Biomarker discovery in Lennox-Gastaut syndrome: Advances and challenges in electrophysiological, genetic, neuroimaging, and neuroinflammatory approaches

In Lennox-Gastaut Syndrome (LGS), a severe developmental and epileptic encephalopathy, the absence of validated biomarkers limits our ability to detect disease early, predict outcomes, and guide treatment strategies. This review synthesizes advances in biomarker research spanning electrophysiological, genetic, neuroimaging, and neuroinflammatory domains. Interictal electroencephalography (EEG) patterns such as slow spike-wave (SSW) and generalized paroxysmal fast activity (GPFA) remain diagnostic hallmarks and show potential as markers of disease progression and treatment response, though further standardization and validation are needed. Genetic testing reveals pathogenic variants in a substantial subset of patients, creating opportunities for precision medicine guided by disease mechanisms. Neuroimaging approaches, including diffusion magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), and EEG-functional magnetic resonance imaging (EEG-fMRI), demonstrate widespread network abnormalities that may provide prognostic or treatment-relevant insights. Circulating molecular and inflammatory markers, such as microRNAs and cytokines, also show promise but remain in early stages of investigation. Overall, the development of reliable biomarkers in LGS will require multimodal integration, multicenter validation, and the application of artificial intelligence to advance toward predictive, preventive, and personalized care.