Seizure Frequency Research Articles

Valproate discontinuation in girls and women of childbearing age with epilepsy: An Italian multicenter retrospective study on prescribing patterns and outcomes.

This study aimed to identify prescribing behaviors in women of childbearing potential (WOCP) with epilepsy already taking valproate (VPA), and to investigate the relationship between VPA maintenance, substitution, reduction, or withdrawal as part of polytherapy, and seizure worsening or relapse. We retrospectively reviewed the prescription behaviors and seizure outcomes in WOCP (16-50 years of age) with epilepsy, referred to eight Italian epilepsy centers, who were taking VPA for at least 1 year between 2014 and 2019. Among 750 women (~12% of all WOCP), 528 (70.4%) maintained VPA unchanged throughout the observation period, 103 (13.7%) replaced VPA with another antiseizure medication (ASM), 90 (12%) reduced VPA, and 29 (3.9%) discontinued VPA in polytherapy. Focal epilepsy was most strongly associated with VPA withdrawal (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.38-6.38), whereas generalized epilepsy was most associated with its non-withdrawal (reduction/switch/maintenance) (OR .31, 95% CI .14-.68). Intellectual disability, higher seizure frequency, and higher VPA doses were linked to VPA continuation. VPA withdrawal from polytherapy was associated with a higher risk of tonic-clonic seizure worsening (OR 2.91, 95% CI 1.09-7.77) compared to non-withdrawal. VPA was rarely withdrawn or substituted in WOCP with epilepsy, in secondary and tertiary care settings following European regulatory restrictions. This likely reflects a population with severe epilepsies where VPA is difficult to replace; whereas women with milder epilepsies likely discontinued VPA earlier, as evidenced by its low overall prescription frequency. Withdrawal of VPA from a polytherapy regimen was associated with a threefold increased risk of seizure exacerbation.

Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes

Variants in genes encoding for voltage-gated K+ (Kv) channels are frequent cause of drug-resistant pediatric epilepsies. Obtaining a molecular diagnosis gives the opportunity to assess the efficacy of pharmacological strategies based on in vitro features of mutant channels. In this retrospective observational study, we selected patients with drug-resistant pediatric epilepsies caused by variants in potassium channel encoding genes, followed at the Fondazione IRCCS Istituto Neurologico Carlo Besta of Milan, Italy. After the experimental characterization of variants’ functional properties in transiently transfected Chinese Hamster Ovary (CHO) cells, we identified drugs to be used as pharmacological approaches. We recruited six patients carrying different missense variants in four Kv channels (Kv7.2, Kv7.3, Kv3.1, and KNa1.1). In vitro experiments demonstrated that variants in Kv7 channels induced loss-of-function (LoF) effects, while those affecting Kv3.1 or KNa1.1 led to gain-of-function (GoF). Moreover, we found that the Kv7 channels activator gabapentin was able to revert the LoF effects caused by Kv7.2/Kv7.3 variants, and the potassium channel-blocker fluoxetine counteracted the GoF effects in Kv3.1 or KNa1.1 variants. According to experimental data, patients carrying Kv7 variants were treated with gabapentin. While this treatment resulted successful in two patients (#1, Kv7.2 G310S variant; #3, Kv7.3 V359L + Kv7.3 D542N), it resulted detrimental in the remaining case (#2, Kv7.2 D535E), requiring drug withdrawal. The application in vivo of fluoxetine to counteract GoF effects induced by Kv3.1 or KNa1.1 variants determined a significant reduction of both seizure frequency and behavior disturbances in patient #4 (Kv3.1 V425M), and in both subjects carrying KNa1.1 variants (#5, S937G and #6, R262Q). However, for the latter case, this drug was halted due to severe behavioral side effects. For most of the patients herein reported, pharmacological strategies, selected according to the in vitro functional properties of Kv-channels pathogenic variants, resulted in a significant improvement of both epileptic and cognitive features.

Cognitive and behavioral impact of antiseizure medications, neuromodulation, ketogenic diet, and surgery in lennox-gastaut syndrome: A comprehensive review.

