Patient with documented keratoconus of the left eye, and a cornea considered to be topographically normal by the neural network, according to calculated Klyce/Maeda indices (Placido topography by OPDSCAN, Nidek). The right eye is asymptomatic (best corrected visual acuity: 12/10). Clinical interview revealed a history of atopy, but the absence of repeated eye rubbing. Due to the presence of advanced keratoconus of the left eye, the cornea of the right eye can be considered to present a subclinical form of keratoconus. According to current definitions, this subclinical form corresponds to forme fruste keratoconus, as it was considered to be normal on the basis of objective analysis by automated Placido videotopography
This is a very useful clinical model, as it can be used to constitute a group of eyes definitely corresponding to an early form of subclinical keratoconus (due to the documented keratoconus observed in the fellow eye) . Most authors deny the existence of strictly unilateral forms of keratoconus [2, 3]. It may be more relevant to include eyes diagnosed as “normal” rather than eyes diagnosed as “keratoconus-suspect”. In the presence of keratoconus-suspect, the indication for corneal refractive surgery may need to be reconsidered, which then raises the problem of whether or not this suspicion is justified and not excessive (false-positive).
The eyes included in our model resembled those that raise diagnostic problems in the context of preoperative assessment prior to refractive surgery (Fig. 9.2): they presented several minor abnormalities but situated below the classical topographic limits of detection . A clinical model based on the study of the less severely affected fellow eye in subjects with highly asymmetric lesions between the two eyes has been used by many authors [5–8]. In view of the rarity of apparently unilateral forms of keratoconus [2, 3], the constitution of a sufficient sample size of eyes known to present forme fruste keratoconus (negative for currently available tests, while the contralateral eye presents keratoconus) proved to be a difficult process: it took us almost 10 years to recruit a sufficiently large sample.
Patient 1 presents very asymmetrical expression of keratoconus between the left and right eyes. This patient presents keratoconus of the left eye, as indicated by the appearance of the topographic map and the calculated values for Klyce/Maeda indices. In the right eye, the automated diagnosis performed with corneal navigator neural network (Nidek) from axial topography (OPDSCAN topographer, Nidek) is negative for keratoconus (KC) and keratoconus-suspect (KCS), and the patient is asymptomatic (best corrected visual acuity: 12/10). There is slight asymmetry, with slight inferior nasal steepening, but this asymmetry is so minimal that all calculated indices are normal. Patient 2 is asymptomatic and presents slight inferior nasal steepening in the right and left eyes. In the right eye, all indices are normal, and, in the left eye, only the OSI is suspicious, but neural network analysis classifies both corneas as normal (NRM). The corneal topography of the right eye of patient 2 strongly resembles that of the right eye of patient 1. Although there may be a doubt concerning a possible forme fruste keratoconus in the corneas of patient 2, the presence of forme fruste keratoconus can be confirmed in the right cornea of patient 1. Other screening indices for forme fruste keratoconus can be defined and tested by using data derived from elevation topography and total pachymetry such as those provided by Orbscan for this type of cornea
9.2 Discriminant Function Analysis
“Placido normal” corneas in patients with a keratoconus genotype (documented lesion in the contralateral eye) were studied by slit-scanning elevation topography (Orbscan, Technolas PV, Germany) and compared to a control group of healthy corneas (Fig. 9.3) in myopic patients operated by LASIK, who did not present any complications after 5 years of postoperative follow-up.
Quad Map of the right cornea with forme fruste keratoconus (FFKC) (patient 1, Fig. 9.1), while the left eye presents clinical keratoconus (KC, Orbscan map, top right). The thickness map (thickness, bottom right) of the cornea of the right eye shows rapid paracentral thinning towards the thinnest point with inferior temporal decentration. The difference between the mean central corneal thickness and the thinnest point is 18 μm. After recentring on the thinnest point, corneal elevation at this point with respect to the best fit sphere is 26 μm. These variables can be used to construct a statistical test for the detection of subclinical fruste form keratoconus
In these eyes with forme fruste keratoconus, many indices calculated from anterior elevation topography, posterior elevation topography and pachymetry were statistically different from those measured in normal eyes . The irregularity of curvature of the anterior corneal surface calculated in the central 3 mm was also significantly increased (0.98 ± 0.34 vs. 1.25 ± 0.38 D). However, comparison of the distributions between the two samples (normal corneas vs. forme fruste keratoconus) revealed a marked overlap of these values (Fig. 9.4). It is noteworthy that, despite the normal Placido indices, a statistical test performed between the group of corneas with forme fruste keratoconus and a group of normal corneas revealed a statistically significant difference for anterior curvature. Normal Placido indices simply mean that the values for the indices calculated for each of these corneas were situated below the cut-offs initially defined for these tests. In absolute terms, the average irregularity of the anterior corneal surface of forme fruste keratoconus remains statistically higher than that of normal corneas. However, the considerable overlap of the values observed in each cornea of the sample means that good sensitivity and specificity is unlikely to be achieved with a test exclusively based on this criterion using a lower cut-off.
Comparison of the distributions of irregularity values measured on the anterior corneal surface (3 mm zone) between a group of eyes with forme fruste keratoconus (FFKC: negative test for Klyce/Maeda criteria, the fellow eye presented advanced keratoconus) and a control group. The mean value (red cross) is significantly higher in the FFKC group than in the control group. Respective median values (almost identical) and the overlap of respective values in each sample strongly suggest that a screening test limited to the use of this index would not be sufficiently discriminant
Statistically significant differences were also observed for other parameters: mean central corneal thickness was decreased (524.3 ± 35 μm vs. 554.6 ± 36 μm), the difference between this value and that of the thinnest point was increased (12.1 ± 5.6 μm vs. 6.8 ± 3.1 μm), the distance from the geometrical centre of the thinnest point was increased (0.95 ± 0.37 vs. 0.64 ± 0.32), and the posterior elevation in relation to the reference sphere calculated after recentring on the thinnest point was greater over this point (26.3 ± 11 μm vs. 19.7 ± 8.6 μm).
