Evidence of a genetic background predisposing to complex regional pain syndrome type 1.

BACKGROUND: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. METHODS: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed. RESULTS: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. CONCLUSION: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.

Legg-Calve-Perthes' disease: an opportunity to prevent blindness?

Legg-Calve-Perthes' disease (LCP) is defined as avascular necrosis of the femoral head in a child and may present to a variety of disciplines from general practice to orthopaedics, paediatrics, rheumatology and more. The Stickler syndromes are a group of disorders of type II, IX and XI collagen associated with hip dysplasia, retinal detachment, deafness and cleft palate. The pathogenesis of LCP disease remains an enigma but there have been a small number of cases reporting variants in the gene encoding the α1 chain of type II collagen (COL2A1). Variants in COL2A1 are known to cause type 1 Stickler syndrome (MIM 108300, 609508), which is a connective tissue disorder with a very high risk of childhood blindness, and it is also associated with dysplastic development of the femoral head. It is unclear whether COL2A1 variants make a definitive contribution to both disorders, or whether the two are indistinguishable using current clinical diagnostic techniques. In this paper, we compare the two conditions and present a case series of 19 patients with genetically confirmed type 1 Stickler syndrome presenting with a historic diagnosis of LCP. In contrast to isolated LCP, children with type 1 Stickler syndrome have a very high risk of blindness from giant retinal tear detachment, but this is now largely preventable if a timely diagnosis is made. This paper highlights the potential for avoidable blindness in children presenting to clinicians with features suggestive of LCP disease but with underlying Stickler syndrome and proposes a simple scoring system to assist clinicians.

Attentional modulation of neural dynamics in tactile perception of complex regional pain syndrome patients.

Body perceptual disturbances are an increasingly acknowledged set of symptoms and possible clinical markers of complex regional pain syndrome (CRPS), but the neurophysiological and neurocognitive changes that underlie them are still far from being clear. We adopted a multivariate and neurodynamical approach to the analysis of EEG modulations evoked by touch to highlight differences between patients and healthy controls, between affected and unaffected side of the body, and between "passive" (i.e., no task demands and equiprobable digit stimulation) and "active" tactile processing (i.e., where a digit discrimination task was administered and spatial probability manipulated). When correct identifications are considered, an early reduction in cortical decodability (28-56 ms) distinguishes CRPS patients from healthy volunteers. However, when error trials are included in the classifier's training, there is an unexpected increased decodability in the CRPS group compared with healthy volunteers (280-320 ms). These group differences in neural processing seemed to be driven by the affected rather than the unaffected side. We corroborated these findings with several exploratory analyses of neural representation dynamics and behavioural modelling, highlighting the need for single participant analyses. Although several limitations impacted the robustness and generalizability of these comparisons, the proposed analytical approach yielded promising insights (as well as possible biomarkers based on neural dynamics) into the relatively unexplored alterations of tactile decision-making and attentional control mechanisms in chronic CRPS.

The efficacy of systemic glucocorticosteroids for pain in rheumatoid arthritis: a systematic literature review and meta-analysis.

OBJECTIVES: Glucocorticosteroids (GCs) are recommended to suppress inflammation in people with active RA. This systematic review and meta-analysis aimed to quantify the effects of systemic GCs on RA pain. METHODS: A systematic literature review of randomized controlled trials (RCTs) in RA comparing systemic GCs to inactive treatment. Three databases were and spontaneous pain and evoked pain outcomes were extracted. Standardized mean differences (SMDs) and mean differences were meta-analysed. Heterogeneity (I2, tau statistics) and bias (funnel plot, Egger's test) were assessed. Subgroup analyses investigated sources of variation. This study was pre-registered (PROSPERO CRD42019111562). RESULTS: A total of 18 903 titles, 880 abstracts and 226 full texts were assessed. Thirty-three RCTs suitable for the meta-analysis included 3123 participants. Pain scores (spontaneous pain) decreased in participants treated with oral GCs; SMD = -0.65 (15 studies, 95% CI -0.82, -0.49, P <0.001) with significant heterogeneity (I2 = 56%, P =0.0002). Efficacy displayed time-related decreases after GC initiation. Mean difference visual analogue scale pain was -15 mm (95% CI -20, -9) greater improvement in GC than control at ≤3 months, -8 mm (95% CI -12, -3) at >3-6 months and -7 mm (95% CI -13, 0) at >6 months. Similar findings were obtained when evoked pain outcomes were examined. Data from five RCTs suggested improvement also in fatigue during GC treatment. CONCLUSION: Oral GCs are analgesic in RA. The benefit is greatest shortly after initiation and GCs might not achieve clinically important pain relief beyond 3 months. Treatments other than anti-inflammatory GCs should be considered to reduce the long-term burden of pain in RA.

