Leveraging expertise and optimizing clinical research: Initial success of a pediatric epilepsy surgery collaborative.

OBJECTIVE: Improve data-driven research to inform clinical decision-making with pediatric epilepsy surgery patients by expanding the Pediatric Epilepsy Research Consortium Epilepsy Surgery (PERC-Surgery) Workgroup to include neuropsychological data. This article reports on the process and initial success of this effort and characterizes the cognitive functioning of the largest multi-site pediatric epilepsy surgery cohort in the United States. METHODS: Pediatric neuropsychologists from 18 institutions completed surveys regarding neuropsychological practice and the impact of involvement in the collaborative. Neuropsychological data were entered through an online database. Descriptive analyses examined the survey responses and cognitive functioning of the cohort. Statistical analyses examined which patients were evaluated and if composite scores differed by domain, demographics, measures used, or epilepsy characteristics. RESULTS: Positive impact of participation was evident by attendance, survey responses, and the neuropsychological data entry of 534 presurgical epilepsy patients. This cohort, ages 6 months to 21 years, were majority White and non-Hispanic, and more likely to have private insurance. Mean intelligence quotient (IQ) scores were below to low average, with weaknesses in working memory and processing speed. Full-scale IQ (FSIQ) was lowest for patients with younger age at seizure onset, daily seizures, and magnetic resonance imaging (MRI) abnormalities. SIGNIFICANCE: We established a collaborative network and fundamental infrastructure to address questions outlined by the Epilepsy Research Benchmarks. There is a wide range in the age and IQ of patients considered for pediatric epilepsy surgery, yet it appears that social determinants of health impact access to care. Consistent with other national cohorts, this US cohort has a downward shift in IQ associated with seizure severity.

Neurocognition as a biomarker in the rare autonomic disorders of CCHS and ROHHAD.

PURPOSE: Congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) are rare disorders of autonomic regulation with risk for disrupted neurocognitive development. Our aim is to summarize research on neurocognitive outcomes in these conditions, advance understanding of how to best support these individuals throughout development, and facilitate future research. METHODS: We conducted a narrative review of literature on neurocognitive outcomes in CCHS and ROHHAD, supplemented with previously unpublished data from patients with CCHS and ROHHAD at our Center for Autonomic Medicine in Pediatrics (CAMP). RESULTS: Individuals with CCHS and ROHHAD experience a wide range of neurocognitive functioning ranging from above average to below average, but are at particular risk for difficulties with working memory, processing speed, perceptual reasoning, and visuographic skills. An assessment framework emphasizing fluid cognition seems especially appropriate for these conditions. Owing to small cohorts and varied methods of data collection, it has been difficult to identify associations between disease factors (including CCHS PHOX2B genotypes) and cognitive outcomes. However, results suggest that early childhood is a period of particular vulnerability, perhaps due to the disruptive impact of recurrent intermittent hypoxic episodes on brain and cognitive development. CONCLUSION: Neurocognitive monitoring is recommended as a component of routine clinical care in CCHS and ROHHAD as a marker of disease status and to ensure that educational support and disability accommodations are provided as early as possible. Collaborative efforts will be essential to obtain samples needed to enhance our understanding of neurocognitive outcomes in CCHS and ROHHAD.

Rare diseases - rare outcomes: Assessing communication abilities for the developmental and epileptic encephalopathies.

