Identification of gene regulatory networks affected across drug-resistant epilepsies.

Epilepsy is a chronic and heterogenous disease characterized by recurrent unprovoked seizures, that are commonly resistant to antiseizure medications. This study applies a transcriptome network-based approach across epilepsies aiming to improve understanding of molecular disease pathobiology, recognize affected biological mechanisms and apply causal reasoning to identify therapeutic hypotheses. This study included the most common drug-resistant epilepsies (DREs), such as temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), and mTOR pathway-related malformations of cortical development (mTORopathies). This systematic comparison characterized the global molecular signature of epilepsies, elucidating the key underlying mechanisms of disease pathology including neurotransmission and synaptic plasticity, brain extracellular matrix and energy metabolism. In addition, specific dysregulations in neuroinflammation and oligodendrocyte function were observed in TLE-HS and mTORopathies, respectively. The aforementioned mechanisms are proposed as molecular hallmarks of DRE with the identified upstream regulators offering opportunities for drug-target discovery and development.

Cannabidiol: metabolism and clinical efficacy in epileptic patients.

INTRODUCTION: The landscape of epilepsy treatment has undergone a significant transformation with the emergence of cannabidiol as a potential therapeutic agent. Epidiolex, a pharmaceutical formulation of highly purified CBD, garnered significant attention not just for its therapeutic potential but also for being the first cannabis-derived medication to obtain approval from regulatory bodies. AREA COVERED: In this narrative review the authors explore the intricate landscape of CBD as an antiseizure medication, deepening into its pharmacological mechanisms and clinical trials involving various epileptic encephalopathies. This exploration serves as a comprehensive guide, shedding light on a compound that holds promise for individuals contending with the significant challenges of drug-resistant epilepsy. EXPERT OPINION: Rigorous studies highlight cannabidiol's efficacy, safety profile, and potential cognitive benefits, warranting further exploration for its approval in various drug-resistant epilepsy forms. As a promising therapeutic option, cannabidiol not only demonstrates efficacy in seizure control but also holds the potential for broader enhancements in the quality of life, especially for patients with epileptic encephalopathies.

A 3.5-year clinical experience with perampanel for refractory epilepsy.

OBJECTIVE: This study aimed to evaluate the efficacy and tolerability of perampanel, which was used in a cohort of patients with refractory epilepsy for up to 3.5 years in a real-world setting in Saudi Arabia. PATIENTS AND METHODS: Data from the medical records of patients treated with perampanel between March 13th, 2017, and September 6th, 2020, at neurology clinics at King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh and Jeddah, Saudi Arabia, was collected. The Liverpool Adverse Events Profile (LAEP) scale was also used to measure the adverse effects of perampanel. RESULTS: Of the 75 included patients, 66.7% responded to perampanel at the last follow-up, including 22.7% seizure-free for at least the last six months, and 44% of patients responded with a ≥ 50% reduction in seizure frequency from baseline. The overall incidence of adverse effects that led to perampanel discontinuation was 13.3%; the most common adverse effect was aggressive behavior followed by sedation. Pre-existing psychiatric comorbidity was significantly associated with the incidence of psychiatric and behavioral adverse effects on perampanel (p = 0.0206). The mean score of LEAP was 40. The most frequently rated adverse effects in LEAP were "feelings of anger and aggression to others", "nervousness and/or agitation" and "sleepiness". The efficacy and tolerability of perampanel were dose-dependent. Dose 6 mg/day was the most frequently used dose that was taken by about one-third of patients at their last visit. CONCLUSIONS: Perampanel was effective as an adjunctive treatment for intractable seizures, with a responder rate of 66.7%. The long-term tolerability of perampanel was generally good. Aggressive behavior was the most common reason for perampanel discontinuation. Patients should be counseled and monitored for these adverse effects, particularly those with a history of previous psychiatric and behavioral problems.

Neuropsychological characteristics of drug resistant epilepsy patients with and without comorbid functional seizures.

