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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.

Background: Although much is known about cognitive dysfunction in attention-deficit/hyperactivity disorder (ADHD), few studies have examined the pathophysiology of disordered motor circuitry. We explored differences in neurometabolite levels and transcranial magnetic stimulation (TMS)-derived corticomotor representations among children with ADHD and typically developing children. Methods: We used magnetic resonance spectroscopy (MRS) protocols to measure excitatory (glutamate + glutamine [Glx]) and inhibitory ([gamma]-aminobutyric acid [GABA]) neurometabolite levels in the dominant primary motor cortex (M1) and the supplementary motor area (SMA) in children with ADHD and typically developing children. We used robotic neuronavigated TMS to measure corticospinal excitability and create corticomotor maps. Results: We collected data from 26 medication-free children with ADHD (aged 7-16 years) and 25 typically developing children (11-16 years). Children with ADHD had lower M1 Glx (p = 0.044, d = 0.6); their mean resting motor threshold was lower (p = 0.029, d = 0.8); their map area was smaller (p = 0.044, d = 0.7); and their hotspot density was higher (p = 0.008, d = 0.9). M1 GABA levels were associated with motor map area (p = 0.036). Limitations: Some TMS data were lost because the threshold of some children exceeded 100% of the machine output. The relatively large MRS voxel required to obtain sufficient signal- to-noise ratio and reliably measure GABA levels encompassed tissue beyond the M1, making this measure less anatomically specific. Conclusion: The neurochemistry and neurophysiology of key nodes in the motor network may be altered in children with ADHD, and the differences appear to be related to each other. These findings suggest potentially novel neuropharmacological and neuromodulatory targets for ADHD., Introduction Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by inattentiveness, impulsivity and motor hyperactivity. (1) It negatively affects individuals' performance at school and at home. (2) ADHD is [...]

Childhood-onset Takayasu arteritis (TA) is a rare, heterogeneous disease with limited diagnostic markers. Our objective was to identify and classify all candidates for biomarkers of TA diagnosis in children reported in the literature. A systematic literature review (PRISMA) of MEDLINE, EMBASE, Wiley Cochrane Library, ClinicalTrias.gov, and WHO ICTRP for articles related to TA in the pediatric age group between January 2000 and August 2023 was performed. Data on demographics, clinical features, laboratory measurements, diagnostic imaging, and genetic analysis were extracted. We identified 2026 potential articles, of which 52 studies (81% case series) met inclusion criteria. A total of 1067 TA patients were included with a peak onset between 10 and 15 years. Childhood-onset TA predominantly presented with cardiovascular, constitutional, and neurological symptoms. Laboratory parameters exhibited a low sensitivity and specificity. Imaging predominantly revealed involvement of the abdominal aorta and renal arteries, with magnetic resonance angiography (MRA) being the preferred imaging modality. Our review confirms the heterogeneous presentation of childhood-onset TA, posing significant challenges to recognition and timely diagnosis. Collaborative, multinational efforts are essential to better understand the natural course of childhood-onset TA and to identify accurate biomarkers to enhance diagnosis and disease management, ultimately improving patient outcomes. [ABSTRACT FROM AUTHOR]

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.

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 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.

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.

Developmental lateralization of brain function is imperative for behavioral specialization, yet few studies have investigated differences between hemispheres in structural connectivity patterns, especially over the course of development. The present study compares the lateralization of structural connectivity patterns, or topology, across children, adolescents, and young adults. We applied a graph theory approach to quantify key topological metrics in each hemisphere including efficiency of information transfer between regions (global efficiency), clustering of connections between regions (clustering coefficient [CC]), presence of hub‐nodes (betweenness centrality [BC]), and connectivity between nodes of high and low complexity (hierarchical complexity [HC]) and investigated changes in these metrics during development. Further, we investigated BC and CC in seven functionally defined networks. Our cross‐sectional study consisted of 211 participants between the ages of 6 and 21 years with 93% being right‐handed and 51% female. Global efficiency, HC, and CC demonstrated a leftward lateralization, compared to a rightward lateralization of BC. The sensorimotor, default mode, salience, and language networks showed a leftward asymmetry of CC. BC was only lateralized in the salience (right lateralized) and dorsal attention (left lateralized) networks. Only a small number of metrics were associated with age, suggesting that topological organization may stay relatively constant throughout school‐age development, despite known underlying changes in white matter properties. Unlike many other imaging biomarkers of brain development, our study suggests topological lateralization is consistent across age, highlighting potential nonlinear mechanisms underlying developmental specialization. [ABSTRACT FROM AUTHOR]