Abstract
This review summarizes content presented at the Pediatric State of the Art Symposium held during the American Epilepsy Society's annual meeting in December 2024. The symposium focused on Lennox-Gastaut syndrome (LGS), a severe developmental and epileptic encephalopathy that emerges in childhood. Despite its diverse etiologies, LGS is defined by a convergent constellation of electroclinical features: multiple seizure types including tonic seizures, slow spike-wave and generalized paroxysmal fast activity on EEG, and intellectual disability. LGS is almost always refractory to available therapies and accounts for substantial costs—in healthcare spending and in quality of life for affected individuals, their families, and caregivers. The symposium highlighted recent breakthroughs in research, clinical care, and outcome measurement that have positioned the clinical, scientific, and patient advocacy communities to usher in a new, more hopeful era of treatment and prevention.
Excerpts
How might preclinical models inform our understanding of LGS pathogenesis and treatment? Promising examples include the recent discovery that increased myelin plasticity exacerbates epilepsy progression in an SCN8A Scn8a+/- mouse model of generalized epilepsy, and that this epilepsy progression can be prevented by suppressing activity-dependent myelination. In zebrafish, high-throughput drug screens in models of Dravet syndrome identified Clemizole, a modifier of serotonin signaling, with potent anti-seizure effects; this has led to ongoing human trials for Clemizole as an adjunctive treatment for Dravet syndrome and LGS (ClinicalTrials.gov IDs: NCT04462770, NCT05066217). Recent studies in which other genes, including some linked to LGS, are engineered into zebrafish have demonstrated their utility as epilepsy models...
Addressing the Under-Utilization of Surgery for LGS
Surgery can be a highly effective treatment for medically refractory epilepsy, but there is increasing recognition that it is underutilized and often delayed in LGS, particularly in those who carry etiologies traditionally perceived as surgically non-remediable (e.g., non-structural genetic causes). In published studies of LGS, the lag time between seizure onset and surgery can be 20 years or more, often after numerous ASM attempts. This contrasts with ILAE guidelines stating that referral for surgical evaluation should occur as soon as drug resistance is ascertained, defined as the failure of adequate trials of two tolerated and appropriately chosen ASMs.
Conclusions
LGS is regularly described as “catastrophic” or “devastating.” While these terms capture the real and profound challenges faced by individuals and caregivers, they risk overshadowing the substantial progress made in understanding and managing LGS. This symposium highlighted recent advances across eight key areas, including the conceptualization of LGS as a secondary network epilepsy, the innovative use of electronic medical data to perform natural history studies and identify gaps in treatment coverage, and the development of preclinical models to explore pathogenesis and treatment. It also reviewed improvements in evidence-based treatment strategies, spanning pharmacotherapies, neuromodulation, surgery, and preventive approaches, alongside a growing emphasis on non-seizure outcomes and tailored assessment tools to measure meaningful, incremental progress. Together, these efforts mark a turning point toward more comprehensive and patient- and caregiver-centered care.
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