Acute CRPS Research Articles

Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome

BackgroundComplex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed.MethodsWe systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells.ResultsIntraepidermal Schwann cells were detected in human skin of the finger—but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other—but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin.ConclusionsDiagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.

Sweating disorders in mice with and without nerve lesions.

Hypersensitivity and altered sweating are often present in neuropathy patients. Nerve lesions are known to produce sudomotor dysfunctions but also patients suffering from complex regional pain syndrome, CRPS1-a condition without a nerve lesion-present with sweating disorders. Using proton nuclear magnetic resonance of sweat water, we quantified sweat output of mice suffering from a nerve lesion or a bone fracture without nerve lesion and correlated their sweating with behavioural paw hypersensitivity accessed in von Frey testings, water applications and weight-bearing measured with an incapacitance metre. Lesioned animals sweat less and are hypersensitive compared to healthy controls, as expected. Fractured animals on the injured side sweat less acutely after the injury but more in the chronic phase. They are hypersensitive acutely as well as chronically after the fracture. These findings resemble human bone trauma patients in the acute phase and CRPS patients in the chronic phase. Sweating disorders are present both in neuropathic animals and in those with a bone fracture without nerve lesions, and autonomic dysfunctions might be considered as an important component in the aetiology of neuropathies. Sweat output changes in mice after bone trauma, potentially indicative of posttraumatic processes leading to CRPS in humans.

Complex regional pain syndrome acute care pathways in England: Do they exist and what do they look like?

Introduction Complex Regional Pain Syndrome is a condition with a high degree of morbidity and health costs to the National Health Service (NHS), characterised by persistent pain, sensory, motor, trophic and autonomic signs and symptoms. The British Orthopaedic Association (BOA) and the Royal College of Physicians (RCP) have recommended treatment guidelines and care pathways for the management of acute Complex Regional Pain Syndrome. The objective of this scoping exercise was to use Freedom of Information (FOI) requests to ascertain whether NHS Trusts in England had such pathways and what they looked like. Methods FOI requests were sent to 126 English NHS Trusts on 9 March 2017 on behalf of the Complex Regional Pain Syndrome Clinical and Research Network UK, asking: “What does your acute Complex Regional Pain Care Syndrome pathway look like?” Results Replies were received by 95 NHS Trusts and of these 84 had relevant services but (82%) had no pathway or agreed initial management. Conclusions It appears to be common for no acute care pathway to exist for CRPS in NHS Trusts in England despite it being a domain in BOA national guidelines. The Royal College of Physicians guidelines also recommend integrated MDT care. Consequentially, BOA and Royal College of Physicians standards in acute CRPS management are not yet being followed in most acute NHS Trusts in England providing trauma care. Where there is a pathway agreed, it is rarely integrated and truly multidisciplinary.

Intravenous Magnesium for Chronic Complex Regional Pain Syndrome Type 1 (CRPS-1)

To assess the effects of intravenous administration of magnesium on complex regional pain syndrome type 1 (CRPS-1), a randomized double-blind placebo-controlled trial was performed. Fifty-six patients with CRPS-1 (International Association for the Study of Pain Orlando criteria) received MgSO(4) 70 mg/kg or placebo (NaCl 0.9%) in 4 hours over 5 consecutive days. Pain (BOX-11 and McGill), the level of impairment (Impairment level Sum Score [ISS]), functional limitations (Radboud Skills Questionnaire, Walking Skills Questionnaire/questionnaire rising and sitting down), participation (Impact on Participation and Autonomy [IPA]), and quality of life (Short Form-36, EuroQol, IPA) were evaluated at baseline and at 1, 3, 6, and 12 weeks. No significant differences were found between MgSO(4) and placebo on the BOX-11 and ISS at different time points during the trial on intention-to-treat and per-protocol analysis. A significant improvement on the BOX-11 was found after the first week of the trial in both groups (mean 0.7; standard deviation 1.1). For the MgSO(4) group, a clinically relevant and statistically significant improvement on the ISS at 1 week (median 5, interquartile range [IQR] -1 to 8) and a significant improvement on the McGill up to 6 weeks (median 2 words, IQR 0-4.5) were found compared with baseline, which were not found in the placebo group. Significant improvement in perceived job participation was found for the MgSO(4) group at 12 weeks (median improvement 1.44-1.17; P = 0.01). ISS improved significantly more in patients with a low Hospital Anxiety and Depression Scale (HADS) score (≤10) in the MgSO(4) group (mean 4.4 vs mean -3.1; P = 0.02). Administration of the physiological competitive N-methyl-D-aspartate receptor antagonist magnesium in chronic CRPS provides insufficient benefit over placebo. Future research should focus on patients with acute CRPS and early signs and symptoms of central sensitization.

