{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T21:09:12Z","timestamp":1769807352815,"version":"3.49.0"},"reference-count":100,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lennox\u2013Gastaut syndrome (LGS) is a rare and severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, mandatory tonic seizures, cognitive and behavioral impairment, and distinctive electroencephalographic features, including slow spike\u2013wave discharges and generalized paroxysmal fast activity. Despite decades of therapeutic advances, LGS remains associated with profound lifelong disability and the absence of a single disease-defining molecular mechanism. Recent advances in genetics, neurophysiology, and network neuroscience have reframed LGS as a convergent network encephalopathy, in which diverse genetic, structural, metabolic, immune, and acquired insults funnel into shared molecular hubs, leading to thalamocortical network dysfunction. This framework helps explain the limited efficacy of purely syndrome-based treatments. This review synthesizes current evidence on electroclinical phenotyping, molecular and network pathogenesis, and contemporary diagnostic workflows and proposes a molecule-to-precision-therapy framework for LGS. We critically appraise pharmacologic, dietary, surgical, and neuromodulatory therapies, emphasizing drop seizures as a major driver of morbidity. Among available treatments, cannabidiol shows the most consistent and clinically meaningful efficacy for drop seizures, with benefits extending beyond seizure counts to seizure-free days and caregiver-relevant outcomes. Finally, we highlight key gaps and future directions, including etiology-stratified trials, network-guided interventions, and outcome measures that capture long-term developmental and quality-of-life impacts.<\/jats:p>","DOI":"10.3390\/ijms27031382","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T08:19:38Z","timestamp":1769761178000},"page":"1382","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling Lennox\u2013Gastaut Syndrome: From Molecular Pathogenesis to Precision Diagnosis and Targeted Therapy Evolving Therapeutic Strategies"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3051-2010","authenticated-orcid":false,"given":"Ji-Hoon","family":"Na","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5838-249X","authenticated-orcid":false,"given":"Young-Mock","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1002\/epi4.13024","article-title":"Long-term outcomes and adaptive behavior in adult patients with Lennox-Gastaut syndrome","volume":"9","author":"Petrungaro","year":"2024","journal-title":"Epilepsia Open"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.seizure.2025.11.001","article-title":"History of Lennox-Gastaut Syndrome: An electro-clinical voyage in search of an epileptic syndrome","volume":"133","author":"Gelisse","year":"2025","journal-title":"Seizure"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1111\/epi.17866","article-title":"A systematic literature review on the global epidemiology of Dravet syndrome and Lennox-Gastaut syndrome: Prevalence, incidence, diagnosis, and mortality","volume":"65","author":"Sullivan","year":"2024","journal-title":"Epilepsia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1152\/physrev.00063.2021","article-title":"Developmental and epileptic encephalopathies: From genetic heterogeneity to phenotypic continuum","volume":"103","author":"Guerrini","year":"2023","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Riva, A., D\u2019Onofrio, G., Amadori, E., Arzimanoglou, A., Auvin, S., Bagnasco, I., Barabino, P., Biagioli, V., Brambilla, I., and Cangemi, G. (2025). Lennox-Gastaut syndrome unveiled: Advancing diagnosis, therapies, and advocacy-insights from the Genoa International Workshop. Epilepsia.","DOI":"10.1111\/epi.18696"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1111\/epi.18338","article-title":"Updated classification of epileptic seizures: Position paper of the International League Against Epilepsy","volume":"66","author":"Beniczky","year":"2025","journal-title":"Epilepsia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1111\/epi.17241","article-title":"International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions","volume":"63","author":"Specchio","year":"2022","journal-title":"Epilepsia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/epi4.13075","article-title":"Refining management strategies for Lennox-Gastaut syndrome: Updated algorithms and practical approaches","volume":"10","author":"Auvin","year":"2025","journal-title":"Epilepsia Open"},{"key":"ref_9","unstructured":"Amrutkar, C.V., and Lui, F. (2025). Lennox-Gastaut Syndrome. StatPearls, StatPearls Publishing LLC."