Navigating Neurogenetics for Child and Adolescent Psychiatry Practice.

Neurodevelopmental disorders (NDDs) are a group of conditions characterized by impairments of brain processes that impact cognition, communication, motor abilities, and/or behavior during development. These conditions typically have significant effects across the life span and impact personal, social, academic, or occupational functioning. The US Centers for Disease Control and report that 1 in 6 children has a developmental disability, making it highly likely for child and adolescent psychiatrists to encounter children with NDDs in daily practice.1 While the etiologies of NDDs are broad, genetic syndromes are a common cause of NDDs. The diagnostic yield of thorough genetic testing for NDDs as a group is about 40% based on meta-analysis, including 30% to 50% yield in patients with global developmental delay (GDD) or intellectual disability (ID) and 15% to 20% yield in patients with in autism spectrum disorder.1-3 The findings are extremely heterogeneous, including chromosomal copy number variants (CNVs) and more than 2,000 known monogenic disorders associated with NDDs.3 Diagnostic yields will increase over time with advances in technology and disease gene discovery.3.

Impact of the COVID-19 Pandemic on the Behavioral Health of People With Intellectual and Developmental Disabilities.

OBJECTIVE: The authors examined how the COVID-19 pandemic affected the behavioral health of people with intellectual and developmental disabilities (IDD). METHODS: A modified version of the Coronavirus Health Impact Survey-Adapted for Autism and Related Neurodevelopmental Conditions was sent to the authors' clinical networks and IDD-affiliated organizations from March to June 2021. RESULTS: In total, 437 people with IDD or their caregivers responded to the survey. Diagnoses included intellectual disability (51%) and autism spectrum disorder (48%). More than half (52%) of respondents reported worsened mental health. Losing access to services correlated with declining mental health. Interventions suggested to improve behavioral health included more time with friends and family (68%), more time outdoors (61%), and access to community activities (59%). CONCLUSIONS: COVID-19 affected the behavioral health of individuals with IDD. Survey results highlight the opportunity to leverage physical activity and pandemic-safe social supports as accessible means to mitigate gaps in services.

Epilepsy Benchmarks Area IV: Limit or Prevent Adverse Consequence of Seizures and Their Treatment Across the Life Span.

Epilepsy represents a complex spectrum disorder, with patients sharing seizures as a common symptom and manifesting a broad array of additional clinical phenotypes. To understand this disorder and treat individuals who live with epilepsy, it is important not only to identify pathogenic mechanisms underlying epilepsy but also to understand their relationships with other health-related factors. Benchmarks Area IV focuses on the impact of seizures and their treatment on quality of life, development, cognitive function, and other aspects and comorbidities that often affect individuals with epilepsy. Included in this review is a discussion on sudden unexpected death in epilepsy and other causes of mortality, a major area of research focus with still many unanswered questions. We also draw attention to special populations, such as individuals with nonepileptic seizures and pregnant women and their offspring. In this study, we review the progress made in these areas since the 2016 review of the Benchmarks Area IV and discuss challenges and opportunities for future study.

Primary caregiver education level and sleep problems in children with autism spectrum disorder.

In children with autism spectrum disorder, there have been equivocal results regarding primary caregiver education level and its influence on sleep. Thus, we assessed if lower primary caregiver education level is associated with more sleep problems. We evaluated 4,636 children with autism spectrum disorder in the Autism Speaks Autism Treatment Network's United States and Canadian registry, whose caregivers completed the Children's Sleep Habits Questionnaire. Using regression analysis, there was an association between lower primary caregiver education level and more sleep problems. Secondary analyses demonstrated that younger age, Hispanic ethnicity, higher IQ, autism diagnosis and lower adaptive function were also associated with more sleep problems. The finding that lower primary caregiver education level was associated with increased sleep problems in a large sample of children with autism spectrum disorder highlights the importance of screening for risk factors affecting sleep to help moderate sleep problems.

Parent Empowerment in Pediatric Healthcare Settings: A Systematic Review of Observational Studies.

