title: Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, Manchester, U.K.
authors: Mitra
authors: M
authors: Tavakoli
authors: Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, Manchester, U.K.
authors: Maryam
authors: M
authors: Ferdousi
authors: Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, Manchester, U.K.
authors: Ioannis N
authors: IN
authors: Petropoulos
authors: Medical Statistics Unit, University of Manchester and University Hospital of South Manchester, Manchester, U.K.
authors: Julie
authors: J
authors: Morris
authors: Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
authors: Nicola
authors: N
authors: Pritchard
authors: Department of Ophthalmology, University of Rostock, Rostock, Germany.
authors: Andrey
authors: A
authors: Zhivov
authors: Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany Department of Endocrinology and Diabetology, University Hospital, Düsseldorf, Germany.
authors: Dan
authors: D
authors: Ziegler
authors: Alberta Children's Hospital, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada.
authors: Danièle
authors: D
authors: Pacaud
authors: Alberta Children's Hospital, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada.
authors: Kenneth
authors: K
authors: Romanchuk
authors: Division of Endocrinology, Leadership Sinai Centre for Diabetes, University of Toronto, Toronto, Canada.
authors: Bruce A
authors: BA
authors: Perkins
authors: Division of Endocrinology, Leadership Sinai Centre for Diabetes, University of Toronto, Toronto, Canada.
authors: Leif E
authors: LE
authors: Lovblom
authors: Division of Neurology, University Health Network, University of Toronto, Toronto, Canada.
authors: Vera
authors: V
authors: Bril
authors: Department of Neurology, University of Utah, Salt Lake City, UT.
authors: J Robinson
authors: JR
authors: Singleton
authors: Department of Neurology, University of Utah, Salt Lake City, UT.
authors: Gordon
authors: G
authors: Smith
authors: Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, Manchester, U.K.
authors: Andrew J M
authors: AJ
authors: Boulton
authors: Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
authors: Nathan
authors: N
authors: Efron
authors: Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, Manchester, U.K. Weill Cornell Medical College in Qatar, Ar Rayyān, Qatar rayaz.a.malik@man.ac.uk.
authors: Rayaz A
authors: RA
authors: Malik
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D003315:Cornea / Q000294:innervation*; D003929:Diabetic Neuropathies / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D016014:Linear Models; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology; D012016:Reference Values; D012737:Sex Factors; D014945:Wound Healing / Q000502:physiology; D055815:Young Adult
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