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Purpose Physiotherapy interventions are prescribed as first-line treatment for people with sciatica; however, their effectiveness remains controversial. The purpose of this systematic review was to establish the short-, medium- and long-term effectiveness of physiotherapy interventions compared to control interventions for people with clinically diagnosed sciatica. Methods This systematic review was registered on PROSPERO CRD42018103900. Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), Embase, PEDro, PubMed, Scopus and grey literature were searched from inception to January 2021 without language restrictions. Inclusion criteria were randomised controlled trials evaluating physiotherapy interventions compared to a control intervention in people with clinical or imaging diagnosis of sciatica. Primary outcome measures were pain and disability. Study selection and data extraction were performed by two independent reviewers with consensus reached by discussion or third-party arbitration if required. Risk of bias was assessed independently by two reviewers using the Cochrane Risk of Bias tool with third-party consensus if required. Meta-analyses and sensitivity analyses were performed with random effects models using Revman v5.4. Subgroup analyses were undertaken to examine the effectiveness of physiotherapy interventions compared to minimal (e.g. advice only) or substantial control interventions (e.g. surgery). Results Three thousand nine hundred and fifty eight records were identified, of which 18 trials were included, with a total number of 2699 participants. All trials had a high or unclear risk of bias. Meta-analysis of trials for the outcome of pain showed no difference in the short (SMD − 0.34 [95%CI − 1.05, 0.37] p = 0.34, I2 = 98%), medium (SMD 0.15 [95%CI − 0.09, 0.38], p = 0.22, I2 = 80%) or long term (SMD 0.09 [95%CI − 0.18, 0.36], p = 0.51, I2 = 82%). For disability there was no difference in the short (SMD − 0.00 [95%CI − 0.36, 0.35], p = 0.98, I2 = 92%, medium (SMD 0.25 [95%CI − 0.04, 0.55] p = 0.09, I2 = 87%), or long term (SMD 0.26 [95%CI − 0.16, 0.68] p = 0.22, I2 = 92%) between physiotherapy and control interventions. Subgroup analysis of studies comparing physiotherapy with minimal intervention favoured physiotherapy for pain at the long-term time points. Large confidence intervals and high heterogeneity indicate substantial uncertainly surrounding these estimates. Many trials evaluating physiotherapy intervention compared to substantial intervention did not use contemporary physiotherapy interventions. Conclusion Based on currently available, mostly high risk of bias and highly heterogeneous data, there is inadequate evidence to make clinical recommendations on the effectiveness of physiotherapy interventions for people with clinically diagnosed sciatica. Future studies should aim to reduce clinical heterogeneity and to use contemporary physiotherapy interventions.

This preclinical systematic review aimed to determine the effectiveness of different types and doses of exercise on pain behaviour and biomarkers in preclinical models of focal neuropathic pain. We searched MEDLINE, EMBASE, Web of Science, PubMed, SCOPUS, CINAHL and Cochrane library from inception to November 2022 for preclinical studies evaluating the effect of exercise compared to control interventions on neuropathic pain behaviour after experimental sciatic nerve injury. If possible, data were meta-analysed using random effect models with inverse-variance weighting. Thirty-seven studies were included and 26 meta-analysed. Risk of bias (SYRCLE tool) remained unclear in most studies and reporting quality (CAMARADES) was variable. Exercise reduced mechanical (SMD 0.53 (95% CI 0.31, 0.74), p= 0.0001, I2=0%, n=364), heat (0.32 (0.07,0.57), p=0.01, I2=0%, n=266) and cold hypersensitivity (0.51 (0.03, 1.0), p=0.04, I2=0%, n=90) compared to control interventions. No relationship was apparent between exercise duration or intensity and antinociception. Exercise modulated biomarkers related to different systems (e.g., immune system, neurotrophins). Whereas firm conclusions are prevented by the use of male animals only, variable reporting quality and unclear risk of bias in many studies, our results suggest that aerobic exercise is a promising tool in the management of focal neuropathic pain. Registration PROSPERO CRD42021231286. Perspective: This systematic review and meta-analysis demonstrates that aerobic exercise reduces neuropathic pain-related behavior in preclinical models of sciatic nerve injury. This effect is accompanied by changes in biomarkers associated with inflammation and neurotrophins among others. These results could help to develop exercise interventions for patients with neuropathic pain.

Background Trigger finger and carpal tunnel syndrome are the two most common non-traumatic connective tissue disorders of the hand. Both of these conditions frequently co-occur, often in patients with rheumatoid arthritis. However, this phenotypic association is poorly understood. Hypothesising that the co-occurrence of trigger finger and carpal tunnel syndrome might be explained by shared germline predisposition, we aimed to identify a specific genetic locus associated with both diseases. Methods In this genome-wide association study (GWAS), we identified 2908 patients with trigger finger and 436 579 controls from the UK Biobank prospective cohort. We conducted a case-control GWAS for trigger finger, followed by co-localisation analyses with carpal tunnel syndrome summary statistics. To identify putative causal variants and establish their biological relevance, we did fine-mapping analyses and expression quantitative trait loci (eQTL) analyses, using fibroblasts from healthy donors (n=79) and tenosynovium samples from patients with carpal tunnel syndrome (n=77). We conducted a Cox regression for time to trigger finger and carpal tunnel syndrome diagnosis against plasma IGF-1 concentrations in the UK Biobank cohort. Findings Phenome-wide analyses confirmed a marked association between carpal tunnel syndrome and trigger finger in the participants from UK Biobank (odds ratio [OR] 11·97, 95% CI 11·1–13·0; p−300). GWAS for trigger finger identified five independent loci, including one locus, DIRC3, that was co-localised with carpal tunnel syndrome and could be fine-mapped to rs62175241 (0·76, 0·68–0·84; p=5·03 × 10−13). eQTL analyses found a fibroblast-specific association between the protective T allele of rs62175241 and increased DIRC3 and IGFBP5 expression. Increased plasma IGF-1 concentrations were associated with both carpal tunnel syndrome and trigger finger in participants from UK Biobank (hazard ratio >1·04, p Interpretation In this GWAS, the DIRC3 locus on chromosome 2 was significantly associated with both carpal tunnel syndrome and trigger finger, possibly explaining their co-occurrence. The disease-protective allele of rs62175241 was associated with increased expression of long non-coding RNA DIRC3 and its transcriptional target, IGBP5, an antagonist of IGF-1 signalling. These findings suggest a model in which IGF-1 is a driver of both carpal tunnel syndrome and trigger finger, and in which the DIRC3-IGFBP5 axis directly antagonises fibroblastic IGF-1 signalling.

