ILAE-YES global webinar series: Integrating clinical and basic science in epilepsy research Cecilie G. Nome, Parthvi Ravat, Fabrice Bartolomei, Marco de Curtis, Rossella Di Sapia, Marian Galovic, Maria Gogou, Lukas Imbach, Julia Jacobs, Katja Kobow, Alice D. Lam, Christos Panagiotis Lisgaras, Elisa Micalizzi, Eleni Nikalexi, Jeffrey L. Noebels, Jeanne T. Paz, Avtar Singh Roopra, Sally Shaaban, Laurent Sheybani, Shobi Sivathamboo, Ana Suller Marti, Adam Williamson, Naoto Kuroda Epilepsia Open, 2026 Summary Bridging clinical and basic research is increasingly recognized as a priority in the epilepsy field, yet opportunities for integration remain limited by the time, space, and financial constraints of scientific meetings. To address this gap, the Research Task Force of the Young Epilepsy Section of the International League Against Epilepsy (ILAE‐YES) organized a free global webinar series designed to promote translational dialogue and provide accessible research education for early‐career clinicians, researchers, and physician‐scientists. Based on a preliminary ILAE‐YES community survey, eight topics of high interest were selected: (1) epigenetics, (2) EEG biomarkers, (3) ictogenesis, (4) thalamo‐cortical network, (5) sudden unexpected death in epilepsy, (6) neurodegeneration and seizures, (7) seizure‐related brain damage, and (8) neuromodulation therapy. From March to June 2025, eight live Zoom webinars were held, each featuring expert speakers representing both basic science and clinical perspectives, with recordings made available as unlisted YouTube videos to ensure on‐demand access. A total of 1199 individuals from 116 countries registered, 63.2% from low‐ and middle‐income countries. Live attendance averaged 50 participants per session, and the mean session duration was 71.6 min, including an average of 16 min of discussion. Post‐session feedback was obtained from 285 respondents; overall satisfaction was high, with 93.3% rating their experience as 4 or 5 on a 5‐point Likert scale. Speaker satisfaction was similarly high (95.4%), and 80.0% reported gaining new research ideas. Although access to YouTube and Google Forms may have limited participation in some regions, the series provided an inclusive and globally accessible platform. These findings demonstrated that free, discussion‐focused online webinars represent a scalable, low‐cost, and reproducible educational model that can effectively promote international engagement and integration between clinical and basic epilepsy research, aligning with the ILAE's global educational mission and complementing WHO IGAP priorities on capacity building and equitable access to knowledge. Plain Language Summary Bringing together basic science and clinical research is important for improving epilepsy care, but many researchers have limited opportunities to learn across these fields. We organized a free global webinar series that helped early‐career clinicians and researchers learn about epilepsy research by combining scientific talks with clinical perspectives and open discussion. More than 1100 participants from over 100 countries joined, and most reported high satisfaction and gaining new research ideas. These results show that free, discussion‐based online webinars can provide an accessible way to support research education and international learning in epilepsy.
A consensus roadmap for post-traumatic epilepsy: Clinical biomarkers, research priorities, policy barriers, and pathways to interventional trials Elisa R. Zanier, Ilaria Lisi, Elaine K. O'Loughlin, Federico Moro, Edilberto Amorim, David L. Brody, Daniel J. Correa, Dominique Duncan, Pavel Klein, Firas H. Kobeissy, Wolfgang Löscher, Edward J. Needham, Asla Pitkänen, Mary Jo Pugh, Jack Somers, Annamaria Vezzani, Amy K. Wagner, Laura S. Lubbers, and Epilepsia, 2026 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.
