Faculty Bibliography

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.

Focal cortical dysplasia (FCD) is the most common cause of pediatric epilepsy and the third most common lesion in adults with treatment-resistant epilepsy. Advances in MRI have revolutionized the diagnosis of FCD, resulting in higher success rates for resective epilepsy surgery. However, many patients with histologically confirmed FCD have normal presurgical MRI studies ('MRI-negative'), making presurgical diagnosis difficult. The purpose of this study was to test whether a novel MRI postprocessing method successfully detects histopathologically verified FCD in a sample of patients without visually appreciable lesions. We applied an automated quantitative morphometry approach which computed five surface-based MRI features and combined them in a machine learning model to classify lesional and nonlesional vertices. Accuracy was defined by classifying contiguous vertices as "lesional" when they fell within the surgical resection region. Our multivariate method correctly detected the lesion in 6 of 7 MRI-positive patients, which is comparable with the detection rates that have been reported in univariate vertex-based morphometry studies. More significantly, in patients that were MRI-negative, machine learning correctly identified 14 out of 24 FCD lesions (58%). This was achieved after separating abnormal thickness and thinness into distinct classifiers, as well as separating sulcal and gyral regions. Results demonstrate that MRI-negative images contain sufficient information to aid in the in vivo detection of visually elusive FCD lesions.

OBJECTIVE: To determine whether a novel endpoint of time to prerandomization monthly seizure count could be used to differentiate efficacious and nonefficacious therapies in clinical trials of new add-on antiepileptic drugs (AEDs). METHODS: This analysis used data from 3 randomized, double-blind, placebo-controlled phase III trials of perampanel as an add-on therapy in patients with epilepsy who were experiencing refractory partial seizures: studies 304 (ClinicalTrials.gov identifier NCT00699972), 305 (NCT00699582), and 306 (NCT00700310). Time to prerandomization monthly seizure count was evaluated post hoc for each trial, and findings were compared with the original primary outcomes (median percent change in seizure frequency and 50% responder rate). Outcomes were assessed for all partial-onset seizures, secondarily generalized (SG) tonic-clonic seizures only, and complex partial plus SG (CP + SG) seizures. RESULTS: Perampanel 4-12 mg significantly prolonged median time to prerandomization monthly seizure count, generally by more than 1 week, compared with placebo, across all 3 studies, consistent with the original primary outcomes. Analysis of SG seizures only, and CP + SG seizures, also indicated a significantly prolonged median time to prerandomization monthly seizure count with perampanel 8 mg and 12 mg compared with placebo. CONCLUSIONS: Time to prerandomization monthly seizure count is a promising novel alternative to the standard endpoints of median percent change in seizure frequency and 50% responder rates used in trials of add-on AEDs. Use of this endpoint could reduce exposure to placebo or ineffective treatments, thereby facilitating trial recruitment and improving safety.

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.

On June 5 and 6, 2014, the Epilepsy Foundation held its 4th Biennial Epilepsy Pipeline Update Conference, an initiative of the Epilepsy Therapy Project, which showcased the most promising epilepsy innovations from health-care companies and academic laboratories dedicated to pioneering and advancing drugs, biologics, technologies, devices, and diagnostics for epilepsy. Speakers and attendees included emerging biotech and medical technology companies, major pharmaceutical and device companies, as well as investigators and innovators at the cutting-edge of epilepsy. The program included panel discussions on collaboration between small and large companies, how to get products in need of funding to the marketplace, who is currently funding epilepsy and CNS innovation, and how the NIH facilitates early-stage drug development. Finally, the conference featured the third annual "Shark Tank" competition. The presentations are summarized in this paper, which is followed by a compilation of the meeting poster abstracts.

The current study examined psychosocial correlates of medication adherence in a socioeconomically and racially diverse sample of patients with epilepsy. Fifty-five patients with epilepsy completed standardized self-report questionnaires measuring depression, stress, social support, and medication and illness beliefs. Antiepileptic drug (AED) adherence was measured using the 8-item Morisky Medication Adherence Scale 36% reported poor adherence. We tested which psychosocial factors were independently and most strongly associated with AED adherence. Stress and depression were negatively correlated with adherence, while perceived social support was positively correlated with adherence (Ps<.05). When all three of these variables and relevant covariates in a multiple regression model were included, only perceived social support remained a significant predictor of adherence (P=.015). This study is one of the first to suggest the importance of targeting social support in screening and intervention approaches in order to improve AED adherence among low-income, racially/ethnically diverse patients with epilepsy.

OBJECTIVE: To provide evidence-based recommendations for treatment of adults with an unprovoked first seizure. METHODS: We defined relevant questions and systematically reviewed published studies according to the American Academy of Neurology's classification of evidence criteria; we based recommendations on evidence level. RESULTS AND RECOMMENDATIONS: Adults with an unprovoked first seizure should be informed that their seizure recurrence risk is greatest early within the first 2 years (21%-45%) (Level A), and clinical variables associated with increased risk may include a prior brain insult (Level A), an EEG with epileptiform abnormalities (Level A), a significant brain-imaging abnormality (Level B), and a nocturnal seizure (Level B). Immediate antiepileptic drug (AED) therapy, as compared with delay of treatment pending a second seizure, is likely to reduce recurrence risk within the first 2 years (Level B) but may not improve quality of life (Level C). Over a longer term (>3 years), immediate AED treatment is unlikely to improve prognosis as measured by sustained seizure remission (Level B). Patients should be advised that risk of AED adverse events (AEs) may range from 7% to 31% (Level B) and that these AEs are likely predominantly mild and reversible. Clinicians' recommendations whether to initiate immediate AED treatment after a first seizure should be based on individualized assessments that weigh the risk of recurrence against the AEs of AED therapy, consider educated patient preferences, and advise that immediate treatment will not improve the long-term prognosis for seizure remission but will reduce seizure risk over the subsequent 2 years.

OBJECTIVE: To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy. METHODS: This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries. RESULTS: The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (>/=50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001). CONCLUSION: Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population. CLASSIFICATION OF EVIDENCE: This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.