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Introduction Case Report Conclusion This case report presents an instance of an S‐Series™ slim paddle lead fracturing during extraction, highlighting potential risks associated with the removal of this lead.A 47‐year‐old male with complex regional pain syndrome type 2, unresponsive to pharmacotherapy, had undergone the implantation of two spinal cord stimulator (SCS) leads, an Octrode™ cylindrical and an S‐series™ slim paddle, using the Epiducer™ system (St Jude Medical) 9 years earlier, with a subsequent intrathecal baclofen pump installed 1 year after SCS. Initially, these interventions stabilized the patient's pain symptoms. However, the diminishing effectiveness of SCS, coupled with a decrease in battery life and increased opioid consumption, necessitated recent surgical procedures. These included the removal and replacement of the implantable pulse generator (IPG) and leads to improve pain management and ensure MRI compatibility. During the removal of the S‐series™ slim paddle type lead, complications arose, leading to the retention of an electrode fragment, which necessitated abandoning the replacement of both the IPG and lead. Post‐surgical assessments revealed no new neurological impairments, and imaging studies confirmed the stable position of the retained fragment. The patient was discharged with a continued comprehensive pain management plan.This case highlights the challenges and risks of percutaneous removal of slim paddle type leads, emphasizing the need for careful procedural planning and consideration of surgical options to avoid complications. Further research is needed to evaluate the long‐term durability and removal risks of various SCS lead types. [ABSTRACT FROM AUTHOR]

Background/Importance: Dietary interventions, vitamins, and nutritional supplementation are playing an increasingly important role in the management of neuropathic pain. Current pharmacological treatments are poorly tolerated and ineffective in many cases. Objective: This systematic review aims to study the efficacy of dietary interventions, vitamins, and nutritional supplementation in the management of chronic neuropathic pain in adults. Evidence Review: The review followed PRISMA guidelines and was registered with PROSPERO (#CRD42022300312). Ten databases and gray literature, including Embase.com, MEDLINE and Web of Science, were systematically searched using a combination of keywords and controlled vocabulary related to chronic neuropathic pain and oral non‐pharmacological supplements. Studies on adult humans published between 2000 and 2021 were considered for inclusion. The Cochrane Handbook was used to assess risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation was used to determine overall quality of evidence. Findings: Forty studies were included in the final review, and results were categorized according to pain type including pain related to chemotherapy‐induced peripheral neuropathy (CIPN, 22 studies, including 3 prospective cohorts), diabetic peripheral neuropathy (DPN, 13 studies, including 2 prospective), complex regional pain syndrome (CRPS‐I, 3 studies, including 1 prospective), and other (2 studies, both RCT). The CIPN studies used various interventions including goshajinkigan (4 studies), vitamin E (5), vitamin B12 (3), glutamine (3), N‐acetyl‐cysteine (2), acetyl‐l‐carnitine (2), guilongtonluofang (1), ninjin'yoeito (1), alpha‐lipoic acid (1), l‐carnosine (1), magnesium and calcium (1), crocin (1), and antioxidants (1), with some studies involving multiple interventions. All CIPN studies involved varying cancers and/or chemotherapies, advising caution for generalizability of results. Interventions for DPN included alpha‐lipoic acid (5 studies), vitamin B12 (3), acetyl‐l‐carnitine (3), vitamin E (1), vitamin D (2), and a low‐fat plant‐based diet (1). Vitamin C was studied to treat CRPS‐I (3 studies, including 1 prospective). Magnesium (1) and St. John's wort (1) were studied for other or mixed neuropathologies. Conclusions: Based on the review, we cannot recommend any supplement use for the management of CIPN, although further research into N‐acetyl‐cysteine, l‐carnosine, crocin, and magnesium is warranted. Acetyl‐l‐carnitine was found to be likely ineffective or harmful. Alpha‐lipoic acid was not found effective. Studies with goshajinkigan, vitamin B12, vitamin E, and glutamine had conflicting results regarding efficacy, with one goshajinkigan study finding it harmful. Guilongtonluofang, ninjin'yoeito, and antioxidants showed various degrees of potential effectiveness. Regarding DPN, our review supports the use of alpha‐lipoic acid, acetyl‐l‐carnitine, and vitamin D. The early use of vitamin C prophylaxis for the development of CRPS‐I also seems promising. Further research is warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

