A prospective multicenter feasibility study of a miniaturized implantable continuous flow ventricular assist device in smaller children with heart failure.

BACKGROUND: There is no FDA-approved left ventricular assist device (LVAD) for smaller children permitting routine hospital discharge. Smaller children supported with LVADs typically remain hospitalized for months awaiting heart transplant-a major burden for families and a challenge for hospitals. We describe the initial outcomes of the Jarvik 2015, a miniaturized implantable continuous flow LVAD, in the NHLBI-funded Pumps for Kids, Infants, and Neonates (PumpKIN) study, for bridge-to-heart transplant. METHODS: Children weighing 8 to 30 kg with severe systolic heart failure and failing optimal medical therapy were recruited at 7 centers in the United States. Patients with severe right heart failure and single-ventricle congenital heart disease were excluded. The primary feasibility endpoint was survival to 30 days without severe stroke or non-operational device failure. RESULTS: Of 7 children implanted, the median age was 2.2 (range 0.7, 7.1) years, median weight 10 (8.2 to 20.7) kilograms; 86% had dilated cardiomyopathy; 29% were INTERMACS profile 1. The median duration of Jarvik 2015 support was 149 (range 5 to 188) days where all 7 children survived including 5 to heart transplant, 1 to recovery, and 1 to conversion to a paracorporeal device. One patient experienced an ischemic stroke on day 53 of device support in the setting of myocardial recovery. One patient required ECMO support for intractable ventricular arrhythmias and was eventually transplanted from paracorporeal biventricular VAD support. The median pump speed was 1600 RPM with power ranging from 1-4 Watts. The median plasma free hemoglobin was 19, 30, 19 and 30 mg/dL at 7, 30, 90 and 180 days or time of explant, respectively. All patients reached the primary feasibility endpoint. Patient-reported outcomes with the device were favorable with respect to participation in a full range of activities. Due to financial issues with the manufacturer, the study was suspended after consent of the eighth patient. CONCLUSION: The Jarvik 2015 LVAD appears to hold important promise as an implantable continuous flow device for smaller children that may support hospital discharge. The FDA has approved the device to proceed to a 22-subject pivotal trial. Whether this device will survive to commercialization remains unclear because of the financial challenges faced by industry seeking to develop pediatric medical devices. (Supported by NIH/NHLBI HHS Contract N268201200001I, clinicaltrials.gov 02954497).

Pediatric Cerebral Sinovenous Thrombosis and Risk for Epilepsy.

BACKGROUND: Cerebral sinovenous thrombosis (CSVT) is a rare form of pediatric stroke with significant morbidity. We determined cumulative incidence and predictors of acute seizures, remote seizures, and epilepsy after pediatric CSVT. METHODS: Retrospective analysis of 131 neonates and children with neuroimaging-confirmed CSVT enrolled between 2008 and 2020 from a single-center prospective consecutive cohort. Acute seizures occurred within 7 days of CSVT. Remote seizures occurred >7 days after CSVT. Epilepsy was defined as 2 or more remote seizures at least 24 hours apart. Survival methods determined the incidence of and risk factors for remote seizures and epilepsy. RESULTS: Acute seizures occurred in 14/33 neonates (42%) and 19/98 children (19%). Among children, hemorrhage predicted acute seizures (OR 6.6, 95% CI 1.9 to 22.4, P = 0.003). Remote seizures occurred in six neonates; five developed epilepsy. Remote seizures occurred in 14 children; 10 developed epilepsy. In neonates, 1- and 3-year epilepsy-free survival were 86% (95% CI 62% to 95%) and 66% (95% CI 32% to 87%). One- and 3-year epilepsy-free survival in children were 88% (95% CI 76% to 92%) and 84% (95% CI 59% to 86%). In multivariable analysis for children, acute seizures predicted epilepsy (HR 3.8, 95% CI 1.1-13.3, P = 0.039). In both cohorts, Pediatric Stroke Outcome Measure scores at last follow-up were worse in those with epilepsy compared to those without. CONCLUSIONS: Acute seizures occurred in approximately one quarter of our cohort and are an epilepsy risk factor in children with CSVT. Neonates and children with epilepsy had worse outcomes than those without.