Neurological testing is essential for screening and diagnosing suspected peripheral neuropathies. Detecting changes in somatosensory and motor nerve function can also have direct implications for management decisions. Nevertheless, there is considerable variation in what is included in a bedside neurological examination, and how it is performed. Neurological examinations are often used as screening tools to detect neurological deficits, but not used to their full potential for monitoring progress or deterioration. Here, we advocate for better use of the neurological examination within a clinical reasoning framework. Constrained by the lack of research in this field, our viewpoint is based on neuroscientific principles. We highlight six challenges for clinicians when conducting neurological examinations, and propose ways to overcome these challenges in clinical practice. We challenge widely held ideas about how the results of neurological examinations for peripheral neuropathies are interpreted and how the examinations are performed in practice.

Nervenkompressionssyndrome („Engpass-Syndrome“) wie Karpaltunnelsyndrom, Radikulopathien oder radikularer Schmerz sind die haufigsten peripheren Nervenlasionen und auch die haufigste Ursache fur neuropathischen Schmerz. Trotz ihrer hohen Pravalenz stellen sie diagnostisch und therapeutisch weiterhin oft eine klinische Herausforderung dar. Die vorliegende Ubersicht bietet aktuelle Informationen zur Atiologie und Pathophysiologie von Nervenkompressionssyndromen; dafur wird die Evidenz aus praklinischen wie auch klinischen Studien zusammengefasst. Mogliche Mechanismen werden in den Kontext klinischer Befunde gestellt. Das aktuelle diagnostische Vorgehen wird erortert, diagnostische Fallstricke werden beleuchtet. Zuletzt fasst der Beitrag die Evidenz fur die nichtinvasive und chirurgische Therapie haufiger Nervenkompressionssyndrome zusammen und zeigt zukunftige Forschungsbereiche auf.

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is “wind-up,” in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting., Neuron, 110 (16)

IntroductionSciatica is a common condition and is associated with higher levels of pain, disability, poorer quality of life, and increased use of health resources compared with low back pain alone. Although many patients recover, a third develop persistent sciatica symptoms. It remains unclear, why some patients develop persistent sciatica as none of the traditionally considered clinical parameters (eg, symptom severity, routine MRI) are consistent prognostic factors.The FORECAST study (factors predicting the transition from acute to persistent pain in people with ‘sciatica’) will take a different approach by exploring mechanism-based subgroups in patients with sciatica and investigate whether a mechanism-based approach can identify factors that predict pain persistence in patients with sciatica.Methods and analysisWe will perform a prospective longitudinal cohort study including 180 people with acute/subacute sciatica. N=168 healthy participants will provide normative data. A detailed set of variables will be assessed within 3 months after sciatica onset. This will include self-reported sensory and psychosocial profiles, quantitative sensory testing, blood inflammatory markers and advanced neuroimaging. We will determine outcome with the Sciatica Bothersomeness Index and a Numerical Pain Rating Scale for leg pain severity at 3 and 12 months.We will use principal component analysis followed by clustering methods to identify subgroups. Univariate associations and machine learning methods optimised for high dimensional small data sets will be used to identify the most powerful predictors and model selection/accuracy.The results will provide crucial information about the pathophysiological drivers of sciatica symptoms and may identify prognostic factors of pain persistence.Ethics and disseminationThe FORECAST study has received ethical approval (South Central Oxford C, 18/SC/0263). The dissemination strategy will be guided by our patient and public engagement activities and will include peer-reviewed publications, conference presentations, social media and podcasts.Trial registration numberISRCTN18170726; Pre-results.

The role that inflammation plays in human nerve injury and neuropathic pain is incompletely understood. Previous studies highlight the role of inflammation in the generation and maintenance of neuropathic pain, but the emerging evidence from the preclinical literature for its role in the resolution of neuropathic pain remains to be explored in humans. Here, we use carpal tunnel syndrome (CTS) as a human model system of nerve injury and neuropathic pain to determine changes in serum cytokine protein levels and gene expression levels before (active stage of disease) and after carpal tunnel decompression surgery (recovery). Fifty-five patients with CTS were studied, and 21 healthy age-matched and gender-matched participants served as controls. In the active stage of the disease (CTS before surgery vs healthy controls), PTGES2 mRNA was decreased in patients (adjusted P = 0.013), while transforming growth factor-β and C-C motif chemokine ligand 5 protein levels were increased (adjusted P = 0.016 and P = 0.047, respectively). In the resolution phase (CTS before surgery vs after surgery), IL-9 mRNA was increased after surgery (adjusted P = 0.014) and expression of IL-6 mRNA and IL-4 protein levels were increased before surgery (adjusted P = 0.034 and P = 0.002, respectively). IL-9 mRNA expression negatively correlated with several (neuropathic) pain scores. By contrast, protein levels of IL-4 positively correlated with pain scores. In conclusion, we demonstrate specific dysregulation of systemic cytokine expression in both the active and resolution phases of nerve injury and neuropathic pain. IL-9 represents an interesting candidate associated with resolution of nerve injury and neuropathic pain.

