How does cognitive behavior therapy for dissociative seizures work? A mediation analysis of the CODES trial.

BACKGROUND: We compared dissociative seizure specific cognitive behavior therapy (DS-CBT) plus standardized medical care (SMC) to SMC alone in a randomized controlled trial. DS-CBT resulted in better outcomes on several secondary trial outcome measures at the 12-month follow-up point. The purpose of this paper is to evaluate putative treatment mechanisms. METHODS: We carried out a secondary mediation analysis of the CODES trial. 368 participants were recruited from the National Health Service in secondary / tertiary care in England, Scotland, and Wales. Sixteen mediation hypotheses corresponding to combinations of important trial outcomes and putative mediators were assessed. Twelve-month trial outcomes considered were final-month seizure frequency, Work and Social Adjustment Scale (WSAS), and the SF-12v2, a quality-of-life measure providing physical (PCS) and mental component summary (MCS) scores. Mediators chosen for analysis at six months (broadly corresponding to completion of DS-CBT) included: (a) beliefs about emotions, (b) a measure of avoidance behavior, (c) anxiety and (d) depression. RESULTS: All putative mediator variables except beliefs about emotions were found to be improved by DS-CBT. We found evidence for DS-CBT effect mediation for the outcome variables dissociative seizures (DS), WSAS and SF-12v2 MCS scores by improvements in target variables avoidance behavior, anxiety, and depression. The only variable to mediate the DS-CBT effect on the SF-12v2 PCS score was avoidance behavior. CONCLUSIONS: Our findings largely confirmed the logic model underlying the development of CBT for patients with DS. Interventions could be additionally developed to specifically address beliefs about emotions to assess whether it improves outcomes.

Statistical learning in epilepsy: Behavioral and anatomical mechanisms in the human brain.

OBJECTIVE: Statistical learning, the fundamental cognitive ability of humans to extract regularities across experiences over time, engages the medial temporal lobe (MTL) in the healthy brain. This leads to the hypothesis that statistical learning (SL) may be impaired in patients with epilepsy (PWE) involving the temporal lobe, and that this impairment could contribute to their varied memory deficits. In turn, studies done in collaboration with PWE, that evaluate the necessity of MTL circuitry through disease and causal perturbations, provide an opportunity to advance basic understanding of SL. METHODS: We implemented behavioral testing, volumetric analysis of the MTL substructures, and direct electrical brain stimulation to examine SL across a cohort of 61 PWE and 28 healthy controls. RESULTS: We found that behavioral performance in an SL task was negatively associated with seizure frequency irrespective of seizure origin. The volume of hippocampal subfields CA1 and CA2/3 correlated with SL performance, suggesting a more specific role of the hippocampus. Transient direct electrical stimulation of the hippocampus disrupted SL. Furthermore, the relationship between SL and seizure frequency was selective, as behavioral performance in an episodic memory task was not impacted by seizure frequency. SIGNIFICANCE: Overall, these results suggest that SL may be hippocampally dependent and that the SL task could serve as a clinically useful behavioral assay of seizure frequency that may complement existing approaches such as seizure diaries. Simple and short SL tasks may thus provide patient-centered endpoints for evaluating the efficacy of novel treatments in epilepsy.

Leukocyte differential gene expression prognostic value for high versus low seizure frequency in temporal lobe epilepsy.

BACKGROUND: This study was performed to test the hypothesis that systemic leukocyte gene expression has prognostic value differentiating low from high seizure frequency refractory temporal lobe epilepsy (TLE). METHODS: A consecutive series of patients with refractory temporal lobe epilepsy was studied. Based on a median baseline seizure frequency of 2.0 seizures per month, low versus high seizure frequency was defined as ≤ 2 seizures/month and > 2 seizures/month, respectively. Systemic leukocyte gene expression was analyzed for prognostic value for TLE seizure frequency. All differentially expressed genes were analyzed, with Ingenuity® Pathway Analysis (IPA®) and Reactome, to identify leukocyte gene expression and biological pathways with prognostic value for seizure frequency. RESULTS: There were ten males and six females with a mean age of 39.4 years (range: 16 to 62 years, standard error of mean: 3.6 years). There were five patients in the high and eleven patients in the low seizure frequency cohorts, respectively. Based on a threshold of twofold change (p < 0.001, FC > 2.0, FDR < 0.05) and expression within at least two pathways from both Reactome and Ingenuity® Pathway Analysis (IPA®), 13 differentially expressed leukocyte genes were identified which were all over-expressed in the low when compared to the high seizure frequency groups, including NCF2, HMOX1, RHOB, FCGR2A, PRKCD, RAC2, TLR1, CHP1, TNFRSF1A, IFNGR1, LYN, MYD88, and CASP1. Similar analysis identified four differentially expressed genes which were all over-expressed in the high when compared to the low seizure frequency groups, including AK1, F2R, GNB5, and TYMS. CONCLUSIONS: Low and high seizure frequency TLE are predicted by the respective upregulation and downregulation of specific leukocyte genes involved in canonical pathways of neuroinflammation, oxidative stress and lipid peroxidation, GABA (γ-aminobutyric acid) inhibition, and AMPA and NMDA receptor signaling. Furthermore, high seizure frequency-TLE is distinguished prognostically from low seizure frequency-TLE by differentially increased specific leukocyte gene expression involved in GABA inhibition and NMDA receptor signaling. High and low seizure frequency patients appear to represent two mechanistically different forms of temporal lobe epilepsy based on leukocyte gene expression.

