Neuroinflammation as a Predictor of Chronicity in Whiplash

Study Overview
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Brief Summary
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Whiplash describes an injury to the neck caused by a rapid movement of the head. It often occurs during a motor vehicle collision, causing considerable pain and distress. Most patients are diagnosed with whiplash associated disorder grade-2 (WAD2). Half of these patients develop chronic pain. Current treatments for patients are ineffective. It is difficult to predict which patients will develop chronic pain, and therefore how to manage these patients. The characteristics of pain felt by many patients with WAD2 suggests that symptoms are caused by an injury to the nerves in the neck and arm. However, on clinical examination there is no indication that these nerves are significantly injured. Work from the investigators' laboratory suggests that nerves may be inflamed. In this study, the contribution of nerve inflammation to symptoms early following whiplash will be established. It will determine whether clinical tests are able to identify those patients with inflamed nerves. It will also determine whether the presence of nerve inflammation can be used to identify patients who develop chronic pain. The study will recruit 115 patients within one month following a whiplash injury and thirty-two healthy volunteers. Participants will undergo a clinical assessment. A blood sample will be taken to look for inflammatory proteins and magnetic resonance imaging will be used to identify nerve inflammation in the neck and wrist. Questionnaires to establish neck disability, pain quality and psychological distress will be completed. MRI findings will be compared to healthy controls. At six-months, patients will be asked to repeat the questionnaires, which will be used to identify those patients who have recovered. Twenty-five recovered and twenty-five non-recovered patients will undergo a repeat MRI and clinical assessment. Although patients on this study will not directly benefit, the findings will help with early diagnosis and could refocus treatment to reduce chronic pain.

Official Title
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Does Peripheral Neuroinflammation Predict Chronicity Following Whiplash?

Conditions
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Whiplash Injuries

Intervention / Treatment
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* Diagnostic Test: MRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients: Male and female patients with chronic whiplash associated disorder that meet the Quebec Task Force Classification of whiplash grade II Within approximately four weeks of their whiplash injury Age 18-60 Participants capable of giving informed consent Healthy Volunteers: Free of neck or upper limb pain No history of a whiplash injury or of neck or arm pain lasting >3 months or any recent cervical or upper limb trauma requiring medical treatment. Age 18-60 Participants capable of giving informed consent Exclusion Criteria: Patients: Diagnosis of whiplash grade I (neck complaints without physical signs), III (obvious neurological signs) or IV (fracture or dislocation) Experienced concussion or loss of consciousness as a result of the accident Previous history of whiplash Previous history of neck pain or headaches that required treatment All participants (patients and healthy volunteers): Unsuitability to undergo MRI (assessed with the MRI screening questionnaire) Pregnant History of inflammatory disease (e.g. autoimmune diseases, rheumatoid arthritis), neuropathy, diabetes, cancer or non-medically controlled hypertension Current ongoing steroid treatment Participants with an inadequate understanding of English will also be excluded

