Monitoring Everyday Upper Extremity Function in Patients with Complex Regional Pain Syndrome: A Secondary, Retrospective Analysis from ncRNAPain.

Objective: Complex regional pain syndrome (CRPS) represents a rare complication following injury to a limb. The DASH questionnaire (disability of arm, shoulder, and hand) evaluates everyday arm function. We assessed the DASH and its subitems in comparison to patients with brachial plexus lesions or fracture controls, analysed it over time, and in relation to active range of motion (ROM), to determine patients' impairment and trajectory. Methods: The dataset included 193 patients with upper extremity CRPS from the noncoding RNA (ncRNA) Pain cohort, 36 fracture controls, and 12 patients with traumatic brachial plexus lesions. For the clinical and psychological characterisation, questionnaires and a goniometer for the measurement of ROM were utilized. Thirty-three patients were followed up after approximately 2.5 years of guideline treatment. Results: CRPS patients had a similar mean DASH of 54.7 (standard deviation (S.D.) ±21) as brachial plexus lesion patients (M = 51.4, S.D. ± 16.1) but different significantly from fracture controls (M = 21.2, S.D. ± 21.1). Pain and older age were predictors of the DASH. Activities requiring force or impact on the arm, shoulder, or hand were mostly affected in patients with CRPS. After 2.5 years of standard treatment, the mean DASH score fell to 41.3 (S.D. ± 25.2), weakness in leisure activities was recuperated, pain feelings were lessened, and ROM, e.g., wrist flexion, recovered by 36°. Two-thirds of patients improved in both the DASH and the ROM. Conclusions: CRPS is as disabling as a complete loss of arm function in brachial plexus lesions and exhibits only partial recovery. Developing QuickDASH versions for CRPS patients could reduce the load of questions in clinical studies. It would be prudent to consider the unexpected age dependency of the DASH in future studies. This trial is registered with DRKS00008964.

Differential effects of everyday-life social support on chronic pain.

BACKGROUND: Social support is a multidimensional construct encompassing emotional support as well as pain-focused care and attention, also known as solicitous support. One the one hand, social support is widely believed to positively influence pain symptoms, their intensity, and the ability to cope and influence pain. On the other hand, social support can be negative if it conflicts with the patient's needs or even causes discomfort. How different types of social support influence pain is not very well understood especially because most of the present research originates from laboratory studies, raising uncertainties about its generalizability to the everyday life of individuals with chronic pain. METHODS: Here, we tested the effects of emotional, solicitous, and negative social support on pain intensity cross-sectionally in everyday life. We collected data from 20 patients with acute complex regional pain syndrome using a smartphone-based Ecological Momentary Assessment with up to 30 survey prompts over a period of five consecutive days. RESULTS: Our results showed that solicitous social support decreased pain, in particular in male patients. Emotional support was beneficial on pain in women but not in men. CONCLUSIONS: Taken together, these findings highlight the differential effects of social support in every-day life on chronic pain.

Avoidance and Endurance Responses to Pain Before and with Advanced Chronification: Preliminary Results from a Questionnaire Survey in Adult Patients with Non-Cancer Pain Conditions.

Purpose: The Avoidance-Endurance Model postulates fear-avoidance responses and endurance responses as important psychological mechanisms in the development and maintenance of chronic pain. The present study aims to investigate potential differences in avoidance and endurance responses to pain before and with advanced chronification. Patients and Methods: Two samples of adults with non-cancer pain at two different stages of chronicity were compared: One with pain and risk factors for chronicity (n=26, part of the PAIN2020 project) and one with chronic pain (n=33 from a pain day care clinic). The German Pain Questionnaire, the Graded Chronic Pain Scale (GCPS) and medical reports were used to measure duration and severity of pain. Responses to pain were assessed with the Avoidance-Endurance Questionnaire (AEQ) and psychological strain with the Depression, Anxiety and Stress Scales (DASS). Results: Both groups were primarily affected by musculoskeletal pain. Although not yet chronified, the risk group reported comparable GCPS levels of pain intensity and disability. Depression and stress ratings were also similar, except for anxiety, which was significantly elevated in the chronic pain sample (p<.001). The AEQ scales did not differ between groups, neither on any of the fear-avoidance- nor endurance-related dimensions. A post-hoc regression analysis revealed a significant prediction of fear-avoidance by pain-related disability (p<.001). The regression model for endurance responses was not significant. Conclusion: Patients with risk factors of chronification experience substantial pain-related burden. Responses to pain in the realm of the Avoidance-Endurance model do not appear to vary as a function of chronification. While fear-avoidance and pain-related disability correlate positively, endurance could not be associated to any of our variables.

