Beyond seizures: the hidden burden of developmental epileptic encephalopathies

Abstract

Developmental and epileptic encephalopathies (DEEs) are a group of severe childhood-onset disorders characterized by drug-resistant epilepsy and a broad spectrum of neurodevelopmental, behavioral, psychiatric, and systemic manifestations. Although seizure control has traditionally been the primary therapeutic goal, growing evidence indicates that non-seizure manifestations often represent the main determinants of long-term disability, quality of life, and caregiver burden. This review highlights the hidden burden of DEEs by focusing on three paradigmatic syndromes: Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC). DS and LGS represent prototypical DEEs, whereas TSC is a multisystem genetic disorder that is frequently, although not invariably, associated with early-onset drug-resistant epilepsy and DEE-like neurodevelopmental trajectories. Across these conditions, the severity and progression of clinical manifestations are influenced by complex interactions between genetic, structural, developmental, and epileptic mechanisms, supporting the concept that epilepsy and associated manifestations represent interconnected features of a broader neurodevelopmental disorder. The review also emphasizes the substantial psychosocial, physical, and economic burden experienced by families and caregivers, which often exceeds the impact of seizures alone. Current management strategies should therefore extend beyond seizure reduction and adopt a multidisciplinary, life-course approach integrating early genetic diagnosis, syndrome-specific surveillance, developmental interventions, rehabilitation, behavioral support, and coordinated multidisciplinary care. Future research should prioritize disease-modifying therapies and personalized strategies aimed at addressing both epileptic and non-epileptic manifestations, ultimately improving functional outcomes and quality of life for individuals with DEEs and their families.