The kynurenine pathway (KP) is the main route for tryptophan (TRP) degradation and plays a crucial role in neuroinflammation, oxidative stress and neurotransmission, which holds significant clinical significance. The dysregulation of this pathway is closely related to neurological disorders such as epilepsy, and its metabolic products can promote the occurrence of epileptic seizures and comorbid depression. This review aims to clarify the complex mechanisms of the KP in the occurrence and development of epilepsy and to explore its potential as a therapeutic target for epilepsy and comorbid depression. This is a narrative review and synthesis of the current literature. We reviewed animal experiments and clinical studies, elaborating in detail on how metabolites of the KP and their key enzymes function in the context of epilepsy by regulating neuroinflammation, oxidative stress, glutamatergic signaling, and the gut-brain axis. We also explored the interaction between antiseizure medications (ASMs) and the KP, and evaluated the potential value of targeting key enzymes (such as indoleamine 2,3-dioxygenase, IDO) as a new therapeutic strategy for epilepsy. This review particularly focuses on the promoting effect of KP imbalance on comorbid depression, clarifying how IDO-mediated TRP metabolism changes constitute a common mechanism basis, jointly leading to the occurrence of epilepsy and depression-like behaviors. The occurrence and development of epilepsy are closely related to the imbalance of the KP, specifically manifested as a decrease in kynurenic acid (KYNA) level and an increase in quinolinic acid (QA) level. The IDO-mediated shift of TRP metabolism towards the KP is established as a critical mechanism underlying depression comorbidity in epilepsy. Therapeutic modulation of this pathway, through targeting key enzymes like IDO and restoring the KYNA/QA balance, presents a viable strategy for improving the cerebral microenvironment. This approach holds promise for enhancing seizure control, counteracting drug resistance, and concurrently alleviating comorbid depressive symptoms.
The primary aim of this systematic review and meta-analysis is to evaluate the impact of educational programs for children with epilepsy and/or their parents on disease management. A comprehensive literature search was performed across eight electronic databases from inception to January 20, 2026, to identify studies evaluating educational interventions for children with epilepsy and/or their parents or caregivers. Following screening and eligibility assessment, ten studies were included in the final systematic review and meta-analysis. Study selection, data extraction, and risk of bias assessment were independently performed by two reviewers using standardized tools. Meta-analyses were conducted using RevMan software, applying fixed- or random-effects models based on heterogeneity, and the certainty of evidence was assessed using the GRADE approach. This meta-analysis included ten randomized controlled trials evaluating educational programs for children with epilepsy and/or their parents. In the analysis of seizure frequency, educational programs showed an effect in reducing the likelihood of seizures, but the result was not statistically significant (OR = 0.62; 95% CI: 0.37-1.03; p = 0.07; I2 = 0%). Educational programs significantly improved parental quality of life (SMD = 0.71; 95% CI: 0.15-1.27; p = 0.01; I2 = 69%). Strong trends were found towards decreased parental anxiety (SMD =  - 0.82; 95% CI: -1.68-0.04; p = 0.06; I2 = 93%) and increased self-efficacy (SMD = 2.63; 95% CI: -0.18-5.44; p = 0.07; I2 = 98%), but these findings did not reach statistical significance. Knowledge level regarding epilepsy significantly increased with educational programs (SMD = 1.29; 95% CI: 0.56-2.02; p = 0.0005; I2 = 87%). Epilepsy management significantly improved with educational programs (MD = 0.48; 95% CI: 0.21-0.76; p = 0.0005; I2 = 0%). This meta-analysis demonstrates consistent and significant benefits of educational programs on epilepsy management, knowledge level, and parental quality of life. While the effects on seizure frequency, parental anxiety, and self-efficacy were not statistically conclusive, the observed effect trends point to clinically positive potential. It supports the inclusion of education-based interventions as a complementary and empowering component in epilepsy care.