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy marked by drug-resistant seizures and profound cognitive and behavioral impairments, with nearly 95% of individuals affected by moderate to severe intellectual disability. This review comprehensively explores the cognitive and behavioral impacts of current treatment options for LGS, including antiseizure medications (ASMs), neuromodulation strategies, the ketogenic diet, and surgical interventions. Given the limited availability of LGS-specific data for several ASMs, the evidence base is supplemented with findings from general epilepsy populations and individuals with epilepsy and intellectual disabilities. The evidence reveals that ASMs exert varied cognitive and behavioral effects in LGS. Medications such as valproate, lamotrigine, cannabidiol, fenfluramine, levetiracetam, brivaracetam, felbamate, and rufinamide generally support cognitive stability, while topiramate and zonisamide are associated with cognitive challenges. Behavioral outcomes also vary: stability is observed with valproate, lamotrigine, rufinamide, cannabidiol, and fenfluramine, whereas medications like levetiracetam, perampanel, brivaracetam, clobazam, and zonisamide can increase aggression or irritability. Nonpharmacological therapies, particularly when they reduce seizure frequency, typically provide greater cognitive and behavioral stability, with some offering improvement. Early intervention-especially through surgical options-appears most beneficial for preserving cognitive function. Additionally, therapies such as the ketogenic diet and neuromodulation may provide independent cognitive benefits beyond seizure control. This review emphasizes the importance of personalized treatment strategies, integrating cognitive and behavioral evaluations in therapy selection. Key components include baseline cognitive and behavioral assessments, followed by regular follow-up evaluations, particularly after therapy changes. Consideration of minimizing ASM polytherapy, careful evaluation of drug-drug interactions, pharmacogenomic implications, and the need for therapeutic drug monitoring in cases of cognitive adverse effects is essential. Future research should focus on developing assessment tools tailored to the unique needs of individuals with LGS, utilizing connectivity measures to assess intervention impacts, and advancing precision therapeutics to improve cognitive and behavioral outcomes.

The impact of ketogenic diet on the frequency of psychogenic non-epileptic seizures (PNES): A feasibility randomized pilot study.

The potential of dietary interventions, particularly the use of the ketogenic diet in patients with Psychogenic Non-Epileptic Seizures (PNES), remains underexplored. This study aimed to assess the feasibility of a 6-week ketogenic diet (Modified Atkins Diet, MAD) intervention in adult patients with PNES and to compare its effects on PNES frequency and other variables against a control healthy diet (CD). A feasibility pilot randomized controlled trial was conducted at a tertiary neurology hospital, enrolling outpatients diagnosed with PNES and assigning them to either MAD or CD. Baseline and follow-up assessments (at 2, 4, and 6 weeks) included evaluation of mental health, PNES frequency, and metabolic measures. Descriptive and inferential methods, including repeated measures ANOVA, were used for statistical analysis. Seventeen patients (mean age 28.23 ± 7.1) were randomly allocated to receive either MAD (n = 12) or CD (n = 5). The entire sample exhibited a significant decrease in monthly PNES frequency (p = 0.01, Hedges ES = 0.618) without differences between groups. The MAD group showed significant improvement in PNES frequency, depression, and anxiety at week six. Results demonstrate that the implementation of MAD is feasible in patients with PNES and suggest that it may reduce seizure frequency and symptoms of depression and anxiety. These findings warrant further investigation in larger, powered studies to demonstrate efficacy. PLAIN LANGUAGE SUMMARY: This study explored the potential benefits of the Modified Atkins Diet (MAD) in reducing the frequency of psychogenic non-epileptic seizures (PNES). The results showed that the diet is safe, well-tolerated, and may decrease the occurrence of PNES, as well as symptoms of depression and anxiety. These findings suggest that dietary modifications could be a helpful complement to PNES treatment, though larger studies are necessary to confirm these outcomes.

Seizure prediction and forecasting: a scoping review.

This scoping review summarizes key developments in the field of seizure forecasting. Developments have been made along several modalities of seizure forecasting, including long term intracranial and subcutaneous encephalogram, wearable physiologic monitoring, and seizure diaries. However, clinical translation of these tools is limited by various factors. One is the lack of validation of these tools on an external dataset. Moreover, the widespread practice of comparing models to a chance forecaster may be inadequate. Instead, the model should be able to at least surpass a moving average forecaster, which serves as a 'napkin test' (i.e., can be computed on the back of a napkin). The impact of seizure frequency on model performance should also be accounted for when comparing performance across studies. Surprisingly, despite the potential for poor quality forecasts, some individuals with epilepsy still want access to imprecise forecasts and some even alter their behavior based upon them. Promising advances have been made in the development of tools for seizure forecasting, but current tools have not yet overcome clinical translation hurdles. Future studies will need to address potentially dangerous patient behaviors as well as account for external validation, the napkin test, seizure frequency dependent metrics.

