Normative values for corneal nerve morphology assessed using corneal confocal microscopy: A multinational normative data set

Mitra Tavakoli, Maryam Ferdousi, Ioannis N. Petropoulos, Julie Morris, Nicola Pritchard, Andrey Zhivov, Dan Ziegler, Danièle Pacaud, Kenneth Romanchuk, Bruce A. Perkins, Leif E. Lovblom, Vera Bril, J. Robinson Singleton, Gordon Smith, Andrew J M Boulton, Nathan Efron, Rayaz Malik

Research output: Contribution to journalArticle

67 Citations (Scopus)


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. RESEARCH DESIGN AND 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./mm2 per year for men, P < 0.01, and -0.161 no./mm2 per year for women, P < 0.01). There was no change with age in CNBD (0.192 no./mm2 per year for men, P = 0.26, and -0.050 no./mm2 per year for women, P = 0.78). CNFL decreased in men (-0.045 mm/mm2 per year, P = 0.07) and women (-0.060 mm/mm2 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.

Original languageEnglish
Pages (from-to)838-843
Number of pages6
JournalDiabetes Care
Issue number5
Publication statusPublished - 1 May 2015


ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialised Nursing
  • Medicine(all)

Cite this

Tavakoli, M., Ferdousi, M., Petropoulos, I. N., Morris, J., Pritchard, N., Zhivov, A., Ziegler, D., Pacaud, D., Romanchuk, K., Perkins, B. A., Lovblom, L. E., Bril, V., Robinson Singleton, J., Smith, G., Boulton, A. J. M., Efron, N., & Malik, R. (2015). Normative values for corneal nerve morphology assessed using corneal confocal microscopy: A multinational normative data set. Diabetes Care, 38(5), 838-843.