The relationship between epilepsy and neurodegeneration has recently been a subject of debate, particularly regarding whether neurodegeneration is a cause or a consequence of epilepsy. Given that the retina is an extension of the brain and closely connected to it, retinal layer thickness can serve as a biological marker of neurodegeneration. The aim of this work was to measure retinal nerve fiber layer (RNFL) thickness in patients with epilepsy in comparison to healthy controls, and to study the impact of epilepsy duration and seizure frequency on RNFL thickness in those patients. This case-control study was conducted on 53 patients matched clinical definition of epilepsy established by the International League Against Epilepsy (ILAE) 2017, and 50 healthy controls. Cognitive assessment using Montreal cognitive assessment scale (MOCA), and measurement of RNFL thickness using Spectral domain Optical Coherence Tomography (SD-OCT), were done to all included patients and controls. The peripapillary RNFL thickness (superior, inferior & average) were all significantly reduced in both eyes in epileptic patients compared to healthy controls (P-value <0.05). There was a statistically significant difference between epileptic patients and controls regarding MOCA score. There was no statistically significant impact of seizure control, history of status epilepticus, anti-epileptic drugs, seizure frequency, or disease duration on RNFL thickness. There was a statistically significant reduction of the retinal nerve fiber layer thickness in epileptic patients in comparison to healthy controls. Epileptic patients had significant impairment in cognitive functions in comparison to healthy controls.
The aim of this study is to evaluate the sleep quality of children with epilepsy and their mothers, and to identify the factors affecting sleep quality. The sample comprised 103 mothers of children with epilepsy aged 318 years. Data were collected during face-to-face interviews using the Children's Sleep Habits Questionnaire (CSHQ) and the Pittsburgh Sleep Quality Index (PSQI). The data were analyzed using one-way analysis of variance (ANOVA), the Mann-Whitney U test, and correlation analysis. According to PSQI, 76.7% of mothers were found to have poor sleep quality. The mean total CSHQ score was 49.99 ± 7.60, indicating clinically significant sleep problems among the children. Mothers' PSQI total scores were significantly associated with income status, number of children, duration of epilepsy, and time spent in digital environments (p < 0.05). Children's CSHQ total scores were significantly associated with age at first seizure, seizure frequency, occurrence of seizures during the last three months, presence of nocturnal seizures, number of antiepileptic drugs used, and ownership of a phone/computer (p < 0.05). It was found that children with epilepsy experienced sleep problems related to bedtime resistance and daytime sleepiness, and that their mothers had poor sleep quality. Therefore, the development of supportive intervention programs is recommended to prevent and manage sleep problems in children with epilepsy and their mothers. Multidisciplinary collaboration and nurse-led interventions should be implemented to promote sleep health and improve the quality of life of children with epilepsy and their families.
The treatment of juvenile myoclonic epilepsy (JME) is limited, with most patients requiring long-term medication and over half experiencing seizure recurrence upon drug withdrawal. As a third-generation antiseizure medication, brivaracetam (BRV) has emerged as a promising therapeutic option. Its efficacy has been investigated in focal epilepsies and genetic generalized epilepsies (GGEs), with promising results. This study aims to evaluate the safety and preliminary efficacy of BRV as an off-label initial monotherapy in patients with newly diagnosed JME, with a specific focus on the control of myoclonic seizures. A prospective, single-center, and observational study. This study prospectively enrolled drug-naïve patients with JME. All participants received BRV monotherapy. Clinical data were collected at baseline and after a 6-month follow-up period, including demographic characteristics, electroencephalography (EEG), cranial magnetic resonance imaging (MRI), and comprehensive neuropsychological assessments. Changes in seizure frequency, cognitive function, levels of anxiety and depression, sleep quality, and quality of life from baseline to the 6-month follow-up were analyzed and compared. A total of 19 patients were included with a mean age of 20.26 ± 6.88 years (median: 18, interquartile range: 8), and a male-to-female ratio of 12:7. The average age of onset was 14.58 ± 3.42 years, and the average duration of epilepsy prior to BRV treatment