Virtual Environment Rehabilitation for Patients with Motor Neglect Trial (VERMONT): A Single-Center Randomized Controlled Feasibility Trial.

BACKGROUND: Motor neglect occurs in patients with chronic pain conditions. Virtual environments (VE) help rehabilitation through biofeedback and improving motivation. AIM: To assess the feasibility of a VE for patients with motor neglect with chronic pain. METHODS: 10 subjects with chronic pain (Fibromyalgia, Sciatica, and Complex Regional Pain Syndrome) underwent a treadmill task three times per week for two weeks. Groups were randomized to receive real-time biofeedback from the VE (intervention) or shown still images (control). Primary outcomes were: (i) distance walked at baseline compared to the final 5 min cycle of week 2; (ii) the Lower Extremity Functional Index (LEFI) questionnaire. A satisfaction questionnaire was used. Follow up was to 24 weeks. RESULTS: Total distance walked was significantly higher in the intervention group (p < 0.05), and 33% (2/6) of the intervention group had a clinically important LEFI improvement compared to 0/4 in the control group at week 2. No secondary outcome measures demonstrated any significant differences. The intervention received high satisfaction scores, significantly greater than the control group at week 24. No harms were recorded. DISCUSSION: This feasibility study showed that VE and treadmill-walking improved walking distances and function for subjects with motor neglect. This is a promising novel approach and requires further validation through larger study.

Successful and unsuccessful recruitment and retainment strategies in a UK multicentre drug trial for a rare chronic pain condition which performed above target.

INTRODUCTION: Recruitment into trials in rare chronic pain conditions can be challenging, so such trials consequently are underpowered or fail. METHODS: Drawing from our experience in conducting, to date, the largest academic trial in a rare chronic pain condition, complex regional pain syndrome, we have identified recruitment and retention strategies for successful trial conduct. RESULTS: We present 13 strategies grouped across the categories of 'setting the recruitment rate', 'networking', 'patient information', 'trial management' and 'patient retention'. Moreover, six recruitment risks are also discussed. A conservative recruitment estimate, based on audits of newly referred patients to the trial centres without taking into account availability of 'old' patients or recruitment from outside centres, and assuming a 55% patient refusal rate yielded accurate numbers. CONCLUSION: Appreciation of these identified recruitment challenges and opportunities may contribute to supporting prospective investigators when they design clinical trials for chronic pain patient population groups where it has been historically difficult to conduct high-quality and robust clinical trials.

Suboptimal learning of tactile-spatial predictions in patients with complex regional pain syndrome.

In complex regional pain syndrome (CRPS), tactile sensory deficits have motivated the therapeutic use of sensory discrimination training. However, the hierarchical organisation of the brain is such that low-level sensory processing can be dynamically influenced by higher-level knowledge, eg, knowledge learnt from statistical regularities in the environment. It is unknown whether the learning of such statistical regularities is impaired in CRPS. Here, we used a hierarchical Bayesian model of predictive coding to investigate statistical learning of tactile-spatial predictions in CRPS. Using a sensory change-detection task, we manipulated bottom-up (spatial displacement of a tactile stimulus) and top-down (probabilistic structure of occurrence) factors to estimate hierarchies of prediction and prediction error signals, as well as their respective precisions or reliability. Behavioural responses to spatial changes were influenced by both the magnitude of spatial displacement (bottom-up) and learnt probabilities of change (top-down). The Bayesian model revealed that patients' predictions (of spatial displacements) was found to be less precise, deviating further from the ideal (statistical optimality) compared with healthy controls. This imprecision was less context dependent, ie, more enduring across changes in the probabilistic context and less finely tuned to statistics of the environment. This caused greater precision on prediction errors, resulting in predictions that were driven more by momentary spatial changes and less by the history of spatial changes. These results suggest inefficiencies in higher-order statistical learning in CRPS. This may have implications for therapies based on sensory retraining whose effects may be more short-lived if success depends on higher-order learning.