Dravet syndrome seizure frequency and clustering: Placebo-treated patients in clinical trials.

OBJECTIVE: Dravet syndrome is a rare developmental epilepsy syndrome associated with severe, treatment-resistant seizures. Since seizures and seizure clusters are linked to morbidity, reduced quality of life, and premature mortality, a greater understanding of these outcomes could improve trial designs. This analysis explored seizure types, seizure clusters, and factors affecting seizure cluster variability in Dravet syndrome patients. METHODS: Pooled post-hoc analyses were performed on data from placebo-treated patients in GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials comparing cannabidiol and placebo in Dravet syndrome patients aged 2-18 years. Multivariate stepwise analysis of covariance of log-transformed convulsive seizure cluster frequency was performed, body weight and body mass index z-scores were calculated, and incidence of adverse events was assessed. Data were summarized in three age groups. RESULTS: We analyzed 124 placebo-treated patients across both studies (2-5 years: n = 35; 6-12 years: n = 52; 13-18 years: n = 37). Generalized tonic-clonic seizures followed by myoclonic seizures were the most frequent seizure types. Mean and median convulsive seizure cluster frequency overall decreased between baseline and maintenance period but did not change significantly during the latter; variation in convulsive seizure cluster frequency was observed across age groups. Multivariate analysis suggested correlations between convulsive seizure cluster frequency and age (positive), and body mass index (BMI) (negative). INTERPRETATION: Post-hoc analyses suggested that potential relationships could exist between BMI, age and convulsive seizure cluster variation. Results suggested that seizure cluster frequency may be a valuable outcome in future trials. Further research is needed to confirm our findings.

Seizure control and complications in patients switching from clobazam to clonazepam due to drug shortage.

BACKGROUND: Antiseizure medication (ASM) shortages are a global problem that have a negative impact on outcomes such as seizure control in patients with epilepsy (PWE). In the case of clobazam (CLB) shortage, there is no study regarding the management strategy. This study aims to investigate the alteration in seizure frequency and the occurrence of side effects in PWE undergoing an abrupt switch from clobazam (CLB) to clonazepam (CLZ), during CLB shortage. MATERIAL AND METHODS: A retrospective study was conducted from electronic health records at our neurology outpatient clinic from January to July 2022. Change in seizure frequency and percentage of CLZ-associated side effects were determined as primary and secondary outcomes, respectively. Potential drug-drug interactions (Level C and above) were evaluated by using Lexicomp Drug Interaction Checker. RESULTS: The analysis included a total of 29 adult patients (15F, median age: 29). The switching ratio was 10 mg CLB for every 1 mg CLZ (10:1). Seizure frequency was higher during the CLZ period compared to the CLB period (p < 0.05), but no status epilepticus cases were observed. All patients exhibited potential drug-drug interactions, leading to reduced CLZ levels in 12 cases. A total of 36 CLZ-associated side effects were identified, with fatigue (19.4 %), drowsiness (16.6 %), and somnolence (13.8 %) being the most prevalent. A positive and strong correlation was found between CLZ dose and the number of side effects (r: 0.556; p: 0.002). CONCLUSION: The abrupt switch from CLB to CLZ was observed to increase seizure frequency without leading to status epilepticus in PWE. CLZ-associated side effects were found to be tolerable despite the abrupt switch. Future studies may explore the effect of alternative switching ratios.

