Epilepsia[JOURNAL]
Sun
200 papers
Current management of low-grade, epilepsy-associated brain tumors in Europe.
Arzimanoglou A, Tchaicha S, Harrington BT … +3 more , Mühlebner A, Najm I, Blümcke I
Epilepsia · 2026 May · PMID 42080219 · Publisher ↗
Low-grade epilepsy-associated brain tumors (LEATs) are a frequent cause of drug-resistant focal epilepsy in both children and adults. Epilepsy surgery is a well-recognized treatment option, with almost 80% of patients be...
Low-grade epilepsy-associated brain tumors (LEATs) are a frequent cause of drug-resistant focal epilepsy in both children and adults. Epilepsy surgery is a well-recognized treatment option, with almost 80% of patients being seizure-free at 1 year, and 50% of children being seizure- and drug-free at 5 years. Despite these outcomes, standardized management guidelines remain lacking. The present study aimed to assess current practices in Europe. A comprehensive web-based survey was conducted by EpiCARE (European Reference Network for Rare and Complex Epilepsies). Responses were collected from 172 clinicians representing 75 institutions in 26 European region countries. The questionnaire addressed institutional protocols, individual practices, referral pathways, presurgical evaluation, histopathology, molecular diagnostics, and follow-up. Clinicians largely agreed that epileptic seizures are a major comorbidity in LEAT patients, and most reported that seizure frequency and duration influence their treatment approach. This reflects an understanding of LEATs not only as an oncological entity, but above all as an epileptogenic lesion with a strong impact on quality of life, systematically requiring a multidisciplinary approach. Significant inconsistencies were identified, particularly regarding referral pathways, presurgical assessment (66% referred systematically to an epilepsy team), and molecular diagnostics. Only 48% of respondents reported having institutional protocols in place. Although the majority supported early referral to an epilepsy surgery team after diagnosis (even in the absence of confirmed drug resistance), 13% still required failure of at least two antiseizure medications. Long-term postsurgical follow-up was recommended by 89% of clinicians beyond 1 year after surgery. Almost all clinicians acknowledged that histopathology influenced clinical decision-making for follow-up, and 87.2% were familiar with the World Health Organization 2021 central nervous system tumor classification and molecular diagnostics. This large European study shows growing alignment with international recommendations, but significant inconsistencies remain in clinical practice, particularly regarding referral pathways, presurgical assessment, and molecular diagnostics. These findings highlight the need for consensus-driven international guidelines for LEAT management.
Effects of fenfluramine and sigma-1-dependent pharmacological and genetic modulation in a mouse kindling model.
von Rüden EL, Buchecker V, Wagner A … +3 more , Stocker VM, Zvejniece L, Potschka H
Epilepsia · 2026 Apr · PMID 42054218 · Publisher ↗
OBJECTIVE: Sigma-1 is a chaperone protein that serves as a key homeostatic regulator, implicated in neuronal excitability and seizure control. Positive allosteric modulators offer a use-dependent means to enhance Sigma-1...
OBJECTIVE: Sigma-1 is a chaperone protein that serves as a key homeostatic regulator, implicated in neuronal excitability and seizure control. Positive allosteric modulators offer a use-dependent means to enhance Sigma-1 activity, potentially with favorable tolerability compared to direct agonists. This study examined the role of sigma-1 in ictogenesis, seizure spread, and termination, and evaluated whether sigma-1 targeting could modify progression in the amygdala kindling model. METHODS: Using the mouse amygdala kindling paradigm, we assessed the effects of subchronic administration of the sigma-1 positive allosteric modulator E1R and of the antiseizure medication fenfluramine on seizure thresholds, severity, duration, and progression of kindling. Tolerability, behavioral outcomes, and potential disease-modifying effects were evaluated. Additional experiments investigated the influence of sigma-1 antagonism (NE-100) and genetic sigma-1 deficiency on E1R efficacy and seizure development. RESULTS: E1R delayed kindling acquisition, increased seizure thresholds in both naïve and kindled animals, and reduced seizure duration without evidence of tolerance or significant adverse effects. Subchronic E1R exposure slowed or prevented progression to generalized seizures, although effects did not persist after drug withdrawal. Sigma-1 deficiency prolonged seizure duration, supporting a role in the termination of endogenous seizures. High-dose NE-100 partially antagonized E1R effects, whereas genetic deficiency did not, possibly due to compensatory mechanisms. Fenfluramine did not affect kindling progression in this model. SIGNIFICANCE: Positive allosteric modulation of sigma-1 attenuates ictogenesis and seizure severity and appears to contribute to endogenous seizure-termination mechanisms. Although E1R influences seizure generation in response to repeated stimulation, it does not produce sustained disease-modifying effects after discontinuation. These findings support a functional role of sigma-1 positive allosteric modulators as promising candidates for seizure management in the model used. The absence of persistent effects after withdrawal argues against disease modification under the current conditions and warrants further investigation in chronic epilepsy models evaluating long-term therapeutic, disease-modifying, or preventive potential.
Integrating benefit and harm in epilepsy treatment: Illustrating the usefulness of the likelihood of being helped versus harmed.
Brigo F
Epilepsia · 2026 Jun · PMID 42054105 · Publisher ↗
Balancing the potential benefits and harms of antiseizure medications (ASMs) remains a central challenge in epilepsy care. Although randomized trials routinely report efficacy and adverse-event outcomes, these are typica...
Balancing the potential benefits and harms of antiseizure medications (ASMs) remains a central challenge in epilepsy care. Although randomized trials routinely report efficacy and adverse-event outcomes, these are typically presented separately, limiting their usefulness for shared decision-making. The Likelihood of Being Helped versus Harmed (LHH)-the ratio of the number needed to harm (NNH) to the number needed to treat (NNT)-offers a simple, intuitive way to integrate these dimensions into a single measure. Using data from a previously published comparative analysis, this brief report illustrates how the LHH can summarize the relative probability of achieving a clinical benefit vs experiencing a treatment-related harm. As an example, an ASM with an LHH of 1.9 would be interpreted as being almost twice as likely to produce a ≥50% seizure reduction as to lead to discontinuation due to adverse effects, whereas an LHH below 1 would indicate that harm is more likely than benefit. These examples demonstrate how the LHH can support clearer communication of benefit-harm trade-offs and complement emerging tools for individualized seizure-risk prediction.
Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep: Pathophysiological insights and treatment options.
Specchio N, Auvin S, Brunklaus A … +9 more , De Giorgis V, Di Micco V, Gardella E, Jansen FE, Nabbout R, Pepi C, Rubboli G, Trivisano M, Curatolo P
Epilepsia · 2026 Apr · PMID 42047579 · Publisher ↗
Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS) represents a rare but severe group of childhood onset epilepsies characterized by sleep-potentiated epileptiform activity,...
Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS) represents a rare but severe group of childhood onset epilepsies characterized by sleep-potentiated epileptiform activity, seizures, and developmental stagnation or regression affecting cognition, language, and behavior. Once considered a self-limited electroencephalographic (EEG) phenomenon, D/EE-SWAS is now recognized as a disorder of brain network dysfunction in which persistent epileptiform discharges during non-rapid eye movement sleep disrupt synaptic plasticity, sleep-dependent memory consolidation, and neurodevelopmental trajectories. This review synthesizes recent advances in clinical phenotyping, genetics, neurophysiology, and therapeutics. Etiologically, D/EE-SWAS is highly heterogeneous, with pathogenic variants identified in nearly half of affected individuals, including copy number variants and single-gene disorders involving ion channels, synaptic proteins, and transcriptional regulators. GRIN2A is the most frequently implicated gene, although marked intrafamilial and interfamilial variability underscores the role of modifying genetic and network-level factors. Structural lesions-particularly those affecting thalamocortical circuits-represent another major disease substrate and are critical for treatment stratification. At the mechanistic level, abnormal thalamocortical oscillations, impaired sleep architecture, and disruption of slow-wave and spindle activity provide a pathophysiological framework linking EEG abnormalities to cognitive and behavioral deterioration. Neuroimaging and EEG-functional magnetic resonance imaging studies support a model of widespread network inhibition and disconnection extending beyond the primary epileptogenic zone. Therapeutically, corticosteroids currently represent the most effective first-line treatment, demonstrating superior cognitive outcomes compared with benzodiazepines, although relapse after tapering is common, and optimal dosing strategies remain undefined. Precision medicine approaches, including N-methyl-D-aspartate receptor-targeted therapies for GRIN variants and channel-specific treatments such as primidone for TRPM3 gain of function, offer promising avenues toward disease modification. Epilepsy surgery should be considered early in children with unilateral structural etiologies, where it can provide substantial neurodevelopmental benefit. Future priorities include standardized outcome measures, integration of sleep-based biomarkers, refinement of steroid protocols, and international collaborative trials to improve long-term neurodevelopmental outcomes in this vulnerable population.
Epilepsy in emerging adulthood: Clinical, psychosocial, and surgical challenges.
McLeod GA, Josephson CB, Wiebe S … +2 more , Calgary Comprehensive Epilepsy Program Collaborators, Epilepsy Surgery Satisfaction Questionnaire Study Group
Epilepsia · 2026 Apr · PMID 42047514 · Publisher ↗
OBJECTIVE: Emerging adulthood (EAs; ages 19-29 years) is a unique developmental stage marked by major psychological, social, and occupational transitions. We sought to characterize the clinical, psychosocial, and surgica...
OBJECTIVE: Emerging adulthood (EAs; ages 19-29 years) is a unique developmental stage marked by major psychological, social, and occupational transitions. We sought to characterize the clinical, psychosocial, and surgical features of epilepsy in emerging adulthood, considering both current age and age at epilepsy onset. METHODS: We conducted cross-sectional analyses in two cohorts, an adult epilepsy registry in Calgary, Canada (single tertiary center; first visits 2007-2024), and a multi-center epilepsy surgery satisfaction cohort recruited from three Canadian centers and Gothenburg, Sweden. Age categories were <19, 19-29, and >29 years. Outcomes included seizure freedom, anti-seizure medications, substance use, patient-reported outcomes measures, and surgical characteristics (procedure type, wait times, seizure and psychosocial outcomes, and satisfaction). RESULTS: Of 7439 registry patients, 1724 (23%) were EAs and 1252 had EA-onset epilepsy. Compared with other ages, EAs had lower 1-year seizure freedom and higher depression, anxiety, disability, and substance use (all p's < .001). EA-onset epilepsy showed similar psychosocial burden, especially for anxiety and substance use. In 240 epilepsy surgery patients (69 EAs), EAs were less likely to undergo selective amygdalohippocampectomy (odds ratio [OR] .17, 95% confidence interval [CI] .03-.94) and had higher rates of permanent complications (OR 6.01, 95% CI 1.45-24.94). EA also spent a greater proportion of life waiting for epilepsy surgery and reported lower post-operative psychosocial satisfaction despite a seizure-freedom rate similar to that for other ages. SIGNIFICANCE: Epilepsy during emerging adulthood is associated with elevated psychosocial morbidity and less seizure freedom, whereas EAs undergoing epilepsy surgery have a distinct case profile with comparable seizure freedom, more complications, and lower post-operative psychosocial satisfaction. These findings highlight the distinctive impact of epilepsy during this developmental stage and underscore the need for targeted transitional care, mental-health support, and timely surgical evaluation. Longitudinal studies are warranted to elucidate causal mechanisms and inform targeted interventions.
Insights from multimodal simultaneous SEEG-EEG and SEEG-MEG recordings: A case of combined generalized and focal epilepsy.
