INTRODUCTION: Carpal tunnel syndrome (CTS) is a relatively common condition caused by compression of one of the main nerves at the wrist, the median nerve. Non-surgical treatments, like steroid injections and physiotherapy, are the first line of treatment for patients with carpal tunnel syndrome. The investigators have previously shown that specific physiotherapeutic exercises (neurodynamic exercises) can reduce the need for carpal tunnel surgery in some patients. Experimental studies in animal models demonstrate that these exercises have an anti-inflammatory effect and can help the nerve to regenerate. However, the exact mechanisms of action of these exercises are not well understood in patients. A better understanding of the mechanisms of action of physiotherapeutic exercises would help clinicians to better target these treatments to those patients who may benefit from them. AIM: To investigate the mechanisms of action of 6 weeks' neurodynamic treatments on nerve function and structure as well as patient-reported outcome measures in patients with CTS compared to a positive control intervention (routine care steroid injection) and a negative control intervention (advice). METHODS AND ANALYSIS: In this single-blind randomised mechanistic trial, patients with confirmed mild to moderate CTS (n=78) and age and gender-matched healthy controls (n=30) will be included. Patients will be randomly allocated to a 6-week neurodynamic exercise group, steroid injection, or advice group. Outcome measures will be explored at baseline (patients and controls), post-intervention (patients), and 6-month follow-up (patients). Outcomes include diffusion-weighted and anatomical MRI of the median nerve at the wrist, quantitative sensory testing, nerve conduction studies, inflammatory markers in blood and skin biopsies, and validated questionnaires for pain, function, and psychological factors. Two-way repeated measures ANCOVAs (factors time and intervention, adjusted for baseline measurements as a continuous covariate) will be performed to identify differences in MRI parameters, clinical assessment, and inflammatory markers between patients in different groups and healthy controls.
Follow-up at 6 months will only include outcome measures from questionnaires. Details on enrollment: Pilot testing of healthy participants who consented to our ethics but will not be included in the study was on 13-April-2023. * First healthy participant enrolled: 17-May-2023. * First patient participant enrolled: 1-June-2023. Details on amendment: * Amendment SA2\_BPOR on 3/Aug/2023 to expand recruitment through registries of patients * Amendment SA3\_REC on 22/Aug/2023 to add Thames Valley Primary Care Research Partnership, musculoskeletal clinics, and media advertisement to help with recruitment of participants.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
SINGLE
Enrollment
108
The neurodynamic exercises will consist of a home-based exercise programme performed over a period of 6 weeks. Patients will attend a single session with an investigator who will instruct them the home exercise programme consisting of nerve and tendon gliding exercises which will be adjusted with pre-specified progressions over the 6 weeks intervention period. Patients will receive a leaflet and a video link detailing these exercises.
Steroid injection (Depomedrone 40mg) into the carpal tunnel as per standard practice in patients with carpal tunnel syndrome
Group receiving advice but no additional treatment
Nuffield Department of Clinical Neurosciences, University of Oxford
Oxford, Oxfordshire, United Kingdom
RECRUITINGMedian nerve fractional anisotropy as determined on diffusion weighted imaging
Fractional anisotropy will be extracted from regions-of-interest in the median nerve and compared to healthy control group
Time frame: Baseline
Change in median nerve fractional anisotropy as determined on diffusion weighted imaging
Change in fractional anisotropy extracted from regions-of-interest in the median nerve at post-intervention (after 6-weeks) compared to baseline
Time frame: From baseline to post-intervention (after 6-weeks)
Nerve markers on diffusion weighted imaging: water diffusivity (mm2/s)
Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data
Time frame: Baseline
Change to nerve markers on diffusion weighted imaging: water diffusivity (mm2/s)
Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data
Time frame: From baseline to post-intervention (after 6-weeks)
Nerve markers on anatomical MRI
Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data
Time frame: Baseline
Change in nerve markers on anatomical MRI
Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data
Time frame: From baseline to post-intervention (after 6-weeks)
Median nerve MRI T2 mapping
ms; continuous data
Time frame: Baseline
Changes in median nerve MRI T2 mapping
ms; continuous data
Time frame: From baseline to post-intervention (after 6-weeks)
Median nerve MRI magnetisation transfer ratio (MTR)
ratio; continuous data
Time frame: Baseline
Changes in median nerve MRI magnetisation transfer ratio (MTR)
ratio; continuous data
Time frame: From baseline to post-intervention (after 6-weeks)
