The eTHINK Study: Cognitive and Behavioral Outcomes in Children with Hemophilia.

OBJECTIVE: To assess cognitive, behavioral, and adaptive functions in children and young adults with hemophilia treated according to contemporary standards of care. STUDY DESIGN: Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK) is a US-based, prospective, cross-sectional, observational study (September 2018 through October 2019). Males (aged 1-21 years) with hemophilia A or B of any severity, with or without inhibitors, were eligible. Participants underwent neurologic examinations and age-appropriate neuropsychological assessments, including standardized tests/ratings scales of early development, cognition, emotional/behavioral adjustment, and adaptive skills. RESULTS: Five hundred and fifty-one males with hemophilia A (n = 433) or B (n = 101) were enrolled. Performance on cognitive tests was largely comparable with that of age-matched US population norms, although participants in certain age groups (4-5 and 10-21 years) performed worse on measures of attention and processing speed. Furthermore, adolescents and young adults and those with comorbid attention-deficit/hyperactivity disorder (ADHD; n = 64) reported more adaptive and executive function problems in daily life. Incidence of ADHD in adolescents (21%) was higher than expected in the general population. CONCLUSIONS: In general, males with hemophilia demonstrated age-appropriate intellectual, behavioral, and adaptive development. However, specific patient/age groups showed poorer attention performance and concerns for executive and adaptive development. This study established a normative data set for monitoring neurodevelopment in individuals with hemophilia and highlight the importance of screening and intervention for challenges with cognitive and adaptive skills in this population. CLINICAL TRIAL REGISTRATION: Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK); NCT03660774; https://clinicaltrials.gov/ct2/show/NCT03660774.

Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders.

PURPOSE: Individuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs. METHODS: We reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect changes in these HRQoL measures. RESULTS: Individuals with UCDs demonstrated worse physical and psychosocial HRQoL than their healthy peers and peers with PKU and diabetes. In children, HRQoL scores did not differ by diagnosis or severity. In adults, individuals with decreased severity had worse psychosocial HRQoL. Finally, we show that a large number of individuals would be required in clinical trials to detect differences in HRQoL in UCDs. CONCLUSION: Individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.

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.

Household Food Insecurity and Cognition in Youth and Young Adults with Youth-Onset Diabetes.

Objective: We evaluated the association of household food insecurity (FI) with cognition in youth and young adults with type 1 diabetes (T1D) or type 2 diabetes (T2D). Design: In this cross-sectional study, age-adjusted scores for composite Fluid Cognition, and sub-domain scores for Receptive Language and Inhibitory Control and Attention, were modeled stratified by diabetes-type using linear regression, with FI in the past year as the predictor, controlling for covariates. Tests for processing speed, inhibitory control/attention, working memory, episodic memory, and cognitive flexibility were administered to measure composite Fluid Cognition score. The NIHT-CB Picture Vocabulary Test was used to assess Crystallized Cognition score and rapid identification of congruent versus noncongruent items were used to assess Inhibitory Control and Attention score. Setting: The SEARCH for Diabetes in Youth study, representative of 5 U.S. states. Participants: Included 1574 youth and young adults with T1D or T2D, mean age of 21 years, mean diabetes duration of 11 years, 51% non-Hispanic white, and 47% had higher HbA1c levels (>9% HbA1c). Results: Approximately 18% of the 1,240 participants with T1D and 31% of the 334 with T2D experienced FI. The food-insecure group with T1D had a lower composite Fluid Cognition score (ß= -2.5, 95% confidence interval (CI)= -4.8, -0.1) and a lower Crystallized Cognition score (ß= -3.4, CI= -5.6, -1.3) than food-secure peers. Findings were attenuated to non-significance after adjustment for demographics. Among T2D participants, no associations were observed. In participants with T1D effect modification by glycemic levels were found in the association between FI and composite Fluid Cognition score but adjustment for socioeconomic characteristics attenuated the interaction (p=0.0531). Conclusions: Food-insecure youth and young adults with T1D or T2D did not have different cognition compared to those who were food-secure after adjustment for confounders. Longitudinal research is needed to further understand relations amongst these factors.

Diabetes complications and cognitive function in young adults with youth-onset type 1 or type 2 diabetes: the SEARCH for Diabetes in Youth Study.