Aung T, Cadet K, Mayoglou L … +3 more , Aydin U, Niranjan A, Bagić AI
Epilepsia · 2026 Jun · PMID 42043307 · Publisher ↗
Despite formal recognition of "combined generalized and focal epilepsy" in the 2017 International League Against Epilepsy classification, its implications for therapeutic decision-making remain ambiguous. We report a cas...
Despite formal recognition of "combined generalized and focal epilepsy" in the 2017 International League Against Epilepsy classification, its implications for therapeutic decision-making remain ambiguous. We report a case demonstrating how focal cortical pathology can interact with distributed epileptic networks using multimodal electrophysiology. A patient with long-standing presumed generalized epilepsy and a left frontal malformation of cortical development (MCD) underwent multimodal evaluation with simultaneous scalp electroencephalography-stereoelectroencephalography (SEEG; left frontal lesion-targeted implantation with a right frontal sentinel electrode) and simultaneous SEEG-magnetoencephalography (MEG). Simultaneous scalp EEG and SEEG demonstrated generalized spike-wave (GSW) discharges with bilateral frontal and thalamic involvement, without focal interictal epileptiform activity at the lesion site. Direct cortical stimulation of SEEG contacts adjacent to the MCD reproduced habitual seizures, producing localized afterdischarges followed by widespread thalamocortical engagement and delayed focal cortical evolution. Simultaneous SEEG-MEG recordings of GSWs revealed early posterior hemispheric involvement with subsequent frontal recruitment, supporting a distributed network mechanism. Left frontal MCD resection was associated with elimination of convulsive seizures, with persistent thalamic spike-wave activity recorded by a responsive neurostimulator that remained inactive for stimulation. Together, these findings demonstrate the limitations of fixed dichotomous focal-generalized distinctions and highlight the value of network-based approaches to epilepsy classification and surgical treatment.
Compound heterozygous SLC12A5 variants expand the molecular and functional spectrum of KCC2-developmental and epileptic encephalopathy.
Hamze M, Whitney R, Ville D … +17 more , Villeneuve N, Hartmann AM, Becker L, Hausmann J, Zhang J, Brier C, Pisella LI, Friedel P, Labalme A, Alix E, Chatron N, Sanlaville D, Gory-Fauré S, Denarier E, Porcher C, Lesca G, Medina I
Epilepsia · 2026 Apr · PMID 42033187 · Publisher ↗
OBJECTIVE: This study was undertaken to characterize the functional impact of novel SLC12A5 variants in two unrelated patients with early onset developmental and epileptic encephalopathy (DEE) and to investigate the mech...
OBJECTIVE: This study was undertaken to characterize the functional impact of novel SLC12A5 variants in two unrelated patients with early onset developmental and epileptic encephalopathy (DEE) and to investigate the mechanisms underlying KCC2 dysfunction. METHODS: Clinical, genetic, and functional analyses were performed in two patients (Cases A and B) with DEE. SLC12A5 encodes two KCC2 splice isoforms (KCC2a and KCC2b). Functional effects of the identified variants on KCC2b ion transport, phosphorylation, mRNA processing, and KCC2-dependent synaptogenesis were assessed using in vitro assays in heterologous expression systems and primary neurons, supported by in silico structural modeling. RESULTS: Both patients developed severe neonatal onset DEE characterized by developmental delay, axial hypotonia, extrapyramidal features, and bilateral migratory seizures within 24 h of birth. Both cases resulted in early mortality (Case A at 9 years; Case B at 6 months). Sequencing revealed distinct biallelic compound heterozygous SLC12A5 variants in both individuals, each inherited from one unaffected parent. Functional analyses demonstrated that in Case A, one variant markedly reduced KCC2-mediated ion transport, whereas the second variant preserved transport activity but exhibited an altered phosphorylation profile at Ser940, located on the intracellular C-terminal region. This variant also disrupted wild-type (WT) KCC2-dependent excitatory synapse formation in immature rat hippocampal neurons. In Case B, one variant disrupted normal mRNA transcript processing consistent with loss of expression, and the second variant exhibited reduced ion transport activity. SIGNIFICANCE: These data demonstrate that SLC12A5-related DEE can result from combined impairment of KCC2-dependent chloride homeostasis and disruption of chloride-independent KCC2 functions critical for early neuronal development. This work expands the mutational and mechanistic spectrum of SLC12A5-DEE and highlights the importance of KCC2 regulatory roles in early brain development, providing new knowledge and tools for basic research and potential avenues for targeted precision therapies.
Plasma neurofilament light chain: A novel biomarker of neuroaxonal injury associated with depressive symptoms in epilepsy.
Chen Z, Sun H, Li J … +5 more , Lin J, Yao J, Zhang W, Hou S, Meng H
Epilepsia · 2026 Apr · PMID 42030091 · Publisher ↗
OBJECTIVE: Depression is the most common psychiatric comorbidity in patients with epilepsy (PWE) but remains frequently underdiagnosed. Identifying objective biomarkers may improve early detection and intervention. Neuro...
OBJECTIVE: Depression is the most common psychiatric comorbidity in patients with epilepsy (PWE) but remains frequently underdiagnosed. Identifying objective biomarkers may improve early detection and intervention. Neurofilament light chain (NfL), a marker of neuroaxonal injury, has been linked to both epilepsy-related neuronal damage and depression, yet its role in comorbidity is unclear. METHODS: We conducted a cross-sectional study including 152 adult PWE recruited from a large tertiary hospital in Northeast China. Depressive symptoms were assessed using the Hamilton Depression Scale (HAMD), and plasma NfL concentrations were measured by enzyme-linked immunosorbent assay. Binary logistic regression models were applied to examine the association between plasma NfL and depressive symptoms, and linear regression models with HAMD scores as a continuous outcome were performed as sensitivity analyses. Both approaches were conducted with adjustment for potential confounders. Receiver operating characteristic (ROC) analysis was conducted to evaluate the discriminative performance of plasma NfL, and k-fold cross-validation (k = 5) was performed to assess the robustness of the ROC analysis. RESULTS: Of the 152 participants, 61 (40.1%) had depressive symptoms. Higher plasma NfL levels were independently associated with both increased odds of depressive symptoms and higher HAMD scores. ROC analysis demonstrated good discriminative accuracy (area under the curve [AUC] = .838), with an optimal cutoff value of 44.85 pg/mL yielding a sensitivity of .82 and a specificity of .74. The mean AUC obtained from k-fold cross-validation was .842, which was consistent with the overall ROC result. SIGNIFICANCE: These findings suggest that plasma NfL may serve as a candidate biomarker for identifying comorbid depression in epilepsy and provide new insight into shared neurobiological mechanisms.
