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Cited by 222Ocular Surface and Contact LensCorneal surgery and disordersGlaucoma and retinal disorders

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

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Tavakoli, Mitra, Ferdousi, Maryam, Petropoulos, Ioannis N., Morris, Julie, Pritchard, Nicola, Zhivov, Andrey, Ziegler, Dan, Pacaud, Danièle +9 more·2015·Diabetes Care
DOI 10.2337/dc14-2311PMC PMC4407754
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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. 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.

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  • Application of published CCM reference values did not reveal intergroup differences.

    “Application of these reference values did not reveal intergroup differences.”

    From Pain and small fiber pathology in men with fibromyalgia syndrome (2024) · cites this paper as [46]

    The Conclusions state that this paper provides normative reference values for corneal nerve parameters. The Results describe values from healthy subjects, but do not report that applying those values revealed no intergroup differences; that outcome is not supported by this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • When comparing with published CCM normative reference values, 3 of 41 (7%) men with fibromyalgia syndrome and 1 of 28 (4%) healthy men showed a pathologically reduced nerve fiber density.

    “When comparing with published CCM normative reference values,46 3 of 41 (7%) men with FMS and 1 of 28 (4%) healthy men showed a pathologically reduced NFD”

    From Pain and small fiber pathology in men with fibromyalgia syndrome (2024) · cites this paper as [46]

  • 1 of 41 (2%) men with fibromyalgia syndrome and none of the controls had a pathologically reduced nerve branch density.

    “1 of 41 (2%) men with FMS and none of the controls had a pathologically reduced NBD”

    From Pain and small fiber pathology in men with fibromyalgia syndrome (2024) · cites this paper as [46]

    The Results describe 343 healthy subjects and report normative values for corneal nerve branch density; the Conclusions explain that such values can help define pathological changes. Our copy does not report a fibromyalgia cohort or the claimed counts of one of 41 men and no controls. Searches for fibromyalgia, 41 men, and pathologically reduced nerve branch density found no passage addressing those counts. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • 21 of 41 (51%) men with fibromyalgia syndrome and 10 of 28 (36%) healthy men had a pathologically reduced nerve fiber length.

    “and 21 of 41 (51%) men with FMS and 10 of 28 (36%) healthy men had a pathological reduced NFL.”

    From Pain and small fiber pathology in men with fibromyalgia syndrome (2024) · cites this paper as [46]

    The Results (page unavailable) describe 343 healthy subjects and report normative corneal nerve measurements, not counts of men with fibromyalgia syndrome. Searches for fibromyalgia, FMS, and the stated counts and percentages found no passage addressing the claimed comparison. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 37

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Cited by

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Authors
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., Singleton, J. R., Smith, G., Boulton, A. J. M., Efron, N., & Malik, R. A.
Affiliations
  • University of Manchester (GB)
  • Queensland University of Technology (AU)
  • University of Rostock (DE)
  • Düsseldorf University Hospital (DE)
  • University of Calgary (CA)
  • University of Toronto (CA)
  • University Health Network (CA)
  • University of Utah (US)
Corresponding author
Malik, Rayaz A.
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2015-01-29
Volume
38
Issue
5
Pages
838-843
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc14-2311
PMC
PMC4407754
OpenAlex
W2143048304
Cited by
222
References
0
Citations by year
2026: 22 · 2025: 26 · 2024: 11 · 2023: 19 · 2022: 32 · 2021: 24 · 2020: 16 · 2019: 22 · 2018: 13 · 2017: 15 · 2016: 11 · 2015: 10
FWCI
17.52
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/site/license (vor, 276 d)
Locations
  • Diabetes Care (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, other-oa)
Funders
  • National Institutes of Health (R1-05991, R01-DK064814)
  • Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW) and the German Federal Ministry of Health
  • Canadian Diabetes Association Operating Grant (OG-3-3123-BP)
  • National Center for Advancing Translational Sciences (NIH 1ULTR001067)
  • JDRF International (17-2008-1032, 17-2008-715, 27-2008- 362)
  • JDRF International -Scholar (R106784)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ocular Surface and Contact Lens
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Corneal surgery and disorders
  • Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
Keywords
corneal confocal microscopy, corneal nerve fiber density, reference values, age-related changes, subbasal nerve plexus, diabetic neuropathy, peripheral neuropathy, corneal nerve fiber length, sex differences, healthy volunteers, Heidelberg Retina Tomograph II, quantile regression
MeSH terms
Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Child, Cornea, Diabetic Neuropathies, Female, Humans, Male, Middle Aged, Nerve Fibers, Reference Values, Sex Factors, Wound Healing, Linear Models, Case-Control Studies, Microscopy, Confocal, Young Adult, Healthy Volunteers

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