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Implementation of a Quality Index for Improvement of Quantification of Corneal Nerves in Corneal Confocal Microcopy Images

A Multicenter Study

Sturm, Dietrich, MD*; Vollert, Jan, PhD†,‡,§; Greiner, Tineke, MA*; Rice, Andrew S. C., MD; Kemp, Harriet, MD; Treede, Rolf-Detlef, MD§; Schuh-Hofer, Sigrid, MD§; Nielsen, Stine E., MD; Eitner, Lynn, MD; Tegenthoff, Martin, MD*; Petropoulos, Ioannis N., PhD; Malik, Rayaz A., MD; Maier, Christoph, MD; Schmidt-Wilcke, Tobias, MD**,††; Schargus, Marc, MD‡‡

doi: 10.1097/ICO.0000000000001949

Purpose: Corneal confocal microscopy (CCM) is an imaging method to detect loss of nerve fibers in the cornea. The impact of image quality on the CCM parameters has not been investigated. We developed a quality index (QI) with 3 stages for CCM images and compared the influence of the image quality on the quantification of corneal nerve parameters using 2 modes of analysis in healthy volunteers and patients with known peripheral neuropathy.

Methods: Images of 75 participants were a posteriori analyzed, including 25 each in 3 image quality groups (QI 1–QI 3). Corneal nerve fiber length (CNFL) was analyzed using automated and semiautomated software, and corneal nerve fiber density and corneal nerve branch density were quantified using automated image analysis. Three masked raters assessed CCM image quality (QI) independently and categorized images into groups QI 1–QI 3. In addition, statistical analysis was used to compare interrater reliability. Analysis of variance was used for analysis between the groups. Interrater reliability analysis between the image ratings was performed by calculating Fleiss' kappa and its 95% confidence interval.

Results: CNFL, corneal nerve fiber density, and corneal nerve branch density increased significantly with QI (P < 0.001, all post hoc tests P < 0.05). CNFL was higher using semiautomated compared with automated nerve analysis, independent of QI. Fleiss kappa coefficient for interrater reliability of QI was 0.72.

Conclusions: The quantification of corneal nerve parameters depends on image quality, and poorer quality images are associated with lower values for corneal nerve parameters. We propose the QI as a tool to reduce variability in quantification of corneal nerve parameters.

*Department of Neurology, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany;

Department of Pain Medicine, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany;

Pain Research, Department of Surgery and Cancer, Imperial College, London, UK;

§Center of Biomedicine and Medical Technology Mannheim CBTM, Medical Faculty Mannheim, Heidelberg University, Germany;

Department of Ophthalmology, Aarhus University Hospital, Denmark;

Weill Cornell Medicine-Qatar, Doha, Qatar;

**St. Mauritius Therapieklinik Meerbusch, Meerbusch, Germany;

††Institute of Clinical Neuroscience and Medical Psychology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany; and

‡‡University Eye Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Correspondence: Dietrich Sturm, MD, Department of Neurology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Ruhr Universität Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany (e-mail:

D. Sturm received funding from the FORUM-program of the Ruhr-University Bochum. J. Vollert, A.S.C. Rice, R.D. Treede, and C. Maier received funding from the Innovative Medicines Initiative under the grant agreement number 115007 (“Europain”), which also partly funded this study. The remaining authors have no funding or conflicts of interest to disclose.

D. Sturm and J. Vollert contributed equally.

Received November 24, 2018

Received in revised form January 27, 2019

Accepted February 24, 2019

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