ObjectiveTo evaluate if short‐term treatment with everolimus was safe and could improve neurocognition and behavior in children with TSC.MethodsThis was a prospective, double‐blind randomized, placebo‐controlled two‐center phase II study. Participants diagnosed with TSC and age 6–21 years were treated with 4.5 mg/m2 per day of oral everolimus (n = 32) or matching placebo (n = 15) taken once daily for 6 months. For efficacy, a comprehensive neurocognitive and behavioral evaluation battery was performed at baseline, 3 months, and 6 months. For safety, adverse events recorded continuously via patient diary were categorized and graded per NCI Common Toxicity Criteria for Adverse Events, version 3.0 (CTCAE 3.0). Analyses were performed on the intention‐to‐treat population (n = 47).ResultsNearly all assessment measures failed to demonstrate significant differences between the two groups at the end of 6 months. Only one measure each of executive function (Cambridge Neuropsychological Test Automated Battery Stockings of Cambridge) favoring placebo (P = 0.025) and social cognition (Social Responsiveness Scale Social Cognition Subscale) favoring everolimus (P = 0.011) was observed. A total of 473 adverse events (AE) were reported. The average number of total AE per subject was similar for both placebo and everolimus. Most were mild or moderate in severity and serious AE were rare.InterpretationWhile safe, oral everolimus administered once daily for 6 months did not significantly improve neurocognitive functioning or behavior in children with TSC.

This paper provides specific guidelines for the neurodevelopmental evaluation of children aged birth through 5 years with complex congenital heart disease. There is wide recognition that children with congenital heart disease are at high risk for neurodevelopmental impairments that are first apparent in infancy and often persist as children mature. Impairments among children with complex congenital heart disease cross developmental domains and affect multiple functional abilities. The guidelines provided are derived from the substantial body of research generated over the past 30 years describing the characteristic developmental profiles and the long-term trajectories of children surviving with complex congenital heart conditions. The content and the timing of the guidelines are consistent with the 2012 American Heart Association and the American Academy of Pediatrics scientific statement documenting the need for ongoing developmental monitoring and assessment from infancy through adolescence. The specific guidelines offered in this article were developed by a multidisciplinary clinical research team affiliated with the Cardiac Neurodevelopmental Outcome Collaborative, a not-for-profit organisation established to determine and implement best neurodevelopmental practices for children with congenital heart disease. The guidelines are designed for use in clinical and research applications and offer an abbreviated core protocol and an extended version that expands the scope of the evaluation. The guidelines emphasise the value of early risk identification, use of evidence-based assessment instruments, consideration of family and cultural preferences, and the importance of providing multidimensional community-based services to remediate risk.