In complex regional pain syndrome (CRPS), the representation area of the affected limb in the primary sensorimotor cortex (SM1) reacts abnormally during sensory stimulation and motor actions. We recorded 3T functional magnetic resonance imaging resting‐state data from 17 upper‐limb CRPS type 1 patients and 19 healthy control subjects to identify alterations of patients' SM1 function during spontaneous pain and to find out how the spatial distribution of these alterations were related to peripheral symptoms. Seed‐based correlations and independent component analyses indicated that patients' upper‐limb SM1 representation areas display (i) reduced interhemispheric connectivity, associated with the combined effect of intensity and spatial extent of limb pain, (ii) increased connectivity with the right anterior insula that positively correlated with the duration of CRPS, (iii) increased connectivity with periaqueductal gray matter, and (iv) disengagement from the other parts of the SM1 network. These findings, now reported for the first time in CRPS, parallel the alterations found in patients suffering from other chronic pain conditions or from limb denervation; they also agree with findings in healthy persons who are exposed to experimental pain or have used their limbs asymmetrically. Our results suggest that CRPS is associated with a sustained and somatotopically specific alteration of SM1 function, that has correspondence to the spatial distribution of the peripheral manifestations and to the duration of the syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Chronic pain associates with various sleep problems. Patients with complex regional pain syndrome (CRPS) often report impaired sleep, but objective measurements of sleep in CRPS patients are scarce. Neuromodulation with repetitive transcranial magnetic stimulation (rTMS) can alleviate pain and improve sleep. Secondary somatosensory cortex (S2) is a possible rTMS target for the treatment of chronic pain, but the effect of S2‐targeted rTMS on sleep is unknown. Methods: This randomized, sham‐controlled trial assessed the effect of S2‐targeted rTMS on sleep in patients with CRPS. Patients (n = 31) received either S2‐targeted rTMS (10 Hz) or sham stimulation for 3 weeks. The effect of treatment on sleep was assessed with validated questionnaires, with a sleep and pain diary, and with a consumer‐grade sleep tracker, the Oura ring. In addition to an ordinary univariate analysis of the results, we conducted multivariate testing of the Oura data using linear discriminant analysis (LDA). Results: S2‐targeted rTMS decreased sleep restlessness that significantly differed between the rTMS and sham stimulation patient groups (p =.028). In the multivariate analysis of the Oura data, LDA classification accuracy to separate the rTMS and sham groups exceeded 95% confidence level in four out of the seven tested models. In the subjective evaluation of sleep, the effect of rTMS and sham did not differ. Conclusion: S2‐targeted rTMS influenced sleep in patients with CRPS. Improved sleep may enhance CRPS symptom alleviation and be of clinical importance. A univariate analysis could separate the rTMS and sham treatments. The multivariate analysis revealed that including multiple sleep‐related parameters can be beneficial when analyzing rTMS effects on sleep. As sleep is related both to pain and quality of life, and sleep rTMS can be directly affected by rTMS, objective monitoring of sleep in various future rTMS trials could be fruitful. [ABSTRACT FROM AUTHOR]

Introduction: Complex regional pain syndrome (CRPS) is characterized by nociplastic pain with alterations in sympathetic function. Neuromodulation could be a useful alternative therapy option. Dorsal root ganglion (DRG) stimulation has demonstrated better results than conventional spinal cord stimulation (SCS) for patients with CRPS in lower limbs. Methods: We report a case series of seven patients treated with cervical DRG stimulation for CRPS of the hand that required neuromodulation for pain relief, after no response with other analgesic techniques (medication and interventional). We report retrospective data collection of seven consecutive patients with a 1‐year follow‐up. Results: Seven patients were trialed, and six were implanted with a permanent pulse generator after achieving more than 50% pain relief during 2–7 days of trial phase. The average pain relief (rated on a standard 100 mm visual analog scale) after 1 year of treatment was 64.3% ± 16.6. No major complications were observed during a 1‐year follow‐up. Discussion: The results for cervical DRG stimulation are similar to other DRG stimulation studies for the treatment of refractory CRPS at lower levels. The cervical DRG implant technique guided with C‐arm fluoroscopy and under conscious sedation could be a safe and effective option for relieving pain of the upper limbs CRPS. Monitoring neural status is required for cervical DRG stimulation either with a responder awake patient or with intraoperative neural monitoring in non‐responder patients. [ABSTRACT FROM AUTHOR]

Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA‐21‐5p (miR‐21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR‐21 in neuropathic pain and its impact on the BNB in a human‐murine back translational approach. MiR‐21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin‐1 in both injured and spared nerves. Moreover, the putative miR‐21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR‐21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR‐21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR‐21 after nerve injury reversed it. In summary, the data support a novel role for miR‐21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9. [ABSTRACT FROM AUTHOR]

CRPS is a type of severe pain syndrome and can be triggered by previous surgery or trauma. CRPS involves vasomotor changes such as changes in color and temperature of the skin, edema, increased sensitivity to touch, and a limited range of movement. Depending on the presence of nerve damage, CRPS is divided into two types. CRPS type II is associated with a confirmed peripheral nerve injury, while CRPS type I is not associated with an apparent peripheral nerve injury. Despite the ongoing therapy, sometimes, patients still have persistent, burning pain. Intractable CRPS that fail more conservative treatments may undergo neuromodulation. We want to present to your attention a case report of the successful treatment of a patient with CRPS type II using epidural unilateral stimulation. The 44‐year‐old woman came to us with complaints of burning pain and numbness of 1–3 fingers of the right hand, the lateral surface of the right wrist, and lower quarter of the forearm, and shooting pain in the projection of the right median nerve from the shoulder to the wrist. A clinical diagnosis was made—CRPS type II. During the stimulation trial, the most effective pain relief was obtained when the electrode was located in the right side of epidural space at the C4‐Th1 level. The implantation of a pulse generator was performed, and the final selection of the stimulation parameters was carried out (Pulse width: 60 ms, Rate: 210 Hz, and Amplitude: 0.9–1.6 V). The severity of pain syndrome was measured using validated scales in the preoperative period (VAS: 8–9, Pain Detect: 22, NTSS‐9: 4.62, and DN4: 8), in the early postoperative period (VAS: 0–1, Pain Detect: 6, NTSS −9: 0.66, and DN4: 1), and after 12 months (VAS: 0–2, Pain Detect: 6, NTSS‐9: 0.99, and DN4: 1). Observation during 12 months showed that a stable analgesic effect of neurostimulation was achieved using standard neuromodulation regimens and the adaptive stim option. Unilateral stimulation is an effective type of SCS in the treatment of pain syndromes. adaptive stim is usually not applicable for lead implantation at the cervical level. Nevertheless, the rational use of stimulation at threshold values allowed our patient to use adaptive stim in a non‐standard situation. [ABSTRACT FROM AUTHOR]