Beyond seizure freedom: Dissecting long-term seizure control after surgical resection for drug-resistant epilepsy.

OBJECTIVE: This study was undertaken to better understand the long-term palliative and disease-modifying effects of surgical resection beyond seizure freedom, including frequency reduction and both late recurrence and remission, in patients with drug-resistant epilepsy. METHODS: This retrospective database-driven cohort study included all patients with >9 years of follow-up at a single high-volume epilepsy center. We included patients who underwent lobectomy, multilobar resection, or lesionectomies for drug-resistant epilepsy; we excluded patients who underwent hemispherectomies. Our main outcomes were (1) reduction in frequency of disabling seizures (at 6 months, each year up to 9 years postoperatively, and at last follow-up), (2) achievement of seizure remission (>6 months, >1 year, and longest duration), and (3) seizure freedom at last follow-up. RESULTS: We included 251 patients; 234 (93.2%) achieved 6 months and 232 (92.4%) experienced 1 year of seizure freedom. Of these, the average period of seizure freedom was 10.3 years. A total of 182 (72.5%) patients were seizure-free at last follow-up (defined as >1 year without seizures), with a median 11.9 years since remission. For patients not completely seizure-free, the mean seizure frequency reduction at each time point was 76.2%, and ranged from 66.6% to 85.0%. Patients decreased their number of antiseizure medications on average by .58, and 53 (21.2%) patients were on no antiseizure medication at last follow-up. Nearly half (47.1%) of those seizure-free at last follow-up were not seizure-free immediately postoperatively. SIGNIFICANCE: Patients who continue to have seizures after resection often have considerable reductions in seizure frequency, and many are able to achieve seizure freedom in a delayed manner.

Genetic influences on epilepsy outcomes: A whole-exome sequencing and health care records data linkage study.

OBJECTIVE: This study was undertaken to develop a novel pathway linking genetic data with routinely collected data for people with epilepsy, and to analyze the influence of rare, deleterious genetic variants on epilepsy outcomes. METHODS: We linked whole-exome sequencing (WES) data with routinely collected primary and secondary care data and natural language processing (NLP)-derived seizure frequency information for people with epilepsy within the Secure Anonymised Information Linkage Databank. The study participants were adults who had consented to participate in the Swansea Neurology Biobank, Wales, between 2016 and 2018. DNA sequencing was carried out as part of the Epi25 collaboration. For each individual, we calculated the total number and cumulative burden of rare and predicted deleterious genetic variants and the total of rare and deleterious variants in epilepsy and drug metabolism genes. We compared these measures with the following outcomes: (1) no unscheduled hospital admissions versus unscheduled admissions for epilepsy, (2) antiseizure medication (ASM) monotherapy versus polytherapy, and (3) at least 1 year of seizure freedom versus <1 year of seizure freedom. RESULTS: We linked genetic data for 107 individuals with epilepsy (52% female) to electronic health records. Twenty-six percent had unscheduled hospital admissions, and 70% were prescribed ASM polytherapy. Seizure frequency information was linked for 100 individuals, and 10 were seizure-free. There was no significant difference between the outcome groups in terms of the exome-wide and gene-based burden of rare and deleterious genetic variants. SIGNIFICANCE: We successfully uploaded, annotated, and linked genetic sequence data and NLP-derived seizure frequency data to anonymized health care records in this proof-of-concept study. We did not detect a genetic influence on real-world epilepsy outcomes, but our study was limited by a small sample size. Future studies will require larger (WES) data to establish genetic variant contribution to epilepsy outcomes.

Long-term epilepsy outcome dynamics revealed by natural language processing of clinic notes.

OBJECTIVE: Electronic medical records allow for retrospective clinical research with large patient cohorts. However, epilepsy outcomes are often contained in free text notes that are difficult to mine. We recently developed and validated novel natural language processing (NLP) algorithms to automatically extract key epilepsy outcome measures from clinic notes. In this study, we assessed the feasibility of extracting these measures to study the natural history of epilepsy at our center. METHODS: We applied our previously validated NLP algorithms to extract seizure freedom, seizure frequency, and date of most recent seizure from outpatient visits at our epilepsy center from 2010 to 2022. We examined the dynamics of seizure outcomes over time using Markov model-based probability and Kaplan-Meier analyses. RESULTS: Performance of our algorithms on classifying seizure freedom was comparable to that of human reviewers (algorithm F1 = .88 vs. human annotator κ = .86). We extracted seizure outcome data from 55 630 clinic notes from 9510 unique patients written by 53 unique authors. Of these, 30% were classified as seizure-free since the last visit, 48% of non-seizure-free visits contained a quantifiable seizure frequency, and 47% of all visits contained the date of most recent seizure occurrence. Among patients with at least five visits, the probabilities of seizure freedom at the next visit ranged from 12% to 80% in patients having seizures or seizure-free at the prior three visits, respectively. Only 25% of patients who were seizure-free for 6 months remained seizure-free after 10 years. SIGNIFICANCE: Our findings demonstrate that epilepsy outcome measures can be extracted accurately from unstructured clinical note text using NLP. At our tertiary center, the disease course often followed a remitting and relapsing pattern. This method represents a powerful new tool for clinical research with many potential uses and extensions to other clinical questions.

