A tiered decisional framework for genetic epileptic syndromes with or without encephalopathies: from standard care to investigational strategies

INTRODUCTION: Developmental and epileptic encephalopathies (DEEs), epilepsy-associated neurodevelopmental disorders (NDD), and epileptic syndromes with or without encephalopathy (ES±E) share overlapping genetic architectures where both etiology and seizures impair development. Despite genomic advances, many patients remain pharmacoresistant, and molecular diagnoses seldom translate into targeted treatments. This review connects mechanistic categories to precision therapies, providing a clinical decision-making framework. AREA COVERED: We outline pharmacological and investigational strategies-including antiseizure medications, dietary therapies, and disease-modifying approaches-across major mechanistic categories, including ion channel/receptor dysfunctions, synaptic/signaling defects, metabolic disorders, and neurodegenerative storage diseases. For each condition, potential therapeutic options are interpreted within a hierarchical precision-based framework, ranging from empiric seizure-type-driven treatments to gene-specific molecular interventions. A narrative literature search was conducted across major databases for English-language articles on DEEs, NDD, ES±E, and precision therapeutic approaches published up to early 2026. We categorized potential therapeutic interventions into five hierarchical tiers based on etiological specificity and evidence. Classification, achieved by expert consensus, distinguishes established (Tiers 1-3) from emerging strategies (Tiers 4-5). EXPERT OPINION: Progress depends on early etiological diagnosis and timely, mechanism-informed therapy. Future advances require expanded genomic testing, natural history studies, mechanism-based biomarkers, and innovative trial designs tailored to complex pediatric populations.