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      Greater corneal nerve loss at the inferior whorl is related to the presence of diabetic neuropathy and painful diabetic neuropathy

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          Abstract

          We assessed whether a measure of more distal corneal nerve fibre loss at the inferior whorl(IW) region is better than proximal measures of central corneal nerve damage in relation to the diagnosis of diabetic peripheral neuropathy(DPN), painful DPN and quality of life(QoL). Participants underwent detailed assessment of neuropathy, QoL using the SF36 questionnaire, pain visual analogue score(VAS), and corneal confocal microscopy(CCM). Corneal nerve fibre density (CNFD), branch density (CNBD) and length (CNFL) at the central cornea and inferior whorl length (IWL) and average(ANFL) and total(TNFL) nerve fibre length were compared in patients with and without DPN and between patients with and without painful DPN and in relation to QoL. All CCM parameters were significantly reduced, but IWL was reduced ~three-fold greater than CNFL in patients with and without DPN compared to controls. IWL(p = 0.001), ANFL(p = 0.01) and TNFL(p = 0.02) were significantly lower in patients with painful compared to painless DPN. The VAS score correlated with IWL(r = −0.36, P = 0.004), ANFL(r = −0.32, P = 0.01) and TNFL(r = −0.32, P = 0.01) and QoL correlated with CNFL(r = 0.35, P = 0.01) and IWL(r = 0.4, P = 0.004). Corneal nerve fibre damage is more prominent at the IW, lower in patients with painful compared to painless neuropathy and relates to their QoL. IWL may provide additional clinical utility for CCM in patients with DPN.

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          Most cited references23

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          Diabetic Neuropathies: A statement by the American Diabetes Association

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            Surrogate markers of small fiber damage in human diabetic neuropathy.

            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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              Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients.

              The accurate detection, characterization and quantification of human diabetic neuropathy are important to define at risk patients, anticipate deterioration, and assess new therapies. Corneal confocal microscopy is a reiterative, rapid, non-invasive in vivo clinical examination technique capable of imaging corneal nerve fibres. The aim of this study was to define the ability of this technique to quantify the extent of degeneration and regeneration of corneal nerve fibres in diabetic patients with increasing neuropathic severity. We scanned the cornea and collected images of Bowman's layer (containing a rich nerve plexus) from 18 diabetic patients and 18 age-matched control subjects. Corneal nerve fibre density (F(3)=9.6, p<0.0001), length (F(3)=23.8, p<0.0001), and branch density (F(3)=13.9, p<0.0001) were reduced in diabetic patients compared with control subjects, with a tendency for greater reduction in these measures with increasing severity of neuropathy. Corneal confocal microscopy is a rapid, non-invasive in vivo clinical examination technique which accurately defines the extent of corneal nerve damage and repair and acts as a surrogate measure of somatic neuropathy in diabetic patients. It could represent an advance to define the severity of neuropathy and expedite assessment of therapeutic efficacy in clinical trials of human diabetic neuropathy.
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                Author and article information

                Contributors
                ram2045@qatar-med.cornell.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                19 February 2018
                19 February 2018
                2018
                : 8
                : 3283
                Affiliations
                [1 ]ISNI 0000000121662407, GRID grid.5379.8, Institute of Cardiovascular Sciences, Cardiac Centre, Faculty of Medical and Human Sciences, , University of Manchester and NIHR/Wellcome Trust Clinical Research Facility, ; Manchester, UK
                [2 ]ISNI 0000 0001 0516 2170, GRID grid.418818.c, Weill Cornell Medicine-Qatar, , Research Division, Qatar Foundation, Education City, ; Doha, Qatar
                [3 ]ISNI 0000000089150953, GRID grid.1024.7, Queensland University of Technology, School of Optometry and Vision Science, ; Brisbane, Australia
                [4 ]ISNI 0000 0004 0480 1382, GRID grid.412966.e, Department of Neurology, School of Mental Health and Neuroscience, , Maastricht University Medical Center, ; Maastricht, The Netherlands
                [5 ]ISNI 0000 0001 0707 5492, GRID grid.417894.7, Neuroalgology Unit, , IRCCS Foundation, “Carlo Besta” Neurological Institute, ; Milan, Italy
                [6 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Biomedical and Clinical Sciences, , “Luigi Sacco”, University of Milan, ; Milan, Italy
                Author information
                http://orcid.org/0000-0002-2467-067X
                Article
                21643
                10.1038/s41598-018-21643-z
                5818543
                29459766
                f8140e05-7d3f-417c-8cdd-434874a01250
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 11 December 2017
                : 7 February 2018
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