Reversal of Acute Complex Regional Pain Syndrome Using the Practical Application of Neurodiagnostic Evaluation Process: A Case Study

In 2005, a patient in my practice developed complex regional pain syndrome type 1 (CRPS 1) after bunion surgery. The condition was properly diagnosed within 4 weeks with a diagnostic technique that I routinely use to diagnose chronic musculoskeletal pain, and it was successfully treated. The tests, which are based on primitive and postural reflexes in infants, were adapted to reflect normal and abnormal motor behaviors in adults after provocation of reflexes of the autonomic nervous system (afferent C fibers in peripheral nerves). Approximately 60 days after my patient's operation, the tests indicated a positive reflex at the posterior tibial nerve in the operated foot. Surgery to remove an accessory ossicle from the talus adjacent to this nerve resolved the CRPS 1 within 2 weeks. Since CRPS 1 is a dysfunctional state of the autonomic regulatory control of pain, it was postulated that a test based on autonomic nerve function could isolate the source of CRPS 1. The Practical Application of Neurodiagnostic Evaluation process was shown to be diagnostic for the cause of acute CRPS 1 and to allow its reversal. Further evaluation of the test for diagnosis and treatment of CRPS is needed.

Leukocytes in Complex Regional Pain Syndrome Type I

The pathophysiology of Complex Regional Pain Syndrome type I (CRPS I) is unclear. An inflammatory reaction may cause the syndrome in which leukocytes may play an important role. In this pilot study of six patients with acute warm CRPS I, we performed radiolabeled autologous leukocyte scans of both hands, in order to assess leukocyte accumulation. Comparison was made with the unaffected limb, and with three control patients with a Colles fracture without CRPS I. Images of the CRPS I patients obtained 4 h after leukocyte injection provided the clearest results. At 4 h post-injection, there was clear, asymmetrical leukocyte accumulation in the affected extremity with a mean ratio of 1.49+/-0.19. In control patients, no asymmetry was observed between hands (mean ratio 1.09+/-0.06), indicating the absence of specific leukocyte accumulation. There was a statistically significant difference between CRPS I and control subjects 4 h post injection (p=0.012). We found a significantly increased accumulation of leukocytes in patients with CRPS I. This is the first study to show a possible role for leukocytes in the pathophysiology of acute CRPS I.

Exaggeration of tissue trauma induces signs and symptoms of acute CRPS I, however displays distinct differences to experimental CRPS II

As CRPS I frequently develops after tissue trauma, we proposed that an exaggerated inflammatory response to tissue trauma may underlie CRPS I. Therefore, we studied the vascular inflammatory, nociceptive and apoptotic sequelae of (i) soft tissue trauma and (ii) exaggerated soft tissue trauma in comparison to those of (iii) sciatic nerve chronic constriction injury, modeling CRPS II. Standardized soft tissue trauma (TR) was induced by means of a controlled impact injury technique in the hind limb of pentobarbital-anesthetized rats. Additional animals received soft tissue trauma and femoral arterial infusion of mediator-enriched supernatant achieved by homogenization and centrifugation of traumatized muscle tissue in order to provoke an exaggerated trauma response (ETR). Infusion of supernatant of non-traumatized muscle served as control intervention (STR, sham trauma response). Neuropathy was induced by chronic constriction injury of the sciatic nerve (CCI). Untreated animals served as controls (CO). Detailed nociceptive testing showed temporarily decreased mechanical pain thresholds in ETR animals that resolved within 14 days, while TR and STR animals, i.e. those with singular limb trauma, and controls remained free of pain. Neither cold- nor heat-evoked allodynia developed in post-traumatic animals, whereas CCI animals presented the well-known pattern of ongoing neuropathic pain. Using high-resolution in vivo multifluorescence microscopy, muscle tissue of traumatized animals revealed an enhanced inflammatory response that was found most pronounced in ETR animals. CCI of the sciatic nerve was not accompanied by tissue inflammation; however, induced myocyte apoptosis. Collectively, these data indicate that exaggeration of trauma response induces signs and symptoms of acute CRPS I. Pain perception displays differences to that in CRPS II. Apoptosis turns out to be a distinctive marker for CRPS, warranting further evaluation in clinical studies.

