Intracerebral electrographic activity following a single dose of diazepam nasal spray: A pilot study.

OBJECTIVE: Rescue benzodiazepine medication can be used to treat seizure clusters, which are intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern. The NeuroPace RNS® System is a device that detects abnormal electrographic activity through intracranial electrodes and administers electrical stimulation to control seizures. Reductions in electrographic activity over days to weeks have been associated with the longer-term efficacy of daily antiseizure medications (ASMs). In this pilot study, electrographic activity over hours to days was examined to assess the impact of a single dose of a proven rescue therapy (diazepam nasal spray) with a rapid onset of action. METHODS: Adult volunteers (>18 years old) with clinically indicated RNS (stable settings and ASM usage) received a weight-based dose of diazepam nasal spray in the absence of a clinical seizure. Descriptive statistics for a number of detections and a sum of durations of detections at 10-min, hourly, and 24-h intervals during the 7-day (predose) baseline period were calculated. Post-dose detections at each time interval were compared with the respective baseline-detection intervals using a 1 SD threshold. The number of long episodes that occurred after dosing also were compared with the baseline. RESULTS: Five participants were enrolled, and four completed the study; the excluded participant had recurrent seizures during the study. There were no consistent changes (difference >1 SD) in detections between post-dose and mean baseline values. Although variability was high (1 SD was often near or exceeded the mean), three participants showed possible trends for reductions in one or more electrographic variables following treatment. SIGNIFICANCE: RNS-assessed electrographic detections and durations were not shown to be sensitive measures of short-term effects associated with a single dose of rescue medication in this small group of participants. The variability of detections may have masked a measurable drug effect. PLAIN LANGUAGE SUMMARY: Rescue drugs are used to treat seizure clusters. Responsive neurostimulation (RNS) devices detect and record epilepsy brain waves and then send a pulse to help stop seizures. This pilot study looked at whether one dose of a rescue treatment changes brain activity detected by RNS. There was a very wide range of detections, which made it difficult to see if or how the drug changed brain activity. New studies should look at other types of brain activity, multiple doses, and larger patient groups.

Anorexia and the hippocampus: A case report.

Eating disorders have been shown to be associated with epilepsy, typically associated with the temporal lobe and usually of non-dominant hemisphere origin. We report the case of a 56-year-old woman with drug resistant epilepsy, localized to the dominant left hippocampus. She experienced an increasing frequency of seizures over a two-year period associated with loss of appetite and substantial weight loss independent of antiseizure medication changes. Extensive workup eliminated gastrointestinal and paraneoplastic etiologies. There was no history of psychiatric illness, including anorexia nervosa. Pre-surgical workup showed mesial temporal sclerosis on MRI and video-EEG was consistent with ipsilateral medial temporal seizure onset. The patient underwent laser interstitial ablation of the left amygdala and hippocampus, which resulted in a cessation of seizures. Within 24 h of the laser ablation, her appetite returned to normal and, within 8 months she regained 26 lbs. To our knowledge, this is the first case report of a patient with dominant temporal lobe epilepsy with anorexia that was temporally associated with escalating seizure frequency and stopped with treatment and cessation of seizures, suggesting a causal and pathogenic relationship.

Indirect treatment comparison of cenobamate to other ASMs for the treatment of uncontrolled focal seizures.