Efficacy of cannabidiol in convulsive and nonconvulsive seizure types associated with treatment-resistant epilepsies in the Expanded Access Program.

The cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure = 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic), nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic absence), and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types (median percentage reduction = 47%-100%), and nonconvulsive seizure types and epileptic spasms (median percentage reduction = 50%-100%) across visit intervals through 144 weeks of treatment. Approximately 50% of patients had ≥50% reduction in convulsive and nonconvulsive seizure types and epileptic spasms at nearly all intervals. These results show a favorable effect of long-term CBD use in patients with TRE, who may experience various convulsive and nonconvulsive seizure types. Future controlled trials are needed to confirm these findings.

The efficacy and safety of patent Foramen Ovale Closure for Refractory Epilepsy (PFOC-RE): a prospectively randomized control trial of an innovative surgical therapy for refractory epilepsy patients with PFO of high-grade right-to-left shunt.

BACKGROUND: A significant proportion of patients with epilepsy have an unknown etiology and lack effective targeted therapeutic drugs. Patent Foramen Ovale (PFO) induces hypoxia and microembolism, leading to cerebral neurological dysfunction and increased epilepsy risk. This study aims to assess the efficacy and safety of PFO closure for relieving epileptic seizures in patients with refractory epilepsy associated with PFO. METHODS/DESIGN: Recruitment takes place at the West China Hospital of Sichuan University, China, for an open-label, randomized controlled clinical trial. The trial will include 110 patients with refractory epilepsy and PFO. Disease diagnoses will conform to the diagnostic criteria of the International League Against Epilepsy (ILAE) for refractory epilepsy and the American Society of Echocardiography (ASE) for PFO. Refractory epilepsy and high-grade right-to-left shunt (RLS) of the PFO will be further diagnosed using 24-hour video electroencephalogram and transthoracic echocardiography with contrast injection, respectively. Eligible participants require a secondary or higher volume of RLS. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2200065681). Registered on November 11, 2022.

Changes in seizure frequency and anti-seizure medication therapy during pregnancy and one year postpregnancy.

Seizure control in women with epilepsy (WWE) during pregnancy is a vital concern. The aim of this study was to compare changes in seizure frequency and anti-seizure medication (ASM ) therapy in WWE in a real-world setting over three epochs (prepregnancy, pregnancy, and postpregnancy). We screened WWE who were pregnant between 1 January 2010 and 31 December 2020 from the epilepsy follow-up registry database of a tertiary hospital in China. We reviewed and collected follow-up data for the following time periods: 12 months before pregnancy (epoch 1), throughout pregnancy and the first 6 weeks postpartum (epoch 2), and from 6 weeks to 12 months postpartum (epoch 3). Seizures were classified into two categories: tonic‒clonic/focal to bilateral tonic‒clonic seizures and non-tonic‒clonic seizures. The main indicator was the seizure-free rate over the three epochs. Using epoch 1 as a reference, we also compared the percentage of women with an increased seizure frequency, as well as changes in ASM treatment, in epochs 2 and 3. Ultimately, 271 eligible pregnancies in 249 women were included. The seizure-free rates in epoch 1, epoch 2, and epoch 3 were 38.4%, 34.7%, and 43.9%, respectively (P = 0.09). The top three ASMs used in the three epochs were lamotrigine, levetiracetam, and oxcarbazepine. Using epoch 1 as a reference, the percentages of women with increased frequencies of tonic‒clonic/focal to bilateral tonic‒clonic seizures in epoch 2 and epoch 3 were 17.0% and 14.8%, respectively, while the percentages of women with an increased frequency of non-tonic‒clonic seizures in epoch 2 and epoch 3 were 31.0% and 21.8% (P = 0.02). The percentage of women whose ASM dosages were increased in epoch 2 was higher than that in epoch 3 (35.8% vs. 27.3%, P = 0.03). The seizure frequency during pregnancy may not differ significantly from that during prepregnancy and postpregnancy if WWE are treated according to the guidelines.