OBJECTIVE: Research reveals mixed evidence for the effects of adenotonsillectomy (AT) on cognitive tests in children with obstructive sleep apnea syndrome (OSAS). The primary aim of the study was to investigate effects of AT on cognitive test scores in the randomized Childhood Adenotonsillectomy Trial. METHODS:Children ages 5 to 9 years with OSAS without prolonged oxyhemoglobin desaturation were randomly assigned to watchful waiting with supportive care (n = 227) or early AT (eAT, n = 226). Neuropsychological tests were administered before the intervention and 7 months after the intervention. Mixed model analysis compared the groups on changes in test scores across follow-up, and regression analysis examined associations of these changes in the eAT group with changes in sleep measures. RESULTS:Mean test scores were within the average range for both groups. Scores improved significantly (P < .05) more across follow-up for the eAT group than for the watchful waiting group. These differences were found only on measures of nonverbal reasoning, fine motor skills, and selective attention and had small effects sizes (Cohen's d,. As additional evidence for AT-related effects on scores, gains in test scores for the eAT group were associated with improvements in sleep measures. CONCLUSIONS:Small and selective effects of AT were observed on cognitive tests in children with OSAS without prolonged desaturation. Relative to evidence from Childhood Adenotonsillectomy Trial for larger effects of surgery on sleep, behavior, and quality of life, AT may have limited benefits in reversing any cognitive effects of OSAS, or these benefits may require more extended follow-up to become manifest. 1 The prevalence of OSAS is ~1% to 6%, with higher rates in African Americans and children from families of lower socioeconomic status. 2 -4 Children with untreated OSAS are at risk for adverse outcomes ranging from daytime sleepiness and compromised cardiovascular health to behavior problems and impairments in cognition and academic performance. 5 -11 Problems in behavior and emotional regulation are common in children with OSAS compared with healthy controls, but evidence for adverse effects of OSAS on children's cognitive abilities is more mixed. 6 Some studies fail to find differences between children with OSAS and healthy controls, 12,13 and those that do report variable associations of measures of sleep disturbance with cognitive test scores. 7, 14 -18 Similarly, studies of outcomes of adenotonsillectomy (AT) in children with OSAS indicate variable benefits on such tests, with little evidence for associations of these effects with the severity of OSAS and sleep disruption. 8, 13, 14, 16, 19 -26 In the recently completed multicenter Childhood Adenotonsillectomy Trial (CHAT), children with OSAS without prolonged oxyhemoglobin desaturation assigned to early AT (eAT) improved more than those assigned to watchful waiting with supportive care (WWSC) on key secondary outcomes. 27 -29 Specifically, the eAT group improved more tha...

Background: Neurodevelopmental impairment is common in children with congenital heart disease (CHD), yet postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedents for neurodevelopmental disabilities might begin in utero , we analyzed whether fetal brain volume predicted subsequent neurodevelopmental outcome in children with CHD. Methods: Fetuses with isolated CHD and sociodemographically comparable healthy control fetuses underwent fetal brain MRI and 2-year neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development (Bayley-III) and the Adaptive Behavior Assessment System (ABAS-3). Hierarchical regression evaluated potential predictors of Bayley-III and ABAS-3 outcomes in the CHD group, including fetal total brain volume adjusted for gestational age and sex, sociodemographic characteristics, birth parameters, and medical history. Results: The CHD group (n=52) had lower Bayley-III cognitive, language, and motor scores than the control group (n=26), but fetal brain volumes were similar. Within the CHD group, larger fetal total brain volume correlated with higher Bayley-III cognitive, language, and motor scores, and ABAS-3 adaptive functioning scores (r=0.32-0.47; all P<0.05), but not in the control group. Fetal brain volume predicted 10 21% of the variance in neurodevelopmental outcome measures in univariate analyses. Multivariable models that also included social class and postnatal factors explained 18-45% of the variance in outcome, depending on developmental domain. Moreover, in final multivariable models, fetal brain volume was the most consistent predictor of neurodevelopmental outcome across domains. Conclusions: Small fetal brain volume is a strong independent predictor of 2-year neurodevelopmental outcomes and may be an important imaging biomarker of future neurodevelopmental risk in CHD. Future studies are needed to support this hypothesis. Our findings support inclusion of fetal brain volume in risk stratification models and as a possible outcome in fetal neuroprotective intervention studies.