INTRODUCTION: Neuropsychological testing is a mandatory component in the evaluation of drug resistant epilepsy. The results of testing may assist with both the localization of an epilepsy as well as assessment of surgical risk. Previous studies have demonstrated differences in the neuropsychological performance of patients with epilepsy and functional seizures. We hypothesized that comorbid functional seizures could potentially influence neuropsychological test performance. Therefore, we evaluated whether there is a difference in the neuropsychological test results between drug resistant epilepsy patients with and without comorbid functional seizures. METHOD: Neuropsychological test results were compared between 25 patients with drug resistant focal epilepsy and 25 patients that also had documented functional seizures. Univariate analyses and multiple logistic regression models were used to both assess performance differences between the groups and to assess whether test results could be used to accurately identify which patients had comorbid functional seizures. RESULTS: Epilepsy patients with comorbid functional seizures performed significantly worse on the FAS Verbal Fluency Test compared to ES patients (p = 0.047). Digit Span Backwards (p = 0.10), Digit Span Forwards (p = 0.14) and Working Memory Index (p = 0.10) tended to be lower in the epilepsy and functional seizures group but was not statistically significant. A multiple logistic regression model using the results of four neuropsychological tests was able to identify patients with comorbid functional seizures with 83.33% accuracy. CONCLUSIONS: There are appeared to be some differences in the neuropsychological performance among drug resistant epilepsy patients based on whether they have comorbid functional seizures. These findings may have relevant implications for the interpretation of neuropsychological test results.

Tracing topics and trends in drug-resistant epilepsy research using a natural language processing-based topic modeling approach.

Epilepsy is a common neurological disorder affecting over 70 million people worldwide. Although many patients achieve seizure control with anti-epileptic drugs (AEDs), 30%-40% develop drug-resistant epilepsy (DRE), where seizures persist despite adequate trials of AEDs. DRE is associated with reduced quality of life, increased mortality and morbidity, and greater socioeconomic challenges. The continued intractability of DRE has fueled exponential growth in research that aims to understand and treat this serious condition. However, synthesizing this vast and continuously expanding DRE literature to derive insights poses considerable difficulties for investigators and clinicians. Conventional review methods are often prolonged, hampering the timely application of findings. More-efficient approaches to analyze the voluminous research are needed. In this study, we utilize a natural language processing (NLP)-based topic modeling approach to examine the DRE publication landscape, uncovering key topics and trends. Documents were retrieved from Scopus, preprocessed, and modeled using BERTopic. This technique employs transformer models like BERT (Bidirectional Encoder Representations from Transformers) for contextual understanding, thereby enabling accurate topic categorization. Analysis revealed 18 distinct topics spanning various DRE research areas. The 10 most common topics, including "AEDs," "Neuromodulation Therapy," and "Genomics," were examined further. "Cannabidiol," "Functional Brain Mapping," and "Autoimmune Encephalitis" emerged as the hottest topics of the current decade, and were examined further. This NLP methodology provided valuable insights into the evolving DRE research landscape, revealing shifting priorities and declining interests. Moreover, we demonstrate an efficient approach to synthesizing and visualizing patterns within extensive literature that could be applied to other research fields.

Effects of midazolam on high-frequency oscillations in amygdala and hippocampus of epilepsy patients.

High-frequency oscillations (HFOs) are associated with normal brain function, but are also increasingly recognized as potential biomarkers of epileptogenic tissue. Considering the important role of interneuron activity in physiological HFO generation, we studied their modulation by midazolam (MDZ), an agonist of γ-aminobutyric acid type A (GABAA)-benzodiazepine receptors. Here, we analyzed 80 intracranial electrode contacts in amygdala and hippocampus of 13 patients with drug-refractory focal epilepsy who had received MDZ for seizure termination during presurgical monitoring. Ripples (80-250 Hz) and fast ripples (FRs; 250-400 Hz) were compared before and after seizures with MDZ application, and according to their origin either within or outside the individual seizure onset zone (SOZ). We found that MDZ distinctly suppressed all HFOs (ripples and FRs), whereas the reduction of ripples was significantly less pronounced inside the SOZ compared to non-SOZ contacts. The rate of FRs inside the SOZ was less affected, especially in hippocampal contacts. In a few cases, even a marked increase of FRs following MDZ administration was seen. Our results demonstrate, for the first time, a significant HFO modulation in amygdala and hippocampus by MDZ, thus giving insights into the malfunction of GABA-mediated inhibition within epileptogenic areas and its role in HFO generation.

