Effect of Type and Dose of Exercise on Neuropathic Pain After Experimental Sciatic Nerve Injury: A Preclinical Systematic Review and Meta-Analysis.

This preclinical systematic review aimed to determine the effectiveness of different types and doses of exercise on pain behavior 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 behavior after experimental sciatic nerve injury. If possible, data were meta-analyzed using random effect models with inverse-variance weighting. Thirty-seven studies were included and 26 meta-analyzed. Risk of bias (SYRCLE tool) remained unclear in most studies and reporting quality (CAMARADES) was variable. Exercise reduced mechanical (standardized mean differences [SMD] .53 (95% CI .31, .74), P = .0001, I2 = 0%, n = 364), heat (.32 (.07, .57), P = .01, I2 = 0%, n = 266) and cold hypersensitivity (.51 (.03, 1.0), P = .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 (eg, 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. 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.

Does peripheral neuroinflammation predict chronicity following whiplash injury? Protocol for a prospective cohort study.

INTRODUCTION: Whiplash-associated disorder grade 2 (WAD2) is characterised by musculoskeletal pain/tenderness but no apparent nerve injury. However, studies have found clinical features indicative of neuropathy and neuropathic pain. These studies may indicate peripheral nerve inflammation, since preclinical neuritis models found mechanical sensitivity in inflamed, intact nociceptors. The primary aim of this study is to establish the contribution of peripheral neuroinflammation to WAD2 and its role in prognosis. Participants will be invited to participate in a sub-study investigating the contribution of cutaneous small fibre pathology to WAD2. METHODS AND ANALYSIS: 115 participants within 1 month following whiplash injury and 34 healthy control participants will be recruited and complete validated questionnaires for pain, function and psychological factors. Data collection will take place at the Universities of Sussex and Oxford, UK. Clinical examination, quantitative sensory testing and blood samples will be undertaken. MRI scans using T2-weighted and diffusion tensor images of the brachial plexus and wrist will determine nerve inflammation and nerve structural changes. Skin biopsies from a substudy will determine structural integrity of dermal and intraepidermal nerve fibres. At 6 months, we will evaluate recovery using Neck Disability Index and a self-rated global recovery question and repeat the outcome measures. Regression analysis will identify differences in MRI parameters, clinical tests and skin biopsies between participants with WAD2 and age/gender-matched controls. Linear and logistic regression analyses will assess if nerve inflammation (MRI parameters) predicts poor outcome. Mixed effects modelling will compare MRI and clinical measures between recovered and non-recovered participants over time. ETHICS AND DISSEMINATION: Ethical approval was received from London-Brighton and Sussex Research Ethics Committee (20/PR/0625) and South Central-Oxford C Ethics Committee (18/SC/0263). Written informed consent will be obtained from participants prior to participation in the study. Results will be disseminated through publications in peer-reviewed journals, presentations at national/international conferences and social media. TRIAL REGISTRATION NUMBER: NCT04940923.

Types and Concentrations of Blood-Based Biomarkers in Adults With Peripheral Neuropathies: A Systematic Review and Meta-analysis.

Importance: Peripheral neuropathies are common conditions and can result in numbness, paresthesia, motor deficits, and pain. There is increasing evidence for the use of biomarkers as clinical indicators of the presence, severity, and prognosis of nerve lesions; however, biomarker identification has largely been focused on disorders of the central nervous system, and less is known about their role in the peripheral nervous system. Objective: To assess blood-based biomarker concentrations associated with nerve involvement in patients with peripheral neuropathy compared with control participants. Data Sources: Ovid, MEDLINE, Embase, and CINAHL were searched from inception to September 23, 2021. Study Selection: Observational studies reporting on blood biomarkers in patients diagnosed with peripheral neuropathy were included. This review was preregistered on PROSPERO and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were abstracted by 1 investigator and independently reviewed by a second. Data Extraction and Synthesis: Data were meta-analyzed when at least 2 studies reported the same biomarker with comparable methodology. Fixed-effects models were used when only 2 studies were included; random-effects models were used when more than 2 studies were included. Main Outcomes and Measures: The outcome of interest was concentration of biomarkers. Results: This review included 36 studies reporting on 4414 participants, including 2113 control participants and 2301 patients with peripheral neuropathy with 13 distinct peripheral neuropathy diagnoses. Diabetic neuropathy was the most common neuropathy diagnosis (13 studies), followed by Charcot-Marie-Tooth disease (6 studies) and Guillain-Barre syndrome (6 studies). Overall, 16 different blood-based biomarkers associated with nerve involvement were evaluated. The most used were neurofilament light chain, S100B, brain-derived neurotrophic factor, and neuron-specific enolase. Patients with peripheral neuropathy demonstrated significantly higher levels of neurofilament light chain compared with controls (standardized mean difference [SMD], 0.93 [95% CI, 0.82 to 1.05]; P < .001). There were no significant differences in levels of S100B (SMD, 1.10 [95% CI, -3.08 to 5.28]; P = .38), brain-derived neurotrophic factor (SMD, -0.52 [95% CI, -2.23 to 1.19]; P = .40), or neuron-specific enolase (SMD, -0.00 [95% CI, -1.99 to 1.98]; P = .10) in patients with peripheral neuropathy compared with control participants. Conclusions and Relevance: The findings of this systematic review and meta-analysis support the use of neurofilament light chain as a blood-based measure associated with the presence of neuronal injury in patients with peripheral neuropathy.

The power of integrating data: advancing pain research using meta-analysis.