International consensus recommendations for the diagnosis and treatment of Rasmussen syndrome: A modified Delphi procedure.
Stredny CM, Steriade C, Papadopoulou MT … +8 more , Pujar S, Kaliakatsos M, Tomko S, Polster T, Cortina C, Zhang B, Wickström R, International Rasmussen Syndrome Consensus Group
Epilepsia · 2026 Apr · PMID 42029183 · Publisher ↗
Rasmussen syndrome (RS) includes a well-described constellation of refractory focal seizures, often including epilepsia partialis continua, hemiplegia with progressive unilateral cortical atrophy, and cognitive/language...
Rasmussen syndrome (RS) includes a well-described constellation of refractory focal seizures, often including epilepsia partialis continua, hemiplegia with progressive unilateral cortical atrophy, and cognitive/language decline. However, the precise early pathogenesis and reliable biomarkers remain elusive. In addition, we lack operational management guidelines, including diagnostic evaluation, disease-monitoring assessments, and medical and surgical treatment approaches. We aimed to create an expert consensus statement to guide and standardize the treatment of RS, with the goal of providing recommendations applicable to a global population. An expert panel was convened to complete three rounds of a modified Delphi procedure given the lack of high-level evidence, with a focus on workup to exclude mimicking diagnoses, disease-activity metrics, and treatment. Consensus was defined as ≥75% of responses being agree/strongly agree in either two subsequent rounds or in the third and final round. A total of 122 of 143 statements met consensus. Proposed diagnostic evaluation in patients with possible RS is outlined, including physical examination, blood/cerebrospinal fluid analyses, neuroimaging, electroencephalography (EEG), and biopsy. Suggested disease-monitoring assessments include neuropsychological testing and serial magnetic resonance imaging (MRI). Intravenous corticosteroids are recommended as first-line, acute immunotherapy for seizure exacerbations and status epilepticus, with or without the addition of intravenous immunoglobulin. Options for maintenance immunotherapy are outlined, with lack of evidence noted for comparing efficacy of these treatments. Hemispheric disconnection remains the most effective seizure treatment, with parameters including age, function, seizure burden, and patient values influencing candidacy for surgery. This consensus statement offers a guideline to standardize management, as well as suggests future directions to further elucidate underlying pathophysiology and target more-effective, better-tolerated treatments.
A consensus roadmap for post-traumatic epilepsy: Clinical biomarkers, research priorities, policy barriers, and pathways to interventional trials.
Zanier ER, Lisi I, O'Loughlin EK … +16 more , Moro F, Amorim E, Brody DL, Correa DJ, Duncan D, Klein P, Kobeissy FH, Löscher W, Needham EJ, Pitkänen A, Pugh MJ, Somers J, Vezzani A, Wagner AK, Lubbers LS, International Conference on PTE Attendees
Epilepsia · 2026 Apr · PMID 42017361 · Publisher ↗
Understanding the mechanisms underlying post-traumatic epilepsy (PTE) following traumatic brain injury (TBI), and developing strategies to prevent or modify its progression, has been the focus of large collaborative effo...
Understanding the mechanisms underlying post-traumatic epilepsy (PTE) following traumatic brain injury (TBI), and developing strategies to prevent or modify its progression, has been the focus of large collaborative efforts within the epilepsy and TBI research communities for over a decade. However, to date, preclinical and clinical researchers with expertise in these areas have not formally convened to discuss ways to move the field forward. To enable communication and collaboration, scientific experts as well as individuals with lived experience of PTE were gathered during the inaugural International Conference on Post-Traumatic Epilepsy (IC-PTE) held in Milan, Italy, in May 2024, to identify challenges and solutions for advancing research toward clinical trials. The IC-PTE focused on potential therapeutic approaches, clinical and preclinical biomarker discovery, and methods to predict PTE risk early following TBI, which is an important consideration in clinical trial design. In addition, conference attendees discussed animal model development with a focus on clinically relevant translational endpoints and data harmonization and sharing across the PTE research community. This article identifies recommendations for the field and outlines a strategic roadmap for interventional trials targeting PTE.
Mental health of children with epilepsy in Ukraine during the war.
Kharytonov V, Cross JH, Dubenko A … +2 more , Wiebe S, ILAE Emergency Task Force for Ukraine
Epilepsia · 2026 Apr · PMID 42011139 · Publisher ↗
OBJECTIVE: The ongoing conflict in Ukraine has created a severe humanitarian crisis, disproportionately affecting vulnerable populations such as children with chronic conditions. We set out to determine information about...