Efficacy of daily versus intermittent low glycemic index therapy diet in children with drug-resistant epilepsy: A randomized controlled trial.

INTRODUCTION: The predominant reason for the discontinuation of low glycemic index therapy (LGIT) in children with epilepsy is the dietary restrictions imposed therein. This trial intended to compare the efficacy of daily and intermittent LGIT in children with drug-resistant epilepsy (DRE). METHODS: This study was performed between February 2018 and January 2019 to compare the efficacy of daily and intermittent LGIT in children aged 1-15 years with DRE following 24 weeks of dietary therapy. Compliance, the difficulty faced by caregivers, adverse effects, impact on behaviour, and social quotient in both arms were compared. Children in the intermittent LGIT arm received a liberalized diet for two days every week (Saturday and Sunday), which also allowed medium glycemic index foods. Carbohydrate calories were allowed up to 20% of the total caloric requirement in the liberalized diet, as compared to only 10% in standard LGIT. RESULTS: Out of 132 children randomized (66 in each group), 122 completed 24 weeks follow up. Mean weekly seizure frequency reduction at 24 weeks in the intermittent LGIT group was comparable with that of the daily LGIT group in both intention-to-treat (ITT) and per-protocol analysis (-50.95%± 22.34% vs -47.16%± 23.41%, p=0.36 in ITT and -53.88%±20.54% vs -49.20%±21.87%, p=0.23) in per-protocol analysis for intermittent and daily LGIT group respectively). The proportion with ≥50% reduction in seizure frequency was also comparable between both groups (p=0.73 and 0.56 in ITT and per protocol analysis respectively). The proportion of patients with adverse events and satisfactory compliance rate also had a trend towards favoring intermittent LGIT (p=0.06 and 0.51, respectively), while caregiver difficulty was lower with intermittent LGIT (p=0.001). CONCLUSIONS: Intermittent LGIT is comparable to daily LGIT in terms of seizure frequency reduction after 24 weeks of dietary therapy. TRIAL REGISTRATION: ClinicalTrials.gov (Registration number- NCT03464487, https://clinicaltrials.gov/ct2/show/NCT03464487).

The longitudinal effects of cannabidiol on brain temperature in patients with treatment-resistant epilepsy.

Neuroinflammation (NI) is a key pathophysiological contributor to treatment-resistant epilepsy (TRE) that remains challenging to observe in vivo. Magnetic resonance spectroscopic imaging and thermometry (MRSI-t) is an emerging technique that can be used to non-invasively map brain temperature, whereby brain temperature elevations serve as a surrogate for the cellular and biochemical processes associated with NI. In a previous multimodal imaging study of focal epilepsy patients, we observed MRSI-t-based brain temperature elevations ipsilateral to the seizure onset zone (SOZ) that were concordant with evidence of edema (Sharma et al., 2023). Despite its potential as tool, it is unclear if MRSI-t can monitor changes in brain temperature in response to treatment. We imaged 25 participants approximately 12-weeks apart. Eight patients with TRE were imaged before receiving highly-purified pharmaceutical grade cannabidiol (CBD; pre-CBD) and after 12-weeks of CBD (on-CBD) therapy. Seventeen healthy controls (HCs) were also imaged twice. Repeated measures t-tests computed changes in TRE patients' seizure symptoms, mood, and brain temperature within their respective SOZs. Repeated measures ANOVAs tested Group*Time changes in imaging data. Participants with TRE had abnormally high peak brain temperatures within their SOZs that decreased after CBD initiation (p < 0.0001). Seizure severity scores also improved after CBD initiation (p < 0.001). These findings provide insights into the possible neural effects of CBD, and further demonstrate MRSI-t's potential as a tool for delineating SOZ. Further investigations into MRSI-t as a longitudinal measure of therapy-induced changes in NI are warranted.

Effect of Cenobamate on Cognition in Patients with Drug-Resistant Epilepsy with Focal Onset Seizures: An Exploratory Study.