Voluntary running wheel activity reduces seizure burden and affords neuroprotection in a mouse model of acquired epilepsy Valentina Kebede, Rossella Di Sapia, Nicole Tonesi, Massimo Rizzi, Silvia Balosso, Daniele Spallaci, Ilaria Craparotta, Laura Pasetto, Valentina Bonetto, Gerardo Marsella, Luca Porcu, Giorgio Rosati, Alessandro Ieraci, Annamaria Vezzani Epilepsia, 2025 ObjectivePhysical exercise may improve neurological deficits and neuronal damage after acute brain injuries and decrease established seizures. We investigated whether voluntary running wheel (RW) activity affects epileptogenesis in a mouse model of acquired epilepsy compared to sedentary mice.MethodsEpilepsy was induced by intra‐amygdala kainate causing status epilepticus (SE) in adult male mice. Sham mice were implanted with electrodes and injected with saline, and matched to experimental mice. In the RW‐1 protocol, SE mice were trained to run for 5 weeks before SE induction and for 6 weeks thereafter. In the RW‐2 protocol, mice began using RWs 24 h post‐SE for 10 weeks. At the end of each protocol, electrocorticography (ECoG) was recorded for 2 weeks (24/7) in the absence of RWs. Matched sedentary mice were kept in home cages without RWs, subjected to SE, and had ECoG monitored. At the end of experiment, all mice were processed for assessing hippocampal neuronal cell loss (Nissl staining), hilar mossy cells (GLUR2/3 staining), and blood–brain barrier (BBB) damage (serum matrix metalloproteinase‐9 [MMP‐9] by enzyme‐linked immunosorbent assay). Neuroinflammation (reverse‐transcriptase quantitative polymerase chain reaction) and albumin level (western blot) were also measured in the hippocampus of RW1 mice 72 h post‐SE, together with serum MMP‐9.ResultsRW activity in SE mice reduced the incidence of epilepsy (RW‐1 by 38%; RW‐2 by 54%, p < .05) and the total time spent in seizures (RW‐1, p < .05; RW‐2, p < .01) compared to sedentary mice. RW‐1 SE mice showed reduced average seizure duration (p < .01), whereas RW‐2 SE mice showed reduced number of seizures (p < .01). Reduction in seizure duration was associated with prevention of GluR2/3‐positive mossy cell loss, which occurs in sedentary SE mice (p < .01 vs sham mice). Seizure duration in epileptic mice was negatively correlated with the number of hilar mossy cells (p < .01). Preventive RW‐1 activity reduced SE duration and severity (p < .05) vs sedentary mice. Aberrant neurogenesis was reduced in the dentate gyrus of SE mice subjected to RWs (p < .01) vs sedentary mice. Serum MMP‐9 and brain albumin levels were reduced in SE mice exposed to running activity (p < .05) compared to sedentary mice.SignificancePhysical exercise reduced seizure burden and neuropathology in mice, offering a strategy to improve disease outcomes after acute brain injury.
WONOEP appraisal: Modeling early onset epilepsies Ann‐Sofie De Meulemeester, Christopher Reid, Stéphane Auvin, Peter L. Carlen, Andrew J. Cole, Roza Szlendak, Rossella Di Sapia, Solomon L. Moshé, Raman Sankar, Terence J. O'Brien, Stéphanie Baulac, David C. Henshall, Özlem Akman, Aristea S. Galanopoulou Epilepsia, 2024 Epilepsy has a peak incidence during the neonatal to early childhood period. These early onset epilepsies may be severe conditions frequently associated with comorbidities such as developmental deficits and intellectual disability and, in a significant percentage of patients, may be medication‐resistant. The use of adult rodent models in the exploration of mechanisms and treatments for early life epilepsies is challenging, as it ignores significant age‐specific developmental differences. More recently, models developed in immature animals, such as rodent pups, or in three‐dimensional organoids may more closely model aspects of the immature brain and could result in more translatable findings. Although models are not perfect, they may offer a more controlled screening platform in studies of mechanisms and treatments, which cannot be done in pediatric patient cohorts. On the other hand, more simplified models with higher throughput capacities are required to deal with the large number of epilepsy candidate genes and the need for new treatment options. Therefore, a combination of different modeling approaches will be beneficial in addressing the unmet needs of pediatric epilepsy patients. In this review, we summarize the discussions on this topic that occurred during the XVI Workshop on Neurobiology of Epilepsy, organized in 2022 by the Neurobiology Commission of the International League Against Epilepsy. We provide an overview of selected models of early onset epilepsies, discussing their advantages and disadvantages. Heterologous expression models provide initial functional insights, and zebrafish, rodent models, and brain organoids present increasingly complex platforms for modeling and validating epilepsy‐related phenomena. Together, these models offer valuable insights into early onset epilepsies and accelerate hypothesis generation and therapy discovery.