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s13023-023-02626-4","article-title":"The burden of illness in Lennox-Gastaut syndrome: A systematic literature review","volume":"18","author":"Strzelczyk","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1007\/s13311-023-01397-x","article-title":"Lennox-Gastaut Syndrome: Current Treatments, Novel Therapeutics, and Future Directions","volume":"20","author":"Nelson","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1056\/NEJMoa1714631","article-title":"Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome","volume":"378","author":"Devinsky","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1111\/epi.18283","article-title":"Stereoelectroencephalographic exploration and surgical outcome in Lennox-Gastaut syndrome","volume":"66","author":"Cho","year":"2025","journal-title":"Epilepsia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107406","DOI":"10.1016\/j.eplepsyres.2024.107406","article-title":"A systematic review of electroencephalographic findings in Lennox-Gastaut syndrome","volume":"205","author":"Nizami","year":"2024","journal-title":"Epilepsy Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Na, J.H., and Lee, Y.M. (2024). Therapeutic outcome of patients with Lennox-Gastaut syndrome with mitochondrial respiratory chain complex I deficiency. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1305404"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"107287","DOI":"10.1016\/j.yebeh.2020.107287","article-title":"Nonseizure consequences of Dravet syndrome, KCNQ2-DEE, KCNB1-DEE, Lennox-Gastaut syndrome, ESES: A functional framework","volume":"111","author":"Berg","year":"2020","journal-title":"Epilepsy Behav."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"106813","DOI":"10.1016\/j.eplepsyres.2021.106813","article-title":"Long-term medical and social outcomes of patients with Lennox-Gastaut syndrome","volume":"178","author":"Bazrafshan","year":"2021","journal-title":"Epilepsy Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1093\/brain\/awaa371","article-title":"Developmental and epileptic encephalopathies: What we do and do not know","volume":"144","author":"Specchio","year":"2021","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5392","DOI":"10.1007\/s00415-024-12465-3","article-title":"Clinical features and underlying etiology of children with Lennox-Gastaut syndrome","volume":"271","author":"Zhou","year":"2024","journal-title":"J. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yang, J.O., Choi, M.H., Yoon, J.Y., Lee, J.J., Nam, S.O., Jun, S.Y., Kwon, H.H., Yun, S., Jeon, S.J., and Byeon, I. (2021). Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families. Front. Genet., 11, Erratum in Front. Genet. 2021, 12, 669107. https:\/\/doi.org\/10.3389\/fgene.2021.669107.","DOI":"10.3389\/fgene.2020.590924"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"fcab207","DOI":"10.1093\/braincomms\/fcab207","article-title":"Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox-Gastaut syndrome","volume":"3","author":"Qaiser","year":"2021","journal-title":"Brain Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1177\/15357597251321926","article-title":"Mobilizing a New Era in Lennox-Gastaut Syndrome Treatment and Prevention","volume":"25","author":"Warren","year":"2025","journal-title":"Epilepsy Curr."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Montebello, G., and Di Giovanni, G. (2025). Dysregulation of the Cannabinoid System in Childhood Epilepsy: From Mechanisms to Therapy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136234"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.5213\/inj.2142166.083","article-title":"Current Pharmacologic Strategies for Treatment of Intractable Epilepsy in Children","volume":"25","author":"Moon","year":"2021","journal-title":"Int. Neurourol. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1007\/s00415-024-12352-x","article-title":"Channelopathies in epilepsy: An overview of clinical presentations, pathogenic mechanisms, and therapeutic insights","volume":"271","author":"Ng","year":"2024","journal-title":"J. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Samanta, D. (2025). Precision Therapeutics in Lennox-Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy. Children, 12.","DOI":"10.3390\/children12040481"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature12439","article-title":"De novo mutations in epileptic encephalopathies","volume":"501","author":"Epi","year":"2013","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/jnc.15120","article-title":"STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies","volume":"157","author":"Abramov","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3134","DOI":"10.1111\/epi.17414","article-title":"Paroxysmal fast activity is a biomarker of treatment response in deep brain stimulation for Lennox-Gastaut syndrome","volume":"63","author":"Dalic","year":"2022","journal-title":"Epilepsia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/j.1528-1167.2010.02948.x","article-title":"EEG-fMRI