Objective Accumulation of hyperphosphorylated tau (pTau) is a proposed mechanism for dementia associated with epileptic seizures but the evidence directly linking seizures and pTau accumulation remains weak. Here, we aimed at determining the burden of pTau pathology in a historical cohort of epilepsy patients who developed dementia hypothesizing an association between seizure onset zone and pTau accumulation. Methods Post-mortem brain tissue was obtained from the Danish Brain Collection comprising autopsies from psychiatric patients that died between 1945-1982. Sections from the middle frontal gyrus, thalamus, and medial temporal lobe from both hemispheres were stained for pTau and beta-amyloid and quantified by a blinded assessor. Comparisons were conducted using non-parametric tests. Results Thirty-two patients (median age 61.5 years, 59.4% men) were included. pTau pathology was detected in 22 brains (68.8%), with Tau Burden Scores (0-100) ranging from 2 (almost undetectable) to 94 (high load; median 6.5). pTau burden was significantly associated with age at death (Spearman’s rho = 0.62, p < 0.001) and duration of epilepsy (Spearman’s rho = 0.47, p = 0.02), but not with other clinical variables. Among 11 patients with focal seizures, a significantly higher pTau (p = 0.02) but not a higher beta-amyloid burden (p = 1.0) was observed in the epileptogenic hemisphere. 81.3% of all patients (n=26) had a competing dementia diagnosis: three patients fulfilled the pathological criteria of Alzheimer’s dementia, 13 patients had clinical and/or autoptic diagnosis of vascular dementia. Significance In this cohort, dementia epileptica was associated with increased pTau burden in the epileptogenic hemisphere and time since diagnosis supporting the concept of seizure-induced pTau accumulation. However, pTau is unlikely to be the primary neuropathological link between epilepsy and dementia in the cohort studied given the overall mild pathology and competing diagnoses.
OBJECTIVE:The study aims to examine the plasma levels of glial fibrillary acidic protein (GFAP) and placental growth factor (PGF) in adult patients with epilepsy and investigate their association with drug resistance after exposure to antiseizure drugs (ASDs). METHODS:The study included 80 patients with newly diagnosed epilepsy and 80 non-epileptic controls. The seizure control of patients was evaluated at 12 months after commencement of the initial ASD regimen. Seizure freedom was defined as a period without seizures for 12 months or 3 times the longest pretreatment seizure-free interval (whichever was longer). Drug resistance was defined as continued seizures despite at least two adequate trials of ASDs. RESULTS:Patients developing drug resistance showed higher pretreatment levels of plasma GFAP and PGF than those achieving seizure freedom and non-epileptic controls (one-way analysis of variance: P < 0.001). Group × time interactions were significant in GFAP [linear mixed-effects model (LMM) analysis: P = 0.021) and PGF (LMM analysis: P = 0.012). Based on LMM analysis, the differences of post-treatment levels of GFAP and PGF between patients achieving seizure freedom and those developing drug resistance were -650 pg/ml (95%CI, -823 to -476) and -4.80 pg/ml (95%CI, -6.06 to -3.54), respectively. The plasma GFAP, plasma PGF, and their combination in predicting drug response presented AUC: 0.78, 0.81, and 0.88, respectively. CONCLUSION:Our findings suggest plasma GFAP and PGF may be associated with drug resistance in adult patients with newly diagnosed epilepsy.
INTRODUCTION:Epilepsy is associated with obesity and metabolic syndrome, reflecting a well-established bidirectional relationship between metabolic health and seizure outcomes. GLP-1 receptor agonists may provide complementary metabolic benefits alongside ketogenic diet therapies; however, evidence regarding their effects on seizure control, safety, and combined use with ketogenic diets in epilepsy remains limited. METHODS:A retrospective chart review was conducted in patients seen at the Johns Hopkins Adult Epilepsy Diet Center between 2010 and 2026 who initiated the modified Atkins diet (MAD) and subsequently started a GLP-1 medication. Clinical, anthropometric, and laboratory data were obtained at various time points to evaluate seizure stability and metabolic trends. RESULTS:Ten patients were included; four remained on the MAD, while six had stopped MAD before starting GLP-1. The median duration on MAD was 3.5 years (IQR 1.5-6.8) and 1.2 years (IQR 0.7-2.1) on GLP-1. On MAD, patients showed improved seizure stability and achieved significant weight loss, from a median 83.3 kg (IQR 77.5-118.7) to 79.9 kg (IQR 67.8-102.1) with a decrease in BMI from 31.1 (IQR 26.8-34.0) to 29.8 (IQR 23.7-31.8) (both p = 0.02), though the majority of patients later regained the weight. After starting GLP-1, patients experienced further weight loss from a median of 82.6 kg (IQR 78.4-112.9) to 74.6 kg (IQR 62.7-94.1) and a decrease in BMI from 30.9 kg/m² (IQR 27.2-34.7) to 25.5 kg/m² (IQR 23.0-31.9) (both p < 0.01). Overall seizure control remained stable, except for two breakthrough seizures. No major adverse effects were reported, and combined MAD and GLP-1 therapy was associated with reduced appetite and carbohydrate cravings. CONCLUSION:GLP-1 receptor agonist therapy was well tolerated in adults with epilepsy and was associated with reduced appetite and food cravings, supporting its potential role as a safe adjunct to improve metabolic health and dietary adherence in patients on MAD.
