Faculty Bibliography

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.

The North American SUDEP Registry (NASR) is a repository of clinical data and biospecimens in cases of sudden unexpected death in epilepsy (SUDEP), a leading cause of epilepsy-related deaths. We assessed whether bereaved families were aware of SUDEP before their family member's death and their preferences for SUDEP disclosure. At enrollment, next-of-kin of SUDEP cases completed an intake interview, including questions assessing premorbid SUDEP discussions. Only 18.1% of the 138 next-of-kin recalled a previous discussion of SUDEP with a healthcare provider or support resource. Of the 112 who did not recall such a discussion, 72.3% wished it was discussed, 10.7% were satisfied it was not discussed, and 17% were unsure. A history of status epilepticus predicted SUDEP discussion. Rates of SUDEP discussion were not significantly higher among SUDEPs after 2013 (the approximate study midpoint) compared with those before then. Our study suggests that SUDEP remains infrequently discussed with family members of persons with epilepsy. Nearly three-quarters of family members wished they had known of SUDEP before the death. However, some were indifferent or were satisfied that this discussion had not occurred. We must balance more systematic education of patients and families about SUDEP while respecting individual preferences about having this discussion.

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

Importance: Children with benign epilepsy with centrotemporal spikes (BECTS) have traditionally been considered to have a uniformly good prognosis. However, benign may be a misnomer because BECTS is linked to cognitive deficits, a more severe phenotype with intractable seizures, and the potential for sudden unexpected death in epilepsy (SUDEP). Objective: To determine if cases of BECTS are present in the North American SUDEP Registry (NASR). Design, Setting, and Participants: The NASR is a clinical and biospecimen repository established in 2011 to promote SUDEP research. The NASR database, which includes medical records, results of electroencephalographic tests, and interviews with family members of patients with epilepsy who died suddenly without other identifiable causes of death, was queried from June 3, 2011, to June 3, 2016, for cases of BECTS. The patients with epilepsy had died suddenly without other identifiable causes of death (eg, drowning, trauma, exposure to toxic substances, or suicide); SUDEP classification was determined by the consensus of 2 epileptologists. Main Outcomes and Measures: Cases of SUDEP among children who received a diagnosis of BECTS among patients reported in the NASR. Results: Three boys (median age at death, 12 years; range, 9-13 years) who received a diagnosis of BECTS by their pediatric epileptologist or neurologists were identified among 189 cases reported in the NASR. The median age of epilepsy onset was 5 years (range, 3-11 years), and the median duration of epilepsy was 4 years (range, 1-10 years). Two deaths were definite SUDEP, and 1 was probable SUDEP. Independent review of clinical and electroencephalographic data supported the diagnosis of BECTS in all 3 patients. None of the patients was prescribed antiseizure drugs, either owing to physician recommendation or mutual decision by the physician and parents. All 3 patients were found dead in circumstances typical of SUDEP. The 3 patients spanned the spectrum of BECTS severity: 1 had only a few seizures, 1 had more than 30 focal motor seizures, and 1 had 4 witnessed generalized tonic-clonic seizures and approximately 30 suspected generalized tonic-clonic seizures. Conclusions and Relevance: Sudden unexpected death in epilepsy is a very rare outcome in BECTS that clinicians should consider discussing in appropriate circumstances and possibly factoring into treatment decisions.

Computational models of Transcranial Electric Stimulation (TES) have been used extensively to predict the precise intensity and distribution of electric fields across the brain. The goal of such modeling is to guide the targeting of particular brain areas for clinical trials and research studies. While computational models have increased in sophistication and detail, to date there has been limited empirical evaluation of their precision. Previous efforts have been limited to comparing model predictions with voltage recordings on the scalp surface. To address the uncertainty of model accuracy inside the head, we recorded intra-cranial electric fields generated by TES in patients undergoing invasive monitoring for epilepsy surgery. Highresolution finite element models were constructed from patient's MRIs at 1 mm³ resolution, and voltage distribution inside the head were simulated for 1 mA currents. Preliminary analysis shows a general correspondence of model predictions and trans-cranial recordings (in over 150 cortical and subcortical electrodes for each of two patients). To determine specific conductivity values in-vivo for different tissues we are in the process of recording from depth electrodes also in rhesus macaque monkey leveraging ongoing neurophysiology experiments with TES. We have already segmented the macaque head anatomy for one subject at 1mm³ resolution and completed current flow modeling. These combined human and nonhuman primate recordings should provide strong constraints for future modeling efforts and will establish a firm empirical foundation for future clinical studies with TES that aim to target specific cortical and sub-cortical brain regions

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.

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.

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.

There has been a dramatic surge in the interest of utilizing cannabis for epilepsy treatment in the US. Yet, access to cannabis for research and therapy is mired in conflicting regulatory policies and shifting public opinion. Understanding the current state of affairs in the medical cannabis debate requires an examination of the history of medical cannabis use. From ancient Chinese pharmacopeias to the current Phase III trials of pharmaceutical grade cannabidiol, this review covers the time span of cannabis use for epilepsy therapy so as to better assess the issues surrounding the modern medical opinion of cannabis use. This article is part of a Special Issue titled Cannabinoids and Epilepsy.

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.