Emerging Diagnostic Biomarkers of Peripheral Neuropathy

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (30 March 2022) | Viewed by 18164

Special Issue Editor

Department of Clinical Neurophysiology, Central Manchester NHS Foundation Trust, Manchester, UK
Interests: electromyography; carpal tunnel syndrome; ulnar neuropathy; peripheral neuropathies; muscle disorders; clinical neurophysiology; entrapment neuropathies; sensory neuropathies; botulinum toxin therapy; painful peripheral neuropathy; diabetic neuropathy; small fiber neuropathy; microneurography

Special Issue Information

Dear Colleagues,

Peripheral neuropathy is a very common neurological disorder. Whilst there are established diagnostic methods (e.g., nerve conduction studies), there remain difficulties with diagnosis, particularly in the case of predominantly small fibre peripheral neuropathies. Furthermore, the determination of the underlying aetiology is often difficult. Even in the case of an established diagnosis, our understanding of how symptoms are generated and, consequently, of directed symptom-based treatment of the condition is often incomplete. The primary goals of this Special Issue are to describe new diagnostic modalities for peripheral neuropathy, emerging mechanistic biomarkers of peripheral neuropathy symptoms (e.g., pain and paraesthesia), and new approaches to understanding the underlying aetiology of neuropathies. Manuscripts covering new approaches to the clinical management of neuropathy and neuropathic symptomsm, particularly mechanism-based approaches, are particularly welcome.

Dr. Andrew G. Marshall
Guest Editor

Manuscript Submission Information

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Keywords

  • Peripheral neuropathy
  • Neuropathic pain
  • Biomarkers
  • Diagnostics

Published Papers (3 papers)

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Research

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12 pages, 884 KiB  
Article
Optimal Utility of H-Reflex RDD as a Biomarker of Spinal Disinhibition in Painful and Painless Diabetic Neuropathy
by Anne Worthington, Alise Kalteniece, Maryam Ferdousi, Luca D’Onofrio, Shaishav Dhage, Shazli Azmi, Clare Adamson, Shaheen Hamdy, Rayaz A. Malik, Nigel A. Calcutt and Andrew G. Marshall
Diagnostics 2021, 11(7), 1247; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11071247 - 12 Jul 2021
Cited by 5 | Viewed by 2128
Abstract
Impaired rate-dependent depression of the Hoffman reflex (HRDD) is a potential biomarker of impaired spinal inhibition in patients with painful diabetic neuropathy. However, the optimum stimulus-response parameters that identify patients with spinal disinhibition are currently unknown. We systematically compared HRDD, performed using trains [...] Read more.
Impaired rate-dependent depression of the Hoffman reflex (HRDD) is a potential biomarker of impaired spinal inhibition in patients with painful diabetic neuropathy. However, the optimum stimulus-response parameters that identify patients with spinal disinhibition are currently unknown. We systematically compared HRDD, performed using trains of 10 stimuli at five stimulation frequencies (0.3, 0.5, 1, 2 and 3 Hz), in 42 subjects with painful and 62 subjects with painless diabetic neuropathy with comparable neuropathy severity, and 34 healthy controls. HRDD was calculated using individual and mean responses compared to the initial response. At stimulation frequencies of 1, 2 and 3 Hz, HRDD was significantly impaired in patients with painful diabetic neuropathy compared to patients with painless diabetic neuropathy for all parameters and for most parameters when compared to healthy controls. HRDD was significantly enhanced in patients with painless diabetic neuropathy compared to controls for responses towards the end of the 1 Hz stimulation train. Receiver operating characteristic curve analysis in patients with and without pain showed that the area under the curve was greatest for response averages of stimuli 2–4 and 2–5 at 1 Hz, AUC = 0.84 (95%CI 0.76–0.92). Trains of 5 stimuli delivered at 1 Hz can segregate patients with painful diabetic neuropathy and spinal disinhibition, whereas longer stimulus trains are required to segregate patients with painless diabetic neuropathy and enhanced spinal inhibition. Full article
(This article belongs to the Special Issue Emerging Diagnostic Biomarkers of Peripheral Neuropathy)
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14 pages, 1855 KiB  
Article
Pharmacological Modulation of Rate-Dependent Depression of the Spinal H-Reflex Predicts Therapeutic Efficacy against Painful Diabetic Neuropathy
by Corinne A. Lee-Kubli, XiaJun Zhou, Corinne G. Jolivalt and Nigel A. Calcutt
Diagnostics 2021, 11(2), 283; https://doi.org/10.3390/diagnostics11020283 - 11 Feb 2021
Cited by 9 | Viewed by 1884
Abstract
Impaired rate-dependent depression (RDD) of the spinal H-reflex occurs in diabetic rodents and a sub-set of patients with painful diabetic neuropathy. RDD is unaffected in animal models of painful neuropathy associated with peripheral pain mechanisms and diabetic patients with painless neuropathy, suggesting RDD [...] Read more.
Impaired rate-dependent depression (RDD) of the spinal H-reflex occurs in diabetic rodents and a sub-set of patients with painful diabetic neuropathy. RDD is unaffected in animal models of painful neuropathy associated with peripheral pain mechanisms and diabetic patients with painless neuropathy, suggesting RDD could serve as a biomarker for individuals in whom spinal disinhibition contributes to painful neuropathy and help identify therapies that target impaired spinal inhibitory function. The spinal pharmacology of RDD was investigated in normal rats and rats after 4 and 8 weeks of streptozotocin-induced diabetes. In normal rats, dependence of RDD on spinal GABAergic inhibitory function encompassed both GABAA and GABAB receptor sub-types. The time-dependent emergence of impaired RDD in diabetic rats was preceded by depletion of potassium-chloride co-transporter 2 (KCC2) protein in the dorsal, but not ventral, spinal cord and by dysfunction of GABAA receptor-mediated inhibition. GABAB receptor-mediated spinal inhibition remained functional and initially compensated for loss of GABAA receptor-mediated inhibition. Administration of the GABAB receptor agonist baclofen restored RDD and alleviated indices of neuropathic pain in diabetic rats, as did spinal delivery of the carbonic anhydrase inhibitor acetazolamide. Pharmacological manipulation of RDD can be used to identify potential therapies that act against neuropathic pain arising from spinal disinhibition. Full article
(This article belongs to the Special Issue Emerging Diagnostic Biomarkers of Peripheral Neuropathy)
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Review

