Faculty Bibliography

PURPOSE: Epilepsy patients have a significantly higher rate of anxiety and depression than the general population, and psychiatric disease is particularly prevalent among drug resistant epilepsy patients. Symptoms of anxiety and depression might serve as a barrier to appropriate epilepsy care. The aim of this study was to determine if drug resistant epilepsy patients with symptoms of anxiety and/or depression receive different epilepsy management than controls. METHOD: We identified 83 patients with drug resistant focal epilepsy seen at the Penn Epilepsy Center. Upon enrollment, all patients completed 3 self-report scales and a neuropsychiatric inventory and were grouped into those with symptoms of anxiety and/or depression and controls. Each patient's medical records were retrospectively reviewed for 1-2 years, and objective measures of outpatient and inpatient epilepsy management were assessed. RESULTS: At baseline, 53% (n=43) of patients screened positive for symptoms of anxiety and/or depression. The remaining 47% (n=38) served as controls. Patients with anxiety and/or depression symptoms had more missed outpatient visits per year compared to controls (median 0.84 vs. 0.48, p=0.02). Patients with symptoms of both anxiety and depression were more likely to undergo an inpatient admission or procedure (56% vs. 24%, p=0.02). CONCLUSION: For most measures of epilepsy management, symptoms of anxiety and/or depression do not alter epilepsy care; however, drug resistant epilepsy patients with anxiety and/or depression symptoms may be more likely to miss outpatient appointments, and those with the highest burden of psychiatric symptoms may be admitted more frequently for inpatient services compared to controls.

Rationale: Seizure misclassification in randomized clinical studies of antiepileptic drugs (AEDs) can negatively impact trial outcomes. To ensure homogeneity and accuracy of seizure classification in clinical trials, The Epilepsy Study Consortium has created a seizure training program for study investigators and site coordinators to enhance the understanding of seizure types and provide independent verification of seizure classification. This prospective training has previously been used in AED clinical trials, including PREVAIL, a recently completed global, phase 3 study evaluating the efficacy and safety of USL255, once-daily extended-release topiramate, as adjunctive therapy in subjects with partial-onset seizures (NCT01142193). Methods: The PREVAIL training program included a seizure identification video providing in-depth descriptions of seizure types and advice for patient interviews. The video was moderated by a Consortium member at the investigator meetings and posted online for those unable to attend. After the video, a quiz was administered and the answers discussed in real time. PREVAIL was the first trial to implement this quiz with the requirement for retraining if a passing score (>70%) was not achieved. Additionally, each site was required to submit a Seizure Identification Form (SIF) for all subjects, which included descriptions of seizures by the subject and/or caregiver, and the investigator's classification(s) of seizure(s). The SIF was reviewed independently by the Consortium immediately after the Screening Visit and was to be approved prior to randomization. To ensure seizures were captured correctly in the case report forms (CRFs) on subsequent study visits, misclassifications were communicated to the study team to allow for subject retraining (as necessary). CRFs were checked by the sponsor/CRO to confirm that classifications matched those approved by the Consortium. Additionally, subject diaries were assessed by centralized CRO reviewers to ensure qualifying seizure type!

Rationale: WEPOD is a multicenter prospective observational study evaluating fertility among women with epilepsy (WWE) compared to healthy controls. WEPOD utilizes a customized mobile electronic patient diary on a commercially available mobile device (Apple's iPod Touch) . A customized diary application made by Irody tracks fertility information, and in WWE, seizures and daily medication use. The app delivers all patient captured information to a cloud database where it is analyzed. We determined the degree of data tracking adherence associated with dropping out of the study. Methods: WWE planning pregnancy enrolled within 6 months of stopping birth control. Subjects were trained to use a customized application (the WEPOD App) for daily data tracking. All subjects were asked to track data daily until delivery or up to 12 months if they did not become pregnant. Data were analyzed by percent of days in the study for which data was tracked. The cut point of percent tracking with the maximum sensitivity and specificity associating with dropping out of the study was determined. Further, the timing of dropping out of the study was evaluated. Results: Of 61 WWE who enrolled before 12/1/12 and tracked data, 9 subjects dropped out and 52 continued in the study. The overall adherence was 92.3%; 36/61 had 100% adherence. Mean percent adherence of the 52 completed subjects was 96.1% (median 100, range 33-100). Of the 9 subjects who dropped out, percent adherence was 6, 22, 55, 77, 86, 87, 90, 100 and 100 for a mean of 69.9 (median 86). Only 4 subjects were less than 90% tracking adherent and completed the study. The optimal percent adherence cut point for associating with dropping out of the study was 96.5% which had a sensitivity of 87% and a specificity of 83% (point A). Given that the cut point of 96.5 % adherence is higher than the overall mean adherence, and that specificity may be less important than sensitivity since other factors accounting for late drop outs are not accounted for, a more reasonabl!

