Reply: The neurological significance of folate deficiency in women with epilepsy

We appreciate Reynolds’ interest1 in our work regarding folate deficiency in women with epilepsy.2 We systematically synthesized evidence on its prevalence, causes, and clinical impact, and evaluated supplementation patterns and barriers to its use. We also identified critical evidence gaps and proposed interventions and research priorities to address ongoing clinical disparities. Reynolds argues that only a small number of the studies we reviewed reported folate biomarkers, and that many were older studies. This is a point we highlighted: studies of folate biomarkers in women with epilepsy are limited, reflecting the current state of the evidence rather than methodological shortcomings. Several studies over the past 60 years have reported a significant reduction of folate levels in people with epilepsy, particularly among those treated with antiseizure medications (ASMs). These studies vary widely in their methodologies, reported biomarkers, applied cut-offs, and age and sex. To reduce heterogeneity, we focused on women of reproductive age. Such studies constantly reported a high prevalence of folate deficiency among women with epilepsy, reaching 80% to 100% in some reports. However, the use of varied methodologies and reference ranges made data aggregation challenging. Additionally, general population surveys, including people with epilepsy, reflect similar trends with deficiency rates between 47% and 100% in countries lacking robust fortification policies.2 Given the additional risk conferred by ASM use and the consistently higher folate deficiency in people with epilepsy, it is reasonable to infer that folate deficiency is also more common among women with epilepsy than in the general population. However, we agree that folate deficiency in women with epilepsy cannot be quantified due to the scarcity of data and lack of population-level biomarker studies, as we highlighted. This is also a research gap requiring urgent attention.2 We have also suggested that implementing a standardized folate deficiency cut-off threshold for women with epilepsy is vital to estimating the prevalence of folate deficiency in this population.