Pediatric complex regional pain syndrome (pCRPS) is a rare, painful state that often occurs as a complication following physical trauma. Diagnosis and treatment require specialist expertise in a multidisciplinary setting. Treatment is focused on pain reduction and improvement in function, which differs from the treatment of adult CRPS. We performed a cross‐sectional survey with the aim of identifying pain centers in the Nordic countries and Germany that specialized in treating children with pain, especially pCRPS, and sought to describe their treatment strategies. Centers and health‐care professionals working with children experiencing chronic pain were identified using internet search engines, phones, or e‐mail. A standardized set of questions and an electronic questionnaire were answered by the participants. A total of 28 participants were identified in 24 centers, which were involved with patients having pCRPS (Germany: 7, Norway: 7, Sweden: 5, Finland: 5, Denmark: 3, and Island: 1). One center in Germany treated more than 20 patients per year. Half of the identified centers (n = 12) treated between 1 and 5 children with pCRPS per year. Guidelines for treating pCRPS were reportedly followed by 9/28 responders (32%), and physiotherapy was reported to be part of the treatment routine in most centers (74%). Interventional anesthesia was rarely used. Psychological therapy: 57% answered that it was always offered, 30% replied that it was proffered in most cases, and 13% responded that it was recommended in only a few patients. Pharmacological treatments were not commonly used. Treatment resources for pCRPS are scarce in the Nordic countries and Germany. Most centers treated very few children with pCRPS and did not have established guidelines. A multidisciplinary approach was used by many centers, most often combining physiotherapy and psychotherapy, and less commonly pharmacological treatment. The difficulties in diagnosing pCRPS and finding official referral units are unfortunate, considering the potentially favorable outcome with adequate treatment. [ABSTRACT FROM AUTHOR]

Complex regional pain syndrome (CRPS) has rarely been reported in the setting of snakebite but might be more common than previously reported. We present the third case of CRPS reported in North America and the first resulting from a pit‐viper's bite. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The philosophy of forecast verification is rather different between deterministic and probabilistic verification metrics: generally speaking, deterministic metrics measure differences, whereas probabilistic metrics assess reliability and sharpness of predictive distributions. This article considers the root‐mean‐square error (RMSE), which can be seen as a deterministic metric, and the probabilistic metric Continuous Ranked Probability Score (CRPS), and demonstrates that under certain conditions, the CRPS can be mathematically expressed in terms of the RMSE when these metrics are aggregated. One of the required conditions is the normality of distributions. The other condition is that, while the forecast ensemble need not be calibrated, any bias or over/underdispersion cannot depend on the forecast distribution itself. Under these conditions, the CRPS is a fraction of the RMSE, and this fraction depends only on the heteroscedasticity of the ensemble spread and the measures of calibration. The derived CRPS–RMSE relationship for the case of perfect ensemble reliability is tested on simulations of idealised two‐dimensional barotropic turbulence. Results suggest that the relationship holds approximately despite the normality condition not being met. [ABSTRACT FROM AUTHOR]

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder that typically occurs in the limbs, usually the upper limb. CRPS usually develops from a peripheral event but its maintenance relies on changes within the central nervous system. While functional abnormalities in the thalamus and primary somatosensory cortex (S1) of the brain are some of the most consistently reported brain findings in CRPS, the mechanisms are yet to be explored in full, not least of all how these two regions interact and how they might relate to clinical deficits, such as the commonly reported poor tactile acuity in this condition. This study recruited 15 upper‐limb CRPS subjects and 30 healthy controls and used functional magnetic resonance imaging (fMRI) to investigate infra‐slow oscillations (ISOs) in critical pain regions of the brain in CRPS. As hypothesised, we found CRPS was associated with increases in resting signal intensity ISOs (0.03–0.06 Hz) in the thalamus contralateral to the painful limb in CRPS subjects. Interestingly, there was no such difference between groups in S1, however CRPS subjects displayed stronger thalamo‐S1 functional connectivity than controls, and this was related to pain. As predicted, CRPS subjects displayed poor tactile acuity on the painful limb which, interestingly, was also related to thalamo‐S1 functional connectivity strength. Our findings provide novel evidence of altered patterns of resting activity and connectivity in CRPS which may underlie altered thalamocortical loop dynamics and the constant perception of pain. [ABSTRACT FROM AUTHOR]

Background: Complex regional pain syndrome (CRPS) is a chronic inflammatory and neurological condition with a complex broad spectrum of symptoms and requires input from various clinical specialists such as orthopedic surgeons, anesthetists, rheumatologists, and rehabilitation physicians. Aim: The aim is to study the awareness of CRPS among medical professionals (Orthopedics, Neurosurgeons, Family physicians, Internists). Method: The study was conducted using a cross‐sectional survey. A postal questionnaire was sent online to different medical professionals. The questionnaire included two sections. The first section was about personal demographic whereas the second section was about the CRPS symptoms, diagnosis criteria, and management. Results: The study resulted in a total number of 97 participants that filled the questionnaire completely with the highest number working at tertiary health centers (59.8%) followed by primary health centers (30.9%) and secondary health centers students (9.3%). Seventeen percent of the participants were aware about the diagnostic criteria of this condition, while only 15.4% have applied these criteria before. Awareness of risk factors and complications were 22.7% and 23.7%; respectively. The mean of the cumulative score out of 11 awareness among our participants was 2.48 (range; 0‐10). 37 (38.1%) of the participant scores 0/11 while none of the participants were able to score 11/11. Our study identified an association between years of experience and the level of awareness with a P value of.007. Conclusion: The awareness of CRPS among medical professionals was not sufficient to met the recommendation of CRPS criteria and guideline. Physicians from different specialties need to increase their knowledge and awareness about this conditions. [ABSTRACT FROM AUTHOR]