Refractory status epilepticus (RSE) is a life-threatening neurological emergency in children. However, real-world evidence on pediatric RSE remains limited. This study characterized treatment patterns, in-hospital outcomes, and predictors of clinical outcomes within a resource-constrained regional referral network. We performed a single-center retrospective cohort study of pediatric patients admitted with RSE between March 2018 and March 2026. Demographic, clinical, treatment, and outcome data were systematically collected. A total of 215 pediatric RSE episodes were included (median age, 8.0 years; interquartile range [IQR], 5.8-11.8 years); 45.1% were female, and 39.5% had a history of epilepsy. All patients received benzodiazepines as first-line therapy, but only 67 episodes received guideline-recommended dosing. Diazepam, levetiracetam, and midazolam infusion were the most commonly used first-, second-, and third-line therapies, respectively. Favorable discharge outcomes were observed in 50.7% of patients and were independently associated with prior epilepsy (odds ratio [OR], 2.379; 95% confidence interval [CI], 1.07-5.27), adequate first-line benzodiazepine dosing (OR, 2.104; 95% CI, 1.02-4.33), and shorter duration of status epilepticus (OR, 1.991; 95% CI, 1.53-2.58). In-hospital mortality was 15.3% and was associated with acute etiologies (OR, 3.265; 95% CI, 1.27-8.40); prior epilepsy was inversely associated with mortality (OR, 0.328; 95% CI: 0.15-0.73). In-hospital mortality in pediatric RSE is associated with acute etiologies, whereas prior epilepsy is associated with lower mortality. Favorable functional outcomes are associated with prompt guideline-concordant first-line treatment and shorter seizure duration. These findings suggest that key prognostic determinants of pediatric RSE are consistent across different resource settings.
BACKGROUND:Febrile status epilepticus (FSE) is associated with the development of acute encephalopathy (AE), and delays in the administration of antiseizure medications have been linked to worse outcomes. However, the effect of treatment timing on subsequent in-hospital management and short-term outcomes in pediatric patients with FSE remains inadequately elucidated. METHODS:We conducted a single-center retrospective cohort study involving children with FSE admitted to our hospital between January 2020 and April 2023. Patients who received benzodiazepines (BZDs) within 80 min of seizure onset were included. Patients were categorized into an early group (EG) (≤40 min) and a late group (LG) (41-80 min) based on the timing of initial BZD administration. Outcomes assessed included impaired consciousness at 6 h, induction of anesthetic coma therapy (ACT), development of AE, and neurological sequelae. RESULTS:A total of 93 children with FSE were analyzed. Impaired consciousness at 6 h was observed in 33 (35.4%) patients, and 16 (17.2%) required ACT. Neurological sequelae occurred in 7 (7.5%) patients, including one death (1.1%). The induction rate of ACT was significantly higher in the LG than in the EG (22.7% vs. 3.7%). Although no statistically significant differences were observed in the incidence of AE or neurological sequelae, the ACT rate increased in a time-dependent manner with delays in BZD administration. CONCLUSIONS:Delayed BZD administration may be associated with an increased likelihood of requiring intensive neurocritical care, including ACT, among children with FSE.
