RARE DISEASE
Lennox-Gastaut syndrome
Lennox-Gastaut syndrome
Lennox-Gastaut syndrome
Drug discovery
27
drugs
With orphan designations
Overview
Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant multiple seizure types (tonic, atonic, atypical absence), slow spike-wave EEG patterns, and intellectual disability. Onset typically occurs between ages 2–5 years, with lifelong treatment challenges due to pharmacoresistance and progressive cognitive/behavioral decline [1][6][11][17].
Therapies
Pharmacologic: 7 FDA-approved antiseizure medications (e.g., cannabidiol, fenfluramine, clobazam), often requiring polytherapy [3][18].
Non-pharmacologic: Ketogenic diet, vagus nerve stimulation (VNS), and corpus callosotomy [3][8][11].
Emerging options include responsive neurostimulation (RNS) and deep brain stimulation (DBS) [8][18].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
1,447 drug discovery papers about Lennox-Gastaut syndrome, with 3 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,447 drug discovery papers about Lennox-Gastaut syndrome, with 3 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-03-01 | Investigating variants in THAP12 as a novel genetic etiology of Lennox-Gastaut syndrome
Le syndrome de Lennox-Gastaut (SLG) est une encéphalopathie développementale et épileptique, caractérisée par des crises sévères et pharmacorésistantes. 25 % des cas de SLG sont idiopathiques, soulignant la nécessité d'identifier de nouveaux facteurs génétiques sous-jacents aux épilepsies infantiles sévères pour une compréhension globale de leur physiopathologie. Récemment, nos collaborateurs ont identifié deux nouveaux variants du gène THAP12 chez un patient atteint de SLG d'étiologie inconnue. De manière remarquable, THAP12 ne possède aucune annotation fonctionnelle connue ni association avec des maladies neurologiques, y compris le SLG, ce qui en fait une cible particulièrement intéressante pour des investigations approfondies. Cette recherche vise à identifier de nouvelles cibles thérapeutiques exploitables pour les encéphalopathies épileptiques telles que le SLG, ouvrant ainsi des perspectives prometteuses pour le développement de futurs traitements. Par des approches multidisciplinaires englobant des études cellulaires, animales et génomiques, nous cherchons à élucider les mécanismes complexes sous-tendant la fonction de THAP12 dans le développement cérébral et les syndromes épileptiques. À l'aide de fibroblastes de patients, nous avons démontré que les mutations identifiées entraînent une perte d'expression de la protéine THAP12, suggérant un mécanisme pathogène de perte de fonction. De plus, nous avons confirmé la pathogénicité de ces mutations chez la souris, où elles ont conduit à une létalité embryonnaire précoce, soulignant le rôle essentiel de THAP12 dans le développement. Afin de contourner cette létalité, nous avons établi un modèle de poisson zèbre thap12-KO, dans lequel les larves mutantes présentaient une survie réduite, une hypotonie, une diminution de la taille du cerveau, des comportements moteurs spontanés évocateurs de crises dans l'obscurité, ainsi qu'une hypersensibilité aux agents pro-convulsivants. Par ailleurs, nos données d'immunofluorescence chez les larves de poisson zèbre thap12-KO révèlent une diminution de la prolifération cellulaire et une augmentation de l'apoptose, suggérant l'importance capitale de THAP12 dans la régulation du cycle cellulaire. Les données de séquençage d'ARN en cellule unique ont révélé que thap12 est exprimé dans des clusters cellulaires associés aux progéniteurs en cycle dans le cerveau, impliquant un rôle critique dans le développement neuronal précoce. Dans l'ensemble, nos résultats confirment le rôle causal de ces nouveaux variants de THAP12 dans le SLG et plaident en faveur d'une exploration approfondie de la fonction de THAP12 au cours du neurodéveloppement, des mécanismes moléculaires aux circuits cérébraux.
2023-08-21 | New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development
The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarises available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABAA receptors and includes Staccato® alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABAA receptor α and β subunits is being investigated, with Lennox–Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management.
2017-04-01 | Adrenocorticotropic hormone protects learning and memory function in epileptic Kcna1 -null mice
ACTH, a member of the melanocortin family of peptides, is often used in the treatment of the developmental epileptic encephalopathy spectrum disorders including, Ohtahara, West, Lennox Gastaut and Landau-Kleffner Syndromes and electrical status epilepticus of sleep. In these disorders, although ACTH is often successful in controlling the seizures and/or inter-ictal EEG abnormalities, it is unknown whether ACTH possesses other beneficial effects independent of seizure control. We tested whether ACTH can ameliorate the intrinsic impairment of hippocampal-based learning and memory in epileptic Kcna1-null (KO) mice. We found that ACTH − administered in the form of Acthar Gel given i.p. four times daily at a dose of 4 IU/kg (16 IU/kg/day) for 7 days – prevented impairment of long-term potentiation (LTP) evoked with high-frequency stimulation in CA1 hippocampus and also restored spatial learning and memory on the Barnes maze test. However, with this treatment regimen, ACTH did not exert a significant effect on the frequency of spontaneous recurrent seizures. Together, our findings indicate that ACTH can ameliorate memory impairment in epileptic Kcna1-null mice separate from seizure control, and suggest that this widely used peptide may exert direct nootropic effects in the epileptic brain.
2015-07-29 | Efficacy of corticosteroid therapy in treating epileptic encephalopathies and refractory epilepsies other than West syndrome
To evaluate the efficacy of steroid therapy in epileptic encephalopathies and refractory epilepsies other than West syndrome. Retrospective analysis of treatment and outcome data of patients treated with steroids for epileptic encephalopathies. Outcome was analyzed in terms of the patient’s epileptic syndrome, age at seizure onset, duration of seizure disorder, age at treatment, abnormalities noted on neurological examination, developmental status and type of steroid. Fifty-eight consecutive patients from six pediatric neurology outpatient clinics were included in the study. The epileptic syndrome and types were as follows: myoclonic epilepsy (n = 16), epilepsy with continuous spike waves during slow-wave sleep (n = 12), partial epilepsy (n = 10), Landau-Kleffner syndrome (n = 6), generalized epilepsy with multiple epileptic seizure types (n = 5), Rasmussen’s encephalitis (n = 3), Lennox-Gastaut syndrome (n = 2), atypical absence (n = 2) and spasms (n = 2). Sixteen patients (27%) had received adrenocorticotrophic hormone (ACTH) and 42 (73%) had received prednisone (22 of the latter patients were given initial pulse methylprednisolone). Complete cessation of seizures as well as disappearance of epileptic discharges in electroencephalogram were achieved in 16 patients (28%); 15 other patients (26%) had improvement of > 50%. Of the 31 patients with > 50% improvement and follow-up of at least 1 year, 16 (52%) subsequently relapsed. ACTH was found to be significantly more efficacious than prednisone in controlling seizures and improving function. Initiation of treatment with high-dose methylprednisolone did not increase efficacy. ACTH may be more efficacious than prednisone in treating epileptic encephalopathies and refractory epilepsies other than West syndrome.
2014-04-29 | Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets
Various ketogenic diet (KD) therapies, including classic KD, medium chain triglyceride administration, low glycemic index treatment, and a modified Atkins diet, have been suggested as useful in patients affected by pharmacoresistant epilepsy. A common goal of these approaches is to achieve an adequate decrease in the plasma glucose level combined with ketogenesis, in order to mimic the metabolic state of fasting. Although several metabolic hypotheses have been advanced to explain the anticonvulsant effect of KDs, including changes in the plasma levels of ketone bodies, polyunsaturated fatty acids, and brain pH, direct modulation of neurotransmitter release, especially purinergic (i.e., adenosine) and γ-aminobutyric acidergic neurotransmission, was also postulated. Neuropeptides and peptide hormones are potent modulators of synaptic activity, and their levels are regulated by metabolic states. This is the case for neuroactive peptides such as neuropeptide Y, galanin, cholecystokinin and peptide hormones such as leptin, adiponectin, and growth hormone-releasing peptides (GHRPs). In particular, the GHRP ghrelin and its related peptide des-acyl ghrelin are well-known controllers of energy homeostasis, food intake, and lipid metabolism. Notably, ghrelin has also been shown to regulate the neuronal excitability and epileptic activation of neuronal networks. Several lines of evidence suggest that GHRPs are upregulated in response to starvation and, particularly, in patients affected by anorexia and cachexia, all conditions in which also ketone bodies are upregulated. Moreover, starvation and anorexia nervosa are accompanied by changes in other peptide hormones such as adiponectin, which has received less attention. Adipocytokines such as adiponectin have also been involved in modulating epileptic activity. Thus, neuroactive peptides whose plasma levels and activity change in the presence of ketogenesis might be potential candidates for elucidating the neurohormonal mechani
small molecules
2026-09-25 | Effect of Fenfluramine on convulsive seizures and rescue medication usage: A case series of adults within the Lennox-Gastaut syndrome spectrum.
Adults with Developmental and epileptic encephalopathies (DEE) within the Lennox-Gastaut Syndrome (LGS) spectrum suffer disabling convulsive seizures which may remain refractory and are associated with increased risk of hospitalisations and death. Fenfluramine (FFA) was licenced in the UK for seizures associated with LGS in March 2025. Adjunctive FFA was assessed in a series of 6 adults with a genetic DEE within the LGS spectrum treated for refractory convulsive seizures. The minimum period of observation was 9 months (range 9-32 months). 3 patients commenced FFA pre-licencing on compassionate grounds. 4 patients had a VNS, 5 patients were prescribed concomitant Cannabidiol. Reduction in convulsive seizures and reduction in use of rescue medications/ frequency of hospitalisations was also assessed. Caregiver responses were recorded using the Clinical Global Improvement of Change (CGI-I). At last follow up, all 6 patients remained on FFA. No significant side effects were observed. There was a significant reduction in seizures at last follow up (p = 0.035), with a corresponding reduction in use of rescue medications and hospitalisations. On the CGI-I, 5 of the 6 patients were rated as much/ very much improved, the remaining patient was rated as minimally improved. Adjunctive FFA was tolerated without significant side effects and associated with a significant reduction in convulsive seizures in this limited cohort. Corresponding reduction in use of rescue medications and hospitalisations has the potential to impact on both patient and caregiver quality of life.
