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

Abstract

OBJECTIVECorneal 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 METHODSA 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.RESULTSThere 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.CONCLUSIONSThis 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.

Comparative quantitative assessment of the human corneal sub-basal nerve plexus by in vivo confocal microscopy and histological staining

“…The results of the current study also revealed a small increase in CNFTo in histology images. Even though the observed difference in our study is in line with the recent report of age-dependent increase in tortuosity, 4 the small sample size examined in our study and the relatively small difference in mean age between the histology and IVCM groups, prevented us from drawing any meaningful conclusions on age-related changes in SBP tortuosity. Furthermore, no clear Figure 2 Local variability of the parameter CNFL.…”

“…Alterations of SBP morphological parameters derived from IVCM images serve as potential biomarkers for early diagnosis of various neurodegenerative diseases. [1][2][3][4] However, the ability of IVCM to adequately resolve intimate details of SBP anatomy remains incompletely understood since the field of view of a conventional IVCM image is relatively small (400 × 400 μm 2 ) and might be insufficient for reliable assessment of SBP morphology. 5 Advancements in imaging extended areas of the corneal SBP by creating large-scale montages [6][7][8] have substantially alleviated this principal limitation of IVCM.…”

Distal Sensorimotor Neuropathy: Improvements in Diagnosis

“…Apart from ageand gender-specific normative values, the paper also standardizes the protocol used to derive such data. A similar endeavor with the CCM, published recently, has pooled 1,965 images form 343 healthy volunteers across Europe, Australia, and North America, allowing practical and singleprotocol-driven use of this technique [146].…”

“…Both the somatic and autonomic peripheral nervous system change with age [1,32,39,146]. It is therefore important that accurate normative data is determined with modern sensitive techniques developed for the detection of DSPN.…”

New technologies for the assessment of neuropathies

“…These fibres can be visualized and quantified by using in vivo corneal confocal microscopy, a noninvasive technique that rapidly evolved from a research technique to an emerging clinical tool 157 . Development of automated corneal nerve image analysis [158][159][160][161] and, most importantly, the establishment of reference values 162 have made corneal confocal microscopy a new and reliable diagnostic tool for SFN. The exact role of the technique in the diagnosis of individual patients with suspected SFN in clinical practice, however, remains to be determined, and requires further studies in future.…”