Classification and characterisation of brain network changes in chronic back pain: A multicenter study.

Background. Chronic pain is a common, often disabling condition thought to involve a combination of peripheral and central neurobiological factors. However, the extent and nature of changes in the brain is poorly understood. Methods. We investigated brain network architecture using resting-state fMRI data in chronic back pain patients in the UK and Japan (41 patients, 56 controls), as well as open data from USA. We applied machine learning and deep learning (conditional variational autoencoder architecture) methods to explore classification of patients/controls based on network connectivity. We then studied the network topology of the data, and developed a multislice modularity method to look for consensus evidence of modular reorganisation in chronic back pain. Results. Machine learning and deep learning allowed reliable classification of patients in a third, independent open data set with an accuracy of 63%, with 68% in cross validation of all data. We identified robust evidence of network hub disruption in chronic pain, most consistently with respect to clustering coefficient and betweenness centrality. We found a consensus pattern of modular reorganisation involving extensive, bilateral regions of sensorimotor cortex, and characterised primarily by negative reorganisation - a tendency for sensorimotor cortex nodes to be less inclined to form pairwise modular links with other brain nodes. Furthermore, these regions were found to display increased connectivity with the pregenual anterior cingulate cortex, a region known to be involved in endogenous pain control. In contrast, intraparietal sulcus displayed a propensity towards positive modular reorganisation, suggesting that it might have a role in forming modules associated with the chronic pain state. Conclusion. The results provide evidence of consistent and characteristic brain network changes in chronic pain, characterised primarily by extensive reorganisation of the network architecture of the sensorimotor cortex.

Altered Neurocognitive Processing of Tactile Stimuli in Patients with Complex Regional Pain Syndrome.

Chronic pain in complex regional pain syndrome (CRPS) has been linked to tactile misperceptions and deficits in somatotopic representation of the affected limb. In this study, we identify altered cognitive processing of tactile stimuli in CRPS patients that we propose marks heterogeneity in tactile decision-making mechanisms. In a case-control design, we compared middle- and late-latency somatosensory evoked potentials in response to pseudorandomized mechanical stimulation of the digits of both hands (including CRPS-affected and nonaffected sides) between 13 CRPS patients and 13 matched healthy controls. During a task to discriminate the digit simulated, patients (compared with controls) had significantly lower accuracy and slowed response times but with high between-subject variability. At middle latencies (124-132 ms), tactile processing in patients relative to controls showed decrements in superior parietal lobe and precuneus (that were independent of task demands) but enhanced activity in superior frontal lobe (that were task-dependent). At late latencies, patients showed an augmented P300-like response under task demands that localized to the supplementary motor area. Source activity in the supplementary motor area correlated with slowed response times, although its scalp representation intriguingly correlated with better functioning of the affected limb, suggesting a compensatory mechanism. Future research should investigate the clinical utility of these putative markers of tactile decision-making mechanisms in CRPS. PERSPECTIVE: We present evidence of altered but highly variable cognitive processing (124-268 ms latency) in response to mechanical tactile stimuli in patients with CRPS compared with healthy controls. Such mid- to late-latency responses could potentially provide convenient and robust biomarkers of abnormal perceptual decision-making mechanisms in CRPS to aid in clinical detection and treatment.

Novel Signs and Their Clinical Utility in Diagnosing Complex Regional Pain Syndrome (CRPS): A Prospective Observational Cohort Study.

OBJECTIVES: Delays in diagnosis occur with complex regional pain syndrome (CRPS). We define and prospectively demonstrate that novel bedside tests measuring body perception disruption can identify patients with CRPS postfracture. METHODS: The objectives of our study were to define and validate 4 bedside tests, to identify the prevalence of positive tests in patients with CRPS and other chronic pain conditions, and to assess the clinical utility (sensitivity, specificity, positive predictive value, negative predictive value) for identifying CRPS within a Fracture cohort. This was a single UK teaching hospital prospective cohort study with 313 recruits from pain-free volunteers and patients with chronic pain conditions.Four novel tests were Finger Perception (FP), Hand Laterality identification (HL), Astereognosis (AS), and Body Scheme (BS) report. Five questionnaires (Brief Pain Inventory, Upper Extremity Functional Index, Lower Extremity Functional Index, Neglect-like Symptom Questionnaire, Hospital Anxiety and Depression Score) assessed the multidimensional pain experience. RESULTS: FP and BS were the best performing tests. Prospective monitoring of fracture patients showed that out of 7 fracture patients (total n=47) who had both finger misperception and abnormal BS report at initial testing, 3 developed persistent pain with 1 having a formal diagnosis of CRPS. DISCUSSION: Novel signs are reliable, easy to perform, and present in chronic pain patients. FP and BS have significant clinical utility in predicting persistent pain in a fracture group thereby allowing targeted early intervention.

