Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Results of the VIPS Study.

Background and purposeChildhood arteriopathies are rare but heterogenous, and difficult to diagnose and classify, especially by nonexperts. We quantified clinical and imaging characteristics associated with childhood arteriopathy subtypes to facilitate their diagnosis and classification in research and clinical settings.Materials and methodsThe Vascular Effects of Infection in Pediatric Stroke (VIPS) study prospectively enrolled 355 children with arterial ischemic stroke (2010-2014). A central team of experts reviewed all data to diagnose childhood arteriopathy and classify subtypes, including arterial dissection and focal cerebral arteriopathy-inflammatory type, which includes transient cerebral arteriopathy, Moyamoya disease, and diffuse/multifocal vasculitis. Only children whose stroke etiology could be conclusively diagnosed were included in these analyses. We constructed logistic regression models to identify characteristics associated with each arteriopathy subtype.ResultsAmong 127 children with definite arteriopathy, the arteriopathy subtype could not be classified in 18 (14%). Moyamoya disease (n = 34) occurred mostly in children younger than 8 years of age; focal cerebral arteriopathy-inflammatory type (n = 25), in children 8-15 years of age; and dissection (n = 26), at all ages. Vertigo at stroke presentation was common in dissection. Dissection affected the cervical arteries, while Moyamoya disease involved the supraclinoid internal carotid arteries. A banded appearance of the M1 segment of the middle cerebral artery was pathognomonic of focal cerebral arteriopathy-inflammatory type but was present in <25% of patients with focal cerebral arteriopathy-inflammatory type; a small lenticulostriate distribution infarct was a more common predictor of focal cerebral arteriopathy-inflammatory type, present in 76%. It remained difficult to distinguish focal cerebral arteriopathy-inflammatory type from intracranial dissection of the anterior circulation. We observed only secondary forms of diffuse/multifocal vasculitis, mostly due to meningitis.ConclusionsChildhood arteriopathy subtypes have some typical features that aid diagnosis. Better imaging methods, including vessel wall imaging, are needed for improved classification of focal cerebral arteriopathy of childhood

Inflammatory Biomarkers in Childhood Arterial Ischemic Stroke: Correlates of Stroke Cause and Recurrence.

Background and purposeAmong children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS.MethodsIn an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-α. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS.ResultsMedian age at index stroke was 8.2 years (interquartile range, 3.6-14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3-10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies.ConclusionsAmong children with AIS, specific inflammatory biomarkers correlate with cause and-in the arteriopathy group-risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials

Evidence of varicella zoster virus (VZV) reactivation in children with arterial ischemic stroke: Results of the VIPS II Study

BACKGROUND: Varicella zoster virus (VZV) has been associated with focal cerebral arteriopathy (FCA) and arterial ischemic stroke (AIS) in childhood. The Vascular effects of Infection in Pediatric Stroke (VIPS) II study aimed to examine this relationship in the modern era when most children in North America and Australia receive VZV vaccination with live, attenuated virus. METHODS: This 22-center prospective cohort study enrolled 205 children (28 days-18 years) with AIS (2017-2022), collected baseline [hyperacute (≤72 hours; n=194) and acute (4-6 days; n=181)] and convalescent (1-6 weeks; n=74) serum samples. Sites enrolled 95 stroke-free controls with single serum samples. A virology research laboratory measured VZV IgM and IgG titers by an in-house enzyme-linked immunosorbent assay (ELISA). Baseline IgG seropositivity indicated prior exposure (vaccination/infection) and elevated IgM titers indicated recent reactivation. RESULTS: Median (IQR) age was 11.6 (5.5-15.6) years for cases and 11.8 (6.8-15.3) years for controls. Baseline serologies indicated prior VZV exposure in 198 cases (97%) and all controls. Parents of cases reported VZV vaccination in 160 (78%) and remote chicken pox in three (1.4%). Twenty cases (9.8%) and three controls (3.1%) had serologic evidence of recent VZV reactivation (p=0.06); all had remote VZV exposure (vaccination in 19 cases and all controls) and all were asymptomatic. Recent VZV reactivation was seen in similar proportions in arteriopathic, cardioembolic, and idiopathic stroke. Of 32 cases of FCA, 4 (12.5%) had recent VZV reactivation, versus no cases of arterial dissection (n=10) or moyamoya (n=16). CONCLUSIONS: Serologic evidence of recent VZV reactivation (≈1-6 weeks prior to stroke) was present in one in 10 cases of childhood AIS, including those without arteriopathy. Clinically silent VZV reactivation may be a childhood stroke trigger despite widespread vaccination. These cases could represent waning immunity with reactivation of either vaccine virus or wild-type virus after an unrecognized secondary VZV infection

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

Background and purposePublished 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.MethodsThe 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.ResultsOf 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.ConclusionsChildren 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

