Plasma Homocysteine Dysregulation in Epilepsy: Antiepileptic Drug Exposure, B-Vitamin Metabolism, and Vascular Risk Across the Lifespan

Abstract

Homocysteine has emerged over several decades as a biologically potent sulfur-containing amino acid whose accumulation in plasma reflects a convergence of nutritional status, genetic susceptibility, and pharmacological exposure, particularly in individuals receiving long-term antiepileptic drug therapy. Early clinical observations linking anticonvulsant use with alterations in folate and vitamin B12 metabolism gradually evolved into a more complex understanding of hyperhomocysteinemia as a multifactorial metabolic disturbance with implications extending far beyond epilepsy control alone. Drawing exclusively upon the existing body of literature referenced in this article, the present study develops an integrative, theory-driven analysis of homocysteine dysregulation in epileptic populations, situating antiepileptic drugs within broader biochemical, genetic, and vascular frameworks.

The abstract synthesis foregrounds three interlocking dimensions: first, the biochemical pathways governing homocysteine metabolism and the essential roles of vitamins B6, B12, and folate; second, the pharmacodynamic and pharmacokinetic mechanisms through which classic and newer antiepileptic drugs disrupt these pathways; and third, the clinical consequences of sustained hyperhomocysteinemia, particularly its association with vascular disease, thrombosis, and neurocognitive outcomes. By integrating early nutritional studies, molecular genetic investigations of methylenetetrahydrofolate reductase polymorphisms, and epidemiological analyses of vascular risk, the article positions epilepsy not merely as a neurological disorder but as a chronic systemic condition shaped by long-term metabolic perturbations.

Methodologically, the study employs an interpretive synthesis approach, systematically contextualizing findings from observational studies, mechanistic investigations, and clinical cohorts without recourse to new empirical data. This approach allows for a nuanced interpretation of convergent and divergent findings, highlighting both consensus and unresolved debates within the field. Particular emphasis is placed on pediatric and adult populations treated with enzyme-inducing antiepileptic drugs, whose vulnerability to B-vitamin depletion and homocysteine elevation underscores important clinical and ethical considerations.

The findings suggest that hyperhomocysteinemia in epilepsy represents a predictable yet frequently under-recognized consequence of chronic antiepileptic therapy, modulated by nutritional intake, genetic variation, and drug-specific metabolic effects. The discussion extends these findings into theoretical and clinical domains, arguing for a reconceptualization of epilepsy management that incorporates metabolic monitoring and preventative strategies against long-term vascular complications. In doing so, the article contributes a comprehensive, interdisciplinary perspective to ongoing scholarly discourse and delineates clear avenues for future research and clinical practice grounded firmly in the existing literature.