OBJECTIVE: Developmental and epileptic encephalopathies (DEE) entail moderate to profound communication and other impairments that are poorly measured by typical clinical outcomes assessments (COA). We examined the potential of alternative approaches, specifically, the use of raw scores and COAs outside of their intended age ranges. METHODS: In a cross-sectional survey, 120 parents of children with Dravet Syndrome, Lennox-Gastaut syndrome, KCNQ2-DEE, KCNB1-DEE, and SCN2A-DEE (ages 1-35 years) completed the Adaptive Behavior Assessment System-3 for ages 0-5 years, modified checklist for autism (mCHAT), communication and social behavior scales (CSBS), communication matrix (CM), and several parent-reported classifiers of communication. Adaptive Behavior Assessment System communication and social raw scores were the primary and adjunctive outcomes. Floor and ceiling effects, dispersion and convergence with related measures were assessed with appropriate parametric and nonparametric statistical techniques. RESULTS: Median chronological age (CA) was 8.7 years (Interquartile range (IQR): 5.3-13.5). Adaptive Behavior Assessment Systemcommunication and social age equivalents were 12.5 months (IQR 7.5-28) and 16.5 months (IQR 9-31). Most raw scores corresponded to standardized scores indicating performance <3 standard deviations below the general population mean. Adaptive Behavior Assessment System raw scores demonstrated minimal floor and ceiling effects (<1-2.5%). In linear regression models, scores correlated with age under 6 years (communication, p = 0.001; social, p = 0.003) but significantly flattened out thereafter. Scores varied substantially by DEE group (both p < 0.001) and decreased with higher convulsive seizure frequency (communication, p = 0.01, social, p = 0.02). There was good convergence with mCHAT, CSBS, and CM scores (all r > 0.8). SIGNIFICANCE: Raw scores and out-of-range COAs may provide measures that are sensitive at the very limited levels of functioning typical of profoundly impaired, older patients with DEEs. To ensure that targeted trial outcomes are responsive to meaningful change, development of these approaches will be essential to clinical trial readiness for novel therapies for rare DEEs.

SCN2A-Developmental and Epileptic Encephalopathies: Challenges to trial-readiness for non-seizure outcomes.

OBJECTIVE: SCN2A-associated developmental and epileptic encephalopathies (DEEs) present with seizures, developmental impairments, and often both. We sought to characterize the level and pattern of development in children with SCN2A variants, and to address the sensitivity of the Vineland Adaptive Behavior Scales (VABS) in measuring changes over time in children with SCN2A-DEEs. METHODS: Clinical histories for participants with pathogenic SCN2A variants in the Simons SearchLight project were analyzed for descriptive purposes. VABS scores obtained at study entry and yearly thereafter were analyzed for floor and ceiling effects, change with age, and association with epilepsy through use of regression and longitudinal regression methods. RESULTS: Sixty-four participants (50 with epilepsy, 30 [47%] female, median age 49 months, interquartile range [IQR] 28 to 101) were included. Histories of birth complications (N = 34, 54%), neonatal neurological signs (N = 45, 74%), and other neurological symptoms (N = 31, 48%) were common and similar in epilepsy and nonepilepsy subgroups. Mean standardized VABS scores (Composite 53.5; Motor, 55.8, Communication, 54.1, Socialization, 59.4, and Daily living skills, 55.1) reflected performance ~3 standard deviations below the normative test average. In longitudinal regression analyses, standardized scores decreased between 1.3 and 2.8 points per year, suggesting regression of abilities. Raw score analyses, however, revealed several subdomains with substantial floor effects (eg, community use); other raw scores increased with increasing age. Participants with epilepsy scored 0.6 to 1 SD lower than those without epilepsy (all P's < .05). SIGNIFICANCE: The VABS, as standardly administered, has shortcomings for addressing growth or regression in individuals with SCN2A-DEEs. Some subdomain raw scores reflected substantial floor effects. Raw scores increased so slowly over time that standardized scores declined. Alternative measures sensitive to incremental meaningful change are required if outcomes such as adaptive behavior are to be primary outcomes in short-term clinical trials.

Evaluation of the Aberrant Behavior Checklist for Developmental and Epileptic Encephalopathies.

