Exploring metabolic biomarkers and pathways in pharmacoresistant epilepsy: A systematic review

Drug-resistant epilepsy (DRE) is characterized by the failure to attain sustained seizure freedom despite adequate trials of two antiseizure medication (ASM) regimens that are well tolerated and appropriately chosen and administered, either as monotherapies or in combination. Despite being a cornerstone of epilepsy treatment, ASMs are ineffective in achieving seizure remission in nearly one-third of patients, who are consequently classified as having DRE. This systematic review aims to determine potential metabolic biomarkers and pathways linked to DRE, which could inform personalized treatment and optimize therapeutic outcomes. A comprehensive search of databases, namely Medline, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) based on predefined inclusion and exclusion criteria yielded 29 eligible studies after full-text screening. The risk of bias from these studies was reviewed using the Office of Health Assessment and Translation (OHAT) risk of bias rating tool. Key information, including study groups, sample size, model types, and main findings were tabulated. Several metabolites were identified, including amino acids (glycine, glutamate, isoleucine), organic acids (lactate), and glucose, which may serve as potential biomarkers for DRE. MetaboAnalyst 6.0 pathway analysis identified the alanine, aspartate and glutamate metabolism, as well as phenylalanine, tyrosine and tryptophan biosynthesis pathways, emerged with significant impact score (≥0.5, p < 0.05). The findings highlight the promising role of these metabolites and pathways as predictive biomarkers for DRE and potential therapeutic targets for novel drug development.