Ketogenic dietary therapies (KDTs) are increasingly used worldwide as a non-pharmacological treatment for epilepsy, including among people of childbearing potential. In many cases, KDTs allow for the reduction of antiseizure medications (ASMs) and lower drug exposure during pregnancy. However, limited evidence on maternal tolerability, fetal safety, and lactation outcomes has led to reluctance among healthcare providers to recommend KDTs during pregnancy. To inform evidence-based counseling, it is crucial to systematically collect data on maternal and offspring outcomes following KDT exposure. Over the past 25 years, international epilepsy pregnancy registries have provided robust data on the teratogenic risks of ASM exposure. Yet, no standardized dataset currently exists for documenting KDT exposure during pregnancy and lactation. The International League Against Epilepsy Ketogenic Dietary Treatments Task Force conducted a structured consensus process to develop the first international core dataset designed to capture maternal KDT exposure within existing pregnancy registries. This dataset provides a standardized, pragmatic framework for recording diet type, exposure duration, maternal-fetal outcomes, and lactation parameters. By harmonizing data collection across registries, this initiative aims to transform isolated case reports into aggregated, high-quality multicenter evidence, closing a critical knowledge gap. Incorporating these standardized questions into epilepsy pregnancy registries represents both a scientific necessity and a call to action to ensure safer, evidence-based care for women with epilepsy and their children. PLAIN LANGUAGE SUMMARY: More people are using ketogenic diets as a treatment for epilepsy around the world, including during pregnancy. It is not yet known if these diets are safe for mothers and babies during pregnancy and breastfeeding. Collecting standardized information about pregnancy outcomes in existing registries will inform us about the safety and effectiveness of these diets. The authors, who are either members of the International League Against Epilepsy dietary task force or specifically chosen by them for their expertise, followed a consensus process to suggest the addition of key standardized questions to the existing international pregnancy outcome registries for epilepsy.

Epilepsy surgery is an established treatment for drug-resistant epilepsy, offering a realistic prospect of seizure freedom in well-selected candidates. However, surgery is sometimes offered to individuals with a low probability of seizure freedom when it is framed as potentially "life-saving" on the basis of the elevated mortality associated with uncontrolled epilepsy. We examined this rationale using absolute risk reduction and number needed to treat (NNT) analyses derived from published mortality rates (deaths per 1000 person-years) in unoperated drug-resistant epilepsy, postoperative seizure-free patients, and postoperative patients who were not seizure-free. Weighted averages were used to estimate ARR and NNT for all-cause and sudden unexpected death in epilepsy (SUDEP) mortality across varying probabilities of seizure freedom and postoperative life expectancy. Compared with unoperated patients, mortality reductions were greatest in those who became seizure-free after surgery but remained modest in patients who did not. At a 50% probability of seizure freedom, the NNT to prevent one all-cause death was 146 person-years and to prevent one SUDEP was 243 person-years; with higher seizure-freedom probabilities (80%), the NNT improved to 124 and 225 person-years, respectively; at 20%, it worsened to 178 and 264 person-years. Lifetime modeling demonstrated that NNT decreases sharply with increasing life expectancy, reaching 3.5 and 4.7 at 60 years postoperative life expectancy for all-cause and SUDEP mortality, respectively. These findings highlight the complexity of invoking a "life-saving" rationale for surgery in poor candidates. Patients with the highest mortality risk, those with frequent generalized seizures, are also those least likely to achieve postoperative seizure freedom and therefore least likely to realize a mortality benefit. Our analyses underscore the need for balanced, data-driven risk-benefit discussions when surgery is considered primarily on mortality grounds. PLAIN LANGUAGE SUMMARY: This study looked at whether epilepsy surgery saves lives for people whose seizures cannot be controlled with medication. We found that surgery lowers the risk of death-especially when it stops seizures completely-but the benefit is smaller for people who continue to have seizures afterwards. Because people with the most severe forms of epilepsy have a lower chance of becoming seizure-free following surgery, the idea that surgery will be "life-saving" for them needs to be considered carefully and discussed with clear, balanced information.

