Faculty Bibliography

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

Despite the current availability in the market of over two dozen antiepileptic drugs (AEDs), about one third of people with epilepsy fail to achieve complete freedom from seizures with existing medications. Moreover, currently available AEDs have significant limitations in terms of safety, tolerability and propensity to cause or be a target for clinically important adverse drug interactions. A review of the evidence shows that there are many misperceptions about the viability of investing into new therapies for epilepsy. In fact, there are clear incentives to develop newer and more efficacious medications. Developing truly innovative drugs requires a shift in the paradigms for drug discovery, which is already taking place by building on greatly expanded knowledge about the mechanisms involved in epileptogenesis, seizure generation, seizure spread and development of co-morbidities. AED development can also benefit by a review of the methodology currently applied in clinical AED development, in order to address a number of ethical and scientific concerns. As discussed in this article, many processes of clinical drug development, from proof-of-concept-studies to ambitious programmes aimed at demonstrating antiepileptogenesis and disease-modification, can be facilitated by a greater integration of preclinical and clinical science, and by application of knowledge acquired during decades of controlled epilepsy trials.

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.

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.

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.

OBJECTIVE: Epilepsy surgery is the most effective treatment for select patients with drug-resistant epilepsy. In this article, we aim to provide an accurate understanding of the current epidemiologic characteristics of this intervention, as this knowledge is critical for guiding educational, academic, and resource priorities. METHODS: We profile the practice of epilepsy surgery between 1991 and 2011 in nine major epilepsy surgery centers in the United States, Germany, and Australia. Clinical, imaging, surgical, and histopathologic data were derived from the surgical databases at various centers. RESULTS: Although five of the centers performed their highest number of surgeries for mesial temporal sclerosis (MTS) in 1991, and three had their highest number of MTS surgeries in 2001, only one center achieved its peak number of MTS surgeries in 2011. The most productive year for MTS surgeries varied then by center; overall, the nine centers surveyed performed 48% (95% confidence interval [CI] -27.3% to -67.4%) fewer such surgeries in 2011 compared to either 1991 or 2001, whichever was higher. There was a parallel increase in the performance of surgery for nonlesional epilepsy. Further analysis of 5/9 centers showed a yearly increase of 0.6 +/- 0.07% in the performance of invasive electroencephalography (EEG) without subsequent resections. Overall, although MTS was the main surgical substrate in 1991 and 2001 (proportion of total surgeries in study centers ranging from 33.3% to 70.2%); it occupied only 33.6% of all resections in 2011 in the context of an overall stable total surgical volume. SIGNIFICANCE: These findings highlight the major aspects of the evolution of epilepsy surgery across the past two decades in a sample of well-established epilepsy surgery centers, and the critical current challenges of this treatment option in addressing complex epilepsy cases requiring detailed evaluations. Possible causes and implications of these findings are discussed.