Central sensitization is a physiological mechanism associated with enhanced sensitivity and pain responses. At present, central sensitization cannot be determined directly in humans, but certain signs and symptoms may be suggestive of it. Although central sensitization has received increasing attention in the clinical literature, there is a risk that certain distinctions are being lost. This paper summarizes current knowledge of the physiology of central sensitization and its possible manifestations in patients, in order to inform a debate about the relevance of central sensitization for physical therapists. It poses 6 challenges associated with the application of central sensitization concepts in clinical practice and makes suggestions for assessment, treatment, and use of terminology. Physical therapists are asked to be mindful of central sensitization and consider potential top-down as well as bottom-up drivers, in the context of a person-centered biopsychosocial approach.

Supplemental Digital Content is Available in the Text. The severity more than the presence of neuropathic pain is related to the extent of neuropathy and a compromise of emotional well-being in entrapment neuropathies., It currently remains unclear why some patients with entrapment neuropathies develop neuropathic pain (neuP), whereas others have non-neuP, presumably of nociceptive character. Studying patients with carpal tunnel syndrome (CTS), this cross-sectional cohort study investigated changes in somatosensory structure and function as well as emotional well-being specific to the presence and severity of neuP. Patients with CTS (n = 108) were subgrouped by the DN4 questionnaire into those without and with neuP. The latter group was further subdivided into mild and moderate/severe neuP using a pain visual analogue scale. N = 32 participants served as healthy controls. All participants underwent a clinical examination, quantitative sensory testing, electrodiagnostic testing (EDT), and skin biopsy to determine the structural integrity of dermal and intraepidermal nerve fibres. Patients also completed questionnaires evaluating symptom severity and functional deficits, pain distribution, sleep quality, and emotional well-being. The overall prevalence of neuP in patients with CTS was 80%, of which 63% had mild neuP. Symptom severity and functional deficits as well as somatosensory dysfunction was more pronounced with the presence and increasing severity of neuP. No difference was identified among patient groups for EDT and nerve fibre integrity on biopsies. The severity of neuP was accompanied by more pronounced deficits in emotional well-being and sleep quality. Intriguingly, extraterritorial spread of symptoms was more prevalent in patients with moderate/severe neuP, indicating the presence of central mechanisms. NeuP is common in patients with CTS, and its severity is related to the extent of somatosensory dysfunction and a compromise of emotional well-being.

Question: In people with carpal tunnel syndrome who are waitlisted for surgical consultation, does a therapist-led care pathway involving education, splinting and exercises reduce the need for surgery and improve patient outcomes? Design: A multicentre, randomised controlled trial with concealed allocation, blinded assessment and intention-to-treat analysis. Participants: One hundred and five people with electrodiagnostically confirmed carpal tunnel syndrome on a waitlist for surgical consultation and recruited from four public hospitals in Australia. Interventions: The experimental group (n = 52) received a one-off group session of education, splinting, and nerve and tendon gliding exercises. The control group (n = 53) continued on the waitlist without additional care. Outcome Measures: The primary outcome measures were conversion to surgery by 24 weeks, the global rating of change (GROC) scale and patient satisfaction. Secondary outcomes included symptom severity and functional limitation. Results: At 24 weeks, conversion to surgery was 59% in the experimental group and 80% in the control group (risk difference −0.21, 95% CI −0.38 to −0.03). More participants in the experimental group identified as improved at 6 weeks (20% vs 4%; risk difference 0.15, 95% CI 0.03 to 0.28) but not at 24 weeks (24% vs 10%; risk difference 0.14, 95% CI −0.01 to 0.29). The intervention was also estimated to be beneficial on some measures of satisfaction, symptom severity and functional limitation. The study’s estimates of the benefits came with some uncertainty, which makes it unclear whether the wider population of people awaiting carpal tunnel surgery would consider that the benefits make the intervention worthwhile. No serious adverse effects were reported. Conclusions: A therapist-led pathway reduced conversion to carpal tunnel surgery and increased perceived improvement and satisfaction in people who were already on a waitlist for surgical consultation. Registration: ACTRN12613001095752.

The purpose of this systematic review was to evaluate the effects of physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain (PNP). The search was performed in Pubmed, Web of Science, EMBASE, Cochrane, Cinhal, Psycinfo, Scopus, Medline, and Science Direct. Studies evaluating any type of physiotherapy intervention for PNP (systemic or traumatic) were included. Eighty-one articles were included in this review. The most common PNP model was chronic constriction injury, and the most frequently studied biomarkers were related to neuro-immune processes. Exercise therapy and Electro-acupuncture were the 2 most frequently studied physiotherapy interventions while acupuncture and joint mobilization were less frequently examined. Most physiotherapeutic interventions modulated the expression of biomarkers related to neuropathic pain. Whereas the results seem promising; they have to be considered with caution due to the high risk of bias of included studies and high heterogeneity of the type and anatomical localization of biomarkers reported. The review protocol is registered on PROSPERO (CRD42019142878). Perspective This article presents the current evidence about physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain. Existing findings are reviewed, and relevant data are provided on the effectiveness of each physiotherapeutic modality, as well as its certainty of evidence and clinical applicability. post-print 761 KB

Purpose Proprioceptive deficits are common in low back pain. The multifidus muscle undergoes substantial structural change after back injury, but whether muscle spindles are affected is unclear. This study investigated whether muscle spindles of the multifidus muscle are changed by intervertebral disc (IVD) degeneration in a large animal model. Methods IVD degeneration was induced by partial thickness annulus fibrosus lesion to the L3-4 IVD in nine sheep. Multifidus muscle tissue at L4 was harvested at six months after lesion, and from six age-/sex-matched naïve control animals. Muscle spindles were identified in Van Gieson’s-stained sections by morphology. The number, location and cross-sectional area (CSA) of spindles, the number, type and CSA of intrafusal fibers, and thickness of the spindle capsule were measured. Immunofluorescence assays examined Collagen I and III expression. Results Multifidus muscle spindles were located centrally in the muscle and generally near connective tissue. There were no differences in the number or location of muscle spindles after IVD degeneration and only changes in the CSA of nuclear chain fibers. The thickness of connective tissue surrounding the muscle spindle was increased as was the expression of Collagen I and III. Conclusion Changes to the connective tissue and collagen expression of the muscle spindle capsule are likely to impact their mechanical properties. Changes in capsule stiffness may impact the transmission of length change to muscle spindles and thus transduction of sensory information. This change in muscle spindle structure may explain some of the proprioceptive deficits identified with low back pain.