OBJECTIVE: The efficacy and safety of cenobamate relative to other antiseizure medications (ASMs) has not been evaluated. An indirect treatment comparison (network meta-analysis) was performed to determine if adjunctive cenobamate increases the odds ratio (OR) for ≥50% responder rate or for withdrawals due to treatment-emergent adverse events (TEAEs) leading to ASM discontinuation versus adjunctive therapy with other ASMs. METHODS: A systematic literature review was conducted to identify randomized, double-blind, placebo-controlled trials (maintenance phase ≥ 12 weeks) assessing adjunctive ASMs in adults with uncontrolled focal seizures. Cenobamate was compared to a group of seven other ASMs, and to subgroups of branded (brivaracetam, eslicarbazepine acetate, lacosamide, and perampanel) and older (lamotrigine, levetiracetam, and topiramate) ASMs at FDA-recommended daily maintenance doses (FDA-RDMD), at all doses, and at maximum and minimum daily doses. Statistical significance was set at p < 0.05. RESULTS: Twenty-one studies were eligible for analysis. The placebo-adjusted ≥ 50% responder rate for FDA-RDMD of cenobamate was superior (OR 4.200; 95% CI 2.279, 7.742) to FDA-RDMD of all seven assessed (OR 2.202 95% CI 1.915, 2.532; p = 0.044) and branded ASMs (OR 2.148; 95% CI 1.849, 2.494; p = 0.037). There was no significant difference for ≥50% responder rate between FDA-RDMD of cenobamate and FDA-RDMD of older ASMs (OR 2.617; 95% CI 1.767, 3.878; p = 0.202). No significant differences were identified for ≥50% responder rate when comparing all doses and maximum/minimum doses of cenobamate to all seven, branded, and older ASMs. Cenobamate demonstrated comparable TEAE withdrawal rates to all seven ASMs, branded ASMs, and older ASMs across each of the four dose ranges (all p > 0.05). SIGNIFICANCE: Patients receiving FDA-RDMD of cenobamate were more likely to have ≥50% seizure reduction compared with FDA-RDMD of the seven assessed ASMs and branded ASMs, without an increase in treatment discontinuation due to TEAEs.

Seizures and Cognitive Outcome After Traumatic Brain Injury: A Post Hoc Analysis.

INTRODUCTION: Seizures and abnormal periodic or rhythmic patterns are observed on continuous electroencephalography monitoring (cEEG) in up to half of patients hospitalized with moderate to severe traumatic brain injury (TBI). We aimed to determine the impact of seizures and abnormal periodic or rhythmic patterns on cognitive outcome 3 months following moderate to severe TBI. METHODS: This was a post hoc analysis of the multicenter randomized controlled phase 2 INTREPID2566 clinical trial conducted from 2010 to 2016 across 20 United States Level I trauma centers. Patients with nonpenetrating TBI and postresuscitation Glasgow Coma Scale scores 4-12 were included. Bedside cEEG was initiated per protocol on admission to intensive care, and the burden of ictal-interictal continuum (IIC) patterns, including seizures, was quantified. A summary global cognition score at 3 months following injury was used as the primary outcome. RESULTS: 142 patients (age mean + / - standard deviation 32 + / - 13 years; 131 [92%] men) survived with a mean global cognition score of 81 + / - 15; nearly one third were considered to have poor functional outcome. 89 of 142 (63%) patients underwent cEEG, of whom 13 of 89 (15%) had severe IIC patterns. The quantitative burden of IIC patterns correlated inversely with the global cognition score (r = - 0.57; p = 0.04). In multiple variable analysis, the log-transformed burden of severe IIC patterns was independently associated with the global cognition score after controlling for demographics, premorbid estimated intelligence, injury severity, sedatives, and antiepileptic drugs (odds ratio 0.73, 95% confidence interval 0.60-0.88; p = 0.002). CONCLUSIONS: The burden of seizures and abnormal periodic or rhythmic patterns was independently associated with worse cognition at 3 months following TBI. Their impact on longer-term cognitive endpoints and the potential benefits of seizure detection and treatment in this population warrant prospective study.

A randomized controlled trial of self-management for people with epilepsy and a history of negative health events (SMART) targeting rural and underserved people with epilepsy: a methodologic report.

BACKGROUND: Many people living with epilepsy (PLWE) reside in rural communities, and epilepsy self-management may help address some of the gaps in epilepsy care for these communities. A prior randomized control trial of a remotely delivered, Web-based group format 12-week self-management program (SMART) conducted in Northeast Ohio, a primarily urban and suburban community, demonstrated improved outcomes in negative health events such as depression symptoms and quality of life. However, there is a paucity of research addressing the needs of PLWE in rural settings. METHODS: The present study leverages collaboration between investigators from 2 mid-western US states (Ohio and Iowa) to replicate testing of the SMART intervention and prioritize delivery to PLWE in rural and semi-rural communities. In phase 1, investigators will refine the SMART program using input from community stakeholders. A Community Advisory Board will then be convened to help identify barriers to trial implementation and strategies to overcome barriers. In phase 2, the investigators will conduct a 6-month prospective randomized control trial of the SMART program compared to 6-month waitlist controls, with the primary outcome being changes in negative health events defined as seizure, self-harm attempt, emergency department visit, or hospitalization. Additional outcomes of interest include quality of life and physical and mental health functioning. The study will also assess process measures of program adopters and system end-users to inform future outreach, education, and self-management strategies for PLWE. DISCUSSION: The method of this study employs lived experience of PLWE and those who provide care for PLWE in rural and underserved populations to refine a remotely delivered Web-based self-management program, to improve recruitment and retention, and to deliver the intervention. Pragmatic outcomes important to PLWE, payers, and policymakers will be assessed. This study will provide valuable insights on implementing future successful self-management programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04705441 . Registered on January 12, 2021.

Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy.

We performed a genome-wide association study (GWAS) to identify genetic variation associated with common forms of idiopathic generalized epilepsy (GE) and focal epilepsy (FE). Using a cohort of 2220 patients and 14,448 controls, we searched for single nucleotide polymorphisms (SNPs) associated with GE, FE and both forms combined. We did not find any SNPs that reached genome-wide statistical significance (p ≤ 5 × 10-8) when comparing all cases to all controls, and few SNPs of interest comparing FE cases to controls. However, we document multiple linked SNPs in the PADI6-PADI4 genes that reach genome-wide significance and are associated with disease when comparing GE cases alone to controls. PADI genes encode enzymes that deiminate arginine to citrulline in molecular pathways related to epigenetic regulation of histones and autoantibody formation. Although epilepsy genetics and treatment are focused strongly on ion channel and neurotransmitter mechanisms, these results suggest that epigenetic control of gene expression and the formation of autoantibodies may also play roles in epileptogenesis.

Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials.

OBJECTIVE: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome. METHODS: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. RESULTS: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients. SIGNIFICANCE: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period.

Smokers with and without Epilepsy show Similar Smoking Rate, Dependence Level, Cessation Attempts, and Motives.

BACKGROUND: Individuals with epilepsy are up to twice as likely to be current cigarette smokers compared to those without. Moreover, one study showed current smoking is associated with an increased likelihood of seizures. However, outside of this one study, there is limited data on the presentation of specific smoking-related behaviors and cognitions in people with epilepsy, inhibiting our understanding of the severity of this behavior and our ability to formulate effective treatments for this population. PURPOSE: The current study examined smoking-related behaviors and cognitions among smokers with epilepsy compared to smokers without epilepsy. METHODS: Participants were 43 smokers with (Mage = 43.4, SD = 11.6) and 43 smokers without (Mage = 45.5, SD = 8.8) epilepsy recruited from an urban, academic setting within the U.S. Separate Analyses of Covariance (ANCOVAs) were conducted to evaluate differences between smokers with and without epilepsy in terms of smoking behavior (i.e., daily smoking rate, nicotine dependence, number of quit attempts, smoking duration, age of smoking onset) and smoking-related cognitive processes (i.e., smoking motives, perceived barriers to smoking cessation, cessation motives) after controlling for race and problematic alcohol use. RESULTS: Smokers with epilepsy did not differ from smokers without epilepsy in terms of smoking rate (p = .51, ηp2 = .01), nicotine dependence (p = .12, ηp2 = .03), age of smoking onset (p = .42, ηp2 = .01), number of quit attempts (p = .43, ηp2 = .01), barriers to cessation (p = .30 to .80, ηp2 = .00 to .01), or cessation motives (p = .28 to .60, ηp2 = .00 to .02). Smokers without epilepsy reported higher levels of smoking for sensorimotor manipulation reasons (p = .03, ηp2 = .06) and longer smoking duration (p = .03, ηp2 = .06) than smokers with epilepsy. CONCLUSIONS: Smokers with epilepsy do not appear to differ significantly from smokers without epilepsy in terms of smoking-related behaviors and cognitions, and may therefore benefit from current evidence-based treatments for smoking cessation that are not contraindicated for epilepsy (i.e., bupropion, varenicline).

Developing epilepsy training capacity for primary care providers using the project ECHO telementoring model.