Early treatment with rifaximin during epileptogenesis reverses gut alterations and reduces seizure duration in a mouse model of acquired epilepsy Valentina Kebede, Teresa Ravizza, Silvia Balosso, Rossella Di Sapia, Luca Canali, Sara Soldi, Serena Galletti, Christina Papazlatani, Panagiotis A. Karas, Sotirios Vasileiadis, Annalisa Sforzini, Laura Pasetto, Valentina Bonetto, Annamaria Vezzani, Loredana Vesci Brain Behavior and Immunity, 2024 The gut microbiota is altered in epilepsy and is emerging as a potential target for new therapies. We studied the effects of rifaximin, a gastrointestinal tract-specific antibiotic, on seizures and neuropathology and on alterations in the gut and its microbiota in a mouse model of temporal lobe epilepsy (TLE). Epilepsy was induced by intra-amygdala kainate injection causing status epilepticus (SE) in C57Bl6 adult male mice. Sham mice were injected with vehicle. Two cohorts of SE mice were fed a rifaximin-supplemented diet for 21 days, starting either at 24 h post-SE (early disease stage) or at day 51 post-SE (chronic disease stage). Corresponding groups of SE mice (one each disease stage) were fed a standard (control) diet. Cortical ECoG recording was done at each disease stage (24/7) for 21 days in all SE mice to measure the number and duration of spontaneous seizures during either rifaximin treatment or control diet. Then, epileptic mice ± rifaximin and respective sham mice were sacrificed and brain, gut and feces collected. Biospecimens were used for: (i) quantitative histological analysis of the gut structural and cellular components; (ii) markers of gut inflammation and intestinal barrier integrity by RTqPCR; (iii) 16S rRNA metagenomics analysis in feces. Hippocampal neuronal cell loss was assessed in epileptic mice killed in the early disease phase. Rifaximin administered for 21 days post-SE (early disease stage) reduced seizure duration (p < 0.01) and prevented hilar mossy cells loss in the hippocampus compared to epileptic mice fed a control diet. Epileptic mice fed a control diet showed a reduction of both villus height and villus height/crypt depth ratio (p < 0.01) and a decreased number of goblet cells (p < 0.01) in the duodenum, as well as increased macrophage (Iba1)-immunostaining in the jejunum (p < 0.05), compared to respective sham mice. Rifaximin's effect on seizures was associated with a reversal of gut structural and cellular changes, except for goblet cells which remained reduced. Seizure duration in epileptic mice was negatively correlated with the number of mossy cells (p < 0.01) and with villus height/crypt depth ratio (p < 0.05). Rifaximin-treated epileptic mice also showed increased tight junctions (occludin and ZO-1, p < 0.01) and decreased TNF mRNA expression (p < 0.01) in the duodenum compared to epileptic mice fed a control diet. Rifaximin administered for 21 days in chronic epileptic mice (chronic disease stage) did not change the number or duration of seizures compared to epileptic mice fed a control diet. Chronic epileptic mice fed a control diet showed an increased crypt depth (p < 0.05) and reduced villus height/crypt depth ratio (p < 0.01) compared to respective sham mice. Rifaximin treatment did not affect these intestinal changes. At both disease stages, rifaximin modified α- and β-diversity in epileptic and sham mice compared to respective mice fed a control diet. The microbiota composition in epileptic mice, as well as the effects of rifaximin at the phylum, family and genus levels, depended on the stage of the disease. During the early disease phase, the abundance of specific taxa was positively correlated with seizure duration in epileptic mice. In conclusion, gut-related alterations reflecting a dysfunctional state, occur during epilepsy development in a TLE mouse model. A short-term treatment with rifaximin during the early phase of the disease, reduced seizure duration and neuropathology, and reversed some intestinal changes, strengthening the therapeutic effects of gut-based therapies in epilepsy.
Identification of an epilepsy-linked gut microbiota signature in a pediatric rat model of acquired epilepsy Antonella Riva, Eray Sahin, Greta Volpedo, Andrea Petretto, Chiara Lavarello, Rossella Di Sapia, Davide Barbarossa, Nasibeh Riahi Zaniani, Ilaria Craparotta, Maria Chiara Barbera, Uğur Sezerman, Annamaria Vezzani, Pasquale Striano, Teresa Ravizza Neurobiology of Disease, 2024 A dysfunctional gut microbiota-brain axis is emerging as a potential pathogenic mechanism in epilepsy, particularly in pediatric forms of epilepsy. To add new insights into gut-related changes in acquired epilepsy that develops early in life, we used a multi-omics approach in a rat model with a 56% incidence of epilepsy. The presence of spontaneous seizures was assessed in adult rats (n = 46) 5 months after status epilepticus induced by intra-amygdala kainate at postnatal day 13, by 2 weeks (24/7) ECoG monitoring. Twenty-six rats developed epilepsy (Epi) while the remaining 20 rats (No-Epi) did not show spontaneous seizures. At the end of ECoG monitoring, all rats and their sham controls (n = 20) were sacrificed for quantitative histopathological and immunohistochemical analyses of the gut structure, glia and macrophages, as well as RTqPCR analysis of inflammation/oxidative stress markers. By comparing Epi, No-Epi rats, and sham controls, we found structural, cellular, and molecular alterations reflecting a dysfunctional gut, which were specifically associated with epilepsy. In particular, the villus height-to-crypt depth ratio and number of Goblet cells were reduced in the duodenum of Epi rats vs both No-Epi rats and sham controls (p < 0.01). Villus height and crypt depth in the duodenum and jejunum (p < 0.01) were increased in No-Epi vs both Epi and sham controls. We also detected enhanced Iba1-positive macrophages, together with increased IL1b and NFE2L2 transcripts and TNF protein, in the small intestine of Epi vs both No-Epi and sham control rats (p < 0.01), denoting the presence of inflammation and oxidative stress. Astroglial GFAP-immunostaining was similar in all experimental groups. Metagenomic analysis in the feces collected 5 months after status epilepticus showed that the ratio of two dominant phyla (Bacteroidota-to-Firmicutes) was similarly increased in Epi and No-Epi rats vs sham control rats. Notably, the relative abundance of families, genera, and species associated with SCFA production differed in Epi vs No-Epi rats, describing a bacterial imprint associated with epilepsy. Furthermore, Epi rats showed a blood metabolic signature characterized by changes in lipid metabolism compared to both No-Epi and sham control rats. Our study provides new evidence of long-term gut alterations, along with microbiota-related metabolic changes, occurring specifically in rats that develop epilepsy after brain injury early in life.
