Faculty Bibliography

Rationale: SUDEP is the most common epilepsy-related cause of death in persons with epilepsy. Evidence supports that increased SUDEP awareness and education can be translated into significantly reduced rates of epilepsy-related deaths. However, there is a lack of consensus regarding how health care practitioners should address SUDEP with patients, and a lack of evidence regarding patient educational interventions. The purpose of this study was to describe various health care providers' practices regarding discussion of SUDEP with their patients. Methods: Separate focus groups were conducted, each involving epileptologists (n=19), neurologists (n=16), or advanced practice nurses (n=8). The focus group moderator asked participants questions pertaining to reasons for and for not discussing SUDEP, and how they discuss SUDEP. Focus group data were analyzed via content analysis per each practitioner group, and comparisons were then made across groups. Data were organized via themes in order to answer the research questions. Results: Table 1 depicts final themes and definitions. Across all disciplines, reasons for discussing SUDEP included Practical Accountability, Moral Accountability, Proactivity, and Reactivity. For nurses only, an additional reason was Patient Advocacy. In terms of when not to discuss SUDEP, for all disciplines involved, and especially the physicians, the theme Not at First emerged. Additional themes that emerged for this question included, in the case of neurologists and epileptologists, Moral Accountability and Out of Options. Ways in which SUDEP is discussed included, in all groups, Discussion and Written Materials. In addition, prevalent in all groups was the finding that procedures for discussing SUDEP with patients and families need to be somewhat standardized, though the discussion should always be tailored to fit the patient's context. As well, more informative written materials should be developed. Conclusions: These results provide an initial view of the way in which var!

Little is known about the ethnic and racial differences in the prevalence of generalized and focal epilepsy among patients with non-acquired epilepsies. In this study, we examined epilepsy classification and race/ethnicity in 813 probands from sibling or parent-child pairs with epilepsy enrolled in the Epilepsy Genome/Phenome Project (EPGP). Subjects were classified as generalized epilepsy (GE), non-acquired focal epilepsy (NAFE), mixed epilepsy syndrome (both generalized and focal), and unclassifiable, based on consensus review of semiology and available clinical, electrophysiology, and neuroimaging data. In this cohort, 628 (77.2%) subjects identified exclusively as Caucasian/white and 65 (8.0%) subjects reported African ancestry, including subjects of mixed-race. Of the Caucasian/white subjects, 357 (56.8%) had GE, 207 (33.0%) had NAFE, 32 (5.1%) had a mixed syndrome, and 32 (5.1%) were unclassifiable. Among subjects of African ancestry, 28 (43.1%) had GE, 27 (41.5%) had NAFE, 2 (3.1%) had a mixed syndrome, and 8 (12.3%) were unclassifiable. There was a higher proportion of subjects with GE compared to other syndromes among Caucasians/whites compared to subjects with African ancestry (OR 1.74, 95% CI: 1.04-2.92, two-tailed Fisher's exact test, p=0.036). There was no difference in the rate of GE among subjects reporting Hispanic ethnicity (7.6% of total) when adjusted for race (Caucasian/white vs non-Caucasian/white; OR 0.65, 95% CI: 0.40-1.06, p>0.05). The proportion of participants with unclassifiable epilepsy was significantly greater in those of African-American descent. In a group of patients with epilepsy of unknown etiology and an affected first degree relative, GE is more common among Caucasian/white subjects than among those with African ancestry. These findings suggest there may be geographical differences in the distribution of epilepsy susceptibility genes and an effect of genetic background on epilepsy phenotype. However, the results should be interpreted with caution because of the low numbers of African-Americans in this cohort and more limited diagnostic data available for epilepsy classification in these subjects compared to Caucasians/whites.

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.

BACKGROUND: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. RESULTS: EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. CONCLUSIONS: EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

Vigabatrin (VGB) has been shown to be particularly effective in the treatment of infantile spasms for those with tuberous sclerosis complex (TSC). However, many patients with TSC continue to have treatment-resistant seizures. For many patients with TSC, partial-onset seizures are prominent. Therefore, we examined the efficacy and tolerability of VGB for treatment of refractory partial-onset seizures. We performed a retrospective cohort study on 49 TSC patients with treatment-resistant seen at our center from 1997 to 2010, examined seizure outcomes, and reported adverse effects. We found that 13 (24.5%) patients became seizure-free or experienced a >90% decrease in seizure episode frequency with the addition of VGB to their regimens. Only one patient stopped VGB use because of excess sedation. The remaining 21 patients discontinued VGB use because of lack of efficacy. We conclude that VGB may be a safe and effective treatment in TSC patients with refractory partial-onset seizures.

A 20-year-old man with intellectual disability and intractable multifocal epilepsy presented to a neurologist for further evaluation and management. His seizures began at 4 months, the night after his first DPT vaccine, and he continued to have frequent tonic-clonic seizures throughout his life. Several weeks after his visit, he was found facedown on the floor, dead, by his family. His autopsy was unremarkable, but genetic testing revealed a frame shift mutation in SCN1A, consistent with severe myoclonic epilepsy of infancy (Dravet syndrome).

Rationale: The Generalized Tonic-Clonic Convulsion (GTCC) is often associated with post-ictal electrographic slowing, and at times suppression. The mechanism of post-ictal EEG suppression is not known but may reflect involvement of bilateral subcortical networks. We examined the electrographic activity occurring after seizures with bilateral movement to determine if there are post-ictal features unique to the GTCC. Methods: We reviewed the video EEG of 100 consecutive inpatients of the NYU Comprehensive Epilepsy Center that had bilateral movement as part of their seizure semiology. Each seizure was reviewed by 2 reviewers; any records in which the patient was obscured on the video were excluded from further analysis. Any seizure with bilateral symmetric tonic, vibratory and clonic phases (defined as bilateral movement > and < 5 Hz respectively) in that order was categorized as "typical GTCC" (tGTCC). If one phase was absent, asymmetric or the progression was different, it was considered an "atypical GTCC" (aGTCC). If two phases were absent it was not a GTCC (nGTCC). All aGTCC were reviewed by at least 3 reviewers. The post-ictal EEG was categorized as: "suppression", defined as background voltage <10uV; "slowing" defined as decreased amplitude and/or frequency compared to baseline while still >10uV; or "no change from baseline." Results: 104 seizures from 100 patients were reviewed, 5 patients were excluded due to obscured video or EEG, leaving 97 seizures reviewed. 41 were tGTCC, 14 were aGTCC and 42 were nGT

Rationale: The Generalized Tonic-Clonic Convulsion (GTCC) has been described as a stereotyped seizure consisting of a symmetric tonic posture, followed by vibratory and clonic phases - defined as movements at a frequency of >5 Hz and <5 Hz respectively. We examined how frequently the classic GTCC occurs in a population and what factors, if any, contributed to deviations from this pattern. Methods: We reviewed the video EEG of 100 consecutive inpatients of the NYU Comprehensive Epilepsy Center that had bilateral limb movements as part of their seizure semiology. Each seizure was reviewed by 2 reviewers; any records in which the patient was obscured on the video were excluded from further analysis. Any seizure with bilateral symmetric tonic, vibratory and clonic phases in that order was categorized as "typical GTCC" (tGTCC), if one phase was absent, asymmetric or in the wrong order of progression it was considered "atypical GTCC" (aGTCC), if two phases were absent it was not a GTCC (nGTCC). All aGTCC were reviewed by at least 3 reviewers. Results: 104 seizures (41 from women) from 100 patients were reviewed, 2 patients were excluded due to obscured video. 45 had a tGTCC while 15 were aGTCC, and 42 were nGT