Expression profiling of spinal cord dorsal horn in a rat model of complex regional pain syndrome type-I uncovers potential mechanisms mediating pain and neuroinflammation responses.

BACKGROUND: Complex regional pain syndrome type-I (CRPS-I) is a progressive and devastating pain condition. The mechanisms of CRPS-I still remain poorly understood. We aim to explore expression profiles of genes relevant to pain and neuroinflammation mechanisms involved in CRPS-I. METHODS: The rat chronic post-ischemic pain (CPIP) model that mimics human CRPS-I was established. RNA-sequencing (RNA-Seq), qPCR, Western blot, immunostaining, and pharmacological studies were used for profiling gene changes in ipsilateral spinal cord dorsal horn (SCDH) of CPIP model rat and further validation. RESULTS: CPIP rats developed persistent mechanical allodynia in bilateral hind paws, accompanied with obvious glial activation in SCDH. RNA-Seq identified a total of 435 differentially expressed genes (DEGs) in ipsilateral SCDH of CPIP rats. qPCR confirmed the expression of several representative genes. Functional analysis of DEGs identified that the most significantly enriched biological processes of upregulated genes include inflammatory and innate immune response. We further identified NLRP3 inflammasome expression to be significantly upregulated in SCDH of CPIP rats. Pharmacological blocking NLRP3 inflammasome reduced IL-1ß overproduction, glial activation in SCDH as well as mechanical allodynia of CPIP rats. CONCLUSION: Our study revealed that immune and inflammatory responses are predominant biological events in SCDH of CPIP rats. We further identified NLRP3 inflammasome in SCDH as a key contributor to the pain and inflammation responses in CPIP rats. Thus, our study provided putative novel targets that may help to develop effective therapeutics against CRPS-I.

[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.

Distrofia simpática refleja: ¿Predisposición genética? / Reflex sympathetic dystrophy: genetic predisposition?

La distrofia simpática refleja (DSR) es una patología compleja que cursa con intenso dolor difuso, está muy poco estudiada y es difícil de definir. Presentamos el caso de dos hermanas con diagnóstico de DSR. En ambos casos la clínica comenzó tras un traumatismo, la primera un esguince de tobillo y la segunda una fractura de Colles. Ambas tuvieron la misma evolución, dolor exacerbado y mantenido en el tiempo, impotencia funcional, cambios tróficos y deformidad. Las dos fueron tratadas con analgésicos, corticoides, neurolépticos,... sin mejoría alguna. Tras distintas pruebas complementarias se llegó al diagnóstico de DSR. Actualmente están sometiéndose a terapia experimental con escasa mejoría. Nos parece de interés para el médico de familia tener en cuenta esta patología ante un trauma y escasa mejoría del dolor. En cuanto a la genética no hay grandes avances pero los casos familiares podrían servir de ayuda a la hora del diagnóstico (AU)

Reflex sympathetic dystrophy (RSD) is a complex pathology characterized by intense and diffuse pain. There are few studies on this syndrome and it is difficult to define. The present study focuses on two sisters diagnosed with RSD. In both cases, symptoms appeared after a trauma, in the first case after a sprained ankle and in the second after a Colles’ fracture. Both evolved in the same way: severe and prolonged pain, functional impotence, trophic changes and deformity. Both were treated with analgesic, corticoid and neuroleptic medication without signs of improvement. After additional tests, they were finally diagnosed with RSD. They are currently undergoing experimental therapy with little improvement. This case may be considered useful to help family doctors take this syndrome into account after a trauma with little lessening of pain. In regards to genetics, there are no great advances, but family cases may help improve diagnosis (AU)

Frequencies of polymorphisms in cytokines, neurotransmitters and adrenergic receptors in patients with complex regional pain syndrome type I after distal radial fracture.