Background: Evaluating the effectiveness of stellate ganglion blockades (SGBs) proves challenging, since the criteria defining a successful blockade are controversial. This may be one reason for the scarcity of studies on this topic, thus forcing clinical guidelines to remain conservative in recommending SGBs. Moreover, factors to predict which patients will benefit from blockade series are not yet available. Objectives: The objectives of this study were to evaluate through a clinical approach SGBs' effectiveness performed under ultrasound guidance (us‐SGB) and to identify factors to predict effectiveness. Methods: We retrospectively analyzed 809 us‐SGBs in 105 patients with complex regional pain syndrome (CRPS) and neuropathic pain syndromes (all potentially including sympathetically maintained pain) regarding pain reduction. Volume and type of local anesthetics, magnitude of pain, temperature of the dorsal hands, heart rate, blood pressure, and occurrence of Horner's syndrome or complications were assessed. Results: Pain reduction after a blockade series was highly significant and showed no significant correlation with change of temperature, vital signs, or Horner's syndrome. For patients with neuropathic pain, the predictive potential for pain reduction following a blockade series lies within the range of pain reduction after the first blockade. In a literature comparison, incidences of complications (hoarseness 3.9%, dysphagia 3.4%, hematoma 0.6%) were lower than in non‐ultrasound‐guided techniques. Conclusions: Data indicate that us‐SGBs are safe and effective in reducing sympathetically maintained pain in patients with CRPS and neuropathic pain syndromes. Pain reduction after the first blockade may predict total pain reduction after a blockade series. Other clinical measures seem unsuitable to predict effectiveness. [ABSTRACT FROM AUTHOR]

Local microvascular dysfunction and consequent tissue ischemia/hypoxia contribute to the symptoms of complex regional pain syndrome (CRPS) and peripheral neuropathic pain. As nitric oxide (NO) is a key regulator of microvascular blood flow, compounds that increase it are potentially therapeutic for these pain conditions. This led us to hypothesize that the topical administration of drugs that modulate local tissue NO levels can alleviate the pain of CRPS and peripheral neuropathic pain. We investigated the anti‐allodynic effect of a combination of two NO‐modulating drugs: meldonium and N‐acetylcysteine (NAC). An equimolar topical formulation of the two drugs was tested on chronic post‐ischemic pain (CPIP), a rat model of CRPS, as well as chronic constriction injury (CCI) of the sciatic nerve and chemotherapy‐induced painful neuropathy (CIPN), rat models of peripheral neuropathic pain. Topical meldonium‐NAC produced significant anti‐allodynia in CPIP, CCI, and CIPN rats. Moreover repeated application of topical meldonium‐NAC produced an increase in the duration of anti‐allodynia in the CPIP and CCI rats. While pre‐treatment with an NO synthase inhibitor attenuated the anti‐allodynic effects of meldonium‐NAC, 30‐min hyperbaric oxygen treatment combined with a non‐effective dose of meldonium‐NAC produced significant anti‐allodynic effects in CPIP rats. Both experiments implicated NO in the drug combination's anti‐allodynic effects. To ascertain the role played by changes in local tissue NO, we performed a quantification of plantar muscle NO in CPIP rats after hind paw topical treatment with meldonium‐NAC and revealed significantly increased plantar muscle NO levels in drug‐treated rats. The drug combination also reversed the reduction in tissue oxygenation normally observed in CPIP hind paws. In addition to introducing a novel topical treatment for mechanical allodynia in CRPS and peripheral neuropathic pain, this work showcases the analgesic potential of locally targeting microvascular dysfunction and tissue ischemia/hypoxia in these conditions, with emphasis on the role of NO. [ABSTRACT FROM AUTHOR]

Extracellular RNA in circulation mediates intercellular communication in normal and pathological processes. One mode of circulating miRNA transport in bodily fluids is within 30–150 nm small extracellular vesicles (sEVs) or exosomes. Uptake of sEVs can regulate gene expression in recipient cells enabling circulating miRNAs to exert paracrine and systemic effects. Complex regional pain syndrome (CRPS) is a debilitating pain disorder characterized by chronic inflammation. Our previous investigations identified a significant decrease of hsa-miR-939 in whole blood from CRPS patients compared to control; we also observed that overexpression of miR-939 can negatively regulate several proinflammatory genes in vitro. Though downregulated in whole blood, miR-939 was significantly upregulated in sEVs isolated from patient serum. Here we investigated miR-939 packaging into sEVs in vitro under inflammation induced by monocyte chemoattractant protein-1 (MCP-1), a chemokine that is upregulated in CRPS patients. Stimulation of THP-1 monocytes by MCP-1 led to elevated levels of miR-939 in sEVs, which was abrogated using inhibitors of exosome secretion. miRNAs loaded into exosomes largely contain short miRNA sequence motifs called EXOmotifs. Mutation analysis of miR-939 showed that EXOmotif is one of the possible cellular mechanisms responsible for packaging miR-939 into sEVs. We confirmed gene expression changes in recipient cells following the uptake of sEVs enriched in miR-939 using RNA sequencing. Additionally, our data from primary immune cell-derived sEVs of CRPS patients and controls demonstrate that while the relative expression of miR-939 is higher in sEVs derived from B cells, T cells and NK cells relative to monocyte-derived sEVs in controls, only the B cell-derived sEVs showed a significantly higher level of miR-939 in CRPS patients. Differential miRNA sorting into exosomes and its functional impact on recipient cells may contribute to the underlying pathophysiology of CRPS. [ABSTRACT FROM AUTHOR]