BACKGROUND No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder (ASD), separately among those with and without cognitive impairment. OBJECTIVE To identify perinatal factors associated with increased risk for ASD with and without intellectual disability (ID: IQ < 70) in children born extremely preterm. STUDY DESIGN This prospective multi-center (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks gestation in 2002-2004 who were evaluated for ASD and ID at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal ‘infection’ refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4) or other/unspecified infection (n=43; e.g., chlamydia, trichomonas or herpes, etc.). We do not know the extent to which ‘infection’ per se was confirmed by microbial colonization. We use the terms ‘fetal growth restriction’ and ‘small for gestational age’ interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth-restriction was defined as a birth weight Z-score for gestational age at delivery < - 2 (i.e., 2 standard deviations or more below the median birth weight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into four groups based on whether or not they met rigorous diagnostic criteria for ASD and ID (ASD+/ID−, ASD+/ID+, ASD−/ID+ and ASD−/ID−). Temporally-ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for ASD and/or ID (ASD+/ID−, ASD+/ID+ and ASD−/ID+). RESULTS 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for ASD; of these, 840 (98%) children were assessed for ID. ASD+/ID− was diagnosed in 3.2% (27/840), ASD+/ID+ in 3.8% (32/840), and ASD−/ID+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal ‘infection’ during pregnancy was associated with increased risk of ASD+/ID+ (odd ratio [OR], 2.7; 95% CI, 1.2-6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of ASD+/ID+ (OR, 2.9; 95% CI, 1.3-6.6) and ASD+/ID− (OR, 4.4; 95% CI, 1.7-11). Severe fetal growth restriction was strongly associated with increased risk for ASD+/ID− (OR, 9.9; 95% CI, 3.3-30), whereas peripartum maternal fever was uniquely associated with increased risk of ASD−/ID+ (OR, 2.9; 95% CI, 1.2-6.7). CONCLUSION Our study confirms that low gestational age is associated with increased risk for ASD irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with ASD without ID. Maternal report of cervical-vaginal infection is associated with increased risk of ASD with ID, and per...

Objective To evaluate the difference in 10-year neurocognitive outcomes among extremely low gestational age newborns without bacteremia or with suspected or confirmed late-onset bacteremia. Study design Neurocognitive function was evaluated at 10 years of age in 889 children born at <28 weeks of gestation and followed from birth. Definite (culture positive) late-onset bacteremia during postnatal weeks 2–4 was identified in 223 children and 129 had suspected bacteremia. Results Infants with the lowest gestational age and birth weight Z-score had the highest prevalence of definite and suspected late-onset bacteremia. When compared with peers with no or suspected bacteremia, infants with definite bacteremia performed worse on tests of general cognitive ability, language, academic achievement, and executive function, even when adjusting for potential confounders. Adjustment for low IQ attenuated associations between bacteremia and all dysfunctions at 10 years. Children who had suspected bacteremia did not differ appreciably from children who did not have any evidence of bacteremia. The motor domain was unaffected. Conclusions Extremely low gestational age newborns who had definite late bacteremia during postnatal weeks 2–4 are at heightened risk of neurocognitive limitations at 10 years of age.

Objective: Mortality rates for children with congenital heart disease (CHD) have significantly declined, resulting in a growing population with associated neurodevelopmental disabilities.American Heart Association guidelines recommend systematic developmental screening for children with CHD. The present study describes results of inpatient newborn neurodevelopmental assessment of infants after open heart surgery. Outcome measures:We evaluated the neurodevelopment of a convenience sample of high-risk infants following cardiac surgery but before hospital discharge using an adaptation of the Newborn Behavioral Observation. Factor analysis examined relationships among assessment items and consolidated them into domains of development. Results:We assessed 237 infants at a median of 11 days (interquartile range [IQR]: 7-19 days) after cardiac surgery and median corrected age of 21 days (IQR: 13-33 days). Autonomic regulation was minimally stressed or well organized in 14% of infants. Upper and lower muscle tone was appropriate in 33% and 35%, respectively. Appropriate response to social stimulation ranged between 7% and 12% depending on task, and state regulation was well organized in 14%. The vast majority (87%) required enhanced examiner facilitation for participation. Factor analyses of assessment items aligned into four domains of development (autonomic, motor, oral motor, and attention organization).Conclusion: At discharge, postoperative infants with CHD had impairments in autonomic, motor, attention, and state regulation following cardiac surgery. Findings highlight the challenges faced by children with CHD relative to healthy peers, suggesting that neurodevelopmental follow-up and intervention should begin early in infancy. K E Y W O R D Sassessment, cardiac, developmental impairments, infancy, neurodevelopment

Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11-q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.