BACKGROUND: Parent empowerment is often an expressed goal in clinical pediatrics and in pediatric research, but the antecedents and consequences of parent empowerment are not well established. OBJECTIVE: The objective of this systematic review was to synthesize potential antecedents and consequences of parent empowerment in healthcare settings. ELIGIBILITY CRITERIA: The inclusion criteria were (1) studies with results about parent empowerment in the context of children's healthcare or healthcare providers; and (2) qualitative studies, observational studies, and systematic reviews of such studies. INFORMATION SOURCES: We searched the databases of PubMed, Web of Science, and Google Scholar (2006-2017) and reference lists. INCLUDED STUDIES: Forty-four articles met the inclusion criteria. SYNTHESIS OF RESULTS: We identified six themes within consequences of empowerment: increased parent involvement in daily care, improved symptom management, enhanced informational needs and tools, increased involvement in care decisions, increased advocacy for child, and engagement in empowering others. Six themes summarizing antecedents of empowerment also emerged: parent-provider relationships, processes of care, experiences with medical care, experiences with community services, receiving informational/emotional support, and building personal capacity and narrative. We synthesized these findings into a conceptual model to guide future intervention development and evaluation. STRENGTHS AND LIMITATIONS OF EVIDENCE: Non-English articles were excluded. INTERPRETATION: Parent empowerment may enhance parent involvement in daily care and care decisions, improve child symptoms, enhance informational needs and skills, and increase advocacy and altruistic behaviors. Parent empowerment may be promoted by the parent-provider relationship and care processes, finding the right fit of medical and community services, and attention to the cognitive and emotional needs of parents. CLINICAL REGISTRATION NO: PROSPERO 2017:CRD42017059478.

A Newborn With Hyperlactatemia and Epileptic Encephalopathy.

The etiology of hyperlactatemia in newborns could be a challenging diagnosis. In this article we are discussing a diagnostic paradigm using the clinical history, laboratory results, and brain imaging that could be helpful in directing the work up.

Delivery of epilepsy care to adults with intellectual and developmental disabilities.

Epilepsy is common in people with intellectual and developmental disabilities (IDD). In adulthood, patients with IDD and epilepsy (IDD-E) have neurologic, psychiatric, medical, and social challenges compounded by fragmented and limited care. With increasing neurologic disability, there is a higher frequency of epilepsy, especially symptomatic generalized and treatment-resistant epilepsies. The causes of IDD-E are increasingly recognized to be genetic based on chromosomal microarray analysis to identify copy number variants, gene panels (epilepsy, autism spectrum disorder, intellectual disability), and whole-exome sequencing. A specific genetic diagnosis may guide care by pointing to comorbid disorders and best therapy. Therapy to control seizures should be individualized, with drug selection based on seizure types, epilepsy syndrome, concomitant medications, and comorbid disorders. There are limited comparative antiepileptic drug data in the IDD-E population. Vagus nerve and responsive neural stimulation therapies and resective surgery should be considered. Among the many comorbid disorders that affect patients with IDD-E, psychiatric and sleep disorders are common but often unrecognized and typically not treated. Transition from holistic and coordinated pediatric to adult care is often a vulnerable period. Communication among adult health care providers is complex but essential to ensure best care when these patients are seen in outpatient, emergency room, and inpatient settings. We propose specific recommendations for minimum care standards for people with IDD-E.

Clinic-friendly screening for cognitive and mental health problems in school-aged youth with epilepsy.

Cognitive, psychiatric, psychosocial, and behavioral difficulties are common in youth with epilepsy. Collectively, these comorbidities can be referred to as mental health problems as they reflect brain and behavioral function. Detection and treatment of mental health problems remain an unmet need in epilepsy care that can impact epilepsy, psychosocial, scholastic, and quality-of-life outcomes. Given limited resources in everyday pediatric epilepsy practice, this targeted review provides a stratified plan and suggested tools for screening school-aged youth with epilepsy for the presence of mental health problems. Comanagement of epilepsy and associated comorbidities is a newer concept that may help address the complex, long-term needs of patients by using a multidisciplinary team approach and by engaging primary care providers.

Craniofacial abnormalities and developmental delay in two families with overlapping 22q12.1 microdeletions involving the MN1 gene.

Deletions spanning the MN1 gene (22q12.1) have recently been proposed as playing a role in craniofacial abnormalities that include cleft palate, as mouse studies have demonstrated that Mn1 haploinsufficiency results in skull abnormalities and secondary cleft palate. We report on four patients (two families) with craniofacial abnormalities and intellectual disability with overlapping microdeletions that span the MN1 gene. Comparative genomic hybridization microarray analysis revealed a 2.76 Mb deletion in the 22q12.1 region, in three family members (Family 1), that contains the MN1 gene. In addition, a complex 22q12 rearrangement, including a 1.61 Mb deletion containing the MN1 gene and a 2.28 Mb deletion encompassing the NF2 gene, has been identified in another unrelated patient (Family 2). Based upon genotype-phenotype correlation among our patients and those previously reported with overlapping 22q12 deletions, we identified a 560 kb critical region containing the MN1 gene that is implicated in human cleft palate formation. Importantly, NF2 was also found within the 22q12 deletion region in several patients which enabled specific clinical management for neurofibromatosis 2.