Comparative Methods for Demystifying Spatial Transcriptomics.

Spatial Transcriptomics (ST), coined as the term for parallel RNA-Seq on cell populations ordered spatially on a histological tissue section, has recently become increasingly popular, especially in experiments where microfluidics-based single-cell sequencing fails, such as assays on neurons. ST platforms, like the 10x Visium technology investigated herein, therefore produce in a single experiment simultaneously thousands of RNA readouts, captured by an array of micrometer scale spots under the histological section. Therefore, a central challenge of analyzing ST experiments consists of analyzing the gene expression morphology of all spots to delineate clusters of similar cell mixtures, which are then compared to each other to identify up- or down-regulated marker genes. Moreover, another level of complexity in ST experiments, compared to traditional RNA-Seq, is imposed by staining the tissue section with protein markers of cells or cell components to identify spots providing relevant information afterward. The corresponding microscopy images need to be analyzed in addition to the RNA-Seq read mappings on the reference genome and transcriptome sequences. Focusing on the software suite provided by the Visium platform manufacturer, we break down the ST analysis pipeline into its four essential steps-the image analysis, the read alignment, the gene quantification, and the spot clustering-and compare results obtained when using reads from different subsets of spots and/or when employing alternative genome or transcriptome references. Our comparative analyses demonstrate the impact of spot selection and the choice of genome/transcriptome references on the analysis results when employing the manufacturer's pipeline.

The Effect of Everyday-Life Social Contact on Pain.

Pain is a biopsychosocial phenomenon, resulting from the interplay between physiological and psychological processes and social factors. Given that humans constantly interact with others, the effect of social factors is particularly relevant. Documenting the significance of the social modulation of pain, an increasing number of studies have investigated the effect of social contact on subjective pain intensity and pain-related physiological changes. While evidence suggests that social contact can alleviate pain, contradictory findings indicate an increase in pain intensity and a deterioration of pain coping strategies. This evidence primarily stems from studies examining the effect of social contact on pain within highly controlled laboratory conditions. Moreover, pain assessments often rely on one-time subjective reports of average pain intensity across a predefined period. Ecological momentary assessments (EMAs) can circumvent these problems, as they can capture diverse aspects of behavior and experiences multiple times a day, in real time, with high resolution, and within naturalistic and ecologically valid settings. These multiple measures allow for the examination of fluctuations of pain symptoms throughout the day in relation to affective, cognitive, behavioral, and social factors. In this opinion paper, we review the current state and future relevance of EMA-based social pain research in daily life. Specifically, we examine whether everyday-life social support reduces or enhances pain. The first part of the paper provides a comprehensive overview of the use of EMA in pain research and summarizes the main findings. The review of the relatively limited number of existing EMA studies shows that the association between pain and social contact in everyday life depends on numerous factors, including pain syndromes, temporal dynamics, the nature of social interactions, and characteristics of the interaction partners. In line with laboratory research, there is evidence that everyday-life social contact can alleviate, but also intensify pain, depending on the type of social support. Everyday-life emotional support seems to reduce pain, while extensive solicitous support was found to have opposite effects. Moreover, positive short-term effects of social support can be overshadowed by other symptoms such as fatigue. Overall, gathering and integrating experiences from a patient's social environment can offer valuable insights. These insights can help interpret dynamics in pain intensity and accompanying symptoms such as depression or fatigue. We conclude that factors determining the reducing versus enhancing effects of social contact on pain need to be investigated more thoroughly. We advocate EMA as the assessment method of the future and highlight open questions that should be addressed in future EMA studies on pain and the potential of ecological momentary interventions for pain treatment.

