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BackgroundThe year 2020 marked a fundamental shift in the pediatric neurology field. An impressive positive trajectory of advances in patient care and research faced sudden global disruptions by the coronavirus disease 2019 pandemic and by an international movement protesting racial, socioeconomic, and health disparities. The disruptions revealed obstacles and fragility within the pediatric neurology research mission. However, renewed commitment offers unique opportunities for the pediatric neurology research community to enhance and prioritize research directions for the coming decades.MethodsThe Research Committee of the Child Neurology Society evaluated the challenges and opportunities facing the pediatric neurology research field, including reviewing published literature, synthesizing publically available data, and conducting a survey of pediatric neurologists.ResultsWe identified three priority domains for the research mission: funding levels, active guidance, and reducing disparities. Funding levels: to increase funding to match the burden of pediatric neurological disease; to tailor funding mechanisms and strategies to support clinical trial efforts unique to pediatric neurology; and to support investigators across their career trajectory. Active guidance: to optimize infrastructure and strategies, to leverage novel therapeutics, enhance data collection, and improve inclusion of children in clinical trials. Reducing disparities: to reduce health disparities in children with neurological disease, to develop proactive measures to enhance workforce diversity and inclusion, and increase avenues to balance work-life obligations for investigators.ConclusionsIn this uniquely challenging epoch, the pediatric neurology research community has a timely and important mission to re-engage the public and government, advancing the health of children with neurological conditions.

ObjectiveTo determine that children with arterial ischemic stroke (AIS) due to an identifiable arteriopathy are distinct from those without arteriopathy and that each arteriopathy subtype has unique and recognizable clinical features.MethodsWe report a large, observational, multicenter cohort of children with AIS, age 1 month to 18 years, enrolled in the International Pediatric Stroke Study from 2003 to 2014. Clinical and demographic differences were compared by use of the Fisher exact test, with linear step-up permutation min-p adjustment for multiple comparisons. Exploratory analyses were conducted to evaluate differences between cases of AIS with and without arteriopathy and between arteriopathy subtypes.ResultsOf 2,127 children with AIS, 725 (34%) had arteriopathy (median age 7.45 years). Arteriopathy subtypes included dissection (27%), moyamoya (24.5%), focal cerebral arteriopathy-inflammatory subtype (FCA-i; 15%), diffuse cerebral vasculitis (15%), and nonspecific arteriopathy (18.5%). Children with arteriopathic AIS were more likely to present between 6 and 9 years of age (odds ratio [OR] 1.93, p = 0.029) with headache (OR 1.55, p = 0.023), multiple infarctions (OR 2.05, p < 0.001), sickle cell anemia (OR 2.9, p = 0.007), and head/neck trauma (OR 1.93, p = 0.018). Antithrombotic use and stroke recurrence were higher in children with arteriopathy. Among arteriopathy subtypes, dissection was associated with male sex, older age, headache, and anticoagulant use; FCA-i was associated with hemiparesis and single infarcts; moyamoya was associated with seizures and recurrent strokes; and vasculitis was associated with bilateral infarctions.ConclusionSpecific clinical profiles are associated with cerebral arteriopathies in children with AIS. These observations may be helpful indicators in guiding early diagnosis and defining subgroups who may benefit most from future therapeutic trials.

BackgroundPediatric cerebral sinovenous thrombosis is a treatable cause of brain injury, acute symptomatic seizures, and remote epilepsy. Our objective was to prospectively study epilepsy and outcomes in neonates and children one year after cerebral sinovenous thrombosis diagnosis.MethodsPatients with cerebral sinovenous thrombosis were enrolled prospectively from 21 international sites through the Seizures in Pediatric Stroke Study. Clinical data, including acute symptomatic seizures and cerebral sinovenous thrombosis risk factors, were collected at diagnosis. A neuroradiologist who was unaware of the diagnosis reviewed acute imaging. At one year, outcomes including seizure recurrence, epilepsy diagnosis, antiepileptic drug use, and modified Engel score were collected. Outcomes were assessed using the modified Rankin score and the King's Outcome Scale for Childhood Head Injury.ResultsTwenty-four participants with cerebral sinovenous thrombosis were enrolled (67% male, 21% neonates). Headache was the most common presenting symptom in non-neonates (47%, nine of 19). Nine (37.5%) presented with acute symptomatic seizures. Six (25%; 95% confidence interval, 10% to 47%) developed epilepsy by one-year follow-up. No clinical predictors associated with epilepsy were identified. King's Outcome Scale for Childhood Head Injury and modified Rankin scores at one year were favorable in 71%. Half of the patients who developed epilepsy (three of six) did not have infarcts, hemorrhage, or seizures identified during the acute hospitalization.ConclusionOur study provides a prospective estimate that epilepsy occurs in approximately one-quarter of patients by one year after diagnosis of cerebral sinovenous thrombosis. Later epilepsy can develop in the absence of acute seizures or parenchymal injury associated with the acute presentation.

