Exploring the role of PD-1 as a marker in drug-refractory epilepsy and its potential indication for valproic acid treatment

Background: The immune checkpoint pathway PD-1/PD-L, known for its role in immunosuppression via regulatory T cells (Tregs) and inflammatory signaling, is implicated in the neuroinflammation of drug-refractory epilepsy (DRE). Given the emerging importance of immune dysregulation in epilepsy, identifying immune-related biomarkers may improve diagnosis and guide treatment strategies. Objective: This study aimed to evaluate the potential of PD-1 as a diagnostic biomarker in the cerebrospinal fluid (CSF) and plasma and to investigate whether the therapeutic effect of valproic acid (VPA) in intractable status epilepticus (ISE) is mediated through immunomodulation. Methods: Tregs and cytokine (IL-10/IL-6) levels at baseline (d0) and after 48 h (d3). VPA concentrations were determined by LC-MS/MS. Results: Tregs at d3, whereas VPA concentrations did not correlate with treatment response. These findings reveal a compartmentalized immune response, with peripheral immunosuppression and localized CNS immune activation in IE. Conclusion: These findings identify PD-1 as a promising immune-inflammatory biomarker for DRE and its severe forms. Moreover, they suggest that the efficacy of VPA in ISE is mediated through the modulation of the PD-1 pathway and related cytokines, rather than a direct concentration-dependent pharmacological effect.