controls, yielding a more than 10-fold independent increase in the risk of CVT (OR=10.7; 95% CI, 2.70 to 42.36; P<0.0001). Among women, the interaction of the H(2) haplotype with hormonal risk factors increased the OR of CVT to almost 70 (P<0.0001). These findings show that a novel GPx-3 promoter haplotype is a strong, independent risk factor for CVT. As we have previously shown that this haplotype is associated with a reduction in transcriptional activity, which compromises antioxidant activity and antithrombotic benefits of the enzyme, these results suggest that a deficiency of GPx-3 leads to a cerebral venous thrombophilic state.

GPx-3 Gene Promoter Variation and the Risk of Arterial Ischemic Stroke

To the Editor: The recently published association of a particular promoter variant of the GPx-3 (plasma glutathione peroxidase) gene with increased risk for arterial ischemic stroke in this journal1 was the result of a long-duration research project. A set of linked polymorphisms in the promotor of the GPx-3 gene was described previously, and it was shown that carriers of a particular haplotype (H2) had a 2-fold increase in risk of ischemic stroke compared with noncarriers.2 The authors had, furthermore, analyzed the regulation of GPx-3 expression in a cultured cell system, identified a novel transcription start site and demonstrated that hypoxia was a strong transcriptional regulator of GPx-3 expression.3 The interest of the research …

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.

Early Stroke and Cerebral Vasculopathy in Children With Facial Hemangiomas and PHACE Association

PHACE association is a rare neurocutaneous syndrome that may include posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, and sternal defects. The arterial abnormalities may be developmental or acquired and usually involve the cervical and cerebral vasculature. We believe that infants with PHACE association are at increased risk of arterial ischemic stroke and describe 5 infants with facial hemangiomas and structural and acquired arterial anomalies, all of whom suffered an arterial ischemic stroke during infancy.