The evaluation of brain changes to a specific pain condition in pediatric and adult patients allows for insights into potential mechanisms of pain chronicity and possibly long‐term brain changes. Here we focused on the primary somatosensory system (SS) involved in pain processing, namely the ventroposterolateral thalamus (VPL) and the primary somatosensory cortex (SI). We evaluated, using MRI, three specific processes: (a) somatotopy of changes in the SS for different pain origins (viz., foot vs. arm); (b) differences in acute (ankle sprain versus complex regional pain syndrome‐CRPS); and (c) differences of the effects of CRPS on SS in pediatric versus adult patients. In all cases, age‐ and sex‐matched individuals were used as controls. Our results suggest a shift in concurrent gray matter density (GMD) and resting functional connectivity strengths (rFC) across pediatric and adult CRPS with (a) differential patterns of GMD (VPL) and rFC (SI) on SS in pediatric vs. adult patterns that are consistent with upper and lower limb somatotopical organization; and (b) widespread GMD alterations in pediatric CRPS from sensory, emotional and descending modulatory processes to more confined sensory‐emotional changes in adult CRPS and rFC patterns from sensory‐sensory alterations in pediatric populations to a sensory‐emotional change in adult populations. These results support the idea that pediatric and adult CRPS are differentially represented and may reflect underlying differences in pain chronification across age groups that may contribute to the well‐known differences between child and adult pain vulnerability and resilience. [ABSTRACT FROM AUTHOR]

Background: Complex regional pain syndrome (CRPS) is a severe post‐traumatic chronic pain condition affecting distal limbs, for which few effective treatments exist. Complex regional pain syndrome is listed in the 2016 American Society for Apheresis guidelines as an indication for plasma exchange treatment, but patient perspectives are lacking. Study design and methods: We convened a "patient and public consultation exercise." Supervised by a clinical ethicist, the case for using therapeutic plasma exchange (TPE) was presented by a researcher and two TPE experts to five patients with severe, long‐standing CRPS and to one relative. Discussions were recorded and transcribed. Results: Participants supported the technology's use but expressed concern that the small trauma of repeat cannulations of CRPS unaffected limbs might theoretically cause a spread of the condition, a risk which requires highlighting when taking consent. For a preliminary trial, the participants proposed to include no less than 10, preferably 20 participants. They suggested that the threshold for a decision to conduct a definite trial based on preliminary trial results should be set no higher than 1/5 patients achieving >30% pain reduction in the preliminary trial, with half of these responders achieving >50%. The use of sham‐TPE and a long trial duration (1 year) of a definite, parallel trial was considered acceptable, provided patients would be offered voluntary swap to the other trial arm at the end of the main trial period. Conclusion: These results provide pertinent patient views about TPE treatment which can inform both clinical consultation and consent procedure and the design of future trials. [ABSTRACT FROM AUTHOR]

Abstract: The detection performance of a conventional control chart is usually degraded by a large sample size as in Wang and Tsung. This paper proposes a new control chart under data‐rich environment. The proposed chart is based on the continuous ranked probability score and aims to simultaneously monitor the location and the scale parameters of any continuous process. We simulate different monitoring schemes with various shift patterns to examine the chart performance. Both in‐control and out‐of‐control performances are studied through simulation studies in terms of the mean, the standard deviation, the median, and some percentiles of the average run length distribution. Simulation results show that the proposed chart keeps a high sensitivity to shifts in location and/or scale without any distributional assumptions, and the outperformance improves, as the sample size becomes larger. Examples are given for illustration. [ABSTRACT FROM AUTHOR]

Desirable attributes of probability forecasts are maximal sharpness, consistent with calibration (‘reliability’). The usual procedure of optimizing ensemble‐postprocessing parameters by minimizing a proper scoring rule such as the continuous ranked probability score or the ‘ignorance’ (i.e. negative log‐likelihood) does not guarantee the necessary calibration condition, potentially compromising the value of the resulting forecasts to users. The calibration condition can be enforced by including a miscalibration penalty in the loss function to be minimized in parameter estimation. The procedure is illustrated using ensemble forecasts for minimum temperatures and wind speeds, postprocessed using member‐by‐member algorithms. [ABSTRACT FROM AUTHOR]

Ensemble forecasting resorts to multiple individual forecasts to produce a discrete probability distribution that represents the uncertainties accurately. Before every forecast, a weighted empirical distribution function is derived from the ensemble, so as to minimize the Continuous Ranked Probability Score (CRPS). We apply online learning techniques that have previously been used for deterministic forecasting and adapt them for the minimization of the CRPS. The proposed method guarantees theoretically that the aggregated forecast competes, in terms of CRPS, against the best weighted empirical distribution function with weights constant in time. This is illustrated on synthetic data. Additionally, our study improves knowledge of the CRPS expectation for model mixtures. We generalize results about the bias of the CRPS computed with ensemble forecasts and propose a new scheme to achieve fair CRPS minimization, without any assumption about the distribution. [ABSTRACT FROM AUTHOR]