There is a paucity of data assessing the accuracy of clinician prognostication for pediatric epilepsy surgery outcomes during multidisciplinary epilepsy surgery conferences (ESCs). This cross-sectional study, completed at Children's Hospital of Colorado (CHCO) and Children's Health Dallas (CHD), compared seizure freedom predictions by the ESC panels (captured via anonymous surveys of ESC members) to estimated outcomes by the Seizure Freedom Score (SFS) and to observed post-operative seizure freedom rates. The sample comprised 20 patients from CHCO (12/2021 - 12/2022) and 10 patients from CHD (6/2022-12/2023) satisfying inclusion criteria of at least 9 months of follow-up and survey completion by ≥ 50% of the ESC panels. Six patients were excluded from ESC prediction analysis for lack of consensus in their predicted prognoses. Predicted seizure freedom probabilities were assigned in ranges. The ESC panels accurately predicted seizure freedom for 80% (n = 8/10) of children for whom they had assigned higher predictive probabilities. Most of these children had known lesions and concordant presurgical data. ESC physicians accurately predicted lack of seizure freedom for 75% (n = 3/4) of children for whom they assigned lower predictive probabilities for seizure freedom. However, for the intermediate probabilities of 50-69%, 27% (n = 3/11) of children achieved seizure freedom. The SFS (scores 3-4) accurately predicted seizure freedom for 69% (n = 9/13) of patients. The ESC panels were most accurate in predicting seizure freedom at the extremes of the predicted probability spectrum and performed similarly to the SFS.
Background and objectives Epilepsy is a complex disorder with multiple provoking factors and etiologies. Certain genetic alterations in certain genes have been related to the development of various types of epilepsy. We performed a systematic review to evaluate associations between four nAChR alpha subunit genes (CHRNA2/3/5/6) and epilepsy subtypes. Methods We searched PubMed, Scopus, Academic Search Ultimate, CINAHL, and MEDLINE Complete (October 2024) for studies linking CHRNA2/3/5/6 mutations to epilepsy. CHRNA4 was excluded because it was recently comprehensively analyzed in a meta-analysis. This study included all original peer-reviewed evidence discussing the association between any nicotinic alpha subunit of cholinergic receptor genes and any epilepsy. There were no date limitations, but studies investigating non-human subjects or written in languages other than English with no translation were excluded, along with any study discussing the mentioned genes or epilepsies without a correlation identification or discussion. This review uses the current ILAE 2022 nomenclature. Results A total of 193 records were identified, of which 39 records have been sought for retrieval, and 21 studies were eventually included in the final review. Thirteen studies discussed CHRNA2, and four studies discussed both CHRNA3 and CHRNA5, while each of these two genes was being discussed alone by only one study, and two studies discussed all four genes, including CHRNA6. Among the four genes examined in this research, CHRNA2 showed the highest frequency of association with pathogenic mutations. Conclusion While many epilepsy patients were found to have no mutation in the four CHRNA genes investigated, some genetic studies showed mutations in CHRNA2 related to ADSHE, while others showed no association, with a possibility of CHRNA5 being related to self-limited epilepsy with centrotemporal spikes (SeLECTS).
The postictal period, which immediately follows a seizure, is associated with several incapacitating symptoms or signs, such as psychosis, confusion, paresis, aphasia and memory loss. These symptoms can last from several minutes to even days and can have a negative impact on the quality of life for people living with epilepsy. However, there is a scarcity of data concerning the neurobiological mechanisms that mediate postictal amnesia and behavioural impairments. In the present study, we examined the impact of a single brief, self-limiting convulsive seizure induced by the chemoconvulsant pentylenetetrazol (PTZ) on trace fear learning. We found that PTZ administration produced a rapid but transient increase in hippocampal PI3K-Akt-mTOR signalling, with phosphorylation of Akt, mTOR, and ribosomal protein S6 peaking between 2 and 6 h post-seizure and returning to baseline by 24 h. This activation coincided with increased expression of plasticity-related markers, including Egr1 and PSD-95, and was associated with impaired memory in a hippocampus-dependent trace fear conditioning task. Administration of the mTORC1 inhibitor rapamycin 30 min post-seizure rescued the memory deficit. These findings suggest that postictal hyperactivation of mTOR signalling disrupts mechanisms of synaptic plasticity through excessive or unregulated protein synthesis, potentially saturating plasticity mechanisms and impairing new memory formation. Taken together, our results identify a critical role for aberrant mTOR signaling in mediating postictal cognitive dysfunction and suggest that targeted inhibition of mTORC1 may represent a therapeutic strategy for preserving memory after seizures.