OBJECTIVE: The ongoing conflict in Ukraine has created a severe humanitarian crisis, disproportionately affecting vulnerable populations such as children with chronic conditions. We set out to determine information about mental health in children with epilepsy in Ukraine affected by the conflict. METHODS: Mental health outcomes in 213 Ukrainian children with epilepsy during the conflict were screened using standardized instruments for post-traumatic stress disorder (PTSD; Harvard Trauma Questionnaire), anxiety (7 item Generalized Anxiety Disorder module, GAD-7), depression (Patient Health Questionnaire-9, PHQ-9), and epilepsy severity (Global Assessment of Severity of Epilepsy scale, GASE). Data were collected between February and June 2023 through self- or proxy-completed surveys. RESULTS: Participants (14.6%) screened positive for PTSD symptoms, with girls significantly more affected than boys. A high proportion screened positive for symptoms of anxiety and depression, with 22% in the range for severe anxiety and 55% in the moderate-to-severe depression range. Epilepsy severity strongly correlated with mental health burden. Access to care was severely disrupted: 76% reported difficulty obtaining antiseizure medications, and 51% struggled to access medical services, contributing to increased seizure frequency in 56% of cases. Regression analyses identified epilepsy severity and barriers to medical care as key predictors of adverse mental health outcomes. SIGNIFICANCE: These findings underscore the compounded impact of war and chronic illness on children's psychological well-being and highlight the urgent need for trauma-informed, multilevel interventions, and improved access to health care for this vulnerable population.
An n-of-1 gene-directed drug repurposing trial for an ultrarare genetic condition.
Jha V, Tsetsos C, Bedford M … +11 more , Costain G, Vohra S, Diaz Martinez JP, Heon E, Vorstman J, Gorodetsky C, Vincent A, Rapley J, Anderson L, Anagnostou E, Baribeau DA
Epilepsia · 2026 Apr · PMID 41999155 · Publisher ↗
OBJECTIVE: Gain-of-function (GoF) variants in the KCNC1 potassium channel subunit gene (Kv3.1) cause motor/cognitive delays and hypotonia and have been associated with seizures. Fluoxetine has inhibitory effects on Kv3.1...
OBJECTIVE: Gain-of-function (GoF) variants in the KCNC1 potassium channel subunit gene (Kv3.1) cause motor/cognitive delays and hypotonia and have been associated with seizures. Fluoxetine has inhibitory effects on Kv3.1. However, open-label nonrandomized administration is insufficient to guide clinical decision-making in ultrarare conditions. This 40-week randomized, double-blind, n-of-1 trial evaluated the safety and effectiveness of fluoxetine for motor development in a 2-year, 10-month-old female child with a GoF KCNC1 variant. METHODS: This study used an ABA phase design (placebo-fluoxetine-placebo), with randomization and blinding of treatment transition moments. The active treatment, fluoxetine powder, was provided at 2.5 mg (low dose) and subsequently 5 mg (target dose) per day. Motor developmental was measured using the parent-reported Early Motor Questionnaire (EMQ), completed weekly. Secondary outcomes included cognitive and adaptive skills and other parent target symptoms (nystagmus, communication, purposeful hand movements). RESULTS: Treatment with fluoxetine was associated with a 6.61-point gain on the EMQ (95% credible interval [CrI] = -.53 to 14.78), beyond the effects of time (.52 points/week, 95% CrI = .28-.91). Treatment was well tolerated; possible withdrawal irritability emerged during the second placebo phase. A higher dose was associated with a larger treatment effect on the EMQ (2.5 mg = 6.81, 95% CrI = -.43 to 14.56; 5 mg = 8.68, 95% CrI = -4.29 to 21.76). Secondary outcomes showed significant improvements in purposeful hand movements (-.65, 95% CrI = -1.27 to -.003, on a 7-point scale), and there were small increases in adaptive behavior and cognitive skills during the trial. Clinical biomarkers suggested a shift toward increased excitation on electroencephalogram and electroretinogram. SIGNIFICANCE: Fluoxetine treatment was possibly associated with increased motor skill development in a young child with KCNC1-related disorder involving a GoF variant. Trials studying developmental endpoints require innovative designs; this study provides a template for treatment assessment in ultrarare genetic neurodevelopmental disorders.
Spatiotemporal dynamics of seizure networks: Progressive posterior hippocampal recruitment in mesial temporal lobe epilepsy.
Wang X, Li F, Hu G … +11 more , Hu W, Zhang C, Fan X, Sang L, Zheng Z, Zhao X, Mo J, Zhao B, Zhang J, Shao X, Zhang K
Epilepsia · 2026 Apr · PMID 41987574 · Publisher ↗
OBJECTIVE: This study aims to characterize the spatiotemporal dynamics of hippocampal atrophy and epileptogenicity in mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS), and to investigate their relations...
OBJECTIVE: This study aims to characterize the spatiotemporal dynamics of hippocampal atrophy and epileptogenicity in mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS), and to investigate their relationship with disease duration. METHODS: We conducted a cross-sectional study integrating structural magnetic resonance imagingandstereoelectroencephalographic (SEEG) data from 156 mTLE-HS patients. Hippocampal subfield volumetry was performed. In patients with SEEG (n = 67), interictal periodic and aperiodic components were quantified using the FOOOF ("fitting oscillations and one over f") algorithm, and ictal epileptogenicity index (EI) was calculated. Correlation analysis, along with linear statistical model and restricted cubic splines (RCS), were employed to examine the relationships between disease duration, hippocampal volumetry, and electrophysiological metrics, focusing on anterior versus posterior hippocampus. RESULTS: Hippocampal volume showed a negative correlation with disease duration in all subfields (head: r = -.185, p = .021; body: r = -.237, p = .003; tail: r = -.253, p = .001). RCS analysis indicated a nonlinear association, where the slope linking disease duration to volume loss appeared steeper (suggestive of accelerated atrophy) beyond approximately 15 years (p < .001). Electrophysiologically, the aperiodic exponent decreased significantly in both anterior (r = -.271, p = .012) and posterior hippocampus (r = -.323, p = .009). A significant positive correlation was found between disease duration and the EI specifically in the posterior hippocampus (r = .550, p < .001), and the group with high EI (≥.3) had a significantly longer disease duration compared to the low EI group (16.0 ± 8.0 vs. 11.3 ± 7.5 years, p = .015). SIGNIFICANCE: mTLE-HS is characterized by a dual pattern of association with disease duration: a nonlinear (potentially accelerating) association with structural atrophy beyond ~15 years and an association between longer duration and higher epileptogenicity in posterior hippocampal regions. This spatiotemporal pattern provides a mechanistic basis for considering individualized extension of surgical resection in chronic cases, a strategy requiring prospective evaluation.