Aims/hypotheses: People with type 1 (T1D) or type 2 diabetes (T2D) who also have diabetes complications can have pronounced cognitive deficits. It remains unknown, however, whether and how multiple diabetes complications co-occur with cognitive dysfunction, particularly in youth-onset diabetes. Methods: Using data from the SEARCH for Diabetes in Youth study cohort, a prospective longitudinal cohort, we examined clustering of complications and their underlying clinical factors with performance on cognitive tests in young adults with youth-onset T1D or T2D. Cognition was assessed via the NIH Toolbox Cognition Battery. The main cognitive variables were age-corrected scores for composite fluid cognition and associated cognitive subdomains. Diabetes complications included retinopathy, microalbuminuria, and peripheral neuropathy (PN). Lipids, systolic blood pressure (SBP), hemoglobin A1c, and other clinical factors were included in the analyses. Clustering was applied separately to each group (T1D=646; T2D=165). A three-cluster(C) solution was identified for each diabetes type. Mean values and frequencies of all factors were compared between resulting clusters. Results: The average age-corrected score for composite fluid cognition differed significantly across clusters for each group (p<0.001). People with T1D and the lowest average fluid cognition scores had the highest frequency of self-reporting at least one episode of hypoglycemia in the year preceding cognitive testing and the highest prevalence of PN. Persons with T2D and the lowest average fluid cognition scores had the highest SBP, the highest central systolic and diastolic blood pressures, and highest prevalence of PN. Conclusions/interpretations: These findings highlight shared (PN) and unique factors (hypoglycemia in T1D; SBP in T2D) that could be targeted to potentially mitigate cognitive issues in young people with youth-onset diabetes.

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.

Prenatal Exposure to Tobacco and Offspring Neurocognitive Development in the Healthy Start Study.

OBJECTIVE: To explore the associations between prenatal exposure to tobacco and neurocognitive development, in the absence of prematurity or low birth weight. STUDY DESIGN: We followed mother-child pairs within Healthy Start through 6 years of age. Children were born at ≥37 weeks of gestation with a birth weight of ≥2500 g. Parents completed the Third Edition Ages and Stages Questionnaire (n = 246) and children completed a subset of the National Institutes of Health Toolbox Cognition Battery (n = 200). The Ages and Stages Questionnaire domains were dichotomized as fail/monitor and pass. Maternal urinary cotinine was measured at approximately 27 weeks of gestation. Separate logistic regression models estimated associations between prenatal exposure to tobacco (cotinine below vs above the limit of detection) and the Ages and Stages Questionnaire domains. Separate linear regression models estimated associations between prenatal exposure to tobacco and fully corrected T-scores for inhibitory control, cognitive flexibility, and receptive language, as assessed by the National Institutes of Health Toolbox. A priori covariates included sex, maternal age, maternal education, daily caloric intake during pregnancy, race/ethnicity, household income, maternal psychiatric disorders, and, in secondary models, postnatal exposure to tobacco. RESULTS: Compared with unexposed offspring, exposed offspring were more likely to receive a fail/monitor score for fine motor skills (OR, 3.9; 95% CI, 1.5-10.3) and decreased inhibitory control (B: -3.0; 95% CI, -6.1 to -0.7). After adjusting for postnatal exposure, only the association with fine motor skills persisted. CONCLUSIONS: Prenatal and postnatal exposures to tobacco may influence neurocognitive development, in the absence of preterm delivery or low birth weight. Increased developmental screening may be warranted for exposed children.

Neuropsychological function in children with hemophilia: A review of the Hemophilia Growth and Development Study and introduction of the current eTHINK study.

Almost all of what is known about neurologic and cognitive development in hemophilia derives from the Hemophilia Growth and Development Study, conducted during an era when treatment regimens and comorbidities differed significantly from the current environment. Results suggested hemophilia and human immunodeficiency virus had independent effects, and hemophilia negatively impacts academic achievement, attention, and behavior. The introduction of prophylaxis treatment in hemophilia has created the need for re-evaluation of the effects of hemophilia on neurodevelopment and cognition. We outline the Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (NCT03660774) study, which aims to meet this need.