OBJECTIVES: The complex regional pain syndrome type I (CRPS I) is one of the main complications after a fracture of the distal radius. The underlying pathology is not fully understood. Different theories have been put forward to explain the pathogenesis of this disease, some including genetic models. The aim of this study was to find a possible genetic involvement in the occurrence of CRPS I. METHODS: We tested for known single nucleotide polymorphisms in cytokines, adrenergic receptors, and inflammatory neuropeptides in a cohort of patients at risk to develop CRPS I after a distal radius fracture. Subjective pain and functional parameters were recorded during the course of 1 year after trauma. RESULTS: Fifteen of 163 patients with fractures of the distal radius were diagnosed with CRPS I according to the International Association for the Study of Pain research criteria. A significant association was detected for the rs1048101 polymorphism of the alpha1a-adrenoceptor. All other tested variants were not associated with CRPS I. Patients with CRPS I fared worse in all functional tests compared with the control group. DISCUSSION: This study suggests the rs1048101 single nucleotide polymorphism within the alpha1a-adrenoceptor as one risk factor for the development of CRPS I after the distal radius fracture.

Systematic mutation analysis of seven dystonia genes in complex regional pain syndrome with fixed dystonia.

Complex regional pain syndrome type 1 (CRPS-1) is a chronic pain disorder that in some patients is associated with fixed dystonia. The pathogenesis of CRPS and its relation to dystonia remain poorly understood. Several genes (so-called DYT genes) identified in other causes of dystonia play a role in mechanisms that have been implicated in CRPS. Because different mutations in the same gene can result in diverse phenotypes, we sequenced all coding exons of the DYT1, DYT5a, DYT5b, DYT6, DYT11, DYT12, and DYT16 genes in 44 CRPS patients with fixed dystonia to investigate whether high-penetrant causal mutations play a role in CRPS. No such mutations were identified, indicating that these genes do not seem to play a major role in CRPS.

Reflex sympathetic dystrophy: complex regional pain syndrome type I in children with mitochondrial disease and maternal inheritance.

OBJECTIVE: Complex regional pain syndrome type I (CRPS-I), previously known as reflex sympathetic dystrophy (RSD), is an idiopathic condition characterised by localised, abnormally intense and prolonged pain, allodynia and autonomic nervous system changes (ie, swelling, skin colour and temperature changes and altered perspiration) that usually appear following a "noxious" trigger such as trauma or surgery. The objective of this report is to demonstrate that children with CRPS-I can have additional dysautonomic conditions secondary to an underlying maternally inherited mitochondrial disease, an association not previously published. METHODS: Medical records of about 500 patients seen by one paediatric metabolic geneticist were reviewed to identify children meeting established CRPS diagnostic criteria. RESULTS: CRPS-I was present in eight children in seven families, each of which also had additional functional/dysautonomic conditions, the most common (> or = 4 cases per condition) being gastrointestinal dysmotility, migraine, cyclic vomiting and chronic fatigue. All seven probands studied met Nijmegen (2002) diagnostic criteria for definite mitochondrial disease on the basis of the clinical signs and symptoms and biochemical analyses. Six of the seven families met our pedigree-based criteria for probable maternal inheritance. CONCLUSION: In one tertiary-care paediatric genetics practice, children meeting the CRPS-I diagnostic criteria frequently had additional autonomic-related conditions secondary to maternally inherited mitochondrial disease, suggesting that mitochondrial DNA sequence variants can predispose children towards the development of CRPS-I and other dysautonomias. CRPS-I should be considered in patients with mitochondrial disease who complain of idiopathic pain. Maternally inherited mitochondrial disease may not be a rare cause of CRPS-I, especially in children who present with other manifestations of dysautonomia.

A contribution to genetic etiology of complex regional pain syndrome type I (algodystropy syndrome) based on quantitative analysis of digitopalmar dermatoglyphics in sixty men.

The patterns of the ridges of the skin of the fingers and palms were determined in sixty men with complex regional pain syndrome (type I) as a measure of disease prevention. The study included 25 dermatoglyphic traits: number of epidermal ridges on all ten fingers; their sum for five and ten fingers; four traits on both palms, i.e. between a-b, b-c and c-d triradii; atd angles: and their bilateral sum. The data obtained were compared with those recorded in a control group of 200 pairs of imprints of phenotipycally healthy male adults from the Zagreb area. Statistically significant difference from control values were found in 12 dermatoglyphic variables, including an increased sum of ridges on nine fingers (except for left second finger pad), and total sum for five and ten fingers. These findings suggested the polygenic system responsible for development of dermatoglyphics to be identical with some polygenic loci for the onset of algodystrophy syndrome, which might prove useful in disease prevention (e.g., taking fingerprints following a trauma and before rehabilitation), and to facilitate identification of risk groups, and thus the treatment for this longterm and yet obscure syndrome.