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement.

Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

Language and developmental plasticity after perinatal stroke.

The mature human brain is lateralized for language, with the left hemisphere (LH) primarily responsible for sentence processing and the right hemisphere (RH) primarily responsible for processing suprasegmental aspects of language such as vocal emotion. However, it has long been hypothesized that in early life there is plasticity for language, allowing young children to acquire language in other cortical regions when LH areas are damaged. If true, what are the constraints on functional reorganization? Which areas of the brain can acquire language, and what happens to the functions these regions ordinarily perform? We address these questions by examining long-term outcomes in adolescents and young adults who, as infants, had a perinatal arterial ischemic stroke to the LH areas ordinarily subserving sentence processing. We compared them with their healthy age-matched siblings. All participants were tested on a battery of behavioral and functional imaging tasks. While stroke participants were impaired in some nonlinguistic cognitive abilities, their processing of sentences and of vocal emotion was normal and equal to that of their healthy siblings. In almost all, these abilities have both developed in the healthy RH. Our results provide insights into the remarkable ability of the young brain to reorganize language. Reorganization is highly constrained, with sentence processing almost always in the RH frontotemporal regions homotopic to their location in the healthy brain. This activation is somewhat segregated from RH emotion processing, suggesting that the two functions perform best when each has its own neural territory.

Prevalence of Patent Foramen Ovale in a Cohort of Children With Cryptogenic Ischemic Stroke.

BACKGROUND AND OBJECTIVES: To determine the significance of patent foramen ovale (PFO) in childhood stroke, we compared PFO prevalence, PFO features, and stroke recurrence risk in 25 children with cryptogenic arterial ischemic stroke (AIS), 54 children with AIS from a known etiology, and 209 healthy controls. METHODS: We performed a case-control analysis of a 14-year prospectively enrolled single-center cohort of children with AIS who underwent transthoracic echocardiogram (TTE) and compared them to TTEs of otherwise healthy children evaluated for benign cardiac concerns. Stroke patients 29 days to 18 years of age at stroke ictus with confirmed acute AIS on imaging, availability of complete diagnostic studies of stroke risk factors, including TTE images available for central review, and at least 1 follow-up evaluation after index stroke were included. Presence of PFO and high-risk PFO features were assessed by 2 independent, blinded reviewers and compared between groups with the Fisher exact test. Stroke/TIA recurrence risk was determined from Cox proportional hazards models. RESULTS: Of 154 children with first-ever AIS, 79 were eligible; 25 had cryptogenic AIS, and 54 had a known cause. PFO prevalence was higher in the cryptogenic group (7, 28%) compared to both the known stroke etiology group (3, 5.6%, p = 0.009) and controls without stroke (24, 11.5%, p = 0.03). There were no significant differences in presence of right-to-left shunt and atrial septal aneurysm. Median follow-up time for entire stroke cohort was 20.9 months. Stroke-free recurrence at 2-years did not differ between children with and without PFO (HR 2.0, 95% CI 0.4-9.3, p = 0.39). DISCUSSION: PFO prevalence was higher in children with cryptogenic stroke compared to patients with AIS with known etiology and healthy controls. PFO was not associated with increased recurrence risk. Optimal secondary preventive treatment in children with cryptogenic stroke and PFO remains uncertain and requires further study. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that children with cryptogenic ischemic stroke have an increased frequency of PFO compared to children with ischemic stroke of known etiology and healthy controls.

Endovascular and thrombolytic treatment eligibility in childhood arterial ischemic stroke.