Purpose- Much has transpired since the last scientific statement on pediatric stroke was published 10 years ago. Although stroke has long been recognized as an adult health problem causing substantial morbidity and mortality, it is also an important cause of acquired brain injury in young patients, occurring most commonly in the neonate and throughout childhood. This scientific statement represents a synthesis of data and a consensus of the leading experts in childhood cardiovascular disease and stroke. Methods- Members of the writing group were appointed by the American Heart Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association's Manuscript Oversight Committee and were chosen to reflect the expertise of the subject matter. The writers used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. This scientific statement is based on expert consensus considerations for clinical practice. Results- Annualized pediatric stroke incidence rates, including both neonatal and later childhood stroke and both ischemic and hemorrhagic stroke, range from 3 to 25 per 100 000 children in developed countries. Newborns have the highest risk ratio: 1 in 4000 live births. Stroke is a clinical syndrome. Delays in diagnosis are common in both perinatal and childhood stroke but for different reasons. To develop new strategies for prevention and treatment, disease processes and risk factors that lead to pediatric stroke are discussed here to aid the clinician in rapid diagnosis and treatment. The many important differences that affect the pathophysiology and treatment of childhood stroke are discussed in each section. Conclusions- Here we provide updates on perinatal and childhood stroke with a focus on the subtypes, including arterial ischemic, venous thrombotic, and hemorrhagic stroke, and updates in regard to areas of childhood stroke that have not received close attention such as sickle cell disease. Each section is highlighted with considerations for clinical practice, attendant controversies, and knowledge gaps. This statement provides the practicing provider with much-needed updated information in this field.

Background and Purpose- Focal cerebral arteriopathy (FCA)-a common cause of arterial ischemic stroke in previously healthy children-often progresses over days to weeks, increasing the risk of recurrent stroke. We developed a novel severity scoring system designed to quantify FCA progression and correlate with clinical outcomes. Methods- The VIPS study (Vascular Effects of Infection in Pediatric Stroke) prospectively enrolled 355 children with arterial ischemic stroke (2010-2014), including 41 with centrally confirmed FCA. Two neuroradiologists independently reviewed FCA cerebrovascular imaging, assigning a graded severity score of zero (no involvement) to 4 (occlusion) to individual arterial segments. The FCA severity score (FCASS) was the unweighted sum. In an iterative process, we modeled scores derived from different combinations of arterial segments to identify the model that optimized correlation with clinical outcome, simplicity, and reliability. Results- The optimal FCASS summed scores from 5 arterial segments: supraclinoid internal carotid artery, A1, A2, M1, and M2. The median (interquartile range) baseline FCASS was 4 (2-6). Of 33 children with follow-up imaging, the maximum FCASS (at any time point) was 7 (5-9). Twenty-four (73%) had FCA progression on follow-up with their maximum FCASS at a median of 8 (5-35.5) days poststroke; their median FCASS increase was 4 (2.5-6). FCASS did not correlate with recurrent arterial ischemic stroke. Maximum (but not baseline) FCASS correlated with 1-year pediatric stroke outcome measures ( P=0.037). Conclusions- Our novel scoring system for FCA severity correlates with neurological outcomes in the VIPS cohort and provides a tool for FCA treatment trials under development.

Background Epilepsy is a common complication of pediatric stroke. Aim In this study, we aim to measure the association between epilepsy and neurologic outcome after childhood arterial ischemic stroke. Methods Prospective cohort study of children (29 days-19 years) enrolled after an acute arterial ischemic stroke at 21 international pediatric stroke centers and followed to identify epilepsy. One year post-stroke, outcomes were scored using the examination-based Pediatric Stroke Outcome Measure (range = 0-10); higher values reflect greater disability. Ordinal logistic regression was used to measure the association of Pediatric Stroke Outcome Measure scores (categorized as 0-1, 1.5-3, 3.5-6, 6.5-10) with epilepsy. Results Investigators enrolled 86 children (median age = 6.1 years, interquartile range (IQR) = 1.4-12.2 years) with acute stroke. At 1 year, 18/80 (23%) remained on an anticonvulsant including 8/80 (10%) with epilepsy. Among the 70 with Pediatric Stroke Outcome Measure scored, the median was 0.5 (IQR = 0-1.5) for children without epilepsy ( n = 63), and 6 (IQR = 0.5-10) for children with epilepsy ( n = 7). In univariable analyses, poorer 1-year outcome was associated with middle cerebral artery stroke, cortical infarcts, hemorrhagic transformation, hospital disposition not to home, and epilepsy. In multivariable analysis, middle cerebral artery stroke (odds ratio (OR) = 4.9, 95% confidence intervals (CI) = 1.1-21.3) and epilepsy (OR = 24.1, CI = 1.5-380) remained associated with poorer outcome. Conclusions Children who developed epilepsy during the first year post-stroke had poorer neurologic outcomes than those without epilepsy.