OBJECTIVES: To determine the suitability of the Aberrant Behavior Checklist (ABC)-a common measure used in clinical trials for treatment of challenging behaviors of autism-as an outcome measure for pharmacological and behavioral interventions for young people with Developmental and Epileptic Encephalopathies (DEEs). METHODS: We assessed score profiles on the ABC in a sample of 122 young people with DEEs, including Dravet and Lennox-Gastaut syndromes, and KCNQ2- SCN2A-, and KCNB1-associated disorders. Then we examined its internal structure using item cluster analysis. We used both unrestricted item cluster analysis to determine the number of item clusters that maximize reliability and restricted analyses in which we pre-specified models with 5-, 6-, and 7-clusters, to examine consistency with previous factor analytic studies. We also conducted validity analysis on the various scoring methods with age, sex, and autism spectrum screening measure scores. RESULTS: Unrestricted item cluster analysis suggested that three clusters maximized reliability of ABC scores. These broadly represented other-directed behaviors (i.e., "externalizing"), self-directed behaviors (i.e., "internalizing"), and inappropriate speech. Restricted models separated item clusters for stereotypy from other self-directed problem behaviors, and self-injurious behaviors from the other externalizing behaviors. Validity analysis also supported these structures. Overall, all scores were low, and less than 20% of DEE participants had symptoms severe enough to qualify for most randomized trials of behavioral therapies. SIGNIFICANCE: These results are broadly consistent with the extant ABC scoring algorithms. They suggest a high internal consistency reliability, which may support the use of the ABC in future clinical trials in patients with DEEs who exhibit the behaviors assessed by the ABC. Alternatively, concerns about overall low scores raise cautions about using the ABC as a measure of behavior in unselected populations with DEE.

Nonseizure consequences of Dravet syndrome, KCNQ2-DEE, KCNB1-DEE, Lennox-Gastaut syndrome, ESES: A functional framework.

RATIONALE: Developmental epilepsies and encephalopathies (DEEs) are characterized by many severe developmental impairments, which are not well-described. A functional framework could facilitate understanding of their nature and severity and guide the selection instruments to measure improvements in therapeutic trials. METHODS: An online survey administered through several parent-organized foundations utilized accepted functional classifications and questionnaires derived from common instruments to determine levels of mobility, fine motor, communication, and feeding functions. Statistical analyses focused on overall levels of function and across-group comparisons adjusted for age. RESULTS: From 6/2018 to 2/2020, 252 parents provided information for one or more functional domains. Median age was 7.2 years (interquartile range (IQR): 3.9 to 11.8), and 128 (51%) were females. DEE groups were Dravet syndrome (N = 72), KCNQ2-DEE (N = 80), KCNB1-DEE, (N = 33), Lennox-Gastaut syndrome (LGS; N = 26), electrographic status epilepticus in sleep (ESES; N = 15), and others (N = 26). Overall, functional hand grasp was absent in 48 (20%). Of children ≥2 years old, 60/214 (28%) could not walk independently, 85 (40%) were dependent on someone else for feeding, and 153 (73%) did not effectively communicate with unfamiliar people. Impairments entailing absence or near absence of independent function (profound impairment) were observed in 0, 1, 2, 3, and 4 domains for 58 (25%), 78 (34%), 40 (17%), 33 (14%), and 22 (10%) children, respectively. After adjustment for age, impairment levels varied substantially across DEE group for mobility (p < 0.0001), feeding (p < 0.0001), communication (p < 0.0001), hand grasp (p < 0.0001), and number of profoundly impaired domains (p < 0.0001). Three or four profoundly affected domains were reported in 44% of KCNQ2-DEE participants, followed by LGS (29%), KCNB1-DEE (27%), ESES (7%), and Dravet syndrome (6%). CONCLUSIONS: Many children with DEEs experience severe functional impairments, and few children have typical function. As precision therapies will emphasize nonseizures consequences of DEEs, understanding the nature of abilities and impairments will be critical to selecting appropriate outcome measures in therapeutic trials.

Parent-reported cognitive function is associated with leukoencephalopathy in children with brain tumors.

