Vagus Nerve Stimulation in Refractory Epilepsy: Effects on Pro- and Anti-Inflammatory Cytokines in Peripheral Blood

Abstract

Objective: The vagus nerve has important immunological functions that may be relevant for its anticonvulsive action. We postulate that this anticonvulsive action is activated by a shift in the immune system resulting in a reduction of neurotoxic and an increase of neuroprotective tryptophan metabolites. Methods: Eleven patients with refractory epilepsy and 11 controls matched for age and gender were included in this study. The primary outcome measure was a 50% seizure reduction. Other variables were pro-inflammatory cytokines IL-6 and TNF-α, anti-inflammatory cytokine IL-10, cortisol, and the tryptophan metabolites 3-hydroxykynurenine (3-OH-KYN), kynurenic acid (KYNA), kynurenine, serotonin (5-HT) and 5-hydroxyindol acetic acid (5-HIAA). Blood samples were scheduled during baseline, and in week 28 of add-on treatment. Results: IL-6 levels were higher in the responders than in the control group, and decreased after vagus nerve stimulation (VNS), whereas IL-10 was low and increased after VNS. In nonresponders, VNS resulted in an increase of IL-6 plasma levels and in a decrease of IL-10. Cortisol concentrations are higher in the epilepsy group than in the control group. After VNS, these concentrations decreased. The concentrations of the tryptophan metabolites were lower in the epilepsy group than in the control group. The KYNA ratios are defined as the ratio of neuroprotective KYNA versus neurotoxic 3-OH-KYN and KYNA versus neurotoxic kynurenine: these ratios were lower in epilepsy patients than in controls, and they both moderately increased after VNS. Conclusion: The outcome of this preliminary study indicates that VNS causes a rebalancing of the immune system. This results in: (1) a reduction of neurotoxic and an increase of neuroprotective kynurenine metabolites and (2) in the normalization of cortisol levels.