BACKGROUND AND OBJECTIVE: Most second and third generation antiseizure medications (ASMs) are associated with cognitive adverse events, which are a major concern for patients. However, the profile of cognitive adverse events differs between ASMs. This study investigated the effects of cenobamate on cognition in patients with drug-resistant epilepsy (DRE) within the Spanish Expanded Access Program (EAP). METHODS: This was a retrospective, observational study. Inclusion criteria were age ≥ 18 years, DRE with focal seizures, and availability of cognition assessments and EAP authorization. Data were sourced from the clinical records of patients who took part in the Spanish cenobamate EAP. Primary endpoints included cognition (based on 20 neuropsychological outcomes, including verbal and visuospatial episodic memory, verbal fluency, executive function, working memory, attention, and speed of processing), seizure frequency, and concomitant antiseizure medication (ASM) usage at 6 months. RESULTS: The study included 20 patients; 10 patients (50%) had daily seizures, 7 (35%) had weekly seizures and 3 (15%) had monthly seizures. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 10 and 3, respectively. Mean cenobamate doses were 12.5 mg/day at baseline and 191.2 mg/day at 6 months. There was a statistically significant improvement in cognitive scores between baseline and 6 months for two measures of verbal episodic memory (p = 0.0056 and p = 0.0013) and one measure of visuospatial episodic memory (p = 0.011), and a significant worsening in cognitive score for attention (p = 0.030). At 6 months, 14 patients (70%) had a ≥ 50% reduction in seizure frequency, 3 patients (15%) had a ≥ 90% reduction, and 1 patient (5%) was seizure free. There were significant decreases in the mean number of concomitant ASMs (p = 0.0009), the sum of the ratios of prescribing daily dose/daily defined dose (total ratio of DDD) for concomitant ASMs (p < 0.0001), and concomitant ASM drug load (p = 0.038) between baseline and 6 months. Total ratio of DDD was significantly lower at 6 months for perampanel (p = 0.0016), benzodiazepines (p = 0.035), and sodium channel blockers (p = 0.0005) compared with baseline. Based on analysis of covariance, cognitive tests related to verbal or visuospatial episodic memory (e.g., RT of FCSRT, or ROCFT), executive functions (e.g., TMT-B), and processing speed (some 5-Digit Test subtests) appeared to be closely related to the reduction in pharmacological burden rather than the improvement in seizure control. CONCLUSIONS: Significant improvements in cognition, seizure frequency, and concomitant ASM usage were observed after the introduction of cenobamate in patients with DRE in a real-world setting. Covariance analysis supports the reduction in concomitant ASMs as the most important factor driving cognitive improvements with cenobamate. As this was an exploratory study with an uncontrolled, retrospective design and a low number of patients, further studies are required to confirm the findings.

Predictors of clinically significant anhedonia in refractory epilepsy.

BACKGROUND: Anhedonia, the inability to feel pleasure or motivation for reward, is a core feature of depression in epilepsy, but can occur independent from depression. It is reported in over a third of people with epilepsy and has a significant impact on quality of life. OBJECTIVES: This study determined whether specific features of medication refractory epilepsy are predictive of anhedonia. DESIGN: We assessed 267 patients with medication refractory epilepsy for anhedonia, primarily using the clinically validated Snaith-Hamilton Pleasure Scale (SHAPS) scale. METHODS: Patients with clinically significant anhedonia were compared with those without for key demographics, epilepsy characteristics and medication using a logistic regression analysis. RESULTS: We found that seizure frequency (p < 0.01) but not duration of epilepsy was significantly associated with anhedonia. We also found that benzodiazepine use was significantly associated (p = 0.01) with anhedonia, and levetiracetam/brivaracetam and sodium valproate were significantly negatively associated with anhedonia (0.01 and 0.03 respectively). CONCLUSION: High seizure burden in medication refractory epilepsy is significantly associated with anhedonia. Specific antiseizure medications are also associated with the development of anhedonia, but it is unclear whether their use is causative or influenced by the presence of anhedonia.

Efficacy and safety of a smartphone application-based treatment of ketogenic diet in pediatric refractory epilepsy.

