20
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objectives

          Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible technique that quantifies small nerve fibres. We have compared the diagnostic capability of CCM against a range of established measures of nerve damage in patients with diabetic neuropathy.

          Methods

          In this cross sectional study, thirty subjects with Type 1 diabetes without neuropathy (T1DM), thirty one T1DM subjects with neuropathy (DSPN) and twenty seven non-diabetic healthy control subjects underwent detailed assessment of neuropathic symptoms and neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy and corneal confocal microscopy (CCM).

          Results

          Subjects with DSPN were older (C vs T1DM vs DSPN: 41.0±14.9 vs 38.8±12.5 vs 53.3±11.9, P = 0.0002), had a longer duration of diabetes (P<0.0001), lower eGFR (P = 0.006) and higher albumin-creatinine ratio (P = 0.03) with no significant difference for HbA1c, BMI, lipids and blood pressure. Patients with DSPN were representative of subjects with diabetic neuropathy with clinical signs and symptoms of neuropathy and greater neuropathy deficits quantified by QST, electrophysiology, intra-epidermal nerve fibre density and CCM. Corneal nerve fibre density (CNFD) (Spearman’s Rho = 0.60 P<0.0001) and IENFD (Spearman’s Rho = 0.56 P<0.0001) were comparable when correlated with peroneal nerve conduction velocity. For the diagnosis of diabetic neuropathy the sensitivity for CNFD was 0.77 and specificity was 0.79 with an area under the ROC curve of 0.81. IENFD had a diagnostic sensitivity of 0.61, specificity of 0.80 and area under the ROC curve of 0.73.

          Conclusions

          CCM is a valid accurate non-invasive method to identify small nerve fibre pathology and is able to diagnose DPN.

          Related collections

          Most cited references34

          • Record: found
          • Abstract: found
          • Article: not found

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy.

            Skin biopsy has become a widely used tool to investigate small calibre sensory nerves including somatic unmyelinated intraepidermal nerve fibres (IENF), dermal myelinated nerve fibres, and autonomic nerve fibres in peripheral neuropathies and other conditions. Different techniques for tissue processing and nerve fibre evaluation have been used. In March 2004, a Task Force was set up under the auspices of the European Federation of Neurological Societies (EFNS) with the aim of developing guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathies. We searched the Medline database from 1989, the year of the first publication describing the innervation of human skin using immunostaining with anti-protein-gene-product 9.5 (PGP 9.5) antibodies, to 31 March 2005. All pertinent papers were rated according to the EFNS guidance. The final version of the guidelines was elaborated after consensus amongst members of the Task Force was reached. For diagnostic purposes in peripheral neuropathies, we recommend performing a 3-mm punch skin biopsy at the distal leg and quantifying the linear density of IENF in at least three 50-mum thick sections per biopsy, fixed in 2% PLP or Zamboni's solution, by bright-field immunohistochemistry or immunofluorescence with anti-PGP 9.5 antibodies (level A recommendation). Quantification of IENF density closely correlated with warm and heat-pain threshold, and appeared more sensitive than sensory nerve conduction study and sural nerve biopsy in diagnosing small-fibre sensory neuropathy. Diagnostic efficiency and predictive values of this technique were very high (level A recommendation). Confocal microscopy may be particularly useful to investigate myelinated nerve fibres, dermal receptors and dermal annex innervation. In future, the diagnostic yield of dermal myelinated nerve fibre quantification and of sweat gland innervation should be addressed. Longitudinal studies of IENF density and regeneration rate are warranted to correlate neuropathological changes with progression of neuropathy and to assess the potential usefulness of skin biopsy as an outcome measure in peripheral neuropathy trials (level B recommendation). In conclusion, punch skin biopsy is a safe and reliable technique (level A recommendation). Training in an established cutaneous nerve laboratory is recommended before using skin biopsy as a diagnostic tool in peripheral neuropathies. Quality control at all levels is mandatory.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              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.
                Bookmark

                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 July 2017
                2017
                : 12
                : 7
                : e0180175
                Affiliations
                [1 ] Diabetes & Endocrinology Research, Department of Eye & Vision Sciences, Institute of Ageing and Chronic Disease, University of Liverpool and Aintree University Hospital NHS Foundation Trust, Liverpool, United Kingdom
                [2 ] Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester and the Manchester Royal Infirmary, Central Manchester Hospital Foundation Trust, Manchester, United Kingdom
                [3 ] Weill Cornell Medicine-Qatar, Doha, Qatar
                [4 ] University of Exeter, Exeter, United Kingdom
                [5 ] Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
                Hirosaki Daigaku, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-3190-1122
                Article
                PONE-D-16-49474
                10.1371/journal.pone.0180175
                5515394
                28719619
                1d36f1cc-e02c-4903-a2cd-6b5604d02bac
                © 2017 Alam et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 14 December 2016
                : 12 June 2017
                Page count
                Figures: 3, Tables: 5, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100008664, Juvenile Diabetes Research Foundation;
                Award ID: 8-2008-362
                Award Recipient :
                This work was funded by the Juvenile Diabetes Research Foundation (Grant No.: 8-2008-362) and the NIHR/Wellcome Trust Clinical Research Facility (Manchester) for their facilitation of the study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Nerve Fibers
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
                Neurons
                Nerve Fibers
                Medicine and Health Sciences
                Neurology
                Neuropathy
                Medicine and Health Sciences
                Endocrinology
                Endocrine Disorders
                Diabetes Mellitus
                Medicine and Health Sciences
                Metabolic Disorders
                Diabetes Mellitus
                Biology and Life Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Cornea
                Medicine and Health Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Cornea
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Biology and Life Sciences
                Neuroscience
                Sensory Perception
                Biology and Life Sciences
                Psychology
                Sensory Perception
                Social Sciences
                Psychology
                Sensory Perception
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Pain
                Neuropathic Pain
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Pain
                Neuropathic Pain
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Neurophysiology
                Nerve Conduction Study
                Custom metadata
                Data are available from Figshare: https://figshare.com/s/483c5ad799d463a348bf.

                Uncategorized
                Uncategorized

                Comments

                Comment on this article