Patterns and predictors of sexual dysfunction in women with epilepsy.

OBJECTIVES: Available data about sexual-related problems among Egyptian women with epilepsy (WWE) are scarce. Hence, this work aimed to study the pattern and predictors of sexual dysfunction in a sample of Egyptian WWE. METHODS: In this cross-sectional study, sexually active WWE and age and years of marriage-matched healthy controls were included. The Female Sexual Function Index questionnaire (FSFI) was used to assess sexual function in both groups. RESULTS: In the patient group (n = 142), the median age was 33 (28-39), whereas the median age of the control group (n = 142) was 33.5 (28-36). Women with epilepsy had significantly lower desire, arousal, pain, and FSFI-total scores than the control group (P = 0.001, 0.001, 0.023, 0.008, respectively). There was a significant difference between the FSFI-total score of women on polytherapy and those on monotherapy (P = 0.042), as well as between those on enzyme-inducing ASMs and those on ASMs that did not affect P450 (P = 0.032). Seizure frequency in the last three months was negatively correlated with scores of desire, arousal, lubrication, orgasm, and satisfaction (P 0.047, 0.02, 0.009, 0.013, 0.046, respectively). By multiple backward linear regression models, age, and seizure frequency were the significant predictors of the FSFI-total score (B -0.219, -0.33, respectively). CONCLUSION: The pattern of sexual dysfunction among Egyptian WWE is characterized by reduced sexual desire, arousal deficits, and sexual-related pain. Seizure frequency, epilepsy duration, enzyme-inducing medications, and multiple anti-seizure medications (ASMs) may adversely affect WWE's sexual health. The only factor that could predict higher sexual dysfunction in WWE was higher seizure frequency.

Was it necessary to change the therapeutic range of topiramate?

AIMS: The Norwegian Association for Clinical Pharmacology in their National Guidelines decreased the therapeutic range (TR) of topiramate (TPM) from 5-20 mg/L to 2-10 mg/L. The objective of this study is to ascertain which TR produces better clinical outcomes. METHODS: The data sources were request forms for routine therapeutic drug monitoring (TDM) of TPM. Concentration dependent adverse drug reactions (ADRs) were evaluated in 1721 samples taken pre-dose. Seizure frequency analysis was performed in 294 samples of monotherapy. Statistical analysis was performed using Prism 5.0, GraphPad Instatt: One-way ANOVA with Bonferroni correction for median plasma level (PL) and χ2 -test with Bonferroni correction for seizure frequency and for distribution of PL according to TR 5-20 mg/L and intervals <2, 2-5, 5-10, 10-20, >20 mg/L. RESULTS: Better seizure control was found in children both in the whole cohort (without seizure 49% vs 37% adults), as well as in monotherapy (56% vs 44%), in children with PL 5-20 mg/L vs <5 mg/L (65% vs 44%) and in children with PL 5-10 mg/L vs <2 mg/L (63 vs 14%). PL in seizure-free patients did not differ from those with seizure. Seizure control was poorer in the period 2003-2005 compared to 2006-2011. ADRs reported in 38 samples (2.8%) were not related to PL. CONCLUSIONS: Change of TR is not recommended.

Psychometric properties of the Lithuanian version of the patient-weighted inventory on quality of life in epilepsy.

