Faculty Bibliography

Several relevant animal models of epileptogenesis and biomarkers have emerged for evaluating the antiepileptogenic potential of an investigational drug. Although several promising candidate compounds and approaches have been identified in these preclinical models, no treatment has yet successfully navigated the path from preclinical efficacy to clinical validation. Until such an agent can move from preclinical proof of concept to clinical success, the need remains to continually develop and optimize preclinical models and clinical trial design in an effort to guide potential clinical investigations. This review describes several available models of disease modification and/or epileptogenesis, preclinical studies in these models and potential biomarkers useful for evaluating the efficacy of a potential therapeutic agent in the preclinical setting. The results that emerge from such efforts may then guide the clinical evaluation of a candidate compound. This review discusses some of the known limitations and hurdles to moving compounds found effective in these models to clinical practice, in the hope that knowledge of this information will facilitate the design and conduct of clinical studies and effectively facilitate the identification of a first-in-class disease-modifying or antiepileptogenic agent.

Clinical practice guidelines (CPGs) contain evidence-based recommendations to guide clinical care, policy development, and quality of care improvement. A recent systematic review of epilepsy guidelines identified considerable variability in the quality of available guidelines. Although excellent frameworks for CPG development exist, processes are not followed uniformly internationally, and resources to develop CPGs may be limited in certain settings. An International League Against Epilepsy (ILAE) working group was charged with proposing methodology to guide the development of future epilepsy-specific CPGs. A comprehensive literature search (1985-2014) identified articles related to CPG development and handbooks. Guideline handbooks were included if they were publicly available, and if their methodology had been used to develop CPGs. The working group's expertise also informed the creation of methodologies and processes to develop future CPGs for the ILAE. Five handbooks from North America (American Academy of Neurology), Europe (Scottish Intercollegiate Guidelines Network & National Institute for Health and Care Excellence), Australia (National Health and Medical Research Council), World Health Organization (WHO), and additional references were identified to produce evidence-based, consensus-driven methodology for development of epilepsy-specific CPGs. Key components of CPG development include the following: identifying the topic and defining the scope; establishing a working group; identifying and evaluating the evidence; formulating recommendations and determining strength of recommendations; obtaining peer reviews; dissemination, implementation, and auditing; and updating and retiring the CPG. A practical handbook and toolkit was developed. The resulting CPG development toolkit should facilitate the development of high-quality ILAE CPGs to improve the care of persons with epilepsy.

Purpose: Patients enrolled in clinical trials should be accurately classified to meet inclusion criteria. We assessed how many patients screened for enrollment in a randomized placebo-controlled study of drug-resistant primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE), using the noncompetitive AMPA receptor antagonist perampanel, were rejected due to inaccurate classification when reviewed independently by The Epilepsy Study Consortium (TESC). Method: Patients were reviewed by TESC to ensure a clear IGE diagnosis. Sites submitted all information used to determine each diagnosis. Patients were excluded if submitted information could not confirm an IGE diagnosis (e.g. only GTC seizures and a normal EEG with no family history or supporting seizure types) or showed an incorrect IGE diagnosis (e.g. slow spike-wave, developmental delay, age of onset <1 year, or symptomatic cause). Patients considered ineligible were sent to a second, independent TESC reviewer. If both reviewers agreed, the patient was screen failed. If they disagreed, a third reviewer made the final decision. Results: Of 307 patients screened, 143 patients failed (not meeting inclusion criteria; n = 117). Of these, 70/117 patients failed only after TESC review (IGE misdiagnosis [n = 35]; insufficient information to confirm diagnosis [n = 35]). A third reviewer made the final decision twice. Ultimately 164 patients received perampanel or placebo (1:1) highlighting that TESC review eliminated 70/234 (29.9%) patients initially considered eligible. The trial demonstrated a median percent change in PGTC seizure frequency per 28 days during Titration/Maintenance Periods versus Baseline of -76.5% perampanel versus -38.4% placebo; p < 0.0001. Conclusion: TESC review eliminated 29.9% inappropriate patients from inclusion. This was the first PGTCS study that used external review to ensure appropriate classification of trial participants. Without such a review, the interpretability of results may be compromised

The current study examined whether negative illness perceptions help explain the link between depression and quality of life. Seventy patients with epilepsy completed standardized self-report questionnaires measuring depression, illness perception, and quality of life (QOL). Illness perception statistically mediated the relationship between depression and QOL (Indirect effect (CI; confidence interval) = -.72, lower limit = -1.7, upper limit = -.22, p < .05). Results held with and without adjusting for potential confounding variables (age, sex, ethnicity, income, and seizure frequency) and when operationalizing depression as a continuous variable that indexed severity of symptoms or as a dichotomous variable that indexed criteria consistent with a diagnosis of major depressive disorder. This study is the first to suggest that illness perceptions may be a useful target in screening and intervention approaches in order to improve QOL among low-income, racially/ethnically diverse patients with epilepsy.

Antiepileptic drugs (AEDs) are the only neurotherapeutics for which regulatory approval is consistently separated into monotherapy or adjunctive-therapy indications. Because head-to-head comparisons of AEDs (used in the European Union to approve drugs for monotherapy) have not shown substantial differences in efficacy between drugs, FDA approval for use of an AED as monotherapy has typically been based on trials with novel designs that have been criticised for reasons of ethics and clinical relevance. Many new-generation AEDs have not been approved for monotherapy, causing drug labelling and real-world use to be increasingly inconsistent, with negative consequences for patients. The regulatory requirement for separate monotherapy and adjunctive-therapy indications in epilepsy is unnecessarily restrictive. We recommend that regulatory agencies approve AEDs for the treatment of specific seizure types or epilepsy syndromes, irrespective of concomitant drug use.

OBJECTIVE: To assess efficacy and safety of adjunctive perampanel in patients with drug-resistant, primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE). METHODS: In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743; funded by Eisai Inc.), patients 12 years or older with PGTC seizures and IGE were randomized to placebo or perampanel during a 4-week titration period (perampanel uptitrated from 2 to 8 mg/d, or highest tolerated dose) and 13-week maintenance period. The primary endpoint was percent change in PGTC seizure frequency per 28 days (titration plus maintenance vs baseline). The key secondary endpoint (primary endpoint for European Union registration) was 50% PGTC seizure responder rate (patients achieving >/=50% reduction in PGTC seizure frequency; maintenance vs baseline). Treatment-emergent adverse events were monitored. RESULTS: Of 164 randomized patients, 162 comprised the full analysis set (placebo, 81; perampanel, 81). Compared with placebo, perampanel conferred a greater median percent change in PGTC seizure frequency per 28 days (-38.4% vs -76.5%; p < 0.0001) and greater 50% PGTC seizure responder rate (39.5% vs 64.2%; p = 0.0019). During maintenance, 12.3% of placebo-treated patients and 30.9% of perampanel-treated patients achieved PGTC seizure freedom. For the safety analysis (placebo, 82; perampanel, 81), the most frequent treatment-emergent adverse events with perampanel were dizziness (32.1%) and fatigue (14.8%). CONCLUSIONS: Adjunctive perampanel was well tolerated and improved control of drug-resistant PGTC seizures in patients with IGE. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that adjunctive perampanel reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC seizures in IGE.