Faculty Bibliography

Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and interrelationships of the common epilepsy syndromes.

Objective: Assess the effect of adjunctive CBD for treatment of drug-resistant seizures in Dravet syndrome. Methods: This double-blind, placebo-controlled trial randomized 120 children aged 2-18 years with Dravet syndrome and drug-resistant seizures to receive CBD oral solution 20 mg/kg/ day (n=61) or placebo (n=59) for 14 weeks (2 week titration; 12 week maintenance). The primary endpoint was the percentage change from baseline in convulsive seizures (tonic-clonic, tonic, clonic, and atonic) frequency over the 14-week treatment period. Results: The groups were well-balanced at baseline for demographics. Mean age was 10 years, with 29% of patients <6 years. Patients had previously tried a median 4 AEDs, and were currently taking a median 3 AEDs. Convulsive seizure frequency per month decreased from a median of 12.4 to 5.9 (median reduction of 39%) with CBD versus 14.9 to 14.1 (median reduction of 13%) with placebo (difference between groups of 23%; p=0.012). The proportion of patients with e50% reduction in convulsive seizure frequency was 42.6% with CBD versus 27.1% with placebo (OR=2.0; p=0.078). Adverse events (AEs) occurred in 93.4% of CBD and 74.6% of placebo patients, and were mostly mild or moderate; the most common were somnolence, diarrhea, and decreased appetite. Serious AEs were reported in 16.4% of CBD and 5.1% of placebo patients, and were considered treatment-related in 8.2% of CBD patients, all of whom discontinued CBD. Some elevations in transaminases were noted without elevations of bilirubin; all were on concomitant valproate and all resolved. There were no deaths in the study. Conclusions: In this study, CBD resulted in a significantly greater reduction in convulsive seizure frequency than placebo; adverse events were more frequent with CBD, but it was generally well tolerated

OBJECTIVE: To determine the definite and potential frequency of seizures and epilepsy as a cause of death (COD) and how often this goes unrecognized. METHODS: Prospective determination of seizures or epilepsy and final COD for individuals aged 18-90 years with out-of-hospital sudden cardiac deaths (SCDs) from the population-based San Francisco POST SCD Study. We compared prospective seizure or epilepsy diagnosis and final COD as adjudicated by a multidisciplinary committee (pathologists, electrophysiologists, and a vascular neurologist) vs retrospective adjudication by 2 epileptologists with expertise in seizure-related mortality. RESULTS: Of 541 SCDs identified during the 37-month study period (mean age 62.8 years, 69% men), 525 (97%) were autopsied; 39/525 (7.4%) had seizures or epilepsy (mean age: 58 years, range: 27-92; 67% men), comprising 17% of 231 nonarrhythmic sudden deaths. The multidisciplinary team identified 15 cases of epilepsy, 6 sudden unexpected deaths in epilepsy (SUDEPs), and no deaths related to acute symptomatic seizures. The epileptologists identified 25 cases of epilepsy and 8 definite SUDEPs, 10 possible SUDEPs, and 5 potential cases of acute symptomatic seizures as a COD. CONCLUSIONS: Among the 25 patients identified with epilepsy by the epileptologists, they found definite or possible SUDEP in 72% (18/25) vs 24% (6/25) by the multidisciplinary group (6/15 cases they identified with epilepsy). The epileptologists identified acute symptomatic seizures as a potential COD in 5/14 patients with alcohol-related seizures. Epilepsy is underdiagnosed among decedents. Among patients with seizures and epilepsy who die suddenly, seizures and SUDEP often go unrecognized as a potential or definite COD.

Transcranial electric stimulation aims to stimulate the brain by applying weak electrical currents at the scalp. However, the magnitude and spatial distribution of electric fields in the human brain are unknown. Here we measure electric potentials intracranially in ten epilepsy patients and estimate electric fields across the entire brain by leveraging calibrated current- flow models. Electric field magnitudes at the cortical surface reach values of 0.4 V/m, which is at the lower limit of effectiveness in animal studies. When individual anatomy is taken into account, the predicted electric field magnitudes correlate with the recorded values (r=0.89 and r=0.84 in cortical and depth electrodes, respectively). Modeling white matter anisotropy and different skull compartments does not improve accuracy, but correct magnitude estimates require an adjustment of conductivity values used in the literature. This is the first study to validate and calibrate current-flow models with in vivo intracranial recordings in humans, providing a solid foundation for targeting of stimulation and interpretation of clinical trials

