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.

Evidence for Increased Magnetic Resonance Imaging Signal Intensity and Morphological Changes in the Brachial Plexus and Median Nerves of Patients With Chronic Arm and Neck Pain Following Whiplash Injury.

Background Whiplash following a motor vehicle accident can result in chronic neck and arm pain. Patients frequently present with cutaneous hypersensitivities and hypoesthesia, but without obvious clinical signs of nerve injury. T2-weighted magnetic resonance imaging (MRI) has previously been used to identify nerve pathology. Objectives To determine whether there are signs of peripheral nerve pathology on MRI in patients with chronic arm and neck pain following whiplash injury. Methods This cross-sectional study used T2-weighted MRI to examine the brachial plexus and median nerve in patients and age-matched, healthy control subjects. Clinical examination included tests of plexus and nerve trunk mechanical sensitivity. Results The T2 signal intensity was greater in the brachial plexus and median nerve at the wrist in the patient group (mean intensity ratio = 0.52 ± 0.13 and 2.09 ± 0.33, respectively) compared to the control group (mean intensity ratio = 0.45 ± 0.07 and 1.38 ± 0.31, respectively; P<.05). Changes in median nerve morphology were also observed, which included an enlargement (mean area: patient group, 8.05 ± 1.29 mm2; control group, 6.52 ± 1.08 mm2; P<.05) and flattening (mean aspect ratio: patient group, 2.46 ± 0.53; control group, 1.62 ± 0.30; P<.05) at the proximal carpal row. All patients demonstrated signs of nerve trunk mechanical sensitivity. Conclusion These findings suggest that patients with chronic whiplash may have inflammatory changes and/or mild neuropathy, which may contribute to symptoms. J Orthop Sports Phys Ther 2018;48(7):523-532. Epub 24 Apr 2018. doi:10.2519/jospt.2018.7875.

Posture-induced changes in peripheral nerve stiffness measured by ultrasound shear-wave elastography.

INTRODUCTION: Peripheral nerves slide and stretch during limb movements. Changes in nerve stiffness associated with such movements have not been examined in detail but may be important in understanding movement-evoked pain in patients with a variety of different musculoskeletal conditions. METHODS: Shear-wave elastography was used to examine stiffness in the median and tibial nerves of healthy individuals during postures used clinically to stretch these nerves. RESULTS: Shear-wave velocity increased when limbs were moved into postures that are thought to increase nerve stiffness (mean increase: median nerve = 208% in arm, 236% in forearm; tibial nerve = 136%). There was a trend toward a negative correlation between age and shear-wave velocity (r = 0.58 for tibial nerve). CONCLUSIONS: Shear-wave elastography provides a tool for examining nerve biomechanics in healthy individuals and patients. However, limb position, age, and effects of nerve tension on neural architecture should be taken into consideration. Muscle Nerve 55: 213-222, 2017.

Magnetic resonance imaging signal hyperintensity of neural tissues in diffuse chronic pain syndromes: a pilot study.

In this pilot study we use T2-weighted magnetic resonance imaging (MRI) to identify possible peripheral nerve inflammation in 4 patients with diffuse chronic pain. In all 4 patients, there was an increase in median and ulnar nerve T2 signal intensity at the wrist (P < 0.05 vs. controls). Positive clinical signs of peripheral nerve mechanosensitivity combined with MRI findings suggest that these patients may have an underlying peripheral nerve pathology.

Longitudinal sliding of the median nerve in patients with non-specific arm pain.

In patients with non-specific arm pain (NSAP; also known as repetitive strain injury), there are clinical signs of altered median nerve sliding. It is possible that a restriction along the nerve course will lead to abnormal increases in local strain during limb movements, possibly contributing to symptoms. The present study uses ultrasound imaging to examine median nerve sliding through the proximal and distal nerve segments in 18 NSAP patients. Longitudinal nerve sliding was measured during metacarpophalangeal, wrist and elbow movements. During elbow movements, the angle of elbow extension at which the nerve begins to move was determined, since this was expected to decrease with a restriction through the shoulder. The results from this study were compared with previously reported data. Nerve movements ranged from 1.26 to 4.73 mm in patients compared with 1.43-5.57 mm in controls. There was no significant difference in nerve sliding (p>0.05) or in the angle of elbow extension at which the nerve began to move (mean=53.4 degrees in patients, 52.0 degrees in controls; p>0.05). In summary, restriction of median nerve sliding is unlikely to play a major role in NSAP. Therefore, painful responses during limb movements which tension the nerve are unlikely to result from abnormal increases in nerve strain.

Workshop: clinical implications for clinicians treating patients with non-specific arm pain, whiplash and carpal tunnel syndrome.

Nerve sheath inflammation without significant axonal degeneration can result in c fibres (both axons in continuity and the nervi nervorum) becoming spontaneously active and mechanically sensitive. This may help explain the painful responses when examining neural dynamics in patients with non specific arm pain, carpal tunnel syndrome and arm pain following whiplash injury, when longitudinal nerve excursion (measured using ultrasound imaging), appears to be within normal ranges. These findings have implications for the clinical examination and treatment of these patients groups.

Effect of straight leg raise examination and treatment on vibration thresholds in the lower limb: a pilot study in asymptomatic subjects.

