[Reliability of venous blood gas analysis and radionuclide angiography in post-traumatic dystrophy]. / Reliabilität der venösen Blutgasanalyse und Radionuklidangiographie bei Posttraumatischer Dystrophie.

BACKGROUND: The diagnosis "post-traumatic dystrophy" (PTD) was first defined with clinical and paraclinical criteria by Scola et al. in 2013. OBJECTIVES: The objectivity and reliability of the paraclinical criteria (venous blood gas analysis [vBGA], radionuclide angiography [RNA]), and recommendations for therapy should be assessed in a prospective study. MATERIALS AND METHODS: In five patients with clinical signs of post-traumatic nonbacterial inflammation of the hand, both diagnosis and a 3­week hospital treatment were carried out in accordance with the publication mentioned above. The primary traumata (four fractures and one soft-tissue injury) were located in either the hand or the forearm. Unsuccessful outpatient treatment always led to hospital admission. One patient with severe osteopenia in the hand skeleton was treated with bisphosphonates for 6 months. RESULTS: All patients fulfilled the clinical and paraclinical criteria for the diagnosis of PTD. On admission, an elevated venous partial pressure of oxygen was found by vBGA in the affected hand (∆pO2 mean 22 ± 3 mm Hg) and a hyperperfusion due to arteriovenous shunts was measured using RNA (mean 75 ± 47%). The symptomatic treatment was extremely well tolerated; by the time of discharge, all patients achieved full functioning of the hand with minor loss of strength (venous ∆pO2 mean 5 ± 3 mm Hg). The osteopenia in the one patient treated with bisphosphonates showed recalcification after 6 months. CONCLUSION: The reliability of clinical and paraclinical criteria for PTD were confirmed. vBGA and RNA seem to be good parameters for confirming the diagnosis of PTD. "Rubor," a symptom traditionally interpreted as "hyperemia," contradicts the paraclinical findings and leads to the assumption that the cause of this post-traumatic syndrome is microvascular dysfunction.

Oxidative stress in Complex Regional Pain Syndrome (CRPS): no systemically elevated levels of malondialdehyde, F2-isoprostanes and 8OHdG in a selected sample of patients.

Exaggerated inflammation and oxidative stress are involved in the pathogenesis of Complex Regional Pain Syndrome (CRPS). However, studies assessing markers for oxidative stress in CRPS patients are limited. In this study, markers for lipid peroxidation (malondialdehyde and F2-isoprostanes) and DNA damage (8-hydroxy-2-deoxyguanosine) were measured in nine patients (mean age 50.1 ± 17.1 years) with short term CRPS-1 (median 3 months) and nine age and sex matched healthy volunteers (mean age 49.3 ± 16.8 years) to assess and compare the level of oxidative stress. No differences were found in plasma between CRPS patients and healthy volunteers for malondialdehyde (5.2 ± 0.9 µmol/L vs. 5.4 ± 0.5 µmol/L) F2-isoprostanes (83.9 ± 18.7 pg/mL vs. 80.5 ± 12.3 pg/mL) and 8-hydroxy-2-deoxyguanosine (92.6 ± 25.5 pmol/L vs. 86.9 ± 19.0 pmol/L). Likewise, in urine, no differences were observed between CRPS patients and healthy volunteers for F2-isoprostanes (117 ng/mmol, IQR 54.5-124.3 vs. 85 ng/mmol, IQR 55.5-110) and 8-hydroxy-2-deoxyguanosine (1.4 ± 0.7 nmol/mmol vs. 1.4 ± 0.5 nmol/mmol). Our data show no elevation of systemic markers of oxidative stress in CRPS patients compared to matched healthy volunteers. Future research should focus on local sampling methods of oxidative stress with adequate patient selection based on CRPS phenotype and lifestyle.

The first scintigraphic detection of tumor necrosis factor-alpha in patients with complex regional pain syndrome type 1.

Tumor necrosis factor (TNF)-alpha has been identified as a pathogenic factor in many immunologically based diseases and complex regional pain syndrome (CRPS). In this case series, we used radiolabeled technetium anti-TNF-alpha antibody to scintigraphically image TNF-alpha in 3 patients with type 1 CRPS. The results show that TNF-alpha was localized only in affected hands of patients with early-stage CRPS. No uptake was seen in clinically unaffected hands and late-stage CRPS. Our findings support the growing evidence for neuroimmune disturbance in patients with CRPS and may have important further implications for specific anticytokine treatment in patients with CRPS.

Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I) - longitudinal investigations and differences to control groups.

OBJECTIVES: The Complex Regional Pain Syndrome I (CRPS I) is a disease that might affect an extremity after trauma or operation. The pathogenesis remains yet unclear. It has clinical signs of severe local inflammation as a result of an exaggerated inflammatory response but neurogenic dysregulation also contributes to it. Some studies investigated the role inflammatory mediators and cytokines; however, few longitudinal studies exist and control groups except healthy controls were not investigated yet. METHODS: To get further insights into the role of systemic inflammatory mediators in CRPS I, we investigated a variety of pro-, anti-, or neuro-inflammatory mediators such as C-Reactive Protein (CRP), White Blood Cell Count (WBC), Interleukins 4, 6, 8, 10, 11, 12 (p70), Interferon gamma, Tumor-Necrosis-Factor alpha (TNF-a) and its soluble Receptors I/II, soluble Selectins (E,L,P), Substance-P (SP), and Calcitonin Gene-Related Peptide (CGRP) at different time points in venous blood from patients with acute (AC) and chronic (CC) CRPS I, patients with forearm fractures (FR), with neuralgia (NE), and from healthy volunteers (C). RESULTS: No significant changes for serum parameters investigated in CRPS compared to control groups were found except for CC/C (CGRP p = 0.007), FR/C (CGRP p = 0.048) and AC/CC (IL-12 p = 0.02; TNFRI/II p = 0.01; SP p = 0.049). High interindividual variations were observed. No intra- or interindividual correlation of parameters with clinical course (e.g. chronification) or outcome was detectable. CONCLUSION: Although clinically appearing as inflammation in acute stages, local rather than systemic inflammatory responses seem to be relevant in CRPS. Variable results from different studies might be explained by unpredictable intermittent release of mediators from local inflammatory processes into the blood combined with high interindividual variabilities. A clinically relevant difference to various control groups was not notable in this pilot study. Determination of systemic inflammatory parameters is not yet helpful in diagnostic and follow-up of CRPS I.

Enhanced anandamide plasma levels in patients with complex regional pain syndrome following traumatic injury: a preliminary report.

The complex regional pain syndrome (CRPS) is a disabling neuropathic pain condition that may develop following injuries of the extremities. The pathogenesis of this syndrome is not clear; however, it includes complex interactions between the nervous and the immune system resulting in chronic inflammation, pain and trophic changes. This interaction may be mediated by chronic stress which is thought to activate the endogenous cannabinoid (endocannabinoid) system (ECS). We conducted an open, prospective, comparative clinical study to determine plasma level of the endocannabinoid anandamide by high-performance liquid chromatography and a tandem mass spectrometry system in 10 patients with CRPS type I versus 10 age- and sex-matched healthy controls. As compared to healthy controls, CRPS patients showed significantly higher plasma concentrations of anandamide. These results indicate that the peripheral ECS is activated in CRPS. Further studies are warranted to evaluate the role of the ECS in the limitation of inflammation and pain.

The serum protease network-one key to understand complex regional pain syndrome pathophysiology.

Complex regional pain syndrome (CRPS) develops after fracture. The acute CRPS phenotype resembles exaggerated inflammation, which is explained by local and systemic activation of a proinflammatory network including peptides and cytokines. Epidemiologic data suggest that inactivation of the peptidase angiotensin-converting enzyme in patients treated for hypertension increases the odds to develop CRPS. This hint leads us to investigate the serum protease network activity in patients with CRPS vs respective controls. For this purpose, we developed a dabsyl-bradykinin (DBK)-based assay and used it to investigate patients with CRPS, as well as healthy and pain (painful diabetic neuropathy [dPNP]) controls. The major result is that the degradation of DBK to fragments 1-8 and 1-5 in healthy control and dPNP is shifted to higher values for DBK1-8 and lower values for DBK1-5 at 1 hour of incubation in patients with CRPS. Using this novel reporter peptide assay, we have been able to show that the resolving protease network for mediators such as BK might be different in patients with CRPS; having a look at the clinical signs, which resemble inflammation, this resolving protease network is probably less effective in CRPS.