2026-09-17 | Nanostructured lipid carriers for intranasal cannabidiol delivery in Dravet and Lennox-Gastaut syndromes: bridging preclinical promise to clinical translation.
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are severe developmental epileptic encephalopathies that appear in early childhood, are unresponsive to medications, and have a dismal neurodevelopmental prognosis. Most patients do not respond well to polytherapy, and the need to fulfill this gap in clinical practice is urgent. Cannabidiol (CBD) has proven to be an effective adjunct drug, but oral preparations have low bioavailability, slow onset and systemic adverse effects. Nanostructured lipid carriers (NLCs) are an innovative therapeutic technology that can deliver CBD directly to the brain via the nose, enhance brain targeting, achieve faster onset, and minimize systemic exposure, which could be a valuable solution to current deficiencies in treatment.Intranasal NLC-CBD has preclinical evidence of increasing brain CBD levels, facilitating anticonvulsant action, and protecting against seizures in established animal models, like pentylenetetrazol-induced convulsions. NLC-based preparations have increased brain-to-plasma ratios and longer central exposure at lower doses in comparison to free or orally administered CBD. Despite these promising findings, there are still translational gaps to be addressed, such as insufficient safety data in the long term, disease-specific DS/LGS genetic models, inconsistencies in the pediatric nasal physiology, and conventional clinical dosing paradigms.Literature for this review was identified through searches of PubMed, Scopus, Web of Science, and Google Scholar, covering studies published up to March 2026 on CBD, NLC, intranasal drug delivery, DS, and LGS.There is a dire need to carry out properly designed clinical trials that would demonstrate the safety, pharmacokinetics (PK) and efficacy of intranasal NLC-CBD in DS and LGS. The first pediatric clinical trials, adaptive trial models and regulatory harmonization are necessary to convert this noble nanomedicine approach into a clinical therapy.
2026-09-17 | Use of Purified Cannabidiol in Treatment-Resistant Pediatric Epilepsy: Beyond Lennox-Gastaut Syndrome, Dravet Syndrome, and Tuberous Sclerosis Complex.
The pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex) is approved by the the US Food and Drug Administration for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis in patients one year of age and older. Among the large volume of drug-resistant cases treated at pediatric Level 4 Epilepsy Centers, many patients fall outside of these categories but are still prescribed CBD for off label use. This study sought to characterize the real-world experience with CBD of a large single pediatric comprehensive epilepsy center and to compare response to CBD within and outside of its FDA-approved indications. A retrospective chart review was performed of patients with a prescription for CBD at our institution between January 2020 and January 2022, excluding patients who were previously included in our center's 2019 analysis. Patients were not included in the analysis if initially prescribed CBD elsewhere, follow-up was outside our institution, medication was not started, patient expired during the study period, or diagnostic data was not available. Between-group differences were assessed via Wilcoxon rank-sum and Fisher exact tests, as appropriate. Of 223 patients with a CBD prescription during the study period, 144 patients had sufficient data available for review. Of these patients, 81 (56%) carried diagnoses of Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis, and 63 (44%) carried other diagnoses outside of FDA-labeled indications. Median (interquartile range) age at initiation was 10.0 years (5.0, 13.0), and median (interquartile range) number of concurrent anti-seizure medications was 3.0 (2.0, 3.0). There was no significant difference in the proportion of patients treated concurrently with vagus nerve stimulation or ketogenic diet between the two groups. The FDA-labeled (63%) group had a significantly higher proportion of patients with tonic seizures compared to the non-FDA labeled (29%) group (P < 0.001), otherwise there were no significant differences in baseline seizure types. Overall, 53 patients (65%) in the FDA-labeled group and 40 (63%) of the non-FDA labeled group had a documented responder rate at least 50% on CBD (P = 0.9). The most common side effects reported were nausea/diarrhea/gastrointestinal upset (19%), agitation (7.6%), insomnia (4.9%), weight loss (6.3%), and secretions/drooling (2.8%, seen only in patients on concurrent clobazam). Among our cohort of treatment-resistant pediatric epilepsy, purified CBD was efficacious in a broad range of pediatric epilepsies and was well tolerated as an adjunctive anti-seizure medication. This medication may be considered in pharmacoresistant pediatric epilepsies in conditions beyond its FDA-labeled indications.
2026-09-10 | Clobazam in pediatric drug-resistant epilepsy: from pharmacology to clinical practice.
To systematically review the current research progress on clobazam in pediatric antiepileptic therapy, focusing on its pharmacological mechanisms, pharmacokinetic properties, clinical efficacy, safety profile, and approaches to individualized treatment, with particular emphasis on the influence of CYP2C19 genetic polymorphisms on pharmacokinetics and therapeutic outcomes, and to provide a comprehensive reference for the rational clinical use of clobazam. This article comprehensively reviews the current research progress on clobazam in pediatric antiepileptic therapy, including evidence of efficacy across different epilepsy syndromes, strategies for managing drug-drug interactions, and individualized dosing regimens based on genotyping and therapeutic drug monitoring. Clobazam is a 1,5-benzodiazepine used as an antiseizure medication. Compared with classical 1,4-benzodiazepines, it demonstrates greater efficacy and fewer sedative adverse effects. Clobazam was approved by the U.S. Food and Drug Administration (FDA) in 2011 as an adjunctive therapy for seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥2 years. Since then, it has been increasingly used as adjunctive therapy for several pediatric epilepsy syndromes, including Dravet syndrome (DS), epilepsy with myoclonic-atonic seizures (EMAS), and epileptic encephalopathy with spike-wave activation during sleep. CYP2C19 genetic polymorphisms significantly influence its pharmacokinetics and therapeutic outcomes. Across the reviewed studies, adjunctive clobazam achieved ≥50% seizure reduction in approximately 53% of children and seizure freedom in approximately 24%. Efficacy was highest in LGS, supported by randomized controlled trials, while evidence for other syndromes was largely observational. CYP2C19 poor metabolizer status significantly increased N-desmethylclobazam exposure, supporting genotype-guided dose initiation. Clobazam demonstrates consistent efficacy as adjunctive therapy in pediatric drug-resistant epilepsy, with the strongest evidence supporting its use in LGS. Individualized treatment informed by CYP2C19 genotyping and therapeutic drug monitoring can optimize clinical outcomes. This review provides a comprehensive reference for the rational clinical use of clobazam.
2026-08-31 | Prospects of the therapeutic approaches of ketogenic diet in epilepsy management
The ketogenic diet (KD) is a low-carbohydrate, high-fat diet. For many patients with uncontrolled epilepsy, KD treatments provide a proven non-pharmacological therapy alternative. This is particularly relevant for children with particular epilepsy syndromes and metabolic abnormalities. The aim of this study was to provide a broad overview of the KD, covering the therapeutic effects, relevant mechanisms, and clinical evidence underlying the implementation of the KD in epilepsy management. The study found that KD efficacy is syndrome-specific and patient-dependent. This diet can lower seizure frequency and, in certain cases, can provide prolonged seizure control when antiseizure medication is no longer effective. Their usage in epilepsy disorders, such as infantile spasms, Dravet syndrome, Lennox-Gastaut syndrome, and other refractory epileptic encephalopathies is most well supported. Restrictive dietary adherence, gastrointestinal and metabolic side effects, nutritional inadequacies, the risk of dyslipidemia and nephrolithiasis, and the requirement for close multidisciplinary monitoring are some of the primary limitations with KD therapies. Therefore, rather than being a general therapeutic approach, KD treatments should be used under specialized supervision and taken into consideration as part of a tailored treatment strategy for drug-resistant epilepsy.
antibodies
2026-09-29 | Long-Term Clinical Burden, Treatment Patterns, and Healthcare Utilization in Children with Lennox–Gastaut Syndrome and Infantile Epileptic Spasms Syndrome: A Nationwide Population-Based Claims Study
Purpose: Lennox-Gastaut syndrome (LGS) and infantile epileptic spasms syndrome (IESS) are severe developmental epileptic encephalopathies associated with substantial treatment burden and healthcare utilization.This study characterized clinical features, treatment burden, complications, and healthcare utilization in a nationwide cohort of patients with LGS and IESS and examined differences according to clinical severity.Methods: We retrospectively analyzed patients diagnosed with LGS or IESS between January 2009 and December 2021 using a nationwide insurance claims database.Clinical characteristics, treatment burden, complications, and healthcare utilization were examined according to recorded intellectual disability (ID) and the operational definition of intractable epilepsy.Results: The analysis included 4,124 patients with LGS or IESS; 64.1% had a recorded diagnosis of ID and 51.2% met the operational definition of intractable epilepsy.The absence of these conditions in some patients' records indicated variability in documented long-term disease burden.Patients with intractable epilepsy had greater treatment burden and healthcare utilization, including the use of more antiseizure medications, more frequent surgical interventions, and higher frequencies of hospitalization, intensive care unit admission, and medical complications.Polypharmacy and healthcare burden increased over time, particularly in these patients.Conclusion: In this nationwide cohort, children with LGS and IESS had substantial treatment burden and healthcare utilization, with differences according to clinical severity.These findings may inform risk stratification and long-term management.
2026-06-27 | SUDEP and mortality in developmental and epileptic encephalopathies: A meta-analysis of randomized clinical trials and extension studies.
