Faculty Bibliography

PURPOSE: To ascertain the cause of mortality and incidence of sudden unexpected death in epilepsy (SUDEP) in patients with supernumerary isodicentric chromosome 15 (idic15). METHODS: Cases were obtained from those reported to the Dup15q Alliance (www.dup15q.org) between April 2006 and June 2012; ~709 families were registered in their database. We performed a case-control study comparing reported SUDEP cases to living patients with epilepsy from the Dup15q Alliance registry who volunteered to be interviewed to examine clinical risk factors. KEY FINDINGS: There were nineteen deaths with idic15; 17 had epilepsy, and nine deaths were due to probable or definite SUDEP (4 females, median age of death was 13.5years, range: 3-26years). Possible SUDEP occurred in 2 others. The remainder died from status epilepticus (3), pneumonia (3), aspiration (1), and drowning (1). Nonambulatory status and lack of seizure control were more common among SUDEP cases than living dup15q patients. SIGNIFICANCE: Our findings suggest that SUDEP is a common cause of death among children and young adults with isodicentric chromosome 15q11.2q13 duplications and patients with the most severe neurologic dysfunction may be at highest risk. Further studies are needed to examine if this specific genetic defect plays a role in the mechanism of SUDEP in these patients.

Reports an error in "Cannabidiol in patients with treatment-resistant epilepsy: An open-label interventional trial" by Orrin Devinsky, Eric Marsh, Daniel Friedman, Elizabeth Thiele, Linda Laux, Joseph Sullivan, Ian Miller, Robert Flamini, Angus Wilfong, Francis Filloux, Matthew Wong, Nicole Tilton, Patricia Bruno, Judith Bluvstein, Julie Hedlund, Rebecca Kamens, Jane Maclean, Srishti Nangia, Nilika Shah Singhal, Carey A. Wilson, Anup Patel and Maria Roberta Cilio (The Lancet Neurology, 2016[Mar], Vol 15[3], 270-278). The appendix of this Article has been resupplied to include the correct number of patients at each study site in supplementary table 1. This correction has been made to the online version as of March 7, 2016. (The following abstract of the original article appeared in record 2016-09081-023). Background: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n = 41 [25%]), decreased appetite (n = 31 [19%]), diarrhoea (n = 31 [19%]), fatigue (n = 21 [13%]), and convulsion (n = 18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n = 9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7). Interpretation: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.

A dominant theory, based on electrophysiological and lesion evidence from nonhuman primate studies, posits that the dorsolateral prefrontal cortex (dlPFC) stores and maintains working memory (WM) representations. Yet, neuroimaging studies have consistently failed to translate these results to humans; these studies normally find that neural activity persists in the human precentral sulcus (PCS) during WM delays. Here, we attempt to resolve this discrepancy. To test the degree to which dlPFC is necessary for WM, we compared the performance of patients with dlPFC lesions and neurologically healthy controls on a memory-guided saccade task that was used in the monkey studies to measure spatial WM. We found that dlPFC damage only impairs the accuracy of memory-guided saccades if the damage impacts the PCS; lesions to dorsolateral dlPFC that spare the PCS have no effect on WM. These results identify the necessary subregion of the frontal cortex for WM and specify how this influential animal model of human cognition must be revised. SIGNIFICANCE STATEMENT: High-level cognition depends on working memory (WM) as a critical building block, and many symptoms of psychiatric disorders may be the direct result of impaired WM. Canonical theory posits a critical role for the dorsolateral prefrontal cortex (dlPFC) in WM based on studies of nonhuman primates. However, we find that spatial WM in humans is intact after dlPFC damage unless it impacts the more caudal PCS. Therefore, the human dlPFC is not necessary for spatial WM and highlights the need for careful translation of animal models of human cognition.

Our objective was to define the EEG features during sleep of children with neurodevelopmental disorders due to copy number gains of 15q11-q13 (Dup15q). We retrospectively reviewed continuous EEG recordings of 42 children with Dup15q (mean age: eight years, 32 with idic15), and data collected included background activity, interictal epileptiform discharges, sleep organization, and ictal activity. Three patterns were recognized: This is the first report of electroencephalographic patterns during sleep of children with Dup15q reporting alpha-delta rhythms, CSWS, and high amplitude fast frequencies. Alpha-delta rhythms are described in children with dysautonomia and/or mood disorders and CSWS in children with developmental regression. The significance of these findings in cognitive function and epilepsy for the children in our cohort needs to be determined with follow-up studies.