BACKGROUND: Primary care providers (PCPs) provide a large proportion of care for people with epilepsy (PWE) and need regular training for updates. However, PCPs treat patients in so many therapeutic areas that epilepsy often becomes a less important concern. We used an established telementoring program, Project ECHO (Extension for Community Healthcare Outcomes), and combined epilepsy education with general neurology topics to generate more interest among PCPs. METHODS: We offered 20 one-hour webinar sessions over a two-year period, each consisting of a panel of neurology experts, with a combination of case presentations, a 20-minute didactic presentation, and live, interactive question and answer. Attendees logged in from their own computers or phones, and all presentations were archived online for future viewing. Interviews with PCPs indicated a combination of epilepsy and general neurology topics would be better received, so epilepsy topics alternated monthly with general neurology topics (e.g., headache, stroke, and dementia). Session evaluation included participants' comfort in treating patients with neurological disorders and confidence in knowledge of the topic area. RESULTS: After the second session, mean attendance was 27.5 participants (range 15-38), with a total of 164 unique individual participants. Attendees were a mix of mostly regional, some out of state, and a few international learners, including practicing PCPs, trainees, and nurse practitioners. Archived presentations on our website were viewed 212 times; seizure topics were the most viewed. Mean evaluation scores for relevance, value, and increased knowledge were all in the "agree to strongly agree" range. Over 97% of respondents reported greater interest in improving care of patients with epilepsy or neurological disorders, and over 98% reported greater comfort and self-efficacy when treating patients with these conditions. Only eight cases were submitted for review prior to the sessions. CONCLUSIONS: We successfully piloted a telementoring program using Project ECHO methodology, which was effective in educating PCPs about epilepsy treatment. Combining epilepsy and other neurology topics was an effective strategy in garnering interest among PCPs, but additional methods are needed to encourage participants to present their own cases.

Coffee and cigarette smoking interactions with lamotrigine.

The objective of this analysis was to determine possible interactions between lamotrigine (LTG) and coffee or cigarette use. As part of the statistical analysis of factors influencing LTG pharmacokinetics (PK) in the Equigen chronic dose study, we collected prospective data from enrolled patients on their use of coffee and cigarettes. Subjects were part of a crossover replication study of generic LTG products with rigorous blood sampling and were instructed to not change their typical consumption of these products for the duration of the study. A total of 35 subjects were enrolled, with 33 subjects having sufficient data for analysis. Higher consumption of coffee was associated with a significantly lower area under the curve (AUC) and maximum concentration (Cmax) of lamotrigine (LTG). Higher cigarette use did not result in a significant change in AUC or Cmax. Coffee, but not cigarette use, either induces LTG metabolism or inhibits LTG absorption.

Characteristics of men with conversion disorder.

OBJECTIVE: Women comprise the majority of subjects with conversion disorders in nearly all studies. The authors previously identified 96 subjects with psychogenic non-epileptic seizures (PNES) and found that female sex, alexithymia and childhood trauma were strongly correlated with the development of PNES. In order to characterize men with PNES, the authors collected questionnaire data on a series of male subjects recruited from an epilepsy monitoring unit (EMU). METHODS: Only male patients admitted to the EMU were asked to complete the Toronto Alexithymia Scale-20 (TAS-20) and the Childhood Trauma Questionnaire (CTQ). Results were correlated with diagnosis at discharge, either epileptic seizures (ES) or PNES. RESULTS: Ninety-two subjects submitted complete questionnaire data. Sixty-nine subjects (74%) were diagnosed with ES, 13 subjects (14%) were diagnosed with PNES and 10 subjects (11%) had an undetermined diagnosis. There were no significant differences on the TAS-20 or the CTQ by diagnosis. CONCLUSION: In this sample of men admitted to an EMU there was no difference in the extent of alexithymia or childhood trauma between men with ES and PNES. There was a small number of men with a PNES diagnosis, which may have limited our ability to identify differences in the groups. The clear correlation of childhood trauma and alexithymia with development of conversion disorder in women could not be demonstrated in men.

Seizure self-prediction in a randomized controlled trial of stress management.

