Immunological markers of drug resistant epilepsy and its response to immunomodulatory therapy with ACTH in children

Introduction:
Drug-resistant epilepsy in infancy and childhood is a devastating condition, frequently associated with neuropsychiatric comorbidities. West syndrome is one of the most severe epilepsy syndromes. Adrenocorticotropic hormone (ACTH) treatment is recommended in such cases, but its mechanism of action is still unknown. We prospectively observed levels of selected cytokines in order to identify biomarkers of response to ACTH and the potential mechanism of its antiseizure effect.

Material and methods:
Fifty-three infants and young children with pharmacoresistant epilepsy receiving ACTH_1-24 were included. There were 2 control groups – children with epilepsy responding to the first medication and children with no history of epilepsy. Blood concentrations of IL-1b, IL-1Ra, IL-6, IL-8, IL-10, TNF-a, IFN-g, MCP-1 and MIP-1a were analyzed at three time points: T0 (before ACTH), T1 (after intensive ACTH treatment) and at T2 (at the end of ACTH withdrawal). The results were correlated with the response to treatment, dose of ACTH and concomitant medications.

Results:
We found statistically significantly higher concentrations of IL-1, IL-8 and MIP-1a at baseline (T0) in the study group compared to the control groups. ACTH significantly lowered levels of IL-6, IFN-g and MCP from time T0 to T1. This effect was short lasting and no significant changes in cytokine levels were found between T2 and T0. We did not find any differences in immunological markers between the responders and non-responders to ACTH. Our research did not allow us to identify any reliable immunological marker of response to ACTH treatment. We did not observe a positive effect of higher ACTH doses on the response rate in the patients. Our study showed significantly lower concentrations of IL-10 and IFN in the group of patients receiving levetiracetam. The concentration of TNF was higher and the concentration of MIP was lower in the group receiving valproic acid.

Conclusions:
Our study indicates that increased levels of IL-1, IL-8 and MIP-1a are associated with drug-resistant epilepsy in infants and young children and might be considered immunological markers. IL-6, IFN-g and MCP-1 take part in the effect of ACTH. Immunological mechanisms seem also to be involved in the mechanism of action of classical antiseizure drugs.