ECoG spiking activity and signal dimension are early predictive measures of epileptogenesis in a translational mouse model of traumatic brain injury Rossella Di Sapia, Massimo Rizzi, Federico Moro, Ilaria Lisi, Alessia Caccamo, Teresa Ravizza, Annamaria Vezzani, Elisa R. Zanier Neurobiology of Disease, 2023 The latency between traumatic brain injury (TBI) and the onset of epilepsy (PTE) represents an opportunity for counteracting epileptogenesis. Antiepileptogenesis trials are hampered by the lack of sensitive biomarkers that allow to enrich patient's population at-risk for PTE. We aimed to assess whether specific ECoG signals predict PTE in a clinically relevant mouse model with ∼60% epilepsy incidence. TBI was provoked in adult CD1 male mice by controlled cortical impact on the left parieto-temporal cortex, then mice were implanted with two perilesional cortical screw electrodes and two similar electrodes in the hemisphere contralateral to the lesion site. Acute seizures and spikes/sharp waves were ECoG-recorded during 1 week post-TBI. These early ECoG events were analyzed according to PTE incidence as assessed by measuring spontaneous recurrent seizures (SRS) at 5 months post-TBI. We found that incidence, number and duration of acute seizures during 3 days post-TBI were similar in PTE mice and mice not developing epilepsy (No SRS mice). Control mice with cortical electrodes (naïve, n = 5) or with electrodes and craniotomy (sham, n = 5) exhibited acute seizures but did not develop epilepsy. The daily number of spikes/sharp waves at the perilesional electrodes was increased similarly in PTE (n = 15) and No SRS (n = 8) mice vs controls (p < 0.05, n = 10) from day 2 post-injury. Differently, the daily number of spikes/sharp waves at both contralateral electrodes showed a progressive increase in PTE mice vs No SRS and control mice. In particular, spikes number was higher in PTE vs No SRS mice (p < 0.05) at 6 and 7 days post-TBI, and this measure predicted epilepsy development with high accuracy (AUC = 0.77, p = 0.03; CI 0.5830-0.9670). The cut-off value was validated in an independent cohort of TBI mice (n = 12). The daily spike number at the contralateral electrodes showed a circadian distribution in PTE mice which was not observed in No SRS mice. Analysis of non-linear dynamics at each electrode site showed changes in dimensionality during 4 days post-TBI. This measure yielded the best discrimination between PTE and No SRS mice (p < 0.01) at the cortical electrodes contralateral to injury. Data show that epileptiform activity contralateral to the lesion site has the the highest predictive value for PTE in this model reinforcing the hypothesis that the hemisphere contralateral to the lesion core may drive epileptogenic networks after TBI.
