Faculty Bibliography

OBJECTIVE: Preapproval randomized controlled trials of antiepileptic drugs provide data in limited patient groups. We assessed the side effect and seizure reduction profile of tiagabine (TGB) in typical clinical practice. METHODS: Investigators recorded adverse effect (AE), seizure, and assessment-of-benefit data prospectively in sequential patients treated open label with TGB. RESULTS: Two hundred ninety-two patients (39 children) were enrolled to be treated long term with TGB. Seizure types were focal-onset (86%), generalized-onset (12%), both focal- and generalized-onset (0.3%), and multiple associated with Lennox-Gastaut Syndrome (2%). Two hundred thirty-one received at least one dose of TGB (median=28mg/day) and had follow-up seizure or AE data reported. Common AEs were fatigue, dizziness, psychomotor slowing, ataxia, gastrointestinal upset, weight change, insomnia, and "others" (mostly behavioral). Serious AEs occurred in 19 patients: behavioral effects (n=12), status epilepticus (n=3), others (n=3), and sudden unexplained death (n=1). No patients experienced suicidal ideation/behavior, rash, nephrolithiasis, or organ failure. Seizure outcomes were seizure freedom (5%), >/=75% reduction (12%), >/=50% reduction (23%), and increased number of seizures (17%), or new seizure type (1%). CONCLUSIONS: Behavioral AEs occurred in a larger proportion of patients compared to those reported in TGB preapproval randomized controlled trials. A moderate percentage of patients had a meaningful reduction in seizure frequency. In clinical practice, TGB remains a useful antiepileptic drug.

A working group was created to address clinical "gaps to care" as well as opportunities for development of new treatment approaches for epilepsy. The working group primarily comprised clinicians, trialists, and pharmacologists. The group identified a need for better animal models for both efficacy and tolerability, and noted that animal models for potential disease-modifying or antiepileptogenic effect should mirror conditions in human trials. For antiseizure drugs (ASDs), current animal models have not been validated with respect to their relationship to efficacy in common epilepsy syndromes. The group performed an "expert opinion" survey of perceived efficacy of the available ASDs, and identified a specific unmet need for ASDs to treat tonic-atonic and myoclonic seizures. No correlation has as yet been demonstrated between animal models of tolerability and adverse effects (AEs), versus tolerability in humans. There is a clear opportunity for improved therapies in relation to dose-related AEs. The group identified common and rare epilepsy syndromes that could represent opportunities for clinical trials. They identified opportunities for antiepileptogenic (AEG) therapies in both adults and children, acknowledging that the presence of a biomarker would substantially improve the chances of a successful trial. However, the group acknowledged that disease-modifying therapies (given after the first seizure or after the development of epilepsy) would be easier to study than AEG therapies.

BACKGROUND: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. RESULTS: EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. CONCLUSIONS: EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

Purpose of Review: Selection of the ideal antiepileptic drug (AED) for an individual patient can be a daunting process. Choice of treatment should be based on several factors, including but not limited to epilepsy classification, AED mechanism of action, AED side-effect profile, and drug interactions. Special consideration must be given to populations such as women, older adults, patients with other medical comorbidities, and patients who are newly diagnosed.Recent Findings: Head-to-head trials between AEDs in newly diagnosed patients rarely demonstrate that one AED is more or less effective. The second-generation drugs, lamotrigine, topiramate, oxcarbazepine, zonisamide, and levetiracetam, have undergone head-to-head trials confirming similar efficacy and equal or better tolerability than standard drugs in focal epilepsy.Summary: A thoughtful approach to the AED selection process must factor in data from clinical AED trials as well as a variety of patient characteristics and confounding factors. When neurologists apply an individualized approach to AED drug selection for their patients, they can find an effective and well-tolerated drug for most patients.

PURPOSE: Three suicidal ideation and suicidal behavior instruments were used to assess the prevalence of lifetime and recent suicidal ideation and suicidal behavior in patients with frequent treatment-resistant focal seizures who would be eligible for randomized clinical trials. This was done to determine which instrument was optimal for use in epilepsy. METHODS: In a cross-sectional study, we compared lifetime and recent suicidal ideation and suicide attempt on the MINI International Neuropsychiatric Interview (MINI), Columbia Suicide Severity Rating Scale (C-SSRS), and Interactive Voice Response System CSSRS (E-CSSRS). A safety algorithm determined treatment referral. Coordinators and participants evaluated experiences with the C-SSRS. The proportion of participants that baseline assessment would exclude from clinical trial enrollment was determined. KEY FINDINGS: Among 208 participants, 1.6-3.9% had recent high risk suicidal ideation and 1.0-4.7% had a recent suicide attempt across all instruments. Lifetime high-risk suicidal ideation occurred in 12.1-14.1%. Lifetime suicide attempt occurred in 10.2-13.1% of participants. Of those with recent suicide attempt, 31.1% required referral to a health professional, and 3.9% needed urgent referral. Lifetime suicidal behavior (including aborted suicide attempt, interrupted suicide attempt, suicide attempt, preparatory acts or behavior, and nonsuicidal self-injurious behavior) was found in 21.1% on the E-CSSRS and 15.5% on the C-SSRS. Agreement (Kappa) was good to excellent for comparisons of all instruments. Fifty-two percent of subjects preferred either the CSSRS or E-CSSRS, whereas the rest had no preference; of those having a preference, 87.5% favored the CSSRS. Of the 18.9% of participants who might have been excluded from trials based on suicidal ideation and suicide attempt, the CSSRS identified high-risk suicidal ideation or suicide attempt in the preceding 2 years in only 4.4%. SIGNIFICANCE: Suicidality screening is feasible in people with epilepsy. Slightly more suicidal behavior is reported with the E-CSSRS than C-SSRS, suggesting the E-CSSRS may be optimal. The proportion of patients who may be excluded from clinical trials based on worrisome suicidal ideation or suicide attempt is small, suggesting that it is possible to enroll most eligible individuals.