OBJECTIVE: We aimed to find predictors for smartphone application-based ketogenic diet (KD) treatment effectiveness and safety. METHODS: The efficacy was evaluated according to the reduction in seizure frequency after the intervention of KD; safety was evaluated based on adverse effects. The ordinal logistic regression analysis was used to explore the influencing factors of efficacy. RESULTS: The study sample included 116 males and 65 females with a median age of 2.27 years. The baseline frequency of seizure was more than five times/day in 123 children, 50.83% of them received three or more antiepileptic drugs (AEDs). Seventy-two patients' KD initiation mode was outpatient, and 73 completed the 12-month follow-up. A total of 88 (48.62%) patients had reported a reduction in seizure ≥50%. Compared with 12 months, those who had received KD therapy for only 3 (P = 0.009) and 6 months (P = 0.005) were more likely to show negative outcomes. Outpatient initiation had better outcomes (P = 0.029) than inpatient initiation. For the number of AEDs applied, patients on two AEDs were more likely to achieve better outcomes (P = 0.001). Adverse events had been noted among 77 patients; BMI Z-score at KD initiation was associated with adverse effects (P = 0.003). SIGNIFICANCE: Our study suggested that outpatient initiation and long-term treatment of KD should be encouraged. PLAIN LANGUAGE SUMMARY: Our research shows that the KD is a helpful treatment for children with refractory epilepsy, reducing seizures by more than 50% in nearly half of the cases, with some experiencing complete seizure freedom. We used a smartphone app to improve communication between patients and their healthcare teams, resulting in a high retention, and app usage was linked to reduced adverse effects. We recommend early consideration of KD treatment for patients failing two AED, encourage outpatient initiation, and advocate for longer-term KD use.

Effectiveness and safety of mono- and add-on perampanel in pediatric patients with epilepsy: Experience from a single-center retrospective study.

OBJECTIVE: To evaluate the effectiveness and safety of perampanel (PER) monotherapy (MT) or add-on therapy (AT) in Chinese children with epilepsy, as well as to evaluate the data from routine therapeutic drug monitoring (TDM) of PER for these pediatric patients. METHODS: This retrospective and observational study was carried out on children with epilepsy (n = 340) from 2020 to 2022 at the Children's Hospital of Nanjing Medical University. Outcome measures were the responder rate (50% or greater seizure reduction), long-term efficacy, and tolerability (number and types of adverse events) in MT and AT groups. Concentrations of plasma PER obtained from these patients, if available, were analyzed too. RESULTS: A total of 279 patients achieved at least 3 months of therapy, and 58.1% responded to PER therapy. 53 of the responders were seizure-free (32.7%). The retention rate dropped from 88.0% at 3 months to 40.6% at 12 months after treatment. Patients with MT achieved better seizure control than those with AT (P < 0.001). Intriguingly, PER exerted a very weak effect on patients who took more than 2 ASMs or were diagnosed with drug-resistant epilepsy. There were no significant differences in tolerability between the two groups. In addition, 179 patients were routinely monitored for PER, and the trough concentrations (C0 ) for these patients ranged from 30.0 to 992.0 ng/mL. However, no significant difference in C0 was observed between responders and nonresponders (333 ng/mL vs 325.5 ng/mL, P = 0.264). SIGNIFICANCE: This study provides effectiveness and safety data on Chinese children with epilepsy treated with PER either as MT or as AT. The efficacy of patients receiving MT was much better than cases administered with more than 2 ASMs or diagnosed with drug-resistant epilepsy. In addition, no association was found between the plasma PER concentration and efficacy or safety. PLAIN LANGUAGE SUMMARY: The study reports the effects of perampanel on seizures and adverse effects in Chinese patients with epilepsy younger than 18 years. Seizures decreased in 58.1% of patients (responders); in a third of these responders, seizures stopped. After treatment was started, 88% of patients were still on perampanel at 3 months and 40.6% at 12 months. People who were treated with perampanel only were more likely to respond than those who received perampanel and other antiseizure treatments, although perampanel was tolerated equally well in these groups. Plasma perampanel concentration did not predict seizure response or adverse effects.

Real-Life Experience With Purified Cannabidiol Treatment for Refractory Epilepsy: A Multicenter Retrospective Study.

