Faculty Bibliography

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

ABSTRACT: We report the case of a 50-year-old man with disabling recurrent hypersomnia with autonomic instability due to catatonia in the setting of atypical bipolar disorder. Treatment with valproic acid for bipolar disorder resulted in complete resolution of symptoms.

Objective: To compare the duration for which pediatric patients with refractory epilepsy who were started on these respective dietary treatments remained in treatment in this single-center cohort Background: The ketogenic diet (KD) is an effective treatment for refractory childhood epilepsy but its restrictiveness has limited widespread use. More recently, a modified Atkins diet (MAD) has been shown to similarly induce ketosis with fewer dietary and lifestyle restrictions. In practice, the benefits of both diets are limited by high discontinuation rates. Whether the less restrictive MAD is correlated with longer treatment adherence is unclear. Design/Methods: From 1/2010 - 6/2015, 148 children with refractory epilepsy were initiated on the classic KD (N=70) or MAD (N=78) in a non-randomized fashion as selected by their caretakers with support from the center's dietitians. Data was collected via retrospective chart review. We performed a Kaplan-Meier survival analysis comparing number of days maintained on the two diets, with further stratification by feeding mode and treatment response (as defined by >=50% reduction in seizure frequency). Results: Patients remained on the classic KD on average 638 +/-490 days, and MAD 348 +/-310 days (Mann-Whitney p<0.001). The mean age of children starting KD was 4 +/-3.9 vs. 8 +/-3.8 for MAD (Mann-Whitney p<0.001). Children assigned to MAD had a lower rate of delayed feeding skills (6.4% vs. 60.9% in KD group; Fisher's exact p <0.001). The 34 patients who were exclusively formula-fed stayed on the classic KD for 614 +/-562 days. When comparing only patients eating solid foods, adherence to KD was longer still (678 +/-411 days vs. 348 +/-310 days; logrank p<0.001. The trend remained when comparing only those with at least 50% treatment response, though sample sizes were small (logrank p=0.120). Conclusions: Further studies are needed to better understand the cause for earlier MAD discontinuation

Objective: Evaluate ability of inhaled alprazolam to rapidly suppress photosensitivity in a double blind placebo- controlled crossover proof of concept study. Background: Alprazolam formulated as an inhaled preparation (Staccato Alprazolam) could represent a rapidly effective rescue medication for epilepsy patients. Time to effect can be assessed in patients with photosensitive epilepsy, in whom epileptiform activity can be elicited at will. Design/Methods: Patients >= 18 y.o with photosensitive epilepsy at 3 sites were tested on a baseline day, and then received in randomized order either inhaled placebo (on 2 days) or .5, 1 or 2 mg inhaled alprazolam delivered using a hand-held Staccato device. Study days were separated by at least 1 week. Presence (and degree) of photosensitivity was measured predose, then at 2 min, 10 min, 30 min, 1, 2, 4 and 6 hours post-dose. Plasma concentration of study drug was measured at each time point. Sedation was assessed at each time point using the 100-mm linear visual analogue scale (VAS). Results: Five patients were enrolled and completed all treatment arms. All doses decreased the mean standardized photosensitivity range (SPR), with maximal or near-maximal effect occurring by 2 minutes post dose. Higher doses produced effects on SPR out to 4 hours. Sedation was dose related, but separated from SPR effects at later timepoints. Treatment was well tolerated with no serious adverse events. Conclusions: Results from this study suggest that inhaled alprazolam strongly suppresses epileptiform activity within 2 minutes. Duration of effect was dose related, as was sedation. This data supports the possibility that inhaled Alprazolam might have utility in stopping a seizure within 2 minutes of use

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

Objective: To assess the utility and patterns of genetic testing in clinical practice in a single epilepsy center cohort. Background: The role of genetics in the etiology of many types of epilepsy has been long established, with approximately 40% of individuals with epilepsy having a genetic etiology (Pong et al., 2011). Genetic studies are often part of epilepsy work ups to confirm, rule out, or isolate suspected genetic causes of epilepsy. Design/Methods: Over two years (2014-2015), 253 Comprehensive and/or Infantile Epilepsy panels were completed by GeneDx for patients of the Comprehensive Epilepsy Center. Medical history and demographics were collected retrospectively using in house medical charts. Fifty-four reports were included in the analysis due to medical chart completeness. Results: The median age was 13.5(3,39), and 37% were female. Eight patients had positive results of clear pathogenicity (SCN1A(2), CLN5(2), TSC2, GABRG2, POLG, PCDH19), 16 negative and 30 of unclear significance. Parental studies were recommended in 7/8; while only five were completed. Single pathogenic mutations were identified in only two parental studies. Two patients were diagnosed with Dravet Syndrome, 2 neuronal-ceroid- lipofuscinosis, 1 Tuberous-sclerosis, 1 GEFS+, 1 Alpers-syndrome, and 1 female-with-dravet-like-syndrome. Of those with results of unclear significance, 60 mutations were considered likely pathogenic, 36 variants-of- unknown-significance, and 22 likely/reportable benign. 76.6% were recommended to have parental testing done, while only 52.2% did. Conclusions: With genetic testing in 44% of patients producing results of known significance, the yield for confirmatory or exclusionary purposes in this single epilepsy center cohort was high. Discrepancies between how often parental testing is recommended versus completed, suggests possible limitations and/or biases, which need to be explored. Further examination of the characteristics of patients with results of known significance are required to understand the full utility of genetic testing, including cost effectiveness

Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 +/- 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo-controlled, double-blind trials are necessary to confirm this finding.

The use of cannabis products in the treatment of epilepsy has long been of interest to researchers and clinicians alike; however, until recently very little published data were available to support its use. This article summarizes the available scientific data of pharmacology from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including 9-tetrahydrocannabinol (9-THC), cannabidiol (CBD), 9-tetrahydrocannabivarin (9-THCV), cannabidivarin (CBDV), and 9-tetrahydrocannabinolic acid (Delta9-THCA). It has long been known that 9-THC has partial agonist activity at the endocannabinoid receptors CB1 and CB2, though it also binds to other targets which may modulate neuronal excitability and neuroinflammation. The actions of Delta9-THCV and Delta9-THCA are less well understood. In contrast to 9-THC, CBD has low affinity for CB1 and CB2 receptors and other targets have been investigated to explain its anticonvulsant properties including TRPV1, voltage gated potassium and sodium channels, and GPR55, among others. We describe the absorption, distribution, metabolism, and excretion of each of the above mentioned compounds. Cannabinoids as a whole are very lipophilic, resulting in decreased bioavailability, which presents challenges in optimal drug delivery. Finally, we discuss the limited drug-drug interaction data available on THC and CBD. As cannabinoids and cannabis-based products are studied for efficacy as anticonvulsants, more investigation is needed regarding the specific targets of action, optimal drug delivery, and potential drug-drug interactions. This article is part of a Special Issue titled Cannabinoids and Epilepsy.