Unraveling Lennox-Gastaut Syndrome: From Molecular Pathogenesis to Precision Diagnosis and Targeted Therapy Evolving Therapeutic Strategies

Abstract

Lennox-Gastaut 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-wave 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.