Socioeconomic determinants of outcome after childhood arterial ischemic stroke

ObjectiveTo determine whether lower socioeconomic status (SES) is associated with worse 1-year neurologic outcomes and reduced access to rehabilitation services in children with arterial ischemic stroke (AIS).MethodsFrom 2010 to 2014, the Vascular effects of Infection in Pediatric Stroke (VIPS) observational study prospectively enrolled and confirmed 355 children (age 29 days-18 years) with AIS at 37 international centers. SES markers measured via parental interview included annual household income (US dollars) at the time of enrollment, maternal education level, and rural/suburban/urban residence. Receipt of rehabilitation services was measured by parental report. Pediatric Stroke Outcome Measure scores were categorized as 0 to 1, 1.5 to 3, 3.5 to 6, and 6.5 to 10. Univariate and multivariable ordinal logistic regression models examined potential predictors of outcome.ResultsAt 12 ± 3 months after stroke, 320 children had documented outcome measurements, including 15 who had died. In univariate analysis, very low income (p = 0.004). In multivariable analysis, including adjustment for stroke etiology, this association persisted (OR 3.17, 95% CI 1.18-8.47, p = 0.02). Income did not correlate with receiving rehabilitation services at 1 year after stroke; however, quality and quantity of services were not assessed.ConclusionsIn a large, multinational, prospective cohort of children with AIS, low income was associated with worse neurologic outcomes compared to higher income levels. This difference was not explained by stroke type, neurologic comorbidities, or reported use of rehabilitation services. The root causes of this disparity are not clear and warrant further investigation

Parvovirus B19 Infection in Children With Arterial Ischemic Stroke.

Background and purposeCase-control studies suggest that acute infection transiently increases the risk of childhood arterial ischemic stroke. We hypothesized that an unbiased pathogen discovery approach utilizing MassTag-polymerase chain reaction would identify pathogens in the blood of childhood arterial ischemic stroke cases.MethodsThe multicenter international VIPS study (Vascular Effects of Infection in Pediatric Stroke) enrolled arterial ischemic stroke cases, and stroke-free controls, aged 29 days through 18 years. Parental interview included questions on recent infections. In this pilot study, we used MassTag-polymerase chain reaction to test the plasma of the first 161 cases and 34 controls enrolled for a panel of 28 common bacterial and viral pathogens.ResultsPathogen DNA was detected in no controls and 14 cases (8.7%): parvovirus B19 (n=10), herpesvirus 6 (n=2), adenovirus (n=1), and rhinovirus 6C (n=1). Parvovirus B19 infection was confirmed by serologies in all 10; infection was subclinical in 8. Four cases with parvovirus B19 had underlying congenital heart disease, whereas another 5 had a distinct arteriopathy involving a long-segment stenosis of the distal internal carotid and proximal middle cerebral arteries.ConclusionsUsing MassTag-polymerase chain reaction, we detected parvovirus B19-a virus known to infect erythrocytes and endothelial cells-in some cases of childhood arterial ischemic stroke. This approach can generate new, testable hypotheses about childhood stroke pathogenesis

Imaging Predictors of Neurologic Outcome After Pediatric Arterial Ischemic Stroke

BACKGROUND AND PURPOSE: To assess whether initial imaging characteristics independently predict 1-year neurological outcomes in childhood arterial ischemic stroke patients. METHODS: We used prospectively collected demographic and clinical data, imaging data, and 1-year outcomes from the VIPS study (Vascular Effects of Infection in Pediatric Stroke). In 288 patients with first-time stroke, we measured infarct volume and location on the acute magnetic resonance imaging studies and hemorrhagic transformation on brain imaging studies during the acute presentation. Neurological outcome was assessed with the Pediatric Stroke Outcome Measure. We used univariate and multivariable ordinal logistic regression models to test the association between imaging characteristics and outcome. RESULTS: Univariate analysis demonstrated that infarcts involving uncinate fasciculus, angular gyrus, insular cortex, or that extended from cortex to the subcortical nuclei were significantly associated with poorer outcomes with odds ratios ranging from 1.95 to 3.95. All locations except the insular cortex remained significant predictors of poor outcome on multivariable analysis. When infarct volume was added to the model, the locations did not remain significant. Larger infarct volumes and younger age at stroke onset were significantly associated with poorer outcome, but the strength of the relationships was weak. Hemorrhagic transformation did not predict outcome. CONCLUSIONS: In the largest pediatric arterial ischemic stroke cohort collected to date, we showed that larger infarct volume and younger age at stroke were associated with poorer outcomes. We made the novel observation that the strength of these associations was modest and limits the ability to use these characteristics to predict outcome in children. Infarcts affecting specific locations were significantly associated with poorer outcomes in univariate and multivariable analyses but lost significance when adjusted for infarct volume. Our findings suggest that infarcts that disrupt critical networks have a disproportionate impact upon outcome after childhood arterial ischemic stroke