Brief cognitive and behavioral screening in children with new-onset epilepsy: a pilot feasibility trial.

BACKGROUND: Minimal work has used psychometrically robust measures in a systematic fashion to identify and monitor children at risk for cognitive and behavioral comorbidities in current epilepsy care. We piloted a computerized cognitive battery and behavioral questionnaire for children with newly diagnosed epilepsy to determine clinical feasibility and acceptability to parents and patients. METHODS: We recruited medication-naïve children (ages 8-17 years) with recent-onset seizures and typical developmental history from an outpatient child neurology clinic. Children completed the CNS Vital Signs computerized battery, whereas parents completed the Strengths and Difficulties Questionnaire. Post-test interviews with parents and patients were completed regarding the acceptability of the assessment procedures. RESULTS: Forty-four families were eligible, and 39 agreed to participate (89%). All assessments were completed in less than 45 minutes. Parents rated testing in clinic as convenient and important, expressing strong interest in the cognitive and behavioral impact of epilepsy and medication. Children also rated the testing procedure as acceptable and agreed that they would recommend it to peers. CONCLUSIONS: Our brief battery was tolerated and well received by children and their parents. Computerized testing of children along with a parent questionnaire is a psychometrically viable approach that is acceptable to families. Our protocol is time efficient for clinical use with the potential to detect early cognitive and behavioral difficulties related to epilepsy. Ongoing longitudinal study will provide further information regarding the success of our screening methods in monitoring for disease- or treatment-related changes.

Investigating inhibitory control in children with epilepsy: an fMRI study.

OBJECTIVE: Deficits in executive function are noted increasingly in children with epilepsy and have been associated with poor academic and psychosocial outcomes. Impaired inhibitory control contributes to executive dysfunction in children with epilepsy; however, its neuroanatomic basis has not yet been investigated. We used functional magnetic resonance imaging (fMRI) to probe the integrity of activation in brain regions underlying inhibitory control in children with epilepsy. METHODS: This cross-sectional study consisted of 34 children aged 8-17 years: 17 with well-controlled epilepsy and 17 age- and sex-matched controls. Participants performed the antisaccade (AS) task, representative of inhibitory control, during fMRI scanning. We compared AS performance during neutral and reward task conditions and evaluated task-related blood oxygen level-dependent (BOLD) activation. RESULTS: Children with epilepsy demonstrated impaired AS performance compared to controls during both neutral (nonreward) and reward trials, but exhibited significant task improvement during reward trials. Post hoc analysis revealed that younger patients made more errors than older patients and all controls. fMRI results showed preserved activation in task-relevant regions in patients and controls, with the exception of increased activation in the left posterior cingulate gyrus in patients specifically with generalized epilepsy across neutral and reward trials. SIGNIFICANCE: Despite impaired inhibitory control, children with epilepsy accessed typical neural pathways as did their peers without epilepsy. Children with epilepsy showed improved behavioral performance in response to the reward condition, suggesting potential benefits of the use of incentives in cognitive remediation.

Developmental stages and sex differences of white matter and behavioral development through adolescence: a longitudinal diffusion tensor imaging (DTI) study.

White matter (WM) continues to mature through adolescence in parallel with gains in cognitive ability. To date, developmental changes in human WM microstructure have been inferred using analyses of cross-sectional or two time-point follow-up studies, limiting our understanding of individual developmental trajectories. The aims of the present longitudinal study were to characterize the timing of WM growth and investigate how sex and behavior are associated with different developmental trajectories. We utilized diffusion tensor imaging (DTI) in 128 individuals aged 8-28, who received annual scans for up to 5 years and completed motor and cognitive tasks. Flexible nonlinear growth curves indicated a hierarchical pattern of WM development. By late childhood, posterior cortical-subcortical connections were similar to adults. During adolescence, WM microstructure reached adult levels, including frontocortical, frontosubcortical and cerebellar connections. Later to mature in adulthood were major corticolimbic association tracts and connections at terminal gray matter sites in cortical and basal ganglia regions. These patterns may reflect adolescent maturation of frontal connectivity supporting cognitive abilities, particularly the protracted refinement of corticolimbic connectivity underlying cognition-emotion interactions. Sex and behavior also played a large role. Males showed continuous WM growth from childhood through early adulthood, whereas females mainly showed growth during mid-adolescence. Further, earlier WM growth in adolescence was associated with faster and more efficient responding and better inhibitory control whereas later growth in adulthood was associated with poorer performance, suggesting that the timing of WM growth is important for cognitive development.