was 5.71 ± 7.40 years (median: 2, interquartile range: 5). The mean frequency of myoclonic seizures at baseline was 38.79 ± 45.60 times per month (median: 10, interquartile range: 86). Eighteen patients (94.73%) experienced both generalized tonic-clonic seizures (GTCS) and myoclonic seizures, one patient only experienced myoclonic seizures, The MRI findings were negative in all patients (100%). The EEG of all patients at baseline was abnormal, revealing 3-5.5 Hz generalized spike-and-wave or polyspike-and-wave discharges. At the 6-month evaluation, all patients achieved seizure-free status (p < 0.001), neuropsychological assessments also demonstrated significant improvement, including Montreal Cognitive Assessment (MoCA; p < 0.001), Hamilton Anxiety Scale (HAMA; p < 0.001), Hamilton Depression Scale (HAMD; p < 0.001), Pittsburgh Sleep Quality Index (PSQI; p < 0.001), and Quality of Life in Epilepsy-31 (QOLIE-31; p < 0.001). Only one patient complained of poor sleep after BRV administration. This study suggests that BRV may offer promising efficacy, specifically in controlling myoclonic seizures and favorable tolerability as an off-label initial monotherapy for JME patients. While the evaluation of efficacy against GTCS requires longer follow-up, our findings support the potential of BRV as a therapeutic option for JME. Further randomized controlled trials are warranted to validate these observations. Is brivaracetam effective and safe as the initial monotherapy for patients with juvenile myoclonic epilepsy? Why was the study done? The treatment of juvenile myoclonic epilepsy (JME) is limited, with most patients requiring long-term medication and over half experiencing seizure recurrence upon drug withdrawal. Brivaracetam (BRV) has shown promising therapeutic potential in focal epilepsies and genetic generalized epilepsies (GGEs). What did the researchers do? This study evaluated the efficacy and safety of BRV as the initial monotherapy in patients with JME in clinical practice. What did the researchers find? A total of nineteen patients were included. Following treatment with BRV, all patients achieved seizure-free status (p<0.001), neuropsychological assessments also demonstrated significant improvement, including Montreal Cognitive Assessment (MoCA) (p<0.001), Hamilton Anxiety Scale (HAMA) (p<0.001), Hamilton Depression Scale (HAMD) (p<0.001), Pittsburgh Sleep Quality Index (PSQI) (p<0.001), and Quality of Life in Epilepsy-31 (QOLIE-31) (p<0.001). Only one patient complained of poor sleep. What do the findings mean? This study suggests that BRV may offer promising efficacy and tolerability as an initial monotherapy for JME, supporting its potential as a first-line treatment option. Further randomized controlled trials involving larger cohorts and extended follow-up periods are required to validate these findings.
To systematically review and meta-analyze COVID-19 vaccine hesitancy among individuals with epilepsy. Following PRISMA 2020 guidelines, we searched Cochrane CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, PsycINFO databases, and grey literature through February 6, 2026. We included studies addressing COVID-19 vaccination hesitancy in adults with epilepsy, with no date or language restrictions. Two reviewers independently screened articles, extracted data, and assessed quality using the Newcastle-Ottawa Scale (NOS). Meta-analyses were conducted using random-effects models, with heterogeneity assessed using I² statistics. The certainty of evidence was evaluated using the GRADE criteria. Fourteen studies comprising 4230 participants were included. Overall vaccination willingness was 51.7% (95% CI: 36.6-68.8%, I²=98%). Among unvaccinated individuals, 44.2% (95% CI: 26.6-61.8%, I²=95%) expressed willingness to be vaccinated. Well-controlled epilepsy was associated with higher vaccination rates (OR 1.91, 95% CI: 1.49-2.46, I²=0%). Conversely, frequent seizures (daily/weekly) were associated with lower vaccination likelihood (OR 0.52, 95% CI: 0.35-0.76, I²=0%). The primary reasons for vaccine hesitancy were fear of seizure worsening (23.8-88.5% across studies) and concerns about side effects (13.0-53.0%). Methodological quality was generally poor, with only one study rated as "satisfactory" using NOS criteria. GRADE assessment indicated very low certainty of evidence due to serious risk of bias, inconsistency, and imprecision. COVID-19 vaccine hesitancy remains present in people with epilepsy, primarily driven by concerns about seizure exacerbation. Individuals with well-controlled epilepsy show higher vaccination acceptance. Healthcare providers should address specific concerns about seizure control while emphasizing vaccine safety data. High-quality prospective studies using validated instruments are recommended.
