Joel Fundaun

All Publications

• The presence and prognosis of nerve pathology following whiplash injury: a prospective cohort study. Brain : a journal of neurology Fundaun, J., Ridehalgh, C., Koushesh, S., Novak, A., Tejos-Bravo, M., Bremner, S., Baskozos, G., Dilley, A., Schmid, A. B. 2025

  Abstract

  Whiplash Associated Disorders (WAD) affect 20-50 million individuals globally each year, with up to 50% developing persistent pain. WAD grade II (WADII) is the most common type and is characterised by neck symptoms and musculoskeletal signs without apparent nerve injury on routine diagnostic testing. However, emerging evidence suggests nerve pathology may be present in some people with WADII. This longitudinal cohort study aimed to comprehensively investigate the presence, temporal patterns, and prognostic value of nerve pathology and neuropathic pain in acute WADII. A prospective longitudinal cohort study was conducted with 129 acute participants with WADII (median age 36.0 years, 58% female) and 36 healthy controls (median age 39.0 years, 61% female). Participants with WADII were recruited within four weeks of injury from local emergency departments. Data collection included bedside neurological assessments, quantitative sensory testing (QST), intraepidermal nerve fibre density, and serum neurofilament light chain (NfL) concentrations. Follow-up assessments were conducted 6-months after injury. Signs of neuropathic pain were present in 65% (84/129) acutely and persisted in 32% (21/66) 6-months post-injury. Bedside neurological assessment revealed somatosensory loss of function was present in 54% (70/129) acutely reducing to 25% (17/67) 6-months post-injury. QST demonstrated significantly reduced cold, warm, thermal sensory limen, mechanical, and vibration detection thresholds in acute WADII compared to controls (d>0.47). Acute loss of function in at least one QST parameter was present in 67.6% (85/126) of WADII. At 6-months, participants with WADII showed persistent hypoaesthesia to warm, thermal sensory limen, and mechanical detection thresholds, and decreased mechanical pain and pressure pain sensitivity compared to controls (d>0.44). These functional neurological changes were accompanied by elevated serum neurofilament light chain levels in acute WADII compared to controls (d=-0.52 (95% confidence interval -0.94, -0.10). Intraepidermal nerve fibre densities at the index finger were not significantly different between groups. However, dermal MBP+/PGP+ myelinated nerve bundles at the index finger were reduced 6-months post-injury in WADII compared to controls (d=0.69 (0.26, 1.11). Multivariable linear regression suggested bedside tests for hypoaesthesia at the index finger were prognostic for whiplash-related upper quadrant pain 6-months post-injury (r2=0.13, p=0.02). In conclusion, two-thirds of participants with acute WADII initially exhibited signs of neuropathic pain and nerve pathology. At the 6-month follow-up, neuropathic pain persisted in one-third of participants with WADII, while nerve pathology persisted in two-thirds. These findings challenge the traditional musculoskeletal classification of WADII and underscore the need for targeted neurological assessments and treatment.

  View details for DOI 10.1093/brain/awaf088

  View details for PubMedID 40042607

• Evidence for peripheral neuroinflammation after acute whiplash. Pain Ridehalgh, C., Fundaun, J., Bremner, S., Cercignani, M., Koushesh, S., Young, R., Novak, A., Greening, J., Schmid, A. B., Dilley, A. 2025

  Abstract

  Whiplash injury is associated with high socioeconomic costs and poor prognosis. Most people are classified as having whiplash-associated disorder grade II (WADII), with neck complaints and musculoskeletal signs, in the absence of frank neurological signs. However, evidence suggests that there is a subgroup with underlying nerve involvement in WADII, such as peripheral neuroinflammation. This study aimed to investigate the presence of neuroinflammation in acute WADII using T2-weighted magnetic resonance imaging of the brachial plexus, dorsal root ganglia and median nerve, and clinical surrogates of neuroinflammation: heightened nerve mechanosensitivity (HNM), raised serum inflammatory mediators, and somatosensory hyperalgesia. One hundred twenty-two WADII participants within 4 weeks of whiplash and 43 healthy controls (HCs) were recruited. Magnetic resonance imaging T2 signal ratio was increased in the C5 root of the brachial plexus and the C5-C8 dorsal root ganglia in WADII participants compared with HCs but not in the distal median nerve trunk. Fifty-five percent of WADII participants had signs of HNM. Inflammatory mediators were also raised compared with HCs, and 47% of WADII participants had somatosensory changes on quantitative sensory testing. In those WADII individuals with HNM, there was hyperalgesia to cold and pressure and an increased proportion of neuropathic pain. Many people with WADII had multiple indicators of neuroinflammation. Overall, our results present a complex phenotypic profile for acute WADII and provide evidence suggestive of peripheral neuroinflammation in a subgroup of individuals. The results suggest that there is a need to reconsider the management of people with WADII.