Clinicians' views on antiepileptic medication management in nonepileptic seizures.

Discontinuation of antiepileptic drugs should be a first step in treatment of nonepileptic seizures without comorbid epilepsy. However, clinical practices vary and standardized guidelines are not available. The aim of this study was to survey members of the American Epilepsy and Child Neurology Societies about factors that influence their decision about antiepileptic drug management in patients with nonepileptic seizures. A total of 236 respondents completed this survey, of whom 84% were academic pediatric neurologists and 96.2% were very willing to discontinue antiepileptic drugs in these patients. Clinicians with sufficient knowledge about nonepileptic seizures had fewer concerns about the potential for medical errors, were less influenced by requests made by patients or parents to continue antiepileptic drugs, and were comfortable making this decision if patients receive ongoing psychiatric care. Results of this survey highlight the need to examine if the same factors are involved in a large sample of community clinicians.

White matter development in adolescence: diffusion tensor imaging and meta-analytic results.

BACKGROUND: In light of the evidence for brain white matter (WM) abnormalities in schizophrenia, study of normal WM maturation in adolescence may provide critical insights relevant to the neurodevelopment of the disorder. Voxel-wise diffusion tensor imaging (DTI) studies have consistently demonstrated increases in fractional anisotropy (FA), a putative measure of WM integrity, from childhood into adolescence. However, the WM tracts that show FA increases have been variable across studies. Here, we aimed to assess which WM tracts show the most pronounced changes across adolescence. METHODS: DTI was performed in 78 healthy subjects aged 8-21 years, and voxel-wise analysis conducted using tract-based spatial statistics (TBSS). In addition, we performed the first meta-analysis of TBSS studies on WM development in adolescence. RESULTS: In our sample, we observed bilateral increases in FA with age, which were most significant in the left superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and anterior thalamic radiation. These findings were confirmed by the meta-analysis, and FA increase in the bilateral SLF was the most consistent finding across studies. Moreover, in our sample, FA of the bilateral SLF showed a positive association with verbal working memory performance and partially mediated increases in verbal fluency as a function of increasing age. CONCLUSIONS: These data highlight increasing connectivity in the SLF during adolescence. In light of evidence for compromised SLF integrity in high-risk and first-episode patients, these data suggest that abnormal maturation of the SLF during adolescence may be a key target in the neurodevelopment of schizophrenia.

Deficits in oculomotor performance in pediatric epilepsy.

PURPOSE: Given evidence of limitations in neuropsychological performance in epilepsy, we probed the integrity of components of cognition--including speed of processing, response inhibition, and spatial working memory--supporting executive function in pediatric epilepsy patients and matched controls. METHODS: A total of 44 pairs of controls and medically treated pediatric epilepsy patients with no known brain pathology completed cognitive oculomotor tasks, computerized neuropsychological testing, and psychiatric assessment. KEY FINDINGS: Patients showed slower reaction time to initiate a saccadic response compared to controls but had intact saccade accuracy. Cognitively driven responses including response inhibition were impaired in the patient group. Patients had increased incidence of comorbid psychopathology, but comorbidity did not predict worse functioning compared to patients with no Attention Deficit Hyperactivity Disorder (ADHD). Epilepsy type and medication status were not predictive of outcome. More complex neuropsychological performance was impaired in tasks requiring visual memory and sequential processing, which was correlated with inhibitory control and antisaccade accuracy. SIGNIFICANCE: Pediatric epilepsy may be associated with vulnerabilities that specifically undermine speed of processing and response inhibition but not working memory, and may underlie known neuropsychological performance limitations. This particular profile of abnormalities may be associated with seizure-mediated compromises in brain maturation early in development.

Pediatric psychogenic nonepileptic seizures: a study of assessment tools.

The goal of this study was to identify assessment tools and associated behavioral domains that differentiate children with psychogenic nonepileptic seizures (PNES) from those with epilepsy. A sample of 24 children with PNES (mean age 14.0 years, 14 female), 24 children with epilepsy (mean age 13.6 years, 13 female), and their parents were recruited from five epilepsy centers in the United States. Participants completed a battery of behavioral questionnaires including somatization, anxiety, and functional disability symptoms. Children with PNES had significantly higher scores on the Childhood Somatization and Functional Disability Inventories, and their parents reported more somatic problems on the Child Behavior Checklist (CBCL). Depression, anxiety, and alexithymia instruments did not differentiate the groups. Measures of somatization and functional disability may be promising tools for differentiating the behavioral profile of PNES from that of epilepsy. Increased somatic awareness and perceived disability emphasize the similarity of PNES to other pediatric somatoform disorders.