CaMKIIβ insufficiency disrupts cortical networks, producing aberrant low-gamma oscillations and seizure susceptibility.
Mutoh H, Aoto K, Fukuda A … +1 more , Saitsu H
Epilepsia · 2026 Apr · PMID 41984532 · Publisher ↗
OBJECTIVE: Pathogenic variants in the calcium/calmodulin-dependent protein kinase II B gene (CAMK2B) have been associated with neurodevelopmental disorders, including epilepsy, yet the mechanisms underlying cortical dysf...
OBJECTIVE: Pathogenic variants in the calcium/calmodulin-dependent protein kinase II B gene (CAMK2B) have been associated with neurodevelopmental disorders, including epilepsy, yet the mechanisms underlying cortical dysfunction remain largely unclear. Building on our previous clinical report of a patient carrying the CaMKIIβ P213L variant and our prior characterization of the corresponding mouse models, we investigated how P213L-associated CaMKIIβ insufficiency alters cortical network dynamics and susceptibility to pentylenetetrazol (PTZ)-induced seizures in vivo. METHODS: We performed electroencephalographic recordings for CaMKIIβ P213L knock-in mice under baseline and pharmacological modulation. Susceptibility to seizure induction by the chemoconvulsant PTZ was assessed. Cortical CaMKIIβ expression and Thr287 phosphorylation levels were quantified and compared to those in CaMKIIβ knockout mice. RESULTS: Heterozygous and homozygous knock-in mice exhibited aberrant low-gamma (20-50 Hz) oscillations during resting state with behavioral immobility. These aberrant low-gamma oscillations were sensitive to γ-aminobutyric acid (GABA)-ergic modulation: pentylenetetrazol (PTZ) induced a downward shift in the gamma-band peak frequency, whereas isoflurane, diazepam, and valproic acid suppressed the aberrant low-gamma oscillations. PTZ administration increased seizure severity in both heterozygous and homozygous knock-in mice, but lethality occurred only in homozygous mice. We quantified cortical CaMKIIβ expression and Thr287 phosphorylation, both of which were reduced in knock-in mice. Knockout mice recapitulated the aberrant low-gamma oscillations and their pharmacological modulation observed in knock-in mice, supporting the role of CaMKIIβ insufficiency in driving the phenotype. SIGNIFICANCE: These findings suggest that CaMKIIβ insufficiency disrupts cortical excitatory-inhibitory balance, leading to the aberrant low-gamma oscillations and increased seizure susceptibility. Our findings establish a mechanistic link between CaMKIIβ deficiency and epilepsy-related phenotypes in neurodevelopmental disorders. The P213L variant represents a loss-of-function variant with reduced CaMKIIβ expression and phosphorylation, and provides a valuable model for investigating disease mechanisms and developing potential therapeutic strategies.
Rehabilitation of cognition and psychosocial well-being in epilepsy: Results of a randomized waiting list-controlled trial.
Puteikis K, Aukselė G, Jakonienė A … +3 more , Jasionis A, Wolf P, Mameniškienė R
Epilepsia · 2026 Apr · PMID 41984512 · Publisher ↗
OBJECTIVE: Limited evidence supports the use of cognitive and psychosocial rehabilitation programs for people with epilepsy (PWE). We assessed the effects of a newly designed cognitive and psychological counseling interv...
OBJECTIVE: Limited evidence supports the use of cognitive and psychosocial rehabilitation programs for people with epilepsy (PWE). We assessed the effects of a newly designed cognitive and psychological counseling intervention on patient-reported and neuropsychological outcomes in a mixed sample of PWE. METHODS: Seventy adult PWE (57.1% female, mean age = 35.9 ± 11.7 years, 57.1% with focal epilepsy) were randomized (1:1) to either an early intervention group (EIG) or a waiting list for a late intervention group (LIG). The intervention consisted of six individual and two group counseling sessions incorporating psychoeducation, cognitive training, coping strategies, and mindfulness. Both groups were assessed at baseline and 4 and 16 weeks. Primary endpoints were quality of life (Patient-Weighted Quality of Life in Epilepsy 31-item inventory [QOLIE-31-P]) and delayed verbal and visual recall at 4 weeks; secondary endpoints included symptoms of anxiety (Generalized Anxiety Disorder seven-item scale), depression (Neurological Disorders Depression Inventory in Epilepsy), and stigma. Linear mixed models with maximum likelihood estimation were used for repeated measures analysis. RESULTS: Follow-up data were available for 66 participants (94.3%) at 4 weeks and 61 (87.1%) at 16 weeks. The EIG showed significant improvements on the QOLIE compared with the LIG (group by time interaction p = .006), which were maintained at both follow-ups. Anxiety symptoms were also significantly reduced in the EIG (group by time interaction p = .006). These effects were observed in both focal and generalized epilepsy. No significant group differences were found for delayed verbal or visual recall over time. However, greater long-term forgetting on the word list task was observed in the LIG at 4 weeks. No significant changes were detected for symptoms of depression or perceived stigma. SIGNIFICANCE: An 8-week cognitive and psychosocial rehabilitation program improved quality of life and reduced anxiety in PWE, with effects sustained for up to 16 weeks. Cognitive benefits were limited, with a possible transient effect on long-term verbal recall. These findings support the use of rehabilitation interventions to enhance patient-reported outcomes across epilepsy subtypes.
Dual role of spreading depolarization in an epileptic focus.
Vinokurova D, Tukhvatullina K, Khazipov R … +1 more , Nasretdinov A
Epilepsia · 2026 Apr · PMID 41984509 · Publisher ↗
OBJECTIVE: Spreading depolarizations (SDs) are often associated with epileptic discharges. Although SDs are traditionally thought to contribute to postictal depression and termination of epileptic discharges, seizures ma...