Long-term outcome and predictors of vagus nerve stimulation for drug-resistant epilepsy: Real-world evidence from the Korean national hospital consortium.

This study aimed to assess the long-term outcome and prognostic factors of vagus nerve stimulation (VNS) for drug-resistant epilepsy (DRE) using real-world data. We included 189 DRE patients who underwent VNS implantation between 2005 and 2018 at nine national hospitals in Korea. Seizure-frequency data obtained quarterly one year before and after surgery and annually up to four years after surgery were collected from medical records. Health resource utilization trends over the four years preceding and following surgery were assessed through linkage with national health insurance data. We performed interrupted time series analysis to examine the trend in seizure frequency before and after one year following surgery. The seizure frequency exhibited a decreasing trend in 27.5 % and an increasing trend in 3.8 % during the first year following VNS implantation without a significant change in efficacy over the subsequent three years. Patients with focal spikes with secondary bilateral synchrony (SBS) in electroencephalography had a higher responder rate (adjusted odds ratio (aOR)= 3.06 [1.36-6.90]), whereas those with Lennox-Gastaut syndrome had a lower responder rate (aOR=0.38 [0.15-0.94]). One-year seizure-freedom was achieved in 6.0 % of patients at some point during the four-year follow-up. Over an eight-year period, the number of antiseizure medications (ASMs) tended to increase before surgery and remained at a median of 5 [4-6] after surgery. While the total medical and epilepsy-related costs tended to decrease after surgery, the ASM cost continued to increase. VNS was substantially beneficial for one in four patients with DRE, offering the chance of seizure-freedom. However, the efficacy of VNS fell within the efficacy range of recently introduced medical treatments and did not lead to a decrease in the ASM burden. Focal spike with SBS is a potential biomarker for a favorable response to VNS.

Association between glymphatic system function and cognitive impairment in elderly patients with late-onset epilepsy.

Recent studies have shown that late-onset epilepsy (LOE) is accompanied with cognitive decline and increased risk of dementia, particularly Alzheimer's disease (AD). However, the pathophysiological mechanism underlying the cognitive decline in LOE remains unclear. The aim of current study was to evaluate the relationship between glymphatic system (GS) function and cognitive decline in LOE patients using the diffusion tensor imaging (DTI) analysis along the perivascular space (DTI-ALPS). Medical records and neuro-imaging data were obtained from 21 LOE patients with cognitive decline, 14 LOE patients without cognitive decline, and 20 age- and sex-matched healthy controls (HCs). Plasma biomarkers including Aβ42 and Aβ40 were examined using single-molecule array (Simoa) assays. The DTI-ALPS parameter was calculated and correlated with the clinical characteristics of LOE, including age, seizure frequency, duration of epilepsy, Mini-Mental State Examination (MMSE), and Aβ42/40. Regression models were used to evaluate the influencing factors of DTI-ALPS index. LOE patients exhibited a decreased ALPS index and Aβ42/40 compared with the HCs. Post-hoc analysis indicated that the DTI-ALPS index and Aβ42/40 in LOE patients with cognitive decline was significantly lower in relative to LOE patients without cognitive decline and HCs. Spearman correlations showed a negative correlation between DTI-ALPS index and age, seizure frequency and disease duration while a positive correlations between the DTI-ALPS index and Aβ42/40 and MMSE scores in LOE patients. Linear regression analysis suggested that the DTI-ALPS index was independently related to age, Aβ42/40 and MMSE score after correcting for gender, education, and vascular risk factors. Our findings using DTI-ALPS method found a positive correlation between cognitive decline and GS dysfunction in LOE patients, and may indicate a potential internal link between age-related LOEU and dementia formation. Therefore, the DTI-ALPS index may serve as a potential imaging marker for diagnosing and monitoring the GS function in LOE patients.

Knowledge, attitude and perception of epilepsy patients toward epilepsy surgery at Jordan University hospital.

