CRPS Bugle Feb 2014

Dear All,

Here is a selection of the latest CRPS research to be published:

J Pain. 2014 Jan 22. pii: S1526-5900(14)00518-5. doi: 10.1016/j.jpain.2014.01.490. 
Activation of cutaneous immune responses in complex regional pain syndrome.

Birklein et al. 

The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but TNF-α and IL-6 are elevated in experimental skin blister fluid fromCRPS affected limbs, as is tryptase, a marker for mast cells. In the rat fracture model of CRPS exaggerated sensory and sympathetic neural signaling stimulate keratinocyte and mast cell proliferation, causing the local production of high levels of inflammatory cytokines leading to pain behavior. The current investigation used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation occur in CRPSskin and to identify the cellular source of the up-regulated TNF-α, IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies were collected from the affected skin and the contralateral mirror site in 55 CRPS patients and the biopsy sections were immunostained for keratinocyte, cell proliferation, mast cell markers, TNF-α, and IL-6. In early CRPS keratinocytes were activated in the affected skin, resulting in proliferation, epidermal thickening, and up-regulated TNF-α and IL-6 expression. In chronic CRPS there was reduced keratinocyte proliferation with epidermal thinning in the affected skin. Acute CRPS patients also had increased mast cell accumulation in the affected skin, but there was no increase in mast cell numbers in chronic CRPS.


The results of this study support the hypotheses that CRPS involves activation of the innate immune system, with keratinocyte and mast cell activation and proliferation, inflammatory mediator release, and pain.


Auton Neurosci. 2013 Dec 22. pii: S1566-0702(13)00781-9. doi: 10.1016/j.autneu.2013.12.011.

Inflammation in CRPS: Role of the sympathetic supply.


Acute Complex Regional Pain Syndrome (CRPS) is associated with signs of inflammation such as increased skin temperature, oedema, skin colour changes and pain. Pro-inflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-1beta, IL-6) are up-regulated, whereas anti-inflammatory cytokines (IL-4, IL-10) are diminished. Adaptive immunity seems to be involved in CRPS pathophysiology as many patients have autoantibodies directed against β2 adrenergic and muscarinic-2 receptors. In an animal tibial fracture model changes in the innate immune response such as up-regulation of keratinocytes are also found. Additionally, CRPS is accompanied by increased neurogenic inflammation which depends mainly on neuropeptides such as CGRP and Substance P. Besides inflammatory signs, sympathetic nervous system involvement in CRPS results in cool skin, increased sweating and sympathetically-maintained pain. The norepinephrine level is lower in the CRPS-affected than contralateral limb, but sympathetic sprouting and up-regulation of alpha-adrenoceptors may result in an adrenergic supersensitivity. The sympathetic nervous system and inflammation interact: norepinephrine influences the immune system and the production of cytokines. There is substantial evidence that this interaction contributes to the pathophysiology and clinical presentation of CRPS, but this interaction is not straightforward. How inflammation inCRPS might be exaggerated by sympathetic transmitters requires further elucidation


Pain. 2014 Jan 18. pii: S0304-3959(14)00022-0. doi: 10.1016/j.pain.2014.01.014.
Osteoprotegerin: A new biomarker for impaired bone metabolism in complex regional pain syndrome?

Krämer et al

Osteoprotegerin (OPG) is important for bone remodeling and may contribute to complex regional pain syndrome (CRPS) pathophysiology. We aimed to assess the value of OPG as a biomarker for CRPS and a possible correlation with radiotracer uptake in 3-phase bone scintigraphy (TPBS). OPG levels were analyzed in 23 CRPS patients (17 women; mean age 50±9.0years; disease duration: 12weeks [IQR 8-24]), 10 controls (6 women; mean age 58±9.6years) and 21 patients after uncomplicated fractures (12 women; mean age: 43±15years; time after fracture: 15weeks [IQR: 6-22]). The CRPS and control patients also underwent TPBS. OPG in CRPS patients was significantly increased by comparison with both control groups (P=0.001; Kruskal-Wallis test; CRPS patients: 74.1pg/mL [IQR: 47.1-100.7]; controls: 46.7pg/mL [IQR: 35.5-55.0]; P=0.004; fracture patients: 45.9pg/mL [IQR: 37.5-56.7]; P=0.001). As a diagnostic test for CRPS, OPG had a sensitivity of 0.74, specificity of 0.80, positive predictive value of 68% and negative predictive value of 84%. Receiver operating characteristic curve analysis showed an area under the curve of 0.80 (CI: 0.68-0.91). For the CRPS-affected hand, a significant correlation between OPG and TPBS region of interest analysis in phase III was detected (carpal bones; r=0.391; P=0.03). The persistent OPG increase in CRPS indicates enhanced osteoblastic activity shown by increased radiotracer uptake in TPBS phase III. A contribution of bone turnover to CRPS pathophysiology is likely. OPG might be useful as a biomarker for CRPS


PLoS One. 2014 Jan 9;9(1):e85372. doi: 10.1371/journal.pone.0085372. FULL ARTICLE HERE
Complex regional pain syndrome type I affects brain structure in prefrontal and motor cortex.
Pleger et al.

The complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder that mostly occurs after injuries to the upper limb. A number of studies indicated altered brain function in CRPS, whereas possible influences on brain structure remain poorly investigated. We acquired structural magnetic resonance imaging data from CRPS type I patients and applied voxel-by-voxel statistics to compare white and gray matter brain segments of CRPS patients with matched controls. Patients and controls were statistically compared in two different ways: First, we applied a 2-sample ttest to compare whole brain white and gray matter structure between patients and controls. Second, we aimed to assess structural alterations specifically of the primary somatosensory (S1) and motor cortex (M1) contralateral to the CRPS affected side. To this end, MRI scans of patients with left-sided CRPS (and matched controls) were horizontally flipped before preprocessing and region-of-interest-based group comparison. The unpaired ttest of the “non-flipped” data revealed that CRPS patients presented increased gray matter density in the dorsomedial prefrontal cortex. The same test applied to the “flipped” data showed further increases in gray matter density, not in the S1, but in the M1 contralateral to the CRPS-affected limb which were inversely related to decreased white matter density of the internal capsule within the ipsilateral brain hemisphere. The gray-white matter interaction between motor cortex and internal capsule suggests compensatory mechanisms within the central motor system possibly due to motor dysfunction. Altered gray matter structure in dorsomedial prefrontal cortex may occur in response to emotional processes such as pain-related suffering or elevated analgesic top-down control.


Eur J Pain. 2014 Jan 2. doi: 10.1002/j.1532-2149.2013.00446.x. 
Force modulation deficits in complex regional pain syndrome: A potential role for impaired sense of force production.
Bank PJ, van Rooijen DE, Marinus J, Reilmann R, van Hilten JJ.
Compelling evidence points at both impaired proprioception and disturbed force control in patients with chronic complex regional pain syndrome (CRPS). Because force modulation at least partly relies on proprioception, we evaluated if impaired sense of force production contributes to disturbances of force control in patients with CRPS.
Characteristics of voluntary force modulation were examined in the affected upper extremity in 28 CRPS patients with abnormal postures, in 12 CRPS patients without abnormal postures, and in 32 healthy controls. Isometric grip-force matching was compared between conditions with and without visual feedback to identify potential deficits in the sense of force production in terms of force reproduction errors.
Voluntary force modulation was impaired in CRPS patients, but more so in patients with abnormal postures. In particular, CRPS patients with abnormal postures were characterized by reduced maximum force, reduced ability to increase force output according to task instructions, higher variability of force output and less adequate correction of deviations from the target force. Although effects of visual feedback removal appeared largely similar for the two patient groups and controls, our findings with respect to force reproduction errors suggested that an impaired sense of force production may contribute to the motor dysfunction in CRPS.
CRPS patients, in particular those with abnormal postures, showed impaired voluntary force control and an impaired sense of force production. This suggests that therapeutic strategies aimed at restoration of proprioceptive impairments, possibly using online visual feedback, may promote the recovery of motor function in CRPS.


Eur J Pain. 2013 Dec 17. doi: 10.1002/j.1532-2149.2013.00434.x. 
Complex regional pain syndrome type I of the knee: A systematic literature review.
van Bussel CM, Stronks DL, Huygen FJ.
In our Center for Pain Medicine, a group of patients reported to have symptoms possibly attributable to complex regional pain syndrome (CRPS) of only the knee(s). Therefore, this study aimed to investigate whether the literature reports on patients with CRPS type I in the knee(s) alone and, if so, to summarize the reported diagnostics, aetiology and treatment strategies of CRPS of the knee(s). Medline, Embase, Cochrane Library, PubMed and Web of Science were searched for articles focusing on a painful disorder of the knee, most likely CRPS type I. Screening on title and abstract was followed by full-text reading and searching of reference lists to determine the final set of relevant articles. Of the 513 articles identified, 31 met the inclusion criteria. These articles reported on a total of 368 patients diagnosed with CRPS of the knee(s) based on the diagnostic criteria used at the time of publication. Knee surgery, especially arthroscopic surgery, was the most common inciting event in developing CRPS of the knee(s). Various treatment strategies were applied with variable outcomes. In conclusion, the scientific literature does report cases of CRPS type I of only the knee(s). This applies when using the diagnostic criteria prevailing at the time of publication and, obviously for a smaller number of cases, also when using the current Budapest criteria set. Arthroscopic knee surgery is described multiple times as the inciting event. We recommend to include CRPS of the knee in future research on the aetiological mechanisms of and optimal treatment for CRPS.


Visit our clinic site here for information about specialist clinics for CRPS and chronic pain: Specialist Pain Physio Clinics, London


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