Inflammation may contribute to drug-resistant epilepsy (DRE) in children and immunomodulatory therapies, including intravenous immunoglobulin (IVIG), have been described to reduce seizure burden. This retrospective study assesses the effect of IVIG on seizures in a tertiary epilepsy center. We performed a retrospective chart review of children with DRE using our Pediatric Epilepsy Outcome-Informatics database, which contains standardized information on 3,650 pediatric epilepsy patients collected at the point of care. Inclusion criteria were refractory seizures, regular follow-up and treatment with IVIG for at least 1 year. Patients with autoimmune encephalitis were excluded from the analysis. Sex, etiology, epilepsy syndromes, seizure types, antiseizure medications (ASM), adverse effects, and seizure frequency scores prior, 3 months post-, and 1-year post-IVIG were collected and statistically compared. Sixty patients aged 2-18 years (mean ± SD, 11.8 ± 4.13) were included. Patients exhibited focal (38.3%, n = 23), generalized (36.7% (n = 22), or both seizure types (25.0%, n = 15). Overall, 36.7% (n = 22) demonstrated at least 50% seizure frequency reduction within 1 year of IVIG use, and 36.4% (n = 8) achieved seizure freedom. A significant reduction of seizures in individual patients was only observed in those with generalized seizures (p = 0.019). These findings could not be explained by changes in other ASMs. Long-term use of IVIG in pediatric patients can be an effective treatment for refractory seizures, even if exact mechanisms remain unclear.
This study aims to examine the impact of epilepsy on suicidal behavior and the mediating roles of depression, stigma, loneliness, and social isolation in this relationship. This descriptive and cross-sectional study included 80 epilepsy patients followed at a university hospital neurology clinic. Data were collected using the Suicidal Behaviors Questionnaire, Personal Impact of Epilepsy Scale, Beck Depression Inventory, and the Stigma Scale, Loneliness Scale, and Social Isolation Scale. Direct and indirect effects were tested using Path Analysis (Maximum Likelihood method) via AMOS Version 24, with age and perceived social support as control variables. Path analysis indicated that the perceived effect of epilepsy was a significant direct predictor of depression (β = 0.337), social isolation (β = 0.311), and loneliness (β = 0.136). Depression significantly predicted loneliness, social isolation, and suicidal behavior. Loneliness was the strongest direct predictor of suicidal behavior (β = 0.556), followed by social isolation (β = 0.279). The model explained 48.6% of the variance in suicidal behavior. Stigma did not have a significant direct effect on suicidal behavior (p > 0.05). The impact of epilepsy on suicidal behavior was associated with indirect pathways through depression, loneliness, and social isolation. Loneliness and social isolation were the main direct predictors, and the model explained a substantial proportion of the variance in suicidal behavior.