Temporal lobe epilepsy (TLE) impacts multiple brain networks. Aberrant functional connectivity has been demonstrated in resting-state networks (RSNs) that mediate higher brain functions in TLE. This study aimed to identify the reproducible patterns of altered functional connectivity in TLE in a large, international cohort through ENIGMA-Epilepsy. Resting-state functional MRI datasets from nine centers across North America, South America, Europe and South Africa, including 442 people with TLE and 387 healthy adults, were analyzed. We examined group differences in whole-brain connectivity in patients compared to controls in seven major RSNs. We also investigated whole-brain connectivity maps for key nodes within the default mode network (DMN). Furthermore, the associations between connectivity patterns and clinical variables were assessed. We found lower within-network connectivity scores (13.6% on average) and higher between-network connectivity scores (129% on average) in non-limbic RSN in TLE. This pattern was reproducible across all seven sites and most robust for DMN and visual networks. Patterns of connectivity were not associated with age of seizure onset or disease duration and were mostly similar in patients with left and right TLE with a few exceptions; isolated regions of high connectivity in left TLE and lower connectivity in right TLE compared to controls. We show strong evidence of lower connectivity within most RSNs and higher connectivity outside of these networks that was highly consistent across geographically diverse sites, demonstrating the robustness and generalizability of our findings. The findings demonstrate a consistent disruption of network organization in TLE that may underlie cognitive co-morbidities and seizure propagation patterns observed in this patient population. In this international ENIGMA-Epilepsy study, resting-state fMRI data from 442 individuals with TLE showed reduced connectivity within major resting-state networks (about 14% lower) and markedly increased connectivity between networks (about 129% higher), compared to 387 healthy controls. These patterns were highly reproducible across sites. Connectivity alterations were not related to age of onset or disease duration and were largely similar across left and right TLE, aside from small, region-specific differences. Overall, the study demonstrates a robust, widespread reorganization of brain network connectivity in TLE, which may help explain associated cognitive difficulties and seizure spread.

The search for a reliable post-ictal biomarker has spanned nearly five decades. Serum prolactin, first proposed by Trimble in 1978,1 requires sampling within 20 min, can also be elevated after syncope, and achieves only moderate sensitivity.2 Creatine kinase peaks too late (48–72 h) for acute decision-making, though may have value in an outpatient setting.3 Lactate, though informative normalizes within 1–2 h and is clinically nonspecific,4 inflammatory markers such as WBC and temperature are also elevated5 but again are clinically nonspecific. The identification of phosphate as the most profoundly altered electrolyte after tonic–clonic seizures by Nass et al. in 20196 opened a new avenue and was subsequently validated in emergency department cohorts in Switzerland, Portugal, and even in canine seizure presentations.7-9 We therefore read with interest the study by Binks and colleagues (Volume 10, Issue 6, December 2025, Pages 2025–2031) extending this evidence into first seizure clinics and neurology consults,10 and sought to review this finding within our own service. We retrospectively reviewed 96 cases presenting to the first seizure clinic at our hospital who had bloods taken at the initial presentation to our Emergency Department. Of these, 89 had a diagnosis made in clinic: 72 epileptic seizures (50 epilepsy, 22 single seizures), 11 non-epileptic attacks, 5 syncopal episodes, and 1 other. Phosphate was available in 77.5% of diagnosed cases, higher than the 49% reported by Binks et al.,10 suggesting routine measurement is both feasible and may already often occur. Mean phosphate was 0.92 mmol/L (SD 0.30) in epileptic seizures and 0.96 mmol/L (SD 0.38) in non-epileptic events. A phosphate below 0.8 mmol/L was present in 37.5% (21/56) of epileptic seizures and 23.1% (3/13) of non-epileptic events. This difference did not reach statistical significance in our cohort (Fisher's exact test, p = 0.52). Mean lactate values (2.93 vs. 1.81 mmol/L) were comparable to those reported by Binks et al. Logistic regression using lactate alone yielded an AUC of 0.793 (95% CI 0.311–0.945) for discriminating epileptic seizures, while the addition of phosphate did not improve discrimination (AUC 0.731, 95% CI 0.527–0.948), likely reflecting the small number of non-epileptic cases with both lactate and phosphate available for model fitting (n = 11). This contrasts with the larger cohort in Binks et al. where a combined lactate–phosphate–calcium model achieved an AUC of 0.825. Exploratory analysis of diagnostic thresholds in our cohort suggested that a lower cutoff of <0.75 mmol/L may optimize the trade-off between sensitivity and specificity, achieving 