OBJECTIVE: Spreading depolarizations (SDs) are often associated with epileptic discharges. Although SDs are traditionally thought to contribute to postictal depression and termination of epileptic discharges, seizures may also occur during SDs or may even follow SDs, suggesting that interactions between SD and seizures are more complex. Here, we examined the interactions between SD and epileptic activity by spatially separating the epileptic focus and the site of SD initiation. METHODS: Subdural electrocorticographic arrays (6 × 10 electrodes) and intracortical silicon probes were used to record SDs and epileptic activity in the rat parietal cortex. An epileptic focus was induced by local intracortical injection of the potassium channel blocker 4-aminopyridine combined with the γ-aminobutyric acid type A receptor antagonist gabazine, whereas extrinsic SDs were evoked by distal high-potassium solution application. RESULTS: We found that extrinsic SDs exerted a biphasic effect; they initially promoted seizurelike events (SLEs) when the SD wave approached the epileptic focus, which was then followed by suppression of epileptic activity after the SD spread through the focus. The timing of SLEs relative to SDs varied at different recording sites, with SLEs occurring before, during, or after SD arrival depending on electrode position along the trajectory of SD propagation between the SD initiation site and the epileptic focus. During intracortical recordings, the proconvulsive effects of SD were associated with a wave of pre-SD neuronal excitation reaching the epileptic focus. The epileptic focus per se also demonstrated resistance to the SD invasion. SIGNIFICANCE: The interactions between SDs and an epileptic focus are not limited to postictal depression, and SDs may also promote epileptic activity in the hyperexcitable cortex.
The small molecule simufilam dose-dependently attenuates the worsening of seizures in a mouse model of tuberous sclerosis complex.
Stansley B, Islam MM, Aguiar DJ … +9 more , Fuchs Z, Catron M, Morairty S, Yuan Y, Santos R, Hou J, de Kater A, Thornton GB, Bordey A
Epilepsia · 2026 Apr · PMID 41978915 · Publisher ↗
OBJECTIVE: Novel epilepsy treatments for patients with tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII) are urgently needed. In these patients, mutations in the mechanistic target of rapamyci...
OBJECTIVE: Novel epilepsy treatments for patients with tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII) are urgently needed. In these patients, mutations in the mechanistic target of rapamycin (mTOR) pathway genes lead to mTOR hyperactivity and focal cortical malformations that frequently cause intractable epilepsy and neurological sequelae. Recent evidence suggests that administration of simufilam, a small molecule thought to modulate the function of filamin A, reduces seizure activity independent of mTOR in a mouse model of FCDII. Here, we tested the hypothesis that simufilam treatment reduces seizure activity in a TSC mouse model and characterized its pharmacokinetic (PK) profile in wild-type mice. METHODS: Seizure activity was recorded via electroencephalography (EEG) in juvenile Tsc1 conditional knockout (cKO) mice treated with simufilam or vehicle twice daily (BID). Simufilam plasma concentrations were measured at study termination using liquid chromatography-tandem mass spectrometry. PK analysis was performed in CD1 mice following daily administration of simufilam for 1 or 7 days at two different doses. RESULTS: Vehicle- and 5 mg/kg-treated Tsc1 cKO mice showed a significant increase in seizure frequency and total ictal duration between the first and the last 5 days of EEG monitoring (Wilcoxon signed-rank test, p < .05), whereas the 10- and 20-mg/kg-treated groups did not. In addition, simufilam treatment shifted the distribution of total ictal durations, with fewer mice exhibiting total ictal durations above the median of the vehicle-treated group (Fisher's exact test, p = .021). Increasing simufilam dose and plasma concentration were associated with fewer daily seizures recorded during the last 5 days of EEG monitoring (p = .017 and p = .012, respectively). Every 100 ng/mL increase in plasma concentration corresponded to a decrease of ~.2 seizures per day during the last 5-day period. SIGNIFICANCE: These findings suggest that simufilam treatment in a TSC mouse model prevented the worsening of seizure activity in a dose-dependent manner and supports clinical investigation of simufilam as a potential therapeutic intervention for seizures in TSC.
Clinical use and radiological yield of magnetic resonance fingerprinting in epilepsy.
Parfyonov M, Su TY, Choi JY … +9 more , Blümcke I, Sakaie K, Morris S, Murakami H, Alexopoulos A, Najm I, Ma D, Jones SE, Wang ZI
Epilepsia · 2026 Jun · PMID 41978567 · Full text
OBJECTIVE: Magnetic resonance fingerprinting (MRF) is a novel paradigm for magnetic resonance imaging (MRI) that efficiently generates multiparametric quantitative tissue property maps with a single acquisition. Its quan...
OBJECTIVE: Magnetic resonance fingerprinting (MRF) is a novel paradigm for magnetic resonance imaging (MRI) that efficiently generates multiparametric quantitative tissue property maps with a single acquisition. Its quantitative nature offers many advantages over conventional MRI. Although interest in MRF for epilepsy research has grown in recent years, systematic evaluation of its radiological and clinical value as a supplementary imaging modality is limited. METHODS: We reviewed the diagnostic utility of MRF imaging for 100 epilepsy patients undergoing presurgical evaluation. MRF quantitative maps (T1, T2, gray matter fraction, and white matter fraction) were generated and reviewed alongside conventional MRI. MRF findings were classified as (1) consistent-MRF findings the same as conventional MRI; (2) additional-MRF revealed findings beyond those seen on conventional MRI; or (3) discrepant-findings on conventional MRI not reproduced on MRF. We further stratified results by radiological diagnosis or pathology if available. Observations were further classified based on whether T1 or T2 MRF maps provided greater diagnostic utility. RESULTS: MRF revealed additional findings in a total of 46 patients (46/100, 46%). In one patient, findings on conventional MRI were not recapitulated on MRF (1/100, 1%). In the remaining 53 patients, MRF findings were consistent with conventional MRI (53/100, 53%). Additional benefits of MRF included the following: improved lesion conspicuity (n = 16), improved visualization of lesion extent (n = 11) or asymmetry between bilateral mesial temporal regions (n = 9), differentiation between multiple lesions (n = 5), new lesion identified (n = 2), and visualization of connection between lesion and other areas (n = 1). Added value from MRF was particularly common in patients with focal cortical dysplasia (FCD) type IIa (p = .009 vs. FCD IIb) and periventricular nodular heterotopia. SIGNIFICANCE: Our findings demonstrate the additional yield from MRF in the identification and definition of the extent of epileptogenic lesions, underscoring its potential as a valuable adjunct in presurgical epilepsy evaluation.
