Neuroinflammation as a Predictor of Chronicity in Whiplash

Does Peripheral Neuroinflammation Predict Chronicity Following Whiplash?

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.

Study Overview

• Status: Recruiting
• Conditions: Whiplash Injuries
• Intervention / Treatment: Diagnostic test: MRI

• Study Type: Observational
• Enrollment (Anticipated): 147

Contacts and Locations

• Study Contact: Name: Andrew Dilley, PhD; Phone Number: +44 1273 877094; Email: a.dilley@bsms.ac.uk
• Study Contact Backup: Name: Colette Ridehalgh, PhD; Phone Number: +44 1273 075260; Email: c.ridehalgh@bsms.ac.uk

Study Locations

• United Kingdom
  • East Sussex
    • Brighton, East Sussex, United Kingdom, BN1 9RY
      • Recruiting
      • Brighton and Sussex Medical School
      • Contact: Colette Ridehalgh, PhD; Phone Number: +441273075260; Email: c.ridehalgh@bsms.ac.uk
      • Contact: Andrew Dilley, PhD; Phone Number: +441273 877094; Email: A.Dilley@BSMS.ac.uk
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • Recruiting
      • Oxford Neuroscience, University of Oxford
      • Contact: Annina Schmid, PhD; Phone Number: +44 1865 223254; Email: annina.schmid@ndcn.ox.ac.uk
      • Contact: Joel Fundaun; Email: joel.fundaun@ndcn.ox.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

People who have sustained a whiplash injury less than 4 weeks prior to their participation in the study.

Healthy volunteers.

Description

Inclusion Criteria:

Patients:

1. Male and female patients with chronic whiplash associated disorder that meet the Quebec Task Force Classification of whiplash grade II
2. Within approximately four weeks of their whiplash injury
3. Age 18-60
4. Participants capable of giving informed consent

Healthy Volunteers:

1. Free of neck or upper limb pain
2. 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.
3. Age 18-60
4. Participants capable of giving informed consent

Exclusion Criteria:

Patients:

1. Diagnosis of whiplash grade I (neck complaints without physical signs), III (obvious neurological signs) or IV (fracture or dislocation)
2. Experienced concussion or loss of consciousness as a result of the accident
3. Previous history of whiplash

4. Previous history of neck pain or headaches that required treatment

   All participants (patients and healthy volunteers):

5. Unsuitability to undergo MRI (assessed with the MRI screening questionnaire)
6. Pregnant
7. History of inflammatory disease (e.g. autoimmune diseases, rheumatoid arthritis), neuropathy, diabetes, cancer or non-medically controlled hypertension
8. Current ongoing steroid treatment
9. Participants with an inadequate understanding of English will also be excluded

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients; Patients within 4 weeks of a whiplash injury.	Diagnostic test: MRI; 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; Other Names: Questionnaires; Quantitative sensory tests; Blood serum tests; Clinical tests
Healthy controls; Age and gender matched healthy controls	Diagnostic test: MRI; 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; Other Names: Questionnaires; Quantitative sensory tests; Blood serum tests; Clinical tests

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Sussex
• Collaborators: University of Oxford
• Investigators: Principal Investigator: Andrew Dilley, PhD, Brighton and Sussex Medical School

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2021
• Primary Completion (Anticipated): March 1, 2023
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: June 9, 2021
• First Submitted That Met QC Criteria: June 17, 2021
• First Posted (Actual): June 28, 2021

Study Record Updates

• Last Update Posted (Actual): November 4, 2022
• Last Update Submitted That Met QC Criteria: November 3, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Prognosis; Magnetic resonance imaging; Pain threshold; Neuritis
• Additional Relevant MeSH Terms: Wounds and Injuries; Neck Injuries; Whiplash Injuries
• Other Study ID Numbers: 278291/ 070 DIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No