Trigger finger (TF) and carpal tunnel syndrome (CTS) are two common non-traumatic hand disorders that frequently co-occur. By identifying TF and CTS cases in UK Biobank (UKB), we confirmed a highly significant phenotypic association between the diseases. To investigate the genetic basis for this association we performed a genome-wide association study (GWAS) including 2,908 TF cases and 436,579 European controls in UKB, identifying five independent loci. Colocalization with CTS summary statistics identified a co-localized locus at DIRC3 (lncRNA), which was replicated in FinnGen and fine-mapped to rs62175241. Single-cell and bulk eQTL analysis in fibroblasts from healthy donors (n=79) and tenosynovium samples from CTS patients (n=77) showed that the disease-protective rs62175241 allele was associated with increased DIRC3 and IGFBP5 expression. IGFBP5 is a secreted antagonist of IGF-1 signaling, and elevated IGF-1 levels were associated with CTS and TF in UKB, thereby implicating IGF-1 as a driver of both diseases.

Objective This study aims to evaluate the effectiveness of neural mobilization (NM) in the management of sensory dysfunction and nerve degeneration related to experimental painful diabetic neuropathy (PDN). Methods This is a pre-clinical animal study performed in the streptozocin-induced diabetic rat model. Three groups were included: a treatment group of rats with PDN receiving NM under anesthesia (PDN-NM, n = 10), a sham treatment group of rats with PDN that received only anesthesia (PDN-Sham, n = 9), and a vehicle control group with nondiabetic animals (Vehicle, n = 10). Rats in the PDN-NM and PDN-Sham groups received 1 treatment session on days 10, 12, and 14 after streptozocin injection, with a 48-hour rest period between sessions. Behavioral tests were performed using von Frey and Plantar tests. Evaluation for peripheral nerve degeneration was performed through measuring protein gene product 9.5-positive intra-epidermal nerve fiber density in hind-paw skin biopsies. All measurements were performed by a blinded investigator. Results The behavioral tests showed that a single NM session could reduce hyperalgesia, which was maintained for 48 hours. The second treatment session further improved this treatment effect, and the third session maintained it. These results suggest that it requires multiple treatment sessions to produce and maintain hypoalgesic effects. Skin biopsy analysis showed that the protein gene product 9.5-positive intra-epidermal nerve fiber density was higher on the experimental side of the PDN-NM group compared with the PDN-Sham group, suggesting NM may mitigate the degeneration of peripheral nerves. Conclusion This study demonstrated that NM may be an effective method to manage experimentally induced PDN, potentially through mitigation of nerve degeneration. Further studies are needed to develop standardized protocols for clinical use. Impact These findings provide neurophysiological evidence for the use of NM in PDN and can form the basis for the development of physical therapy-based programs in clinics.

Entrapment neuropathies such as carpal tunnel syndrome, radiculopathies, or radicular pain are the most common peripheral neuropathies and also the most common cause for neuropathic pain. Despite their high prevalence, they often remain challenging to diagnose and manage in a clinical setting. Summarising the evidence from both preclinical and clinical studies, this review provides an update on the aetiology and pathophysiology of entrapment neuropathies. Potenzial mechanisms are put in perspective with clinical findings. The contemporary assessment is discussed and diagnostic pitfalls highlighted. The evidence for the noninvasive and surgical management of common entrapment neuropathies is summarised and future areas of research are identified.Nervenkompressionssyndrome („Engpass-Syndrome“) wie Karpaltunnelsyndrom, Radikulopathien oder radikulärer Schmerz sind die häufigsten peripheren Nervenläsionen und auch die häufigste Ursache für neuropathischen Schmerz. Trotz ihrer hohen Prävalenz stellen sie diagnostisch und therapeutisch weiterhin oft eine klinische Herausforderung dar. Die vorliegende Übersicht bietet aktuelle Informationen zur Ätiologie und Pathophysiologie von Nervenkompressionssyndromen; dafür wird die Evidenz aus präklinischen wie auch klinischen Studien zusammengefasst. Mögliche Mechanismen werden in den Kontext klinischer Befunde gestellt. Das aktuelle diagnostische Vorgehen wird erörtert, diagnostische Fallstricke werden beleuchtet. Zuletzt fasst der Beitrag die Evidenz für die nichtinvasive und chirurgische Therapie häufiger Nervenkompressionssyndrome zusammen und zeigt zukünftige Forschungsbereiche auf.

There is no clear understanding of the mechanisms causing persistent pain in patients with whiplash-associated disorder (WAD). The aim of this systematic review was to assess the evidence for nerve pathology and neuropathic pain in patients with WAD. EMBASE, PubMed, CINAHL (EBSCO), and MEDLINE were searched from inception to September 1, 2020. Study quality and risk of bias were assessed using the Newcastle-Ottawa Quality Assessment Scales. Fifty-four studies reporting on 390,644 patients and 918 controls were included. Clinical questionnaires suggested symptoms of predominant neuropathic characteristic in 34% of patients (range 25%-75%). The mean prevalence of nerve pathology detected with neurological examination was 13% (0%-100%) and 32% (10%-100%) with electrodiagnostic testing. Patients independent of WAD severity (Quebec Task Force grades I-IV) demonstrated significantly impaired sensory detection thresholds of the index finger compared with controls, including mechanical (SMD 0.65 [0.30; 1.00] P0.005), current (SMD 0.82 [0.25; 1.39] P = 0.0165), cold (SMD -0.43 [-0.73; -0.13] P = 0.0204), and warm detection (SMD 0.84 [0.25; 1.42] P = 0.0200). Patients with WAD had significantly heightened nerve mechanosensitivity compared with controls on median nerve pressure pain thresholds (SMD -1.10 [-1.50; -0.70], P0.0001) and neurodynamic tests (SMD 1.68 [0.92; 2.44], P = 0.0004). Similar sensory dysfunction and nerve mechanosensitivity was seen in WAD grade II, which contradicts its traditional definition of absent nerve involvement. Our findings strongly suggest a subset of patients with WAD demonstrate signs of peripheral nerve pathology and neuropathic pain. Although there was heterogeneity among some studies, typical WAD classifications may need to be reconsidered and include detailed clinical assessments for nerve integrity.