AIM: To describe factors affecting eligibility for, and rates of utilization of, hyperacute therapy in children with acute ischemic stroke (AIS) following establishment of our institutional acute stroke treatment pathway in 2005. METHODS: A retrospective analysis of a prospectively enrolled, single-center cohort was performed including children age 2 - <18 years with acute AIS from 2005 through 2017. Descriptive statistics were used to summarize clinical characteristics, presentation data, and Pediatric NIH Stroke Scale (PedNIHSS) scores that were abstracted from medical records. Assessment for eligibility and administration of hyperacute therapy was determined at the time of presentation according to the institutional stroke pathway. RESULTS: Of 90 children (median age at presentation 11.3 years, 36% female) with acute AIS, 5 (6%) received hyperacute therapy: 3 received intravenous tissue plasminogen activator (IV-tPA) alone, 1 received endovascular therapy (EVT) alone, and 1 received IV-tPA and EVT. Of 54 children (60%) who presented within 4.5 h of time last seen well, 6 had PedNIHSS scores 6-24, no medical contraindication to IV-tPA, and a partial or complete vessel occlusion. Of 7 children >3 years old who presented after EVT became available at our hospital and within 6 h of time last seen well with a PedNIHSS score 6-24, 3 (43%) had a large vessel occlusion (LVO). Two patients underwent EVT and the other patient was not transferred until >6 h from time last seen well. CONCLUSIONS: Delay to presentation and diagnosis of childhood acute AIS, mild neurologic deficits at presentation, medical contraindications to IV-tPA, and lack of vessel occlusion on acute neuroimaging contribute to low rates of hyperacute treatment in children with acute AIS.

Association of Pediatric ASPECTS and NIH Stroke Scale, Hemorrhagic Transformation, and 12-Month Outcome in Children With Acute Ischemic Stroke.

OBJECTIVE: We aimed to determine whether a modified pediatric Alberta Stroke Program Early CT Score (modASPECTS) is associated with clinical stroke severity, hemorrhagic transformation, and 12-month functional outcomes in children with acute AIS. METHODS: Children (29 days to <18 years) with acute AIS enrolled in two institutional prospective stroke registries at Children's Hospital of Philadelphia and Royal Children's Hospital Melbourne, Australia were retrospectively analyzed to determine whether modASPECTS, in which higher scores are worse, correlated with acute Pediatric NIH Stroke Scale (PedNIHSS) scores (children ≥2 years of age), was associated with hemorrhagic transformation on acute MRI, and correlated with 12-month functional outcome on the Pediatric Stroke Outcome Measure (PSOM). RESULTS: 131 children were included; 91 were ≥2 years of age. Median days from stroke to MRI was 1 (interquartile range [IQR] 0-1). Median modASPECTS was 4 (IQR 3-7). ModASPECTS correlated with PedNIHSS (rho=0.40, P=0.0001). ModASPECTS was associated with hemorrhagic transformation (OR 1.13 95% CI 1.02-1.25, P=0.018). Among children with follow-up (N=128, median 12.2 months, IQR 9.5-15.4 months), worse outcomes were associated with higher modASPECTS (common OR 1.14, 95%CI 1.04-1.24, P=0.005). The association between modASPECTS and outcome persisted when we adjusted for age at stroke ictus and the presence of tumor or meningitis as stroke risk factors (common OR 1.14, 95%CI 1.03-1.25, P=0.008). CONCLUSIONS: ModASPECTS correlates with PedNIHSS scores, hemorrhagic transformation, and 12-month functional outcome in children with acute AIS. Future pediatric studies should evaluate its usefulness in predicting symptomatic intracranial hemorrhage and outcome after acute revascularization therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the modified pediatric ASPECTS on MRI is associated with stroke severity (as measured by the baseline pediatric NIH Stroke Scale), hemorrhagic transformation, and 12-month outcome in children with acute supratentorial ischemic stroke.

Outcome Trajectories after Primary Perinatal Hemorrhagic Stroke.