BACKGROUND: Drug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this population. METHODS: A retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018 to 2022 at five medical centers in Israel. RESULTS: The most common diagnosis was Lennox-Gastaut syndrome (37.4%) followed by Dravet syndrome (16.5%) and tuberous sclerosis complex (16.5%). Median purified CBD dose was 12.5 mg/kg (range 2.5 to 20.0), and median treatment duration was 9.0 months (range 0.5 to 48.0). Most patients (92.2%) had a reduced seizure frequency following treatment initiation; 41.1% had >50% reduction. Fifty-three patients (38.1%) had positive effects: improved alertness (31.7%), improved speech (10.1%), and achievement of new developmental milestones (2.2%). A multivariate linear model assessing predictive factors for seizure reduction demonstrated that patients previously treated with CBD oils, especially those with >50% seizure reduction on prior treatment, were also more likely to have a reduced seizure frequency while they were treated with purified CBD (P = 0.01, P < 0.0001). Development, diagnosis, age, purified CBD dose (0 to 10 mg/kg/day vs 10 to 20 mg/kg/day), and concomitant treatment with clobazam, valproic acid, or everolimus did not affect seizure reduction by purified CBD. The most common adverse events were irritability (20.9%) and drowsiness (12.9%). CONCLUSION: Purified CBD is well-tolerated and effective in reducing seizure frequency in children and young adults with DRE.

Expanding eligibility for intracranial electroencephalography using Dexmedetomidine Hydrochloride in children with behavioral dyscontrol.

INTRODUCTION: Invasive intracranial electroencephalography (IEEG) is advantageous for identifying epileptogenic foci in pediatric patients with medically intractable epilepsy. Patients with behavioral challenges due to autism, intellectual disabilities, and hyperactivity have greater difficulty tolerating prolonged IEEG recording and risk injuring themselves or others. There is a need for therapies that increase the safety of IEEG but do not interfere with IEEG recording or prolong hospitalization. Dexmedetomidine Hydrochloride's (DH) use has been reported to improve safety in patients with behavioral challenges during routine surface EEG recording but has not been characterized during IEEG. Here we evaluated DH administration in pediatric patients undergoing IEEG to assess its safety and impact on the IEEG recordings. METHODS: A retrospective review identified all pediatric patients undergoing IEEG between January 2016 and September 2022. Patient demographics, DH administration, DH dose, hospital duration, and IEEG seizure data were analyzed. The number of seizures recorded for each patient was divided by the days each patient was monitored with IEEG. The total number of seizures, as well as seizures per day, were compared between DH and non-DH patients via summary statistics, multivariable linear regression, and univariate analysis. Other data were compared across groups with univariate statistics. RESULTS: Eighty-four pediatric patients met the inclusion criteria. Eighteen (21.4 %) received DH treatment during their IEEG recording. There were no statistical differences between the DH and non-DH groups' demographic data, length of hospital stays, or seizure burden. Non-DH patients had a median age of 12.0 years (interquartile range: 7.25-15.00), while DH-receiving patients had a median age of 8.0 years old (interquartile range: 3.00-13.50) (p = 0.07). The non-DH cohort was 57.6 % male, and the DH cohort was 50.0 % male (p = 0.76). The median length of IEEG recordings was 5.0 days (interquartile range: 4.00-6.25) for DH patients versus 6.0 days (interquartile range: 4.00-8.00) for non-DH patients (p = 0.25). Median total seizures recorded in the non-DH group was 8.0 (interquartile range: 5.00-13.25) versus 15.0 in the DH group (interquartile range: 5.00-22.25) (p = 0.33). Median total seizures per day of IEEG monitoring were comparable across groups: 1.50 (interquartile range: 0.65-3.17) for non-DH patients compared to 2.83 (interquartile range: 0.89-4.35) (p = 0.25) for those who received DH. Lastly, non-DH patients were hospitalized for a median of 8.0 days (interquartile range: 6.00-11.25), while DH patients had a median length of stay of 7.00 days (interquartile range: 5.00-8.25) (p = 0.27). No adverse events were reported because of DH administration. CONCLUSIONS: Administration of DH was not associated with adverse events. Additionally, the frequency of seizures captured on the IEEG, as well as the duration of hospitalization, were not significantly different between patients receiving and not receiving DH during IEEG. Incorporating DH into the management of patients with behavioral dyscontrol and intractable epilepsy may expand the use of IEEG to patients who previously could not tolerate it, improve safety, and preserve epileptic activity during the recording period.