Increased plasma serotonin in complex regional pain syndrome type 1.

BACKGROUND: In patients with complex regional pain syndrome type 1 (CRPS1), some improvement can be achieved by the administration of ketanserin, a 5-HT(2A) receptor antagonist. We measured plasma levels of serotonin (5-HT) during CRPS1 and correlated these levels with disease characteristics. METHODS: Plasma 5-HT was measured in 35 patients who had CRPS1 for 3 yr and compared with 35 age-matched healthy controls. RESULTS: The plasma 5-HT levels were 411 +/- 263 nmol/L and 29 +/- 18 nmol/L, respectively (P < 0.001). No correlations with disease characteristics were observed. CONCLUSIONS: The markedly elevated levels of plasma 5-HT in CRPS1 patients suggest a role for 5-HT during the course of this disease. However, because of the lack of correlations with distinct disease characteristics, 5-HT is probably one of a number of mediators in CRPS1.

Increased plasma glutamate, glycine, and arginine levels in complex regional pain syndrome type 1.

BACKGROUND: Various inflammatory mediators have been identified as potential contributors to complex regional pain syndrome type 1 (CRPS1), but these mediators do not entirely explain certain manifestations of the syndrome, such as pain. The objective of this study was to investigate the role of amino acids in the pathogenesis of CRPS1. METHODS: We used HPLC to determine plasma concentrations of 16 amino acids, especially those related to the NMDA receptor (e.g., glutamate and glycine) and nitric oxide (NO) synthesis (e.g., arginine and citrulline) in patients with CRPS1 (n=64) and age- and sex-matched healthy controls (n=51). Patients rated pain intensity (visual analog scale) and the subjective experience of pain intensity (McGill Pain Questionnaire). Psychological dysfunction was assessed using the SCL-90. RESULTS: Relative to controls, in CRPS1 patients, plasma levels of glutamate, arginine, taurine, and glycine were increased, and plasma levels of glutamine and the ratio of citrulline to arginine were decreased. Remarkably, in CRPS1 patients there was a highly significant inverse correlation between glutamine and glutamate, although the sum of molar concentrations of glutamate and glutamine remains unchanged. Subjective measures of pain and indicators of psychoneuroticism and emotional instability did not correlate with amino acid levels. CONCLUSION: This study shows for the first time a pronounced increase in amino acid levels in this chronic pain syndrome. The marked differences in glutamate, glutamine, glycine, taurine and arginine levels between patients and controls suggest the involvement of both the NDMA receptor and the endothelium-dependent arginine-NO system in CRPS1.

Endocrine disorders in women with complex regional pain syndrome type I.

BACKGROUND: The question of hormonal dysregulation in patients with CRPS I in whole was investigated very scantily. There are only a few studies concerning catecholamines, oestrogens and endorphins independently. Other hormones were studied in patients with different other chronic pain conditions. Considering the accumulation of sufficient knowledge about the role of disadaptation processes in CRPS I pathogenesis and the role of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-ovarian systems in the process of adaptation it was logical and consistent to define the role of hormonal dysregulation of these systems in patients with CRPS I. OBJECTIVES: Our objective was to determine the role of hypothalamic-pituitary-adrenal and hypothalamic-pituitary-ovarian systems in pathogenesis of complex regional pain syndrome type I (CRPS I) in women. METHODS: We investigated the pituitary gonadotropic function and the function of sex glands in women with CRPS I and healthy volunteers by measuring the plasma levels of estradiol (E2 ), follicle-stimulating hormone, luteinizing hormone, prolactin, adrenocorticotropic hormone, and cortisol, and urinary excretion of 17-ketosteroids, 17-oxycocorticosteroids, epinephrine and norepinephrine. RESULTS: Women with CRPS I were characterized by the decreased content of oestrogens in the blood plasma and increased pituitary gonadotrophic function. The disturbed ratio of anabolic and catabolic steroids in women with CRPS I was detected due to lower adrenal cortex function. CONCLUSIONS: In patients with CRPS I endocrine status is characterized by hormonal imbalances of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal systems. The changes in reproductive and adaptation homeostasis characterize CRPS I as a form of the disease of disadaptation. SIGNIFICANCE: This study determined the role of hypothalamic-pituitary-adrenal and hypothalamic-pituitary-ovarian systems in pathogenesis of CRPS I.

Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Increased skin lactate in complex regional pain syndrome: evidence for tissue hypoxia?

To investigate oxygen metabolism in complex regional pain syndrome (CRPS), the authors measured skin lactate via dermal microdialysis performed on patients with CRPS (n = 11) and healthy control subjects (n = 11). In addition, they measured blood lactate. Although venous lactate was unaltered, skin lactate was increased in patients with CRPS (2.95 mmol/L; control subjects 1.74 mmol/L; p < 0.005). These results suggest enhanced anaerobic glycolysis, probably as a result of chronic tissue hypoxia.

Norepinephrine and epinephrine levels in affected versus unaffected limbs in sympathetically maintained pain.

OBJECTIVE: To test the hypothesis that there is relative sympathetic hyperactivity in the affected limb in patients with sympathetically maintained pain syndromes by measuring serum norepinephrine and epinephrine in the affected versus the unaffected sides. DESIGN: Venous pool samples were drawn just proximal to the affected area and from an identical site on the unaffected side. Serum norepinephrine and epinephrine were measured by high-pressure liquid chromatography with electrochemical detection. SUBJECTS: Sixteen women and seven men with a mean age of 44.4 years diagnosed as having sympathetically maintained pain on the basis of a positive response to paravertebral block and a criteria-based diagnostic scheme. RESULTS: The serum norepinephrine level was significantly lower in the affected limbs than the unaffected limbs (p = 0.024). The serum epinephrine level was not significantly different. CONCLUSIONS: These results are not consistent with the hypothesis of segmental sympathetic hyperactivity in the affected limb in sympathetically maintained pain and support a hypothesis of peripheral receptor upregulation with pathologic response to circulating catecholamines. Other possible explanations are discussed.

Screening of patients with complex regional pain syndrome for antecedent infections.

OBJECTIVE: This study was designed to investigate whether Complex Regional Pain Syndrome type I (CRPS I) could be linked to any previous infection. PATIENTS: Fifty-two patients with CRPS I of one extremity were screened for the presence of antibodies against mostly neurotropic microorganisms. RESULTS: Of these 52 patients, none had antibodies against Treponema pallidum, Borrelia burgdorferi, or HTLV-1. Only four patients were positive for Campylobacter jejuni. For cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and Toxoplasma gondii, seroprevalences were similar to control values. The total seroprevalence of Parvovirus B 19 in our CRPS population was 77%, which was significantly higher than in an independent Dutch population group (59%). Seroprevalence in lower extremity CRPS 1 (94%) was significantly higher than in upper extremity CRPS I patients (68%). In this study all patients were seropositive for varicella zoster virus (VZV) antibodies, but a high prevalence of VZV antibodies is similar to its prevalence in a normal population (>90%). CONCLUSIONS: In this study we found a significantly higher seroprevalence of Parvovirus B19 in CRPS I and this is most striking in lower extremity CRPS I patients. Further serologic research in other geographic areas is needed to provide additional information about a potential role of Parvovirus B 19 or other microorganisms in the etiopathogenesis of CRPS I.

Type IV hyperlipoproteinemia in patients with algodystrophy.

The present work studies lipid metabolism in patients with algodystrophy (AD). A correct positive correlation (r = 0.75) between the triglyceride levels and low density lipoprotein (LDL)/very low density lipoprotein (VLDL) ratio and the VLDL increase observed by gel disk electrophoresis confirm that a type IV hyperlipoproteinemia is associated with AD. In contrast, the degree of high density lipoprotein (HDL) saturation in cholesterol (HDL-cholesterol/HDL-phospholipids) and the classical atherogenous index (cholesterol/HDL-cholesterol) were not modified. The decrease of plasma post-heparin lipolytic activities (PHLA) was not significant but further studies should be performed to correlate PHLA with a reduced activity of the adipose tissue lipoprotein lipase.