Neurocognitive and Neuroplastic Mechanisms of Novel Clinical Signs in CRPS.

Complex regional pain syndrome (CRPS) is a chronic, debilitating pain condition that usually arises after trauma to a limb, but its precise etiology remains elusive. Novel clinical signs based on body perceptual disturbances have been reported, but their pathophysiological mechanisms remain poorly understood. Investigators have used functional neuroimaging techniques (including MEG, EEG, fMRI, and PET) to study changes mainly within the somatosensory and motor cortices. Here, we provide a focused review of the neuroimaging research findings that have generated insights into the potential neurocognitive and neuroplastic mechanisms underlying perceptual disturbances in CRPS. Neuroimaging findings, particularly with regard to somatosensory processing, have been promising but limited by a number of technique-specific factors (such as the complexity of neuroimaging investigations, poor spatial resolution of EEG/MEG, and use of modeling procedures that do not draw causal inferences) and more general factors including small samples sizes and poorly characterized patients. These factors have led to an underappreciation of the potential heterogeneity of pathophysiology that may underlie variable clinical presentation in CRPS. Also, until now, neurological deficits have been predominantly investigated separately from perceptual and cognitive disturbances. Here, we highlight the need to identify neurocognitive phenotypes of patients with CRPS that are underpinned by causal explanations for perceptual disturbances. We suggest that a combination of larger cohorts, patient phenotyping, the use of both high temporal, and spatial resolution neuroimaging methods, and the identification of simplified biomarkers is likely to be the most fruitful approach to identifying neurocognitive phenotypes in CRPS. Based on our review, we explain how such phenotypes could be characterized in terms of hierarchical models of perception and corresponding disturbances in recurrent processing involving the somatosensory, salience and executive brain networks. We also draw attention to complementary neurological factors that may explain some CRPS symptoms, including the possibility of central neuroinflammation and neuronal atrophy, and how these phenomena may overlap but be partially separable from neurocognitive deficits.

Tetrahydrobiopterin Supplementation Improves Endothelial Function But Does Not Alter Aortic Stiffness in Patients With Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. We hypothesized that supplementation with tetrahydrobiopterin (BH4) would recouple endothelial nitric oxide synthase and thus improve endothelial function and consequently reduce aortic stiffness. METHODS AND RESULTS: We conducted 2 randomized, double-blinded, placebo-controlled crossover studies examining 2 separate regimens: an acute regimen, with a single dose of BH4 400 mg versus placebo (n=18), and a short-term regimen, composed of a 1-week treatment with BH4 400 mg once daily versus placebo (n=15). Flow-mediated dilatation and aortic pulse wave velocity were studied 4 times, before and after each treatment phase. Acute BH4 supplementation led to an improvement of flow-mediated dilatation, whereas placebo had no effect (mean±SD of effect difference 2.56±4.79%; P=0.03). Similarly, 1-week treatment with BH4 improved endothelial function, but there was no change with placebo (mean±SD of effect difference 3.50±5.05%; P=0.02). There was no change in aortic pulse wave velocity following acute or short-term BH4 supplementation or placebo (mean±SD of effect difference: acute 0.09±0.67 m/s, P=0.6; short-term 0.03±1.46 m/s, P=0.9). CONCLUSION: Both acute and short-term supplementation with oral BH4 improved endothelial function but not aortic stiffness. This result suggests that BH4 supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. There appears to be no causal relationship between endothelial function and aortic stiffness, suggesting that they occur in parallel, although they may share common risk factors such as inflammation.

Establishing the characteristics for patients with chronic Complex Regional Pain Syndrome: the value of the CRPS-UK Registry.