BACKGROUND:Seizure emergencies, include prolonged seizures and status epilepticus (SE). Benzodiazepines are recommended as first-line rescue therapy. We investigate prescribing practices, emergency planning, and clinician experiences regarding rescue medication in Hungary and compare findings with those from the United Kingdom and Norway. METHODS:A cross-sectional online survey (CHERRIES-compliant) was conducted between March and October 2025 among neurologists and pediatric neurologists in Hungary. The questionnaire explored demographics, prescribing behaviours, emergency management planning, and training practices. Descriptive statistics were used for Hungarian data, and comparative analyses with the combined UK and Norwegian cohorts were performed using chi-squared, Fisher's exact, and Mann-Whitney U tests with Bonferroni correction. RESULTS:Fifty-six clinicians participated in Hungary, predominantly neurologists (67.9%), with 60.7% having over 10 years' experience. Midazolam was prescribed by 69% of respondents, significantly lower than in the UK and Norway (100%, p < 0.01). Concerns regarding inappropriate use were reported by 27% in Hungary versus 72% in comparator countries (p < 0.01). A maximum 24-hour dose of 20 mg was most reported (58.5%). Prescribing preferences differed by seizure type, with greater use of nasal midazolam and rectal diazepam in Hungary, while buccal midazolam predominated in the UK and Norway. Emergency plan review frequency and training modalities also varied, with Hungary relying more on face-to-face training. CONCLUSION:While midazolam was widely prescribed, significant international differences were observed in prescribing patterns, administration routes, and training practices. Further research is needed to determine whether guidelines standardisation, training frameworks, and improved access to rescue therapies could reduce these differences across healthcare settings.
OBJECTIVE:To investigate the epileptogenicity of the hippocampus in patients with PNH using functional connectivity (FC). METHODS:PNH patients with intracranial electrodes implanted in both heterotopic nodules (HNs) and the hippocampus, and who achieved seizure freedom postoperatively, were retrospectively enrolled.Hippocampal epileptogenicity was determined based on the surgical outcomes after hippocampus coagulation or not. The epileptogenicity index (EI) was calculated for both HNs and hippocampal channels. Interchannel FC during the interictal state (cortico-cortical evoked potential, CCEP) and ictal state (h2 coefficient) was calculated and compared. A logistic regression model was developed using significant ictal FC biomarkers to predict hippocampal epileptogenicity. RESULTS:A total of 8 patients were enrolled, with 6 undergoing CCEP. No significant EI differ-ences were observed between HNs and hippocampal channels. In patients with hippocampal epileptogenicity, connectivity from the hippocampus to HNs was stronger during both interictal and ictal states compared to the reverse. This trend was not seen in patients without hippocampal epileptogenicity. A logistic regression model incorporating ictal FC differences distinguished hippocampal epileptogenicity with an ac-curacy of 0.79 and an AUC of 0.81. CONCLUSION:A classification model based on ictal FC effectively differentiates hippocampal epileptogenicity in PNH patients and may serve as a valuable tool for guiding surgical decisions.
Epilepsy is a chronic neurological disorder characterized by recurrent, spontaneous seizures. In addition to seizures, patients experience additional adverse outcomes, including increased risk of psychiatric comorbidities and premature mortality. Stress is the most commonly reported trigger for seizures and particularly severe or chronic stress has been linked to the development of epilepsy itself. Stress has also been found to worsen psychiatric illness and is a risk factor for sudden death in individuals with and without epilepsy. The body's response to stress is coordinated by the hypothalamic-pituitary-adrenal (HPA) axis. Perturbations in stress hormone levels and their receptors are associated with psychiatric illness as well as sudden unexpected death in epilepsy (SUDEP), which is the leading cause of death in patients with refractory epilepsy. This review examines our present understanding of the relationship between stress, HPA axis dysfunction, and epilepsy sequela. We highlight stress and HPA axis dysfunction as salient risk factors for epilepsy patients that may directly contribute to their prognoses. A better understanding of how stress facilitates deleterious outcomes in epilepsy will inform interventions to improve the quality of life and increase longevity in people with epilepsy.