AMPK role in epilepsy: a promising therapeutic target?

Epilepsy is a complex and multifaceted neurological disorder characterized by spontaneous and recurring seizures. It poses significant therapeutic challenges due to its diverse etiology and often-refractory nature. This comprehensive review highlights the pivotal role of AMP-activated protein kinase (AMPK), a key metabolic regulator involved in cellular energy homeostasis, which may be a promising therapeutic target for epilepsy. Current therapeutic strategies such as antiseizure medication (ASMs) can alleviate seizures (up to 70%). However, 30% of epileptic patients may develop refractory epilepsy. Due to the complicated nature of refractory epilepsy, other treatment options such as ketogenic dieting, adjunctive therapy, and in limited cases, surgical interventions are employed. These therapy options are only suitable for a select group of patients and have limitations of their own. Current treatment options for epilepsy need to be improved. Emerging evidence underscores a potential association between impaired AMPK functionality in the brain and the onset of epilepsy, prompting an in-depth examination of AMPK's influence on neural excitability and ion channel regulation, both critical factors implicated in epileptic seizures. AMPK activation through agents such as metformin has shown promising antiepileptic effects in various preclinical and clinical settings. These effects are primarily mediated through the inhibition of the mTOR signaling pathway, activation of the AMPK-PI3K-c-Jun pathway, and stimulation of the PGC-1α pathway. Despite the potential of AMPK-targeted therapies, several aspects warrant further exploration, including the detailed mechanisms of AMPK's role in different brain regions, the impact of AMPK under various conditional circumstances such as neural injury and zinc toxicity, the long-term safety and efficacy of chronic metformin use in epilepsy treatment, and the potential benefits of combination therapy involving AMPK activators. Moreover, the efficacy of AMPK activators in refractory epilepsy remains an open question. This review sets the stage for further research with the aim of enhancing our understanding of the role of AMPK in epilepsy, potentially leading to the development of more effective, AMPK-targeted therapeutic strategies for this challenging and debilitating disorder.

Effect of drug treatment changes and seizure outcomes on depression and suicidality in adults with drug-resistant focal epilepsy.

OBJECTIVE: To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after the addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy. METHODS: Seven hundred seventy consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model. RESULTS: At baseline, 50% of patients had a positive screening test result for depression and 13% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. In addition, the number of ASMs taken at baseline correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients who were initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to the type of ASM introduced, sociodemographic variables, or seizure outcomes. SIGNIFICANCE: Almost 1 in 5 adults with drug-resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. At re-assessment 6 months later, 6.1% who screen initially negative for passive suicidal ideation become positive. These changes in screening status are independent of type of ASM introduced or seizure outcomes but correlate with psychiatric status at baseline.

Favorable combinations of antiseizure medication with vagus nerve stimulation to improve health-related quality of life in patients with epilepsy.

BACKGROUND: Vagus nerve stimulation (VNS) is a non-pharmacological treatment of refractory epilepsy, which also has an antidepressive effect. The favorable combinations of VNS with specific mechanisms of action of antiseizure medication (ASM) on mood and health-related quality of life (HrQol) have not yet been studied. The objective was to identify favourable combinations of specific ASMs with VNS for the HrQoL and depression in refractory epilepsy. METHODS: We performed an observational study including patients with refractory epilepsy and an implanted VNS (N = 151). In the first 24 months after VNS implantation, all patients were on stable ASM therapy. We used the standardized questionnaires QOLIE10, EQVAS and EQ5D to evaluate HrQoL as well as the Beck Depression Inventory (BDI). Multiple regression analysis was performed to evaluate the synergistic combinations of ASM with VNS for HrQoL. RESULTS: At the year-two follow-up (N = 151, age 45.2 ± 17.0 years), significant improvement (p < 0.05) in BDI scores was found for combination of VNS with SV2A modulators (58.4 %) or AMPA antagonists (44.4 %). A significant increase of HrQoL by at least 30 % (p < 0.05) was measured for a combination of VNS with SV2A modulators (brivaracetam, levetiracetam) or slow sodium channel inhibitors (eslicarbazepine, lacosamide). CONCLUSION: The results of our study suggests a favorable effect of the combination of SV2A modulators or slow sodium channel inhibitors with VNS on the HrQoL in comparison to other ASMs. Besides the possible synergistic effects on the seizure frequency, the amelioration of behavioral side effects of SV2A modulators by VNS is an important factor of HrQoL-improvement in these combinations.