Inflammatory Mediators are Altered in the Acute Phase of Posttraumatic Complex Regional Pain Syndrome

Complex regional pain syndrome type 1 (CRPS 1) is a disorder that can affect an extremity after minor trauma or surgery. The pathogenesis of this syndrome is unclear. It has clinical signs of severe local inflammation as a result of an exaggerated inflammatory response, but neurogenic dysregulation also may contribute to it. For further insights into the pathogenesis of CRPS 1, the authors investigated inflammatory and neurogenic mediators-C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), soluble tumor necrosis factor receptor I/II (sTNFR I/II), sE-selectin, sL-selectin, sP-selectin, substance P, neuropeptide Y, and calcitonin gene-related peptide-in venous blood from both the healthy arm and the arm with acute CRPS I from 25 patients and from 30 healthy volunteers. Levels of IL-8 and sTNFR I/II were significantly elevated in patients, whereas all soluble forms of selectins were significantly suppressed. There was no significant difference in white blood cell count (WBC), CRP, and IL-6. Substance P was significantly elevated in patients. The other two neuropeptides were unchanged. None of the parameters studied showed any differences between the CRPS I-affected arm and the normal arm. Elevated IL-8 and sTNFR I/II levels indicate an association between CRPS I and an inflammatory process. Normal WBC, CRP, and IL-6 give evidence for localized inflammation. The hypothesis of neurogenic-induced inflammation mediated by neuropeptides is supported by elevated substance P levels.

Efficacy of salmon calcitonin in complex regional pain syndrome (type 1) in addition to physical therapy

The aim of the study was to assess the efficacy of salmon calcitonin, which was suggested as effective in the treatment of complex regional pain syndrome type 1 (CRPS 1). Patients who had suffered trauma to their upper extremities and developed CRPS 1 were included into this randomised, controlled single-blind study. The diagnosis was made according to the clinical examination and scintigraphy. The evaluation parameters were: pain [visual analogue scale (VAS)], the angle of dorsiflexion (DF) and palmar flexion (PF) of the wrist, distance between the fingertip and distal palmar crease (FT-DPC), allodynia, hyperalgesia and trophic changes. One group received paracetamol 1500 m/day and the other group salmon calcitonin 200 IU/day for 2 months. All of the patients participated in a physical therapy and exercise programme. A total of 35 patients were divided into two groups, who were found to be similar for age, body mass index, period of trauma, period of rest in a plaster splint or bandage, the duration of symptoms, VAS, DF and PF angle, FT-DPC, presence of allodynia, hyperalgesia and trophic changes (p>0.05). The control examination showed similar results for allodynia, hyperalgesia and trophic changes, whereas remarkable improvement was observed in the rest of the parameters within groups. On the other hand, between the two groups there was no significant difference in any of the parameters (p>0.05) This randomised, single-blind study showed that all of the patients with acute CRPS 1 in their upper extremities after trauma, who were treated with either paracetamol or calcitonin along with physical therapy, recovered in all parameters significantly, but without any difference between groups. We can conclude that calcitonin does not make any favourable contribution in the treatment of patients with acute CRPS 1; physical therapy combined with only a simple analgesic is an efficient means of therapy.