Developmental and epileptic encephalopathies (DEEs) are associated with high premature mortality and increased risk of sudden unexpected death in epilepsy (SUDEP). However, epidemiological data remain limited, particularly for specific syndromes such as Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and infantile epileptic spasms syndrome (IESS). To address this gap, we conducted a Bayesian meta-analysis of randomized controlled trials (RCTs) and corresponding long-term open-label extension (OLE) studies. All-cause mortality and SUDEP incidence rates were estimated using hierarchical Bayesian models with moderately informative priors derived from the literature. A negative binomial likelihood was used for all-cause mortality, whereas a Poisson likelihood was used for SUDEP. Subgroup analysis were conducted for DS, LGS, and IESS. Thirty-seven RCTs and 15 OLE studies were included, comprising 3757 patients with DEEs (2221 LGS, 998 DS, 369 IESS, and 169 other DEEs). Across pooled data, 37 deaths occurred, including 2 definite, 12 probable, and 1 possible SUDEP. In the overall DEE population, the Bayesian posterior median estimated mortality rate was 8.76 per 1000 person-years (PY; 95% credible interval [CrI], 5.50-13.89), and SUDEP rate was 4.32 per 1000 PY (95% CrI, 2.66-6.64). In LGS, mortality was 7.05 per 1000 PY and SUDEP was 3.4 per 1000 PY. In DS, mortality was 8.0 per 1000 PY, with a SUDEP rate of 7.59 per 1000 PY. In IESS, mortality was 9.41 per 1000 PY and SUDEP was 2.79 per 1000 PY. SUDEP accounted for approximately half of deaths in the overall DEE population and in LGS, with a proportionally greater contribution in DS. Potential trial-related underestimation should be considered when interpreting these findings, as features of trial-based datasets could have contributed to lower observed mortality and SUDEP estimates. Prospective population-based studies are needed to more accurately define the real-world incidence of SUDEP in DEEs.
2025-09-08 | Distinct T Cell Dysregulation Reflects Disease Severity and Progression in Infantile Epileptic Spasms Syndrome and Lennox-Gastaut Syndrome.
Developmental and epileptic encephalopathies (DEEs), including Infantile Epileptic Spasms Syndrome (IESS) and Lennox-Gastaut Syndrome (LGS), are severe pediatric conditions characterized by profound developmental delays and treatment-resistant epilepsy. Although steroid therapies provide some clinical benefits, the underlying immunological mechanisms remain poorly understood. In this study, we performed comprehensive immune profiling using multi-parametric flow cytometry on PBMCs from IESS (n=25) and LGS (n=9) patients, comparing them with age-matched healthy controls (n=54). Our findings identified distinct patterns of immune dysregulation: IESS patients exhibited reduced naïve CD4+ T cells, an altered CD4/CD8 ratio, and diminished TNFα production in CD4+ T cells. Conversely, LGS patients demonstrated an increase in central memory CD4+ T cells, marked dysfunction of Tregs, and heightened activation of CD8+ T cells. Notably, elevated activated CD8+ T cells in IESS patients correlated significantly with clinical severity and demonstrated enhanced responsiveness to viral peptides, suggesting prior viral infections may exacerbate disease progression. Collectively, our findings demonstrate distinct immune signatures associated with disease severity and progression in DEE, suggesting their potential utility as biomarkers. Further studies are necessary to determine whether targeting these immune pathways could provide clinical benefits.
2025-07-28 | Nuclear neuroimaging in childhood epilepsy syndromes: A systematic review.
Childhood epilepsy syndromes (CES) are a group of epilepsy disorders with significant variability in prognosis, treatment, and underlying etiology. This systematic review aims to shed light on the role of nuclear brain imaging in diagnosis, pretreatment assessment, and understanding pathophysiology. A comprehensive search of PubMed, Embase, Scopus, and Web of Science was conducted to identify studies evaluating positron emission tomography (PET) and single-photon emission computed tomography (SPECT) in CES. A risk of bias assessment was performed using the Newcastle-Ottawa Scale. A total of 100 studies were analyzed. PET was the most utilized modality (65%), with the most common radiotracer being fluorine-18 fluorodeoxyglucose ([18F]FDG). PET findings highlighted metabolic abnormalities correlating with seizure foci and surgical outcomes, while SPECT provided critical insights into perfusion changes during ictal, interictal, and postictal phases. Multimodal imaging techniques, such as PET combined with magnetic resonance imaging (PET/MRI) and subtraction ictal SPECT co-registered to MRI (SISCOM), further enhanced diagnostic accuracy. This study highlights the key role of PET and SPECT imaging in childhood epilepsy syndromes, particularly in localizing epileptogenic zones (EZ) when magnetic resonance imaging (MRI) and electroencephalography (EEG) are inconclusive. Nuclear imaging expands understanding of pathophysiology and disease progression in many syndromes, including childhood absence epilepsy (CAE), benign Rolandic epilepsy (BRE), Sturge-Weber syndrome (SWS), Dravet syndrome (DS), Landau-Kleffner syndrome (LKS), and Lennox-Gastaut syndrome (LGS). In conditions such as focal cortical dysplasia and tuberous sclerosis complex, nuclear neuroimaging effectively guides surgical decisions by accurately localizing the EZ.
2024-10-09 | Comparative Analysis of Lennox-Gastaut Syndrome With Different Subtypes of Tonic Seizures: A Single-Center Retrospective Cohort Study.
Lennox-Gastaut syndrome (LGS) is one of the most severe childhood-onset epileptic encephalopathies, primarily characterized by tonic seizures. In clinical practice, we have identified various subtypes of tonic seizures in LGS. This study aimed to analyze the clinical characteristics, electrographic features, treatment responses, and prognosis across different subtypes of LGS. This retrospective cohort study included 46 patients diagnosed with LGS at our center between January 2017 and January 2020. Patients were classified into four groups based on tonic seizure subtypes: Group A (tonic), Group B (spasm-tonic), Group C (myoclonic-tonic), and Group D (combination of spasm-tonic and myoclonic-tonic). Comprehensive clinical data were collected and analyzed. Of the 46 patients, 33 were male. The mean age of onset for Group B (12.38 ± 7.85 months) was significantly less than those of the other three groups (P = 0.02). No significant differences in etiology were found among the groups. Genetic analysis identified mutations in SCN8A, MCCC2, STXBP1, GABRB3, and CACNA1H. After a minimum follow-up of 24 months, the treatment outcomes were more favorable in Groups A and C, whereas psychomotor development was notably poorer in Groups B and D. The findings of this study suggest that LGS may present with distinct subtypes of tonic seizures, with spasm-tonic seizures presenting at an earlier age. Patients with LGS experiencing spasm-tonic seizures, with or without myoclonic-tonic seizures, exhibited poorer treatment responses and psychomotor development than those with other subtypes.
gene therapies
2026-04-11 | Preclinical models of Lennox-Gastaut syndrome: Progress and priorities.
In the last decade, the increasing availability of genetic testing and rapid discovery of genes causing developmental and epileptic encephalopathies such as Lennox-Gastaut syndrome (LGS), together with technology such as CRISPR/Cas9 gene editing, has enabled the generation of new preclinical models, particularly using mice. Mice engineered to express disease-causing genetic changes, through either gene "knock-out" or "knock-in" of specific variants, recapitulate key features of LGS. In this review, we review past and recently developed preclinical models of LGS, and we highlight select insights already gleaned in preclinical studies. We argue that the availability of these new preclinical models should prompt renewed attention to basic and translational studies aimed at understanding fundamental biological mechanisms that enable secondary network evolution to LGS as well as novel, mechanistically informed therapeutic strategies.
2025-10-29 | Lennox-Gastaut syndrome unveiled: Advancing diagnosis, therapies, and advocacy-insights from the Genoa International Workshop.
Lennox-Gastaut syndrome (LGS) is one of the most severe, yet one of the most discussed, childhood-onset developmental and epileptic encephalopathies (DEEs). Dissent among epileptologists on the definition and minimum set of electroclinical features derives from the high etiological heterogeneity within the syndrome, which could make its prevalence overestimated. However, in recent years, our diagnostic strategies, including both high-resolution magnetic resonance imaging and next-generation sequencing techniques, have enabled us to disentangle many cases previously classified as "idiopathic." In addition, some electroencephalographic and circulating biomarkers have been identified that could predict disease progression and treatment response if confirmed in larger patient populations. As our diagnostic capacity increases, so do our treatment strategies. Although progress has been made, the implementation of better clinical trial designs, individualized treatments, and therapies that address the genetic roots of the disease remains necessary in clinical practice. A lot is being done in this direction, thanks to the involvement of families and the creation of international networks, such as the ERNs, which are rapidly promoting collaboration among highly specialized centers and the establishment of disease registries to shed light on the natural history of LGS. Yet, many unmet needs still afflict patients and their families, including uncertainties arising from the transition process and a lack of administrative support and comprehensive care as patients transition into adulthood. This article summarizes these key challenges in diagnosing, treating, and caring for patients with LGS, as well as the roadmap to enhanced future care discussed during the international LGS meeting held in Genoa.
2025-06-05 | Current and emerging pharmacotherapies in Lennox-Gastaut syndrome.
Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizures, cognitive impairments, and distinctive EEG patterns. Given its profound impact on patients' quality of life, developing effective pharmacotherapies remains a critical clinical challenge. This review examines FDA-approved medications for LGS (clonazepam, felbamate, lamotrigine, topiramate, rufinamide, clobazam, cannabidiol, and fenfluramine), commonly used off-label antiseizure medications, emerging treatments in clinical trials, and precision therapeutics targeting etiology-specific mechanisms. The literature encompasses randomized controlled trials, observational studies, and expert consensus statements on treatment approaches and challenges. Despite therapeutic advances, most patients with LGS lack individualized treatment plans with regular adjustments. Current management requires a multimodal approach integrating pharmacotherapy with other interventions. Future progress depends on improved natural history studies, standardized data collection, advanced preclinical models, innovative trial designs, and addressing healthcare inequities. While emerging precision therapies targeting genetic causes show promise, the field urgently needs better strategies to optimize existing treatments while developing disease-modifying approaches that address both seizures and non-seizure outcomes.
2025-05-01 | Precision Therapeutics in Lennox-Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy.
Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30-40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.
2024-03-23 | NUS1 Variants Cause Lennox-Gastaut Syndrome Related to Unfolded Protein Reaction Activation.