Rationale: YKP3089, a tetrazole alkyl carbamate derivative, is a new investigational antiepileptic drug (AED) with a potentially unique mechanism of action. YKP3089 displayed activity in a broad array of screening models, including the LTG-resistant amygdala-kindled rat and the 6 Hz model. The exact mechanism of action is unclear, although it appears to enhance GABA-induced currents without binding to GABAA subunits. It is an inhibitor of the inactivated state of Na+ channels. In early clinical studies, YKP3089 demonstrated a PK profile suited to clinical use, including once-daily dosing. Plasma concentrations correlated with PD effect in the human photosensitivity model. This is the first Phase 2 randomized, doubleblind, placebo-controlled study of YKP3089 to assess efficacy and tolerability in patients with partial-onset seizures. Methods: Design: After an 8-wk baseline, patients were randomized to either placebo or YKP3089 titrated over 6 wks to 200 mg (50 mg increments at 2-wk intervals), followed by a 6-wk maintenance phase. Population: Adults with inadequately controlled partial-onset seizures (>3 seizures/month in baseline) despite therapy with 1-3 AEDs. Population for primary analyses was ITT. The primary endpoint was median % reduction from baseline 28-day seizure frequency. Secondary endpoints included 50% responder rate; % of study completers with no seizures in maintenance phase; and median % seizure reduction by seizure type. Results: ITT population: YKP3089, N=113; placebo, N=108. Mean ages: 36 yr (YKP3089) and 37 yr (placebo); gender: 51% female (YKP3089) and 46% female (placebo). At baseline, median 28-day seizure frequency was 7.5 (YKP3089) and 5.5 (placebo). In patients receiving YKP3089, median % seizure reduction was 55.6% vs 21.5% (P<0.0001) with placebo. The 50% responder rates were 50.4% and 22.2% (P<0.0001), for YKP3089 and placebo, respectively. Among study completers, 27.5% receiving YKP3089 and 9.1% receiving placebo had no seizures during the maintenance phase. Media!

Advances in MRI have transformed the in vivo detection of brain abnormalities in neurological disease. However, many subtle structural abnormalities remain undetected, especially in individual patients, where clinical relevance is highest. We present a quantitative, multifeature morphometry approach combined with machine learning algorithms for detecting structural cortical abnormalities in epilepsy patients with focal cortical dysplasia (FCD). FCD is a malformation of cortical development and is the most common etiology in pediatric epilepsy and the second most common etiology in adults with treatment resistant epilepsy. Lesions may occur anywhere in cortex. Seizure freedom after surgery is reported at 66% with a detected lesion, but only 29% in MRI-negative patients. Yet, 70% to 80% of histologically confirmed FCD cases go undetected by visual inspection of the MRI. Sixty-one controls and 23 MRI-negative patients in whom no focal lesion was detected during routine visual radiological analysis and 7 MRI-positive patients were scanned before surgery at 3 T using a T1-weighted MRI sequence. All patients subsequently underwent intracranial EEG monitoring and resection of the epileptic focus and pathology confirmed FCD. Morphometric routines with surface-based spherical averaging techniques were used to align anatomical structures between individual brains and to calculate 6 features at each vertex, including cortical thickness, gray-white contrast, local gyrification, sulcal depth, Jacobian distance, and curvature. A logistic regression classifier was trained on normal control data and the data from the FCD region of MRI-positive patients to classify, in MRI-negative patients, vertices into lesional and nonlesional. The logistic regression approach correctly classified lesions within the resection zone in 14 out of the 24 (58%) MRInegative patients. The overall false positive rate (by vertex) was never greater than 1.05%. Quantitative MRI can aid in the presurgical detection of FCD lesions, even !

Despite the expanding treatment options in the past two decades, a third of patients with epilepsy remain treatment resistant, and there is a continued need for new therapies. After many years of repeated success, several late-stage clinical development programs for antiseizure drugs have seen unexpected failures to demonstrate superiority of the experimental drug over placebo, which has led to a re-examination of how clinical trials are conducted in this heterogeneous and often unpredictable condition. There are numerous sources of variability in epilepsy trials that can reduce effect size. Methods to improve diagnostic accuracy and outcome assessment are needed to ensure that promising compounds have the best chance to get to patients. 2013 Future Science Ltd

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.