Background: Low back pain is one of the most common musculoskeletal disorders. It leads to major costs in health care systems and causes significant personal and social burdens. Current research focuses on the processes of the central nervous system such as cortical changes in pain perception to discover new and more efficient ways to treat chronic low back pain (CLBP). Several clinical tests have been suggested that might correlate with altered cortical representation. These include back-photo assessment (BPA), movement control tests (MCI) and two-point discrimination thresholds (TPD).Objective: The aim of this study was to determine whether BPA, MCI and TPD tests can discriminate between CLBP patients with altered body perception and healthy controls.Design: A case-control study matched by gender and age.Methods: Using MCI, BPA and TPD tests on the lower back, thirty patients with CLBP and thirty healthy controls were investigated at one point in time. Participants were also required to complete three questionnaires: the ‘Fear Avoidance Belief Questionnaire’, the ‘Hospital Anxiety and Depression Scale’ and the ‘Fremantle Back Awareness Questionnaire’. Correlations among the main covariates and odds ratios for group differences were calculated.Results: The MCI showed a statistically significant odds ratio for the presence of CLBP of 0.65 (p< 0.05), whereas TPD and BPA did not determine differences between the groups.Conclusion: The movement control test was found to be the only suitable test to discriminate CLBP patients from healthy controls.Trial registration: The study was approved by the Swiss Ethical Commission Northwest and Central Switzerland (EKNZ) and registered at 21.8.2015, reference number 2015-243.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. \ud \ud \ud METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. \ud \ud \ud FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. \ud \ud \ud INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. \ud \ud \ud FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

BACKGROUND: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19, in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

Supplemental Digital Content is Available in the Text. The efficacy and safety of physiotherapy in the management of people with peripheral neuropathies is explored. Potential ways forward based on promising data are suggested., Pharmacological treatment for peripheral neuropathic pain has only modest effects and is often limited by serious adverse responses. Alternative treatment approaches including physiotherapy management have thus gained interest in the management of people with peripheral neuropathies. This narrative review summarises the current literature on the efficacy and safety of physiotherapy to reduce pain and disability in people with radicular pain and chemotherapy-induced peripheral neuropathy, 2 common peripheral neuropathies. For chemotherapy-induced peripheral neuropathy, the current evidence based on 8 randomised controlled trials suggests that exercise may reduce symptoms in patients with established neuropathy, but there is a lack of evidence for its preventative effect in patients who do not yet have symptoms. For radicular pain, most of the 21 trials investigated interventions targeted at improving motor control or reducing neural mechanosensitivity. The results were equivocal, with some indication that neural tissue management may show some benefits in reducing pain. Adverse events to physiotherapy seemed rare; however, these were not consistently reported across all studies. Although it is encouraging to see that the evidence base for physiotherapy in the treatment of peripheral neuropathic pain is growing steadily, the mixed quality of available studies currently prevents firm treatment recommendations. Based on promising preliminary data, suggestions are made on potential directions to move the field forward.

Entrapment neuropathies are a heterogenous condition reflecting distinct underlying pathomechanisms. A contemporary assessment aimed at identifying potential mechanisms may help target management for these patients., Entrapment neuropathies such as carpal tunnel syndrome, radiculopathies, or radicular pain are the most common peripheral neuropathies and also the most common cause for neuropathic pain. Despite their high prevalence, they often remain challenging to diagnose and manage in a clinical setting. Summarising the evidence from both preclinical and clinical studies, this review provides an update on the aetiology and pathophysiology of entrapment neuropathies. Potential mechanisms are put in perspective with clinical findings. The contemporary assessment is discussed and diagnostic pitfalls highlighted. The evidence for the noninvasive and surgical management of common entrapment neuropathies is summarised and future areas of research are identified.

Carpal tunnel release provides an opportunity to study sensory nerve regeneration in humans. Schmid et al. show that cutaneous reinnervation correlates with symptom improvement after surgery. ADCYAP1 (encoding PACAP) expression is associated with sensory reinnervation in vivo and facilitates neuron outgrowth in vitro., We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P

ZusammenfassungWir kennen neurodynamische Tests und Behandlungsmethoden, nutzen diese alltäglich in der Praxis und gehen auf Kurse, um mehr darüber zu lernen. Aber was verstehen wir tatsächlich darunter? Kommen wir in unserem Verständnis darüber auf einen gemeinsamen Nenner? Dieser Artikel gibt einen Einblick in die Thematik Neurodynamik. Bisherige Überzeugungen stehen dabei auf dem Prüfstand.