NUS1 encodes the Nogo-B receptor, a critical regulator for unfolded protein reaction (UPR) signaling. Although several loss-of-function variants of NUS1 have been identified in patients with developmental and epileptic encephalopathy (DEE), the role of the NUS1 variant in Lennox-Gastaut syndrome (LGS), a severe child-onset DEE, remains unknown. In this study, we identified two de novo variants of NUS1, a missense variant (c.868 C > T/p.R290C) and a splice site variant (c.792-2 A > G), in two unrelated LGS patients using trio-based whole-exome sequencing performed in a cohort of 165 LGS patients. Both variants were absent in the gnomAD population and showed a significantly higher observed number of variants than expected genome-wide. The R290C variant was predicted to damage NUS1 and decrease its protein stability. The c.792-2 A > G variant caused premature termination of the protein. Knockdown of NUS1 activated the UPR pathway, resulting in apoptosis of HEK293T cells. Supplementing cells with expression of wild-type NUS1, but not the mutant (R290C), rescued UPR activation and apoptosis in NUS1 knockdown cells. Compared to wild-type Drosophila, seizure-like behaviors and excitability in projection neurons were significantly increased in Tango14 (homolog of human NUS1) knockdown and Tango14R290C/+ knock-in Drosophila. Additionally, abnormal development and a small body size were observed in both mutants. Activated UPR signaling was also detected in both mutants. Thus, NUS1 is a causative gene for LGS with dominant inheritance. The pathogenicity of these variants is related to the UPR signaling activation, which may be a common pathogenic mechanism of DEE.
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2026-04-23 | Stem cell therapy for rare neurological diseases: translational research opportunities
Stem cell therapy is being explored for several rare neurological conditions in humans given their potential immunomodulatory, reparative, and regenerative capabilities. Existing standard treatments for most neuroinflammatory and neurodegenerative disorders are primarily palliative, focusing on symptom management rather than addressing underlying disease pathology. The genetic and pathophysiological parallels between many human and animal neurological diseases suggest that companion animals may serve as valuable translational models to drive stem cell research forward. Several rare human neurological conditions with companion animal (particularly canine) correlates include fulminant multiple sclerosis (MS), myasthenia gravis, amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Dravet and Lennox-Gastaut Syndromes, Globoid Cell Leukodystrophy/Krabbe Disease, viral encephalitis, and glioblastoma multiforme (GBM). Validating the safety and feasibility of stem cell transplantation in companion animal models has enabled the development and expansion of innovative therapies. Stem cell therapy may hold promise as a novel treatment option for some rare and aggressive human and companion animal neurological diseases with limited treatment options.
2026-03-07 | Clinical outcomes and resting-state brain activity alterations following centromedian thalamic nucleus deep brain stimulation in drug-resistant epilepsy
To assess the clinical efficacy of centromedian nucleus deep brain stimulation (CM-DBS) for drug-resistant epilepsy and explore its effects on neural activity using resting-state functional magnetic resonance imaging. Ten patients, comprising four with Lennox–Gastaut syndrome (LGS), three with generalized epilepsy (GE) and three with multifocal epilepsy, underwent CM-DBS using thalamic segmentation for localization. Efficacy was assessed by calculating seizure frequency reduction from baseline. Two measures of resting brain activity—the amplitude of low-frequency fluctuations (ALFF), reflecting the strength of spontaneous brain signals, and regional homogeneity (ReHo), indicating the synchrony of neighboring brain regions—were analyzed to evaluate postoperative changes. Mean seizure reduction across all patients was 61.8%. Six patients, comprising four with LGS and two with GE, demonstrated > 50% reduction in seizure frequency. ALFF decreased in the right putamen, left inferior temporal, left putamen, right supplementary motor area, right para-hippocampal gyrus, right thalamus, left superior frontal gyrus, left cerebellar vermis IV–V, and right post cingulate gyrus. ReHo decreased in the left inferior temporal gyrus, left anterior cingulate gyrus, and right cerebellar lobe III but increased in the left inferior occipital gyrus, left middle occipital gyrus, right middle occipital gyrus, left cuneus, and right calcarine. Our preliminary findings in a small cohort show that CM-DBS may be effective for certain drug-resistant epilepsies, such as LGS and GE. Thalamic segmentation also enhanced visualization of target structures for clinical use. ALFF/ReHo changes reflect neural reorganization and reveal key epileptic network nodes, potentially reducing CM-DBS seizure frequency.
2025-09-22 | Optimal stimulation of the thalamic centromedian nucleus in children with Lennox-Gastaut syndrome: patient series.
Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple seizure types, intellectual disability, and distinctive EEG findings. Deep brain stimulation of the centromedian nucleus (CM-DBS) is an emerging therapy for LGS, but pediatric experience remains limited. The authors report a single-center experience with CM-DBS in 6 children and adolescents (ages 12-18 years) with LGS. One patient experienced infection-related device removal after 2 months. The remaining 5 received sustained stimulation for 2.5-5 years. All 5 showed caregiver-reported improvements in seizure burden and alertness, with corroborating Clinical Global Impression-Improvement scores. Three patients exhibited marked seizure reduction following targeted reprogramming toward a previously identified optimal target of stimulation in the anterolateral CM. Pre- and post-DBS scalp EEG recordings were available in 1 patient and showed a reduced burden of interictal discharges. CM-DBS is a promising treatment for pediatric, medically refractory LGS when resective approaches are unsuitable. Benefits were sustained over years. Lead localization and direction of stimulation appear important to optimize clinical benefit. These findings support the feasibility and safety of pediatric CM-DBS and highlight the need for prospective trials incorporating EEG-based outcomes and patient-centered measures including comorbidities and quality of life. Early, network-targeted neuromodulation may improve long-term outcomes. https://thejns.org/doi/10.3171/CASE25478.
2025-09-19 | Neuromodulation for Epilepsy.
In patients with an unresectable epileptic focus, such as an undefined focus or epileptic focus within functional areas, various neuromodulation therapies, including vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation, have been adopted as alternative treatment modalities. Vagus nerve stimulation, the earliest approved neuromodulation therapy in Japan, may be indicated irrespective of the epilepsy type and offers several advantages, including craniotomy not being required; however, its efficacy remains limited. Among deep brain stimulation targets, the anterior nucleus of the thalamus has the most established efficacy, and anterior nucleus of the thalamus-deep brain stimulation has been covered by the national health insurance system of Japan for the treatment of epilepsy since 2023. It is considered to be particularly effective for seizures originating from the limbic structures. Although it is not approved for insurance coverage in either Japan or the United States, another effective target is the centromedian nucleus of the thalamus, particularly for generalized epilepsies, including Lennox-Gastaut syndrome. While evidence is limited, deep brain stimulation targeting the hippocampus, subthalamic nucleus, pulvinar nucleus, posteromedial hypothalamus, nucleus accumbens, and cerebellum has also been reported. Responsive neurostimulation, though not yet approved in Japan, records electroencephalographic activity via intracranial electrodes and delivers automatic electrical stimulation upon seizure detection. It is useful for patients with an unresectable seizure focus, that is, eloquent cortex involvement or bilateral temporal lobe epilepsy. This review outlines neuromodulation therapies for epilepsy.
2025-09-01 | Effects of Centromedian Nucleus Stimulation on Interictal Scalp EEG Burden in Lennox-Gastaut Syndrome.
Deep brain stimulation (DBS) of the centromedian (CM) thalamic nucleus is a potential therapy for Lennox-Gastaut syndrome (LGS), a severe and drug-resistant epileptic encephalopathy. While long-term seizure outcomes with CM-DBS have been described, its acute electrophysiological effects and predictive value remain uncertain. We examined whether short-term changes in interictal epileptiform discharges (IEDs) following CM-DBS relate to seizure outcomes at 1 year. Ten patients with LGS underwent CM-DBS implantation. About 1 month post-surgery, each patient had a 1-h scalp EEG. After a 10-min baseline, stimulation began at 1 V for 5 min, increasing in 1 V increments to 5 V or until paresthesias occurred. IEDs were detected automatically (Persyst v14c) and verified by an expert reviewer. Patients were followed for 1 year, with clinical response defined as ≥50% seizure reduction, i.e., responder. Correlations between acute IED change and seizure outcomes were assessed using Spearman's rank correlation. Nine of 10 patients showed reduced IED burden during acute stimulation (31%-100%). At 1 year, 8 were responders and 2 nonresponders. Overall, acute IED reduction did not correlate with seizure outcome (Spearman's ρ = 0.3, p = 0.35). A ≥50% reduction in IED burden was seen in 7 of 7 responders versus 1 of 3 nonresponders, suggesting a nonsignificant trend toward predictive value (p = 0.06). Acute CM-DBS reduced IED burden in most patients with LGS but did not significantly predict long-term seizure outcomes. A trend toward greater IED reduction in responders suggests possible biomarker potential, though findings are preliminary and hypothesis-generating. Limitations include small sample size, high responder rate, and short EEG duration. Larger studies with extended monitoring are needed to clarify the clinical utility of acute EEG changes as predictors of CM-DBS efficacy.