OBJECTIVE: Sudden unexplained death in epilepsy is the leading cause of death in young adult epilepsy patients, typically occurring during the early postictal period, presumably resulting from brainstem and cardiorespiratory dysfunction. We hypothesized that ictal discharges in the brainstem disrupt the cardiorespiratory network, causing mortality. To study this hypothesis, we chose an animal model comprising focal unilateral hippocampal injection of 4-aminopyridine (4-AP), which produced focal recurrent hippocampal seizures with secondary generalization in awake, behaving rats. METHODS: We studied ictal and interictal intracranial electrographic activity (iEEG) in 23 rats implanted with a custom electrode array into the hippocampus, the contralateral cortex, and brainstem. The hippocampal electrodes contained a cannula to administer the potassium channel blocker and convulsant (4-AP). iEEG was recorded continuously before, during, and after seizures induced by 4-AP infusion into the hippocampus. RESULTS: The control group (n = 5) was monitored for 2-3 months, and the weekly baseline iEEG recordings showed long-term stability. The low-dose group (1 muL 4-AP, 40 mm, n = 5) exhibited local electrographic seizures without spread to the contralateral cerebral cortex or brainstem. The high-dose group (5 muL 4-AP, 40 mm, n = 3) had several hippocampal electrographic seizures, which spread contralaterally and triggered brainstem discharges within 40 min, and were associated with violent motor seizures followed by dyspnea and respiratory arrest, with cortical and hippocampal iEEG flattening. The group that received high-dose 4-AP without brainstem implantation (n = 5) had similar seizure-related respiratory difficulties. Finally, five rats that received high-dose 4-AP without EEG recording also developed violent motor seizures with postictal respiratory arrest. Following visualized respiratory arrest in groups III, IV, and V, manual respiratory resuscitation was successful in five of 13 animals. SIGNIFICANCE: These studies show that hippocampal seizure activity can spread or trigger brainstem epileptiform discharges that may cause mortality, possibly mediated by respiratory network dysfunction.

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient-parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population

In this exciting era, we are coming closer and closer to bringing an anti-inflammatory therapy to the clinic for the purpose of seizure prevention, modification, and/or suppression. At present, it is unclear what this approach might entail, and what form it will take. Irrespective of the therapy that ultimately reaches the clinic, there will be some commonalities with regard to clinical trials. A number of animal models have now been used to identify inflammation as a major underlying mechanism of both chronic seizures and the epileptogenic process. These models have demonstrated that specific anti-inflammatory treatments can be effective at both suppressing chronic seizures and interfering with the process of epileptogenesis. Some of these have already been evaluated in early phase clinical trials. It can be expected that there will soon be more clinical trials of both "conventional, broad spectrum" anti-inflammatory agents and novel new approaches to utilizing specific anti-inflammatory therapies with drugs or other therapeutic interventions. A summary of some of those approaches appears below, as well as a discussion of the issues facing clinical trials in this new domain.

Objective: In this study, we tested the hypothesis that chances of subjective prediction of seizure freedom by experienced epileptologists at a Level IV epilepsy center are comparable to results actually achieved post-surgery. Background: In the era of evidence based medicine, the use of grading and scoring tools in guiding and prognosticating patient care has become a cornerstone of medical practice. However, care in the epilepsy world still remains more physician experience based, where outcome measures that predict the likelihood of post-surgical outcomes still remain underutilized. Design/Methods: We evaluated a cohort of 49 patients with treatment resistant epilepsy who were presented in multidisciplinary surgical conference (MDC) at our institution. At least two epileptologists with over 10 years of experience estimated chances of post-surgical seizure remission at the MDC. 33 of 49 patients (67%) discussed underwent intracranial EEG monitoring and resective epilepsy surgery. Seizure freedom was assessed at 1-year and 2-years post-surgery. Methods: To this end, we evaluated a cohort of 49 refractory epilepsy patients discussed at the multidisciplinary epilepsy conference (MDC) at our institution. Clinical history, imaging, EEG and neuro-psychology data was reviewed at the conference. At least two fellowship trained experts with more than 10 years of experience estimated chances of seizure remission post-surgery at the time of MDC. 33 of 49 patients (67%) discussed underwent surgery. Seizure freedom was assessed at 6-months, 1-year and 2-years post-surgery. Results: 23 of 33 patients who underwent surgery had Engel I outcomes at 2-year clinical follow-ups. Only 7 of 23 patients (30%) that achieved an Engel I outcome were estimated by expert physicians to have a 50% or more chance of seizure freedom post-surgery. Conclusions: Our results demonstrate that even experienced specialists in the field are conservative at predicting post-surgical seizure outcomes and highlight the need for development and utilization of better objective tools in the field