Different pain phenotypes are associated with anti-Caspr2 autoantibodies.

Autoantibodies against contactin-associated protein 2 (Caspr2) not only induce limbic autoimmune encephalitis but are also associated with pain conditions. Here, we analyzed clinical data on pain in a large cohort of patients included into the German Network for Research in Autoimmune Encephalitis. Out of 102 patients in our cohort, pain was a frequent symptom (36% of all patients), often severe (63.6% of the patients with pain) and/or even the major symptom (55.6% of the patients with pain). Pain phenotypes differed between patients. Cluster analysis revealed two major phenotypes including mostly distal-symmetric burning pain and widespread pain with myalgia and cramps. Almost all patients had IgG4 autoantibodies and some additional IgG1, 2, and/or 3 autoantibodies, but IgG subclasses, titers, and presence or absence of intrathecal synthesis were not associated with the occurrence of pain. However, certain pre-existing risk factors for chronic pain like diabetes mellitus, peripheral neuropathy, or preexisting chronic back pain tended to occur more frequently in patients with anti-Caspr2 autoantibodies and pain. Our data show that pain is a relevant symptom in patients with anti-Caspr2 autoantibodies and support the idea of decreased algesic thresholds leading to pain. Testing for anti-Caspr2 autoantibodies needs to be considered in patients with various pain phenotypes.

Bilateral deficiency of Meissner corpuscles and papillary microvessels in patients with acute complex regional pain syndrome.

ABSTRACT: Complex regional pain syndrome (CRPS) presents postinjury with disproportionate pain and neuropathic, autonomic, motor symptoms, and skin texture affection. However, the origin of these multiplex changes is unclear. Skin biopsies offer a window to analyze the somatosensory and vascular system as well as skin trophicity with their protecting barriers. In previous studies, barrier-protective exosomal microRNAs were altered in CRPS. We here postulated that tissue architecture and barrier proteins are already altered at the beginning of CRPS. We analyzed ipsilateral and contralateral skin biopsies of 20 fully phenotyped early CRPS patients compared with 20 age- and sex-matched healthy controls. We established several automated unbiased methods to comprehensively analyze microvessels and somatosensory receptors as well as barrier proteins, including claudin-1, claudin-5, and claudin-19. Meissner corpuscles in the skin were bilaterally reduced in acute CRPS patients with some of them lacking these completely. The number of Merkel cells and the intraepidermal nerve fiber density were not different between the groups. Dermal papillary microvessels were bilaterally less abundant in CRPS, especially in patients with allodynia. Barrier proteins in keratinocytes, perineurium of dermal nerves, Schwann cells, and papillary microvessels were not affected in early CRPS. Bilateral changes in the tissue architecture in early CRPS might indicate a predisposition for CRPS that manifests after injury. Further studies should evaluate whether these changes might be used to identify risk patients for CRPS after trauma and as biomarkers for outcome.

Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed. METHODS: We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells. RESULTS: Intraepidermal Schwann cells were detected in human skin of the finger-but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other-but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin. CONCLUSIONS: Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.

Lessons learned in translating pain knowledge into practice.

Introduction: During the past 2 decades, basic research deciphering the underlying mechanisms of nociception and chronic pain was thought to finally step beyond opioids and nonsteroidals and provide patients with new analgesics. But apart from calcitonin gene-related peptide antagonists, nothing arrived in hands of clinicians. Objectives: To present existing evidence of 3 representative target molecules in the development of novel pain treatment that, so far, did not result in approved drugs. Methods: This Clinical Update aligns with the 2022 IASP Global Year Translating Pain Knowledge into Practice and selectively reviews best available evidence and practice. Results: We highlight 3 targets: a ion channel, a neuronal growth factor, and a neuropeptide to explore why these drug targets have been dropped in clinical phase II-III trials. Antibodies to nerve growth factor had very good effects in musculoskeletal pain but resulted into more patients requiring joint replacements. Blockers of NaV1.7 were often not effective enough-at least if patients were not stratified. Blockers of neurokinin receptor were similarly not successful enough. In general, failure was most often to the result of a lack of effect and to a lesser extend because of unexpected severe side effects. However, all studies and trials lead to an enormous move in the scientific community to better preclinical models and testing as well as revised methods to molecularly phenotype and stratify patients. Conclusion: All stakeholders in the process can help in the future: better preclinical studies, phenotyping and stratifying patients, and participation in clinical trials to move the discovery of analgesics forward.