Changes in median nerve conduction velocities from electrodiagnostic studies (m/s)
m/s; continuous data
Time frame: From baseline to post-intervention (after 6-weeks)
Changes in median sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs): amplitudes (mV)
mV; continuous data
Time frame: From baseline to post-intervention (after 6-weeks)
Thermal detection thresholds as assessed in Quantitative Sensory testing - warm and cold detection threshold; thermal sensory limen
Thermal detection thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Data is measured in degrees celsius (point at which cold or warm is detected)
Time frame: Baseline
Change in thermal detection thresholds as assessed in Quantitative Sensory testing- warm and cold detection threshold; thermal sensory limen
Thermal detection thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Data is measured in degrees celsius (point at which cold or warm is detected)
Time frame: From baseline to post-intervention (after 6-weeks)
Thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold
Pain thermal thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger) and over the contralateral lower limb (tibial anterior). Data is measured in degrees celsius (point at which cold or warm is initially detected as painful)
Time frame: Baseline
Change in thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold
Pain thermal thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger) and over the contralateral lower limb (tibial anterior). Data is measured in degrees celsius (point at which cold or warm is initially detected as painful)
Time frame: From baseline to post-intervention (after 6-weeks)
Mechanical detection thresholds as assessed in Quantitative sensory testing
Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean will be calculated
Time frame: Baseline
Change in mechanical detection thresholds as assessed in Quantitative sensory testing
Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean wil be calculated
Time frame: From baseline to post-intervention (after 6-weeks)
Mechanical pain thresholds as assessed in Quantitative sensory testing
Mechanical pain thresholds will be assessed using a series of weighted pin prick stimulators (mN). They will be assessed over the index finger and over the contralateral lower limb (tibial anterior).
Time frame: Baseline
Change in mechanical pain thresholds as assessed in Quantitative sensory testing
Mechanical pain thresholds will be assessed using a series of weighted pin prick stimulators (mN). They will be assessed over the index finger and over the contralateral lower limb (tibial anterior).
Time frame: From baseline to post-intervention (after 6-weeks)
Mechanical pain sensitivity as assessed in Quantitative sensory testing
Mechanical pain sensitivity will be assessed using a series of weighted pin prick stimulators (mN) over the index finger. Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean of all numerical ratings for pinprick stimuli will be calculated
Time frame: Baseline
Change in mechanical pain sensitivity as assessed in Quantitative sensory testing
Mechanical pain sensitivity will be assessed using a series of weighted pin prick stimulators (mN) over the index finger. Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean of all numerical ratings for pinprick stimuli will be calculated
Time frame: From baseline to post-intervention (after 6-weeks)
Dynamic mechanical allodynia as assessed in Quantitative sensory testing
Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean (compound measure) of all numerical ratings across light touch stimulators over the index finger
Time frame: Baseline
Change in dynamic mechanical allodynia as assessed in Quantitative sensory testing
Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean (compound measure) of all numerical ratings across light touch stimulators over the index finger
Time frame: From baseline to post-intervention (after 6-weeks)
Wind-up ratio as assessed in Quantitative sensory testing
Wind-up ration will be assessed using a pin prick (mN) over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Ratio, continous data
Time frame: Baseline
Change in wind-up ratio as assessed in Quantitative sensory testing
Change in wind-up ration will be assessed using a pin prick (mN) over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Ratio, continuous data
Time frame: From baseline to post-intervention (after 6-weeks)
Vibration detection thresholds as assessed in Quantitative sensory testing
Vibration detection thresholds will be assessed using a tuning fork (64 Hz, 8/8 scale) over a bony prominence over (e.g., palmar side of the distal end of the second metacarpal)
Time frame: Baseline
Change in vibration detection thresholds as assessed in Quantitative sensory testing
Change in vibration detection thresholds will be assessed using a tuning fork (64 Hz, 8/8 scale) over a bony prominence over (e.g., palmar side of the distal end of the second metacarpal)
Time frame: From baseline to post-intervention (after 6-weeks)
Pressure pain thresholds as assessed in Quantitative sensory testing
Pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior)
Time frame: Baseline
Change in pressure pain thresholds as assessed in Quantitative sensory testing
Change in pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior)
Time frame: From baseline to post-intervention (after 6-weeks)
Pinch strength test - maximum isometric strength
Pinch grip dynamometry. Continuous data, kg
Time frame: Baseline
Change in pinch strength test - maximum isometric strength
Pinch grip dynamometry. Continuous data, kg
Time frame: From baseline to post-intervention (after 6-weeks)
Nerve mechanosensitivity- upper limb neurodynamic test (median nerve)
Evaluation of nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees)
Time frame: Baseline
Change in nerve mechanosensitivity- upper limb neurodynamic test (median nerve)
Change in nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees)
Time frame: From baseline to post-intervention (after 6-weeks)
Nerve mechanosensitivity - positive upper limb neurodynamic tests
Upper limb neurodynamic tests will be assessed to determine the presence of increased mechanosensitivity. The neurodynamic test will be graded as 'positive', when there is at least partial reproduction of symptoms plus when symptoms can be modified with structural differentiation. Otherwise, the neurodynamic test will be graded as 'negative'
Time frame: Baseline
Change in nerve mechanosensitivity - positive upper limb neurodynamic tests
Upper limb neurodynamic tests will be assessed to determine the presence of increased mechanosensitivity. The neurodynamic test will be graded as 'positive', when there is at least partial reproduction of symptoms and when symptoms can be modified with structural differentiation. Otherwise, the neurodynamic test will be graded as 'negative'
Time frame: From baseline to post-intervention (after 6-weeks)
Symptom severity and limitations in hand function as assessed by the Boston carpal tunnel syndrome questionnaire
Patient reported symptoms and limitations on the Boston carpal tunnel syndrome questionnaire
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Symptom intensity levels on a Visual Analogue Scale (VAS)
Patient reported average intensity of pain, paraesthesia and numbness on 10cm visual analogue scales, ranging from no symptoms to worst symptoms ever
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Location of symptoms in a body and a hand diagram
Patient reported location of symptoms in a body diagram and a hand diagram.
Time frame: Baseline, post-intervention (after 6 weeks)
Presence of central sensitisation as assessed with the Central Sensitisation Inventory
Patient reported central sensitisation on the Central Sensitisation Inventory
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Functional deficits- Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire
Participant reported outcomes on ability to perform activities as per quick DASH questionnaire
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Functional deficits- Patient specific functional scale (PSFS)
Participant reported outcomes on the patient specific functional scale
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of neuropathic pain - DN4
Patient screened for neuropathic pain using DN4
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of neuropathic pain - pain DETECT
Patient screened for neuropathic pain using pain DETECT
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Neuropathic pain symptoms - Neuropathic Pain Symptom Inventory
Patient reported outcomes on neuropathic pain symptoms as assessed on Neuropathic Pain Symptom Inventory.
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of psychological co-morbidities - The Depression, Anxiety, and Positive Outlook Scale (DAPOS)
Participant reported outcomes on depression and anxiety as per DAPOS
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of psychological co-morbidities - short-form Pain Anxiety Symptoms Scale (PASS-20)
Participant reported outcomes on depression and anxiety as per short-form Pain Anxiety Symptoms Scale (PASS-20)
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of psychological co-morbidities - pain catastrophizing scale (PCS)
Participant reported outcomes on depression and anxiety as per pain catastrophising scale (PCS)
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Assessment of quality of life - EQ-5D-5L
Participant reported outcomes on quality of life as per EQ-5D-5L questionnaire
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Assessment of sleep interference - Insomnia Severity Index
Participant reported outcomes on sleep interference with the Insomnia Severity Index.
Time frame: Baseline, post-intervention (after 6 weeks), 6-months follow up
Adverse and serious adverse events
Patient self-reported adverse events
Time frame: From start of intervention until end of intervention (6 weeks)
Exercise adherence to the neurodynamic home-based intervention - number of sessions
Patient self-reported number of sessions per day throughout the intervention in an exercise diary
Time frame: From start of intervention until end of intervention (6 weeks)
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