Influence of calcitonin treatment on the osteocalcin concentration in the algodystrophy of bone.

Algodystrophy (AD) attacks all tissues in the affected region and results in the rapid demineralization of bones. Osteocalcin (OC) and alkaline phosphatase (AP) are markers of bone turnover. Calcitonin is the treatment of choice of AD. Two groups of patients were studied: Group I (n = 8)--acute stage of AD (before and during the calcitonin treatment), Group II (n = 5)--late chronic stage of AD. In the acute stage of AD both OC level and AP activity were increased. They were normal in the chronic stage of AD. During the calcitonin treatment OC level normalized after 14 days and then increased again. During the treatment, AP activity temporarily increased and then returned to the initial level. We confirm that an increased bone turnover is observed in the acute stage of AD. Discrepancy between OC level and AP activity reflects the local metabolic disturbances. Salmon calcitonin inhibits the algodystrophic process and probably contributes to the activation of the skeletal restoration.

Is hyperlipidaemia a contributing factor to algodystrophy (reflex sympathetic dystrophy)?

To appreciate hyperlipidaemia as a contributing factor to reflex sympathetic dystrophy (RSD), we have evaluated basal lipidic values (cholesterol, HDL-cholesterol, triglycerides, apolipoproteins A1, B) and frequency of hypertriglyceridaemia (Turpin's diagnosis criteria) in 75 cases of RSD and in 75 paired controls. No difference exists in both groups with regard to frequency of hypertriglyceridaemia or basal lipidic values. These values seem independent of age, sex, duration of localization or etiology (traumatic or nontraumatic) of RSD. Hyperlipidaemia does not seem a contributing factor to RSD.

[Clinical experience with human calcitonin]. / Esperienza clinica con calcitonina umana.

The Authors report the results of treatment with synthetic human calcitonin in patients suffering from Paget's disease, osteoporosis, Sudeck's disease, osteolytic metastases and in one case adults Cooley's anaemia. They summarize the characteristic blood chemistry changes due to calcitonin in some cases and report a marked clinical improvement in the majority of the patients.

Normal sympathetic nervous system response in reflex sympathetic dystrophy.

We evaluated sympathetic nervous system activity by sympathetic skin response (SSR) recording and we further investigated sympathetic and opioid outflow indirectly in patients with features of reflex sympathetic dystrophy by measuring concentrations of plasma catecholamines (CAs) and their metabolites and plasma metenkephalin (ME), before and after corticoid treatment. Six patients were studied. Basal SSR latencies, morphologies and amplitudes were normal in five patients. In one woman, latency and amplitude were also normal but the morphology was disturbed. Basal plasma ME, CA and metabolite levels were similar in the affected and non-affected limbs and a significant increase in plasma ME concentrations was observed in both affected and non-affected limbs after two weeks of steroid treatment. Altogether these results point to an adaptive supersensitivity rather than a sympathetic hyperactivity in this syndrome; also, they indicate that the therapeutic effect of steroids adds, to their known anti-inflammatory action, a stimulatory action on the endogenous opioid system.

[Vascular explorations in the diagnosis of algodystrophy]. / Aportación de las exploraciones vasculares al conocimiento de la algodistrofia.

We applied to a group of 44 patients, clinically affected by algodystrophy, a protocol of vascular explorations (Doppler, capillaroscopy, basal plethysmography, reactive hyperemia test and measurements of the oxygen transcutaneous pressure) in order to analyze their contribution to the detection of such disease, concluding that Doppler, capillaroscopy and plethysmography do not contribute with quantifiable results. On the contrary, the reactive hyperemia test and the measurements of the oxygen transcutaneous pressure showed up as explorations able to quantify the degree of microcirculatory disorder in the algodystrophy and to allow its evolutive follow-up.

[Experience with physiotherapy in a posttraumatic neurodystrophic syndrome of the extremities]. / Opyt fizioterapii pri posttravmaticheskom neirodistroficheskom sindrome konechnostei.

Combined pathogenetic treatment including physiotherapy, drugs, massage, exercise was tested in 98 patients with posttraumatic neurodystrophic syndrome in phase II and III. The responses achieved made it possible to recommend the above regimen for wide application in rehabilitation centers and clinics.