Does peripheral neuroinflammation predict chronicity following whiplash injury?: Protocol for a prospective cohort study

Colette Ridehalgh; Joel Fundaun; Stephen Bremner; Mara Cercignani; Rupert Young; Chetan Trivedy; Alex Novak; Jane Greening; Annina Schmid; Andrew Dilley

doi:10.1136/bmjopen-2022-066021

Does peripheral neuroinflammation predict chronicity following whiplash injury? Protocol for a prospective cohort study

Colette Ridehalgh, Joel Fundaun, Stephen Bremner, Mara Cercignani, Rupert Young, Chetan Trivedy, Alex Novak, Jane Greening, Annina Schmid, Andrew Dilley

School of Sport and Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

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. 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. 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. NCT04940923. [Abstract copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.]

Original language	English
Article number	e066021
Number of pages	9
Journal	BMJ Open
Volume	12
Issue number	12
DOIs	https://doi.org/10.1136/bmjopen-2022-066021
Publication status	Published - 15 Dec 2022

Bibliographical note

Funding Information:
This work is supported by a Pain Challenge Grant from Versus Arthritis (number (22465)). AS is supported by a Wellcome Trust Clinical Career Development Fellowship (222101/Z/20/Z) and the Medical Research Foundation (MRF-160-0013-ELP-SCHM-C0842). Her research is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. This research was funded in whole, or in part, by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Publisher Copyright:
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Keywords

Emergency medicine
1506
1691
neuroradiology
trauma management
neurophysiology
accident & emergency medicine
neurological pain

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Cite this

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title = "Does peripheral neuroinflammation predict chronicity following whiplash injury?: Protocol for a prospective cohort study",

abstract = "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. 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. 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. NCT04940923. [Abstract copyright: {\textcopyright} Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.]",

keywords = "Emergency medicine, 1506, 1691, neuroradiology, trauma management, neurophysiology, accident & emergency medicine, neurological pain",

author = "Colette Ridehalgh and Joel Fundaun and Stephen Bremner and Mara Cercignani and Rupert Young and Chetan Trivedy and Alex Novak and Jane Greening and Annina Schmid and Andrew Dilley",

note = "Funding Information: This work is supported by a Pain Challenge Grant from Versus Arthritis (number (22465)). AS is supported by a Wellcome Trust Clinical Career Development Fellowship (222101/Z/20/Z) and the Medical Research Foundation (MRF-160-0013-ELP-SCHM-C0842). Her research is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. This research was funded in whole, or in part, by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.",

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T1 - Does peripheral neuroinflammation predict chronicity following whiplash injury?

T2 - Protocol for a prospective cohort study

AU - Ridehalgh, Colette

AU - Fundaun, Joel

AU - Bremner, Stephen

AU - Cercignani, Mara

AU - Young, Rupert

AU - Trivedy, Chetan

AU - Novak, Alex

AU - Greening, Jane

AU - Schmid, Annina

AU - Dilley, Andrew

N1 - Funding Information: This work is supported by a Pain Challenge Grant from Versus Arthritis (number (22465)). AS is supported by a Wellcome Trust Clinical Career Development Fellowship (222101/Z/20/Z) and the Medical Research Foundation (MRF-160-0013-ELP-SCHM-C0842). Her research is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. This research was funded in whole, or in part, by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

PY - 2022/12/15

Y1 - 2022/12/15

N2 - 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. 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. 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. NCT04940923. [Abstract copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.]

AB - 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. 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. 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. NCT04940923. [Abstract copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.]

KW - Emergency medicine

KW - 1506

KW - 1691

KW - neuroradiology

KW - trauma management

KW - neurophysiology

KW - accident & emergency medicine

KW - neurological pain

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U2 - 10.1136/bmjopen-2022-066021

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