PURPOSE: Cognitive dysfunction is a major concern for children with brain tumors. A valid, user-friendly screening tool could facilitate prompt referral for comprehensive neuropsychological assessments and therefore early intervention. Applications of the pediatric perceived cognitive function item bank (pedsPCF) such as computerized adaptive testing can potentially serve as such a tool given its brevity and user-friendly nature. This study aimed to evaluate whether pedsPCF was a valid indicator of cerebral compromise using the criterion of structural brain changes indicated by leukoencephalopathy grades. METHODS: Data from 99 children (mean age = 12.6 years) with brain tumors and their parents were analyzed. Average time since diagnosis was 5.8 years; time since last treatment was 4.3 years. Leukoencephalopathy grade (range 0-4) was based on white matter damage and degree of deep white matter volume loss shown on MRI. Parents of patients completed the pedsPCF. Scores were based on the US general population-based T-score metric (mean = 50; SD = 10). Higher scores reflect better function. RESULTS: Leukoencephalopathy grade distributions were as follows: 36 grade 0, 27 grade 1, 22 grade 2, 13 grade 3, and 1 grade 4. The mean pedsPCF T-score was 48.3 (SD = 8.3; range 30.5-63.7). The pedsPCF scores significantly discriminated patients with different leukoencephalopathy grades, F = 4.14, p = 0.0084. Effect sizes ranged from 0.09 (grade 0 vs. 1) to 1.22 (grade 0 vs. 3/4). CONCLUSION: This study demonstrates that the pedsPCF is a valid indicator of leukoencephalopathy and provides support for its use as a screening tool for more comprehensive neurocognitive testing.

A simple behavioral-developmental checklist versus formal screening for children in an epilepsy center.

We compare a 7-item checklist for developmental and behavioral concerns to formal screening with the Ages & Stages Questionnaires, Third Edition (ASQ-3) in children aged 1-5.5years old seen in a tertiary epilepsy care setting. The checklist was derived from a 35-item parent questionnaire used as a routine component of pediatric neuropsychology evaluations at our center. In our sample of 104 children, having even one checklist item endorsed was associated with a 97% (66/68) positive predictive value for screening positive on the ASQ-3. Fifty percent of children for whom no items were endorsed on the checklist scored negative for developmental concerns on the ASQ-3. The overall sensitivity of the checklist to a positive ASQ-3 screen was 83%, and the specificity was 88%. Use of this simple checklist may facilitate screening in the outpatient epilepsy care setting where time and resources are often limited.

Validation of the Neuro-QoL measurement system in children with epilepsy.

OBJECTIVE: Children with epilepsy often face complex psychosocial consequences that are not fully captured by existing patient-reported outcome (PRO) measures. The Neurology Quality of Life Measurement System "Neuro-QoL" was developed to provide a set of common PRO measures that address issues important to people with neurologic disorders. This paper reports Neuro-QoL (anxiety, depression, interaction with peers, fatigue, pain, cognitive function, stigma, and upper and lower extremity functions) validation in children with epilepsy. METHOD: Patients (aged 10-18years) diagnosed with epilepsy completed Neuro-QoL and legacy measures at time 1 (initial study visit) and 6-month follow-up. Internal consistency reliability was also evaluated. Concurrent validity was assessed by comparing Neuro-QoL measures with more established "legacy" measures of the same concepts. Clinical validity was evaluated by comparing mean Neuro-QoL scores of patients grouped by clinical anchors such as disease severity. Responsiveness of the Neuro-QoL from time 1 (initial study visit) to 6months was evaluated using self-reported change as the primary anchor. RESULTS: Sixty-one patients (mean age=13.4years; 62.3% male, 75.9% white) participated. Most patients (64.2%) had been seizure-free in the 3months prior to participation, and seizure frequency was otherwise described as follows: 17.8% daily, 13.3% weekly, 35.6% monthly, and 33.3% yearly. All patients were taking antiepileptic drugs. Patients reported better function/less symptoms compared to the reference groups. Internal consistency (alpha) coefficients ranged from 0.76 to 0.87. Patients with different seizure frequencies differed on anxiety (p<.01) and cognitive function (p<.05). Compared to patients on polytherapy, those on monotherapy had better upper extremity scores (p<.05). Compared to those with localized seizures, those experiencing generalized seizures reported worse stigma (p<.05). Depression, anxiety, lower extremity, fatigue, pain, interaction with peers, and stigma also significantly discriminated patients with different levels of quality of life (p≤.05). All Neuro-QoL measures were significantly correlated with other measures assessing similar domains. Stigma was related to self-reported change in several areas of functioning but in sometimes unexpected directions. SIGNIFICANCE: The Neurology Quality of Life Measurement System is a valid and reliable assessment tool for children with epilepsy and can be used in research and clinical settings.