reveals activation of brainstem and thalamus in patients with Lennox-Gastaut syndrome","volume":"52","author":"Siniatchkin","year":"2011","journal-title":"Epilepsia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"fcae161","DOI":"10.1093\/braincomms\/fcae161","article-title":"Targeting thalamocortical circuits for closed-loop stimulation in Lennox-Gastaut syndrome","volume":"6","author":"Warren","year":"2024","journal-title":"Brain Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"106094","DOI":"10.1016\/j.nbd.2023.106094","article-title":"Thalamocortical circuits in generalized epilepsy: Pathophysiologic mechanisms and therapeutic targets","volume":"181","author":"Lindquist","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1097\/WCO.0000000000001008","article-title":"Network dysfunction in pre and postsurgical epilepsy: Connectomics as a tool and not a destination","volume":"35","author":"Johnson","year":"2022","journal-title":"Curr. Opin. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/ana.27041","article-title":"Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D\/EE-SWAS)","volume":"96","author":"Viswanathan","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Medyanik, A.D., Anisimova, P.E., Kustova, A.O., Tarabykin, V.S., and Kondakova, E.V. (2025). Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies. Biomolecules, 15.","DOI":"10.3390\/biom15010133"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1177\/15357597251320142","article-title":"Merritt-Putnam Symposium | Developmental and Epileptic Encephalopathies-Current Concepts and Novel Approaches","volume":"25","author":"Scott","year":"2025","journal-title":"Epilepsy Curr."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"He, Q., Zhuang, J., Wen, Q., Li, Z., Wang, D., Sun, X., and Xie, Y. (2022). Epilepsy Combined With Multiple Gene Heterozygous Mutation. Front. Pediatr., 10.","DOI":"10.3389\/fped.2022.763642"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s40263-020-00784-8","article-title":"Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies","volume":"35","author":"Strzelczyk","year":"2021","journal-title":"CNS Drugs"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1111\/epi.17547","article-title":"Genes4Epilepsy: An epilepsy gene resource","volume":"64","author":"Oliver","year":"2023","journal-title":"Epilepsia"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Romero Mila, B., Liu, V.B., Smith, R.J., Hu, D.K., Benneian, N.A., Hussain, S.A., Steenari, M., Phillips, D., Adams, D., and Skora, C. (2025). EEG functional connectivity as a marker of evolution from infantile epileptic spasms syndrome to Lennox-Gastaut syndrome. Epilepsia.","DOI":"10.1111\/epi.70003"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107146","DOI":"10.1016\/j.yebeh.2020.107146","article-title":"Expert opinion: Proposed diagnostic and treatment algorithms for Lennox-Gastaut syndrome in adult patients","volume":"110","author":"Montouris","year":"2020","journal-title":"Epilepsy Behav."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.seizure.2023.06.017","article-title":"The genetic landscape of developmental and epileptic encephalopathy with spike-and-wave activation in sleep","volume":"110","author":"Freibauer","year":"2023","journal-title":"Seizure"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Borowicz-Reutt, K., Czernia, J., and Krawczyk, M. (2023). Genetic Background of Epilepsy and Antiepileptic Treatments. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216280"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1111\/epi.15612","article-title":"Recommendations for the use of structural magnetic resonance imaging in the care of patients with epilepsy: A consensus report from the International League Against Epilepsy Neuroimaging Task Force","volume":"60","author":"Bernasconi","year":"2019","journal-title":"Epilepsia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1111\/epi.17141","article-title":"Genetic testing for the epilepsies: A systematic review","volume":"63","author":"Sheidley","year":"2022","journal-title":"Epilepsia"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.braindev.2020.02.004","article-title":"Targeted gene panel sequencing in early infantile onset developmental and epileptic encephalopathy","volume":"42","author":"Na","year":"2020","journal-title":"Brain Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41436-018-0011-y","article-title":"Evaluating the pathogenic potential of genes with de novo variants in epileptic encephalopathies","volume":"21","author":"He","year":"2019","journal-title":"Genet. