Systemic low-grade C-reactive protein is associated with proximal symptom spread in carpal tunnel syndrome.

Introduction: Neuropathic pain is a highly prevalent condition associated with persistent disability. Some patients with neuropathic pain experience symptom spread outside neuroanatomical boundaries; these patients report more severe sensory symptoms and greater disability. However, the mechanisms behind such symptom spread are not fully understood. Objective: We used pre-surgical carpal tunnel syndrome (CTS) as a human model system of neuropathic pain to identify differences in the concentration of serologic inflammatory mediators between patients with CTS with territorial symptoms and those with proximal symptom spread to either the elbow or shoulder/neck. Methods: We performed a post-hoc analysis, comparing levels of serologic inflammatory mediators in a discovery cohort among 3 symptoms spread profiles (n = 55; n = 25 no spread, n = 21 spread to elbow, n = 9 spread to shoulder/neck). We then de-novo analysed the significantly dysregulated mediators in an independent validation cohort (n = 72; n = 34 no spread, n = 16 spread to elbow, n = 22 spread to shoulder/neck). Results: The discovery cohort revealed higher serum concentrations of C-reactive protein (CRP) and interleukin-6 in patients with any symptom spread proximal to the wrist; interferon-γ was higher in patients with symptom spread to the elbow compared with those without proximal spread. The validation study replicated the association of higher CRP concentrations in patients with proximal spread to the elbow (no spread: median [interquartile range] 2.5 [5.4]; spread to elbow 6.2 [4.6]; spread to shoulder/neck 2.6 [3.7], P = 0.006). No other markers replicated in the validation cohort. Conclusions: Our findings suggest that proximal symptom spread in the context of neuropathic symptoms is associated with low-grade inflammation.

Higher densities of T-lymphocytes in the subsynovial connective tissue of people with carpal tunnel syndrome.

Symptoms in people with carpal tunnel syndrome (CTS) are traditionally attributed to neural tissue, but recent studies suggest that the subsynovial connective tissue (SSCT) may also play a role in CTS. The SSCT undergoes fibrotic thickening which is generally described as "non-inflammatory" based on basic histology. This study uses immunohistochemistry to determine the presence of macrophages and T-cells within SSCT and their relationship with symptoms in people with CTS. SSCT was collected from twenty people with CTS and eight controls undergoing wrist fracture surgery. Immunohistochemical quantification of CD3+ T-cells and CD68+ macrophage densities as well as CD4+/CD8+ T-cell subpopulations were compared between groups using independent t-tests. Spearman correlations were used to identify associations between immune cell densities and CTS symptom scores. The density of CD3+ T-cells was significantly higher in SSCT of people with CTS compared to controls (CTS mean 26.7 (SD 13.7); controls 6.78 (6.3), p = 0.0005) while the density of CD68+ macrophages was lower (CTS mean 9.5 (SD 6.0); controls 17.7 (8.2), p = 0.0058). Neither CD68+ nor CD3+ cell densities correlated with symptom scores. In contrast to previous assumptions, our data show that the SSCT in the carpal tunnel in both people with CTS and controls is not devoid of immune cells. Whereas the higher density of CD68+ macrophages in control participants may be associated with their early recruitment after acute fracture, CD3+ cells within the SSCT may play a role in chronic CTS.