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

Hong Tang

doi:10.1016/j.bbih.2026.101238

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

Brain Behav Immun Health. 2026 Apr 12:54:101238. doi: 10.1016/j.bbih.2026.101238. eCollection 2026 Jul.

Author

Hong Tang¹

Affiliation

¹ Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Abstract

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: A cohort of 74 patients with DRE (46 with partial seizures (PS) and 28 with ISE) and 25 healthy controls was enrolled. PD-1 levels in CSF and plasma were quantified by flow cytometry and ELISA. In a VPA-treatment sub-study of 25 ISE patients, serial samples were analyzed for PD-1⁺CD4⁺CD25^high 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: Significantly elevated PD-1 levels were observed in both plasma and CSF of epilepsy patients compared to controls, with the highest levels in the ISE subgroup. IL-10 and IL-6 levels were also elevated in intractable epilepsy (IE) patients compared to controls. Critically, clinical improvement was associated with a reduction in PD-1⁺ 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.

Keywords: Drug-refractory epilepsy; IL-10; IL-6; PD-1; Status epilepticus; T regulatory cells; Valproic acid.