Longitudinal study of cognitive and academic outcomes after pediatric liver transplantation.

OBJECTIVE: To determine the evolution of cognitive and academic deficits and risk factors in children after liver transplantation. STUDY DESIGN: Patients ≥2 years after liver transplantation were recruited through Studies of Pediatric Liver Transplantation. Participants age 5-6 years at Time 1 completed the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, Wide Range Achievement Test, 4th edition, and Behavior Rating Inventory of Executive Function (BRIEF). Participants were retested at age 7-9 years, Time 2 (T2), by use of the Wechsler Intelligence Scales for Children, 4th edition, Wide Range Achievement Test, 4th edition, and BRIEF. Medical and demographic variables significant at P ≤ .10 in univariate analysis were fitted to repeated measures modeling predicting Full Scale IQ (FSIQ). RESULTS: Of 144 patients tested at time 1, 93 (65%) completed T2; returning patients did not differ on medical or demographic variables. At T2, more participants than expected had below-average FSIQ, Verbal Comprehension, Working Memory, and Math Computation, as well as increased executive deficits on teacher BRIEF. Processing Speed approached significance. At T2, 29% (14% expected) had FSIQ = 71-85, and 7% (2% expected) had FSIQ ≤70 (P = .0001). A total of 42% received special education. Paired comparisons revealed that, over time, cognitive and math deficits persisted; only reading improved. Modeling identified household status (P < .002), parent education (P < .01), weight z-score at liver transplantation (P < .03), and transfusion volume during liver transplantation (P < .0001) as predictors of FSIQ. CONCLUSIONS: More young liver transplantation recipients than expected are at increased risk for lasting cognitive and academic deficits. Pretransplant markers of nutritional status and operative complications predicted intellectual outcome.

Brain morphometric changes associated with childhood-onset systemic lupus erythematosus and neurocognitive deficit.

OBJECTIVE: To use structural magnetic resonance imaging (MRI) to characterize changes in gray matter and white matter volumes between patients with childhood-onset systemic lupus erythematosus (SLE) and matched controls, between patients with childhood-onset SLE with and those without neurocognitive deficit, and in relation to disease duration and treatment with steroids. METHODS: Twenty-two patients with childhood-onset SLE and 19 healthy controls underwent high-resolution structural MRI. Probability density maps for gray matter and white matter were compared between groups. RESULTS: Neuropsychological testing confirmed the presence of neurocognitive deficit in 8 patients with childhood-onset SLE. Multiple brain regions had reduced gray matter volume in the patients with childhood- onset SLE with neurocognitive deficit versus controls or patients with childhood-onset SLE without neurocognitive deficit. Neither disease duration nor cumulative oral or intravenous steroid doses accounted for decreases in gray matter. White matter volume was also reduced in patients with childhood-onset SLE with neurocognitive deficit, and the reduction was positively associated with both disease duration and cumulative oral steroid dose. Conversely, higher cumulative intravenous steroid doses were associated with higher white matter volumes. CONCLUSION: Neurocognitive deficit in patients with childhood-onset SLE is associated with multifocal decreases in both gray and white matter volumes. Since only white matter volume changes are related to disease duration and cumulative oral steroid use, this may suggest that gray and white matter alterations relate to different underlying mechanisms. Further work is needed to understand the relationship between gray and white matter alterations in childhood-onset SLE, whether the underlying mechanisms relate to immunologic, vascular, or other causes, and whether the changes are reversible or preventable. Likewise, the protective properties of intravenous steroids in maintaining white matter volumes require confirmation in larger cohorts.