Sympathetic dysfunction as a temporary phenomenon in acute posttraumatic CRPS I

Sympathetic testing was carried out in patients in the acute phase of "complex regional pain syndrome type I" (CRPS I) shortly after trauma to the upper limb. Repeated measurements were used to detect changes in peripheral sympathetic function during the course of the disease. In a busy trauma center, 10 consecutive patients who developed CRPS I following trauma or surgery of the upper limb were diagnosed according to the 1999 modified IASP diagnostic criteria for CRPS I. Clinical signs and symptoms and bilateral hand temperature (infrared thermometry) were recorded. Vasoconstrictor response to sympathetic provocation (inspiratory gasp, contralateral cooling) at the tip of the middle finger of both hands was measured employing laser Doppler flowmetry (LDF). Sympathetic reaction was quantified by the magnitude of blood flow decrease after provocation (SRF parameter). The diagnosis CRPS I could be established 63 days (46-72 days) post-injury. The mean follow-up time after diagnosis was 83+/-15 days. Pain measured by a visual analog scale (VAS 0-10) showed an average of 5.0+/-2.0 at the time of diagnosis and decreased to 1.7+/-1.9 at the last examination. Edema and active range of motion improved substantially during the follow-up period. On the ipsilateral hand marked sympathetic dysfunction was seen early after the onset of CRPS I (mean SRF parameter: 0.14+/-0.01), slowly returning to normal sympathetic reaction three months after the onset of symptoms (mean SRF parameter: 0.42+/-0.21). Diminished sympathetic function was seen even on the contralateral hand. Sympathetic dysfunction is regularly seen at the onset of CRPS I and normalizes during the course of the disease. This temporary phenomenon suggests a posttraumatic sympathetic deficit playing a decisive role in the genesis of CRPS I.

Capillary blood gas analysis in complex regional pain syndrome: a pilot study.

The pathophysiology of complex regional pain syndrome type 1 (CRPS 1) is still a matter of debate. An inflammatory reaction may cause the syndrome. Increasing evidence points to a role for impairment of oxygen metabolism in the affected limb. In this pilot study (16 patients) we performed capillary blood gas analysis in extremities with acute CRPS 1, in order to assess oxygen saturation and lactate concentrations. Comparison was made with the unaffected limb for capillary blood pH, pO(2), SaO(2), and lactate and glucose concentrations. No statistically significant differences could be found. Capillary blood gas analysis is not useful to detect changes in oxygen saturation and lactate concentrations in CRPS 1.

α‐adrenergic supersensitivity of the sudomotor nerve in complex regional pain syndrome

alpha-Adrenoreceptor supersensitivity in many tissues has been described in patients with complex regional pain syndrome type I (CRPS I). Because excessive sweating of the affected limb is an important feature of CRPS I, we investigated whether this supersensitivity also occurs in the sudomotor system. We compared the sweat response to iontophoresis of an alpha-adrenergic agent (phenylephrine) in 4 patients with acute CRPS I and 3 patients with resolved CRPS I with that in 9 control subjects using the methodology of the quantitative sudomotor axon reflex test (QSART). A significantly higher sweat response was observed in the affected limb of patients with acute CRPS I compared to their unaffected limb (p = 0.03), to control subjects (p > 0.018), and to the affected or unaffected limbs of patients with resolved CRPS I (p = 0.02), whose sweat response was not significantly different from that of control subjects. We conclude that the abnormal response in patients with acute CRPS I is most likely mediated by an axon reflex and that alpha-adrenoreceptor supersensitivity occurs in the presynaptic portion of the postganglionic sudomotor axon. This supersensitivity is reversed when CRPS I resolves.

Autonomic failure after stroke--is it indicative for pathophysiology of complex regional pain syndrome?

In order to find pieces of evidence for a central origin of autonomic failure in complex regional pain syndrome I (CRPS I), the pattern of autonomic symptoms in CRPS I patients was compared to patients a few days after stroke. Autonomic failure in the latter group is assumed to represent definite CNS origin. Seventeen stroke patients, 21 patients in the acute and late stage of CRPS I and a control group of 23 healthy subjects were investigated. Detailed neurological examination was performed, sweating was induced centrally (thermoregulatory sweating, TST) and peripherally by carbachol iontophoresis (QSART) and quantified by evaporation hygrometry. Skin temperature was assessed by infrared thermography. The incidence of motor-sensory dysfunction (without pain) and the incidence of edema was strikingly similar in stroke and CRPS patients. Furthermore, stroke patients had increased TST but not QSART responses on the contralesional limb (P < 0.05) and skin temperature was decreased (P < 0.001). The same pattern of autonomic failure was found in late CRPS (TST: P < 0.02, skin temperature: P < 0.01) whereas in acute CRPS additional, presumably peripheral mechanisms, contribute to sympathetic symptoms. In conclusion, our investigation suggests that many clinical symptoms and the main features of sympathetic dysfunction in CRPS could be explained by a CNS pathophysiology.