Novel and Emerging Electrophysiological Biomarkers of Diabetic Neuropathy and Painful Diabetic Neuropathy.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. Small and large peripheral nerve fibers can be involved in DPN. Large nerve fiber damage causes paresthesia, sensory loss, and muscle weakness, and small nerve fiber damage is associated with pain, anesthesia, foot ulcer, and autonomic symptoms. Treatments for DPN and painful DPN (pDPN) pose considerable challenges due to the lack of effective therapies. To meet these challenges, there is a major need to develop biomarkers that can reliably diagnose and monitor progression of nerve damage and, for pDPN, facilitate personalized treatment based on underlying pain mechanisms. This study involved a comprehensive literature review, incorporating article searches in electronic databases (Google Scholar, PubMed, and OVID) and reference lists of relevant articles with the authors' substantial expertise in DPN. This review considered seminal and novel research and summarizes emerging biomarkers of DPN and pDPN that are based on neurophysiological methods. From the evidence gathered from 145 papers, this submission describes emerging clinical neurophysiological methods with potential to act as biomarkers for the diagnosis and monitoring of DPN as well as putative future roles as predictors of response to antineuropathic pain medication in pDPN. Nerve conduction studies only detect large fiber damage and do not capture pathology or dysfunction of small fibers. Because small nerve fiber damage is prominent in DPN, additional biomarkers of small nerve fiber function are needed. Activation of peripheral nociceptor fibers using laser, heat, or targeted electrical stimuli can generate pain-related evoked potentials, which are an objective neurophysiological measure of damage along the small fiber pathways. Assessment of nerve excitability, which provides a surrogate of axonal properties, may detect alterations in function before abnormalities are detected by nerve conduction studies. Microneurography and rate-dependent depression of the Hoffmann-reflex can be used to dissect underlying pain-generating mechanisms arising from the periphery and spinal cord, respectively. Their role in informing mechanistic-based treatment of pDPN as well as facilitating clinical trials design is discussed. The neurophysiological methods discussed, although currently not practical for use in busy outpatient settings, detect small fiber and early large fiber damage in DPN as well as disclosing dominant pain mechanisms in pDPN. They are suited as diagnostic and predictive biomarkers as well as end points in mechanistic clinical trials of DPN and pDPN.

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Conflicts of Interest The authors have indicated that they have no conflicts of interest regarding the content of this article.