Voltage-gated sodium channel (VGSC) dysregulation, particularly of the Nav1.6 subtype, is a core mechanism underlying epileptogenesis and its associated neuropsychiatric comorbidities. The scorpion venom peptide BmK AS has demonstrated anticonvulsant potential, but its efficacy in chronic epilepsy and the precise mechanisms of action remain undefined. Here, we show that BmK AS exerts robust anti-epileptic and neuroprotective effects through converging mechanisms. In a kainic acid-induced mouse model, BmK AS treatment reduced mortality and seizure parameters. Electrophysiological studies assessed BmK AS modulation of VGSC subtypes. The functional relevance of Nav1.6 targeting was confirmed by the loss of BmK AS's anti-seizure efficacy upon its pharmacological blockade in a PTZ-induced model. Furthermore, in both KA-induced chronic epilepsy models and native hippocampal neurons, BmK AS was evaluated for neuronal hyperexcitability and NLRP1 inflammasome-mediated pyroptosis. BmK AS reduced mortality to 0% (vs. 40% in the model group) and significantly reduced seizure duration by 10.5% and the frequency of severe (stages 4 and 5) seizures by 68.8%. It also improved cognitive and psychiatric outcomes, significantly reversing epilepsy-associated spatial memory deficits and anxiety-/depression-like behaviors. Electrophysiological studies show that BmK AS nonlinearly inhibited multiple VGSC subtypes, with pronounced potency against Nav1.6, reducing the peak sodium current to 43% of control at 5 nM. BmK AS attenuated neuronal hyperexcitability and suppressed neuroinflammation by inhibiting the NLRP1 inflammasome pathway and the associated pyroptosis. Our findings establish BmK AS as a promising multimechanistic therapeutic candidate, highlighting the strategic value of dual therapeutic actions, namely, Nav1.6 modulation and neuroinflammation inhibition, for epilepsy treatment.
Optically pumped magnetometers magnetoencephalography (OPM-MEG) have demonstrated their value in the diagnosis and mapping of epilepsy, as well as their advantages in pediatric applications. We present a case of 8-year-old boy with drug-resistant epilepsy, whose epileptogenic lesion is in left Broca's region. The boy underwent language function evaluation and localization by on-scalp OPM-MEG before surgery. Dipole clusters and Dipole Density of epileptogenic signals by OPM-MEG were located in the left inferior frontal gyrus, though language verbal generation mapping of OPM-MEG signals were mainly located in left frontal orbital gyrus, indicating a localization of the language function area. Seizure freedom and no loss of language function were achieved after MRI-guided laser interstitial thermal therapy. This article underscores the feasibility of using OPM-MEG to record abnormal discharges of seizure and assess language function area in children, especially in drug-resistant epilepsy surgery involving brain functional areas.
Epileptology has an urgent need for easily accessible fluid biomarkers for improving diagnosis, subclassification and prognostication. In various neurological diseases Neurofilament Light chain (NfL) and Glial Fibrillary Acidic Protein (GFAP) have emerged as promising blood biomarkers of neuroaxonal damage and astrocytic activation, respectively. Their role in epileptic seizures and epilepsy has so far been scarcely explored and their potential has not been assessed systematically in patients with epileptic conditions. We systematically assessed the role of serum NfL and GFAP in our single-centered prospective cohort of 108 patients with epileptic seizures and epilepsy. We analyzed biomarker levels in clinical subgroups and a control group of 48 individuals without any degenerative or structural neurological disease. We further compared the value of NfL and GFAP to well-established markers such as lactate, creatine kinase and myoglobin. Elevated GFAP but not NfL levels were associated with recent epileptic seizures (n = 25, GFAP p = 0.0227, NfL p = 0.1227) and epilepsy (n = 83, GFAP p = 0.008, NfL p = 0.076) in general and in various subgroups when compared to controls. In patients with single seizures and sampling obtained shortly after a seizure (n = 25) myoglobin (p = 0.0021, AUC=0.847) performed better than NfL (p = 0.1227, AUC=0.73) or GFAP (p = 0.0227, AUC=0.682). Neither NfL nor GFAP could distinguish between semiological or etiological subgroups. None of the biomarkers showed prognostic potential regarding seizure recurrence. Serum NfL and GFAP represent novel biomarkers for patients with epileptic conditions and show a dynamic profile after seizure.