Parent-reported cognition of children with cancer and its potential clinical usefulness.

PURPOSE: Cognitive dysfunction is a common concern for children with brain tumors (BTs) or those receiving central nervous system (CNS) toxic cancer treatments. Perceived cognitive function (PCF) is an economical screening that may be used to trigger full, formal cognitive testing. We assessed the potential clinical utility of PCF by comparing parent-reported scores for children with cancer with scores from the general US population. METHODS: Children (n = 515; mean age = 13.5 years; 57.0 % male) and one of their parents were recruited from pediatric oncology clinics. Most children (53.3 %) had a diagnosis of CNS tumor with an average time since diagnosis of 5.6 years. PCF was evaluated using the pediatric PCF item bank (pedsPCF), which was developed and normed on a sample drawn from the US general pediatric population. Children also completed computer-based neuropsychological tests. We tested relationships between PCF and clinical variables. Differential item functioning (DIF) was used to evaluate measurement bias between the samples. RESULTS: No item showed DIF, supporting the use of pedsPCF in the cancer sample. PedsPCF differentiated children with (vs. without) a BT, p < 0.01, and groups defined by years since diagnosis, p < 0.01. It significantly (p < 0.05) correlated with computerized neuropsychological tests in 40 of 60 comparisons. Children with BTs were rated as having worse pedsPCF scores than the norm, regardless of years since diagnosis. CONCLUSIONS: PCF significantly differentiated cancer survivors with various clinical characteristics. It is brief and easy to implement. PCF should be considered for routine care of pediatric cancer survivors.

Child Neurology: Reversible Dementia in an 18-Year-Old Woman Due to Undiagnosed Cobalamin-G Deficiency: A Case Report.

Cobalamin-G deficiency is an inborn error of metabolism which disrupts the biochemical utilization of vitamin B12 to covert homocysteine to methionine in the remethylation pathway. Typically, affected patients present within the first year of life with anemia, developmental delay, and metabolic crisis. Few case reports of cobalamin-G deficiency reference a later onset phenotype primarily defined by neuropsychiatric symptoms. We report an 18-year-old woman who presented with a 4-year history of progressively worsening dementia, encephalopathy, epilepsy, and regression of adaptive functioning, with an initially normal metabolic workup. Whole-exome sequencing identified variants in the MTR gene, suspicious for cobalamin-G deficiency. Additional biochemical testing after genetic testing supported this diagnosis. Since treatment with leucovorin, betaine, and B12 injections, we have seen a gradual return to normal cognitive function. This case report expands the phenotypic range of cobalamin-G deficiency and offers rationale for genetic and metabolic testing in cases of dementia in the second decade of life.

Ventilatory and Orthostatic Challenges Reveal Biomarkers for Neurocognition in Children and Young Adults With Congenital Central Hypoventilation Syndrome.