  View details for DOI 10.1097/j.pain.0000000000003560

  View details for PubMedID 40035629

• Effect of Type and Dose of Exercise on Neuropathic Pain After Experimental Sciatic Nerve Injury: A Preclinical Systematic Review and Meta-Analysis. The journal of pain Matesanz-García, L., Billerot, C., Fundaun, J., Schmid, A. B. 2023; 24 (6): 921-938

  Abstract

  This preclinical systematic review aimed to determine the effectiveness of different types and doses of exercise on pain behavior and biomarkers in preclinical models of focal neuropathic pain. We searched MEDLINE, EMBASE, Web of Science, PubMed, SCOPUS, CINAHL, and Cochrane library from inception to November 2022 for preclinical studies evaluating the effect of exercise compared to control interventions on neuropathic pain behavior after experimental sciatic nerve injury. If possible, data were meta-analyzed using random effect models with inverse-variance weighting. Thirty-seven studies were included and 26 meta-analyzed. Risk of bias (SYRCLE tool) remained unclear in most studies and reporting quality (CAMARADES) was variable. Exercise reduced mechanical (standardized mean differences [SMD] .53 (95% CI .31, .74), P = .0001, I2 = 0%, n = 364), heat (.32 (.07, .57), P = .01, I2 = 0%, n = 266) and cold hypersensitivity (.51 (.03, 1.0), P = .04, I2 = 0%, n = 90) compared to control interventions. No relationship was apparent between exercise duration or intensity and antinociception. Exercise modulated biomarkers related to different systems (eg, immune system, neurotrophins). Whereas firm conclusions are prevented by the use of male animals only, variable reporting quality and unclear risk of bias in many studies, our results suggest that aerobic exercise is a promising tool in the management of focal neuropathic pain. PERSPECTIVE: This systematic review and meta-analysis demonstrates that aerobic exercise reduces neuropathic pain-related behavior in preclinical models of sciatic nerve injury. This effect is accompanied by changes in biomarkers associated with inflammation and neurotrophins among others. These results could help to develop exercise interventions for patients with neuropathic pain.

  View details for DOI 10.1016/j.jpain.2023.01.011

  View details for PubMedID 36690283

• Does peripheral neuroinflammation predict chronicity following whiplash injury? Protocol for a prospective cohort study. BMJ open Ridehalgh, C., Fundaun, J., Bremner, S., Cercignani, M., Young, R., Trivedy, C., Novak, A., Greening, J., Schmid, A., Dilley, A. 2022; 12 (12): e066021

  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.

  View details for DOI 10.1136/bmjopen-2022-066021

  View details for PubMedID 36521884

  View details for PubMedCentralID PMC9756191

• Types and Concentrations of Blood-Based Biomarkers in Adults With Peripheral Neuropathies: A Systematic Review and Meta-analysis. JAMA network open Fundaun, J., Kolski, M., Molina-Álvarez, M., Baskozos, G., Schmid, A. B. 2022; 5 (12): e2248593