Animal models of epilepsy are critical in drug development and therapeutic testing. However, dominant methods for evaluating epilepsy treatments face a tradeoff between higher throughput and etiological relevance. Screening models are either based on acutely induced seizures in wild-type, naive animals or spontaneous seizures in chronically epileptic animals. Each has its disadvantages - acute convulsant or kindling-induced seizures do not account for the myriad neuropathological changes in the diseased, epileptic brains, and spontaneous behavioral seizures are sparse in chronically epileptic models, making it time-intensive to sufficiently power experiments. In this study, we developed the Opto-IHK (optogenetically induced seizures in intrahippocampal kainate mice) model, a mechanistic approach to precipitate seizures 'on demand' in chronically epileptic mice. We briefly synchronized principal cells in the CA1 region of the diseased hippocampus to reliably induce stereotyped on-demand behavioral seizures. These induced seizures resembled naturally occurring spontaneous seizures in the epileptic animals and could be stopped by commonly prescribed anti-seizure medications such as levetiracetam and diazepam. Furthermore, we showed that seizures induced in chronically epileptic animals differed from those in naive animals, highlighting the importance of evaluating therapeutics in the diseased circuit. Taken together, we envision the Opto-IHK model to accelerate the evaluation of both pharmacological and closed-loop interventions for epilepsy.
To evaluate the prevalence and speech characteristics of post-ictal aphasia (P-IA) in people with epilepsy (PWE) undergoing long-term video-EEG (VEEG) monitoring (LTM). To investigate the relationship between anatomical and electroclinical data and specific post-ictal speech deficits. A multidisciplinary team reviewed the medical records of PWE admitted to the Epilepsy Monitoring Unit between 2017-2020, selecting those who experienced at least one seizure during LTM and underwent postictal speech assessment. Clinical data were compared between patients with and without P-IA. In P-IA group, speech analysis was conducted by transcribing communicative interactions to identify specific language deficits and explore their associations with clinical data. From a pool of 114 PWE we included a total of 811 recorded events belonging to 77 patients. Adequate speech analysis was possible in 46 of these patients, and 20 of them exhibited P-IA. Patients with P-IA more frequently presented seizures with impaired awareness, a temporal lobe epileptogenic zone, ictal EEG patterns with contralateral diffusion and unilateral post-ictal focal slowing. With more thorough evaluation the detection rate rose from 26% in the overall cohort to 43.5%, reflecting improved diagnostic accuracy rather than a true increase in prevalence. The likelihood of detecting P-IA increases with comprehensive post-ictal language testing. P-IA in current study showed no clear lateralizing value. The contralateral spread of seizure was the most relevant finding correlated with P-IA. More than four post-ictal language deficits were correlated with onset in the temporal lobe.
CACNA1A encodes the Cav2.1 (P/Q-type) channel whose spectrum extends from FHM1/EA2/SCA6 to epilepsy and vertigo, but penetrance-especially sex differences-remains unclear. We report a three-generation family with CACNA1A c.5610del, detail electroclinical features, assess sex-stratified penetrance, and discuss individualised therapy. We retrospectively reviewed histories, neurological exams, EEG, treatments, and follow-up. Trio whole-exome sequencing across 13 relatives was Sanger-confirmed and interpreted per ACMG; gnomAD/ClinVar were queried. Sex-stratified penetrance was summarised with exact binomial 95% CIs. The female proband developed clinically focal seizures with preserved awareness in 2019. Valproate reduced but did not abolish seizures; after oxcarbazepine, EA2-like paroxysmal symptoms emerged and responded to acetazolamide. Since 2023, she has experienced episodic diplopia, vertigo, bilateral tinnitus, and pulsatile temporal headaches consistent with FHM-like features, typically independent of epileptic seizures. Video-EEG monitoring demonstrated generalised, bilaterally synchronous spike-and-slow-wave discharges with frontal predominance, with a reduction in interictal epileptiform burden observed after treatment optimisation. Genetic analysis identified a heterozygous CACNA1A c.5610del (p.His1871IlefsTer30) variant, absent from population databases and classified as pathogenic (PVS1 + PM2 + PP3). Segregation analysis revealed epilepsy or vestibular symptoms among female carriers, whereas male carriers were asymptomatic at last follow-up, suggesting possible sex-biased penetrance within the pedigree. This pedigree supports Cav2.1 loss-of-function presenting with epilepsy, EA2, and FHM features plus BPPV. Within this family, clinical expression to date appears female-skewed while male carriers remained asymptomatic at last follow-up; this observation is hypothesis-generating. Mechanism-aware ASM selection and structured family counselling may aid management; larger cohorts and functional studies are needed.