92.3% specificity and 93.8% PPV (Youden's J = 0.191) compared with 76.9% specificity at the <0.8 mmol/L threshold used by Binks et al., while the <0.6 mmol/L cutoff proposed by Barras et al. offered no further gain in specificity but halved sensitivity (12.5% vs. 26.8%). When pooled with the data from Binks et al., the combined estimate showed low phosphate in 32.8% (38/116) of epileptic seizures versus 11.6% (5/43) of non-epileptic events (Fisher's exact test, p = 0.009). This combined effect size is consistent with the odds ratios of 3.5–5.5 reported across the literature.7, 9, 10 The proposed mechanisms behind post ictal hypophosphatemia, catecholamine-driven cellular uptake, respiratory alkalosis from post-ictal hyperventilation, and glycolytic phosphate consumption during intense muscular contraction6 predict that hypophosphatemia should be largely specific to convulsive seizures and absent in non-epileptic attacks (NEA), where these processes do not occur. The low rate of hypophosphatemia in NEA observed by both Binks et al. (1/15) and in our cohort (3/13) supports this. A limitation of our analysis is the absence of ictal onset timing in many cases, preventing replication of the 6-h diagnostic window identified by Binks et al. and earlier by Nass et al. We also did not categorize seizures as convulsive or not, which likely increased our mean phosphate levels; however, it is true to routine clinical practice. Nevertheless, this data strengthens the case for adding serum phosphate to initial investigations in TLoC. Given its low cost, widespread availability, and a practical diagnostic window, phosphate represents an accessible addition to the TLoC assessment toolkit—particularly where episodes are unwitnessed or the history is unclear. Prospective studies should look to evaluate combined biomarker panels incorporating phosphate, lactate, calcium, and CK focusing on evaluating thresholds. TA and AG have no conflicts of interest to disclose. RHT has received honoraria from Angelini, Bial, Biocodex, Eisai, Jazz, LivaNova, Paladin, Neuraxpharm, Sanofi, Takeda, and UCB Pharma. Meeting support from Angelini, UCB Pharma. Unrestricted research funding from Angelini. Joint working partnership with UCB Pharma. CI on BioHaven and Lundbeck RCTs. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

With keen interest we read Ooi et al.'s recent publication,1 and we congratulate the authors on their impressive work. The authors show that machine-learning models incorporating advanced quantitative MRI features (e.g., cortical folding and interhemispheric asymmetry) meaningfully improve seizure recurrence predictions after a first seizure compared with clinical features alone (AUC 0.65 vs. 0.57), in a carefully selected cohort of adult patients with nondiagnostic MRI and EEG. Importantly, by excluding patients with epileptogenic MRI findings (and epileptiform EEG abnormalities), the authors avoid incorporation bias—the methodological error of using predictor variables that directly define the outcome, which can artificially inflate model performance.2, 3 This makes the study particularly compelling, as it offers insight into novel imaging-based predictors beyond traditional clinical and demographic variables, which are known to have limited predictive value.4, 5 Because MRI and EEG findings are an integral part of clinical decision-making in practice5-8 previously published models have included them as predictors.9, 10 One of these models,10 as mentioned by Ooi et al.,1 included patients with epileptogenic MRI lesions known to be associated with the outcome (seizure recurrence), and the high discriminatory ability of that model may be attributed to this.1 Similarly, our model published in 2018 on childhood epilepsy prediction showed that including EEG findings—including epileptiform EEG abnormalities—as a predictor substantially increased model performance compared to clinical features alone (AUC 0.86 vs. 0.67).9 Since the presence of epileptiform EEG or epileptogenic MRI findings after a first seizure is often considered sufficient for an epilepsy diagnosis, including them as predictors is methodologically suboptimal.2, 5, 11 We therefore agree with Ooi et al.'s approach of excluding patients with these diagnostic features when assessing the added predictive value of potential new diagnostic or prognostic biomarkers. In this letter we seek to point out these contrasting modeling strategies—specifically, the choice to include or exclude diagnostic features—and to encourage researchers and clinicians to explicitly balance the risk of incorporation bias against clinical applicability. Excluding diagnostically decisive features during model development inevitably limits a model's ability to capture the full range of relevant information. However, it also produces more realistic predictions, enabling discovery of new biomarkers.12 We advocate for broader dialogue to harmonize study designs in first-seizure research, and echo Ooi et al.'s view that integrating novel biomarkers13 may meaningfully advance clinical prediction models. We thank the authors for their important contribution to the