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      Normative Values for Corneal Nerve Morphology Assessed Using Corneal Confocal Microscopy: A Multinational Normative Data Set

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          Corneal confocal microscopy is a novel diagnostic technique for the detection of nerve damage and repair in a range of peripheral neuropathies, in particular diabetic neuropathy. Normative reference values are required to enable clinical translation and wider use of this technique. We have therefore undertaken a multicenter collaboration to provide worldwide age-adjusted normative values of corneal nerve fiber parameters.


          A total of 1,965 corneal nerve images from 343 healthy volunteers were pooled from six clinical academic centers. All subjects underwent examination with the Heidelberg Retina Tomograph corneal confocal microscope. Images of the central corneal subbasal nerve plexus were acquired by each center using a standard protocol and analyzed by three trained examiners using manual tracing and semiautomated software (CCMetrics). Age trends were established using simple linear regression, and normative corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), corneal nerve fiber length (CNFL), and corneal nerve fiber tortuosity (CNFT) reference values were calculated using quantile regression analysis.


          There was a significant linear age-dependent decrease in CNFD (−0.164 no./mm 2 per year for men, P < 0.01, and −0.161 no./mm 2 per year for women, P < 0.01). There was no change with age in CNBD (0.192 no./mm 2 per year for men, P = 0.26, and −0.050 no./mm 2 per year for women, P = 0.78). CNFL decreased in men (−0.045 mm/mm 2 per year, P = 0.07) and women (−0.060 mm/mm 2 per year, P = 0.02). CNFT increased with age in men (0.044 per year, P < 0.01) and women (0.046 per year, P < 0.01). Height, weight, and BMI did not influence the 5th percentile normative values for any corneal nerve parameter.


          This study provides robust worldwide normative reference values for corneal nerve parameters to be used in research and clinical practice in the study of diabetic and other peripheral neuropathies.

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          Most cited references 30

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          Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study.

          The diagnostic reliability of skin biopsy in small fiber neuropathy depends on the availability of normative reference values. We performed a multicenter study to assess the normative values of intraepidermal nerve fiber (IENF) density at distal leg stratified by age deciles. Eight skin biopsy laboratories from Europe, USA, and Asia submitted eligible data. Inclusion criteria of raw data were healthy subjects 18 years or older; known age and gender; 3-mm skin biopsy performed 10-cm above the lateral malleolus; bright-field immunohistochemistry protocol, and quantification of linear IENF density in three 50-µm sections according to published guidelines. Data on height and weight were recorded, and body mass index (BMI) was calculated in subjects with both available data. Normative IENF density reference values were calculated through quantile regression analysis; influence of height, weight, or BMI was determined by regression analyses. IENF densities from 550 participants (285 women, 265 men) were pooled. We found a significant age-dependent decrease of IENF density in both genders (women p < 0.001; men p = 0.002). Height, weight, or BMI did not influence the calculated 5th percentile IENF normative densities in both genders. Our study provides IENF density normative reference values at the distal leg to be used in clinical practice. © 2010 Peripheral Nerve Society.
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            Is Open Access

            Corneal Confocal Microscopy

            OBJECTIVE The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies. RESEARCH DESIGN AND METHODS 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). RESULTS Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P 3) defined an NFD of 6) defined a NFD cutoff of <20.8/mm2 with a sensitivity of 0.71 (0.42–0.92) and specificity of 0.64 (0.54–0.74). CONCLUSIONS 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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              Morphology of corneal nerves using confocal microscopy.

               N Efron,  P Soto (2001)
              The aim of the current study was to evaluate the distribution and morphology of corneal nerves as seen by means of white light confocal microscopy. This study analyzed images of corneal nerves that were obtained using the Tomey Confoscan slit scanning confocal microscope (40x/0.75 objective lens). The images were classified according to their location within the cornea. The objective and subjective evaluation of the images involved measuring, grading, or judging a number of parameters from both individual pictures and from each single nerve fiber within any image. The in vivo observations made in this work are in agreement with those of previous histologic studies. The general scheme of corneal innervation is described as originating from thick and straight stromal nerve trunks that extend lateral and anteriorly and give rise to plexiform arrangements of progressively thinner nerve fibers at several levels within the stroma. From there, nerve fibers perforate Bowman's layer and eventually form a dense neural plexus just beneath the basal epithelial cell layer, which is characterized by tortuous and thin beaded nerve fibers interconnected by numerous nerve elements; nerve fibers from this plexus are known to be responsible for the innervation of the epithelium. This study provides convincing evidence of the suitability of confocal microscopy to image corneal nerves, the only drawback being the limited resolution in terms of the differentiation of the ultrastructure of nerve bundles.

                Author and article information

                Diabetes Care
                Diabetes Care
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                May 2015
                29 January 2015
                : 38
                : 5
                : 838-843
                1Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, Manchester, U.K.
                2Medical Statistics Unit, University of Manchester and University Hospital of South Manchester, Manchester, U.K.
                3Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
                4Department of Ophthalmology, University of Rostock, Rostock, Germany
                5Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
                6Department of Endocrinology and Diabetology, University Hospital, Düsseldorf, Germany
                7Alberta Children’s Hospital, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
                8Division of Endocrinology, Leadership Sinai Centre for Diabetes, University of Toronto, Toronto, Canada
                9Division of Neurology, University Health Network, University of Toronto, Toronto, Canada
                10Department of Neurology, University of Utah, Salt Lake City, UT
                11Weill Cornell Medical College in Qatar, Ar Rayyān, Qatar
                Author notes
                Corresponding author: Rayaz A. Malik, rayaz.a.malik@ 123456man.ac.uk .
                © 2015 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.
                Page count
                Pages: 6

                Endocrinology & Diabetes


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