OBJECTIVE: The long-term prognosis of patients with Complex Regional Pain Syndrome (CRPS) is unknown with no reported prospective studies from the United Kingdom longer than 18 months. The CRPS-UK Network aims to study this by use of a Registry. The aims of this article are, to outline the CRPS-UK Registry, assess the validity of the data and to describe the characteristics of a sample of the UK CRPS population. METHODS: A web-based CRPS-UK Registry was developed and made accessible to centres experienced in diagnosing and managing patients with CRPS. Pragmatic annual follow-up questions were agreed. RESULTS: Up until July 2013, the Registry has recruited 240 patients. A blinded, validation study of 20 consecutive patients from two centres (10 each) demonstrated 95.6% completion and 99.4% accuracy of a random sample of the recorded data. These patients had chronic disease (median duration: 29 months); 72.5% were female (2.6:1), with a mean age at symptoms onset of 43 years, and were left-handed more than expected (21.8% versus 10% in the general population). Patients reported a delayed diagnosis, with the median time between symptom onset and diagnosis of 6 months. In all, 30 patients (12.5%) had multiple limb involvement and (83.3%) had a contiguous spread of CRPS. CONCLUSION: CRPS-UK Registry is a validated method for actively recruiting well-characterised patients with CRPS to provide further information on the long-term outcome.

Low-dose intravenous immunoglobulin treatment for complex regional pain syndrome (LIPS): study protocol for a randomized controlled trial.

BACKGROUND: Longstanding complex regional pain syndrome (CRPS) is refractory to treatment with established analgesic drugs in most cases, and for many patients, alternative pain treatment approaches, such as with neuromodulation devices or rehabilitation methods, also do not work. The development of novel, effective treatment technologies is, therefore, important. There are preliminary data suggesting that low-dose immunoglobulin treatment may significantly reduce pain from longstanding CRPS. METHODS/DESIGN: LIPS is a multicentre (United Kingdom), double-blind, randomised parallel group, placebo-controlled trial, designed to evaluate the efficacy, safety, and tolerability of intravenous immunoglobulin (IVIg) 0.5 g/kg plus standard treatment, versus matched placebo plus standard treatment in 108 patients with longstanding complex regional pain syndrome. Participants with moderate or severe CRPS of between 1 and 5 years duration will be randomly allocated to receive IVIg 0.5 g/kg (IntratectTM 50 g/l solution for infusion) or matching placebo administered day 1 and day 22 after randomisation, followed by two optional doses of open-label medication on day 43 after randomisation and on day 64 after randomisation. The primary outcome is the patients' pain intensity in the IVIG group compared with the placebo group, between 6 and 42 days after randomisation. The primary trial objective is to confirm the efficacy and confidently determine the effect size of the IVIG treatment technology in this group of patients. TRIAL REGISTRATION: ISRCTN42179756 (Registered 28 June 13).

How to investigate: Chronic pain.

Chronic pain is defined as an unpleasant sensory and emotional experience persisting longer than the normal process of healing, usually longer than 3 months. About a fifth of the world's population is believed to suffer from chronic pain. In Europe, chronic pain accounts for nearly 500 m lost working days, and it costs the European economy >€34 billion (£28 billion) every year. Establishing a reliable diagnosis is the primary challenge in evaluating a patient with chronic pain. Common diagnoses not to miss include seronegative spondyloarthritides, endocrine abnormalities including severe vitamin D deficiency and polymyalgia rheumatica. Once important or treatable diagnoses have been ruled out, the history can be used as a tool to establish a therapeutic plan for shared decision-making using the biopsychosocial model. Onward referral to pain clinics can be helpful for more involved patient management, but often good outcomes are achieved with the support of primary care.

Pharmacological modulation of central nociception in the management of chronic musculoskeletal pain.

SUMMARY Chronic musculoskeletal pain, defined as pain lasting beyond the usual healing time of 6 weeks to 3 months, is a very common condition. It adversely affects the quality of life of patients and has a significant economic impact on our society. There is an ever increasing understanding of the pathophysiology of chronic pain. This has resulted in the effective use of various medications aimed at modulating both central and peripheral sensitizations. There are also new agents being developed based on fundamental research. The pharmacological agents used in the modulation of central nociception in chronic musculoskeletal pain are reviewed in this article.