BACKGROUND: Perinatal hemorrhagic stroke in late preterm and term neonates is understudied. We describe two-month and two-year neurological outcomes in a prospective cohort. METHODS: Neonates ≥36 weeks' gestation with spontaneous hemorrhagic stroke (parenchymal and intraventricular) presenting at age ≤28 days were enrolled between March 2007 and May 2015 at three tertiary pediatric centers. Hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis was excluded. The Pediatric Stroke Outcome Measure (PSOM) assessed outcomes. Wilcoxon signed-rank tests evaluated change over time. RESULTS: Twenty-six neonates were included (median age: 1 day, interquartile range [IQR] 0 to 16; median gestational age: 38.3 weeks, IQR 37.0 to 39.0). Hemorrhage was isolated intraventricular in seven (27%), isolated intraparenchymal in six (23%), and a combination in 10 (39%). Three neonates (12%) died during hospitalization; one died later due to cardiac disease. Among 22 survivors, outcomes were assessed at a median of 2.1 months (IQR 1.7 to 3.3) in 96% and 1.9 years (IQR 1.3 to 2.0) in 73%. Median PSOM scores were 0.0 (IQR 0.0 to 1.0) and 0.25 (IQR 0.0 to 1.3), respectively. At two years, 45% of patients had no or nonimpairing deficits (PSOM <1.0), 30% had mild deficits (PSOM 1.0 to 2.0), and 5% had moderate deficits (PSOM 2.5 to 4.5). Over time, 31% worsened and 6% improved. Although total PSOM scores did not change significantly (P = 0.08), language subscores worsened (P = 0.009). No child developed epilepsy. CONCLUSIONS: Perinatal hemorrhagic stroke survivors had favorable outcomes in early childhood; at two years moderate to severe deficits occurred in 5%. Language deficits may emerge over time, warranting close follow-up.

Risk of Intracranial Hemorrhage Following Intravenous tPA (Tissue-Type Plasminogen Activator) for Acute Stroke Is Low in Children.

Background and Purpose- Data regarding the safety and efficacy of intravenous tPA (tissue-type plasminogen activator) in childhood acute arterial ischemic stroke are inadequate. The TIPS trial (Thrombolysis in Pediatric Stroke; National Institutes of Health grant R01NS065848)-a prospective safety and dose-finding trial of intravenous tPA in acute childhood stroke-was closed for lack of accrual. TIPS sites have subsequently treated children with acute stroke in accordance with established institutional protocols supporting data collection on outcomes. Methods- Data on children treated with intravenous tPA for neuroimaging-confirmed arterial ischemic stroke were collected retrospectively from 16 former TIPS sites to establish preliminary safety data. Participating sites were required to report all children who were treated with intravenous tPA to minimize reporting bias. Symptomatic intracranial hemorrhage (SICH) was defined as ECASS (European Cooperative Acute Stroke Study) II parenchymal hematoma type 2 or any intracranial hemorrhage associated with neurological deterioration within 36 following tPA administration. A Bayesian beta-binomial model for risk of SICH following intravenous tPA was fit using a prior distribution based on the risk level in young adults (1.7%); to test for robustness, the model was also fit with uninformative and conservative priors. Results- Twenty-six children (age range, 1.1-17 years; median, 14 years; 12 boys) with stroke and a median pediatric National Institutes of Health Stroke Scale score of 14 were treated with intravenous tPA within 2 to 4.5 hours (median, 3.0 hours) after stroke onset. No patient had SICH. Two children developed epistaxis. Conclusions- The estimated risk of SICH after tPA in children is 2.1% (95% highest posterior density interval, 0.0%-6.7%; mode, 0.9%). Regardless of prior assumption, there is at least a 98% chance that the risk is <15% and at least a 93% chance that the risk is <10%. These results suggest that the overall risk of SICH after intravenous tPA in children with acute arterial ischemic stroke, when given within 4.5 hours after symptom onset, is low.

Arteriopathy Influences Pediatric Ischemic Stroke Presentation, but Sickle Cell Disease Influences Stroke Management.

