Epithelial remodeling as basis for machine-based identification of keratoconus

Abstract

Purpose: To develop and evaluate automated computerized algorithms for differentiation of normal and keratoconus corneas based solely on epithelial and stromal thickness data.

Methods: Maps of the corneal epithelial and stromal thickness were generated from Artemis-1 very high-frequency ultrasound arc-scans of 130 normal and 74 keratoconic subjects diagnosed by combined topography and tomography examination. Keratoconus severity was graded based on anterior curvature, minimum corneal thickness, and refractive error. Computer analysis of maps produced 161 features for one randomly selected eye per subject. Stepwise linear discriminant analysis (LDA) and neural network (NN) analysis were then performed to develop multivariate models based on combinations of selected features to correctly classify cases. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were determined for each classifier.

Results: Stepwise LDA resulted in a six-variable model that provided an AUC of 100%, indicative of complete separation of keratoconic from normal corneas. Leave-one-out analysis resulted in 99.2% specificity and 94.6% sensitivity. Neural network analysis using the same six variables resulted in an AUC of 100% for the training set. Test set performance averaged over 10 trials gave a specificity of 99.5 ± 1.5% and sensitivity of 98.9 ± 1.9%. The LDA function values correlated with keratoconus severity grade.

Conclusions: The results demonstrate that epithelial remodeling in keratoconus represents an independent means for differentiation of normal from advanced keratoconus corneas.

Keywords: corneal epithelium; high‐frequency ultrasound; keratoconus; pachymetry.

Figure 1

Examples of epithelial and stromal thickness maps for a representative normal and a keratoconus cornea. The horizontal (x) scale is plotted from temporal (T) to nasal (N). In the normal eye, the epithelium is somewhat thickened inferiorly to a maximum of approximately 60 μm, with central thickness of approximately 52 μm. The stroma is thinnest centrally. In the keratoconus eye, a prominent epithelial defect is located 1 mm inferior to center, with the epithelium measuring only 35 μm. The epithelium thickens concentrically about the defect, reaching a maximum of 70 μm superiorly. The stroma shows a defect coincident with the position of the epithelial defect, where it is approximately 350 μm in thickness.

Figure 2

Epithelial and stromal thickness maps averaged over all normal (n = 130) and keratoconus (n = 74) eyes. The horizontal (x) scale is plotted from temporal (T) to nasal (N). The average maps show patterns much like those shown in Figure 1 in representative individual eyes. The average normal map shows a smooth epithelium, with slight thickening inferiorly. The normal stroma is smooth and symmetric. In contrast, the average keratoconus cornea shows a defect inferotemporally characterized by epithelial thinning, with a surrounding annulus of thickened epithelium. The stroma shows a thinning defect at approximately the same position as the epithelial defect.

Figure 3

Epithelial thickness maps averaged over all normal corneas and each keratoconus (KC) grade. The departure from the normal epithelial distribution is evident even in grade 1 KC, but becomes more obvious with severity.

Figure 4

Box and whisker plot of discriminant function value versus keratoconus severity grade. Grade 0 represents normal subjects. Grades 1 to 4 are based on Krumeich classification as defined in Table 4. Boxes represent ±1 quartile about median value (horizontal line), and whiskers represent full range of values for each group. Circles indicate outliers.