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      Corneal Confocal Microscopy : A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy

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          The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies.


          A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM).


          Corneal sensation decreased significantly ( P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) ( r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) ( P < 0.0001), nerve fiber length (NFL), ( P < 0.0001), and nerve branch density (NBD) ( P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = −0.475, P < 0.0001; NBD r = −0.511, P < 0.0001; and NFL r = −0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds ( P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm 2 with a sensitivity of 0.82 (95% CI 0.68–0.92) and specificity of 0.52 (0.40–0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm 2 with a sensitivity of 0.71 (0.42–0.92) and specificity of 0.64 (0.54–0.74).


          CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity.

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          Most cited references 19

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          The spectrum of neuropathy in diabetes and impaired glucose tolerance.

          To compare the neuropathy associated with impaired glucose tolerance (IGT) and diabetes mellitus (DM) determined by oral glucose tolerance testing (OGTT). Patients with peripheral neuropathy of unknown cause were prescribed OGTT. Duration of neuropathic symptoms, neuropathic pain, neuropathy classification, nerve conduction test results, and intraepidermal nerve fiber densities (IENFD) were compared between IGT and DM groups. Seventy-three patients completed OGTT; 41 (56%) had abnormal results. Of these 41 patients, 26 had IGT and 15 had DM. Patients with IGT had less severe neuropathy than patients with diabetes, as measured by sural nerve amplitudes (p = 0.056), sural nerve conduction velocities (p = 0.03), and distal leg IENFD (p = 0.01). Patients with IGT had predominantly small fiber neuropathy, compared to patients with DM (p = 0.05), who had more involvement of large nerve fibers. The neuropathy associated with IGT is milder than the neuropathy associated with DM. Small nerve fibers are prominently affected and may be the earliest detectable sign of neuropathy in glucose dysmetabolism. OGTT is appropriate in patients with idiopathic neuropathy.
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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.

                Author and article information

                Diabetes Care
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                August 2010
                30 April 2010
                : 33
                : 8
                : 1792-1797
                1Division of Cardiovascular Medicine, University of Manchester and Central Manchester Foundation Trust, Manchester, U.K.;
                2Department of Neurophysiology, Central Manchester Foundation Trust, Manchester, U.K.;
                3Eurolens Research Group, University of Manchester, Manchester, U.K.;
                4Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
                Author notes
                Corresponding author: Rayaz A. Malik, rayaz.a.malik@ 123456man.ac.uk .
                © 2010 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                Original Research

                Endocrinology & Diabetes


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