Ketamine in super-refractory status epilepticus: Combined value of inflammatory biomarkers and EEG features.
Pavan S, Mazzon G, Furlanis G … +8 more , Stokelj D, Cegalin M, Della Toffola J, Castellabate C, Cecchinato V, Roman-Pognuz E, Tomaselli M, Manganotti P
Epilepsia · 2026 Apr · PMID 41973529 · Publisher ↗
OBJECTIVE: This study aimed to evaluate the efficacy and safety of intravenous ketamine in a cohort of patients with super-refractory status epilepticus (SRSE) and to explore whether specific clinical, laboratory, and EE...
OBJECTIVE: This study aimed to evaluate the efficacy and safety of intravenous ketamine in a cohort of patients with super-refractory status epilepticus (SRSE) and to explore whether specific clinical, laboratory, and EEG patterns could predict treatment response. METHODS: This single-center retrospective observational study included all adult patients treated with intravenous ketamine for SRSE between August 2020 and September 2025, at the University Hospital of Trieste. Demographic, clinical, laboratory, and EEG data were collected from medical records. EEG recordings obtained during and after ketamine infusion were analyzed according to American Clinical Neurophysiology Society (ACNS) terminology. Associations between baseline characteristics, clinical outcomes, and laboratory and EEG patterns were examined using univariate statistics, and an exploratory EEG severity score, the KEOS (Ketamine EEG Outcome Score), was constructed to assess predictive accuracy. RESULTS: Twelve patients met the inclusion criteria. The sustained response rate, defined as seizure cessation without recurrence after complete anesthetic withdrawal, was 58%. Non-responders exhibited a profound hyperinflammatory state at the onset of status epilepticus, with significantly higher levels of composite indices such as the neutrophil-to-lymphocyte ratio (NLR), Systemic Inflammation Response Index (SIRI), and Systemic Immune-Inflammation Index (SII). Moreover, a "beta background" pattern was significantly more frequent among responders, whereas discontinuous or burst-suppression backgrounds were associated with poor outcomes. The KEOS demonstrated excellent discrimination (area under the curve [AUC] = .97, sensitivity = 100%, specificity = 85.7%). Adverse events were mild, with transient liver enzyme elevation in 42% of patients. SIGNIFICANCE: Intravenous ketamine showed moderate efficacy and a favorable safety profile in this SRSE cohort. The identification of specific EEG signatures together with systemic inflammatory biomarkers suggests the potential for a more biologically informed approach to ketamine monitoring and treatment optimization. However, given the limited sample size, these findings should be interpreted as hypothesis-generating and warrant validation in larger, prospective multicenter studies.
Cortical and etiological determinants of stimulation-induced seizures in children undergoing stereo-EEG.
Chiarello D, Mercier M, Carfi-Pavia G … +6 more , Luisi C, Pepi C, De Benedictis A, Marras CE, Specchio N, de Palma L
Epilepsia · 2026 Apr · PMID 41973515 · Publisher ↗
OBJECTIVE: Electrical stimulation during stereo-electroencephalography (SEEG) is used for functional mapping and seizure induction in epilepsy surgery candidates. However, its effects in pediatric populations remain unde...
OBJECTIVE: Electrical stimulation during stereo-electroencephalography (SEEG) is used for functional mapping and seizure induction in epilepsy surgery candidates. However, its effects in pediatric populations remain underexplored. The aim of this study is to characterize stimulation-induced seizures (SISs) in children undergoing SEEG and evaluate associations with stimulation parameters, cortical architecture, etiology, and surgical outcome. METHODS: We retrospectively analyzed 78 children with drug-resistant focal epilepsy (median age at epilepsy onset=2.8 years ± SD=4.4) who underwent SEEG with low-frequency (1-3 Hz) and/or high-frequency (50 Hz) stimulation. SISs were categorized as low-frequency seizures (LF-ISs) or high-frequency seizures (HF-ISs) and analyzed by anatomic site, cytoarchitectonics, cortical hierarchy, and etiology. Post-surgical outcomes were assessed using Engel classification. RESULTS: SISs occurred in 43.6% of patients (LF-IS: 21.8%, HF-IS: 32.1%). Focal cortical dysplasia type II (FCD II)-particularly FCD IIb-was significantly associated with SISs (LFS: p = .016; HFS: p = .001). Interictal SEEG biomarkers such as brushes and suppression predicted SISs (p = .002). LF-ISs predominantly involved the orbitofrontal and insular regions, whereas HF-ISs clustered in the cingulate and central areas (p = .029). Stimulation type correlated with cortical hierarchy (p = .005) but not cytoarchitecture. SISs were marginally associated with favorable surgical outcome (Engel class Ia; p = .046). SIGNIFICANCE: This is the first study to systematically assess SISs in a pediatric cohort. Findings suggest that SISs-especially in FCD II and heteromodal cortical areas-may serve as biomarkers of epileptogenicity and predictors of surgical outcome. These insights can guide SEEG planning and interpretation in pediatric epilepsy surgery.
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