  Abstract

  Peripheral neuropathies are common conditions and can result in numbness, paresthesia, motor deficits, and pain. There is increasing evidence for the use of biomarkers as clinical indicators of the presence, severity, and prognosis of nerve lesions; however, biomarker identification has largely been focused on disorders of the central nervous system, and less is known about their role in the peripheral nervous system.To assess blood-based biomarker concentrations associated with nerve involvement in patients with peripheral neuropathy compared with control participants.Ovid, MEDLINE, Embase, and CINAHL were searched from inception to September 23, 2021.Observational studies reporting on blood biomarkers in patients diagnosed with peripheral neuropathy were included. This review was preregistered on PROSPERO and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were abstracted by 1 investigator and independently reviewed by a second.Data were meta-analyzed when at least 2 studies reported the same biomarker with comparable methodology. Fixed-effects models were used when only 2 studies were included; random-effects models were used when more than 2 studies were included.The outcome of interest was concentration of biomarkers.This review included 36 studies reporting on 4414 participants, including 2113 control participants and 2301 patients with peripheral neuropathy with 13 distinct peripheral neuropathy diagnoses. Diabetic neuropathy was the most common neuropathy diagnosis (13 studies), followed by Charcot-Marie-Tooth disease (6 studies) and Guillain-Barre syndrome (6 studies). Overall, 16 different blood-based biomarkers associated with nerve involvement were evaluated. The most used were neurofilament light chain, S100B, brain-derived neurotrophic factor, and neuron-specific enolase. Patients with peripheral neuropathy demonstrated significantly higher levels of neurofilament light chain compared with controls (standardized mean difference [SMD], 0.93 [95% CI, 0.82 to 1.05]; P < .001). There were no significant differences in levels of S100B (SMD, 1.10 [95% CI, -3.08 to 5.28]; P = .38), brain-derived neurotrophic factor (SMD, -0.52 [95% CI, -2.23 to 1.19]; P = .40), or neuron-specific enolase (SMD, -0.00 [95% CI, -1.99 to 1.98]; P = .10) in patients with peripheral neuropathy compared with control participants.The findings of this systematic review and meta-analysis support the use of neurofilament light chain as a blood-based measure associated with the presence of neuronal injury in patients with peripheral neuropathy.

  View details for DOI 10.1001/jamanetworkopen.2022.48593

  View details for PubMedID 36574244

  View details for PubMedCentralID PMC9857490

• The power of integrating data: advancing pain research using meta-analysis. Pain reports Fundaun, J., Thomas, E. T., Schmid, A. B., Baskozos, G. 2022; 7 (6): e1038

  Abstract

  Publications related to pain research have increased significantly in recent years. The abundance of new evidence creates challenges staying up to date with the latest information. A comprehensive understanding of the literature is important for both clinicians and investigators involved in pain research. One commonly used method to combine and analyse data in health care research is meta-analysis. The primary aim of a meta-analysis is to quantitatively synthesise the results of multiple studies focused on the same research question. Meta-analysis is a powerful tool that can be used to advance pain research. However, there are inherent challenges when combining data from multiple sources. There are also numerous models and statistical considerations when undertaking a meta-analysis. This review aims to discuss the planning and preparation for completing a meta-analysis, review commonly used meta-analysis models, and evaluate the clinical implications of meta-analysis in pain research.

  View details for DOI 10.1097/PR9.0000000000001038

  View details for PubMedID 36213594

  View details for PubMedCentralID PMC9534369

• Nerve pathology and neuropathic pain after whiplash injury: a systematic review and meta-analysis. Pain Fundaun, J., Kolski, M., Baskozos, G., Dilley, A., Sterling, M., Schmid, A. B. 2022; 163 (7): e789-e811

  Abstract

  There is no clear understanding of the mechanisms causing persistent pain in patients with whiplash-associated disorder (WAD). The aim of this systematic review was to assess the evidence for nerve pathology and neuropathic pain in patients with WAD. EMBASE, PubMed, CINAHL (EBSCO), and MEDLINE were searched from inception to September 1, 2020. Study quality and risk of bias were assessed using the Newcastle-Ottawa Quality Assessment Scales. Fifty-four studies reporting on 390,644 patients and 918 controls were included. Clinical questionnaires suggested symptoms of predominant neuropathic characteristic in 34% of patients (range 25%-75%). The mean prevalence of nerve pathology detected with neurological examination was 13% (0%-100%) and 32% (10%-100%) with electrodiagnostic testing. Patients independent of WAD severity (Quebec Task Force grades I-IV) demonstrated significantly impaired sensory detection thresholds of the index finger compared with controls, including mechanical (SMD 0.65 [0.30; 1.00] P < 0.005), current (SMD 0.82 [0.25; 1.39] P = 0.0165), cold (SMD -0.43 [-0.73; -0.13] P = 0.0204), and warm detection (SMD 0.84 [0.25; 1.42] P = 0.0200). Patients with WAD had significantly heightened nerve mechanosensitivity compared with controls on median nerve pressure pain thresholds (SMD -1.10 [-1.50; -0.70], P < 0.0001) and neurodynamic tests (SMD 1.68 [0.92; 2.44], P = 0.0004). Similar sensory dysfunction and nerve mechanosensitivity was seen in WAD grade II, which contradicts its traditional definition of absent nerve involvement. Our findings strongly suggest a subset of patients with WAD demonstrate signs of peripheral nerve pathology and neuropathic pain. Although there was heterogeneity among some studies, typical WAD classifications may need to be reconsidered and include detailed clinical assessments for nerve integrity.