The thickening gradient of the corneal wall towards the periphery was more marked than in normal corneas. An equivalent but more clinically relevant interpretation of this criterion is that it reflects steeper thinning from the periphery towards the centre. Although the respective values for the apical curvatures of the anterior and posterior surfaces were not significantly different between the two groups, a significant difference was nevertheless observed for the local variation of these curvatures, which was steeper in the paracentral zone and mid-periphery for corneas with forme fruste keratoconus.
As indicated above, although the mean values calculated for each of these parameters were significantly different, in view of their overlap, they cannot be considered to be clinically significant and cannot be used, on their own, as the basis for a sufficiently sensitive and specific screening test. Nevertheless, the thinning gradient of the cornea from the periphery to the centre, the topographic irregularity index at 3 mm, the vertical decentration of the thinnest point, the difference between central pachymetry and the thinnest pachymetry and the difference between mean inferior keratometry and mean superior keratometry measured 5 mm from the vertex are indices that have been demonstrated to be potentially discriminant. However, isolated use of each of these indices is unable to differentiate, with sufficient sensitivity and specificity, normal corneas from the corneas of the study group because of the considerable overlap of the values obtained for the corneas included in the sample.
In contrast, combined use of these criteria, based on calculation of a composite index using a discriminant analysis technique (see Chap. 11), resulted in a more sensitive and specific diagnostic test. The control group used to construct this test was composed of the eyes of myopic patients under the age of 50 years, operated by myopic LASIK with no complications (particularly corneal ectasia) after at least 5 years of follow-up. The study group was composed of eyes considered to be normal on Placido topography and neural network analysis based on Klyce/Maeda indices. However, these eyes can evolve spontaneously (and especially in the case of corneal surgery) to a form of ectasia. The choice of optimal cut-off resulted in a sensitivity of 93% and a specificity of 92% for the detection of forme fruste keratoconus (Fig. 9.5).
ROC (receiver operating characteristic) curves for various combinations of topographic and tomographic indices for the diagnosis of forme fruste keratoconus. FA, all indices; FT, elevation and decentration at the thinnest point; FPTI, percentage variation of corneal thickness between the centre and the periphery; FPVAK, percentage variation of anterior curvature between the centre and the periphery; FPVPK, percentage variation of posterior curvature between the centre and the periphery; FI, anterior irregularity at 3 and 5 mm. FA is the most sensitive and specific function (area under the curve = 0.98). The choice of an optimal cut-off provides a sensitivity of 92.5% and a specificity of 92%
These results constituted the basis for the design of a new algorithm, called SCORE Analyzer (SCORE: Screening Corneal Objective Risk of Ectasia), based on the use of a combination of Placido topography and corneal elevation indices presenting a certain discriminant property (statistically significant difference of the means calculated between the groups tested for each of these indices). Twelve of the most discriminant indices with a statistically significant difference between the two groups were included in the algorithm. Each of these indices contributed to calculation of the final score, based on linear discriminant function analysis.
The score obtained can be used to classify cases according to the degree of similarity with corneas likely to spontaneously progress to ectasia (progression to a more pronounced form of keratoconus). The cut-off adopted, which corresponds to the limit allowing the two study samples to be discriminated with maximum sensitivity and specificity, was adjusted to take the “zero” value.
A positive score (>0) is predictive of keratoconus-suspect, while a negative score (<0) is predictive of a normal cornea. The higher the positive score, the more closely the topographic characteristics of the cornea examined resemble those of keratoconus, and vice versa. The indication for corneal refractive surgery should be reconsidered in patients with a positive score, or even a slightly negative score, depending on the clinical context (high myopic correction, atopic predisposition, etc.)
9.3 Presentation of SCORE Software
SCORE software uses data acquired with the Orbscan Placido-based and corneal elevation topographer. In its current configuration, data acquired by the Orbscan (*.exm file) must be exported in a proprietary format (*.ote) prior to import and analysis by SCORE software, which completes the classical Quad Map display by adding new quantitative indices (Fig. 9.6). Particular importance is attributed to tomographic data (corneal thickness variations). Certain indices and the two pachymetric curves are calculated after recentring the data measured on the thinnest point.
SCORE software display: the map uses the classical Orbscan Quad Map display. The value of the SCORE corresponds to calculation of a discriminant function established from 12 indices. The optimal cut-off value is zero. In this example, the calculated score of 2.1 suggests the presence of subclinical keratoconus. This map (left eye) was obtained in a patient with advanced keratoconus of the right eye. Despite negative screening based on Placido topography alone (OPD Scan III, Klyce/Maeda indices, corneal navigator software), the score was strongly positive. Calculation of the score is based on 12 Placido topography, elevation and pachymetry indices
SCORE software should be used for screening of early subclinical forms of keratoconus in myopic subjects under the age of 50 years, who have never undergone refractive surgery (these characteristics are derived from those of the eyes included in the control group) . The Orbscan acoustic factor (allowing modulation of the corneal thickness value in relation to a standard such as ultrasound pachymetry) must be adjusted to a value of 0.92.