Reflex sympathetic dystrophy, also known as complex regional pain syndrome (CRPS), has recently been shown to be associated with autoantibodies against β2-adrenergic and muscarinic M2 receptors. In addition to pain and sudomotor/vasomotor symptoms, dysautonomia is also observed in a subset of CRPS patients. Despite its severity, there are few effective therapies for CRPS described to date. We report a case of a 14-year-old girl with CRPS of her right leg and dysautonomia (gastroparesis, postural tachycardia) refractory to multiple therapies, successfully treated with therapeutic plasma exchange (TPE) with albumin replacement. The patient, who has serum anti β2-adrenergic and muscarinic M2 receptor autoantibodies in addition to nicotinic acetylcholine receptor ganglionic autoantibodies, underwent an initial course of five TPEs over a 2-week period. She demonstrated a clinical response to TPE as manifested by a rapid improvement in her fatigue and gastroparesis, with a gradual yet significant improvement in her leg pain and sudomotor/vasomotor flares. Following the loading procedures, the patient was treated with rituximab. She continues to require periodic TPE to maintain a remission, with additional immunosuppression being considered long term. Although further studies are needed, TPE (in combination with immunosuppression) may be an appropriate therapy for CRPS patients with detectable autoantibodies, as it is for better characterized diseases with autoantibodies against neuronal surface receptors such as myasthenia gravis or Lambert Eaton myasthenic syndrome. J. Clin. Apheresis 31:368-374, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Complex regional pain syndrome ( CRPS) is multifactorial condition with complex pathogenesis characterized by spontaneous or stimulus-induced pain that is disproportionate to the inciting event. It is also commonly accompanied by a myriad of autonomic and motor disturbances in highly variable combinations. This condition has been underreported in children until recently. Consequently, the management of CRPS in the pediatric population presents an even greater challenge than in adults, partly because there is a lack of clinical data concerning the efficacy of the diverse treatment methods available, and partly because successful treatment of CRPS involves a multidisciplinary approach. In this retrospective case series, a multidisciplinary management plan is presented in 10 children for whom the standard noninvasive treatment was unsuccessful. Within this management plan, novel drugs were included such as the capsaicin 8% patch, in addition to invasive techniques in patients who did not respond to noninvasive therapies. [ABSTRACT FROM AUTHOR]

Background Few studies have investigated the relationship between injury location, mechanism and their association with complex regional pain syndrome ( CRPS). We conducted a nationwide database survey to explore this issue. Methods This was a population-based case-control study. Five hundred and eighty-nine patients with at least one ambulatory visit or admission with a principal diagnosis of CRPS from 2004 to 2009 were selected. For each CRPS patient, ten age- and sex-matched non- CRPS subjects were randomly selected. The odds ratios ( PLoS One. 2013;8:e57205) and 95% confidence intervals (95% CIs) of risk factors for CRPS were derived from multivariate logistic regression models. Results Injury was a risk factor for CRPS ( OR, 2.96; 95% CI, 2.18 to 4.02) independent of age and sex. In adjusted models, open wound on the upper limbs ( OR 1.25, 95% CI 1.02 to 1.54) conferred higher CRPS risk. Injury mechanisms including nerve and spinal cord injury ( OR 2.42, 95% CI 1.44 to 4.08), muscle and joint sprain and strain ( OR 1.69, 95% CI 1.40 to 2.03), superficial injury ( OR 1.23, 95% CI 1.00 to 1.51), and contusion ( OR 1.44, 95% CI 1.20 to 1.74), but not fracture, increased the risk of CRPS. Conclusion Injury in the extremities rather than the trunk is an important risk factor for CRPS. Certain injury mechanisms confer higher risk of CRPS. This nationwide study demonstrated that injury increased CRPS nearly threefold. Open wound, sprain and strain, superficial injury, contusion, and nerve and spinal cord injury are main injury mechanisms. Injury in the extremities confers a higher risk of CRPS. [ABSTRACT FROM AUTHOR]

Objectives Our goal was to ascertain the prevalence of widespread pain in our cohort of patients with complex regional pain syndrome ( CRPS). Methods We conducted a retrospective analysis of clinical letters and notes. We assessed data from consecutive patients diagnosed with CRPS according to the Budapest criteria, after a referral to one consultant at a tertiary Pain Medicine referral center. Results Between July 2007 and September 2012, 190 patients (149 females) received a diagnosis of CRPS according to the Budapest criteria, and an additional 26 patients received the diagnosis of CRPS NOS (not otherwise specified). The CRPS patients were an average of 44 years of age, and had a median disease duration of 18 months. Before the CRPS incident trigger, a third had already experienced other than everyday pains in the now CRPS-affected limb. Twenty-one patients (11.1%) experienced widespread pain in clinic, which was often not communicated in the referral letters. The types of triggering traumata and frequencies of Budapest signs and symptoms did not differ between patients with or without widespread pain. All patients considered their widespread pain as an important factor affecting their quality of life; for the majority it was of similar severity to the CRPS pain. Additional patients reported CRPS-concomitant regional pains, most commonly headaches/migraines, lower back pain, and irritable bowel syndrome. Discussion In this systematic assessment of the incidence of widespread pain in a large cohort of patients with CRPS, important widespread pain affected > 10% of patients. Our data support the inclusion of routine enquiries about additional pains in the clinical assessment of patients with CRPS. [ABSTRACT FROM AUTHOR]