Background Mechanisms underpinning ongoing symptoms in chronic whiplash associated‐disorder (WAD) are not well understood. People with chronic WAD can exhibit sensory dysfunction consistent with small nerve fibre pathology, including thermal hypoaesthesia and hyperalgesia. This study investigated small fibre structure and function in chronic WAD. Methods Twenty‐four people with chronic WAD (median [IQR] age 49 [15] years, 16 females) and 24 pain‐free controls (50 [17] years, 16 females) were recruited. Intraepidermal nerve fibre density (IENFD) and dermal innervation were assessed by skin biopsy. This was performed at (a) the lateral index finger on the primary side of pain and (b) superior to the lateral malleolus on the contralateral side. Quantitative sensory testing was performed over the hand. Results The WAD group exhibited lower IENFD at the finger (WAD: median [IQR] 4.5 [4.9] fibres/mm; control 7.3 [3.9]; p = .010), but not the ankle (WAD: mean [SD] 7.3 [3.7] fibres/mm; control 9.3 [3.8]; p = .09). Dermal innervation was lower in the WAD group at the finger (WAD: median [IQR] 3.7 [2.8] nerve bundles/mm2; controls: 4.9 [2.1]; p = .017) but not the ankle (WAD: median [IQR] 2.1 [1.9] nerve bundles/mm2; controls: 1.8 [1.8]; p = .70). In the WAD group, hand thermal and light touch detection were impaired, and heat pain thresholds were lowered (p ≤ .037). Conclusions Findings suggest small fibre structural and functional deficits in chronic WAD, implicating potential involvement of small fibre pathology. Significance Our study found decreased intraepidermal nerve fibre density, reduced dermal innervation, thermal hypoaesthesia and hypersensitivity in people with chronic WAD, suggestive of small fibre pathology. This observation of peripheral nervous system pathology in chronic whiplash provides novel insights on mechanisms underpinning symptoms and challenges commonly held beliefs regarding this condition.

Background: This study describes a low‐cost and time‐efficient clinical sensory test (CST) battery and evaluates its concurrent validity as a screening tool to detect somatosensory dysfunction as determined using quantitative sensory testing (QST). Method: Three patient cohorts with carpal tunnel syndrome (CTS, n = 76), non‐specific neck and arm pain (NSNAP, n = 40) and lumbar radicular pain/radiculopathy (LR, n = 26) were included. The CST consisted of 13 tests, each corresponding to a QST parameter and evaluating a broad spectrum of sensory functions using thermal (coins, ice cube, hot test tube) and mechanical (cotton wool, von Frey hairs, tuning fork, toothpicks, thumb and eraser pressure) detection and pain thresholds testing both loss and gain of function. Agreement rate, statistical significance and strength of correlation (phi coefficient) between CST and QST parameters were calculated. Results: Several CST parameters (cold, warm and mechanical detection thresholds as well as cold and pressure pain thresholds) were significantly correlated with QST, with a majority demonstrating >60% agreement rates and moderate to relatively strong correlations. However, agreement varied among cohorts. Gain of function parameters showed stronger agreement in the CTS and LR cohorts, whereas loss of function parameters had better agreement in the NSNAP cohort. Other CST parameters (16 mN von Frey tests, vibration detection, heat and mechanical pain thresholds, wind‐up ratio) did not significantly correlate with QST. Conclusion: Some of the tests in the CST could help detect somatosensory dysfunction as determined with QST. Parts of the CST could therefore be used as a low‐cost screening tool in a clinical setting. Significance: Quantitative sensory testing, albeit considered the gold standard to evaluate somatosensory dysfunction, requires expensive equipment, specialized examiner training and substantial time commitment which challenges its use in a clinical setting. Our study describes a CST as a low‐cost and time‐efficient alternative. Some of the CST tools (cold, warm, mechanical detection thresholds; pressure pain thresholds) significantly correlated with the respective QST parameters, suggesting that they may be useful in a clinical setting to detect sensory dysfunction.

We only have a rudimentary understanding of the molecular and cellular determinants of human nerve regeneration. Here, we use carpal tunnel syndrome (CTS) as a human model system to prospectively evaluate correlates of neural regeneration and their relationship with clinical recovery after decompression surgery. At 6 months post-surgery, we noted a significant improvement of median nerve neurophysiological and somatosensory function. Serial skin biopsies revealed a partial recovery of intraepidermal innervation, whose extent correlated with symptom improvement. In myelinated afferents, nodal length increased postoperatively. Transcriptional profiling of the skin revealed 23 differentially expressed genes following decompression, with ADCYAP1 (encoding PACAP) being the most strongly upregulated and showing an association with regeneration of intraepidermal nerve fibres. Using human induced pluripotent stem cell-derived sensory neurons, we confirmed that PACAP significantly enhances axon outgrowth in vivo. Since PACAP signals through G-protein receptors, this pathway provides an interesting therapeutic target for human sensory nerve regeneration.

Study design Longitudinal case-controlled animal study. Objective To investigate putative cellular mechanisms to explain structural changes in muscle and adipose and connective tissues of the back muscles after intervertebral disc (IVD) injury. Summary of background data Structural back muscle changes are ubiquitous with back pain/injury and considered relevant for outcome, but their exact nature, time course, and cellular mechanisms remain elusive. We used an animal model that produces phenotypic back muscle changes after IVD injury to study these issues at the cellular/molecular level. Methods Multifidus muscle was harvested from both sides of the spine at L1-L2 and L3-L4 IVDs in 27 castrated male sheep at 3 (n = 10) or 6 (n = 17) months after a surgical anterolateral IVD injury at both levels. Ten control sheep underwent no surgery (3 mo, n = 4; 6 mo, n = 6). Tissue was harvested at L4 for histological analysis of cross-sectional area of muscle and adipose and connective tissue (whole muscle), plus immunohistochemistry to identify proportion and cross-sectional area of individual muscle fiber types in the deepest fascicle. Quantitative polymerase chain reaction measured gene expression of typical cytokines/signaling molecules at L2. Results Contrary to predictions, there was no multifidus muscle atrophy (whole muscle or individual fiber). There was increased adipose and connective tissue (fibrotic proliferation) cross-sectional area and slow-to-fast muscle fiber transition at 6 but not 3 months. Within the multifidus muscle, increases in the expression of several cytokines (tumor necrosis factor α and interleukin-1β) and molecules that signal trophic/atrophic processes for the 3 tissue types (e.g., growth factor pathway [IGF-1, PI3k, Akt1, mTOR], potent tissue modifiers [calcineurin, PCG-1α, and myostatin]) were present. Conclusion This study provides cellular evidence that refutes the presence of multifidus muscle atrophy accompanying IVD degeneration at this intermediate time point. Instead, adipose/connective tissue increased in parallel with the expression of the genes that provide putative mechanisms for multifidus structural remodeling. This provides novel targets for pharmacological and physical interventions. Level of evidence N/A.