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.

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.

On June 5, 2015 the International Pediatric Stroke Study and the Stroke Imaging Laboratory for Children cohosted a unique workshop focused on developing neuroimaging research in pediatric stroke. Pediatric neurologists, neuroradiologists, interventional neuroradiologists, physicists, nurse practitioners, neuropsychologists, and imaging research scientists from around the world attended this one-day meeting. Our objectives were to (1) establish a group of experts to collaborate in advancing pediatric neuroimaging for stroke, (2) develop consensus clinical and research magnetic resonance imaging protocols for pediatric stroke patients, and (3) develop imaging-based research strategies in pediatric ischemic stroke. This article provides a summary of the meeting proceedings focusing on identified challenges and solutions and outcomes from the meeting. Further details on the workshop contents and outcomes are provided in three additional articles in the current issue of Pediatric Neurology.

AimTo determine epilepsy risk factors after pediatric stroke.MethodA cohort of children with arterial ischemic stroke (birth-18y) was enrolled at 21 centers and followed for 1 year. Acute seizures (≤7d after stroke) and active epilepsy (at least one unprovoked remote seizure plus maintenance anticonvulsant at 1y) were identified. Predictors were determined using logistic regression.ResultsAmong 114 patients (28 neonates and 86 children) enrolled, 26 neonates (93%) and 32 children (37%) had an acute seizure. Acute seizures lasted longer than 5 minutes in 23 patients (40%) and were frequently recurrent: 33 (57%) had 2 to 10 seizures and 11 (19%) had more than 10. Among 109 patients with 1-year follow-up, 11 (10%) had active epilepsy. For each year younger, active epilepsy was 20% more likely (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.6-0.99, p=0.041). Prolonged or recurrent acute seizures also increased epilepsy risk. Each additional 10 minutes of the longest acute seizure increased epilepsy risk fivefold (OR 4.7, 95% CI 1.7-13). Patients with more than 10 acute seizures had a 30-fold increased epilepsy risk (OR 30, 95% CI 2.9-305).InterpretationPediatric stroke survivors, especially younger children, have a high risk of epilepsy 1 year after stroke. Prolonged or recurrent acute seizures increase epilepsy risk in a dose-dependent manner.

Background and purposeThere are limited data about the reliability of subtype classification in childhood arterial ischemic stroke, an issue that prompted the IPSS (International Pediatric Stroke Study) to develop the CASCADE criteria (Childhood AIS Standardized Classification and Diagnostic Evaluation). Our purpose was to determine the CASCADE criteria's reliability in a population of children with stroke.MethodsEight raters from the IPSS reviewed neuroimaging and clinical records of 64 cases (16 cases each) randomly selected from a prospectively collected cohort of 113 children with arterial ischemic stroke and classified them using the CASCADE criteria. Clinical data abstracted included history of present illness, risk factors, and acute imaging. Agreement among raters was measured by unweighted κ statistic.ResultsThe CASCADE criteria demonstrated a moderate inter-rater reliability, with an overall κ statistic of 0.53 (95% confidence interval [CI]=0.39-0.67). Cardioembolic and bilateral cerebral arteriopathy subtypes had much higher agreement (κ=0.84; 95% CI=0.70-0.99; and κ=0.90; 95% CI=0.71-1.00, respectively) than cases of aortic/cervical arteriopathy (κ=0.36; 95% CI=0.01-0.71), unilateral focal cerebral arteriopathy of childhood (FCA; κ=0.49; 95% CI=0.23-0.76), and small vessel arteriopathy of childhood (κ=-0.012; 95% CI=-0.04 to 0.01).ConclusionsThe CASCADE criteria have moderate reliability when used by trained and experienced raters, which suggests that it can be used for classification in multicenter pediatric stroke studies. However, the moderate reliability of the arteriopathic subtypes suggests that further refinement is needed for defining subtypes. Such revisions may reduce the variability in the literature describing risk factors, recurrence, and outcomes associated with childhood arteriopathy.

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.

