Berl, Madison M.

Abstract Objective Dravet syndrome (DS) is the prototypic developmental and epileptic encephalopathy, characterized by drug‐resistant seizures, developmental slowing, and many other morbidities. Detailed characterization of behavioral phenotypes and social–emotional skill development are limited. Methods We prospectively assessed behavioral and social–emotional problems in the ENVISION natural history study (NCT04537832) of children with DS associated with SCN1A pathogenic variants ( SCN1A + DS) enrolled at <5 years of age. Assessments every 3 months for up to 2 years included the Child Behavior Checklist (CBCL), Strengths and Difficulties Questionnaire (SDQ), Brief Infant‐Toddler Social and Emotional Assessment (BITSEA), and Vineland Adaptive Behavior Scales, 3rd Edition (VABS‐3). Results Fifty‐eight children with DS enrolled at 16 sites worldwide. Problematic behaviors—inattention, aggressive or oppositional behaviors, and withdrawn and autistic behaviors—began before age 3 years, became more evident with age, and were clinically significant in many children by age 3–4 years. CBCL Total, Externalizing, and Internalizing Problems T‐scores rose by approximately 3 points per year, and BITSEA Problem scale scores increased by 2.3 points annually ( p = .002). SDQ Hyperactivity scores worsened over time ( p = .013), whereas emotional difficulties remained stable. VABS‐3 Socialization domain scores, which were already more than 1 SD below the normative mean at baseline, decreased further, particularly in younger participants. Correlation analyses showed that poorer communication abilities were associated with increased problematic behaviors ( R = −.55 for CBCL Total Problems and VABS‐3 Communication scores). Mixed‐effects modeling identified age as the strongest predictor of worsening behavioral outcomes. Significance We found that behavioral and social–emotional problems are inherent components of DS that present in toddlerhood and worsen throughout early childhood. This highlights the need to diagnose and manage these issues early. Targeted therapy may alleviate the wide‐ranging morbidities that are intrinsic to DS, including the social–emotional and behavior problems that frequently emerge.

Abstract Objective Despite being safe and effective, surgery for pediatric epilepsy is underutilized. Social determinants of health (SDoH) are important to consider when examining this treatment gap. This study examined the potential systemic inequities at three different stages in the journey toward epilepsy surgery across the Pediatric Epilepsy Research Consortium (PERC). Methods Any youth in the PERC prospective surgery database (≤18 years) was eligible and included if sociodemographic factors were also available. We examined if there were differences in disparity factors in: (1) referral to Phase I evaluation, (2) offering of surgery, and (3) completion of surgery. Results Of 1309 patients, the majority were male (53%, p = .04), White (82.2%, p < .001), not Hispanic or Latino (84.3%, p < .001), and privately insured (56.3%, p < .001). Of the youth who were offered surgical treatment ( n = 1103, 84.3%), there were no significant differences in race/ethnicity or sex. Those with a structural lesion were more likely to be offered surgery, and historically marginalized youth were more likely to have a lesion. Of patients who completed surgery ( n = 927, 84.0%), White patients were 1.88 times (95% confidence interval [CI]: 1.14–3.04) more likely than Black patients to complete surgery ( p = .01). Significance Youth who began surgery evaluation are not representative of the demographics of those with epilepsy in the United States, with greater representation of White, non‐Hispanic male individuals. In addition, youth who began surgery evaluation disproportionally have private insurance. At the next stage of offering surgery, there were no differences based on SDoH. However, there is evidence that underrepresented youth that were magnetic resonance negative were less likely to be referred for surgical workup and that Black youth were less likely to undergo surgery. Therefore, efforts to provide equitable opportunity for all youth with refractory epilepsy should be concentrated at the referral for surgery evaluation point of care; however, additional efforts are also needed at later stages.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug‐resistant seizures and developmental slowing. Although cognitive and executive function deficits have been described, their early trajectory is not well understood. Methods The prospective ENVISION natural history study (NCT04537832) assessed cognitive, executive, and adaptive function in children younger than 5 years of age with SCN1A + DS every 6 months for up to 2 years using Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID‐III), Wechsler Preschool & Primary Scale of Intelligence, 4th Edition (WPPSI‐IV), Vineland Adaptive Behavior Scales, 3rd Edition (VABS‐3), Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF‐P), and Pediatric Evaluation of Disability Inventory (PEDI). Results Fifty‐eight children were enrolled, with 47% younger than age 2 years. At least 80% of children did not achieve age‐appropriate milestones. Mean BSID‐III Cognitive raw scores increased minimally, with age‐equivalent gains of only 3 months over 1.5 years. Mean Cognitive Composite scores declined significantly by Month 12 (from 81.6 to 72.2; change: –11.0, 95% confidence interval [CI]: −15.3 to −6.8), signaling a widening gap compared with neurotypical development. Executive function worsened, with mean BRIEF‐P Global Executive Composite T‐scores increasing by 3.2 points/year. For some participants, scores were 5 standard deviations (SD) above the normative mean, reflecting abilities profoundly below age expectations (bottom .00003% of the population). Adaptive functioning worsened, with mean VABS‐3 Adaptive Behavior Composite decreasing from 78.7 to 68.1 over 1.5 years (change: –9.0, 95% CI: −11.9 to −6.1) and greater decline among children <2 years at enrollment, with scores decreasing by ~15 points (1 SD). Over half of children >3 years could not remove clothing independently; and when placed on a toilet, 48% could not use it. Significance Infants and young children with SCN1A + DS show significant and progressive developmental slowing across several domains, highlighting urgent need for therapies to mitigate the devastating impact on individuals and families.