Epilepsy is a condition associated with stigma and considerable morbidity, placing a significant burden on patients and their families. It is fundamental to be mindful of the fact that a substantial number of patients remain unaware of the effective surgical procedures that have shown great success in many cases, drawing upon the global underutilization of epilepsy surgery (ES). In this study, we explore the knowledge and attitudes of epilepsy patients towards ES at Jordan University Hospital (JUH). This study aims to evaluate epilepsy patients' attitudes and knowledge regarding ES at JUH, identify the variables affecting their attitudes, and compare the results with other Middle Eastern and Western reports. In this cross-sectional study, conducted between the 1st of March and the 1st of September 2023, we gathered and analyzed data from epilepsy patients in the neurology clinic at JUH. A self-administered questionnaire was utilized, with questions emphasizing patients' demographics, disease status, and their knowledge and attitude toward ES. In order to determine the predictors of attitude, logistic regression was performed on the univariate analysis using the SPSS software. This study included 145 participants, most of them within the 17 and 29 age group, and a mean age at first seizure of 21.6years. Our sample included more generalized than focal epilepsy patients, with an additional 30% of patients being unaware of their specific seizure type. 46% of patients were on at least 2 antiepileptic drugs (AEDs), especially among the focal epilepsy group and 61% were non-adherent to their medications. Eighty-two participants (57%) were aware of ES, yet only twenty-five have shown a high level of understanding. The majority of patients (77%) have expressed a positive attitude towards ES. Although patients' attitude was significantly associated with their first impression towards ES, age, age at first seizure and not possessing a driving license, the regression model did not reveal significant predictors. Despite the perception of 94% of the patients that ES has a moderate to high risk, this did not have any significant influence on their final attitude. Furthermore, our results concluded that income, insurance type, educational level, frequency of seizures, and poor academic outcome played no significant role in patients' final attitude towards ES. ES is no longer considered an "experimental" or "last resort" treatment option. The results emphasize the importance of adapting educational interventions to improve knowledge and understanding of ES and implement measures to surgically pre-evaluate potential candidates. Further research should be done to overcome and address this gap in underutilization. In our study, we conclude that this gap is still present especially in people who are in need and may potentially be candidates for ES, but with the displayed positive attitude in the majority of our patients we are optimistic that the remaining barriers can be overcome, and that the results obtained from our study will be helpful for positive advancements in patients' quality of life.

Impact of the COVID-19 Pandemic on Seizure Control in Pediatric Epilepsy: Risk Factors and Clinical Outcomes.

Background: Epilepsy is a common neurological disorder in children, associated with significant morbidity and socioeconomic burden. The coronavirus disease 2019 (COVID-19) pandemic disrupted healthcare delivery, potentially exacerbating seizure control among pediatric epilepsy patients. This study aimed to evaluate the pandemic's impact on seizure characteristics and identify risk factors contributing to seizure exacerbation in children with epilepsy. Methods: A retrospective cohort study was conducted using medical records of 84 pediatric epilepsy patients at The Catholic University of Korea Yeouido St. Mary's Hospital from July 2019 to July 2022. Data were collected on demographics, epilepsy characteristics, and healthcare accessibility. Changes in seizure outcomes were analyzed alongside potential risk factors, including infections and socioeconomic variables. Statistical analyses assessed correlations between these factors and seizure exacerbations. Results: Among the 84 pediatric epilepsy patients, 25% experienced significant seizure exacerbations during the COVID-19 pandemic. These included increased seizure frequency (18%), prolonged duration (13%), emergence of new seizure types (4%), and status epilepticus requiring hospitalization (5%). Multivariate analysis identified recent epilepsy diagnosis (<1 year) and low socioeconomic status as independent predictors of seizure worsening (p < 0.05). Infections with non-COVID-19 respiratory viruses, such as RSV and influenza, were strongly associated with exacerbated seizure activity (p < 0.001). Dissatisfaction with access to epilepsy care further increased the risk of poor seizure control, reflecting the challenges posed by disrupted healthcare systems. Notably, no significant relationship was observed between SARS-CoV-2 infection and seizure outcomes, suggesting that indirect factors, rather than direct viral effects, were primary contributors to seizure exacerbation. Conclusions: This study highlights the compounded impact of disrupted healthcare access, socioeconomic challenges, and respiratory viral infections on seizure control during the COVID-19 pandemic. Strategies such as telehealth expansion, regular monitoring, and vaccination against respiratory pathogens are essential to optimize seizure management in future health crises.

Temporal lobe epilepsy with isolated amygdala enlargement: anatomo-electro-clinical features and long-term outcome.