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2026-03-01 | Investigating variants in THAP12 as a novel genetic etiology of Lennox-Gastaut syndrome
Le syndrome de Lennox-Gastaut (SLG) est une encéphalopathie développementale et épileptique, caractérisée par des crises sévères et pharmacorésistantes. 25 % des cas de SLG sont idiopathiques, soulignant la nécessité d'identifier de nouveaux facteurs génétiques sous-jacents aux épilepsies infantiles sévères pour une compréhension globale de leur physiopathologie. Récemment, nos collaborateurs ont identifié deux nouveaux variants du gène THAP12 chez un patient atteint de SLG d'étiologie inconnue. De manière remarquable, THAP12 ne possède aucune annotation fonctionnelle connue ni association avec des maladies neurologiques, y compris le SLG, ce qui en fait une cible particulièrement intéressante pour des investigations approfondies. Cette recherche vise à identifier de nouvelles cibles thérapeutiques exploitables pour les encéphalopathies épileptiques telles que le SLG, ouvrant ainsi des perspectives prometteuses pour le développement de futurs traitements. Par des approches multidisciplinaires englobant des études cellulaires, animales et génomiques, nous cherchons à élucider les mécanismes complexes sous-tendant la fonction de THAP12 dans le développement cérébral et les syndromes épileptiques. À l'aide de fibroblastes de patients, nous avons démontré que les mutations identifiées entraînent une perte d'expression de la protéine THAP12, suggérant un mécanisme pathogène de perte de fonction. De plus, nous avons confirmé la pathogénicité de ces mutations chez la souris, où elles ont conduit à une létalité embryonnaire précoce, soulignant le rôle essentiel de THAP12 dans le développement. Afin de contourner cette létalité, nous avons établi un modèle de poisson zèbre thap12-KO, dans lequel les larves mutantes présentaient une survie réduite, une hypotonie, une diminution de la taille du cerveau, des comportements moteurs spontanés évocateurs de crises dans l'obscurité, ainsi qu'une hypersensibilité aux agents pro-convulsivants. Par ailleurs, nos données d'immunofluorescence chez les larves de poisson zèbre thap12-KO révèlent une diminution de la prolifération cellulaire et une augmentation de l'apoptose, suggérant l'importance capitale de THAP12 dans la régulation du cycle cellulaire. Les données de séquençage d'ARN en cellule unique ont révélé que thap12 est exprimé dans des clusters cellulaires associés aux progéniteurs en cycle dans le cerveau, impliquant un rôle critique dans le développement neuronal précoce. Dans l'ensemble, nos résultats confirment le rôle causal de ces nouveaux variants de THAP12 dans le SLG et plaident en faveur d'une exploration approfondie de la fonction de THAP12 au cours du neurodéveloppement, des mécanismes moléculaires aux circuits cérébraux.
2023-08-21 | New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development
The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarises available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABAA receptors and includes Staccato® alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABAA receptor α and β subunits is being investigated, with Lennox–Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management.
2017-04-01 | Adrenocorticotropic hormone protects learning and memory function in epileptic Kcna1 -null mice
ACTH, a member of the melanocortin family of peptides, is often used in the treatment of the developmental epileptic encephalopathy spectrum disorders including, Ohtahara, West, Lennox Gastaut and Landau-Kleffner Syndromes and electrical status epilepticus of sleep. In these disorders, although ACTH is often successful in controlling the seizures and/or inter-ictal EEG abnormalities, it is unknown whether ACTH possesses other beneficial effects independent of seizure control. We tested whether ACTH can ameliorate the intrinsic impairment of hippocampal-based learning and memory in epileptic Kcna1-null (KO) mice. We found that ACTH − administered in the form of Acthar Gel given i.p. four times daily at a dose of 4 IU/kg (16 IU/kg/day) for 7 days – prevented impairment of long-term potentiation (LTP) evoked with high-frequency stimulation in CA1 hippocampus and also restored spatial learning and memory on the Barnes maze test. However, with this treatment regimen, ACTH did not exert a significant effect on the frequency of spontaneous recurrent seizures. Together, our findings indicate that ACTH can ameliorate memory impairment in epileptic Kcna1-null mice separate from seizure control, and suggest that this widely used peptide may exert direct nootropic effects in the epileptic brain.
2015-07-29 | Efficacy of corticosteroid therapy in treating epileptic encephalopathies and refractory epilepsies other than West syndrome
To evaluate the efficacy of steroid therapy in epileptic encephalopathies and refractory epilepsies other than West syndrome. Retrospective analysis of treatment and outcome data of patients treated with steroids for epileptic encephalopathies. Outcome was analyzed in terms of the patient’s epileptic syndrome, age at seizure onset, duration of seizure disorder, age at treatment, abnormalities noted on neurological examination, developmental status and type of steroid. Fifty-eight consecutive patients from six pediatric neurology outpatient clinics were included in the study. The epileptic syndrome and types were as follows: myoclonic epilepsy (n = 16), epilepsy with continuous spike waves during slow-wave sleep (n = 12), partial epilepsy (n = 10), Landau-Kleffner syndrome (n = 6), generalized epilepsy with multiple epileptic seizure types (n = 5), Rasmussen’s encephalitis (n = 3), Lennox-Gastaut syndrome (n = 2), atypical absence (n = 2) and spasms (n = 2). Sixteen patients (27%) had received adrenocorticotrophic hormone (ACTH) and 42 (73%) had received prednisone (22 of the latter patients were given initial pulse methylprednisolone). Complete cessation of seizures as well as disappearance of epileptic discharges in electroencephalogram were achieved in 16 patients (28%); 15 other patients (26%) had improvement of > 50%. Of the 31 patients with > 50% improvement and follow-up of at least 1 year, 16 (52%) subsequently relapsed. ACTH was found to be significantly more efficacious than prednisone in controlling seizures and improving function. Initiation of treatment with high-dose methylprednisolone did not increase efficacy. ACTH may be more efficacious than prednisone in treating epileptic encephalopathies and refractory epilepsies other than West syndrome.
2014-04-29 | Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets
Various ketogenic diet (KD) therapies, including classic KD, medium chain triglyceride administration, low glycemic index treatment, and a modified Atkins diet, have been suggested as useful in patients affected by pharmacoresistant epilepsy. A common goal of these approaches is to achieve an adequate decrease in the plasma glucose level combined with ketogenesis, in order to mimic the metabolic state of fasting. Although several metabolic hypotheses have been advanced to explain the anticonvulsant effect of KDs, including changes in the plasma levels of ketone bodies, polyunsaturated fatty acids, and brain pH, direct modulation of neurotransmitter release, especially purinergic (i.e., adenosine) and γ-aminobutyric acidergic neurotransmission, was also postulated. Neuropeptides and peptide hormones are potent modulators of synaptic activity, and their levels are regulated by metabolic states. This is the case for neuroactive peptides such as neuropeptide Y, galanin, cholecystokinin and peptide hormones such as leptin, adiponectin, and growth hormone-releasing peptides (GHRPs). In particular, the GHRP ghrelin and its related peptide des-acyl ghrelin are well-known controllers of energy homeostasis, food intake, and lipid metabolism. Notably, ghrelin has also been shown to regulate the neuronal excitability and epileptic activation of neuronal networks. Several lines of evidence suggest that GHRPs are upregulated in response to starvation and, particularly, in patients affected by anorexia and cachexia, all conditions in which also ketone bodies are upregulated. Moreover, starvation and anorexia nervosa are accompanied by changes in other peptide hormones such as adiponectin, which has received less attention. Adipocytokines such as adiponectin have also been involved in modulating epileptic activity. Thus, neuroactive peptides whose plasma levels and activity change in the presence of ketogenesis might be potential candidates for elucidating the neurohormonal mechani
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2026-09-25 | Effect of Fenfluramine on convulsive seizures and rescue medication usage: A case series of adults within the Lennox-Gastaut syndrome spectrum.
Adults with Developmental and epileptic encephalopathies (DEE) within the Lennox-Gastaut Syndrome (LGS) spectrum suffer disabling convulsive seizures which may remain refractory and are associated with increased risk of hospitalisations and death. Fenfluramine (FFA) was licenced in the UK for seizures associated with LGS in March 2025. Adjunctive FFA was assessed in a series of 6 adults with a genetic DEE within the LGS spectrum treated for refractory convulsive seizures. The minimum period of observation was 9 months (range 9-32 months). 3 patients commenced FFA pre-licencing on compassionate grounds. 4 patients had a VNS, 5 patients were prescribed concomitant Cannabidiol. Reduction in convulsive seizures and reduction in use of rescue medications/ frequency of hospitalisations was also assessed. Caregiver responses were recorded using the Clinical Global Improvement of Change (CGI-I). At last follow up, all 6 patients remained on FFA. No significant side effects were observed. There was a significant reduction in seizures at last follow up (p = 0.035), with a corresponding reduction in use of rescue medications and hospitalisations. On the CGI-I, 5 of the 6 patients were rated as much/ very much improved, the remaining patient was rated as minimally improved. Adjunctive FFA was tolerated without significant side effects and associated with a significant reduction in convulsive seizures in this limited cohort. Corresponding reduction in use of rescue medications and hospitalisations has the potential to impact on both patient and caregiver quality of life.
2026-09-17 | Nanostructured lipid carriers for intranasal cannabidiol delivery in Dravet and Lennox-Gastaut syndromes: bridging preclinical promise to clinical translation.
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are severe developmental epileptic encephalopathies that appear in early childhood, are unresponsive to medications, and have a dismal neurodevelopmental prognosis. Most patients do not respond well to polytherapy, and the need to fulfill this gap in clinical practice is urgent. Cannabidiol (CBD) has proven to be an effective adjunct drug, but oral preparations have low bioavailability, slow onset and systemic adverse effects. Nanostructured lipid carriers (NLCs) are an innovative therapeutic technology that can deliver CBD directly to the brain via the nose, enhance brain targeting, achieve faster onset, and minimize systemic exposure, which could be a valuable solution to current deficiencies in treatment.Intranasal NLC-CBD has preclinical evidence of increasing brain CBD levels, facilitating anticonvulsant action, and protecting against seizures in established animal models, like pentylenetetrazol-induced convulsions. NLC-based preparations have increased brain-to-plasma ratios and longer central exposure at lower doses in comparison to free or orally administered CBD. Despite these promising findings, there are still translational gaps to be addressed, such as insufficient safety data in the long term, disease-specific DS/LGS genetic models, inconsistencies in the pediatric nasal physiology, and conventional clinical dosing paradigms.Literature for this review was identified through searches of PubMed, Scopus, Web of Science, and Google Scholar, covering studies published up to March 2026 on CBD, NLC, intranasal drug delivery, DS, and LGS.There is a dire need to carry out properly designed clinical trials that would demonstrate the safety, pharmacokinetics (PK) and efficacy of intranasal NLC-CBD in DS and LGS. The first pediatric clinical trials, adaptive trial models and regulatory harmonization are necessary to convert this noble nanomedicine approach into a clinical therapy.