Myelin barrier breakdown, mechanical hypersensitivity, and painfulness in polyneuropathy with claudin-12 deficiency.

BACKGROUND: The blood-nerve and myelin barrier shield peripheral neurons and their axons. These barriers are sealed by tight junction proteins, which control the passage of potentially noxious molecules including proinflammatory cytokines via paracellular pathways. Peripheral nerve barrier breakdown occurs in various neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and traumatic neuropathy. Here, we studied the functional role of the tight junction protein claudin-12 in regulating peripheral nerve barrier integrity and CIDP pathogenesis. METHODS: Sections from sural nerve biopsies from 23 patients with CIDP and non-inflammatory idiopathic polyneuropathy (PNP) were analyzed for claudin-12 and -19 immunoreactivity. Cldn12-KO mice were generated and subjected to the chronic constriction injury (CCI) model of neuropathy. These mice were then characterized using a battery of barrier and behavioral tests, histology, immunohistochemistry, and mRNA/protein expression. In phenotype rescue experiments, the proinflammatory cytokine TNFα was neutralized with the anti-TNFα antibody etanercept; the peripheral nerve barrier was stabilized with the sonic hedgehog agonist smoothened (SAG). RESULTS: Compared to those without pain, patients with painful neuropathy exhibited reduced claudin-12 expression independently of fiber loss. Accordingly, global Cldn12-KO in male mice, but not fertile female mice, selectively caused mechanical allodynia associated with a leaky myelin barrier, increased TNFα, decreased sonic hedgehog (SHH), and loss of small axons accompanied by reduced peripheral myelin protein 22 (Pmp22). Other barriers and neurological functions remained intact. The Cldn12-KO phenotype could be rescued either by neutralizing TNFα with etanercept or stabilizing the barrier with SAG, which both also upregulated the Schwann cell barrier proteins Cldn19 and Pmp22. CONCLUSION: These results point to a critical role for claudin-12 in maintaining the myelin barrier presumably via Pmp22 and highlight restoration of the hedgehog pathway as a potential treatment strategy for painful inflammatory neuropathy.

Stabilizing the neural barrier - A novel approach in pain therapy.

Chronic and neuropathic pain are a widespread burden. Incomplete understanding of underlying pathomechanisms is one crucial factor for insufficient treatment. Recently, impairment of the blood nerve barrier (BNB) has emerged as one key aspect of pain initiation and maintenance. In this narrative review, we discuss several mechanisms and putative targets for novel treatment strategies. Cells such as pericytes, local mediators like netrin-1 and specialized proresolving mediators (SPMs), will be covered as well as circulating factors including the hormones cortisol and oestrogen and microRNAs. They are crucial in either the BNB or similar barriers and associated with pain. While clinical studies are still scarce, these findings might provide valuable insight into mechanisms and nurture development of therapeutic approaches.

Bortezomib induced peripheral neuropathy and single nucleotide polymorphisms in PKNOX1.

We analyzed single nucleotide polymorphisms (SNPs) in PKNOX1 (rs2839629) and in the intergenic region between PKNOX1 and CBS (rs915854) by Sanger sequencing in 88 patients with multiple myeloma treated with bortezomib. All patients (n = 13) harboring a homozygous mutation in PKNOX1 (rs2839629) also had a homozygous mutated rs915854 genotype. Homozygous mutated genotypes of rs2839629 and rs915854 were significantly enriched in patients with painful peripheral neuropathy (PNP) (P < 0.0001), and homozygous mutated rs2839629 genotype was significantly enriched in patients with pain compared to patients with no pain (P = 0.04). In summary, both SNPs rs2839629 and/or rs915854 may be potential biomarkers predicting an increased risk to develop painful PNP under bortezomib.