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>Patients within 4 weeks of a whiplash injury. | Diagnostic Test: MRI<br>* T2 weighted and DTI MRI images of brachial plexus and wrist. Quantitative sensory tests include warm and cold detection and pain thresholds, paradoxical heat sensation, mechanical detection thresholds, mechanical pain sensation and thresholds, wind up ratios, vibration thresholds and pressure pain thresholds. Clinical tests include standard neurological tests and test for heightened nerve mechanosensitivity. Blood serum to analyse inflammatory proteins. Questionnaires include neck disability index, painDETECT, PTSD8, pain catastrophising scale, eq-5D-5L, DASS 42 and global perceived recovery<br>* Other names: Questionnaires;|
| Healthy controls<br>Age and gender matched healthy controls | Diagnostic Test: MRI<br>* T2 weighted and DTI MRI images of brachial plexus and wrist. Quantitative sensory tests include warm and cold detection and pain thresholds, paradoxical heat sensation, mechanical detection thresholds, mechanical pain sensation and thresholds, wind up ratios, vibration thresholds and pressure pain thresholds. Clinical tests include standard neurological tests and test for heightened nerve mechanosensitivity. Blood serum to analyse inflammatory proteins. Questionnaires include neck disability index, painDETECT, PTSD8, pain catastrophising scale, eq-5D-5L, DASS 42 and global perceived recovery<br>* Other names: Questionnaires;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI T2-weighted nerve signal strength | T2-weighted nerve signal strength in the brachial plexus and median nerve compared to healthy control group | Baseline | 
| Change in MRI T2-weighted nerve signal strength | Change in T2-weighted nerve signal strength in the brachial plexus and median nerve at 6 months compared to baseline | From baseline to 6 months | 
| Fractional anisotropy from diffusion tensor images | Fractional anisotropy measurements from brachial plexus and median nerve compared to healthy controls | Baseline | 
| Change in fractional anisotropy from Diffusion tensor images | Fractional anisotropy from brachial plexus and median nerve compared to baseline | From baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T1 MRI median nerve morphology | ratio/mm2; continuous data | Baseline | 
| Changes to T1 MRI median nerve morphology | ratio/mm2; continuous data | From baseline to 6 months | 
| Pro-inflammatory cytokine levels | Proinflammatory cytokine assay (pg/ml) continuous data | Baseline | 
| Change in Pro-inflammatory cytokine levels | Proinflammatory cytokine assay (pg/ml) continuous data | From baseline to 6 months | 
| Tests for heightened nerve mechanosensitivity- upper limb neurodynamic test (median nerve) | Measures heightened response to tensile load applied to the nerve. Range of elbow extension at point of symptoms (degrees) | Baseline | 
| Change to tests for heightened nerve mechanosensitivity- upper limb neurodynamic test (median nerve) | Measures heightened response to tensile load applied to the nerve. Range of elbow extension at point of symptoms (degrees) | From baseline to 6 months | 
| Tests for heightened nerve mechanosensitivity- Pressure pain threshold | Algometer applied to ulnar nerve at the cubital tunnel and median nerve at carpal tunnel. Pressure pain threshold (Kg) at point of change from pressure to pain. | Baseline | 
| Change in heightened nerve mechanosensitivity- Pressure pain threshold | Algometer applied to ulnar nerve at the cubital tunnel and median nerve at carpal tunnel. Pressure pain threshold (Kg) at point of change from pressure to pain. | From baseline to 6 months | 
| Quantitative sensory testing- warm and cold pain thresholds | Thresholds measured over index finger using a thermotester- continuous data measured in degrees Celsius (point at which the probe changes to warm pain or cold pain) | Baseline | 
| Change to Quantitative sensory testing- warm and cold pain thresholds | Thresholds measured over index finger using a thermotester- continuous measured in degrees Celsius (point at which the probe changes to warm pain or cold pain) | From baseline to 6 months | 
| Quantitative sensory testing- Mechanical pain threshold | Thresholds measured over index finger using a series of weighted pin prick stimulators (mN). Participant scores pain from 0-100 for each stimulus applied. Geometric mean calculated | Baseline | 
| Change in Quantitative sensory testing- Mechanical pain threshold | Thresholds measured over index finger using a series of weighted pin prick stimulators (mN). Participant scores pain from 0-100 for each stimulus applied. Geometric mean calculated | From baseline to 6 months | 
| Quantitative sensory testing- Pressure pain threshold | Thresholds measured over thenar eminance using an algometer (Kg). Pressure applied and participant indicates when pressure changes to pain (mean of 3) | Baseline | 
| Change in quantitative sensory testing- Pressure pain threshold | Thresholds measured over thenar eminance using an algometer (Kg). Pressure applied and participant indicates when pressure changes to pain (mean of 3) | From baseline to 6 months | 
| Changes in Pain levels on Visual analogue scale | Participant indicated pain level on a 10cm scale of 0-10 | From baseline to 6 months | 
| Change in Neck disability index | Neck disability index. Scale -10 questions each scored 0-5. Total score /50 | From baseline to 6 months | 
| Change in painDETECT questionnaire | A measure of neuropathic pain. A continuous scale: 0-38 or trichotomised: no, unclear, yes. A score of >19 suggests neuropathic pain. | From baseline to 6 months | 
| Change in Short post-traumatic stress inventory | A measure of post traumatic stress - 8 questions scale of 0-3 | From baseline to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Magnetic resonance imaging, Pain threshold, Neuritis, Prognosis