2026-09-17 | Use of Purified Cannabidiol in Treatment-Resistant Pediatric Epilepsy: Beyond Lennox-Gastaut Syndrome, Dravet Syndrome, and Tuberous Sclerosis Complex.
The pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex) is approved by the the US Food and Drug Administration for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis in patients one year of age and older. Among the large volume of drug-resistant cases treated at pediatric Level 4 Epilepsy Centers, many patients fall outside of these categories but are still prescribed CBD for off label use. This study sought to characterize the real-world experience with CBD of a large single pediatric comprehensive epilepsy center and to compare response to CBD within and outside of its FDA-approved indications. A retrospective chart review was performed of patients with a prescription for CBD at our institution between January 2020 and January 2022, excluding patients who were previously included in our center's 2019 analysis. Patients were not included in the analysis if initially prescribed CBD elsewhere, follow-up was outside our institution, medication was not started, patient expired during the study period, or diagnostic data was not available. Between-group differences were assessed via Wilcoxon rank-sum and Fisher exact tests, as appropriate. Of 223 patients with a CBD prescription during the study period, 144 patients had sufficient data available for review. Of these patients, 81 (56%) carried diagnoses of Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis, and 63 (44%) carried other diagnoses outside of FDA-labeled indications. Median (interquartile range) age at initiation was 10.0 years (5.0, 13.0), and median (interquartile range) number of concurrent anti-seizure medications was 3.0 (2.0, 3.0). There was no significant difference in the proportion of patients treated concurrently with vagus nerve stimulation or ketogenic diet between the two groups. The FDA-labeled (63%) group had a significantly higher proportion of patients with tonic seizures compared to the non-FDA labeled (29%) group (P < 0.001), otherwise there were no significant differences in baseline seizure types. Overall, 53 patients (65%) in the FDA-labeled group and 40 (63%) of the non-FDA labeled group had a documented responder rate at least 50% on CBD (P = 0.9). The most common side effects reported were nausea/diarrhea/gastrointestinal upset (19%), agitation (7.6%), insomnia (4.9%), weight loss (6.3%), and secretions/drooling (2.8%, seen only in patients on concurrent clobazam). Among our cohort of treatment-resistant pediatric epilepsy, purified CBD was efficacious in a broad range of pediatric epilepsies and was well tolerated as an adjunctive anti-seizure medication. This medication may be considered in pharmacoresistant pediatric epilepsies in conditions beyond its FDA-labeled indications.
2026-09-10 | Clobazam in pediatric drug-resistant epilepsy: from pharmacology to clinical practice.
To systematically review the current research progress on clobazam in pediatric antiepileptic therapy, focusing on its pharmacological mechanisms, pharmacokinetic properties, clinical efficacy, safety profile, and approaches to individualized treatment, with particular emphasis on the influence of CYP2C19 genetic polymorphisms on pharmacokinetics and therapeutic outcomes, and to provide a comprehensive reference for the rational clinical use of clobazam. This article comprehensively reviews the current research progress on clobazam in pediatric antiepileptic therapy, including evidence of efficacy across different epilepsy syndromes, strategies for managing drug-drug interactions, and individualized dosing regimens based on genotyping and therapeutic drug monitoring. Clobazam is a 1,5-benzodiazepine used as an antiseizure medication. Compared with classical 1,4-benzodiazepines, it demonstrates greater efficacy and fewer sedative adverse effects. Clobazam was approved by the U.S. Food and Drug Administration (FDA) in 2011 as an adjunctive therapy for seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥2 years. Since then, it has been increasingly used as adjunctive therapy for several pediatric epilepsy syndromes, including Dravet syndrome (DS), epilepsy with myoclonic-atonic seizures (EMAS), and epileptic encephalopathy with spike-wave activation during sleep. CYP2C19 genetic polymorphisms significantly influence its pharmacokinetics and therapeutic outcomes. Across the reviewed studies, adjunctive clobazam achieved ≥50% seizure reduction in approximately 53% of children and seizure freedom in approximately 24%. Efficacy was highest in LGS, supported by randomized controlled trials, while evidence for other syndromes was largely observational. CYP2C19 poor metabolizer status significantly increased N-desmethylclobazam exposure, supporting genotype-guided dose initiation. Clobazam demonstrates consistent efficacy as adjunctive therapy in pediatric drug-resistant epilepsy, with the strongest evidence supporting its use in LGS. Individualized treatment informed by CYP2C19 genotyping and therapeutic drug monitoring can optimize clinical outcomes. This review provides a comprehensive reference for the rational clinical use of clobazam.
2026-08-31 | Prospects of the therapeutic approaches of ketogenic diet in epilepsy management
The ketogenic diet (KD) is a low-carbohydrate, high-fat diet. For many patients with uncontrolled epilepsy, KD treatments provide a proven non-pharmacological therapy alternative. This is particularly relevant for children with particular epilepsy syndromes and metabolic abnormalities. The aim of this study was to provide a broad overview of the KD, covering the therapeutic effects, relevant mechanisms, and clinical evidence underlying the implementation of the KD in epilepsy management. The study found that KD efficacy is syndrome-specific and patient-dependent. This diet can lower seizure frequency and, in certain cases, can provide prolonged seizure control when antiseizure medication is no longer effective. Their usage in epilepsy disorders, such as infantile spasms, Dravet syndrome, Lennox-Gastaut syndrome, and other refractory epileptic encephalopathies is most well supported. Restrictive dietary adherence, gastrointestinal and metabolic side effects, nutritional inadequacies, the risk of dyslipidemia and nephrolithiasis, and the requirement for close multidisciplinary monitoring are some of the primary limitations with KD therapies. Therefore, rather than being a general therapeutic approach, KD treatments should be used under specialized supervision and taken into consideration as part of a tailored treatment strategy for drug-resistant epilepsy.
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2026-09-29 | Long-Term Clinical Burden, Treatment Patterns, and Healthcare Utilization in Children with Lennox–Gastaut Syndrome and Infantile Epileptic Spasms Syndrome: A Nationwide Population-Based Claims Study
Purpose: Lennox-Gastaut syndrome (LGS) and infantile epileptic spasms syndrome (IESS) are severe developmental epileptic encephalopathies associated with substantial treatment burden and healthcare utilization.This study characterized clinical features, treatment burden, complications, and healthcare utilization in a nationwide cohort of patients with LGS and IESS and examined differences according to clinical severity.Methods: We retrospectively analyzed patients diagnosed with LGS or IESS between January 2009 and December 2021 using a nationwide insurance claims database.Clinical characteristics, treatment burden, complications, and healthcare utilization were examined according to recorded intellectual disability (ID) and the operational definition of intractable epilepsy.Results: The analysis included 4,124 patients with LGS or IESS; 64.1% had a recorded diagnosis of ID and 51.2% met the operational definition of intractable epilepsy.The absence of these conditions in some patients' records indicated variability in documented long-term disease burden.Patients with intractable epilepsy had greater treatment burden and healthcare utilization, including the use of more antiseizure medications, more frequent surgical interventions, and higher frequencies of hospitalization, intensive care unit admission, and medical complications.Polypharmacy and healthcare burden increased over time, particularly in these patients.Conclusion: In this nationwide cohort, children with LGS and IESS had substantial treatment burden and healthcare utilization, with differences according to clinical severity.These findings may inform risk stratification and long-term management.
2026-06-27 | SUDEP and mortality in developmental and epileptic encephalopathies: A meta-analysis of randomized clinical trials and extension studies.
Developmental and epileptic encephalopathies (DEEs) are associated with high premature mortality and increased risk of sudden unexpected death in epilepsy (SUDEP). However, epidemiological data remain limited, particularly for specific syndromes such as Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and infantile epileptic spasms syndrome (IESS). To address this gap, we conducted a Bayesian meta-analysis of randomized controlled trials (RCTs) and corresponding long-term open-label extension (OLE) studies. All-cause mortality and SUDEP incidence rates were estimated using hierarchical Bayesian models with moderately informative priors derived from the literature. A negative binomial likelihood was used for all-cause mortality, whereas a Poisson likelihood was used for SUDEP. Subgroup analysis were conducted for DS, LGS, and IESS. Thirty-seven RCTs and 15 OLE studies were included, comprising 3757 patients with DEEs (2221 LGS, 998 DS, 369 IESS, and 169 other DEEs). Across pooled data, 37 deaths occurred, including 2 definite, 12 probable, and 1 possible SUDEP. In the overall DEE population, the Bayesian posterior median estimated mortality rate was 8.76 per 1000 person-years (PY; 95% credible interval [CrI], 5.50-13.89), and SUDEP rate was 4.32 per 1000 PY (95% CrI, 2.66-6.64). In LGS, mortality was 7.05 per 1000 PY and SUDEP was 3.4 per 1000 PY. In DS, mortality was 8.0 per 1000 PY, with a SUDEP rate of 7.59 per 1000 PY. In IESS, mortality was 9.41 per 1000 PY and SUDEP was 2.79 per 1000 PY. SUDEP accounted for approximately half of deaths in the overall DEE population and in LGS, with a proportionally greater contribution in DS. Potential trial-related underestimation should be considered when interpreting these findings, as features of trial-based datasets could have contributed to lower observed mortality and SUDEP estimates. Prospective population-based studies are needed to more accurately define the real-world incidence of SUDEP in DEEs.
2025-09-08 | Distinct T Cell Dysregulation Reflects Disease Severity and Progression in Infantile Epileptic Spasms Syndrome and Lennox-Gastaut Syndrome.