This study aimed to gather UK clinician, patient, and carer perspectives on vagus nerve stimulation (VNS) and deep brain stimulation (DBS) to inform the design of clinical trials comparing these treatments for drug-resistant epilepsy (DRE). To assess stakeholder views on these treatments and their willingness to participate in a clinical trial comparing VNS and DBS for DRE. Two surveys were conducted: one for clinicians in neurology, neurophysiology, and neurosurgery, and another for patients/carers. The estimated response rates were 2.7% and 0.008% for the surveys respectively. Among the 32 clinician responses all agreed VNS has a role in treating DRE, as did 94% for DBS. While 84% felt VNS had sufficient evidence for routine use, only 23% said the same for DBS. Median minimum age for treatment consideration was 5 years for VNS and 8 years for DBS. Clinicians agreed on the proposed trial's scientific validity (median Likert score 4/5) and interest in efficacy comparison (5/5); 72% would refer patients for the trial. Of the 38 patient/carer responses, 13% had VNS. Around one-third would consider VNS (32%) or DBS (34%). Concerns included procedure anxiety, side effects, and battery changes. While 53% were willing to enter the proposed trial, 84% preferred to choose their treatment.Key outcomes identified included seizure reduction, seizure freedom, quality of life, and SUDEP risk. Clinician, patient, and carer insights highlight the need for robust evidence on VNS and DBS efficacy. These findings will guide future trials in managing DRE.
We aimed to assess differences in auditory deviance detection and the underlying sources' effective connectivity between participants with juvenile myoclonic epilepsy (JME) (N = 60) and healthy controls (N = 39). 256-channel EEG data were recorded during an auditory roving oddball paradigm. Dynamic causal modeling (DCM) was used to estimate effective connectivity between brain regions involved in generation of auditory mismatch negativity (MMN) and P3a component of event-related potentials (ERPs). Between-group statistics were used to compare the MMN and P3a amplitudes. DCM and Parametric Empirical Bayes (PEB) were used to model experimental perturbations in cortical connectivity and assess between-group differences. Hypothesis-driven correlation tests between the sensor space MMN and P3a amplitudes, as well as DCM connectivity estimates, with heavy executive function load cognitive tests were also evaluated. MMN and P3a amplitudes were significantly smaller in the JME patients group compared to controls. DCM and PEB analyses revealed group-level differences in cortical connectivity as the result of experimental effects (i.e., differential response to the deviant stimuli in relation to the standard ones): (1) Significantly reduced extrinsic connectivity for JME participants versus controls between right superior temporal gyrus (r-STG) and right inferior frontal gyrus (r-IFG), as well as (2) Increase in intrinsic (within a region) excitability in left STG. Weak-to-moderate associations were found between the electrophysiological variables under study and neuropsychological tests of executive function. Reduced auditory deviance detection, as well as a decreased right-sided feedforward connectivity in our JME cohort, correlated with cognitive test performance. These findings reflect aberrant neurophysiology underlying JME warranting potential interventions.
