Exploratory Dietary Approaches for Drug-Resistant Epilepsy Beyond Standard Ketogenic Diet and Fish Oil: A Systematic...

Background: Standard ketogenic diets (KD) and fish oil have established efficacy for drug-resistant epilepsy (DRE), but adherence and variability remain challenging. Objective: The objective of this study is to provide the first systematic evaluation of clinical evidence for emerging dietary interventions for epilepsy-specifically those other than standard KD and fish oil-and to rigorously evaluate their effectiveness and certainty of evidence to address the current gap in dietary management literature. Unlike prior reviews focused on standard KD or carbohydrate-modified versions, this study is the first to synthesize evidence for "non-standard" interventions-including olive oil-based KDs, probiotics, and restrictive gluten/glutamate-free diets-which are typically excluded from traditional dietary meta-analyses. Methods: Following PRISMA 2020 guidelines, we searched PubMed, Web of Science, Cochrane, and Google Scholar up to March 2025. Randomized Controlled Trials (RCTs) and Non-Randomized Studies of Interventions (NRSIs) were included, with quality assessed using RoB 2 and ROBINS-I tools. Results: Eight studies (total n = 675) were identified, comprising 2 RCTs and 6 NRSIs. These included olive oil-based KDs (n = 1), probiotic/synbiotic supplementation (n = 2), medium-chain triglyceride (MCT) additions (n = 2), and gluten-free (n = 1) or glutamate-free (n = 1) diets. Evidence quality is generally low, with 75% of studies at high risk of bias. Preliminary responder rates reached 83.1% in uncontrolled olive oil-based KD studies, whereas the only RCT evaluating a low-glutamate diet showed no significant seizure reduction (p = 0.57). Conclusion: Evidence for emerging dietary interventions beyond standard KD is nascent and of low certainty. Interpretation: While preliminary signals exist for olive oil-based KDs and probiotics, current data are insufficient for clinical recommendation; this review identifies these as promising exploratory targets requiring validation through rigorous, blinded RCTs.