10-kHz High-Frequency Spinal Cord Stimulation Significantly Reduces Proinflammatory Cytokines and Distinct Populations of T Lymphocytes in Patients With Persistent Spinal Pain Syndrome Type 2.

Abstract

Objectives: Persistent spinal pain syndrome type 2 (PSPS-T2) is a chronic mixed nociceptive and neuropathic pain condition that results after lumbar spinal surgery. PSPS-T2 is a highly treatment-resistant condition with less than half of patients receiving adequate pain relief from conventional medications. 10-kHz high-frequency (HF) spinal cord stimulation (SCS) is a highly effective therapy for treatment-resistant PSPS-T2 that can often provide a >50% reduction in pain. This study aimed to systematically investigate the peripheral immune environment in PSPS-T2 compared with that in healthy controls, before assessing the immune effects of 10-kHZ SCS in PSPS-T2.

Materials and methods: This study used high-parameter mass cytometry and a multiplex cytokine assay to characterize the peripheral immune environment in healthy controls (n = 16) compared with patients with PSPS-T2 before (n = 16) and after seven to ten days of HF SCS treatment (n = 12).

Results: Compared with healthy controls, there was a significant increase in proinflammatory signaling through nuclear factor-κB, p38 mitogen-activated protein kinase, and signal transducer and activator of transcription 3 pathways in natural killer (NK), CD4⁺ "terminally differentiated effector memory cells re-expressing CD45RA" (TEMRA), central memory CD8⁺, and "effector-like" CD8⁺ T lymphocyte populations in PSPS-T2. Seven to ten days of HF SCS treatment led to significant pain relief in 75% of patients with PSPS-T2, improved psychologic measures, and induced multiple antiinflammatory effects, including a reduction in the abundance of central memory CD4⁺ T helper 17 (T_H17) lymphocytes and natural killer T (NKT) cell populations, that were correlated with pain relief. Furthermore, the expression of granzyme B, a major cytotoxic effector molecule, was reduced in the CD8⁺ T lymphocyte compartment. These changes in immune cell number and function were associated with a significant reduction in plasma levels of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12, interferon (IFN)-α, IFN-γ, and IFN-λ1, and a greater reduction in tumor necrosis factor-α plasma levels in those patients with greatest pain relief, representing an antiinflammatory shift.

Conclusions: These changes suggest that PSPS-T2 is a chronic inflammatory condition characterized by cytotoxic and exhausted immune cell populations. The resolution of this inflammation by distinct immune cell populations induced by SCS may contribute to pain relief, and specific populations, such as T_H17 and NKT cells, may represent useful biomarkers of treatment effectiveness.