Background and Purpose- Sickle cell disease (SCD) and arteriopathy are pediatric stroke risk factors that are not mutually exclusive. The relative contributions of sickled red blood cells and arteriopathy to stroke risk are unknown, resulting in unclear guidelines for primary and secondary stroke prevention when both risk factors are present. We hypothesized that despite similarities in clinical presentation and radiographic appearance of arteriopathies, stroke evaluation and management differ in children with SCD compared with those without SCD. Methods- We compared presentation and management of children with and without SCD enrolled in the IPSS (International Pediatric Stroke Study) with acute arterial ischemic stroke, according to SCD and arteriopathy status. Regression modeling determined relative contribution of SCD and arteriopathy in variables with significant frequency differences. Results- Among 930 childhood arterial ischemic strokes, there were 98 children with SCD, 67 of whom had arteriopathy, and 466 without SCD, 392 of whom had arteriopathy. Arteriopathy, regardless of SCD status, increased likelihood of hemiparesis (odds ratio [OR], 1.94; 95% CI, 1.46-2.56) and speech abnormalities (OR, 1.67; 95% CI, 1.29-2.19). Arteriopathy also increased likelihood of headache but only among those without SCD (OR, 1.89; 95% CI, 1.40-2.55). Echocardiograms were less frequently obtained in children with SCD (OR, 0.58; 95% CI, 0.37-0.93), but the frequency of identified cardiac abnormalities was similar in both groups ( P=0.57). Children with SCD were less likely to receive antithrombotic therapy, even in the presence of arteriopathy (OR, 0.14; 95% CI, 0.08-0.22). Arteriopathy was associated with a significantly higher likelihood of antithrombotic therapy in children without SCD (OR, 5.36; 95% CI, 3.55-8.09). Conclusions- Arteriopathy, and not SCD status, was most influential of stroke presentation. However, SCD status influenced stroke management because children with SCD were less likely to have echocardiograms or receive antithrombotic therapy. Further work is needed to determine whether management differences are warranted.

Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association.

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.

Socioeconomic determinants of outcome after childhood arterial ischemic stroke.

OBJECTIVE: To 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). METHODS: From 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. RESULTS: At 12 ± 3 months after stroke, 320 children had documented outcome measurements, including 15 who had died. In univariate analysis, very low income (

Neurologic Outcome Predictors in Pediatric Intracerebral Hemorrhage: A Prospective Study.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage is a considerable source of morbidity and mortality. This 3-center study describes outcomes of pediatric intracerebral hemorrhage and identifies 2-year neurological outcome predictors. METHODS: Children 29 days to 18 years of age presenting with intracerebral hemorrhage from March 2007 to May 2015 were enrolled prospectively. Exclusion criteria included trauma; intracranial tumor; hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis; isolated subdural, epidural, or subarachnoid hemorrhage; and abnormal baseline neurological function. Intracerebral hemorrhage and total brain volumes were measured on neuroimaging. The Pediatric Stroke Outcome Measure assessed outcomes. RESULTS: Sixty-nine children were included (median age: 9.7 years; interquartile range: 2.2-14). Six children (9%) died during hospitalization. Outcomes in survivors were assessed at early follow-up in 98% (median 3.1 months; interquartile range: 3.1-3.8) and at later follow-up in 94% (median: 2.1 years; interquartile range: 1.3-2.8). Over a third had a significant disability at 2 years (Pediatric Stroke Outcome Measure >2). Total Pediatric Stroke Outcome Measure score improved over time (P=0.0003), paralleling improvements in the sensorimotor subscore (P=0.0004). Altered mental status (odds ratio, 13; 95% confidence interval, 3.9-46; P<0.001), hemorrhage volume ≥4% of total brain volume (odds ratio, 17; 95% confidence interval, 1.9-156; P=0.01), and intensive care unit length of stay (odds ratio, 1.1; 95% confidence interval, 1.0-1.2; P=0.002) were significantly associated with poor 2-year outcome. CONCLUSIONS: Over one third of children experienced significant disability at 2 years. Improvements in outcomes were driven by recovery of sensorimotor function. Altered mental status, hemorrhage volume ≥4% of total brain volume, and intensive care unit length of stay were independent predictors of significant disability at 2 years.