Parents of children with chromosome 15q duplication syndrome (Dup15q) have anecdotally reported high pain threshold as a feature of the disorder. The purpose of this study was to document parental-reported estimates of the frequency of high pain tolerance and the stimuli that fail to evoke a normal pain response. We sent an online survey to 840 families with children with Dup15q to explore the frequency and clinical manifestations of high pain threshold. There were 216 respondents (25.7%). A high pain threshold was reported in 87% of children at some time. There was a trend (p=0.06) for high pain threshold to be more commonly observed among children with the isodicentric (85.6%) and other genetic variants (95%) than interstitial (69.6%) duplications. There was no association between reports of high pain threshold and reports of an intellectual disability (91% of cases), autism spectrum disorder (83% of cases), or self-injurious behavior (40% of cases). Reports included many dramatic cases such as severe burns, broken bones, and electrical traumas, which were associated with little or no evidence of a painful stimulus. A high pain threshold is reported in other disorders associated with intellectual disability and autism; the underlying mechanism in Dup15q and other disorders remains undefined.

PURPOSE: A UCB-IBM collaboration explored the application of machine learning to large claims databases to construct an algorithm for antiepileptic drug (AED) choice for individual patients. METHODS: Claims data were collected between January 2006 and September 2011 for patients with epilepsy >16years of age. A subset of patient claims with a valid index date of AED treatment change (new, add, or switch) were used to train the AED prediction model by retrospectively evaluating an index date treatment for subsequent treatment change. Based on the trained model, a model-predicted AED regimen with the lowest likelihood of treatment change was assigned to each patient in the group of test claims, and outcomes were evaluated to test model validity. RESULTS: The model had 72% area under receiver operator characteristic curve, indicating good predictive power. Patients who were given the model-predicted AED regimen had significantly longer survival rates (time until a treatment change event) and lower expected health resource utilization on average than those who received another treatment. The actual prescribed AED regimen at the index date matched the model-predicted AED regimen in only 13% of cases; there were large discrepancies in the frequency of use of certain AEDs/combinations between model-predicted AED regimens and those actually prescribed. CONCLUSIONS: Chances of treatment success were improved if patients received the model-predicted treatment. Using the model's prediction system may enable personalized, evidence-based epilepsy care, accelerating the match between patients and their ideal therapy, thereby delivering significantly better health outcomes for patients and providing health-care savings by applying resources more efficiently. Our goal will be to strengthen the predictive power of the model by integrating diverse data sets and potentially moving to prospective data collection.

INTRODUCTION: Felbamate was approved in 1993 to treat partial seizures with and without secondary generalization in adults and in Lennox-Gastaut Syndrome in children. Its use was later restricted when rare but fatal cases of aplastic anemia and hepatic failure were identified. METHODS: This single center analysis retrospectively evaluated the safety and efficacy of felbamate in a cohort of children, adolescents, and adults with epilepsy. RESULTS: A chart review identified 103 patients taking felbamate. The range of felbamate dose was 300-4500mg (mean: 1800+/-900mg). The duration of therapy ranged from 1month to 20years (mean duration: 35+/-45months). Eighteen (17.5%) subjects experienced adverse events including insomnia, nausea, vomiting, decreased appetite, weight loss, gastric discomfort, diarrhea, mood and behavioral problems, high blood pressure, headache, and elevated liver enzymes. Out of these, 6 (5.9%) patients discontinued the therapy. No hepatic failure or agranulocytosis was observed. Fifty-nine (57.72%) patients achieved >/=50% reduction in seizure frequency, and 30 (29.12%) patients achieved seizure freedom. CONCLUSIONS: These findings suggest that felbamate is safe, well tolerated, and effective in treatment of various types of epilepsy syndromes.

INTRODUCTION: Depression and memory dysfunction significantly impact the quality of life of patients with epilepsy. Current therapies for these cognitive and psychiatric comorbidities are limited. We explored the efficacy and safety of transcranial direct current stimulation (TDCS) for treating depression and memory dysfunction in patients with temporal lobe epilepsy (TLE). METHODS: Thirty-seven (37) adults with well-controlled TLE were enrolled in a double-blinded, sham-controlled, randomized, parallel-group study of 5days of fixed-dose (2mA, 20min) TDCS. Subjects were randomized to receive either real or sham TDCS, both delivered over the left dorsolateral prefrontal cortex. Patients received neuropsychological testing and a 20-minute scalp EEG at baseline immediately after the TDCS course and at 2- and 4-week follow-up. RESULTS: There was improvement in depression scores immediately after real TDCS, but not sham TDCS, as measured by changes in the Beck Depression Inventory (BDI change: -1.68 vs. 1.27, p<0.05) and NDDI-E (-0.83 vs. 0.9091, p=0.05). There was no difference between the groups at the 2- or 4-week follow-up. There was no effect on delayed or working memory performance. Transcranial direct current stimulation was well-tolerated and did not increase seizure frequency or interictal discharge frequency. Transcranial direct current stimulation induced an increase in delta frequency band power over the frontal region and delta, alpha, and theta band power in the occipital region after real stimulation compared to sham stimulation, although the difference did not reach statistical significance. DISCUSSION: This study provides evidence for the use of TDCS as a safe and well-tolerated nonpharmacologic approach to improving depressive symptoms in patients with well-controlled TLE. However, there were no changes in memory function immediately following or persisting after a stimulation course. Further studies may determine optimal stimulation parameters for maximal mood benefit.