Ketogenic diet therapy in developmental and epileptic encephalopathies: toward syndrome- and gene-informed precision therapy

Background Developmental and epileptic encephalopathies (DEEs) are severe, early-onset, frequently drug-resistant epilepsies in which recurrent seizures and epileptiform activity contribute to cognitive impairment beyond the underlying etiology. Ketogenic dietary therapies (KDTs) exert broad, multimodal antiseizure and neuroprotective effects and occupy a distinct position among nonpharmacologic treatments for DEEs. Objective To synthesize the evidence for KDT across the principal electroclinical DEE syndromes, an expanding spectrum of gene-specific DEEs, and acute presentations such as febrile infection-related epilepsy syndrome (FIRES) and new-onset refractory status epilepticus (NORSE), with attention to outcome measures, mechanisms, adverse effects, and monitoring. Methods A narrative review of the literature on the classic ketogenic diet (KD), modified Atkins diet, medium-chain triglyceride diet, and low-glycemic-index treatment in DEEs, drawing on randomized controlled trials, cohort studies, systematic reviews, and meta-analyses. Results KDT has the strongest and most methodologically rigorous evidence base in infantile epileptic spasms syndrome, including comparative-effectiveness data vs. hormonal therapy, followed by strong consensus supporting early use in epilepsy with myoclonic-atonic seizures. Meaningful benefit has also been reported in Dravet syndrome and, to a somewhat lesser extent, Lennox–Gastaut syndrome. Responses are more variable in early-infantile developmental and epileptic encephalopathy, epilepsy of infancy with migrating focal seizures, developmental and epileptic encephalopathy with spike-wave activation in sleep, and hemiconvulsion–hemiplegia–epilepsy syndrome, with tolerability and long-term adherence often declining over time. In FIRES/NORSE, KDT may serve as an acute anti-inflammatory treatment for super-refractory status epilepticus. Gene-specific responses vary substantially, with the most favorable outcomes observed in transporter-related disorders, followed by conditions involving other membrane-associated proteins, including ion channels and neurotransmitter receptors, whereas disorders affecting cellular structural integrity or homeostatic regulation appear less responsive. Conclusions KDT has an increasingly well-supported, syndrome- and endpoint-specific role across DEEs. Future research should prioritize comparative-effectiveness trials, standardized outcome measures, predictors of response, better-tolerated formulations, and equitable access to dietary therapy.