Background and purposeArteriopathy is the leading cause of childhood arterial ischemic stroke. Mechanisms are poorly understood but may include inherent abnormalities of arterial structure. Extracranial dissection is associated with connective tissue disorders in adult stroke. Focal cerebral arteriopathy is a common syndrome where pathophysiology is unknown but may include intracranial dissection or transient cerebral arteriopathy. We aimed to quantify cerebral arterial tortuosity in childhood arterial ischemic stroke, hypothesizing increased tortuosity in dissection.MethodsChildren (1 month to 18 years) with arterial ischemic stroke were recruited within the Vascular Effects of Infection in Pediatric Stroke (VIPS) study with controls from the Calgary Pediatric Stroke Program. Objective, multi-investigator review defined diagnostic categories. A validated imaging software method calculated the mean arterial tortuosity of the major cerebral arteries using 3-dimensional time-of-flight magnetic resonance angiographic source images. Tortuosity of unaffected vessels was compared between children with dissection, transient cerebral arteriopathy, meningitis, moyamoya, cardioembolic strokes, and controls (ANOVA and post hoc Tukey). Trauma-related versus spontaneous dissection was compared (Student t test).ResultsOne hundred fifteen children were studied (median, 6.8 years; 43% women). Age and sex were similar across groups. Tortuosity means and variances were consistent with validation studies. Tortuosity in controls (1.346±0.074; n=15) was comparable with moyamoya (1.324±0.038; n=15; P=0.998), meningitis (1.348±0.052; n=11; P=0.989), and cardioembolic (1.379±0.056; n=27; P=0.190) cases. Tortuosity was higher in both extracranial dissection (1.404±0.084; n=22; P=0.021) and transient cerebral arteriopathy (1.390±0.040; n=27; P=0.001) children. Tortuosity was not different between traumatic versus spontaneous dissections (P=0.70).ConclusionsIn children with dissection and transient cerebral arteriopathy, cerebral arteries demonstrate increased tortuosity. Quantified arterial tortuosity may represent a clinically relevant imaging biomarker of vascular biology in pediatric stroke.

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.

ObjectivesMinor 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.MethodsThe 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.ResultsMedian (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).ConclusionsInfection 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.

BackgroundCardiac disease is a leading cause of stroke in children, yet limited data support the current stroke prevention and treatment recommendations. A multidisciplinary panel of clinicians was convened in February 2014 by the International Pediatric Stroke Study group to identify knowledge gaps and prioritize clinical research efforts for children with cardiac disease and stroke.ResultsSignificant knowledge gaps exist, including a lack of data on stroke incidence, predictors, primary and secondary stroke prevention, hyperacute treatment, and outcome in children with cardiac disease. Commonly used diagnostic techniques including brain computed tomography and ultrasound have low rates of stroke detection, and diagnosis is frequently delayed. The challenges of research studies in this population include epidemiologic barriers to research such as small patient numbers, heterogeneity of cardiac disease, and coexistence of multiple risk factors. Based on stroke burden and study feasibility, studies involving mechanical circulatory support, single ventricle patients, early stroke detection strategies, and understanding secondary stroke risk factors and prevention are the highest research priorities over the next 5-10 years. The development of large-scale multicenter and multispecialty collaborative research is a critical next step. The designation of centers of expertise will assist in clinical care and research.ConclusionsThere is an urgent need for additional research to improve the quality of evidence in guideline recommendations for cardiogenic stroke in children. Although significant barriers to clinical research exist, multicenter and multispecialty collaboration is an important step toward advancing clinical care and research for children with cardiac disease and stroke.

Background and purposeAlthough arteriopathies are the most common cause of childhood arterial ischemic stroke, and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with arterial ischemic stroke.MethodsVascular effects of infection in pediatric stroke, an international prospective study, enrolled 355 cases of arterial ischemic stroke (age, 29 days to 18 years) at 39 centers. A neuroradiologist and stroke neurologist independently reviewed vascular imaging of the brain (mandatory for inclusion) and neck to establish a diagnosis of arteriopathy (definite, possible, or absent) in 3 steps: (1) baseline imaging alone; (2) plus clinical data; (3) plus follow-up imaging. A 4-person committee, including a second neuroradiologist and stroke neurologist, adjudicated disagreements. Using the final diagnosis as the gold standard, we calculated the sensitivity and specificity of each step.ResultsCases were aged median 7.6 years (interquartile range, 2.8-14 years); 56% boys. The majority (52%) was previously healthy; 41% had follow-up vascular imaging. Only 56 (16%) required adjudication. The gold standard diagnosis was definite arteriopathy in 127 (36%), possible in 34 (9.6%), and absent in 194 (55%). Sensitivity was 79% at step 1, 90% at step 2, and 94% at step 3; specificity was high throughout (99%, 100%, and 100%), as was agreement between reviewers (κ=0.77, 0.81, and 0.78).ConclusionsClinical data and follow-up imaging help, yet uncertainty in the diagnosis of childhood arteriopathy remains. This presents a challenge to better understanding the mechanisms underlying these arteriopathies and designing strategies for prevention of childhood arterial ischemic stroke.

Background and purposeThe 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.MethodsUsing 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.ResultsIn 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]).ConclusionsA 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.