The Saga of Late-Onset Unexplained Epilepsy

Late-onset epilepsy is increasingly recognized as a major and growing neurological condition in older adults, driven by population aging and rising incidence rates, yet approximately one-third of cases remain unexplained (late-onset unexplained epilepsy, LoUE). LoUE is diagnostically challenging, as seizures are often subtle and nonconvulsive, routine EEG has limited sensitivity. Converging evidence from animal models and clinical studies suggests that aging-related reductions in seizure threshold, vascular dysfunction, neurodegenerative processes, and immune dysregulation ("inflammaging") all contribute to epileptogenesis, often through interacting and cumulative pathways. Clinically, while many patients respond to antiseizure medications, a subset experience refractory disease. Importantly, LoUE should not be viewed as a single entity but rather as a heterogeneous syndrome arising within diverse biological contexts shaped by lifetime exposures, comorbidities, and underlying pathology. Advancing the field will require prospective, multimodal studies integrating neuroimaging, fluid biomarkers, and detailed phenotyping to define mechanistic subtypes and enable a transition toward precision medicine approaches aimed at reducing the burden of seizures and their downstream consequences in older adults.