Temporal lobe epilepsy with isolated amygdala enlargement (TLE-AE) still lacks a definite characterization and controversies exist. We conducted a retrospective study identifying brain MRI scans with isolated AE between 2015 and 2021. We collected clinical and paraclinical data of patients with TLE-AE and evaluated the outcome. Forty-one subjects were included (20 males; AE: right 13; left 24; bilateral 4). A strong correlation was found between AE and MRI T2-hyperintensity (right: p < 0.005; left: p < 0.003). There was no history of febrile seizures; 85,4% had focal seizures with impaired awareness, 78,1% reported auras (epigastric sensation, déjà-vu, anxiety), 37% had psychiatric disturbances, 48,6% presented with cognitive impairment. We report that AE correlates with FDG-PET temporomesial hypometabolism (right: p = 0.022; left: p = 0.053), temporal interictal activity on EEG (n = 41), and temporal ictal findings during long-term video-EEG monitoring (n = 23). Epilepsy surgery (n = 17) revealed gliosis (n = 4), inflammatory infiltrates (n = 4), or low-grade epilepsy-associated neuroepithelial tumors (n = 5) in the amygdala. Other treatments were immunotherapy (n = 6) and only antiseizure medications (n = 17), with good prognosis (58,1% seizure-free and 17,1% only with auras at last follow-up). There was no correlation between longitudinal changes in seizure frequency and amygdala size (p = 0.848) and T2-hyperintensity (p = 0.909). AE should be searched in TLE patients with typical aura, psychiatric and/or neurocognitive disturbances. The strong correlations found between AE lateralization and neurophysiological, FDG-PET, and MRI data supportinvolvement of AE in the epileptogenic network. Drug resistance should prompt presurgical study. Inflammation in amygdala specimens and response after immunotherapy suggest an immune-mediated etiology in some TLE-AE cases.

Age-associated differences in FIRES: Characterizing prodromal presentation and long-term outcomes via the web-based NORSE/FIRES Family Registry.

Febrile infection-related epilepsy syndrome (FIRES) is a rare clinical presentation of refractory status epilepticus following a febrile infection. This study analyzes data from the NORSE/FIRES Family Registry, an international web-based registry available in six languages with data entered by patients, families, and clinicians to explore clinical presentations, survivorship, and long-term outcomes in adult and pediatric FIRES patients. We characterize and examine differences in demographics, prodromal symptoms, seizure frequency, anti-seizure medications (ASMs), quality of life, cognition, mood, and anxiety in adults vs pediatric populations with FIRES. Eighty-six participants were included in the study. Pediatric patients (n = 54) were predominantly male (77.8%) and experienced a significantly higher post-FIRES seizure burden than adult survivors (67.7% ≥12 seizures/month in pediatrics vs 11.8% in adults, p <.001). Adults (n = 32) were more likely to be female (59.4%) and have flu-like prodromal symptoms (90.6%). At ≥6 months post-FIRES, both groups exhibited high ASM use, with the majority (87.5%) taking three or more medications. Pediatric patients reported worse mood and anxiety outcomes compared to adults (p <.005). Self-reported quality of life and cognition were rated as moderate across in adults (5.2/10) and pediatric(4.7/10) patients, although pediatric patients indicated poorer cognition. Our findings highlight the challenges in managing post-FIRES outcomes across different age groups, particularly in pediatric patients who face a higher seizure burden and report worse cognitive outcomes.

Temporal Lobe Epilepsy Perturbs the Brain-Wide Excitation-Inhibition Balance: Associations with Microcircuit Organization, Clinical Parameters, and Cognitive Dysfunction.

Excitation-inhibition (E/I) imbalance is theorized as a key mechanism in the pathophysiology of epilepsy, with ample research focusing on elucidating its cellular manifestations. However, few studies investigate E/I imbalance at the macroscale, whole-brain level, and its microcircuit-level mechanisms and clinical significance remain incompletely understood. Here, the Hurst exponent, an index of the E/I ratio, is computed from resting-state fMRI time series, and microcircuit parameters are simulatedusing biophysical models. A broad decrease in the Hurst exponent is observed in pharmaco-resistant temporal lobe epilepsy (TLE), suggesting more excitable network dynamics. Connectome decoders point to temporolimbic and frontocentral cortices as plausible network epicenters of E/I imbalance. Furthermore, computational simulations reveal that enhancing cortical excitability in TLE reflects atypical increases in recurrent connection strength of local neuronal ensembles. Mixed cross-sectional and longitudinal analyses show stronger E/I ratio elevation in patientswith longer disease duration, more frequent electroclinical seizures as well as interictal epileptic spikes, and worse cognitive functioning. Hurst exponent-informed classifiers discriminate patients from healthy controls with high accuracy (72.4% [57.5%-82.5%]). Replicated in an independent dataset, this work provides in vivo evidence of a macroscale shift in E/I balance in TLE patients and points to progressive functional imbalances that relate to cognitive decline.

