Model-Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy.

Ethosuximide was identified as the optimal option for new-onset childhood absence epilepsy (CAE) in a randomized, two-phase dose escalation comparative effectiveness trial of ethosuximide, lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short-term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure-response relationship and to propose model-informed precision dosing guidance.

Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance.

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.

Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen.

Pretreatment behavior and subsequent medication effects in childhood absence epilepsy.

Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE).

Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16-20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure.

Pretreatment seizure semiology in childhood absence epilepsy.

Objective: To determine seizure semiology in children with newly diagnosed childhood absence epilepsy and to evaluate associations with short-term treatment outcomes.

Methods: For participants enrolled in a multicenter, randomized, double-blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit.

Results: Video of 1,932 electrographic absence seizures from 416 participants was evaluated.

Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy.

Objective: To determine whether common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short-term seizure outcome in childhood absence epilepsy (CAE).

Methods: Four hundred forty-six CAE children in a randomized double-blind trial of ethosuximide, lamotrigine, and valproate had short-term seizure outcome determined. Associations between polymorphisms (minor allele frequency ≥ 15%) in 4 genes and seizure outcomes were assessed.

Second monotherapy in childhood absence epilepsy.

Objective: To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure.

Methods: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16-20 and month 12 visits after randomization.

Obesity and overweight as CAE comorbidities and differential drug response modifiers.

Objective: This study examined whether overweight and obesity are pretreatment comorbidities and predictors of short-term drug response in newly diagnosed untreated childhood absence epilepsy (CAE). We also examined whether dietary intake accounts for observed pretreatment body mass index (BMI) distribution.

Methods: Pretreatment height and weight were available for 445 of 446 participants in the NIH-funded CAE comparative effectiveness trial (NCT00088452).

Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial.

Objective: To determine incidence and early predictors of generalized tonic-clonic seizures (GTCs) in children with childhood absence epilepsy (CAE).

Methods: Occurrence of GTCs was determined in 446 children with CAE who participated in a randomized clinical trial comparing ethosuximide, lamotrigine, and valproate as initial therapy for CAE.

Results: As of June 2014, the cohort had been followed for a median of 7.

Pretreatment cognitive deficits and treatment effects on attention in childhood absence epilepsy.

Objective: To determine the neurocognitive deficits associated with newly diagnosed untreated childhood absence epilepsy (CAE), develop a model describing the factorial structure of items measuring academic achievement and 3 neuropsychological constructs, and determine short-term differential neuropsychological effects on attention among ethosuximide, valproic acid, and lamotrigine.

Methods: Subjects with newly diagnosed CAE entering a double-blind, randomized controlled clinical trial had neuropsychological testing including assessments of general intellectual functioning, attention, memory, executive function, and achievement. Attention was reassessed at the week 16-20 visit.

Pretreatment EEG in childhood absence epilepsy: associations with attention and treatment outcome.

Objective: In children with newly diagnosed childhood absence epilepsy (CAE), determine pretreatment EEG features and their associations with baseline neuropsychological function and short-term treatment outcome.

Methods: In a multicenter, randomized clinical trial, patients with CAE underwent a pretreatment, 1-hour video-EEG and neuropsychological testing with freedom-from-failure and seizure-freedom (SF) outcome assessed at the 16- to 20-week visit.

Results: Detailed evaluation of the pretreatment EEG was possible for 99.

Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months.

Purpose: Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy (CAE) based on 12 months of double-blind therapy.

Methods: A double-blind, randomized controlled clinical trial compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed CAE. Study medications were titrated to clinical response, and subjects remained in the trial unless they reached a treatment failure criterion.

Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy.

Background: Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined.

Methods: In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy.

Mental Health Issues.

The following overview discusses and compares the findings and implications of the articles in this issue of the Health Care Financing Review that deal with mental health topics-particularly children's mental health- in the Medicaid context. It also briefly describes articles concerning prospective payments for psychiatric patients under Medicare.