field. None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Dravet syndrome (DS) is a drug-resistant developmental and epileptic encephalopathy, often requiring three or more antiseizure medications (ASMs). Consequently, the therapeutic landscape is highly complex, combining DS-specific agents (stiripentol, STP; cannabidiol, CBD; fenfluramine, FFA), non-specific ASMs, and non-pharmacologic options such as dietary therapy or neuromodulation. In addition, recognition of patients' changing needs across the lifespan, together with the essential contribution of caregiver education to effective treatment oversight-including awareness of potential drug-drug interactions and adverse events-emphasizes the value of an integrated and forward-looking approach. A consensus initiative was developed to guide clinicians in the management of patients with DS, with a particular focus on STP-containing regimens. Based on a literature review and clinical vignette discussions, a nominal group of five international DS experts developed 38 statements across six themes: (i) general principles, (ii) guiding physicians to empower families, (iii) STP as add-on to specific and non-specific Dravet ASMs, (iv) FFA in regimens containing STP, (v) CBD in regimens containing STP, and (vi) patient follow-up during treatment initiation. Statements were scored on a 9-point Likert scale (1 = strongly disagree, 9 = strongly agree) first by the nominal group and then by an international panel of 59 DS clinicians. Consensus was defined as ≥75% rating ≥7 and/or a median ≥8. Thirty-four of the 38 statements (89%) reached consensus among both the nominal group and the international panel; one did not reach consensus in either, and three reached consensus only among the nominal group. Both panels agreed on the importance of involving families in treatment decisions and follow-up, as well as on key aspects of polytherapy management, including ASM initiation, treatment adjustments, and adverse event management. This international consensus integrates evidence and clinical expertise to establish shared principles that address a long-standing gap in the polytherapeutic management of Dravet syndrome. Dravet syndrome is a rare and severe form of epilepsy that begins in early childhood, with seizures that often persist throughout life. Because the disease is highly drug resistant, most patients are treated with polytherapy, making clinical management complex for clinicians. This consensus brings together published evidence and expert experience to provide practical guidance on the management of polytherapy in Dravet syndrome, supporting clinicians in optimizing patient care.

Ketogenic dietary therapies (KDTs) are the treatment of choice for Glut1 Deficiency Syndrome (Glut1DS), providing dietary ketones as an alternative fuel to the brain and effectively controlling seizures. Recent evidence indicates insufficient seizure control in Glut1DS patients despite adequate KDT and ketosis. Fifty-three patients, diagnosed with Glut1DS and treated by KDT, were followed in a single-center outpatient clinic from 2000 to 2023. Epilepsy, present in 44 patients, was analyzed for seizure control, EEG changes, and potential correlations to clinical and genetic features. Epilepsy response to KDT was defined as a >90% seizure reduction on KDT monotherapy. On KDT monotherapy 27/44 (61%) patients became >90% seizure free, rated as responders. 17/44 were non-responders. Within this group, 10/17 patients responded to KDT plus antiseizure comedication. In 7 patients, KDT plus antiseizure comedication failed to control seizures. No correlations of seizure control to gender, age at start or type of KDT, or SLC2A1 variants were observed. In responders (n = 27), EEG epileptic activity, evident in 15/27 patients, improved on KDT in 5 patients. In non-responders (n = 17), EEG epileptic activity was evident in 14/17 and improved on KDT in 9 patients. EEG background slowing prior to KDT normalized in KDT in all responders (4/27), but in none of the non-responders (4/17). Epilepsy is a dominant feature of Glut1DS. KDT provides efficient seizure control, but failure to control epilepsy is more common than expected. KDT epilepsy response did not correlate with seizure type, clinical, or genetic features, emphasizing the complexity of this entity. Add-on antiseizure medication can be effective in some patients, without individual drug superiority. Epileptic activity on EEG did not prove a good marker for outcome, but reversible EEG background slowing on KDT might be predictive for favorable seizure control. Impaired glucose transport into the brain causes a brain energy crisis termed Glut1 Deficiency. Ketogenic diets mimic fasting, provide ketones as an alternative fuel, and effectively restore brain function. In our study, this worked for ca. 60% of patients. To our surprise, epilepsy persisted in about 40% of patients despite ketogenic diets for reasons unknown. Additional medication against epilepsy randomly helped in some patients. We analyzed many parameters without finding obvious explanations. Electrical brain activity improvement on ketogenic diets might be a future marker for efficient seizure control.