The 2023 American Epilepsy Society Annual Course “It’s About Time” addressed timing in epilepsy evaluation and treatment with respect to health disparity and vulnerable populations and diagnostic, clinical, and epilepsy surgery evaluation. This comprehensive course included topics on gaps in epilepsy care and optimization of behavioral health for patients with epilepsy. The summary details current knowledge in areas of seizure forecasting and epileptogenesis. Intricacies and controversies over timing were discussed for treatment of nonconvulsive seizures and ictal-interictal patterns, acute symptomatic seizures, neuromodulation versus surgery, and epilepsy surgery in status epilepticus. Timing regarding clinical care in autoimmune-associated epilepsy, developmental and epileptic encephalopathy, and dietary therapy were examined. Additionally, salient topics on using novel biomarkers and collaboration with neuropsychological outcomes were also tackled in this all-encompassing lecture series.

AbstractObjectiveImprove 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.MethodsPediatric 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.ResultsPositive 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.SignificanceWe 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.

SummaryAttention‐deficit/hyperactivity disorder (ADHD) is a common and challenging comorbidity affecting many children with epilepsy. A working group under the International League Against Epilepsy (ILAE) Pediatric Commission identified key questions on the identification and management of ADHD in children with epilepsy. Systematic reviews of the evidence to support approaches to these questions were collated and graded using criteria from the American Academy of Neurology Practice Parameter. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) requirements were followed, with PROSPERO registration (CRD42018094617). No increased risk of ADHD in boys with epilepsy compared to girls with epilepsy was found (Level A). Valproate use in pregnancy is associated with inattentiveness and hyperactivity in offspring (1 class I study), and children with intellectual and developmental disabilities are at increased risk of ADHD (Level A). Impact of early seizure onset on development of ADHD was unclear (Level U), but more evident with poor seizure control (Level B). ADHD screening should be performed from 6 years of age, or at diagnosis, and repeated annually (Level U) and reevaluated after change of antiepileptic drug (AED) (Level U). Diagnosis should involve health practitioners with expert training in ADHD (Level U). Use of the Strength and Difficulties Questionnaire screening tool is supported (Level B). Formal cognitive testing is strongly recommended in children with epilepsy who are struggling at school (Level U). Behavioral problems are more likely with polytherapy than monotherapy (Level C). Valproate can exacerbate attentional issues in children with childhood absence epilepsy (Level A). Methylphenidate is tolerated and effective in children with epilepsy (Level B). Limited evidence supports that atomoxetine is tolerated (Level C). Multidisciplinary involvement in transition and adult ADHD clinics is essential (Level U). In conclusion, although recommendations could be proposed for some of the study questions, this systematic review highlighted the need for more comprehensive and targeted large‐population prospective studies.