[Polytopic and recurrent reflex sympathetic dystrophy in lower limbs in two siblings]. / Distrofia simpático refleja de extremidades inferiores, politópica y recurrente en dos hermanos.

Reflex sympathetic dystrophy (RSD) has been related to a variety of inciting and predisposing factors. However, there are few reports of a familiar or genetic background in RSD. This paper describes two cases of RSD polytopic and recurrent in lower limbs of two brothers with similar HLA.

A polymorphic locus in the intron 16 of the human angiotensin-converting enzyme (ACE) gene is not correlated with complex regional pain syndrome I (CRPS I).

Exaggerated neurogenic inflammation has been recognized to be one reason for many CRPS symptoms. Since angiotensin-converting enzyme (ACE) is a key enzyme for the termination of neurogenic inflammation, it has been selected as a candidate gene for CRPS predisposition. A previous report of an insertion/deletion (I/D) polymorphism in intron 16 within the ACE gene implicated an increased risk to develop CRPS I associated with the D allele. However, in the present study the D allele frequency was not increased in CRPS I cases (0.51 for D allele, 0.49 for I allele). Furthermore, there was no co-segregation of any genotype (DD, ID, II) with the CRPS phenotype in 12 selected familial CRPS I cases from six CRPS I families. In conclusion, the results presented herein render this particular ACE gene polymorphism unlikely to be a predisposing factor for CRPS I.

Profile of Caucasian women with possible genetic predisposition to reflex sympathetic dystrophy: a pilot study.

OBJECTIVES: To test possible human lymphocyte antigen (HLA) associations in subjects with reflex sympathetic dystrophy (RSD), and to determine correlation of HLA associations to treatment outcomes. DESIGN: Identification of class I (HLA-A, B, C) and class II (HLA-DR and DQ) (MHC) antigens by well-defined reagents in patients with RSD. SETTING AND PATIENTS: The HLA analysis was performed on 15 Caucasian women attending a university pain clinic and diagnosed with RSD on the basis of strict inclusion and exclusion criteria. OUTCOME MEASURES: Resistance to treatment was defined on the basis of lack of response to conservative management, failure to experience long-term symptom relief after sympathetic blocks, recurrence of pain after sympathectomy, need for palliative treatment, and degree of residual disability at the end of all treatments. RESULTS: A twofold increase of A3, B7, and DR2(15) MHC antigens was observed in the study population compared to control frequencies. Eighty (five of six) of DR2(15)-positive patients proved to be resistant to treatment. CONCLUSIONS: The results of this pilot study are the first to suggest a possible genetic diathesis in RSD patients with poor treatment outcome. If this finding can be confirmed in larger studies, strictly defined RSD could constitute the third neuroimmune disorder (besides multiple sclerosis and narcolepsy) associated with DR2(15). Gene(s) conferring susceptibility to RSD may be present within or near the MHC region of the short arm of chromosome 6. Due to the small size of our study group it is imperative that larger studies be done in RSD patients employing strict diagnostic criteria to confirm or refute our original observations.

Transient migratory osteoporosis: a variant of reflex sympathetic dystrophy? Report of 3 cases and literature review.

Three cases of transient migratory osteoporosis treated with sympathetic blocks are described. Review of the literature in conjunction with the presentation and treatment of these 3 cases led to the formulation of a hypothesis of a common mechanism (mediated through the sympathetic nervous system) responsible for the profound osteoporosis and pain of reflex sympathetic dystrophy and transient migratory osteoporosis. Arguments are presented supporting transient migratory osteoporosis as a variant of the classical reflex sympathetic dystrophy.

Three brothers with algodystrophy of the hip.

We describe the clinical features of algodystrophy of the hip in 3 brothers, probably the first familial presentation of this disease to be reported. The symptoms and evolution of the disease are as usually described. The familial presentation suggests a genetic predisposition. HLA typing showed an identity of antigenic formula in the 3 brothers, a rare coincidence.