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s13041-018-0392-5","article-title":"Novel and de novo mutations in pediatric refractory epilepsy","volume":"11","author":"Liu","year":"2018","journal-title":"Mol. Brain"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Pippucci, T., Parmeggiani, A., Palombo, F., Maresca, A., Angius, A., Crisponi, L., Cucca, F., Liguori, R., Valentino, M.L., and Seri, M. (2013). A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082154"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1111\/dmcn.12976","article-title":"GABRB3 mutations: A new and emerging cause of early infantile epileptic encephalopathy","volume":"58","author":"Papandreou","year":"2016","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"112973","DOI":"10.1016\/j.expneurol.2019.112973","article-title":"A missense mutation in SLC6A1 associated with Lennox-Gastaut syndrome impairs GABA transporter 1 protein trafficking and function","volume":"320","author":"Cai","year":"2019","journal-title":"Exp. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1177\/0883073817696814","article-title":"Targeting the Mammalian Target of Rapamycin for Epileptic Encephalopathies and Malformations of Cortical Development","volume":"33","author":"Jeong","year":"2018","journal-title":"J. Child. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Zhao, T., Chen, F., Cao, B., Yang, L., Yin, J., Li, Y., and Feng, F. (2025). Case Report: Unraveling clinical heterogeneity in DEPDC5-related epilepsy: A genotype-phenotype correlation study in eight pediatric cases. Front. Neurosci., 19.","DOI":"10.3389\/fnins.2025.1595667"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.neuron.2018.05.039","article-title":"Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination","volume":"99","author":"Park","year":"2018","journal-title":"Neuron"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1089\/gtmb.2019.0177","article-title":"A Novel X-Linked Variant of IQSEC2 is Associated with Lennox-Gastaut Syndrome and Mild Intellectual Disability in Three Generations of a Korean Family","volume":"24","author":"Choi","year":"2020","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s10072-017-3188-y","article-title":"Lennox-Gastaut syndrome: A comprehensive review","volume":"39","year":"2018","journal-title":"Neurol. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s00439-017-1795-6","article-title":"Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability","volume":"136","author":"Bramswig","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e63975","DOI":"10.1002\/ajmg.a.63975","article-title":"De Novo Chromosomes 3q and 5q Chromothripsis Leads to a 5q14.3 Microdeletion Syndrome Presentation: Case Report and Review of the Literature","volume":"197","author":"Corriveau","year":"2025","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.seizure.2025.08.002","article-title":"Antiseizure medications in CDKL5 encephalopathy-systematic review","volume":"131","author":"Strzelczyk","year":"2025","journal-title":"Seizure"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1055\/s-0037-1601324","article-title":"Lennox-Gastaut Syndrome: A State of the Art Review","volume":"48","author":"Mastrangelo","year":"2017","journal-title":"Neuropediatrics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.ajhg.2017.08.013","article-title":"De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures","volume":"101","author":"Myers","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40478-020-01085-3","article-title":"Frequent SLC35A2 brain mosaicism in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)","volume":"9","author":"Bonduelle","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_63","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). Beta-Propeller Protein-Associated Neurodegeneration. GeneReviews\u00ae, University of Washington."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e116","DOI":"10.1111\/epi.12800","article-title":"A case of Lennox-Gastaut syndrome in a patient with FOXG1-related disorder","volume":"55","author":"Terrone","year":"2014","journal-title":"Epilepsia"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1515\/tnsci-2018-0029","article-title":"Novel Homozygous Mutation in the WWOX Gene Causes Seizures and Global Developmental Delay: Report and Review","volume":"9","author":"Ehaideb","year":"2018","journal-title":"Transl. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1002\/ana.25619","article-title":"The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures","volume":"86","author":"Burgess","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1080\/14656566.2025.2516630","article-title":"Current and emerging pharmacotherapies in Lennox-Gastaut syndrome","volume":"26","author":"Samanta","year":"2025","journal-title":"Expert. Opin. Pharmacother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"110261","DOI":"10.1016\/j.yebeh.2024.110261","article-title":"Antiseizure medications for Lennox-Gastaut Syndrome: Comprehensive review and proposed consensus treatment algorithm","volume":"164","author":"Samanta","year":"2025","journal-title":"Epilepsy Behav."