BACKGROUND: We aimed (1) to confirm that the Lithuanian version of the patient-weighted 31-item Quality of Life in Epilepsy Inventory (QOLIE-31-P) is a valid and reliable tool to be used among patients with epilepsy (PWE) in Lithuania and (2) to determine how the quality of life (QoL) is associated with demographic and clinical variables, adverse effects of antiseizure medication as well symptoms of depression and anxiety in this population. METHODS: We used a translated and adapted Lithuanian version of the patient-weighted 31-item Quality of Life in Epilepsy Inventory (QOLIE-31-P) and conducted a cross-sectional anonymous survey among 303 adult PWE at a tertiary epilepsy center at Vilnius University Hospital Santaros Klinikos. The questionnaire also included the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), the Generalized anxiety disorder scale-7 (GAD-7), and the Liverpool Adverse Events Profile scale (LAEP). Missing values were replaced after performing multiple imputation (MI). RESULTS: QOLIE-31-P had high internal consistency (Cronbach's α = 0.933 for all items and α = 0.676 to 0.906 for individual subscales). Its factor structure (71.2% of variance explained) consisted of seven factors, some of which overlapped ("Emotional Well-Being" and "Overall QoL") or were split ("Social Function") in comparison to the pre-defined content of the subscales. Multitrait-scaling revealed that each item is better correlated with the subscale it is included in than other subscales, suggesting good convergent and discriminant validity. On average, PWE scored 69.9 ±â€¯16.8 (n = 164, mean = 64.9 after MI) on the QOLIE-31-P. Results were higher among male PWE, those employed or studying and having a higher level of education. In a pooled multiple regression model (adjusted R¯2 = 0.700, p < 0.001), the NDDIE (ßst = -0.230, p < 0.001), the GAD-7 (ßst = -0.226, p < 0.001), the LAEP (ßst = -0.406, p < 0.001), and seizure frequency (ßst = -0.156, p < 0.001) were statistically significantly associated with total QOLIE-31-P scores. CONCLUSION: The Lithuanian version of the QOLIE-31-P demonstrates optimal reliability and construct validity to be applied in this population. It is strongly associated with seizure frequency as well as short instruments used to measure anxiety, depression, and adverse medication effects.

Impact of exercise as a complementary management strategy in people with epilepsy: A randomized controlled trial.

OBJECTIVE: To measure the impact of 12 weeks of physical exercise as complementary management strategy on quality of life (QOL) in people with epilepsy (PWE). METHODS: In a parallel-group, randomized controlled study with blinded outcome assessment, PWE of 18-65 years old, smartphone users were randomized into two groups. The exercise group was advised minimum 150 min per week of moderate-intense aerobic activity, as per current WHO recommendation [1], in addition to standard medical care; the control group received only standard medical care. QOL was assessed using Quality of Life in Epilepsy (QOLIE-31) inventory [2,3]; physical activity, with Global Physical Activity Questionnaire version 2 (GPAQ), and Pedometer Step Counter (a smartphone-based activity tracker application), at baseline and after 12 weeks. Body weight, body mass index, seizure frequency, and stigma scores (Epilepsy Stigma Scale Austin and colleagues) [4] were also noted. RESULTS: One hundred and seventeen PWE were recruited (58 exercise, 59 control). Although there was an improvement in the physical activity correlates after 12 weeks compared to mean values at baseline, the differences were not significant between the groups. The total QOL mean scores at baseline in the exercise and control groups were 64.9 and 63.7 (p = 0.597) and after 12 weeks, 68.4 and 66.9 (p = 0.660), respectively. However, intragroup comparison of energy/fatigue score in the exercise group showed significant change with a p value of 0.009 and intragroup comparison of Overall QOL score in the control group showed a significant change with a p value of 0.003. Similar improvement was seen in stigma scores (p = 0.500) and seizure frequency (p = 0.388) at 12 weeks in exercise and control groups. After 12 weeks, mean values of METS ((metabolic equivalents) were 794.81 and 714.27 (p = 0.159), steps per day were 4018.32 and 3730.0 (p = 0.314), calories spent per day were 173.85 and 159.68 (p = 0.320 and distance walked per day in meters were 2576.52 and 2198.42 (p = 0.072), in the exercise and control groups, respectively. SIGNIFICANCE: Regular physical activity for at least 150 min per week, in the form of moderate-intense aerobic exercises resulted in positive yet non-significant improvement of QOL, seizure frequency, and stigma in PWE.

Effects of physical exercise in people with epilepsy: A systematic review and meta-analysis.