Despite normal neurological integrity tests, some patients with non-specific neck-arm pain (NSNAP) have heightened nerve mechanosensitivity upon neurodynamic testing. The aim of this study was to determine whether or not a nerve dysfunction is present in patients with positive neurodynamic tests compared to those with negative neurodynamic tests or healthy controls. Somatosensory profiling using quantitative sensory testing (QST) was established in 40 consecutive patients with unilateral NSNAP; 23 had positive upper limb neurodynamic tests (ULNTPOS) and 17 had negative neurodynamic tests (ULNTNEG) and in 26 healthy controls. QST included measurement of thermal and mechanical detection and pain thresholds in the maximal pain area on the symptomatic side as well as the corresponding contralateral area. Fifty-seven percent of patients with NSNAP had positive neurodynamic tests. Somatosensory profiling revealed a loss of function phenotype in NSNAP patients compared to healthy controls both in the maximal pain area and asymptomatic side. Hyperalgesia (cold, heat and pressure) was present bilaterally in both NSNAP groups. Direct comparison between the patient groups revealed no significant differences in somatosensory profiles. However, the ULNTPOS group demonstrated sensory loss compared to healthy controls in more parameters than the ULNTNEG group. The ULNTNEG subgroup represented an intermediate phenotype between ULNTPOS patients and healthy controls in most detection thresholds as well as thermal and pressure pain thresholds. Even though patients with NSNAP present as a spectrum, it remains unclear whether the sensory changes are indicative of a nerve dysfunction/lesion or rather a marker of altered central pain processing.

Purpose Intervertebral disk (IVD) lesion and its subsequent degeneration have a profound effect on the multifidus muscle. The subacute/early chronic phase of multifidus remodeling after IVD lesion has been proposed to be regulated by inflammatory processes. The balance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages plays an important role in maintaining tissue integrity after injury. The localization, polarization of macrophage subtypes and their mediation of the pro-inflammatory cytokine tumor necrosis factor (TNF) are unknown in paraspinal muscles during IVD degeneration. A sheep model of IVD degeneration was used to investigate the role of macrophages and TNF in the structural alterations that occur within the multifidus muscle. Methods Anterolateral lesions were induced at L3–4 IVD in sheep. Multifidus muscle tissue at L4 was harvested 3 and 6 months after lesion and used for immunofluorescence assays to examine total macrophage number, macrophage polarization between M1 and M2, and to assess the localization of TNF expression in muscle, adipose and connective tissues from injured and naïve control animals. Results A greater proportion of M1 macrophages is present in muscle at both 3 and 6 months after IVD lesion, and adipose tissue at 6 months. Total number of macrophages is unchanged. At 6 months, expression of TNF is increased in adipose and connective tissue and the proportion of TNF expressed by M1 macrophages is increased. Conclusions These data support the proposal that macrophages and TNF (pro-inflammatory cytokine) play an active role in the subacute/early chronic phase of remodeling in muscle, adipose and connective tissues of the multifidus during IVD degeneration. This presents a novel target for treatment.

BACKGROUND Small-nerve fiber, or small-fiber, degeneration commonly occurs in patients with peripheral neuropathies, resulting in a deterioration of nerve function. Currently, the gold standard to identify small-fiber degeneration is through skin biopsy. Simple clinical tests aim to identify small-fiber degeneration, but their validity remains unknown. OBJECTIVES To examine the validity of clinical tests to assess small-nerve fiber degeneration, using carpal tunnel syndrome as a model neuropathy. METHODS One hundred seven participants (22 healthy, 85 with carpal tunnel syndrome) in this prospective, cross-sectional diagnostic accuracy study underwent pinprick testing of the index finger and were assessed for cold detection threshold and warm detection threshold using quantitative sensory testing. In a subgroup of patients with carpal tunnel syndrome (n = 51), cold and warm sensations were also tested, using coins at room and body temperature, respectively. The validity of these clinical tests was established against intra-epidermal nerve fiber density measured in skin biopsies from the index finger. RESULTS Optimal validity occurred with clusters of tests. Specifically, normal warm or cold sensation is highly sensitive to rule out small-fiber degeneration (sensitivity, 0.98; 95% confidence interval [CI]: 0.85, 0.99), but has a low specificity (0.20; 95% CI: 0.03, 0.52). By contrast, a reduction in pinprick is highly specific (0.88; 95% CI: 0.72, 0.95), and so can be used to rule in small-fiber degeneration. For quantitative sensory testing, the highest specificity (0.83) occurs for warm detection threshold and the highest sensitivity (0.84; 95% CI: 0.72, 0.91) for cold detection threshold or warm detection threshold. CONCLUSION Pinprick testing, followed by warm and cold tests if pinprick is normal, is a valid and cost-effective method to detect small-fiber degeneration. For quantitative sensory testing, warm detection threshold is useful for ruling in small-fiber degeneration. To rule out small-fiber degeneration, both cold detection threshold and warm detection threshold must be negative. LEVEL OF EVIDENCE Diagnosis, level 2. J Orthop Sports Phys Ther 2018;48(10):767-774. Epub 22 Jun 2018. doi:10.2519/jospt.2018.8230.

Entrapment neuropathies are the most prevalent type of peripheral neuropathy and often a challenge to diagnose and treat. To a large extent, our current knowledge is based on empirical concepts and early (often biomechanical) studies. This Viewpoint will challenge some of the current beliefs with recent advances in both basic and clinical neurosciences. J Orthop Sports Phys Ther 2018;48(2):58-62. doi:10.2519/jospt.2018.0603.