Treatment selection for infantile epileptic spasms syndrome (IESS) is complex and multifaceted, and currently no electroencephalogram (EEG) biomarkers can guide this decision by predicting treatment response. We tested the predictive value of phase-amplitude coupling (PAC) as IESS patients are known to have elevated PAC. We analyzed retrospective EEG recordings from 40 IESS patients, before and after treatment, and 20 healthy controls. Patients were classified as responders (n = 25) or nonresponders (n = 15) based on short-term treatment outcomes. We measured PAC in each EEG using modulation index (MI) and mean vector length (MVL) and analyzed the relationship between pre- and posttreatment values and the ability of pretreatment values to predict response. MI and MVL values decreased with treatment in almost all subjects. However, nonresponders had significantly higher pretreatment MI than responders (p < 0.05), suggesting utility for predicting treatment response. Logistic regression modeling suggested that a 0.5-unit decrease in ln(MI), which is approximately one IQR of the pretreatment ln(MI) values, results in a 3.5-fold increase in odds of positive treatment response. MI reflects short-term treatment response and is a candidate predictive EEG biomarker for IESS. MI may offer individualized insights for treatment selection and management strategies for IESS. We examined brain activity in infants with infantile epileptic spasms syndrome (IESS) to predict which infants' seizures would stop with standard medication. Specifically, we measured coupling between slow and fast brain waves in both healthy infants and those with IESS. Infants for whom medication failed had stronger coupling, even before the treatment was started, while those with weaker coupling (more similar to healthy infants) were more likely to have their seizures stop after treatment. These findings suggest that brain wave coupling could help doctors predict which infants will need more aggressive treatment.

First seizure events are common and may exert an immediate and profound impact on people's lives. Less understood are their long-term consequences. This prospective, longitudinal study aimed to measure and compare psychosocial and health-related work productivity trajectories following first seizure events of various etiologies. Adults with first seizure events were recruited from five epilepsy centers in Australia and the US between 2020 and 2023. Participants completed questionnaires covering health-related quality of life (HRQOL; EQ-5D-5L, QOLIE-31), anxiety and depressive symptomatology (HADS), and productivity (WPAI) within 6 weeks of their first seizure event, and 6- and 12 months later. One hundred ninety-six participants (median age 42 years, 55.6% male) met inclusion criteria. 101 (51.5%) had newly-diagnosed epilepsy, 46 (23.4%) had acute symptomatic seizures, and 49 (25.0%) had syncope (seizure mimic). Compared to baseline, at 12-month follow-up, the acute symptomatic seizure group showed significant improvement in EQ-5D-5L utility (p = 0.001). The newly diagnosed epilepsy and acute symptomatic seizure groups both demonstrated improved QOLIE-31 scores over 12 months (acute symptomatic seizure p = 0.025; newly diagnosed epilepsy p < 0.001). The newly diagnosed epilepsy group showed significant reductions in absenteeism (p < 0.001), presenteeism (p < 0.001), overall work impairment (p < 0.001), and activity impairment (p = 0.002). The acute symptomatic seizure group had a significant reduction in informal care needs (p < 0.001). Anxiety and depressive symptomatology remained unchanged across all groups. HRQOL improved for people with acute symptomatic seizures and newly diagnosed epilepsy over time, but anxiety and depressive symptomatology remained unchanged. Future studies may explore interventions to improve screening and treatment of anxiety and depression for people following first seizure events. This study investigated changes in quality of life, anxiety and depressive symptomatology, and health-related work productivity over a 12-month period for adults with first seizure events. Participants reported improvements in quality of life, reduced sick days, increased productivity at work, and less need for informal care. Concerningly, there was no change in their anxiety and depressive symptoms. The findings of this study may prompt first seizure clinicians to regularly screen patients for anxiety and depressive disorders, and treat these appropriately.

Human telomerase reverse transcriptase (hTERT) is a key determinant of telomere maintenance and cellular aging. Oxidative stress plays a role in neurodegenerative processes by causing cellular damage through increased reactive oxygen species. Our study aimed to reveal the relationship between hTERT and oxidative stress in the pathophysiology of epilepsy. The study included 45 individuals diagnosed with epilepsy and 55 healthy controls. hTERT concentration, total oxidant status (TOS), total antioxidant status (TAS), superoxide dismutase (SOD), and thiol-disulfide homeostasis were measured in serum samples. A significant decrease in hTERT levels, an increase in oxidative stress markers (TOS, OSI), and a decrease in antioxidant levels (TAS, SOD), and total and native thiol levels were determined in epilepsy patients. In addition, a significant and negative correlation was found between hTERT and native thiol. Our study suggested that the interaction between oxidative stress and hTERT levels in the pathophysiology of epilepsy may play an important role in seizure generation and progressive neural damage. This study will form the basis for further research and guide the identification of potential biomarkers for treating epilepsy. We measured the levels of a protective protein that helps preserve chromosomes and several markers of cell stress in people with epilepsy and healthy volunteers. People with epilepsy showed lower levels of this protective protein, weaker antioxidant defenses, and higher oxidative stress. We also found that lower protein levels were linked to fewer molecules that guard cells from damage. These changes may help explain why seizures occur and why the brain can suffer ongoing injury in epilepsy.