Efficacy of neuromodulation of the pulvinar nucleus for drug-resistant epilepsy.

The pulvinar nucleus of the thalamus has extensive cortical connections with the temporal, parietal, and occipital lobes. Deep brain stimulation (DBS) targeting the pulvinar nucleus, therefore, carries the potential for therapeutic benefit in patients with drug-resistant posterior quadrant epilepsy (PQE) and neocortical temporal lobe epilepsy (TLE). Here, we present a single-center experience of patients managed via bilateral DBS of the pulvinar nucleus. A single-institution retrospective review of five patients who underwent bilateral pulvinar DBS for drug-resistant TLE or PQE was performed. Stimulation parameters were adjusted monthly as needed, and side effects were monitored. The primary outcome was the percentage reduction in patient-reported seizure frequency in comparison to the preimplant baseline. The location of the active electrode contacts in relation to pulvinar thalami that produced the best seizure outcome was identified. Chronic sensing of the pulvinar local field potentials (LFPs) and circadian pattern of modulation of the LFP amplitudes were analyzed. Four patients (80%) experienced a >70% reduction in seizure frequency, whereas one patient had >50% reduction in seizure. Mean seizure reduction was 79% at a median follow-up of 13 months (range = 9-21 months). No significant side effects were noted. Of all the pulvinar subnuclei, stimulation of the medial pulvinar nucleus (MPN) produced the best seizure outcome in all patients except for two, in whom active contacts in the MPN but also in more lateral and inferior locations resulted in the most significant reduction in seizures. Chronic timeline data identified changes in LFP amplitude associated with stimulation and seizure occurrences. In this first ever report on a series of patients undergoing bilateral pulvinar DBS for drug-resistant epilepsy, we demonstrate that stimulation of the pulvinar and in particular the MPN is a safe and viable option for patients with nonlesional PQE or TLE. The optimal target for stimulation and relative merits of open versus closed loop stimulation should be delineated in future studies.

Ganaxolone: A Review in Epileptic Seizures Associated with Cyclin-Dependent Kinase-Like 5 Deficiency Disorder.

Oral ganaxolone (ZTALMY®), a synthetic analogue of the endogenous neuroactive steroid allopregnanolone, acts as a positive allosteric modulator of synaptic and extra-synaptic γ-aminobutyric acid(GABA) type A receptor function in the CNS. In the EU and the UK, it is approved for the adjunctive treatment of epileptic seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2-17 years. In a multinational phase III study (Marigold), 17weeks' therapy with adjunctive ganaxolone, administered orally three times daily with food, significantly reduced 28-day major motor seizure frequency from baseline versus placebo in patients aged 2-19years with CDD-associated refractory epilepsy. Antiepileptic efficacy was generally sustained through 2years of treatment. Ganaxolone was generally well tolerated in Marigold. While somnolence and sedation are related to the dose of ganaxolone, they appear early in treatment and may decrease with continued therapy. Thus, although current evidence is somewhat limited,adjunctive ganaxolone could be a valuable therapeutic option for patients aged 2-17years with epileptic seizures associated with CDD.

De novo KCNB1 missense variant causing developmental and epileptic encephalopathy: Two case reports.

Developmental and epileptic encephalopathy (DEE) defines a group of severe and heterogeneous neurodevelopmental disorders. The voltage-gated potassium channel subfamily 2 voltage-gated potassium channel α subunit encoded by the KCNB1 gene is essential for neuronal excitability. Previous studies have shown that KCNB1 variants can cause DEE. Herein, we report the cases of 2 children with DEE caused by pathogenic variants in the KCNB1 gene. Trio whole-exome sequencing identified novel KCNB1 genotypes, c. 1160C > A and c.1012C > T, which had not been reported previously, in 2 unrelated patients. Two children were admitted to our hospital for a detailed evaluation of frequent seizures. And both of these children have abnormal electroencephalogram and brain magnetic resonance imaging results, accompanied by developmental delay. A genetic study using trio-whole-exome sequencing confirmed the diagnosis of KCNB1-related developmental and epileptic encephalopathy. Both patients accepted the treatment of antiepileptic drugs. 1 patient had seizure remission with a combination of sodium valproate and lamotrigine, and the other was lost to follow-up. Trio-whole-exome sequencing technology was used to determine the etiology of the 2 children with DEE. This study confirmed that genetic testing provides a basis for the diagnosis of children with abnormal electroencephalogram and brain magnetic resonance imaging findings and developmental delay, and provides data supporting a future phenotype-genotype correlation study.