Publications related to pain research have increased significantly in recent years. The abundance of new evidence creates challenges staying up to date with the latest information. A comprehensive understanding of the literature is important for both clinicians and investigators involved in pain research. One commonly used method to combine and analyse data in health care research is meta-analysis. The primary aim of a meta-analysis is to quantitatively synthesise the results of multiple studies focused on the same research question. Meta-analysis is a powerful tool that can be used to advance pain research. However, there are inherent challenges when combining data from multiple sources. There are also numerous models and statistical considerations when undertaking a meta-analysis. This review aims to discuss the planning and preparation for completing a meta-analysis, review commonly used meta-analysis models, and evaluate the clinical implications of meta-analysis in pain research.

Nerve pathology and neuropathic pain after whiplash injury: a systematic review and meta-analysis.

ABSTRACT: 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] P < 0.005), 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], P < 0.0001) 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.

[Entrapment neuropathies: a contemporary approach to pathophysiology, clinical assessment, and management : German version]. / Nervenkompressionssyndrome ­ eine aktuelle Betrachtung von Pathophysiologie, klinischer Untersuchung und Management : Deutsche Fassung.

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.

Entrapment neuropathies: a contemporary approach to pathophysiology, clinical assessment, and management.

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.

Muscle fat infiltration following whiplash: A computed tomography and magnetic resonance imaging comparison.

Here we present a secondary analysis from a parent database of 97 acutely injured participants enrolled in a prospective inception cohort study of whiplash recovery after motor vehicle collision (MVC). The purpose was to investigate the deep and superficial neck extensor muscles with peri-traumatic computed tomography (CT) and longitudinal measures of magnetic resonance imaging (MRI) in participants with varying levels of whiplash-related disability. Thirty-six underwent standard care imaging of the cervical spine with CT at a level-1 trauma designated emergency department. All 36 participants were assessed with MRI of the cervical spine at <1-week, 2-weeks, 3-, and 12-months post-injury and classified into three groups using initial pain severity and percentage scores on the Neck Disability Index (recovered (NDI of 0-8%), mild (NDI of 10-28%), or severe (NDI ≥ 30%)) at 3-months post MVC. CT muscle attenuation values were significantly correlated to muscle fat infiltration (MFI) on MRI at one-week post MVC. There was no significant difference in muscle attenuation across groups at the time of enrollment. A trend of lower muscle attenuation in the deep compared to the superficial extensors was observed in the severe group. MFI values in the deep muscles on MRI were significantly higher in the severe group when compared to the mild group at 1-year post MVC. This study provides further evidence that the magnitude of 1) deep MFI appears unique to those at risk of and eventually transitioning to chronic WAD and that 2) pre- or peri-traumatic muscular health, determined by CT muscle attenuation, may be contribute to our understanding of long-term recovery.

Does Overall Cervical Spine Pathology Relate to the Clinical Heterogeneity of Chronic Whiplash?

BACKGROUND AND PURPOSE: There remains limited evidence for the clinical importance of most imaging findings in whiplash. However, it is possible the type and number of findings on Computed Tomography (CT) may contribute to prognostic recovery models. The purpose is to interpret cervical spine pathologies in the context of known factors influencing recovery. MATERIALS AND METHODS: This is a secondary analysis from a database of 97 acutely injured participants enrolled in a prospective inception cohort study. Thirty-eight participants underwent standard of care cervical spine CT in the emergency medicine department. All 38 participants were assessed at <1-week, 2-weeks, and 3-months post-injury and classified using percentage scores on the Neck Disability Index (recovered/mild (NDI of 0-28%) or moderate/severe (NDI ≥ 30%)). Between-group comparison of categorical variables (gender (male/female), presence of at least one CT finding (yes/no), and presence of ≥3 pathologies on CT (yes/no)) was conducted using 2-tailed Fisher's exact test. RESULTS: Participants from both groups demonstrated at least one observable pathology. The group with persistent moderate/severe symptoms presented with significantly more pathology at baseline than those who later reported recovery or milder symptoms at 3-months post injury (p = 0.02). CONCLUSIONS: This preliminary study, which needs replication in a larger cohort, provides foundation that the number of degenerative pathologies seen on initial post MVC CT may be associated with the subsequent clinical course of whiplash.

The use of a static measure to predict foot posture at midstance during walking.

Previous studies have successfully used the longitudinal arch angle (LAA) to assess foot posture, but the measurement consistency and ability of the LAA to predict dynamic foot posture during activity in a variety of foot types have not been evaluated. The purpose of this study was to determine the reliability of the LAA as well as if the clinical method of assessing the LAA could be used to predict the LAA at midstance during walking for supinated, normal, and pronated foot types. The Arch Height Ratio was used to select 35 participants with 12 supinated, 46 normal, and 12 pronated feet. A standard goniometer was used to measure the LAA (CLINIC_LAA) on both feet while standing. Both feet were then filmed using a high speed camera while walking on a treadmill. The LAA was determined by the angle formed by two lines drawn between the markers placed on the first metatatarsal and medial malleolus with the apex the navicular tuberosity. The LAA in midstance (WALK_LAA) was determined using the mean of five walking trials. The reliability of the CLINIC_LAA assessed on both feet by two raters over two days were excellent. There was no difference between the left and right foot for the CLINIC_LAA. The Pearson correlation between CLINIC_LAA and WALK_LAA for all 70 feet was r=0.96 (r2=0.92). The results indicate the LAA is highly predictive of foot posture at midstance in walking explaining over 90% of the variance for a wide range of foot types.