People with epilepsy (PWE), particularly Native Hawaiians and Pacific Islanders (NHPI), face significant cardiometabolic disparities. This study characterized the "triple burden" of obesity, diabetes, and tobacco use across White, Asian, and NHPI PWE in Hawaii and identified factors associated with seizure control. A retrospective chart review of 403 adult PWE (41.2% White, 24.1% Asian, 34.7% NHPI) was conducted at a Hawaii-based clinic. Multivariable logistic regression compared comorbidity profiles and identified factors associated with poor seizure control (breakthrough or drug-resistant). After adjustment, NHPI patients faced significantly higher odds of obesity (OR=2.03, 95% CI [1.26-3.28]), diabetes (OR=2.97, 95% CI [1.42-6.21]), and tobacco use (OR=1.89, 95% CI [1.06-3.34]) compared to White patients. Current tobacco use was the strongest factor associated with poor seizure control (OR=2.08, 95% CI [1.12-3.89], p = 0.021). Obesity (p = 0.149) and diabetes (p = 0.933) were not significantly associated with seizure outcomes. NHPI PWE face a disproportionate triple burden of cardiometabolic risks. While all are critical for health, tobacco use was the only factor independently associated with poor seizure control. These findings underscore the importance of culturally tailored smoking cessation programs to address risk as both a behavioral and cardiometabolic condition as a supportive intervention to improve neurologic outcomes in this population.
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Mitochondrial encephalomyopathy with lactic acidemia and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder caused by mutations in mitochondrial DNA, most commonly the m.3243A>G variant. This mutation impairs oxidative phosphorylation, leading to inadequate cellular energy production, particularly in high-demand tissues such as the brain and muscles. The resultant energy deficit manifests as neurological and muscular dysfunction, including stroke-like episodes, seizures, and lactic acidosis. Twin brothers presented with heterogeneous clinical characteristics. The elder twin experienced seizures, blurred vision, hypertrichosis, exercise intolerance, and had learning difficulties since age 10. The younger twin developed hearing loss at age 12, followed by persistent epileptic seizures 3 months later. Both had a history of progressive neurological and multisystemic symptoms suggestive of a metabolic disorder. Diagnostic evaluations included electroencephalography (EEG), which showed widespread mixed high-amplitude slow waves, and cranial magnetic resonance imaging, which revealed migratory lesions that changed with recurrent episodes. Genetic testing confirmed the m.3243A>G mutation in both twins. Their mother was identified as an asymptomatic carrier with an estimated heteroplasmy level of 30.79%. The elder twin was initially treated with acyclovir (antiviral) and methylprednisolone (anti-inflammatory) for suspected viral encephalitis, with symptomatic support. After genetic confirmation of MELAS, supportive therapies included coenzyme Q10, adenosine triphosphate disodium, levocarnitine, and arginine. During recurrent admissions for status epilepticus, antiepileptic regimens were maintained or adjusted, and imaging (magnetic resonance imaging/electroencephalogram) was repeatedly used for monitoring. His brother received similar interventions - levetiracetam, coenzyme Q10, and adenosine triphosphate disodium - upon diagnosis, with additional management for seizures, headaches, and gastrointestinal symptoms. Both twins were definitively diagnosed with MELAS syndrome. The elder twin was diagnosed first based on clinical and genetic findings, while the younger twin was diagnosed after the emergence of hearing loss and seizures. The condition highlights the progressive and variable nature of MELAS. The case underscores the significant phenotypic heterogeneity of MELAS, which often leads to misdiagnosis or delayed diagnosis. Early genetic testing is critical for accurate identification and prompt intervention. Family screening is recommended due to the maternal inheritance pattern, and tailored management should address the multifaceted clinical manifestations.
Severe drug-resistant childhood epilepsy is caused by KCNT1 gain-of-function genetic variants, resulting in increased KNa1.1 channel activity. KCNT1-associated epilepsy is thought to affect around 1 in 300,000 births worldwide. Current treatment for KCNT1 epilepsy only provides mild symptomatic relief and uses a cocktail of experimental medications which must be personalised for the individual and are often poorly tolerated. Critically, with many patients, no therapeutic benefit is achieved. We sought to address this by using large-scale virtual screening to accelerate the development of a molecule which binds directly to KCNT1 to supress overactivity. We purchased a total of 71 compounds and using a combination of fluorescent thallium flux assays and patch clamp electrophysiology, identified a series of eight structurally diverse, novel inhibitors of the KNa1.1 channel with potency in the low micromolar range. These provide potential starting points for further development of drugs to treat KCNT1-associated epilepsy.