Developmental and epileptic encephalopathies (DEEs), including Infantile Epileptic Spasms Syndrome (IESS) and Lennox-Gastaut Syndrome (LGS), are severe pediatric conditions characterized by profound developmental delays and treatment-resistant epilepsy. Although steroid therapies provide some clinical benefits, the underlying immunological mechanisms remain poorly understood. In this study, we performed comprehensive immune profiling using multi-parametric flow cytometry on PBMCs from IESS (n=25) and LGS (n=9) patients, comparing them with age-matched healthy controls (n=54). Our findings identified distinct patterns of immune dysregulation: IESS patients exhibited reduced naïve CD4+ T cells, an altered CD4/CD8 ratio, and diminished TNFα production in CD4+ T cells. Conversely, LGS patients demonstrated an increase in central memory CD4+ T cells, marked dysfunction of Tregs, and heightened activation of CD8+ T cells. Notably, elevated activated CD8+ T cells in IESS patients correlated significantly with clinical severity and demonstrated enhanced responsiveness to viral peptides, suggesting prior viral infections may exacerbate disease progression. Collectively, our findings demonstrate distinct immune signatures associated with disease severity and progression in DEE, suggesting their potential utility as biomarkers. Further studies are necessary to determine whether targeting these immune pathways could provide clinical benefits.
2025-07-28 | Nuclear neuroimaging in childhood epilepsy syndromes: A systematic review.
Childhood epilepsy syndromes (CES) are a group of epilepsy disorders with significant variability in prognosis, treatment, and underlying etiology. This systematic review aims to shed light on the role of nuclear brain imaging in diagnosis, pretreatment assessment, and understanding pathophysiology. A comprehensive search of PubMed, Embase, Scopus, and Web of Science was conducted to identify studies evaluating positron emission tomography (PET) and single-photon emission computed tomography (SPECT) in CES. A risk of bias assessment was performed using the Newcastle-Ottawa Scale. A total of 100 studies were analyzed. PET was the most utilized modality (65%), with the most common radiotracer being fluorine-18 fluorodeoxyglucose ([18F]FDG). PET findings highlighted metabolic abnormalities correlating with seizure foci and surgical outcomes, while SPECT provided critical insights into perfusion changes during ictal, interictal, and postictal phases. Multimodal imaging techniques, such as PET combined with magnetic resonance imaging (PET/MRI) and subtraction ictal SPECT co-registered to MRI (SISCOM), further enhanced diagnostic accuracy. This study highlights the key role of PET and SPECT imaging in childhood epilepsy syndromes, particularly in localizing epileptogenic zones (EZ) when magnetic resonance imaging (MRI) and electroencephalography (EEG) are inconclusive. Nuclear imaging expands understanding of pathophysiology and disease progression in many syndromes, including childhood absence epilepsy (CAE), benign Rolandic epilepsy (BRE), Sturge-Weber syndrome (SWS), Dravet syndrome (DS), Landau-Kleffner syndrome (LKS), and Lennox-Gastaut syndrome (LGS). In conditions such as focal cortical dysplasia and tuberous sclerosis complex, nuclear neuroimaging effectively guides surgical decisions by accurately localizing the EZ.
2024-10-09 | Comparative Analysis of Lennox-Gastaut Syndrome With Different Subtypes of Tonic Seizures: A Single-Center Retrospective Cohort Study.
Lennox-Gastaut syndrome (LGS) is one of the most severe childhood-onset epileptic encephalopathies, primarily characterized by tonic seizures. In clinical practice, we have identified various subtypes of tonic seizures in LGS. This study aimed to analyze the clinical characteristics, electrographic features, treatment responses, and prognosis across different subtypes of LGS. This retrospective cohort study included 46 patients diagnosed with LGS at our center between January 2017 and January 2020. Patients were classified into four groups based on tonic seizure subtypes: Group A (tonic), Group B (spasm-tonic), Group C (myoclonic-tonic), and Group D (combination of spasm-tonic and myoclonic-tonic). Comprehensive clinical data were collected and analyzed. Of the 46 patients, 33 were male. The mean age of onset for Group B (12.38 ± 7.85 months) was significantly less than those of the other three groups (P = 0.02). No significant differences in etiology were found among the groups. Genetic analysis identified mutations in SCN8A, MCCC2, STXBP1, GABRB3, and CACNA1H. After a minimum follow-up of 24 months, the treatment outcomes were more favorable in Groups A and C, whereas psychomotor development was notably poorer in Groups B and D. The findings of this study suggest that LGS may present with distinct subtypes of tonic seizures, with spasm-tonic seizures presenting at an earlier age. Patients with LGS experiencing spasm-tonic seizures, with or without myoclonic-tonic seizures, exhibited poorer treatment responses and psychomotor development than those with other subtypes.
gene therapies
2026-04-11 | Preclinical models of Lennox-Gastaut syndrome: Progress and priorities.
In the last decade, the increasing availability of genetic testing and rapid discovery of genes causing developmental and epileptic encephalopathies such as Lennox-Gastaut syndrome (LGS), together with technology such as CRISPR/Cas9 gene editing, has enabled the generation of new preclinical models, particularly using mice. Mice engineered to express disease-causing genetic changes, through either gene "knock-out" or "knock-in" of specific variants, recapitulate key features of LGS. In this review, we review past and recently developed preclinical models of LGS, and we highlight select insights already gleaned in preclinical studies. We argue that the availability of these new preclinical models should prompt renewed attention to basic and translational studies aimed at understanding fundamental biological mechanisms that enable secondary network evolution to LGS as well as novel, mechanistically informed therapeutic strategies.
2025-10-29 | Lennox-Gastaut syndrome unveiled: Advancing diagnosis, therapies, and advocacy-insights from the Genoa International Workshop.
Lennox-Gastaut syndrome (LGS) is one of the most severe, yet one of the most discussed, childhood-onset developmental and epileptic encephalopathies (DEEs). Dissent among epileptologists on the definition and minimum set of electroclinical features derives from the high etiological heterogeneity within the syndrome, which could make its prevalence overestimated. However, in recent years, our diagnostic strategies, including both high-resolution magnetic resonance imaging and next-generation sequencing techniques, have enabled us to disentangle many cases previously classified as "idiopathic." In addition, some electroencephalographic and circulating biomarkers have been identified that could predict disease progression and treatment response if confirmed in larger patient populations. As our diagnostic capacity increases, so do our treatment strategies. Although progress has been made, the implementation of better clinical trial designs, individualized treatments, and therapies that address the genetic roots of the disease remains necessary in clinical practice. A lot is being done in this direction, thanks to the involvement of families and the creation of international networks, such as the ERNs, which are rapidly promoting collaboration among highly specialized centers and the establishment of disease registries to shed light on the natural history of LGS. Yet, many unmet needs still afflict patients and their families, including uncertainties arising from the transition process and a lack of administrative support and comprehensive care as patients transition into adulthood. This article summarizes these key challenges in diagnosing, treating, and caring for patients with LGS, as well as the roadmap to enhanced future care discussed during the international LGS meeting held in Genoa.
2025-06-05 | Current and emerging pharmacotherapies in Lennox-Gastaut syndrome.
Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizures, cognitive impairments, and distinctive EEG patterns. Given its profound impact on patients' quality of life, developing effective pharmacotherapies remains a critical clinical challenge. This review examines FDA-approved medications for LGS (clonazepam, felbamate, lamotrigine, topiramate, rufinamide, clobazam, cannabidiol, and fenfluramine), commonly used off-label antiseizure medications, emerging treatments in clinical trials, and precision therapeutics targeting etiology-specific mechanisms. The literature encompasses randomized controlled trials, observational studies, and expert consensus statements on treatment approaches and challenges. Despite therapeutic advances, most patients with LGS lack individualized treatment plans with regular adjustments. Current management requires a multimodal approach integrating pharmacotherapy with other interventions. Future progress depends on improved natural history studies, standardized data collection, advanced preclinical models, innovative trial designs, and addressing healthcare inequities. While emerging precision therapies targeting genetic causes show promise, the field urgently needs better strategies to optimize existing treatments while developing disease-modifying approaches that address both seizures and non-seizure outcomes.
2025-05-01 | Precision Therapeutics in Lennox-Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy.
Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30-40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.
2024-03-23 | NUS1 Variants Cause Lennox-Gastaut Syndrome Related to Unfolded Protein Reaction Activation.
NUS1 encodes the Nogo-B receptor, a critical regulator for unfolded protein reaction (UPR) signaling. Although several loss-of-function variants of NUS1 have been identified in patients with developmental and epileptic encephalopathy (DEE), the role of the NUS1 variant in Lennox-Gastaut syndrome (LGS), a severe child-onset DEE, remains unknown. In this study, we identified two de novo variants of NUS1, a missense variant (c.868 C > T/p.R290C) and a splice site variant (c.792-2 A > G), in two unrelated LGS patients using trio-based whole-exome sequencing performed in a cohort of 165 LGS patients. Both variants were absent in the gnomAD population and showed a significantly higher observed number of variants than expected genome-wide. The R290C variant was predicted to damage NUS1 and decrease its protein stability. The c.792-2 A > G variant caused premature termination of the protein. Knockdown of NUS1 activated the UPR pathway, resulting in apoptosis of HEK293T cells. Supplementing cells with expression of wild-type NUS1, but not the mutant (R290C), rescued UPR activation and apoptosis in NUS1 knockdown cells. Compared to wild-type Drosophila, seizure-like behaviors and excitability in projection neurons were significantly increased in Tango14 (homolog of human NUS1) knockdown and Tango14R290C/+ knock-in Drosophila. Additionally, abnormal development and a small body size were observed in both mutants. Activated UPR signaling was also detected in both mutants. Thus, NUS1 is a causative gene for LGS with dominant inheritance. The pathogenicity of these variants is related to the UPR signaling activation, which may be a common pathogenic mechanism of DEE.
other
2026-04-23 | Stem cell therapy for rare neurological diseases: translational research opportunities
Stem cell therapy is being explored for several rare neurological conditions in humans given their potential immunomodulatory, reparative, and regenerative capabilities. Existing standard treatments for most neuroinflammatory and neurodegenerative disorders are primarily palliative, focusing on symptom management rather than addressing underlying disease pathology. The genetic and pathophysiological parallels between many human and animal neurological diseases suggest that companion animals may serve as valuable translational models to drive stem cell research forward. Several rare human neurological conditions with companion animal (particularly canine) correlates include fulminant multiple sclerosis (MS), myasthenia gravis, amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Dravet and Lennox-Gastaut Syndromes, Globoid Cell Leukodystrophy/Krabbe Disease, viral encephalitis, and glioblastoma multiforme (GBM). Validating the safety and feasibility of stem cell transplantation in companion animal models has enabled the development and expansion of innovative therapies. Stem cell therapy may hold promise as a novel treatment option for some rare and aggressive human and companion animal neurological diseases with limited treatment options.