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39 pages, 1481 KiB  
Review
Early Detection of Diabetic Peripheral Neuropathy: A Focus on Small Nerve Fibres
by Jamie Burgess, Bernhard Frank, Andrew Marshall, Rashaad S. Khalil, Georgios Ponirakis, Ioannis N. Petropoulos, Daniel J. Cuthbertson, Rayaz A. Malik and Uazman Alam
Diagnostics 2021, 11(2), 165; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11020165 - 24 Jan 2021
Cited by 41 | Viewed by 12697
Abstract
Diabetic peripheral neuropathy (DPN) is the most common complication of both type 1 and 2 diabetes. As a result, neuropathic pain, diabetic foot ulcers and lower-limb amputations impact drastically on quality of life, contributing to the individual, societal, financial and healthcare burden of [...] Read more.
Diabetic peripheral neuropathy (DPN) is the most common complication of both type 1 and 2 diabetes. As a result, neuropathic pain, diabetic foot ulcers and lower-limb amputations impact drastically on quality of life, contributing to the individual, societal, financial and healthcare burden of diabetes. DPN is diagnosed at a late, often pre-ulcerative stage due to a lack of early systematic screening and the endorsement of monofilament testing which identifies advanced neuropathy only. Compared to the success of the diabetic eye and kidney screening programmes there is clearly an unmet need for an objective reliable biomarker for the detection of early DPN. This article critically appraises research and clinical methods for the diagnosis or screening of early DPN. In brief, functional measures are subjective and are difficult to implement due to technical complexity. Moreover, skin biopsy is invasive, expensive and lacks diagnostic laboratory capacity. Indeed, point-of-care nerve conduction tests are convenient and easy to implement however questions are raised regarding their suitability for use in screening due to the lack of small nerve fibre evaluation. Corneal confocal microscopy (CCM) is a rapid, non-invasive, and reproducible technique to quantify small nerve fibre damage and repair which can be conducted alongside retinopathy screening. CCM identifies early sub-clinical DPN, predicts the development and allows staging of DPN severity. Automated quantification of CCM with AI has enabled enhanced unbiased quantification of small nerve fibres and potentially early diagnosis of DPN. Improved screening tools will prevent and reduce the burden of foot ulceration and amputations with the primary aim of reducing the prevalence of this common microvascular complication. Full article
(This article belongs to the Special Issue Emerging Diagnostic Biomarkers of Peripheral Neuropathy)
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