Richard Chin

BACKGROUND AND OBJECTIVES: Epilepsy affects 0.5% to 1% of children and is the most frequent chronic neurologic condition in childhood. Incidence rates appear to be declining in high-income countries. The validity of epilepsy diagnoses from different data sources varies, and contemporary population-based incidence studies are needed. METHODS: The study was based on the Norwegian Mother and Child Cohort Study. Potential epilepsy cases were identified through registry linkages and parental questionnaires. Cases were validated through medical record reviews and telephone interviews of parents. RESULTS: The study population included 112 744 children aged 3 to 13 years (mean 7.4 years) at end of registry follow-up (December 31, 2012). Of these, 896 had registry recordings and/or questionnaire reports of epilepsy. After validation, 587 (66%) met the criteria for an epilepsy diagnosis. The incidence rate of epilepsy was 144 per 100 000 person-years in the first year of life and 58 per 100 000 for ages 1 to 10 years. The cumulative incidence of epilepsy was 0.66% at age 10 years, with 0.62% having active epilepsy. The 309 children (34%) with erroneous reports of epilepsy from the registry and/or the questionnaires had mostly been evaluated for nonepileptic paroxysmal events, or they had undergone electroencephalography examinations because of other developmental or neurocognitive difficulties. CONCLUSIONS: Approximately 1 out of 150 children is diagnosed with epilepsy during the first 10 years of life, with the highest incidence rate observed during infancy. Validation of epilepsy diagnoses in administrative data and cohort studies is crucial because reported diagnoses may not meet diagnostic criteria for epilepsy.

<h3>Objective</h3> To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome. <h3>Methods</h3> Patients aged 4–10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite <i>N</i>-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality. <h3>Results</h3> Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC_0–t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed. <h3>Conclusions</h3> Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated. <h3>Classification of evidence</h3> This study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.

BACKGROUND: In addition to recurrent epileptic seizures, children with epilepsy can have coexisting cognitive and behavioral difficulties but the spectrum and prevalence of such difficulties are uncertain. METHODS: The Children with Epilepsy in Sussex Schools study is a prospective, community-based study involving school-aged children (5–15 years) with active epilepsy in a defined geographical area in the United Kingdom. Participants underwent comprehensive psychological assessment, including measures of cognition, behavior, and motor functioning. Consensus neurobehavioral diagnoses were made with respect to Diagnostic and Statistical Manual, Fourth Edition-Text Revision (DSM-IV-TR) criteria. RESULTS: A total of 85 children (74% of eligible population) were enrolled; 80% of children with active epilepsy had a DSM-IV-TR behavioral disorder and/or cognitive impairment (IQ ,85). Intellectual disability (ID) (IQ ,70) (40%), attention-deficit/hyperactivity disorder (ADHD) (33%), and autism spectrum disorder (ASD) (21%) were the most common neurobehavioral diagnoses. Of those who met criteria for a DSM-IV-TR behavioral disorder, only one-third had previously been diagnosed. Logistic regression revealed that seizures in the first 24 months compared with first seizures at 24 to 60 or 61+ months (odds ratio [OR] 13, 95% confidence interval 2.2–76.9; OR 21.3, 3.2–148.9) and polytherapy (OR 7.7, 1.6–36.3) were independently associated with ID and the presence of ID was associated with a diagnosis of ASD (OR 14.1, 2.3–87.1) after Bonferroni adjustment. Epilepsy-related factors did not independently predict the presence of behavioral disorders. CONCLUSIONS: Screening for neurobehavioral comorbidities should be an integral part of management in children with “active” epilepsy. There is a need for research to identify neurobiological mechanisms underpinning neurobehavioral impairments and studies to evaluate possible treatments.