Add-on treatment with cenobamate is already effective at low doses in refractory focal epilepsy: A prospective observational study.

OBJECTIVE: Cenobamate, a novel antiseizure medication with a dual mechanism of action, has been shown in pivotal trials to significantly improve seizure control in treatment-resistant focal epilepsy. We aimed to evaluate whether these promising results could be confirmed in a real-world setting with a follow-up period of up to 12 months. METHODS: Patients from a tertiary epilepsy center who received cenobamate add-on between June 2021 and October 2023 were followed up prospectively at 3, 6, and 12 months after treatment initiation for assessment of seizure outcomes and treatment-related adverse events. RESULTS: The clinical cohort included 112 adult patients with 30% nonlesional cases and a wide spectrum of epileptogenic lesions underlying refractory focal epilepsy. We observed a significant reduction in monthly seizure frequency of all seizure types already after 3 months of treatment at a median cenobamate dose of 100 mg/day. Forty-six percent of patients were responders with a ≥50% seizure reduction, 26% had a ≥75% seizure reduction, and 9% became seizure-free. Among the 74 patients with available follow-up of 12 months, the responder rates reached 55%, 35%, and 19% for ≥50%, ≥75%, and 100% seizure reduction, respectively. After 3 months of treatment, 38% of patients reported adverse effects, mainly (84%) mild to moderate in intensity. Adjustment of comedication allowed successful management of adverse effects in 32% of patients. At a group level, there was no correlation between the cenobamate daily dose and the incidence of adverse events. SIGNIFICANCE: We found a clinically relevant response to cenobamate already at a low daily dose of 100 mg also in a patient cohort with a higher degree of drug resistance than in pivotal trials. Our prospectively collected data provide real-world evidence for high efficacy and good tolerability of the drug, although no standardized treatment protocol or comparison with a control group was applied.

WRAPPER study: Real-world effectiveness and tolerability of adjunctive perampanel for people with drug-resistant epilepsy in Hong Kong.

OBJECTIVE: The Prince of Wales Hospital (PWH) Real-world Analysis of People with Drug-Resistant Epilepsy (DRE) on PERampanel (WRAPPER) study assessed effectiveness and tolerability of adjunctive perampanel in people with DRE attending PWH. METHODS: This was a prospective single-center real-world observational study involving 70 people with DRE between July 2016 and June 2021. A post hoc analysis after the initial study period of 16 weeks assessed outcomes for an extended period up to 52 weeks. RESULTS: After 16 weeks, median dose of perampanel was 2 mg (IQR 24 mg). 50% responder rates were 40.0%, 41.5%, and 48.7% at 16, 26, and 52 weeks. Seizure freedom was 12.9%, 20.7%, and 25.6% at 16, 26, and 52 weeks. Monthly seizure frequency reduced from 3.0 (IQR 3.0-6.6) at baseline to 2.0 (IQR 2.0-6.0, p = 0.005) at 16 weeks; 2.0 (IQR 2.0-5.0, p = 0.01) at 26 weeks; and 2.0 (IQR 0.0-4.0, p = 0.018) at 52 weeks. Older age predicted 50% responders (OR 1.08, 95% CI 1.01-1.14, p = 0.048). At 16 weeks, 51.4% (36/70) had treatment-emergent adverse effects (TEAEs). Most common was seizure exacerbation at 35.7% (25/70) followed by fatigue at 15.7% (11/70). NPI-12 and ZBI scores indicated no increase in neuropsychiatric symptoms on perampanel. SIGNIFICANCE: Low-dose 2-4 mg adjunctive perampanel for people with DRE conferred appreciable improvements in seizure reduction without significant neuropsychiatric adverse effects in the real-world setting at a tertiary center in Hong Kong and had better antiseizure effect with advancing age. PLAIN LANGUAGE SUMMARY: This real-world study from Hong Kong found low-dose perampanel was effective and tolerable for people with drug-resistant epilepsy. Furthermore, perampanel was also potentially more effective with advancing age.