Incidence and predictors of epilepsy after pediatric arterial ischemic stroke.

OBJECTIVE: To determine the cumulative incidence and clinical predictors of remote symptomatic seizures and epilepsy after pediatric arterial ischemic stroke (AIS). METHODS: We performed a retrospective analysis of 218 participants with neonatal AIS (NAIS), presumed perinatal AIS (PPAIS), and childhood AIS (CAIS) from a single-center prospective consecutive cohort enrolled from 2006 to 2014. Medical records were reviewed for timing, semiology, and treatment of acute symptomatic seizures, remote symptomatic seizures (RSS), and epilepsy. Cumulative incidence of RSS and epilepsy were assessed using survival analysis. RESULTS: Acute symptomatic seizures occurred in 94% of NAIS (n = 70/74) and 17% of CAIS (n = 18/105). Younger children were more likely to present with seizures at stroke ictus, and acute symptomatic seizures were predictive of later RSS and epilepsy in CAIS. Median follow-up for the entire cohort was 34 months, interquartile range 44.9 months (16.3-61.2). Estimated cumulative incidence of RSS at 2 years was 19% in NAIS, 24% in PPAIS, and 7% in CAIS. Estimated cumulative incidence of epilepsy at 2 years was 11% in NAIS, 19% in PPAIS, and 7% in CAIS. The median time to these outcomes was <2 years in all stroke subtypes. Among participants developing epilepsy (n = 34), seizures were often well-controlled at last follow-up with median Engel class of ≤2 (<1 seizure/month). CONCLUSIONS: RSS and epilepsy are important neurologic sequelae of pediatric AIS. Children with perinatal stroke and CAIS with acute symptomatic seizures are at increased risk of these outcomes. These cohorts need further study to identify biomarkers and potential therapeutic targets for epileptogenesis.

Incidence of Recurrence in Posterior Circulation Childhood Arterial Ischemic Stroke.

Importance: Childhood arterial ischemic stroke (CAIS) affects approximately 1.6 per 100 000 children per year, while stroke recurs in up to 20% of patients at 5 years. Factors determining the risk of recurrence are incompletely understood. Objective: To investigate the incidence of the recurrence of CAIS in the posterior and anterior circulations to determine if the risk differs between the 2 locations. Design, Setting, and Participants: A retrospective analysis of CAIS was conducted among children enrolled in a single-center prospective consecutive cohort at The Children's Hospital of Philadelphia between January 1, 2006, and January 1, 2015. Children with confirmed CAIS occurring between 29 days and 17.99 years were evaluated for inclusion. Patients were excluded if infarcts were located in both the anterior and posterior distributions or if CAIS occurred as a complication of intracranial surgery or brain tumor. Main Outcomes and Measures: Stroke recurrence. Results: The study population included 107 patients (75 boys [70.1%] and 32 girls [29.9%]; median age at AIS, 7.7 years [interquartile range, 3.1-13.6 years]). Sixty-one children had anterior circulation CAIS (ACAIS) and 46 had posterior circulation CAIS (PCAIS). Median follow-up was 20.9 months (interquartile range, 8.7-40.4 months). For ACAIS, recurrence-free survival was 100% at 1 month and 96% (95% CI, 85%-99%) at 1 and 3 years. For PCAIS, recurrence-free survival was 88% (95% CI, 75%-95%) at 1 month and 81% (95% CI, 66%-90%) at 1 and 3 years. The hazard ratio for recurrence after PCAIS compared with ACAIS was 6.4 (95% CI, 1.4-29.8; P = .02) in univariable analysis and 5.3 (95% CI, 1.1-26.4; P = .04) after adjusting for sex and cervical dissection. Conclusions and Relevance: We identified a subgroup of patients that comprise more than 80% of recurrences of CAIS. Three years after incident stroke, 19% of children with PCAIS had a recurrence compared with 4% of patients with ACAIS. Different mechanisms of stroke may account for this difference. Children with PCAIS may warrant increased monitoring. This study highlights the necessity for further research focused on recurrence prevention.