  View details for DOI 10.1097/j.pain.0000000000002509

  View details for PubMedID 35050963

  View details for PubMedCentralID PMC7612893

• [Entrapment neuropathies: a contemporary approach to pathophysiology, clinical assessment, and management : German version]. Schmerz (Berlin, Germany) Schmid, A. B., Fundaun, J., Tampin, B. 2021; 35 (6): 419-433

  Abstract

  Entrapment neuropathies such as carpal tunnel syndrome, radiculopathies, or radicular pain are the most common peripheral neuropathies and also the most common cause for neuropathic pain. Despite their high prevalence, they often remain challenging to diagnose and manage in a clinical setting. Summarising the evidence from both preclinical and clinical studies, this review provides an update on the aetiology and pathophysiology of entrapment neuropathies. Potenzial mechanisms are put in perspective with clinical findings. The contemporary assessment is discussed and diagnostic pitfalls highlighted. The evidence for the noninvasive and surgical management of common entrapment neuropathies is summarised and future areas of research are identified.

  View details for DOI 10.1007/s00482-021-00584-z

  View details for PubMedID 34505948

  View details for PubMedCentralID 5908728

• Entrapment neuropathies: a contemporary approach to pathophysiology, clinical assessment, and management. Pain reports Schmid, A. B., Fundaun, J., Tampin, B. 2020; 5 (4): e829

  Abstract

  Entrapment neuropathies such as carpal tunnel syndrome, radiculopathies, or radicular pain are the most common peripheral neuropathies and also the most common cause for neuropathic pain. Despite their high prevalence, they often remain challenging to diagnose and manage in a clinical setting. Summarising the evidence from both preclinical and clinical studies, this review provides an update on the aetiology and pathophysiology of entrapment neuropathies. Potential mechanisms are put in perspective with clinical findings. The contemporary assessment is discussed and diagnostic pitfalls highlighted. The evidence for the noninvasive and surgical management of common entrapment neuropathies is summarised and future areas of research are identified.

  View details for DOI 10.1097/PR9.0000000000000829

  View details for PubMedID 32766466

  View details for PubMedCentralID PMC7382548

• Does Overall Cervical Spine Pathology Relate to the Clinical Heterogeneity of Chronic Whiplash? The American journal of emergency medicine Elliott, J. M., Parrish, T. B., Walton, D. M., Vassallo, A. J., Fundaun, J., Wasielewski, M., Courtney, D. M. 2020; 38 (5): 869-873

  Abstract

  There remains limited evidence for the clinical importance of most imaging findings in whiplash. However, it is possible the type and number of findings on Computed Tomography (CT) may contribute to prognostic recovery models. The purpose is to interpret cervical spine pathologies in the context of known factors influencing recovery.This is a secondary analysis from a database of 97 acutely injured participants enrolled in a prospective inception cohort study. Thirty-eight participants underwent standard of care cervical spine CT in the emergency medicine department. All 38 participants were assessed at <1-week, 2-weeks, and 3-months post-injury and classified using percentage scores on the Neck Disability Index (recovered/mild (NDI of 0-28%) or moderate/severe (NDI ≥ 30%)). Between-group comparison of categorical variables (gender (male/female), presence of at least one CT finding (yes/no), and presence of ≥3 pathologies on CT (yes/no)) was conducted using 2-tailed Fisher's exact test.Participants from both groups demonstrated at least one observable pathology. The group with persistent moderate/severe symptoms presented with significantly more pathology at baseline than those who later reported recovery or milder symptoms at 3-months post injury (p = 0.02).This preliminary study, which needs replication in a larger cohort, provides foundation that the number of degenerative pathologies seen on initial post MVC CT may be associated with the subsequent clinical course of whiplash.

