Pathogenesis Of Complex Regional Pain Syndrome Research Articles

Complex regional pain syndrome: A vitamin K dependent entity?

Complex regional pain syndrome (CRPS) is the complication of some injuries, such as a fracture, which affects the distal end of the injured extremity characterized by pain, allodynia, hyperalgesia, edema, abnormal vasomotor and sudomotor activity, movement disorders, joint stiffness, regional osteoporosis, and dystrophic changes in soft tissue. Exact pathogenic mechanism of CRPS is still unclear. Suggested pathogenic mechanisms of CRPS are evaluated in four major groups consist of classic inflammation, hypoxic changes and chronic ischemia, neurogenic inflammation and sympathetic dysregulation. All of these suggested pathogenic mechanisms produced by inflammatory cytokines mediated by nuclear factor kappaB. Vitamin K is a family of structurally similar, fat-soluble, 2-methyl-1,4-naphthoquinones. Vitamin K exerts a powerful influence on bone formation, especially in osteoporosis. Fat in bone stores some vitamin K. Gamma-carboxylation of the glutamic acid in osteocalcin is vitamin K dependent. Osteocalcin plays a role in calcium uptake and bone mineralization. Osteocalcin, the most abundant non-collagenous protein in bone, is produced by osteoblasts during bone matrix formation. Because osteocalcin is not carboxylated in case of vitamin K deficiency at the distal site of fracture or injury, it cannot bind to hydroxyapatite causing osteoporosis. Fracture starts a local inflammatory process in the fracture site and adjacent tissues as seen in CRPS. Vitamin K was shown to suppress the inflammatory cytokines and NF-kappaB and prevent oxidative, hypoxic, ischemic injury (which have key role in both initiation and progression of CRPS) to oligodendrocytes and neurons. We hypothesized that vitamin K has a key role and modulatory effect in CRPS pathogenesis. Vitamin K deficiency at the distal site of fracture occurs because of diminished and slowed circulation, local immobilization after extremity fracture or injury and use of vitamin K store at the distal site of the injured extremity and in the circulation for fracture healing and bone remodelling. In case of vitamin K deficiency at the distal site of fracture, classic inflammation starts with fracture at the distal tissues could not be restricted and classic inflammation, hypoxic changes, chronic ischemia, neurogenic inflammation, sympathetic dysregulation, which are the pathogenic mechanisms of CRPS, and patchy osteoporosis which occur due to high level of under-carboxylated osteocalcin could not be prevented. Briefly vitamin K level decreases in the distal site of the injured extremity consequently resulting in patchy osteoporosis due to high level of under-carboxylated osteocalcin and unrestricted inflammation which are the cause for both initiation and progression of CRPS.

頸部術後にＣＲＰＳ（Ｃｏｍｐｌｅｘ Ｒｅｇｉｏｎａｌ Ｐａｉｎ Ｓｙｎｄｒｏｍｅ）ｔｙｐｅ Ｉを生じた１例

We report on a case of complex regional pain syndrome (CRPS) type I. A 27-year-old woman underwent lymph node biopsy of the neck to confirm a diagnosis of histiocytic necrotizing lymphadenitis. Four days after the biopsy, she complained of hyperpathia and limited range of motion on the thumb, forefinger and middle finger of the right hand. She was diagnosed as having CRPS with thermography and treated with glucocorticoid, mecobalamin, and nonsteroidal anti-inflammatory drugs (NSAIDs). The symptoms disappeared within a month and no relapse was seen. CRPS is a disorder of the extremities that is characterized by pain, swelling, limited range of motion, vasomotor instability, skin changes, and patchy bone demineralization. It frequently begins after an injury, surgery, or vascular events, e.g., myocardial infarction or stroke. Tonsillectomy and free forearm flap can cause CRPS. Two types of CRPS have been reported: type I corresponds to patients with CRPS without a definable nerve lesion. Type II which was formerly termed causalgia refers to cases with a definable nerve lesion. The pathogenesis of CRPS is still unclear. CRPS might be caused by the formation of an abnormal reflex arc between the sympathetic nervous system and peripheral vascular components after a causative event. The diagnosis of CRPS is difficult, however, symptoms such as characteristic pain including allodynia and hyperpathia, and altered skin temperature are helpful. Autonomic testing such as thermography and bone scintigraphy are also useful. Prevention and early diagnois are important to treat CRPS. Therefore careful examination and a good understanding of CRPS are recommended.

<b>Evaluation of brain metabolite in patients with Complex Regional Pain Syndrome </b><b>by MR spectroscopy </b>

Recently brain imaging studies have shown that patients with chronic pain have an altered cortical processing of nociceptive inputs. We evaluated brain metabolites in patients with complex regional pain syndrome (CRPS) using MR spectroscopy. Absolute concentrations of N-acetylaspartate (NAA) and choline (Cho) were measured in anterior cingulate (ACC) and prefrontal cortices (PFC) of patients and volunteers as matched control. Psychological aspects of patients were also evaluated with Hospital Anxiety and Depression (HAD) scale, in addition to the intensity of pain by visual analog scale. In the ACC, CRPS patients had a significant decrease of NAA and a significant increase of Cho compared to the control. Furthermore, patients with anxiety scored by HAD scale had reduced NAA concentration in ACC compared to the patients without anxiety. In the PFC,there was a reduction of NAA in the patients compared with that in control. No correlation was observed between intensity of pain and these metabolites. These results suggest that metabolite changes in ACC and PFC could reflect the pathogenesis of CRPS.