BACKGROUND: Studies suggest that physical exercise lead to improvements in the psychosocial dimension, associated comorbidities as well as to a higher quality of life (QoL) in people with epilepsy. However, there is a need to provide evidence-based guidelines for its prescription. Therefore, this review aimed to systematically evaluate and meta-analyze the available data on the potential effects of physical exercise training programs in people with epilepsy. METHODS: Four electronic databases (MEDLINE/PubMed, PEDro, SPORTDiscuss and Scopus) were searched systematically from their inception until April 2022 for randomized controlled trials (RCTs), comparative studies and non-controlled studies that provided information regarding the effects of physical exercise training programs on people with epilepsy. The studies' methodological quality assessment was performed using the PEDro, the MINORS and the Quality Assessment Tool for Before-After Studies with No Control Group scales. For the meta-analysis, inverse variance or generic inverse variance was use to report mean difference or standardized mean difference for continuous data and their 95% confidence intervals (CI). Heterogeneity was assessed with the Chi-squared test and I2 test. RESULTS: After removing duplicated studies, 82 results were retrieved by the literature search and 14 were eligible for full text search. Finally, 14 studies with a methodological quality ranging from good to low quality met the inclusion criteria. Totally, 331 people with epilepsy were evaluated. Significant changes between preand post-intervention results in the exercise intervention groups were observed for QoL, fitness level, psycho-affective and neurocognitive outcomes. Findings from the meta-analysis indicated that moderate exercise led to a non-significant decrease (p = 0.08, Chi-squared test) in seizure frequency (SMD 0.33 95% CI 0.04; 0.70), while a significant effect of exercise was observed on QoL with a mean improvement of 4.72 percentage points (95% CI 0.58; 8.86, p = 0.03). CONCLUSION: Improvements on QoL, fitness level, psycho-affective and neurocognitive outcomes can be achieved through exercise training in people with epilepsy. Altogether, the findings suggest that people with epilepsy can benefit from exercising.

Inflammatory and neurotrophic factor plasma levels are related to epilepsy independently of etiology.

OBJECTIVE: Inflammation plays an essential role in epilepsy. Studies indicate that cytokines and neurotrophic factors can act in neuroexcitability and epileptogenesis. We aimed to investigate the association between plasma inflammatory and neurotrophic markers, seizure frequency, and chronic epilepsy subtypes. METHODS: We studied 446 patients with epilepsy and 166 healthy controls. We classified patients according to etiology and seizure frequency. We measured plasma levels of interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), soluble TNF receptor 1 (sTNFr1), sTNFr2, brain-derived neurotrophic factor (BDNF), neurotrophic factor 3 (NT3), NT4/5, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) by enzyme-linked immunosorbent assay or cytometric bead array. RESULTS: The plasma levels of BDNF, NT3, NGF, and sTNFr2 were higher, whereas IL-2, IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα, CNTF, and sTNFr1 were lower in patients than controls. IL1, GDNF, and NT4/5 were similar between groups. These markers did not correlate with age, sex, and epilepsy duration. The molecule sTNFr2 was the best marker to discriminate patients from controls (area under the curve = .857), also differing between patients with frequent and infrequent seizures. SIGNIFICANCE: This large cohort confirmed that patients with epilepsy have abnormal levels of plasma inflammatory and neurotrophic markers independent of the underlying etiology. Plasma level of sTNFr2 was related to seizure frequency and discriminated people with or without epilepsy with good accuracy, making it a potential biomarker for epilepsy and seizure burden.

Assessing seizure burden in pediatric epilepsy using an electronic medical record-based tool through a common data element approach.

OBJECTIVE: Improvement in epilepsy care requires standardized methods to assess disease severity. We report the results of implementing common data elements (CDEs) to document epilepsy history data in the electronic medical record (EMR) after 12 months of clinical use in outpatient encounters. METHODS: Data regarding seizure frequency were collected during routine clinical encounters using a CDE-based form within our EMR. We extracted CDE data from the EMR and developed measurements for seizure severity and seizure improvement scores. Seizure burden and improvement was evaluated by patient demographic and encounter variables for in-person and telemedicine encounters. RESULTS: We assessed a total of 1696 encounters in 1038 individuals with childhood epilepsies between September 6, 2019 and September 11, 2020 contributed by 32 distinct providers. Childhood absence epilepsy (n = 121), Lennox-Gastaut syndrome (n = 86), and Dravet syndrome (n = 42) were the most common epilepsy syndromes. Overall, 43% (737/1696) of individuals had at least monthly seizures, 17% (296/1696) had a least daily seizures, and 18% (311/1696) were seizure-free for >12 months. Quantification of absolute seizure burden and changes in seizure burden over time differed between epilepsy syndromes, including high and persistent seizure burden in patients with Lennox-Gastaut syndrome. Individuals seen via telemedicine or in-person encounters had comparable seizure frequencies. Individuals identifying as Hispanic/Latino, particularly from postal codes with lower median household incomes, were more likely to have ongoing seizures that worsened over time. SIGNIFICANCE: Standardized documentation of clinical data in childhood epilepsies through CDE can be implemented in routine clinical care at scale and enables assessment of disease burden, including characterization of seizure burden over time. Our data provide insights into heterogeneous patterns of seizure control in common pediatric epilepsy syndromes and will inform future initiatives focusing on patient-centered outcomes in childhood epilepsies, including the impact of telemedicine and health care disparities.

