Impact of medium-chain triglyceride with and without ketogenic diet in the management of drug-resistant epilepsy: a systematic review

Background: Ketogenic dietary therapies, including the medium-chain triglyceride ketogenic diet (MCT KD), are established non-pharmacological treatments for drug-resistant epilepsy (DRE). MCTs may also exert antiseizure effects partly independent of ketosis. This review evaluated the effectiveness, tolerability, safety, and adherence of MCT-based interventions used with or without a ketogenic diet. Methods: PubMed, Web of Science, Scopus, and the Cochrane Library were searched from inception to April 2025. Randomized controlled trials (RCTs) and cohort studies in patients with DRE were included. Methodological quality was assessed using Joanna Briggs Institute tools and certainty of evidence using GRADE. Owing to substantial heterogeneity, findings were synthesized using a structured Synthesis Without Meta-analysis approach. Results: Twelve studies were included: three RCTs and nine observational studies. One paediatric RCT found no clear difference in seizure outcomes between MCT KD and the classical ketogenic diet (CKD), despite higher ketone levels with CKD; however, equivalence was not established. A small paediatric crossover trial suggested possible benefit from a C10-enriched KD, while a small adult RCT indicated a possible therapeutic signal from MCT supplementation. Observational studies generally reported improvement from baseline but were limited by methodological weaknesses. Gastrointestinal adverse events were common but often manageable. Certainty of evidence was low to very low. Conclusion: MCT-based interventions may offer a flexible option for DRE. Low-certainty evidence suggests that MCT KD may achieve seizure outcomes similar to CKD, but equivalence remains unproven. Evidence for MCT supplementation without a strict KD is very uncertain.