The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS

Antihypertensive drugs interact with mediators that are also involved in complex regional pain syndrome (CRPS), such a neuropeptides, adrenergic receptors, and vascular tone modulators. Therefore, we aimed to study the association between the use of antihypertensive drugs and CRPS onset. We conducted a population-based case-control study in the Integrated Primary Care Information (IPCI) database in the Netherlands. Cases were identified from electronic records (1996–2005) and included if they were confirmed during an expert visit (using IASP criteria), or if they had been diagnosed by a medical specialist. Up to four controls per cases were selected, matched on gender, age, calendar time, and injury. Exposure to angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β-blockers, calcium channel blockers, and diuretics was assessed from the automated prescription records. Data were analyzed using multivariate conditional logistic regression. A total of 186 cases were matched to 697 controls (102 confirmed during an expert visit plus 84 with a specialist diagnosis). Current use of ACE inhibitors was associated with an increased risk of CRPS (OR adjusted: 2.7, 95% CI: 1.1–6.8). The association was stronger if ACE inhibitors were used for a longer time period (OR adjusted: 3.0, 95% CI: 1.1–8.1) and in higher dosages (OR adjusted: 4.3, 95% CI: 1.4–13.7). None of the other antihypertensive drug classes was significantly associated with CRPS. We conclude that ACE inhibitor use is associated with CRPS onset and hypothesize that ACE inhibitors influence the neuro-inflammatory mechanisms that underlie CRPS by their interaction with the catabolism of substance P and bradykinin.

Functional MRI findings showing cortical reorganization in a patient with type 2 complex regional pain syndrome: A case report.

The patients suffering with complex regional pain syndrome (CRPS) reveal sensory, motor and autonomic abnormalities. The pathogenesis of CRPS is poorly understood. Some recent studies have reported that the functional magnetic resonance image (fMRI) findings support that cortical reorganization occurred in the patients with CRPS. We compared the cortical responses on fMRI in a 54-year-old right-handed male patient who suffered with type 2 CRPS on his left hand following an injury 4 years ago. He complained of severe pain and allodynia on the left hand that spread up to the left chest, and he showed abnormal involuntary movement and significant hypothermia on the left hand. The fMRI findings, when a mechanical stimulus was applied on both hands with a brush, showed significantly increased abnormal cortical responses on the primary and secondary somatosensory areas and the distinct parietal association area on the contra-lateral side of the brain to the stimuli on the affected painful hand relative to the stimuli on the unaffected hand. We report on the fMRI findings showing the cortical reorganization in a patient with type 2 CRPS.

Increased pain and neurogenic inflammation in mice deficient of neutral endopeptidase

The complex regional pain syndrome (CRPS) is characterized by enhanced neurogenic inflammation, mediated by neuropeptides. Neutral endopeptidase (NEP) is a key enzyme in neuropeptide catabolism. We used NEP knock out (ko) mice to investigate whether NEP deficiency leads to increased pain behavior and signs of neurogenic inflammation after soft tissue trauma with and without nerve injury. After chronic constriction injury (CCI) of the right sciatic nerve, NEP ko mice were more sensitive to heat, to mechanical stimuli, and to cold than wild type mice. Tissue injury without nerve injury produced no differences between genotypes. After CCI, NEP ko mice showed increased hind paw edema but lower skin temperatures than wild type mice. Substance P (SP) and endothelin 1 (ET 1) determined by enzyme immuno assay (EIA) were increased in sciatic nerves from NEP ko mice after CCI. Tissue CGRP content did not differ between the genotypes. The results provide evidence that pain behavior and neurogenic inflammation are enhanced in NEP ko mice after nerve injury. These findings resemble human ‘cold’ CRPS and suggest that ET 1 plays an important role in the pathogenesis of CRPS with nerve injury.

Increased seroprevalence of parvovirus B 19 IgG in complex regional pain syndrome is not associated with antiendothelial autoimmunity

The etiology of complex regional pain syndrome (CRPS) is unclear yet. Recently autoantibodies and antecedent viral infections have been discussed to be involved in the pathogenesis of CRPS. We investigated sera from 39 CRPS patients and healthy controls for parvovirus B19 IgG and the occurrence of antiendothelial autoantibodies (AECA). CRPS patients showed a higher seroprevalence of parvovirus B19 IgG than controls ( p < 0.01). All CRPS 2 patients were positive. 10.2% of the CRPS patients and 10.0% of the controls had AECA (n.s.) and AECA were not associated with parvovirus B19 seropositivity. Our findings suggest the involvement of parvovirus B19, but not autoantibody-mediated endothelial cell damage, in the pathogenesis of CRPS.

Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS

Complex Regional Pain Syndrome (CRPS) Types I and II are characterized by various combinations of sensory, autonomic and motor abnormalities. Pain disproportionate to the severity and duration of the inciting event is the most devastating symptom. In animal studies, conditions resulting in exaggerated pain states demonstrate elevated pro-inflammatory cytokines. In addition, pro-inflammatory cytokines have been shown to induce or increase neuropathic and inflammatory pain. Utilizing high sensitivity enzyme linked immunosorbent assay (ELISA), we compared the levels of the pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) in the cerebrospinal fluid (CSF) of patients afflicted with CRPS to CSF levels found in other patients with and without painful conditions. The results from this study demonstrated significant increases in IL-1β and IL-6, but not TNF-α in the CSF of individuals afflicted with CRPS as compared to controls. CSF cytokine levels in controls with painful conditions did not differ from levels in controls without pain. These increases showed no correlation with the patient's gender or weight. These results are consistent with studies that suggest that the pathogenesis of CRPS is due in part to central neuroimmune activation.

Plasma endothelin-1 levels in patients with complex regional pain syndrome

The clinical characteristics of complex regional pain syndrome (CRPS) – spontaneous and stimulus-evoked pain, autonomic abnormalities, motor dysfunction, and trophic changes in the affected limb – are well known. However, its pathogenesis is unclear, and the diagnosis is often delayed, in part due to lack of objective laboratory tests. Endothelin-1 (ET-1) is a potent vasoconstrictor that has recently been shown to produce pain, allodynia, edema, and muscle weakness, as well as to exert a direct excitatory effect on nociceptive afferents. Furthermore, new evidence indicates that ET-1 is involved in various cancer- and non-cancer-related painful conditions. The aim of the present explorative study was to determine the ET-1 plasma levels in patients with CRPS in an attempt to identify a `laboratory marker' for CRPS and to search for evidence suggesting that ET-1 may be involved in the pathogenesis of CRPS. ET-1 plasma levels were determined in 20 severely affected CRPS patients, in eight patients with non-CRPS chronic painful conditions, and in 10 healthy volunteers. The results showed that there were no significant differences in ET-1 plasma levels between the three groups. We conclude that the plasma level of ET-1 cannot be regarded as a `marker' for CRPS. Yet, the possibility that ET-1 is involved in the pathophysiology of CRPS has not been excluded and deserves further investigation.

Can complex regional pain syndrome be painless?

While spontaneous and stimulus-evoked pain are the hallmarks of complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy, autonomic abnormalities, motor dysfunction, and trophic changes in the affected limb are additional clinical characteristics distinguishing this syndrome. Even though the exact underlying mechanisms of the syndrome remain obscure, a recent hypothesis suggests that the abnormal response of neural nociceptive tissue plays a major role in the pathogenesis of CRPS via the mechanism known as ‘neurogenic inflammation’. The group of patients presented here exhibited all the clinical characteristics of CRPS but had no pain, thereby indicating that ongoing or evoked pain is not a necessary condition for CRPS to be maintained. We suggest the term complex regional painless syndrome to describe this syndrome.

Hemisensory impairment in patients with complex regional pain syndrome

The purpose of the present study was to investigate the extent and quality of sensory impairment and their relation to pain characteristics and movement disorders in patients suffering from complex regional pain syndrome (CRPS) type I. Neurological testing was performed independently by two examiners in 24 patients with CRPS type I. In eight patients (33%), a hemisensory impairment with decreased temperature and pinprick sensation ipsilateral to the limb affected by CRPS could be observed. In four patients (17%), a sensory deficit in the upper quadrant of the body could be demonstrated and in eight patients (33%), sensory impairment was limited to the limb affected by CRPS. Mechanical allodynia and mechanical hyperalgesia could be observed in a higher percentage of patients with hemisensory deficit or sensory impairment in the upper quadrant (92%), than in those patients with sensory impairment limited to the affected limb (17%) ( P<0.005). In patients with left-sided CRPS, sensory abnormalities in the upper quadrant or hemisensory impairment were more frequently demonstrated (77%) than in patients with right-sided CRPS (18%) ( P<0.005). There was a high correlation (92%) for the sensory findings between the two examiners, and hemisensory abnormalities were stable over a period of 3–6 months in all six patients with repeated examinations. Motor impairment (contractures, weakness, tremor or difficulties in initiating movement) could be observed in a higher percentage in patients with sensory abnormalities in the upper quadrant or hemisensory impairment (83%) than in patients with sensory impairment limited to the affected limb (42%) ( P<0.05) and was significantly correlated with allodynia/hyperalgesia ( P<0.005). The results demonstrated that sensory deficits in patients with CRPS, frequently extend past the painful area of the affected limb. The increased frequency of mechanical allodynia and movement disorders in patients with hemisensory impairment or sensory deficits in the upper quadrant, might indicate that central mechanisms are involved in the pathogenesis of CRPS in these patients.