Disorders of the skeleton are one of the most common causes of chronic pain and long-term physical disability in the world. Chronic skeletal pain is caused by a remarkably diverse group of conditions including trauma-induced fracture, osteoarthritis, osteoporosis, low back pain, orthopedic procedures, celiac disease, sickle cell disease and bone cancer. While these disorders are diverse, what they share in common is that when chronic skeletal pain occurs in these disorders, there are currently few therapies that can fully control the pain without significant unwanted side effects. In this review we focus on recent advances in our knowledge concerning the unique population of primary afferent sensory nerve fibers that innervate the skeleton, the nociceptive and neuropathic mechanisms that are involved in driving skeletal pain, and the neurochemical and structural changes that can occur in sensory and sympathetic nerve fibers and the CNS in chronic skeletal pain. We also discuss therapies targeting nerve growth factor or sclerostin for treating skeletal pain. These therapies have provided unique insight into the factors that drive skeletal pain and the structural decline that occurs in the aging skeleton. We conclude by discussing how these advances have changed our understanding and potentially the therapeutic options for treating and/or preventing chronic pain in the injured, diseased and aged skeleton. [ABSTRACT FROM AUTHOR]

Background and aims Evidence suggests tumor necrosis factor-alpha (TNF-α) mediates, at least in part, symptoms and signs in complex regional pain syndrome (CRPS). Here, we present a case series of patients with CRPS type 1, in whom the response to the anti- TNF-α adalimumab was assessed. Methods Ten patients with CRPS type 1 were recruited. Assessments were performed before treatment, at 1 week, and 1, 3, and 6 months following 3 biweekly subcutaneous injections (40 mg/0.8 mL) adalimumab (Humira®) and included the followings: Pain intensity using a 0-10 cm visual analog scale; the Short Form of the McGill Pain Questionnaire; the Beck Depression Inventory; the SF-36 questionnaire and mechanical and thermal thresholds (Von frey hair and Thermal Sensory Analyzer, respectively). In addition to the description of individual patient responses, both intention to treat (ITT) and per-protocol (PP) analyses were performed for the entire group. Results Three subgroups of patients were identified (3 patients in each): 'nonresponders', 'partial responders', and 'robust responders' in whom improvement in almost all parameters was noted. Both the ITT and PP analyses demonstrated only a trend toward improvement in mechanical pain thresholds following treatment (ITT χ² = 13.83, P = 0.008; PP χ² = 10.29, P = 0.036). Conclusion These results suggest adalimumab, and possibly other anti- TNF-α, can be potentially useful in some (although not in all) patients with CRPS type 1. These preliminary results along with the growing body of evidence which points to the involvement of TNF-α in the pathogenesis of CRPS justify further studies in this area. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic–pharmacodynamic (PK–PD) modeling study on the effect of S(+)-ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Methods: Sixty CRPS-1 patients were randomly allocated to received a 100-h infusion of S(+)-ketamine or placebo. The drug infusion rate was slowly increased from 5mg/h (per 70kg) to 20mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11weeks. A population PK–PD model was developed to analyze the S(+)-ketamine-pain data. Results: Plasma concentrations of S(+)-ketamine and its metabolite decreased rapidly upon the termination of S(+)-ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 67±10% and 23±9% (population value±SE), respectively. The pain data were well described by the PK–PD model with parameters C 50 =10.5±4.8ng/ml (95% ci 4.37–21.2ng/ml) and t½ for onset/offset=10.9±4.0days (5.3–20.5days). Discussion: Long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present. [Copyright &y& Elsevier]

Abstract: Aims: The aim of the study was to explore the analgesic effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Methods: Ten patients suffering from chronic CRPS-1 and with a Visual Analogue pain Score (VAS) of >5 were recruited. Seven intravenous 5-min low-dose S(+)-ketamine infusions with increasing doses at 20-min intervals were applied. Spontaneous pain ratings and VAS responses to experimental heat stimuli were obtained during infusion and for 3-h following infusion. Results: CRPS pain: Ketamine produced potent analgesia with a significant VAS reduction from 6.2±0.2 to 0.4±0.3cm at the end of infusion. Analgesia persisted beyond the infusion period (VAS =2.8±1.0cm at 5-h), when measured plasma ketamine concentrations were low (<100ng/ml). Experimental pain: Ketamine had a dose-dependent antinociceptive effect on experimental pain that ended immediately upon the termination of infusion. Discussion: The data indicate that while ketamine’s effect on acute experimental pain is driven by pharmacokinetics, its effect on CRPS pain persisted beyond the infusion period when drug concentrations were below the analgesia threshold for acute pain. This indicates a disease modulatory role for ketamine in CRPS-1 pain, possibly via desensitization of NMDAR in the spinal cord or restoration of inhibitory sensory control in the brain. [Copyright &y& Elsevier]

Abstract: After amputation, most patients experience a phenomenon known as a phantom limb (PL). A variety of PL experiences appear to be associated with neural plasticity within the CNS. However, due to the subjective nature of PL experiences, there was no definitive way to reliably assess PL experiences other than using patients’ direct reports. Here, we were able to obtain patients’ indirect responses to PL experiences, for a more objective evaluation. First, we conducted a study with normals and 17 non-PL patients experiencing pathological pain in one hand. We took digital photographs of their affected and unaffected hands, altered the sizes of the images digitally, and then asked each subject to choose the image that most closely matched the actual size of their own hands (from a series of images presented on a video screen). Subjective size perceptions of the hands were homologous, regardless of the pathological condition of one hand (p <0.0001, Spearman R 2 =0.82). Next, we used the same method for total 19 patients with a phantom hand. The intact hand-size perception was linearly correlated with phantom hand-size perception (weighted linear regression analysis: p <0.0001, R 2 =0.75, adjusted R 2 =0.73, F-value=50.1, degree of freedom=18). Thus, without requiring a subjective description about PL, the patients’ evaluation of the intact hand-size precisely but indirectly indicated whether the PL was perceived to be telescoped (shrunken), normal or enlarged. This more objective evaluation of PL phenomena could become a key tool for disentangling the neural mechanisms involved. [Copyright &y& Elsevier]

