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Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy

¹ Division of Cardiovascular Medicine, University of Manchester, Manchester Diabetes Centre and Manchester Royal Infirmary, Manchester, U.K
² Division of Regenerative Medicine, University of Manchester, Manchester, U.K
³ Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield, U.K
⁴ Department of Neurophysiology, Manchester Royal Infirmary, Manchester, U.K
⁵ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia

Address correspondence and reprint requests to Dr. R.A. Malik, Division of Cardiovascular Medicine, University of Manchester, Manchester, M13 9NT, U.K. E-mail: rayaz.a.malik{at}man.ac.uk

Abbreviations: CCM, corneal confocal microscopy; CDT, cooling detection threshold; CNBD, corneal nerve branch density; CNF, corneal nerve fiber; CNFD, corneal nerve fiber density; CNFL, corneal nerve fiber length; DB-HRV, deep breathing heart rate variability; HP-VAS 0.5, 5.0, and 0.5–5.0, heat-as-pain visual analog score minimal threshold, intermediate threshold, and differential threshold expressing pain tolerance, respectively; IENF, intraepidermal nerve fiber; IENFBD, intraepidermal nerve fiber branch density; IENFD, intraepidermal nerve fiber density; IENFL, intraepidermal nerve fiber length; NDS, neuropathy disability score; PNAP, peroneal nerve amplitude potential; PNCV, peroneal nerve conduction velocity; PNFL, peroneal nerve F-wave latency; PNOL, peroneal nerve onset latency; QST, quantitative sensory testing; SNAP, sural nerve amplitude potential; SNCV, sural nerve conduction velocity; SNOL, sural nerve onset latency; TNAP, tibial nerve amplitude potential; TNCV, tibial nerve conduction velocity; TNFL, tibial nerve F-wave latency; TNOL, tibial nerve onset latency

Surrogate markers of diabetic neuropathy are being actively sought to facilitate the diagnosis, measure the progression, and assess the benefits of therapeutic intervention in patients with diabetic neuropathy. We have quantified small nerve fiber pathological changes using the technique of intraepidermal nerve fiber (IENF) assessment and the novel in vivo technique of corneal confocal microscopy (CCM). Fifty-four diabetic patients stratified for neuropathy, using neurological evaluation, neurophysiology, and quantitative sensory testing, and 15 control subjects were studied. They underwent a punch skin biopsy to quantify IENFs and CCM to quantify corneal nerve fibers. IENF density (IENFD), branch density, and branch length showed a progressive reduction with increasing severity of neuropathy, which was significant in patients with mild, moderate, and severe neuropathy. CCM also showed a progressive reduction in corneal nerve fiber density (CNFD) and branch density, but the latter was significantly reduced even in diabetic patients without neuropathy. Both IENFD and CNFD correlated significantly with cold detection and heat as pain thresholds. Intraepidermal and corneal nerve fiber lengths were reduced in patients with painful compared with painless diabetic neuropathy. Both IENF and CCM assessment accurately quantify small nerve fiber damage in diabetic patients. However, CCM quantifies small fiber damage rapidly and noninvasively and detects earlier stages of nerve damage compared with IENF pathology. This may make it an ideal technique to accurately diagnose and assess progression of human diabetic neuropathy.

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