BACKGROUND: Children and young adults with congenital central hypoventilation syndrome (CCHS) are at risk of cognitive deficits. They experience autonomic dysfunction and chemoreceptor insensitivity measured during ventilatory and orthostatic challenges, but relationships between these features are undefined. RESEARCH QUESTION: Can a biomarker be identified from physiologic responses to ventilatory and orthostatic challenges that is related to neurocognitive outcomes in CCHS? STUDY DESIGN AND METHODS: This retrospective study included 25 children and young adults with CCHS tested over an inpatient stay. Relationships between physiologic measurements during hypercarbic and hypoxic ventilatory challenges, hypoxic ventilatory challenges, and orthostatic challenges and neurocognitive outcomes (by Wechsler intelligence indexes) were examined. Independent variable inclusion was determined by significant associations in Pearson's analyses. Multivariate linear regressions were used to assess relationships between measured physiologic responses to challenges and neurocognitive scores. RESULTS: Significant relationships were identified between areas of fluid intelligence and measures of oxygen saturation (SpO2) and heart rate (HR) during challenges. Specifically, perceptual reasoning was related to HR (adjusted regression [ß] coefficient, -0.68; 95% CI, 1.24 to -0.12; P = .02) during orthostasis. Working memory was related to change in HR (ß, -1.33; 95% CI, -2.61 to -0.05; P = .042) during the hypoxic ventilatory challenge. Processing speed was related to HR (ß, -1.19; 95% CI, -1.93 to -0.46; P = .003) during orthostasis, to baseline SpO2 (hypercarbic and hypoxic ß, 8.57 [95% CI, 1.63-15.51]; hypoxic ß, 8.37 [95% CI, 3.65-13.11]; P = .002 for both) during the ventilatory challenges, and to intrachallenge SpO2 (ß, 5.89; 95% CI, 0.71-11.07; P = .028) during the hypoxic ventilatory challenge. INTERPRETATION: In children and young adults with CCHS, SpO2 and HR-or change in HR-at rest and as a response to hypoxia and orthostasis are related to cognitive outcomes in domains of known risk, particularly fluid reasoning. These findings can guide additional research on the usefulness of these as biomarkers in understanding the impact of daily physical stressors on neurodevelopment in this high-risk group.

Cognitive proficiency in pediatric epilepsy.

Cognitive proficiency (CP) is a sensitive gauge of neurological status, but it is not typically viewed in relation to focal cerebral function. We examined CP and its relationship to general intellectual ability and seizure focus in 90 patients with pediatric epilepsy. CP was significantly lower than general ability (GA) in the overall sample. In particular, it was more deficient than GA in patients with right- than left-lateralized epilepsy onset, and in patients with frontal- than temporal-onset epilepsy. The discrepancy between CP and GA varied with participants' overall intelligence, being more pronounced (i.e., GA-CP difference larger) in individuals of lower overall ability. Deficits in CP are a defining characteristic of pediatric epilepsy and serve as an important marker of neurocognitive status, especially when seizures originate from a primary epileptogenic focus within the right hemisphere or the frontal lobe.

Neurocognitive monitoring in congenital central hypoventilation syndrome with the NIH Toolbox®.

Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, caused by mutations in the paired-like homeobox gene PHOX2B, which alters control of breathing and autonomic nervous system regulation, necessitating artificial ventilation as life-support. A broad range of neurocognitive performance has been reported in CCHS, including an array of cognitive deficits. We administered the NIH Toolbox® Cognition Battery (NTCB), a novel technology comprised of seven tasks presented via an interactive computer tablet application, to a CCHS cohort and studied its convergent and divergent validity relative to traditional clinical neurocognitive measures. The NTCB was administered to 51 CCHS participants, including a subcohort of 24 who also received traditional clinical neurocognitive testing (Wechsler Intelligence Scales). Age-corrected NTCB scores from the overall sample and subcohort were compared to population norms. Associations between NTCB indices and Wechsler Intelligence scores were studied to determine the convergent and divergent validity of the NTCB. NTCB test results indicated reduced Fluid Cognition, which measures new learning and speeded information processing (p < 0.001), but intact Crystallized Cognition, which measures past learning, in CCHS relative to population norms. Moderate to strong associations (r > 0.60) were found between age-corrected NTCB Fluid and Crystallized indices and comparable Wechsler indices, supporting the convergent and discriminant validity of the NTCB. Results reveal deficits of Fluid Cognition in individuals with CCHS and indicate that the NTCB is a valid and sensitive measure of cognitive outcomes in this population. Our findings suggest that the NTCB may play a useful role in tracking neurocognition in CCHS.