Sex-specific differences in mortality and neurocardiac interactions in the Kv1.1 knockout mouse model of sudden unexpected death in epilepsy (SUDEP).

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy with possible sex-specific risk factors, although the exact relationship between sex and SUDEP remains unclear. To investigate this, we studiedKcna1knockout (Kcna1-/-) mice, which lack voltage-gated Kv1.1 channel subunits and are widely used as a SUDEP model that mirrors key features in humans.To assess sex differences, we first performedsurvival analysis, EEG-ECG recordings, seizure threshold testing and retrospective analysis of previous intracardiac pacing data. We then applied a novel modelling approach across organs (organomics) to uncover potential sex-specific differences in brain-heart communication. Our findings revealed femaleKcna1-/-mice have significantly longer lifespans than males, suggesting lower SUDEP rates. Although no sex differences were found in seizure frequency, duration, burden, susceptibility or interictal heart rate variability, females showed a higher incidence of bradycardia during spontaneous seizuresthan males, as well asresistance to inducible ventricular tachyarrhythmias in response to programmed electrical stimulation.Two captured SUDEP events, one per sex,displayed similar patterns of ictal bradycardiain both sexes,progressing to postictal cardiorespiratory failure. Going beyond traditional seizure and cardiac metrics, organomics analysis revealed that seizures affect brain-heart communication differently between sexes. Females exhibited more effective resetting of brain-heart interactions postictally than males.This finding may contribute to the lower SUDEP risk in females and underscores the complex interplay between sex, cardiac function and brain-heart communication in determining SUDEP susceptibility. Furthermore, seizure-resetting measures could represent a promising class of biomarkers for SUDEP risk stratification. KEY POINTS: Female Kcna1-/- mice live longer than males, suggesting lower sudden unexpected death in epilepsy (SUDEP) rates. There are no sex differences in seizure metrics or interictal heart rate variability. Females show more bradycardia during seizures and are resistant to inducible ventricular tachyarrhythmias. Seizures affect brain-heart communication differently between the sexes. Seizures in females reset brain-heart interactions more effectively postictally, potentially lowering SUDEP risk.

Long-Term Seizure Reduction Associated with Vagal Nerve Stimulation in Dravet Syndrome.

SCN1A variants cause a range of epilepsy syndromes, including Dravet syndrome, leading to early cognitive and functional impairment. Despite advances in medical management, drug-resistant epilepsy remains common. Vagal nerve stimulation (VNS) has been suggested reducing seizure frequency in these patients but there is a lack of long-term follow-up, quantitative analysis that corrected for confounding factors such as antiseizure medications (ASMs) and the impact of VNS settings on response. This two-center, retrospective cohort study analyzed 12-month and for the first time up to ten-year seizure outcomes in therapy-refractory epilepsy patients with loss-of-function SCN1A variants (93.75% Dravet Syndrome) who underwent VNS implantation. A ≥50% seizure frequency reduction was observed in 93.75% (15/16) of patients in the 12-month and 87.5% (14/15) in the ten-year period. Median seizure frequency was significantly lower in both follow-up periods than in the pre-implantation period. Linear mixed-effects regression showed that the reduction in seizure burden was independent of ASM use, and the VNS duty cycle was significantly associated with seizure reduction. Three individuals (18.8%) experienced minor side effects. Our results highlight the benefits of genotype-driven therapeutic interventions such as VNS in patients with SCN1A -related epilepsy. This study emphasizes the need for further implementation of genotype-driven clinical decision-making.

Introducing the Index of Response to Stimulation (IRES): A Novel Metric for Assessing Vagus Nerve Stimulation Outcomes in Drug-Resistant Epilepsy.