Individuals who participate in repetitive functional activities may have alteration in large diameter neural activity. It has been proposed that neurodynamic examination and treatment may affect large diameter afferent activity, and that neurological integrity tests should be carried out prior to neurodynamic testing. Vibration threshold testing (VTT) has been shown to be a valid measure of large diameter afferent conduction. The aim of this study was to assess whether examination and treatment of straight leg raise with plantar flexion and inversion (SLR) has an effect on the conduction of large diameter afferents supplying the lower leg in normal subjects and in a group of runners. Twenty sedentary asymptomatic subjects and 10 asymptomatic runners underwent VTT at the second and fourth metatarsals (representing the distribution of the superficial peroneal nerve) before and after examination of the SLR and after a mimicked treatment with SLR (VTT carried out immediately and 10min after treatment). A repeated measures ANOVA revealed no significant baseline differences in VT between runners and non-runners (P=0.171), or between any of the four test conditions in either group (P=0.5). Although not significant there was a trend for runners to have raised mean VT compared to non-runners, and for SLR treatment to cause an elevation in VT in both groups. These results suggest that examination and treatment of SLR may not be detrimental to function of the large diameter afferents in asymptomatic subjects.

In vivo study of nerve movement and mechanosensitivity of the median nerve in whiplash and non-specific arm pain patients.

Chronic pain following whiplash injury and non-specific arm pain (NSAP, previously termed diffuse repetitive strain injury) present clinicians with problems of diagnosis and management. In both patient groups there are clinical signs of altered nerve movement and increased nerve trunk mechanosensitivity. Previous studies of NSAP patients have identified altered median nerve movement at the wrist. The present study uses high frequency ultrasound imaging to examine changes to median nerve movement and clinical examination to assess altered mechanosensitivity of the median nerve. Longitudinal median nerve movement was measured in the forearm during maximal inspiration in nine post-whiplash patients with chronic neck and arm pain and eight controls subjects. Eight NSAP patients and seven controls were also studied. Transverse median nerve movement at the proximal carpal tunnel during 30 degrees wrist extension to 30 degrees flexion was also measured. A clinical examination of nerve trunk allodynia was performed in all subjects. Longitudinal nerve movement in the forearm was reduced by 71% in the post-whiplash patients and by 68% in NSAP patients compared to controls. In the whiplash patients the pattern of transverse median nerve movement at the proximal carpal tunnel was significantly different to controls (patient mean=2.57+/-0.80 mm (SEM) in a radial direction; control mean=0.39+/-0.52 mm in an ulnar direction). Signs of neural mechanosensitivity (i.e. painful responses to median nerve trunk and brachial plexus pressure and stretch) were apparent in both patients groups. Change in nerve tension and neural mechanosensitivity may contribute to symptoms in whiplash and NSAP patients.

Quantitative in vivo studies of median nerve sliding in response to wrist, elbow, shoulder and neck movements.

OBJECTIVE: To examine median nerve sliding in response to upper limb movements in vivo. To determine whether the median nerve can be unloaded. DESIGN: Exploratory study in healthy subjects.Background. Impaired sliding may lead to neuropathic symptoms. In vivo results for neural dynamics in normal subjects are essential to understand changes in upper limb disorders. METHODS: Ultrasound imaging of the median nerve during 40 degrees wrist extension, 80 degrees shoulder abduction, 90 degrees elbow extension, and 35 degrees contralateral neck side flexion. Frame by frame cross-correlation of image sequences to measure nerve sliding and strain. RESULTS: Nerve excursion in the forearm and upper arm ranged from 0.3 mm for neck side flexion to 10.4 mm for elbow extension. Additional strain in the forearm for wrist extension was 1.1% (SEM, 0.2%), for shoulder abduction 1.0% (SEM, 0.2%), and for neck side flexion 0.1% (SEM, 0.1%). With the limb flexed, sliding was delayed and sometimes the nerve or the nerve fascicles had a wavy appearance. CONCLUSION: The median nerve is unloaded when the shoulder is adducted or elbow flexed. When the arm is extended (90 degrees shoulder abduction, 60 degrees wrist extension, and elbow straight) the total additional strain in the forearm will be 2.5-3.0%. Even in this position the strain is likely to be below levels that impair blood flow or conduction. Therefore, the median nerve appears well designed to cope with changes in bed length caused by limb movements. RELEVANCE: These results will provide baseline data that can be used to examine entrapment neuropathies.

Sensory and autonomic function in the hands of patients with non-specific arm pain (NSAP) and asymptomatic office workers.

Chronic pain in the upper limb associated with repetitive movements of the arm and hand is often seen in patients in the absence of specific pathology such as epicondylitis, carpal tunnel syndrome and tenosynovitis. This condition has been given many names and will be referred to here as non-specific arm pain (NSAP). Previous work has shown elevated vibration thresholds and reduced flare suggesting a neuropathic cause for this condition. In order to examine this further the present study has assessed functions that involve both large sensory nerve fibres (vibration) and small dorsal root fibres (flare) and sympathetic fibres (vasoconstriction). NSAP patients and also a group of office workers who intensively used display screen equipment but who did not have NSAP were also studied along with an age-matched control group. In the median innervated area of the hand we measured flare responses to iontophoresis of histamine (a sensory C-fibre effect), and sympathetic vasoconstrictor responses to ice stimulation over C7. To tie in with previous studies, vibration threshold over areas of the hand innervated by the median, ulnar and radial nerves was also evaluated. All measures were carried out over both hands in each subject. Significant differences from controls were found on all three measures for the NSAP patient group and on two measures for the office workers. Flare area was reduced by 33% in the patients and by 30% in the office workers. Reflex vasoconstriction was reduced by 20% in the patient group but was not altered in office worker group. Over the median innervated area on the hand, vibration threshold was elevated by 47% in the patients and by 21% in the office workers. These results confirm previous findings showing reduced function associated with both small and large sensory fibres in the NSAP patients and additionally, for the first time, demonstrate a functional change related to sympathetic fibres. Office workers demonstrate a similar but smaller trend for reduced nerve function associated with both small and large sensory fibre function, but had no change in the sympathetic reflex.