Evolution of physiologic and autonomic phenotype in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation over a decade from age at diagnosis.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare cause of syndromic obesity with risk of cardiorespiratory arrest and neural crest tumor. No ROHHAD-specific genetic test exists at present. Rapid weight gain of 20-30 pounds, typically between ages 2-7 years in an otherwise healthy child, followed by multiple endocrine abnormalities herald the ROHHAD phenotype. Vigilant monitoring for asleep hypoventilation (and later awake) is mandatory as hypoventilation and altered control of breathing can emerge rapidly, necessitating artificial ventilation as life support. Recurrent hypoxemia may lead to cor pulmonale and/or right ventricular hypertrophy. Autonomic dysregulation is variably manifest. Here we describe the disease onset with "unfolding" of the phenotype in a child with ROHHAD, demonstrating the presentation complexity, need for a well-synchronized team approach, and optimized management that led to notable improvement ("refolding") in many aspects of the child's ROHHAD phenotype over 10 years of care. CITATION: Khaytin I, Stewart TM, Zelko FA, et al. Evolution of physiologic and autonomic phenotype in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation over a decade from age at diagnosis. J Clin Sleep Med. 2022;18(3):937-944.

Special education participation in children with epilepsy: what does it reflect?

Epilepsy is associated with academic and neurocognitive disorders, with the latter often assumed to explain the former. We examined utilization of special education services (SpES) in relation to neurocognitive test scores in a case-matched sibling control study. In a follow-up assessment 8-9 years after entry into a prospective study of childhood-onset epilepsy, cases and siblings participated in an interview and standardized neurocognitive testing. Analyses included 142 pairs in which both had Full Scale IQ ≥ 80 and the case had normal examination and imaging. Sixty-four (45%) cases and 25 (17.6%) controls reported SpES utilization, (matched odds ratio [mOR]=5.3, P<0.0001). Adjustment for neurocognitive test scores resulted in a mOR of 4.6 (P<0.0001). Types and duration of services were similar in cases and controls. Twenty-four percent of school-aged cases were already receiving services at the time of initial epilepsy diagnosis. Young people with epilepsy have academic difficulties that are not explained simply by cognitive test scores.

Development of a parent-report cognitive function item bank using item response theory and exploration of its clinical utility in computerized adaptive testing.

OBJECTIVE: The purpose of this study is to report the reliability, validity, and clinical utility of a parent-report perceived cognitive function (pedsPCF) item bank. METHODS: From the U.S. general population, 1,409 parents of children aged 7-17 years completed 45 pedsPCF items. Their psychometric properties were evaluated using Item Response Theory (IRT) approaches. Receiver operating characteristic (ROC) curves and discriminant function analysis were used to predict clinical problems on child behavior checklist (CBCL) scales. A computerized adaptive testing (CAT) simulation was used to evaluate clinical utility. RESULTS: The final 43-item pedsPCF item bank demonstrates no item bias, has acceptable IRT parameters, and provides good prediction of related clinical problems. CAT simulation resulted in correlations of 0.98 between CAT and the full-length pedsPCF. CONCLUSIONS: The pedsPCF has sound psychometric properties, U.S. general population norms, and a brief-yet-precise CAT version is available. Future work will evaluate pedsPCF in other clinical populations in which cognitive function is important.

Parent-perceived child cognitive function: results from a sample drawn from the US general population.

PURPOSES: This paper reports the development and evaluation of a perceived cognitive function (pedsPCF) item bank reported by parents of the pediatric US general population. METHODS: Based on feedback from clinicians, parents, and children, we developed a scale sampling concerns related to children's cognitive functioning. We administered the scale to 1,409 parents of children aged 7-17 years; of them, 319 had a neurological diagnosis. Dimensionality of the pedsPCF was evaluated via factor analyses and its clinical utility studied by comparing parent ratings in patient groups and symptom cluster defined by the Child Behavior Checklist (CBCL). RESULTS: Forty-four of 45 items met criteria for unidimensionality. The pedsPCF significantly differentiated samples defined by medication use, repeated grades, special education status, neurologic diagnosis, and relevant symptom clusters with large effect sizes (>0.8). It can predicted children symptoms with the correction rates ranging 79-89%. CONCLUSIONS: We have provided empirical support for the unidimensionality of the pedsPCF item bank and evidence for its potential clinical utility. The pedsPCF is a promising measurement tool to screen children for further comprehensive cognitive tests.