Background and Objectives: The Index of Response to Stimulation (IRES) is a new index that we introduce in this study to grade the effectiveness of vagus nerve stimulation in the treatment of drug-resistant epilepsy. We assessed 76 patients at 6, 12, and 18 months after VNS evaluating improvement with the IRES in four key dimensions: seizure duration decrease, seizure intensity decrease, improvement in quality of life, and seizure frequency decrease. This scale goes from 0, meaning no improvement, to 8, meaning maximal improvement, making the scale a really good measure of clinical utility. Materials and Methods: This retrospective study followed 76 patients aged 20-65, assessing changes in their IRES scores after VNS therapy using the ASPIRE SR 106 device. Therapy settings were adjusted biweekly to optimize efficacy and patient tolerance. Results: There were improvements in the control of the seizures, measured in terms of increased IRES scores. Improvements were associated with quality-of-life enhancements for the patient and a lesser frequency and intensity of the seizures, testifying further to the predictive ability of the IRES toward successful outcomes. This fact reveals that epilepsy treatment must be individual, according to the profile of the patient. Conclusions: The study confirms the IRES to be a valid tool for the assessment of the impact of VNS on drug-resistant epilepsy and promotes it as an integral part of the evaluation of the patient for personalized therapy. The findings encourage the use of IRES among the elements that support patient selection and insist on its role in the advancement of precision medicine and optimization of treatment.

Ramadan fasting in adolescents with epilepsy: Seizure control and behavioral outcome.

Data about the effect of Ramadan fasting on seizure control among adolescents with epilepsy (AWE) is scarce. Several psycho-behavioral problems have also been encountered in this teenage group. This study aimed to assess seizure frequency and behavioral outcomes after Ramadan fasting in a sample of AWE METHODS: In this prospective study, AWE who completed fasting during Ramadan 2024 were evaluated regarding the seizure frequency of each type during Shaban (the month immediately preceding Ramadan) and Ramadan. Three questionnaires were requested to be answered at the end of two months. They were Patient Health Questionnaire (PHQ-9), Modified Overt Aggression Scale (MOAS), and Barratt Impulsiveness Scale-Short Form (BIS-11-SF) for assessment of depression, aggression, and impulsivity, respectively RESULTS: One hundred twenty AWE, with a median age of 15 and IQR 13-17, were evaluated. There was a statistically significant reduction in seizure frequency regarding focal onset seizures during Ramadan compared to Shaaban (P 0.009), as well as generalized non-motor (absence) seizures (P 0.027). The MOAS-total scores significantly reduced during Ramadan than Shaaban (P 0.003), as well as the scores of non-planning impulsivity of BIS-11-SF (P 0.005). On the other hand, depression assessed by PHQ-9 did not significantly differ between the two months CONCLUSION: Fasting Ramadan is associated with better control of multiple seizure types, including focal and generalized-onset non-motor (absence) seizures, besides psycho-behavioral aspects of aggression & non-planning impulsivity, without worsening of other seizure types nor depression, among AWE.

Decreased Structural Connectivity Between Thalamic Nuclei and Hippocampus in Temporal Lobe Epilepsy-A Diffusion Tensor Imaging-Based Study.

Temporal lobe epilepsy (TLE) can lead to structural brain abnormalities, with thalamus atrophy being the most common extratemporal alteration. This study used probabilistic tractography to investigate the structural connectivity between individual thalamic nuclei and the hippocampus in TLE. Thirty-six TLE patients who underwent pre-surgical 3 Tesla magnetic resonance imaging (MRI) and 18 healthy controls were enrolled in this study. Patients were subdivided into TLE with HS (TLE-HS) and MRI-negative TLE (TLE-MRneg). Tractography and whole brain segmentation, including thalamus parcellation, were performed to determine the number of streamlines per mm3 between the thalamic nuclei and hippocampus. Connectivity strength and volume of regions were correlated with clinical data. The volume of the entire thalamus ipsilateral to seizure onset was significantly decreased in TLE-HS compared to controls (Mann-Whitney-U test: pFDR < 0.01) with the anterior thalamic nuclei (ANT) as important contributor. Furthermore, decreased ipsilateral connectivity strength between the hippocampus and ANT was detected in TLE-HS (pFDR < 0.01) compared to TLE-MRneg and controls which correlated negatively with the duration of epilepsy (ρ = -0.512, p = 0.025) and positively with seizure frequency (ρ = 0.603, p = 0.006). Moreover, ANT volume correlated negatively with epilepsy duration in TLE-HS (ρ = -0.471, p = 0.042). ANT showed atrophy and decreased connectivity in TLE-HS, which correlated with epilepsy duration and seizure frequency. Understanding the dynamics of epileptogenic networks has the potential to shed light on surgery-resistant epilepsy and refine the selection process for ideal neurosurgical candidates, consequently enhancing post-surgical outcomes.