Sex differences in seizure effects on social anxiety in persons with epilepsy.

PURPOSE: We investigated sex differences in the effect of seizures on social anxiety in persons with epilepsy. METHOD: In this cross-sectional multicenter study, social anxiety was measured using the short forms of the Social Phobia Scale (SPS-6) and Social Interaction Anxiety Scale (SIAS-6). SPS-6 scores ≥ 9 and SIAS-6 scores ≥ 12 were considered to indicate social phobia and social interaction anxiety, respectively. The Patient Health Questionnaire-9, Stigma Scale-Revised, and Family Adaptation-Partnership-Growth-Affection-Resolve scale were also completed. A logistic regression analysis with an interaction term was used to analyze the data. RESULTS: Out of 285 participants, a SPS-6 score ≥ 9 and a SIAS-6 score ≥ 12 were noted in 62 (21.8%) and 36 (12.6%) of participants, respectively. There was no difference in the prevalence of social anxiety between men and women. Intractable seizures and lack of seizure freedom were associated with a SPS-6 score ≥ 9 and a SIAS-6 score ≥ 12, but statistical significance was lost in the adjusted models. However, intractable seizures and lack of seizure freedom significantly interacted with sex for a SPS-6 score ≥ 9 (p = 0.018) and a SIAS-6 score ≥ 12 (p = 0.048) in both the separate and adjusted models. Specifically, intractable seizures tended to be positively associated with SPS-6 scores ≥ 9 than non-intractable seizures in men only (odds ratio = 2.602, p = 0.068), whereas lack of seizure freedom tended to be negatively associated with SIAS-6 scores ≥ 12 than seizure freedom in women only (odds ratio = 4.804, p = 0.053). CONCLUSION: We found significant sex differences in seizure effects on social anxiety. Intractable seizures were associated with social phobia in men, whereas lack of seizure freedom in the last year was associated with social interaction anxiety in women.

Long-term safety and efficacy of highly purified cannabidiol for treatment refractory epilepsy.

OBJECTIVE: To evaluate the safety, efficacy, and tolerability of highly purified cannabidiol (CBD) for the treatment of seizures in children and adults with treatment-resistant epilepsy (TRE) in an open-label, expanded access program (EAP). METHODS: One hundred sixty-nine participants (89 children and 80 adults) with TRE received plant-derived highly purified CBD (Epidiolex® in the U.S.; 100 mg/mL oral solution) with a starting dose of 5 mg/kg/day divided twice per day and titrated to a maximum dose of 50 mg/kg/day over the study period to seizure control and tolerability and followed for up to 2 years. Seizure frequency (calendars) and severity (Chalfont Seizure Severity Score; CSSS) were collected at every study visit. Adverse Events were reported at/between study visits as required, and participants also completed Adverse Events Profile (AEP) which generates a numerical representation of AEs. Response to CBD was defined as ≥50% reduction in seizure frequency. Given non-normal distribution of seizure frequency, a log transformation was applied after which the generalized least squares regression model for longitudinal data was used. RESULTS: Evidence from the adjusted model revealed a significant mean reduction in seizure frequency compared to baseline in children and adults at all time points (1 month and 1 and 2 years). Percentage of children achieving ≥50% seizure frequency reduction was 44% at month 1, and 41% at year 1, and 61% reduction at year 2, while adult responder rates were 34% at month 1, 53% at year 1, and 71% at year 2 (all P < 0.0001). CSSS showed a sustained reduction from baseline to all 3 time points. Children displayed 52% seizure reduction at month 1, a 51% reduction at year 1, and 75% reduction at year 2. Seizure reductions in adults were 60%, 81%, and 85%, respectively (all P < 0.0001). While there were no significant differences between seizure frequency reduction between children and adults at all time points, there was a significant difference in seizure severity reduction at year 1, with adults reporting greater improvement in seizure severity (P < 0.001). The most commonly reported adverse events in the study period were diarrhea, sedation, and decreased appetite. AEP revealed significant improvement from baseline at multiple time points in adults and children, and the mean AEP scores were always lower compared to baseline over the duration of the study. SIGNIFICANCE: Our study provides further evidence of sustained seizure frequency and severity reduction over two years of treatment with highly purified CBD in TRE. In addition, CBD was generally well tolerated with minority of participants experiencing adverse events resulting in stopping CBD.