Systemic inflammatory markers in patients with polyneuropathies.

Introduction: In patients with peripheral neuropathies (PNP), neuropathic pain is present in 50% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation. Methods: To test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls. Results: While we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction. Conclusion: In patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies.

Neurofilament light chain levels indicate acute axonal damage under bortezomib treatment.

INTRODUCTION: Bortezomib (BTZ) is a selective and reversible proteasome inhibitor and first line treatment for multiple myeloma (MM). One of the side effects is BTZ-induced peripheral neuropathy (BIPN). Until now there is no biomarker which can predict this side effect and its severity. Neurofilament light chain (NfL) is a neuron specific cytoskeletal protein, of which higher levels can be detected in peripheral blood in case of axon damage. In this study, we aimed to evaluate the relationship between NfL serum levels and characteristics of BIPN. METHODS: We performed a first interim analysis of a monocentric, non-randomized, observational clinical trial including 70 patients (DRKS00025422) diagnosed with MM in the inclusion period of June 2021 until March 2022. Two groups of patients-one with ongoing BTZ treatment at the time of recruiting, and one with BTZ treatment in the past-were compared to controls. NfL in serum was analyzed via the ELLA™ device. RESULTS: Both patients with previous and ongoing BTZ treatment had higher serum NfL levels than controls, and patients with ongoing BTZ treatment had higher NfL levels than patients with BTZ treatment in the past. Serum NfL levels correlated with electrophysiological measures of axonal damage in the group with ongoing BTZ treatment. CONCLUSION: Elevated NfL levels indicate acute axonal damage under BTZ in MM patients.

Molecular and clinical markers of pain relief in complex regional pain syndrome: An observational study.

BACKGROUND: Complex regional pain syndrome (CRPS) is marked by disproportionate pain after trauma. Whilst the long-term outcome is crucial to patients, predictors or biomarkers of the course of pain or CRPS symptoms are still lacking. In particular, microRNAs, such as miR-223, decreased in CRPS, have been described only in cross-sectional studies. METHODS: In this study, we characterised CRPS patients over a course of 2.5 years of standard treatment. The patient underwent clinical examination including pain measurement, symptom questionnaires, quantitative sensory testing (QST) and blood sampling. Exosomal microRNA levels were measured via qPCR. After follow-up, patients were stratified into 'pain relief' (mean pain reduced by ≥2 numeric rating scale) or 'persistence' (mean pain unchanged or worsened). The primary outcome was miR-223 and miR-939 expression, secondary outcomes were differences in clinical parameters between groups and time points. RESULTS: Thirty-nine patients were included, 33 of whom qualified for stratification. Overall, patients reported lower pain and improved clinical characteristics after 2.5 years, but no significant changes in QST or miR-223 and miR-939 expression levels. 16 patients met the criteria for pain relief. This was associated with stable exosomal miR-223 expression, whilst levels further decreased in pain persistence. Clinically, pain relief was marked by shorter disease duration and correlated positively with high initial pain. CONCLUSION: We identified progressively reduced miR-223 as a putative biomarker of chronic CRPS pain. Clinically, this study underlines the importance of early diagnosis and treatment showing that high initial pain does not predict an unfavourable outcome. Finally, pain relief and recovery of sensory disturbances seem independent processes.

Unbiased analysis of the dorsal root ganglion after peripheral nerve injury: no neuronal loss, no gliosis, but satellite glial cell plasticity.