Neuroimmunology of status epilepticus Annamaria Vezzani, Rossella Di Sapia, Valentina Kebede, Silvia Balosso, Teresa Ravizza Epilepsy and Behavior, 2023
Cholesterol 24-hydroxylase is a novel pharmacological target for anti-ictogenic and disease modification effects in epilepsy Alessia Salamone, Gaetano Terrone, Rossella Di Sapia, Silvia Balosso, Teresa Ravizza, Luca Beltrame, Ilaria Craparotta, Laura Mannarino, Sara Raimondi Cominesi, Massimo Rizzi, Alberto Pauletti, Sergio Marchini, Luca Porcu, Till S. Zimmer, Eleonora Aronica, Matthew During, Brett Abrahams, Shinichi Kondo, Toshiya Nishi, Annamaria Vezzani Neurobiology of Disease, 2022 Therapies for epilepsy mainly provide symptomatic control of seizures since most of the available drugs do not target disease mechanisms. Moreover, about one-third of patients fail to achieve seizure control. To address the clinical need for disease-modifying therapies, research should focus on targets which permit interventions finely balanced between optimal efficacy and safety. One potential candidate is the brain-specific enzyme cholesterol 24-hydroxylase. This enzyme converts cholesterol to 24S-hydroxycholesterol, a metabolite which among its biological roles modulates neuronal functions relevant for hyperexcitability underlying seizures. To study the role of cholesterol 24-hydroxylase in epileptogenesis, we administered soticlestat (TAK-935/OV935), a potent and selective brain-penetrant inhibitor of the enzyme, during the early disease phase in a mouse model of acquired epilepsy using a clinically relevant dose. During soticlestat treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased by about 3-fold compared to vehicle-treated mice, as assessed by EEG monitoring. Notably, the therapeutic effect was maintained 6.5 weeks after drug wash-out when seizure number was reduced by about 4-fold and their duration by 2-fold. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells as assessed by post-mortem brain histology. High throughput RNA-sequencing of hippocampal neurons and glia in mice treated with soticlestat during epileptogenesis showed that inhibition of cholesterol 24-hydroxylase did not directly affect the epileptogenic transcriptional network, but rather modulated a non-overlapping set of genes that might oppose the pathogenic mechanisms of the disease. In human temporal lobe epileptic foci, we determined that cholesterol 24-hydroxylase expression trends higher in neurons, similarly to epileptic mice, while the enzyme is ectopically induced in astrocytes compared to control specimens. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy. Data show that cholesterol 24-hydroxylase contributes to spontaneous seizures and is involved in disease progression, thus it represents a novel target for chronic seizures inhibition and disease-modification therapy in epilepsy.
A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies Andre Altmann, Mina Ryten, Martina Di Nunzio, Teresa Ravizza, Daniele Tolomeo, Regina H. Reynolds, Alyma Somani, Marco Bacigaluppi, Valentina Iori, Edoardo Micotti, Rossella Di Sapia, Milica Cerovic, Eleonora Palma, Gabriele Ruffolo, Juan A. Botía, Julie Absil, Saud Alhusaini, Marina K. M. Alvim, Pia Auvinen, Nuria Bargallo, Emanuele Bartolini, Benjamin Bender, Felipe P. G. Bergo, Tauana Bernardes, Andrea Bernasconi, Neda Bernasconi, Boris C. Bernhardt, Karen Blackmon, Barbara Braga, Maria Eugenia Caligiuri, Anna Calvo, Chad Carlson, Sarah J. A. Carr, Gianpiero L. Cavalleri, Fernando Cendes, Jian Chen, Shuai Chen, Andrea Cherubini, Luis Concha, Philippe David, Norman Delanty, Chantal Depondt, Orrin Devinsky, Colin P. Doherty, Martin Domin, Niels K. Focke, Sonya Foley, Wendy Franca, Antonio Gambardella, Renzo Guerrini, Khalid Hamandi, Derrek P. Hibar, Dmitry Isaev, Graeme D. Jackson, Neda Jahanshad, Reetta Kälviäinen, Simon S. Keller, Peter Kochunov, Raviteja Kotikalapudi, Magdalena A. Kowalczyk, Ruben Kuzniecky, Patrick Kwan, Angelo Labate, Soenke Langner, Matteo Lenge, Min Liu, Pascal Martin, Mario Mascalchi, Stefano Meletti, Marcia E. Morita‐Sherman, Terence J. O'Brien, Jose C. Pariente, Mark P. Richardson, Raul Rodriguez‐Cruces, Christian Rummel, Taavi Saavalainen, Mira K. Semmelroch, Mariasavina Severino, Pasquale Striano, Thomas Thesen, Rhys H. Thomas, Manuela Tondelli, Domenico Tortora, Anna Elisabetta Vaudano, Lucy Vivash, Felix von Podewils, Jan Wagner, Bernd Weber, Roland Wiest, Clarissa L. Yasuda, Guohao Zhang, Junsong Zhang, , Costin Leu, Andreja Avbersek, , Maria Thom, Christopher D. Whelan, Paul Thompson, Carrie R. McDonald, Annamaria Vezzani, Sanjay M. Sisodiya Neuropathology and Applied Neurobiology, 2022