OBJECTIVE: Using electronic diaries as part of a randomized controlled trial of stress reduction for epilepsy, we evaluated factors associated with successful seizure self-prediction. METHODS: Adults with medication-resistant focal epilepsy were recruited from 3 centers and randomized to treatment with progressive muscle relaxation or control focused attention. An 8-week baseline was followed by 12 weeks of double-blind treatment. Twice daily, participants rated the likelihood of a seizure in the next 24 hours on a 5-point scale from very unlikely to almost certain, along with mood, premonitory symptoms, stress ratings, and seizure counts. We analyzed the association of mood, premonitory symptoms, stress, and circadian influences on seizure self-prediction. RESULTS: Sixty-four participants completed the trial (3,126 seizures). Diary entry adherence was >82%. Participant self-prediction was associated with seizure occurrence at 6, 12, and 24 hours (p < 0.0001). Odds ratio (OR) of seizure prediction increased systematically with participants' prediction of seizure likelihood (p < 0.0001, all levels of prediction and all time intervals). For the 12-hour prediction window, median specificity for seizure prediction was 0.94 and negative predictive value 0.94; median sensitivity was 0.10 and positive predictive value 0.13. A subset of 13 participants (20% of sample) met criteria for good predictors (median OR for seizure prediction 5.25). Mood, stress, premonitory symptoms, seizure time, and randomized group were not associated with seizure occurrence. CONCLUSION: In this prospective study, participants' prediction of a high probability of seizure was significantly associated with subsequent seizure occurrence within 24 hours. Future studies should focus on understanding factors that drive self-prediction. CLINICALTRIALSGOV IDENTIFIER: NCT01444183.

Physician Burnout and Barriers to Care on Professional Applications.

We surveyed New York physicians to study their perceptions of reporting requirements related to their own mental health care on professional applications, including whether they were experiencing symptoms of burnout. Over half of the responding physicians reported experiencing symptoms of burnout and these physicians were at increased odds of perceiving a barrier to seeking mental health care if they had to report such care on professional applications and renewals for medical licensure, malpractice, and hospital privileges and credentialing compared to physicians not experiencing symptoms of burnout. As state medical boards, hospitals, and insurers seek information to help assess risks posed by physicians, it is essential to strike an appropriate balance between their duty to protect the public and the physician's right to confidentiality. This balance can be assessed based on the questions that are asked on various professional applications and how information gleaned through physician responses is used. Overly intrusive questions, though well intentioned to protect the public, may run counter to current interpretations of federal law and may inhibit care-seeking among physicians, which is critical to both patient safety and physician health.

Evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus.

Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug-drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3-fold increase in dose-normalized tacrolimus concentrations while receiving 2000-2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA-approved CBD product. Larger studies are needed to better understand the impact of this drug-drug interaction in solid organ transplant recipients.

The role of cigarette smoking in epilepsy severity and epilepsy-related quality of life.

Empirical evidence suggests that cigarette smoking is common among individuals with epilepsy. However, little is known about relationship between smoking and clinical features of epilepsy. Thus, the aim of the current study was to examine the differences between smokers (n = 43; 58.1% female, Mage = 43.4 years, SD = 11.6) and nonsmokers (n = 49; 63.3% female, Mage = 48.5 years, SD = 15.9) with epilepsy in terms of epilepsy severity (i.e., presence of seizures in the past year, refractory epilepsy status) and epilepsy-related quality of life. As hypothesized, smokers with epilepsy, compared with nonsmokers with epilepsy, were at an increased risk to have experienced seizures in the past year after controlling for the effect of Medicaid status as a proxy for socioeconomic status (odds ratio [OR] = 3.61). Positive smoking status was also associated with lower levels of epilepsy-related quality of life; however, this finding did not remain significant when Medicaid status was taken into consideration. Contrary to the hypotheses, smokers with epilepsy were not at an increased risk of having refractory epilepsy compared with nonsmokers with epilepsy. These findings suggest that cigarette smoking is associated with at least one aspect of epilepsy severity. Thus, in addition to the broader health benefits, smokers with epilepsy should be advised of the increased seizure risk associated with current cigarette smoking. Future work should examine the longitudinal impact of smoking on epilepsy severity, including whether successful smoking cessation ameliorates the seizure risk found in this cross-sectional study.