Carpal Tunnel Syndrome, Neurodynamic Treatment, Nerve Mobilisation, Diffusion MRI, Physiotherapy, Mechanistic Trial
Conditions
Brief summary
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.
Detailed description
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.
Interventions
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.
DRUGSteroid injection (Depomedrone 40mg)
Steroid injection (Depomedrone 40mg) into the carpal tunnel as per standard practice in patients with carpal tunnel syndrome
OTHERAdvice
Group receiving advice but no additional treatment
Sponsors
Wellcome Trust
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Masking description
The outcomes assessor and the person responsible for the statistical analysis will be blinded to the participants' allocation.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Patients: 1. Patients who have a diagnosis of mild to moderate carpal tunnel syndrome based on a clinical assessment and confirmed with nerve conduction studies. 2. Male or Female, aged 18 years or above. 3. Patient is willing and able to give informed consent for participation in the study. Healthy participants: 1. Male or female aged 18 years or above. 2. Participant is willing and able to give informed consent for participation in the study. 3. No history of hand or arm symptoms 4. No history of neck pain in the past 3 months 5. No systemic medical condition 6. No strong anticoagulant medication or altered coagulation (e.g., hemophilia) preventing skin biopsies 7. Severe anxiety or depression 8. Participants are required to be age- & sex-matched to patient participants 9. No contraindications for magnetic resonance scanning at 3T 10. Sufficient command of the English language
Exclusion criteria
Patients: 1. Patients who already had surgery for their carpal tunnel syndrome (CTS) or are planning to undergo surgery in the next 6 weeks (patients with unilateral surgery who have unoperated CTS on the other hand are eligible to participate) 2. Patients who had a steroid injection for their CTS in the 6 months prior to the study enrolment or who had already more than 1 steroid injection into the study wrist. 3. Patients who have a diagnosis of severe carpal tunnel syndrome based on a clinical assessment and confirmed with electrodiagnostic testing 4. Electrodiagnostic testing revealing abnormalities other than CTS 5. Any other upper limb or neck problem for which they have sought treatment in the past 3 months 6. History of significant trauma to the upper limb or neck 7. Diabetes 8. Hypothyroidism 9. Severe anxiety or depression 10. Patient who is pregnant, lactating, or planning pregnancy during the study. 11. Patients on strong anticoagulant medication or altered coagulation preventing skin biopsies. 12. Contraindications for magnetic resonance imaging (assessed with MRI safety screening questionnaire). 13. Contraindications for steroid injections 14. Insufficient command of the English language
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median nerve fractional anisotropy as determined on diffusion weighted imaging | Baseline | Fractional anisotropy will be extracted from regions-of-interest in the median nerve and compared to healthy control group |
| Change in median nerve fractional anisotropy as determined on diffusion weighted imaging | From baseline to post-intervention (after 6-weeks) | Change in fractional anisotropy extracted from regions-of-interest in the median nerve at post-intervention (after 6-weeks) compared to baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nerve markers on anatomical MRI | Baseline | Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data |
| Change in nerve markers on anatomical MRI | From baseline to post-intervention (after 6-weeks) | Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data |
| Median nerve MRI T2 mapping | Baseline | ms; continuous data |
| Changes in median nerve MRI T2 mapping | From baseline to post-intervention (after 6-weeks) | ms; continuous data |
| Median nerve MRI magnetisation transfer ratio (MTR) | Baseline | ratio; continuous data |
| Changes in median nerve MRI magnetisation transfer ratio (MTR) | From baseline to post-intervention (after 6-weeks) | ratio; continuous data |
| Changes in median nerve conduction velocities from electrodiagnostic studies (m/s) | From baseline to post-intervention (after 6-weeks) | m/s; continuous data |
| Changes in median sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs): amplitudes (mV) | From baseline to post-intervention (after 6-weeks) | mV; continuous data |
| Thermal detection thresholds as assessed in Quantitative Sensory testing - warm and cold detection threshold; thermal sensory limen | Baseline | 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) |