Abstract: Recent research suggests that changes in cortical structures can contribute to the pathophysiology of Complex Regional Pain Syndrome (CRPS). This review provides an overview of studies showing cortical involvement in CRPS, including mislocalizations of tactile stimuli, changes in size and organization of the somatosensory map, changes in motor cortex representation and body perception disturbances. In addition, we review experimental treatment approaches, such as mirror therapy and motor imagery programs, aimed at restoring the integrity of neural processing in the sensory-motor cortex in individuals with CRPS. The intervention effects are promising and can be theoretically motivated on the basis of established principles of neural organization, although important questions concerning the precise neural mechanisms of action remain unanswered. [Copyright &y& Elsevier]

Abstract: Background: The injection of low dose buprenorphine to the sympathetic ganglia, termed “GLOA”, Ganglionide Local Opioid Analgesia, is used to treat chronic pain in several European centres. It is not known whether the clinically observed GLOA effect in chronic pain syndromes is due to a specific effect of buprenorphine at the ganglia. We assessed whether GLOA, plus intramuscular saline, was more efficacious than the reverse, saline injection to the stellate plus intramuscular buprenorphine, termed SSB. Methods: We devised a randomized, double-blinded, controlled crossover trial to treat patients with chronic upper body pain syndromes. Patients first received either GLOA or SSB. Pain was assessed using pain diaries both before injection and over the first 8h and 6days afterwards, and was expressed as relative pain intensity post versus pre-injection pain. Results: The median relative pain intensity after injections did not differ between GLOA and SSB. Four patients reported a low, <50%, relative pain level over the first 8h after SSB only. Four patients did not complete the trial and were excluded. One patient with cardiomyopathy became acutely diaphoretic and fatigued after GLOA, his vital signs however remained stable. Conclusions: We failed to show a superiority of GLOA over SSB. Our results suggest it unlikely that the clinically observed effect after a single GLOA injection is due to a specific action of buprenorphine at the stellate ganglion. The efficacy of GLOA is hereby questioned. The use of GLOA in patients with cardiomyopathy should be cautioned. Trial registration: ISRCTN59287260; http://www.controlled-trials.com/ [Copyright &y& Elsevier]

Abstract: Patients with chronic neuropathic pain (non-CRPS) and brush-evoked allodynia watched a reflected image of their corresponding but opposite skin region being brushed in a mirror. Unlike complex regional pain syndrome Type 1, this process did not evoke any sensation at the affected area (‘dysynchiria’). We conclude that central nociceptive sensitisation alone is not sufficient to cause dysynchiria in neuropathic pain. The results imply a difference in cortical pain processing between complex regional pain syndrome and other chronic neuropathic pain. [Copyright &y& Elsevier]

Abstract: Complex regional pain syndromes (CRPS) are disabling pain syndromes that can develop after trauma or minor tissue injury affecting a limb. Characteristics of CRPS are sensory signs and symptoms, autonomic abnormalities, trophic changes and an impaired motor function. Pathophysiological mechanisms for the development of CRPS are still a matter of investigation. Based on clinical data and investigations of CRPS patients it is hypothesized that tissue hypoxia and inflammation are important for the development of CRPS. The aim of the current study was therefore to examine if direct ischemia-reperfusion injury can induce behavior in rats with symptoms present in patients with CRPS. After baseline behavior measurements the femoral artery of Wistar rats was ligated for 3h with consecutive reperfusion. Sham-operated rats underwent the same preparation except ligation of the artery. Subsequent behavioral testing (observations of spontaneous pain behavior, paw withdrawal to mechanical, noxious mechanical, cold and heat stimuli) was performed up to two months after surgery. Both in rats that underwent ischemia and in sham-operated rats no obvious changes of hindpaw tissue were observed after ischemia-reperfusion injury (trophic changes, edema, differences in skin color or temperature). In behavioral tests only minor changes were observed, these being not different between postischemic rats and sham-operated rats. Using Wistar rats, our data do not support the idea that an ischemia-reperfusion injury can play a major role in the development of CRPS. [Copyright &y& Elsevier]

Abstract: Complex regional pain syndrome (CRPS) is a disorder characterised by pain, sensory and motor disturbances and represents a significant medical entity. This report discusses two cases of CRPS in children and adolescents, highlighting several critical issues for clinicians in the diagnosis and management of CRPS in these populations. Early diagnosis, referral and appropriate intervention are essential in decreasing pain, suffering and resorting function for children and adolescents with CRPS. [Copyright &y& Elsevier]

Stellate ganglion block is used for the diagnosis and treatment of sympathetically maintained pain syndromes. Multiple anatomic variations and inaccurate sympathetic block may mislead the diagnosis and prevent patients from receiving potentially beneficial interventions. We describe a novel approach to blockade of the sympathetic chain at C7 and at T2 to T3 with a single-needle injection. With the patient in supine position, the uncinate process of C7 is identified fluoroscopically as a target for insertion of a catheter through a Touhy needle. The catheter is directed caudally to the junction of T2 and T3. Contrast injection confirms the spread to the appropriate levels before injection of local anesthetic. This novel approach to blockade of the upper extremity sympathetic innervation may enhance diagnostic accuracy and therapeutic benefit as compared with traditional approaches to the stellate ganglion alone. This approach may be expected to decrease the risk of pneumothorax when compared with the posterior approach to T2 to T3. [ABSTRACT FROM AUTHOR]