Vagus nerve stimulation: anti-inflammatory effects in epilepsy.

Abstract

Introduction: Vagus Nerve Stimulation (VNS) is an established standard of care for drug-resistant epilepsy; however, the biological mechanisms underlying its cumulative therapeutic effect remain incompletely understood. This study aims to evaluate the monitoring value of neuroinflammation and neurodegeneration biomarkers to objectify the therapeutic response.

Methods: In this prospective longitudinal study, we evaluated 40 pediatric patients (20 receiving active VNS therapy and 20 age-matched controls). Plasma levels of UCHL-1, HMGB1, and NSE were investigated as potential indicators of blood-brain barrier status, neuroinflammation, and metabolic stress, respectively. Measurements were performed at baseline and after 3, 6, and 12 months of treatment. Clinical efficacy was defined by the reduction in seizure frequency.

Results: The primary focus of the analysis was on the active VNS therapy group, where median seizure frequency decreased by 44.4% (p < 0.001) by month 12. For comparison, the clinical profile and biomarker levels in the control cohort did not change significantly throughout the year (all p > 0.05), confirming the specificity of neurostimulation effects. In the active group, biomarker profiling revealed a temporal dissociation in the biological response. UCH-L1 levels demonstrated a significant decrease by month 6 (p = 0.009), potentially reflecting an early functional stabilization of the blood-brain barrier. In contrast, HMGB1 concentrations showed a significant reduction only by month 12 (p < 0.001), which strongly correlated with clinical improvement (r = 0.63). Notably, NSE levels exhibited no significant longitudinal changes during the observation period.

Conclusion: VNS efficacy appears to be associated with a complex, multi-phasic biological response. The temporal dynamics of peripheral biomarkers may reflect a potential early stabilization of the blood-brain barrier, followed by delayed systemic immunomodulation. While blood-based analysis precludes direct conclusions regarding central neuroinflammation, the delayed reduction of circulating inflammatory signals points to a systemic anti-inflammatory effect that likely contributes to the cumulative therapeutic benefits. Thus, dynamic assessment of these accessible neuroimmune proteins provides an objective systemic correlate of clinical improvement. This biomarker panel may serve as a valuable supportive tool for monitoring VNS therapeutic response and guiding personalized neuromodulation parameters.