From clinical practice to mechanistic insights in ketogenic diets for epilepsy

Ketogenic diet therapies, including the classic ketogenic diet, modified Atkins diet, and low glycaemic index treatment, have shown effectiveness in controlling seizures, in part by shifting metabolism from glucose to ketone bodies. They improve mitochondrial function, reduce neuroinflammation, and modulate neurotransmitters. Ketogenic diet therapies also affect the gut microbiome, potentially impacting neurotransmitter balance in ways that contribute to seizure control. A classic ketogenic diet is effective yet restrictive, whereas the modified Atkins diet and low glycaemic index treatment offer greater flexibility, tolerability, and ease of implementation, particularly in resource-limited settings. Cochrane reviews and meta-analyses rank the certainty of randomised controlled trial evidence for ketogenic diet therapies as limited. Early initiation of ketogenic diet therapies, particularly in children or patients with metabolic epilepsies, improves seizure outcomes, potentially preventing further mitochondrial and neuronal damage and reducing the risk of developing resistance to antiseizure medications. Research using rigorous, large-scale comparative effectiveness study designs that accounts for differences in age, epilepsy type, dietary therapy modality, sociodemographic background, care delivery contexts, and that minimises performance and observation bias is needed to resolve remaining uncertainties regarding the efficacy and real-world challenges of ketogenic diet therapies in epilepsy.