Electrographic Seizures in Children and Neonates Undergoing Extracorporeal Membrane Oxygenation.

OBJECTIVE: We aimed to determine the prevalence and risk factors for electrographic seizures in neonates and children requiring extracorporeal membrane oxygenation support. DESIGN: Prospective quality improvement project. SETTING: Quaternary care pediatric institution. PATIENTS: Consistent with American Clinical Neurophysiology Society electroencephalographic monitoring recommendations, neonates and children requiring extracorporeal membrane oxygenation support underwent clinically indicated electroencephalographic monitoring. INTERVENTIONS: We performed a 2-year quality improvement study from July 2013 to June 2015 evaluating electrographic seizure prevalence and risk factors. MAIN RESULTS: Ninety-nine of 112 patients (88%) requiring extracorporeal membrane oxygenation support underwent electroencephalographic monitoring. Electrographic seizures occurred in 18 patients (18%), of whom 11 patients (61%) had electrographic status epilepticus and 15 patients (83%) had exclusively electrographic-only seizures. Electrographic seizures were more common in patients with low cardiac output syndrome (p = 0.03). Patients with electrographic seizures were more likely to die prior to discharge (72% vs 30%; p = 0.01) and have unfavorable outcomes (54% vs 17%; p = 0.004) than those without electrographic seizures. CONCLUSIONS: Electrographic seizures occurred in 18% of neonates and children requiring extracorporeal membrane oxygenation support, often constituted electrographic status epilepticus, and were often electrographic-only thereby requiring electroencephalographic monitoring for identification. Low cardiac output syndrome was associated with an increased risk for electrographic seizures. Electrographic seizures were associated with higher mortality and unfavorable outcomes. Further investigation is needed to determine whether electrographic seizures identification and management improves outcomes.

Inter-Rater Reliability of the CASCADE Criteria: Challenges in Classifying Arteriopathies.

BACKGROUND AND PURPOSE: There 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. METHODS: Eight 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. RESULTS: The 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). CONCLUSIONS: The 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.

Educational Placement After Pediatric Intracerebral Hemorrhage.

BACKGROUND: This study describes educational placement of school-aged children after spontaneous intracerebral hemorrhage and examines whether educational placement is associated with severity of neurological deficits. METHODS: Children with spontaneous intracerebral hemorrhage presenting from 2007 to 2013 were prospectively enrolled at three tertiary children's hospitals. The Pediatric Stroke Outcome Measure and parental interview gathered information about neurological outcome, school attendance, and educational placement. RESULTS: The cohort of 92 enrolled children included 42 school-aged children (6 to 17 years) with intracerebral hemorrhage. Four children died; one was excluded because of preexisting cognitive deficits. Thirty-seven children completed three-month follow-up, and 30 completed 12-month follow-up. At 12 months, 14 children (46.7%) received regular age-appropriate programming, 12 (40%) attended school with in-class services, three (10%) were in special education programs, and one child (3.3%) received home-based services because of intracerebral hemorrhage-related deficits. Of 30 children with three- and 12-month follow-up, 14 (46.7%) improved their education status, 13 (43.3%) remained at the same education level, and three (10%) began to receive in-class services. An increasing Pediatric Stroke Outcome Measure score predicted the need for educational modifications at three months (odds ratio, 3.3; 95% confidence interval, 1.4 to 7.9; P = 0.007) and at 12 months (odds ratio, 2.1; 95% confidence interval, 1.1 to 3.9; P = 0.025). CONCLUSIONS: Most children returned to school within a year after intracerebral hemorrhage, and many had a reduction in the intensity of educational support. However, a great need for educational services persisted at 12 months after intracerebral hemorrhage with fewer than half enrolled in regular age-appropriate classes. Worse deficits on the Pediatric Stroke Outcome Measure were associated with remedial educational placement.