Objective: Distal and proximal entrapment neuropathies such as carpal tunnel syndrome (CTS) and cervical radiculopathy (CR) share similar etiologies. Experimental models suggest that, despite comparable etiology, pathomechanisms associated with injuries of the peripheral and central axon branches are distinct. This study therefore compared self-reported and elicited sensory profiles in patients with distal and proximal entrapment neuropathies. Methods: Patients with electrodiagnostically confirmed CTS (n = 103) and patients with CR (n = 23) were included in this study. A group of healthy participants served as controls (n = 39). Symptoms and sensory profiles were evaluated using quantitative sensory testing (QST) and a self-reported neuropathic pain questionnaire (painDETECT). Results: Both patient groups were characterized by a loss of function in thermal and mechanical detection in the main pain area and dermatome compared to healthy reference data (p ≺ .001). There was no significant difference between patients with CTS and CR in pain and detection thresholds except for reduced vibration sense in the main pain area (p ≺ .001) and reduced pressure pain sensitivity in the dermatome in patients with CR (p ≺ .001). However, patients with CR reported higher pain intensities (p = .008), more severe pain attacks (p = .009) and evoked pain by light pressure (p = .002) compared to patients with CTS. Conclusion: While QST profiles were similar between patients with CTS and CR, self-reported pain profiles differed and may suggest distinct underlying mechanisms in these patient cohorts.

Reduced pain perception during painful stimulation to another body region (ie, conditioned pain modulation [CPM]) is considered important for pain modulation and development of pain disorders. The various methods used to study CPM limit comparison of findings. We investigated the influence of key methodologic variations on CPM and the properties of CPM when the back is used for the test stimulus or the conditioning stimulus (CS). Two different test stimuli (pressure pain threshold and pain response to suprathreshold heat [Pain-45, ie, pain rated at 45 on a 0-100 numeric rating scale]) were assessed before and during application of a noxious or non-noxious (sham) CS. Eight blocks of trials varied the anatomic location (back and forearms) and arrangement (body side) of the stimuli. Pressure pain threshold (as the test stimulus) increased during application of noxious, but not non-noxious, CS when stimuli were applied to opposite body sides or heterotopic sites on one body side. Inconsistent with pain-induced CPM, Pain-45 decreased during both noxious and non-noxious CS. These findings indicate that 1) pressure pain threshold can be more confidently interpreted with respect to CPM evoked by a painful stimulus than Pain-45, 2) the back and forearm are equally effective as sites for stimuli, and 3) stimuli arrangement does not influence CPM, except for identical anatomic regions on the same body side. Perspective: This study indicates that pressure pain threshold as the test stimulus provides a more valid measure of pain-induced CPM than pain response to a suprathreshold heat stimulus. Induction and magnitude of CPM is independent of stimuli arrangement, as long as ipsilateral homotopic sites are avoided. These findings clarify methods to study CPM. (C) 2015 by the American Pain Society Refereed/Peer-reviewed

Preliminary evidence from studies using quantitative sensory testing suggests the presence of central mechanisms in patients with carpal tunnel syndrome (CTS) as apparent by widespread hyperalgesia. Hallmarks of central mechanisms after nerve injuries include nociceptive facilitation and reduced endogenous pain inhibition. Methods to study nociceptive facilitation in CTS so far have been limited to quantitative sensory testing and the integrity of endogenous inhibition remains unexamined. The aim of this study was therefore to investigate changes in facilitatory and inhibitory processing in patients with CTS by studying hypersensitivity following experimentally induced pain (facilitatory mechanisms) and the efficacy of conditioned pain modulation (CPM, inhibitory mechanisms). Twenty-five patients with mild to moderate CTS and 25 age and sex matched control participants without CTS were recruited. Increased pain facilitation was evaluated via injection of hypertonic saline into the upper trapezius. Altered pain inhibition through CPM was investigated through cold water immersion of the foot as the conditioning stimulus and pressure pain threshold over the thenar and hypothenar eminence bilaterally as the test stimulus. The results demonstrated that patients with CTS showed a greater duration (p = 0.047), intensity (p = 0.044) and area (p = 0.012) of pain in response to experimentally induced pain in the upper trapezius and impaired CPM compared to the control participants (p = 0.006). Although typically considered to be driven by peripheral mechanisms, these findings indicate that CTS demonstrates characteristics of altered central processing with increased pain facilitation and reduced endogenous pain inhibition.

The diagnosis of entrapment neuropathies can be difficult because symptoms and signs often do not follow textbook descriptions and vary significantly between patients with the same diagnosis. Signs and symptoms which spread outside of the innervation territory of the affected nerve or nerve root are common. This Masterclass provides insight into relevant mechanisms that may account for this extraterritorial spread in patients with entrapment neuropathies, with an emphasis on neuroinflammation at the level of the dorsal root ganglia and spinal cord, as well as changes in subcortical and cortical regions. Furthermore, we describe how clinical tests and technical investigations may identify these mechanisms if interpreted in the context of gain or loss of function. The management of neuropathies also remains challenging. Common treatment strategies such as joint mobilisation, neurodynamic exercises, education, and medications are discussed in terms of their potential to influence certain mechanisms at the site of nerve injury or in the central nervous system. The mechanism-oriented approach for this Masterclass seems warranted given the limitations in the current evidence for the diagnosis and management of entrapment neuropathies.

Diverse klinische Praxisrichtlinien empfehlen Manuelle Therapie nicht nur bei Bewegungseinschrankungen, sondern auch bei muskuloskeletalen Schmerzen 2 , 55 . Dr. Annina Schmid interessiert sich fur die Wirkungsweise von Manueller Therapie. In diesem Artikel fasst sie die drei Hauptwirkungsweisen zusammen, die eine Schmerzlinderung durch Manuelle Therapie erklaren konnten.