| Change in thermal detection thresholds as assessed in Quantitative Sensory testing- warm and cold detection threshold; thermal sensory limen | From baseline to post-intervention (after 6-weeks) | 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) |
| Thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold | Baseline | 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) |
| Change in thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold | From baseline to post-intervention (after 6-weeks) | 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) |
| Nerve markers on diffusion weighted imaging: water diffusivity (mm2/s) | Baseline | Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data |
| Change in mechanical detection thresholds as assessed in Quantitative sensory testing | From baseline to post-intervention (after 6-weeks) | Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean wil be calculated |
| Mechanical pain thresholds as assessed in Quantitative sensory testing | Baseline | 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). |
| Change in mechanical pain thresholds as assessed in Quantitative sensory testing | From baseline to post-intervention (after 6-weeks) | 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). |
| Mechanical pain sensitivity as assessed in Quantitative sensory testing | Baseline | 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 |
| Change in mechanical pain sensitivity as assessed in Quantitative sensory testing | From baseline to post-intervention (after 6-weeks) | 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 |
| Dynamic mechanical allodynia as assessed in Quantitative sensory testing | Baseline | 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 |
| Change in dynamic mechanical allodynia as assessed in Quantitative sensory testing | From baseline to post-intervention (after 6-weeks) | 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 |
| Wind-up ratio as assessed in Quantitative sensory testing | Baseline | 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 |
| Change in wind-up ratio as assessed in Quantitative sensory testing | From baseline to post-intervention (after 6-weeks) | 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 |
| Vibration detection thresholds as assessed in Quantitative sensory testing | Baseline | 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) |
| Change in vibration detection thresholds as assessed in Quantitative sensory testing | From baseline to post-intervention (after 6-weeks) | 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) |
| Pressure pain thresholds as assessed in Quantitative sensory testing | Baseline | Pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior) |
| Change in pressure pain thresholds as assessed in Quantitative sensory testing | From baseline to post-intervention (after 6-weeks) | Change in pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior) |
| Pinch strength test - maximum isometric strength | Baseline | Pinch grip dynamometry. Continuous data, kg |
| Change in pinch strength test - maximum isometric strength | From baseline to post-intervention (after 6-weeks) | Pinch grip dynamometry. Continuous data, kg |
| Nerve mechanosensitivity- upper limb neurodynamic test (median nerve) | Baseline | Evaluation of nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees) |
| Change in nerve mechanosensitivity- upper limb neurodynamic test (median nerve) | From baseline to post-intervention (after 6-weeks) | Change in nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees) |
| Nerve mechanosensitivity - positive upper limb neurodynamic tests | Baseline | 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' |
| Change in nerve mechanosensitivity - positive upper limb neurodynamic tests | From baseline to post-intervention (after 6-weeks) | 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' |
| Presence of neuropathic pain - DN4 | Baseline, post-intervention (after 6 weeks), 6-months follow up | Patient screened for neuropathic pain using DN4 |
| Symptom severity and limitations in hand function as assessed by the Boston carpal tunnel syndrome questionnaire | Baseline, post-intervention (after 6 weeks), 6-months follow up | Patient reported symptoms and limitations on the Boston carpal tunnel syndrome questionnaire |
| Symptom intensity levels on a Visual Analogue Scale (VAS) | Baseline, post-intervention (after 6 weeks), 6-months follow up | Patient reported average intensity of pain, paraesthesia and numbness on 10cm visual analogue scales, ranging from no symptoms to worst symptoms ever |
| Location of symptoms in a body and a hand diagram | Baseline, post-intervention (after 6 weeks) | Patient reported location of symptoms in a body diagram and a hand diagram. |
