Faculty Bibliography

OBJECTIVE: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium (K+ ) channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. METHODS: We analysed clinical, electroclinical and neuroimaging data for twenty patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch clamp to explore biophysical properties of wild-type and mutant KV 3.1 channels. RESULTS: Symptoms began between 3-15 years (median 9.5) with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early but quickly became overshadowed by myoclonus; ten patients were wheelchair-bound by late teenage. Mild cognitive decline occurred in half. Early death was not observed. EEG showed generalized spike and polyspike wave discharges with documented photosensitivity in most. Polygraphic EEG-EMG studies demonstrated a cortical origin for myoclonus and striking co-activation of agonist and antagonist muscles. MRI revealed symmetrical cerebellar atrophy, that appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in six patients. To explore this, we performed high temperature in vitro recordings. At elevated temperatures there was a robust left-shift in activation of wild-type KV 3.1 increasing channel availability. INTERPRETATION: MEAK has a relatively homogeneous presentation resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent left-shift in activation of wild-type KV 3.1 subunit containing channels that would counter the loss-of-function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics

RATIONALE: Epilepsy is a chronic neurological condition that causes substantial burden on patients and families. Quality of life may be reduced due to the stress of coping with epilepsy. For nearly a decade, the Centers for Disease Control (CDC) Prevention Research Center's Managing Epilepsy Well (MEW) Network has been conducting research on epilepsy self-management to address research and practice gaps. Studies have been conducted by independent centers across the U.S. Recently, the MEW Network sites, collaboratively, began compiling an integrated database to facilitate aggregate secondary analysis of completed and ongoing studies. In this preliminary analysis, correlates of quality of life in people with epilepsy (PWE) were analyzed from pooled baseline data from the MEW Network. METHODS: For this analysis, data originated from 6 epilepsy studies conducted across 4 research sites and comprised 459 PWE. Descriptive comparisons assessed common data elements that included gender, age, ethnicity, race, education, employment, income, seizure frequency, quality of life, and depression. Standardized rating scales were used for quality of life (QOLIE-10) and for depression (Patient Health Questionnaire, PHQ-9). RESULTS: While not all datasets included all common data elements, baseline descriptive analysis found a mean age of 42 (SD 13.22), 289 women (63.0%), 59 African Americans (13.7%), and 58 Hispanics (18.5%). Most, 422 (92.8%), completed at least high school, while 169 (61.7%) were unmarried, divorced/separated, or widowed. Median 30-day seizure frequency was 0.71 (range 0-308). Depression at baseline was common, with a mean PHQ-9 score of 8.32 (SD 6.04); 69 (29.0%) had depression in the mild range (PHQ-9 score 5-9) and 92 (38.7%) had depression in the moderate to severe range (PHQ-9 score >9). Lower baseline quality of life was associated with greater depressive severity (p<.001), more frequent seizures (p<.04) and lower income (p<.05). CONCLUSIONS: The MEW Network Integrated Database offers a unique opportunity for secondary analysis of data from multiple community-based epilepsy research studies. While findings must be tempered by potential sample bias, i.e. a relative under-representation of men and relatively small sample of some racial/ethnic subgroups, results of analyses derived from this first integrated epilepsy self-management database have potential to be useful to the field. Associations between depression severity and lower QOL in PWE are consistent with previous studies derived from clinical samples. Self-management efforts that focus on mental health comorbidity and seizure control may be one way to address modifiable factors that affect quality of life in PWE.

PURPOSE: We examined the incidence of seizures following ischemic stroke in a community-based sample. METHODS: All subjects with incident ischemic strokes in the Framingham Original and Offspring cohorts between 1982 and 2003 were identified and followed for up to 20 years to determine incidence of seizures. Seizure-type was based on the 2010 International League Against Epilepsy (ILAE) classification. Disability was stratified into mild/none, moderate and severe, based on post-stroke neurological deficit documentation according to the Framingham Heart Study (FHS) protocol and functional status was determined using the Barthel Index. RESULTS: An initial ischemic stroke occurred in 469 subjects in the cohort and seizures occurred in 25 (5.3%) of these subjects. Seizure incidence was similar in both large artery atherosclerosis (LAA) (6.8%) and cardio-embolic (CE) (6.2%) strokes. No seizures occurred following lacunar strokes. The predominant seizure type was focal seizure with or without evolution to bilateral convulsive seizure. One third of participants had seizures within the first 24h from stroke onset and half of all seizures occurred within the first 30days. On multivariate analysis, moderate and severe disability following stroke was associated with increased risk of incident seizure. CONCLUSIONS: Seizures occurred in approximately 5% of subjects after an ischemic stroke. One third of these seizures occurred in the first 24h after stroke and none followed lacunar strokes. Focal seizures with or without evolution in bilateral convulsive seizures were the most common seizure type. Moderate and severe disability was predictive of incident seizures.

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

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. We measured electric potentials intracranially in ten epilepsy patients and estimate electric fields across the entire brain by leveraging calibrated current-flow models. When stimulating at 2 mA, cortical electric fields reach 0.4 V/m, the lower limit of effectiveness in animal studies. When individual whole-head anatomy is considered, the predicted electric field magnitudes correlate with the recorded values in cortical (r=0.89) and depth (r=0.84) electrodes. Accurate models require adjustment of tissue conductivity values reported in the literature, but accuracy is not improved when incorporating white matter anisotropy or different skull compartments. This is the first study to validate and calibrate current-flow models with in vivo intracranial recordings in humans, providing a solid foundation to target stimulation and interpret clinical trials.

Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2.3, 95% CI 1.7-3.2, p=9.1 x 10(-8); familial non acquired focal epilepsy 3.6, 2.7-4.9, p=1.1 x 10(17)). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5.8 x 10(-8)) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection I between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future.

Verbal working memory (vWM) involves storing and manipulating information in phonological sensory input. An influential theory of vWM proposes that manipulation is carried out by a central executive while storage is performed by two interacting systems: a phonological input buffer that captures sound-based information and an articulatory rehearsal system that controls speech motor output. Whether, when and how neural activity in the brain encodes these components remains unknown. Here we read out the contents of vWM from neural activity in human subjects as they manipulated stored speech sounds. As predicted, we identified storage systems that contained both phonological sensory and articulatory motor representations. Unexpectedly, however, we found that manipulation did not involve a single central executive but rather involved two systems with distinct contributions to successful manipulation. We propose, therefore, that multiple subsystems comprise the central executive needed to manipulate stored phonological input for articulatory motor output in vWM.