  View details for DOI 10.1016/j.ajem.2019.06.052

  View details for PubMedID 31285071

  View details for PubMedCentralID PMC7338223

• Muscle fat infiltration following whiplash: A computed tomography and magnetic resonance imaging comparison. PloS one Elliott, J. M., Smith, A. C., Hoggarth, M. A., Albin, S. R., Weber, K. A., Haager, M. n., Fundaun, J. n., Wasielewski, M. n., Courtney, D. M., Parrish, T. B. 2020; 15 (6): e0234061

  Abstract

  Here we present a secondary analysis from a parent database of 97 acutely injured participants enrolled in a prospective inception cohort study of whiplash recovery after motor vehicle collision (MVC). The purpose was to investigate the deep and superficial neck extensor muscles with peri-traumatic computed tomography (CT) and longitudinal measures of magnetic resonance imaging (MRI) in participants with varying levels of whiplash-related disability. Thirty-six underwent standard care imaging of the cervical spine with CT at a level-1 trauma designated emergency department. All 36 participants were assessed with MRI of the cervical spine at <1-week, 2-weeks, 3-, and 12-months post-injury and classified into three groups using initial pain severity and percentage scores on the Neck Disability Index (recovered (NDI of 0-8%), mild (NDI of 10-28%), or severe (NDI ≥ 30%)) at 3-months post MVC. CT muscle attenuation values were significantly correlated to muscle fat infiltration (MFI) on MRI at one-week post MVC. There was no significant difference in muscle attenuation across groups at the time of enrollment. A trend of lower muscle attenuation in the deep compared to the superficial extensors was observed in the severe group. MFI values in the deep muscles on MRI were significantly higher in the severe group when compared to the mild group at 1-year post MVC. This study provides further evidence that the magnitude of 1) deep MFI appears unique to those at risk of and eventually transitioning to chronic WAD and that 2) pre- or peri-traumatic muscular health, determined by CT muscle attenuation, may be contribute to our understanding of long-term recovery.

  View details for DOI 10.1371/journal.pone.0234061

  View details for PubMedID 32484835

• The use of a static measure to predict foot posture at midstance during walking. Foot (Edinburgh, Scotland) McPoil, T. G., Ford, J., Fundaun, J., Gallegos, C., Kinney, A., McMillan, P., Murphy, J., Sky, E., Torba, D., Bade, M. 2016; 28: 47-53

  Abstract

  Previous studies have successfully used the longitudinal arch angle (LAA) to assess foot posture, but the measurement consistency and ability of the LAA to predict dynamic foot posture during activity in a variety of foot types have not been evaluated. The purpose of this study was to determine the reliability of the LAA as well as if the clinical method of assessing the LAA could be used to predict the LAA at midstance during walking for supinated, normal, and pronated foot types. The Arch Height Ratio was used to select 35 participants with 12 supinated, 46 normal, and 12 pronated feet. A standard goniometer was used to measure the LAA (CLINIC_LAA) on both feet while standing. Both feet were then filmed using a high speed camera while walking on a treadmill. The LAA was determined by the angle formed by two lines drawn between the markers placed on the first metatatarsal and medial malleolus with the apex the navicular tuberosity. The LAA in midstance (WALK_LAA) was determined using the mean of five walking trials. The reliability of the CLINIC_LAA assessed on both feet by two raters over two days were excellent. There was no difference between the left and right foot for the CLINIC_LAA. The Pearson correlation between CLINIC_LAA and WALK_LAA for all 70 feet was r=0.96 (r2=0.92). The results indicate the LAA is highly predictive of foot posture at midstance in walking explaining over 90% of the variance for a wide range of foot types.

  View details for DOI 10.1016/j.foot.2016.09.001

  View details for PubMedID 27736722