BACKGROUND:Lennox-Gastaut Syndrome (LGS) is a severe, treatment-resistant developmental and epileptic encephalopathy associated with high morbidity and mortality. The heterogeneous presentation of LGS, and similarities with other childhood epileptic syndromes, makes it difficult to diagnose and treat. While several studies have investigated caregiver experiences and clinical outcomes, no studies to our knowledge have investigated caregiver-identified priorities for future research or research dissemination for individuals with LGS. This community-focused study aims to characterize LGS caregivers' preferences in receiving information about current comparative effectiveness research studies and their priorities for future research for this population. METHODS:Caregivers of children and adults with LGS attended a focus group session at the 9th International Family and Professional Conference hosted by the LGS Foundation. The focus groups were facilitated by healthcare professionals and explored a range of concepts including diagnosis, access to LGS information, and improvement of care. RESULTS:Nineteen LGS caregivers participated. There were three focus groups of six to seven people each. Across the focus groups, thematic analysis revealed four themes (with subthemes) related to the experiences and preferences of caregivers of patients with LGS: (1) access to care, (2) access to information, (3) improvement in transitional care, and (4) improvement in care coordination. Challenges in accessing treatment, including delays in diagnosis due to lack of physician knowledge about the condition, permeated the themes and informed the recommendations. CONCLUSIONS:Future work should improve healthcare provider knowledge, care coordination, transitional care, and caregiver resources that fit the unique needs of this population.
INTRODUCTION:Epilepsy is a common pediatric neurologic disorder, and its surgical management has increased over time. To characterize longitudinal changes in patient selection, surgical approach and outcomes, we report a 30-year retrospective review at a high-volume level 4 epilepsy center. METHODS:Consecutive epilepsy surgeries from 1989 to 2018 were analyzed and grouped into early (1989-2003) and late (2004-2018) 15-year eras. Demographic, clinical, radiographic, surgical, and 2-year Engel outcome data were collected and analyzed. Multivariable logistic regression assessed independent associations between era, patient characteristics, imaging findings, surgical procedures, and seizure outcomes. RESULTS:Of 1241 surgical records, 1128 pediatric cases were included (415 early, 713 late; 55.50% male). Patients in the late era were older at surgery (10.27 vs. 8.53 years, p < .001), and repeat surgery was more common (p < .001). Focal (OR 1.72, p = .005) and cerebral insult related (OR 2.74, p < .001) MRI abnormalities were more frequently treated in the late era. Hemispherectomies, lobectomies and corpus callosotomies were performed less often (all p ≤ .001), while focal and multilobar resections remained stable (p > .05). Use of invasive monitoring and electrical stimulation mapping declined over time (p < .001). Seizure freedom rates were stable, however, ≥ 90% seizure reduction was more common in the late era (OR 1.60, p = .038). CONCLUSION:Over three decades, pediatric epilepsy surgical volume increased, surgery shifted towards older patients, with reduced extensive resection and reduced reliance on invasive monitoring. Despite these changes, seizure freedom rates remained stable, with improved near-complete seizure control in the later era.
BACKGROUND:Lennox-Gastaut syndrome (LGS) is a rare developmental and epileptic encephalopathy associated with treatment-resistant seizures, profound neurodevelopmental impairments, and high caregiver burden. While seizure control is often prioritized in clinical trials, caregivers emphasize the importance of assessing behavior, communication, and quality of life. This study explored the perspectives of caregivers, clinicians, and advocates on existing instruments for measuring these domains in individuals with LGS. METHODS:We conducted four focus groups with caregivers (n = 22), epilepsy advocates (n = 5), and clinicians (n = 6). Participants reviewed pre-selected instruments for each domain before the sessions. Questions elicited feedback on instruments assessing the three domains, as well as other relevant domains for LGS. Discussions were recorded, transcribed, and thematically analyzed. RESULTS:Five themes emerged: (1) Behavior instruments - the Aberrant Behavior Checklist was favored for relevance and ease, while the Adaptive Behavior Assessment System-3 and Vineland Adaptive Behavior Scales-3 were viewed as lengthy or developmentally mismatched; (2) Communication instruments - the Communication Matrix was preferred for capturing nonverbal and alternative communication, while the Communication and Symbolic Behavior Scales lacked relevance; (3) Quality of life instruments - no clear preference emerged between Quality of Life Inventory-Disability and CDKL5 Deficiency Disorder Severity Assessment; (4) Impact on caregivers - negative language, time burden, and administration logistics posed challenges; and (5) Unaddressed gaps - sleep, gastrointestinal health, caregiver burden, socialization, and safety were noted as insufficiently captured. CONCLUSION:Participants identified strengths and limitations of existing instruments and highlighted several unmet measurement needs. These insights underscore the need for relevant, inclusive tools that are aligned with the lived experiences of individuals with LGS and their families.
