Faculty Bibliography

Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

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!

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!

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.

A study of epilepsy patients with a reproducible range of photoparoxysmal responses (PPR) (epileptiform discharges evoked by flashing lights) has been used as a "proof-of-concept" trial to determine if novel potential antiepileptic drugs (AEDs) should proceed in development. The standard design for this trial requires a 3-day inpatient stay and is single-blind. We evaluated two marketed and effective AEDs-one narrow-spectrum [carbamazepine (CBZ)], and one broad-spectrum [levetiracetam (LEV)]-using a novel double-blinded, cross-over outpatient version of the trial to detect acute drug effects of the two marketed AEDs on photosensitivity. We tested 6 patients with a known stable photosensitivity response, using single oral doses of CBZ 400 mg and LEV 1000 mg, compared to 2 test days with single placebo doses. Patients who received LEV had the lowest mean PPR (compared with placebo and CBZ). The mixed effect model showed a significant effect of LEV in all eye closure conditions (p < 0.001). There was no evidence of a significant change in PPR after CBZ or placebo treatment. In conclusion, LEV 1000 mg, but not CBZ 400 mg, was effective in suppressing photosensitivity within a 6-h period compared with placebo showing the ability of our novel photosensitivity trial design to demonstrate effects of broad-spectrum AEDs. We cannot confirm the ability of the photosensitivity trial to detect the narrow-spectrum AED CBZ in our design. The novel outpatient study design is feasible and is expected to reduce costs compared with previous methodology.

Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in human MRI studies. While probabilistic maps for estimating septal volume on MRI are now available, they have not been independently validated against manual tracing of MRI, typically considered the gold standard for delineating brain structures. We developed a protocol for manual tracing of the human septal region on MRI based on examination of neuroanatomical specimens. We applied this tracing protocol to T1 MRI scans (n=86) from subjects with temporal epilepsy and healthy controls to measure septal volume. To assess the inter-rater reliability of the protocol, a second tracer used the same protocol on 20 scans that were randomly selected from the 72 healthy controls. In addition to measuring septal volume, maximum septal thickness between the ventricles was measured and recorded. The same scans (n=86) were also analysed using septal probabilistic maps and Dartel toolbox in SPM. Results show that our manual tracing algorithm is reliable, and that septal volume measurements obtained via manual and automated methods correlate significantly with each other (p<.001). Both manual and automated methods detected significantly enlarged septal nuclei in patients with temporal lobe epilepsy in accord with a proposed compensatory neuroplastic process related to the strong connections between septal nuclei and hippocampi. Septal thickness, which was simple to measure with excellent inter-rater reliability, correlated well with both manual and automated septal volume, suggesting it could serve as an easy-to-measure surrogate for septal volume in future studies. Our results call attention to the important though understudied human septal region, confirm its enlargement in temporal lobe epilepsy, and provide a reliable new manual delineation protocol that will facilitate continued study of this critical region.

OBJECTIVE: To better understand the relationship between efficacy and perampanel dose, integrated actual (last) dose data from three phase III trials and an extension study (blinded Conversion Period; open-label Maintenance Period) were analyzed. METHODS: Seizure frequency data were analyzed in patients who were randomized to and completed the 13-week Maintenance Period of the phase III studies on perampanel 8 mg, and who received an actual (last) dose of 12 mg during (1) the extension 16-week blinded Conversion Period or (2) weeks 1-13 of the extension Maintenance Period. Due to a treatment-by-region interaction (p = 0.042), analyses excluded patients from the Latin America region (n = 162/1,480; 10.9% of the treated cohort). RESULTS: Of 372 patients randomized to 8 mg in the phase III studies, 273 completed the Maintenance Period at 8 mg and 267 entered the extension study. In patients who then had an actual (last) dose of 12 mg during the extension blinded Conversion Period (n = 217), median percent change in seizure frequency per 28 days improved from -32.4% (8 mg, phase III Maintenance Period) to -44.2% (12 mg, extension blinded Conversion Period); 50% responder rates increased slightly from 37.3% to 42.9%. In patients who completed the phase III studies on 8 mg and had an actual (last) dose of 12 mg during weeks 1-13 of the extension Maintenance Period (n = 181), median percent change in seizure frequency per 28 days improved from -34.1% (phase III Maintenance Period) to -46.0% (weeks 1-13 extension Maintenance Period); 50% responder rates were 39.2% and 46.4%. Seizure control remained substantially unchanged in patients who completed the phase III studies at 12 mg and continued on that dose during the extension. SIGNIFICANCE: Increasing perampanel dose from 8 to 12 mg can produce additional benefits in seizure control in at least some patients who tolerate the higher dose.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of once-daily 1200 mg and 2400 mg SPN-804 (Oxtellar XR, Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization. METHODS: The Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double-blind, parallel-group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week double-blind treatment period in the intent-to-treat (ITT) population with analyzable seizure data. Other efficacy analyses included proportion of patients with >/= 50% seizure reduction, proportion of patients seizure free, and the relationship between clinical response and plasma concentration. RESULTS: Median percent reduction was -28.7% for placebo, -38.2% (P = 0.08 vs placebo) for once-daily SPN-804 1200 mg, and -42.9% (P = 0.003) for SPN-804 2400 mg. Responder rates were 28.1%, 36.1% (P = 0.08), and 40.7% (P = 0.02); 16-week seizure-free rates in a pragmatic ITT analysis were 3.3%, 4.9% (P = 0.59), and 11.4% (P = 0.008), respectively. When data were analyzed separately for study site clusters, a post hoc analysis demonstrated that both SPN-804 dosages were significantly superior to placebo in median percent seizure reduction (placebo: -13.3%; 1200 mg: -34.5%, P = 0.02; 2400 mg: -52.7%, P = 0.006) in the North American study site cluster. A concentration-response analysis also supported a clinically meaningful effect for 1200 mg. Adverse event types reflected the drug's established profile. Adverse event frequency was consistent with a pharmacokinetic profile in which SPN-804 produces lower peak plasma concentrations vs immediate-release OXC. Once-daily dosing was not associated with any new safety signals. CONCLUSIONS: Adjunctive once-daily SPN-804 improved seizure control in patients with inadequately controlled partial-onset seizures. Adverse event occurrence and discontinuations due to adverse events suggest improved tolerability vs previously published data with immediate-release OXC.

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.