| Presence of central sensitisation as assessed with the Central Sensitisation Inventory | Baseline, post-intervention (after 6 weeks), 6-months follow up | Patient reported central sensitisation on the Central Sensitisation Inventory |
| Functional deficits- Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire | Baseline, post-intervention (after 6 weeks), 6-months follow up | Participant reported outcomes on ability to perform activities as per quick DASH questionnaire |
| Functional deficits- Patient specific functional scale (PSFS) | Baseline, post-intervention (after 6 weeks), 6-months follow up | Participant reported outcomes on the patient specific functional scale |
| Presence of neuropathic pain - pain DETECT | Baseline, post-intervention (after 6 weeks), 6-months follow up | Patient screened for neuropathic pain using pain DETECT |
| Neuropathic pain symptoms - Neuropathic Pain Symptom Inventory | Baseline, post-intervention (after 6 weeks), 6-months follow up | Patient reported outcomes on neuropathic pain symptoms as assessed on Neuropathic Pain Symptom Inventory. |
| Presence of psychological co-morbidities - The Depression, Anxiety, and Positive Outlook Scale (DAPOS) | Baseline, post-intervention (after 6 weeks), 6-months follow up | Participant reported outcomes on depression and anxiety as per DAPOS |
| Presence of psychological co-morbidities - short-form Pain Anxiety Symptoms Scale (PASS-20) | Baseline, post-intervention (after 6 weeks), 6-months follow up | Participant reported outcomes on depression and anxiety as per short-form Pain Anxiety Symptoms Scale (PASS-20) |
| Presence of psychological co-morbidities - pain catastrophizing scale (PCS) | Baseline, post-intervention (after 6 weeks), 6-months follow up | Participant reported outcomes on depression and anxiety as per pain catastrophising scale (PCS) |
| Assessment of quality of life - EQ-5D-5L | Baseline, post-intervention (after 6 weeks), 6-months follow up | Participant reported outcomes on quality of life as per EQ-5D-5L questionnaire |
| Assessment of sleep interference - Insomnia Severity Index | Baseline, post-intervention (after 6 weeks), 6-months follow up | Participant reported outcomes on sleep interference with the Insomnia Severity Index. |
| Adverse and serious adverse events | From start of intervention until end of intervention (6 weeks) | Patient self-reported adverse events |
| Exercise adherence to the neurodynamic home-based intervention - number of sessions | From start of intervention until end of intervention (6 weeks) | Patient self-reported number of sessions per day throughout the intervention in an exercise diary |
| Mechanical detection thresholds as assessed in Quantitative sensory testing | Baseline | Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean will be calculated |
| Change to nerve markers on diffusion weighted imaging: water diffusivity (mm2/s) | From baseline to post-intervention (after 6-weeks) | Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data |
Other
| Measure | Time frame | Description |
|---|---|---|
| Blood samples - DNA | Baseline | Blood samples coupled with detailed phenotype data will investigate potential gene associations in CTS and recovery |
| Change in blood samples - DNA | From baseline to post-intervention (after 6-weeks) | Change in blood samples coupled with detailed phenotype data will investigate potential gene associations in CTS and recovery |
| Concentration of serum inflammatory markers - metabolomics | Baseline | Concentrations of inflammatory markers in serum |
| Change in the concentration of serum inflammatory markers - metabolomics | From baseline to post-intervention (after 6-weeks) | Change in the concentrations of inflammatory markers in serum |
| Pro-inflammatory cytokine levels | Baseline | Proinflammatory cytokine assay (pg/ml); continuous data |
| Change in pro-inflammatory cytokine levels | From baseline to post-intervention (after 6-weeks) | Change in proinflammatory cytokine assay (pg/ml); continuous data |
| Concentration of inflammatory markers in serial skin biopsies | Baseline | Concentration of inflammatory markers in skin biopsies. Baseline biopsy will be performed in the most distal part of the ventrolateral side of the proximal phalanx of the index finger. The 6-weeks biopsy will be performed proximally, avoiding the primary biopsy site |
| Change in concentration of inflammatory markers in serial skin biopsies | From baseline to post-intervention (after 6-weeks) | Change in concentration of inflammatory markers in skin biopsies. Baseline biopsy will be performed in the most distal part of the ventrolateral side of the proximal phalanx of the index finger. The 6-weeks biopsy will be performed proximally, avoiding the primary biopsy site |
Countries
United Kingdom
Contacts
Primary ContactAnnina Schmid, PhD
Backup ContactEva Sierra-Silvestre, PhD
Outcome results
None listed