ABSTRACT: Pain syndromes are often accompanied by complex molecular and cellular changes in dorsal root ganglia (DRG). However, the evaluation of cellular plasticity in the DRG is often performed by heuristic manual analysis of a small number of representative microscopy image fields. In this study, we introduce a deep learning-based strategy for objective and unbiased analysis of neurons and satellite glial cells (SGCs) in the DRG. To validate the approach experimentally, we examined serial sections of the rat DRG after spared nerve injury (SNI) or sham surgery. Sections were stained for neurofilament, glial fibrillary acidic protein (GFAP), and glutamine synthetase (GS) and imaged using high-resolution large-field (tile) microscopy. After training of deep learning models on consensus information of different experts, thousands of image features in DRG sections were analyzed. We used known (GFAP upregulation), controversial (neuronal loss), and novel (SGC phenotype switch) changes to evaluate the method. In our data, the number of DRG neurons was similar 14 d after SNI vs sham. In GFAP-positive subareas, the percentage of neurons in proximity to GFAP-positive cells increased after SNI. In contrast, GS-positive signals, and the percentage of neurons in proximity to GS-positive SGCs decreased after SNI. Changes in GS and GFAP levels could be linked to specific DRG neuron subgroups of different size. Hence, we could not detect gliosis but plasticity changes in the SGC marker expression. Our objective analysis of DRG tissue after peripheral nerve injury shows cellular plasticity responses of SGCs in the whole DRG but neither injury-induced neuronal death nor gliosis.

MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury.

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.

Transient hypoalgesia after COVID-19 infection.

Introduction: Loss of smell or taste are often-cited complications during COVID-19 disease, but there is no clear evidence for affection of the peripheral nervous system. Methods: Here, we report a 48-year-old man presenting with persistent dysgeusia and hypoalgesia of the lower legs, hands, and cheeks after COVID-19 infection in Spring 2020. Results: Upon clinical examination 7 months after the infection, the patient could not feel pain after pinprick stimuli. Quantitative sensory testing revealed increased thermal detection thresholds at the face but no changes at the foot. Electrical C-fiber stimulation elicited lower pain ratings at the distal leg compared with the proximal leg, but overall higher pain ratings than in healthy control subjects. The axon flare reaction in response to histamine and acetylcholine was almost absent with no pain sensation. Skin punch biopsy revealed a reduced intraepidermal nerve fiber density at the lower leg, and transient receptor potential vanilloid 1 and calcitonin gene-related peptide immunoreactivity were similar to a healthy control. Symptoms and positive tests improved 5 months later. Conclusion: In summary, we describe a case of hypoalgesia after COVID-19 disease. Studies investigating long-COVID syndrome should test not only for painful neuropathic symptoms but also for hypoalgesia, especially in patients with prolonged dysgeusia.

Microvascular Barrier Protection by microRNA-183 via FoxO1 Repression: A Pathway Disturbed in Neuropathy and Complex Regional Pain Syndrome.

Blood nerve barrier disruption and edema are common in neuropathic pain as well as in complex regional pain syndrome (CRPS). MicroRNAs (miRNA) are epigenetic multitarget switches controlling neuronal and non-neuronal cells in pain. The miR-183 complex attenuates hyperexcitability in nociceptors, but additional non-neuronal effects via transcription factors could contribute as well. This study explored exosomal miR-183 in CRPS and murine neuropathy, its effect on the microvascular barrier via transcription factor FoxO1 and tight junction protein claudin-5, and its antihyperalgesic potential. Sciatic miR-183 decreased after CCI. Substitution with perineural miR-183 mimic attenuated mechanical hypersensitivity and restored blood nerve barrier function. In vitro, serum from CCI mice und CRPS patients weakened the microvascular barrier of murine cerebellar endothelial cells, increased active FoxO1 and reduced claudin-5, concomitant with a lack of exosomal miR-183 in CRPS patients. Cellular stress also compromised the microvascular barrier which was rescued either by miR-183 mimic via FoxO1 repression or by prior silencing of Foxo1. PERSPECTIVE: Low miR-183 leading to barrier impairment via FoxO1 and subsequent claudin-5 suppression is a new aspect in the pathophysiology of CRPS and neuropathic pain. This pathway might help untangle the wide symptomatic range of CRPS and nurture further research into miRNA mimics or FoxO1 inhibitors.