Abstract
BackgroundComplex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed.MethodsWe characterised 14 participants as meeting the Budapest clinical criteria for CRPS and assessed their pain ratings and psychological state using a series of questionnaires. Next, we performed immunophenotyping on blood samples from the 14 CRPS participants as well as 14 healthy pain-free controls using mass cytometry. Using a panel of 38 phenotypic and activation markers, we characterised the numbers and intracellular activation status of all major leukocyte populations using manual gating strategies and unsupervised cluster analysis.ResultsWe have shown expansion and activation of several distinct populations of central memory T lymphocytes in CRPS. The number of central memory CD8+ T cells was increased 2.15-fold; furthermore, this cell group had increased phosphorylation of NFkB and STAT1 compared to controls. Regarding central memory CD4+ T lymphocytes, the number of Th1 and Treg cells was increased 4.98-fold and 2.18-fold respectively, with increased phosphorylation of NFkB in both populations. We also found decreased numbers of CD1c+ myeloid dendritic cells, although with increased p38 phosphorylation. These changes could indicate dendritic cell tissue trafficking, as well as their involvement in lymphocyte activation.ConclusionsThese findings represent the first mass cytometry immunophenotyping study in any chronic pain state and provide preliminary evidence of an antigen-mediated T lymphocyte response in CRPS. In particular, the presence of increased numbers of long-lived central memory CD4+ and CD8+ T lymphocytes with increased activation of pro-inflammatory signalling pathways may indicate ongoing inflammation and cellular damage in CRPS.
Highlights
Complex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury
Severe pain was confirmed in the CRPS group, with a mean pain rating of 69/100 on a visual analogue scale (VAS) and a mean score of 114/ 220 on the Short-form McGill Pain Questionnaire (SF-MPQ2), both significantly higher than the control group
Note: colour scales vary for each marker lymphocytes persist in the blood, maintaining a strong proliferative capacity, but with reduced effector functions compared to other CD8+ T lymphocytes [46]
Summary
Complex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. Complex regional pain syndrome (CRPS) is a disease that has perplexed clinicians and basic scientists alike, for the refractory nature of the condition and for its protean nature. It can manifest in any given individual, it is more common in females, and many of its features are difficult to explain on a pathological level. Regardless of subtype, the pain is disproportionate to the initiating event and is persistent It is associated with some degree of swelling of the distal limb, colour change, temperature change, sweating change and motor impairment (weakness, tremor, dystonic posture). A ‘CRPS-not otherwise specified’ label may be applied to those few patients in whom some of these symptoms resolve over time but significant pain remains [6]
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