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1080\/17425255.2025.2510302","article-title":"Drug-drug interaction between anti-seizure medications in Dravet syndrome and Lennox-Gastaut syndrome","volume":"21","author":"Roberti","year":"2025","journal-title":"Expert. Opin. Drug Metab. Toxicol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Samanta, D. (2025). Perampanel, Brivaracetam, Cenobamate, Stiripentol, and Ganaxolone in Lennox-Gastaut Syndrome: A Comprehensive Narrative Review. J. Clin. Med., 14.","DOI":"10.3390\/jcm14176302"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"101242","DOI":"10.1016\/j.spen.2025.101242","article-title":"Expanding the toolkit: An update on the evolution of new therapies for Lennox-Gastaut Syndrome","volume":"56","author":"Pong","year":"2025","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/epi4.12956","article-title":"Consensus panel recommendations for the optimization of EPIDIOLEX(R) treatment for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex","volume":"9","author":"Wechsler","year":"2024","journal-title":"Epilepsia Open"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Na, J.-H., and Lee, Y.-M. (2025). Pharmacological and Pharmacokinetic Profile of Cannabidiol in Human Epilepsy: A Review of Metabolism, Therapeutic Drug Monitoring, and Interactions with Antiseizure Medications. Biomolecules, 15.","DOI":"10.3390\/biom15121668"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Abbotts, K.S.S., Ewell, T.R., Butterklee, H.M., Bomar, M.C., Akagi, N., Dooley, G.P., and Bell, C. (2022). Cannabidiol and Cannabidiol Metabolites: Pharmacokinetics, Interaction with Food, and Influence on Liver Function. Nutrients, 14.","DOI":"10.3390\/nu14102152"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.seizure.2025.11.016","article-title":"Efficacy and safety of cenobamate in developmental and epileptic encephalopathies: A systematic review and meta-analysis","volume":"134","author":"Samanta","year":"2025","journal-title":"Seizure"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"110660","DOI":"10.1016\/j.yebeh.2025.110660","article-title":"Efficacy, safety and tolerability of adjunctive cenobamate in pediatric and adult patients with Lennox Gastaut Syndrome","volume":"172","author":"Pong","year":"2025","journal-title":"Epilepsy Behav."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Skrobas, U., Duda, P., Brylinski, L., Drozak, P., Pelczar, M., and Rejdak, K. (2022). Ketogenic Diets in the Management of Lennox-Gastaut Syndrome-Review of Literature. Nutrients, 14.","DOI":"10.3390\/nu14234977"},{"key":"ref_78","first-page":"CD001903","article-title":"Ketogenic diets for drug-resistant epilepsy","volume":"6","author":"Bresnahan","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Duda, P., Granat, M., Czuczwar, S.J., and Miziak, B. (2025). Non-Pharmacological Treatment Methods of Lennox-Gastaut Syndrome-Review of the Literature. Biomedicines, 13.","DOI":"10.3390\/biomedicines13092247"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"17562864221108012","DOI":"10.1177\/17562864221108012","article-title":"Treatment strategies for Lennox-Gastaut syndrome: Outcomes of multimodal treatment approaches","volume":"15","author":"Na","year":"2022","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Na, J.H., Lee, H., and Lee, Y.M. (2025). Clinical Efficacy and Safety of the Ketogenic Diet in Patients with Genetic Confirmation of Drug-Resistant Epilepsy. Nutrients, 17.","DOI":"10.3390\/nu17060979"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"110272","DOI":"10.1016\/j.yebeh.2025.110272","article-title":"Cognitive and behavioral impact of antiseizure medications, neuromodulation, ketogenic diet, and surgery in Lennox-Gastaut syndrome: A comprehensive review","volume":"164","author":"Samanta","year":"2025","journal-title":"Epilepsy Behav."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"107499","DOI":"10.1016\/j.eplepsyres.2024.107499","article-title":"Neuromodulation Strategies in Lennox-Gastaut Syndrome: Practical Clinical Guidance from the Pediatric Epilepsy Research Consortium","volume":"210","author":"Samanta","year":"2025","journal-title":"Epilepsy Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.neurom.2022.06.005","article-title":"Callosotomy vs Vagus Nerve Stimulation in the Treatment of Lennox-Gastaut Syndrome: A Systematic Review With Meta-Analysis","volume":"26","year":"2023","journal-title":"Neuromodulation"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1111\/epi.18289","article-title":"Vagus nerve stimulation in Lennox-Gastaut syndrome: Twenty-four-month data and experience from the CORE-VNS study","volume":"66","author":"Lyons","year":"2025","journal-title":"Epilepsia"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e00308","DOI":"10.1016\/j.neurot.2023.e00308","article-title":"Neurostimulation treatments for epilepsy: Deep brain stimulation, responsive neurostimulation and vagus nerve stimulation","volume":"21","author":"Gouveia","year":"2024","journal-title":"Neurotherapeutics"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Al-Ramadhani, R., Hect, J.L., and Abel, T.J. (2024). The changing landscape of palliative epilepsy surgery for Lennox Gastaut Syndrome. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1380423"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"CASE25478","DOI":"10.3171\/CASE25478","article-title":"Optimal Stimulation of the Thalamic Centromedian Nucleus in Children with Lennox\u2013Gastaut Syndrome: Patient Series","volume":"10","author":"Warren","year":"2025","journal-title":"J. Neurosurg. Case Lessons"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"101235","DOI":"10.1016\/j.spen.2025.101235","article-title":"Surgical management of Lennox-Gastaut syndrome: A focused update on resective surgery and corpus callosotomy","volume":"56","author":"Hagen","year":"2025","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e20180449","DOI":"10.1542\/peds.2018-0449","article-title":"Long-term Outcome of Resective Epilepsy Surgery in Patients With Lennox-Gastaut Syndrome","volume":"142","author":"Kang","year":"2018","journal-title":"Pediatrics"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.1111\/epi.17796","article-title":"Added value of corpus callosotomy following vagus nerve stimulation in children with Lennox-Gastaut syndrome: A multicenter, multinational study","volume":"64","author":"Roth","year":"2023","journal-title":"Epilepsia"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Lam, S., Rosenman, M., Dixon-Salazar, T., Knupp, K.G., Thio, L.L., Abel, T.J., Welch, W.P., Reed, L., Randle, S.C., and Garcia-Sosa, R. (2025). Comparative effectiveness of epilepsy surgery versus additional anti-seizure medications for Lennox-Gastaut syndrome: Study protocol for a multicenter, mixed-methods study. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1569551"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.pediatrneurol.2025.04.010","article-title":"Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies","volume":"168","author":"Samanta","year":"2025","journal-title":"Pediatr. Neurol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"110472","DOI":"10.1016\/j.yebeh.2025.110472","article-title":"Seizure-type-specific treatment responses in Lennox-Gastaut Syndrome: A comprehensive review of pharmacological, neuromodulatory, dietary, and surgical therapies","volume":"170","author":"Samanta","year":"2025","journal-title":"Epilepsy Behav."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4324","DOI":"10.1111\/epi.18544","article-title":"Comparative efficacy of neuromodulation therapies in Lennox-Gastaut syndrome: A systematic review and meta-analysis of vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation","volume":"66","author":"Samanta","year":"2025","journal-title":"Epilepsia"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1002\/epi4.70144","article-title":"Current practices and trends in surgical decision-making for children with Lennox-Gastaut syndrome: A cross-sectional survey by the Pediatric Epilepsy Research Consortium","volume":"10","author":"Chiu","year":"2025","journal-title":"Epilepsia Open"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1111\/epi.17618","article-title":"Seizure-free days as a novel outcome in patients with Lennox-Gastaut syndrome: Post hoc analysis of patients receiving cannabidiol in two randomized controlled trials","volume":"64","author":"Auvin","year":"2023","journal-title":"Epilepsia"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.seizure.2025.12.004","article-title":"History of lennox-gastaut syndrome: Sixty years of advancements in therapeutic practices","volume":"134","author":"Gelisse","year":"2025","journal-title":"Seizure"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Zhu, Z., Zhang, Z., Xiao, W., Wang, C., and Liang, R. (2025). Efficacy and safety of pharmacological and non-pharmacological therapies in Lennox-Gastaut syndrome: A systematic review and network meta-analysis. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1522543"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Zhang, L., Jiang, N., and Wang, C. (2025). Efficacy, safety, and tolerability of soticlestat (TAK-935) as adjunctive therapy in pediatric patients with dravet syndrome and Lennox-Gastaut syndrome: A meta-analysis of 3 randomized controlled trials. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1586098"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1382\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T08:21:41Z","timestamp":1769761301000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":100,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27031382"],"URL":"https:\/\/doi.org\/10.3390\/ijms27031382","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,30]]}}}