2026-03-07 | Clinical outcomes and resting-state brain activity alterations following centromedian thalamic nucleus deep brain stimulation in drug-resistant epilepsy
To assess the clinical efficacy of centromedian nucleus deep brain stimulation (CM-DBS) for drug-resistant epilepsy and explore its effects on neural activity using resting-state functional magnetic resonance imaging. Ten patients, comprising four with Lennox–Gastaut syndrome (LGS), three with generalized epilepsy (GE) and three with multifocal epilepsy, underwent CM-DBS using thalamic segmentation for localization. Efficacy was assessed by calculating seizure frequency reduction from baseline. Two measures of resting brain activity—the amplitude of low-frequency fluctuations (ALFF), reflecting the strength of spontaneous brain signals, and regional homogeneity (ReHo), indicating the synchrony of neighboring brain regions—were analyzed to evaluate postoperative changes. Mean seizure reduction across all patients was 61.8%. Six patients, comprising four with LGS and two with GE, demonstrated > 50% reduction in seizure frequency. ALFF decreased in the right putamen, left inferior temporal, left putamen, right supplementary motor area, right para-hippocampal gyrus, right thalamus, left superior frontal gyrus, left cerebellar vermis IV–V, and right post cingulate gyrus. ReHo decreased in the left inferior temporal gyrus, left anterior cingulate gyrus, and right cerebellar lobe III but increased in the left inferior occipital gyrus, left middle occipital gyrus, right middle occipital gyrus, left cuneus, and right calcarine. Our preliminary findings in a small cohort show that CM-DBS may be effective for certain drug-resistant epilepsies, such as LGS and GE. Thalamic segmentation also enhanced visualization of target structures for clinical use. ALFF/ReHo changes reflect neural reorganization and reveal key epileptic network nodes, potentially reducing CM-DBS seizure frequency.
2025-09-22 | Optimal stimulation of the thalamic centromedian nucleus in children with Lennox-Gastaut syndrome: patient series.
Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple seizure types, intellectual disability, and distinctive EEG findings. Deep brain stimulation of the centromedian nucleus (CM-DBS) is an emerging therapy for LGS, but pediatric experience remains limited. The authors report a single-center experience with CM-DBS in 6 children and adolescents (ages 12-18 years) with LGS. One patient experienced infection-related device removal after 2 months. The remaining 5 received sustained stimulation for 2.5-5 years. All 5 showed caregiver-reported improvements in seizure burden and alertness, with corroborating Clinical Global Impression-Improvement scores. Three patients exhibited marked seizure reduction following targeted reprogramming toward a previously identified optimal target of stimulation in the anterolateral CM. Pre- and post-DBS scalp EEG recordings were available in 1 patient and showed a reduced burden of interictal discharges. CM-DBS is a promising treatment for pediatric, medically refractory LGS when resective approaches are unsuitable. Benefits were sustained over years. Lead localization and direction of stimulation appear important to optimize clinical benefit. These findings support the feasibility and safety of pediatric CM-DBS and highlight the need for prospective trials incorporating EEG-based outcomes and patient-centered measures including comorbidities and quality of life. Early, network-targeted neuromodulation may improve long-term outcomes. https://thejns.org/doi/10.3171/CASE25478.
2025-09-19 | Neuromodulation for Epilepsy.
In patients with an unresectable epileptic focus, such as an undefined focus or epileptic focus within functional areas, various neuromodulation therapies, including vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation, have been adopted as alternative treatment modalities. Vagus nerve stimulation, the earliest approved neuromodulation therapy in Japan, may be indicated irrespective of the epilepsy type and offers several advantages, including craniotomy not being required; however, its efficacy remains limited. Among deep brain stimulation targets, the anterior nucleus of the thalamus has the most established efficacy, and anterior nucleus of the thalamus-deep brain stimulation has been covered by the national health insurance system of Japan for the treatment of epilepsy since 2023. It is considered to be particularly effective for seizures originating from the limbic structures. Although it is not approved for insurance coverage in either Japan or the United States, another effective target is the centromedian nucleus of the thalamus, particularly for generalized epilepsies, including Lennox-Gastaut syndrome. While evidence is limited, deep brain stimulation targeting the hippocampus, subthalamic nucleus, pulvinar nucleus, posteromedial hypothalamus, nucleus accumbens, and cerebellum has also been reported. Responsive neurostimulation, though not yet approved in Japan, records electroencephalographic activity via intracranial electrodes and delivers automatic electrical stimulation upon seizure detection. It is useful for patients with an unresectable seizure focus, that is, eloquent cortex involvement or bilateral temporal lobe epilepsy. This review outlines neuromodulation therapies for epilepsy.
2025-09-01 | Effects of Centromedian Nucleus Stimulation on Interictal Scalp EEG Burden in Lennox-Gastaut Syndrome.
Deep brain stimulation (DBS) of the centromedian (CM) thalamic nucleus is a potential therapy for Lennox-Gastaut syndrome (LGS), a severe and drug-resistant epileptic encephalopathy. While long-term seizure outcomes with CM-DBS have been described, its acute electrophysiological effects and predictive value remain uncertain. We examined whether short-term changes in interictal epileptiform discharges (IEDs) following CM-DBS relate to seizure outcomes at 1 year. Ten patients with LGS underwent CM-DBS implantation. About 1 month post-surgery, each patient had a 1-h scalp EEG. After a 10-min baseline, stimulation began at 1 V for 5 min, increasing in 1 V increments to 5 V or until paresthesias occurred. IEDs were detected automatically (Persyst v14c) and verified by an expert reviewer. Patients were followed for 1 year, with clinical response defined as ≥50% seizure reduction, i.e., responder. Correlations between acute IED change and seizure outcomes were assessed using Spearman's rank correlation. Nine of 10 patients showed reduced IED burden during acute stimulation (31%-100%). At 1 year, 8 were responders and 2 nonresponders. Overall, acute IED reduction did not correlate with seizure outcome (Spearman's ρ = 0.3, p = 0.35). A ≥50% reduction in IED burden was seen in 7 of 7 responders versus 1 of 3 nonresponders, suggesting a nonsignificant trend toward predictive value (p = 0.06). Acute CM-DBS reduced IED burden in most patients with LGS but did not significantly predict long-term seizure outcomes. A trend toward greater IED reduction in responders suggests possible biomarker potential, though findings are preliminary and hypothesis-generating. Limitations include small sample size, high responder rate, and short EEG duration. Larger studies with extended monitoring are needed to clarify the clinical utility of acute EEG changes as predictors of CM-DBS efficacy.
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Drug Discovery Landscape
27 orphan drug designations for Lennox-Gastaut syndrome, including 10 approved therapies.
27 orphan drug designations for Lennox-Gastaut syndrome, including 10 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
(+)-((1S, 2S)-2-(5-Fluoro-2-propoxyphenyl)cyclopropyl)methanamine hydrochloride | small molecules | FDA | Bright Minds Biosciences, Inc. | |
bexicaserin hydrochloride | small molecules | FDA | Longboard Pharmaceuticals, Inc. | |
ganaxolone | small molecules | FDA | Immedica Pharma AB | |
Soticlestat | small molecules | EMA | Takeda Pharmaceuticals International AG Ireland Branch | |
Clemizole | small molecules | FDA | Epygenix Therapeutics, Inc. | |
Lorcaserin Hydrochloride | small molecules | FDA | — | Epygenix Therapeutics, Inc. |
a peptidomimetic protein peptide with sequence H-Gly-Arg-Arg-Ala-Ala-Pro-Gly-Arg-Aib-Gly-Gly-NH2 | proteins | FDA | — | CuroNZ Ltd |
(-)-huperzine A | small molecules | FDA | — | Supernus Pharmaceuticals, Inc. |
cholesterol 24S-hydroxylase inhibitor | small molecules | FDA | Takeda Development Center Americas, Inc. | |
cannabidiol (CBD) | small molecules | FDA | AXIUM Pharmaceuticals, Inc. | |
carisbamate | small molecules | FDA | SK Life Sciences, Inc. | |
fenfluramine [Fintepla] | small molecules | FDA | Approved | UCB, Inc. |
Cannabidiol [Epidyolex] | small molecules | EMA | Approved | Jazz Pharmaceuticals Ireland Limited |
Fenfluramine hydrochloride [Fintepla] | small molecules | EMA | Approved | UCB Pharma |
propofol hemisuccinate | small molecules | FDA | — | EpaleX Corporation |
diazepam subcutaneous injection | small molecules | FDA | Xeris Pharmaceuticals, Inc. | |
diazepam (intranasal) [VALTOCO] | small molecules | FDA | Approved | Neurelis Pharmaceuticals, Inc. |
cannabidiol | small molecules | FDA | Insys Development Company, Inc. | |
cannabidiol [Epidiolex] | small molecules | FDA | Approved | Jazz Pharmaceuticals Research UK Limited |
perampanel | small molecules | FDA | Eisai Inc. | |
diazepam (intranasal) | small molecules | FDA | SK Life Sciences Inc. | |
clobazam [Onfi] | small molecules | FDA | Approved | Lundbeck, Inc. |
Rufinamide [Inovelon] | small molecules | EMA | Eisai GmbH | |
rufinamide [Banzel] | small molecules | FDA | Approved | Eisai, Inc. |
Lamotrigine [Lamictal] | small molecules | FDA | Approved | Glaxo Wellcome Research and Development |
Topiramate [Topamax] | small molecules | FDA | Approved | Johnson & Johnson Pharmaceutical R & D, LLC |
Felbamate [Felbatol] | small molecules | FDA | Approved | Wallace Laboratories |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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