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Posterior corneal elevation and back difference corneal elevation in diagnosing forme fruste keratoconus in the fellow eyes of unilateral keratoconus patients
ARTICLE
Posterior corneal elevation and back difference corneal elevation in diagnosing forme fruste keratoconus in the fellow eyes of unilateral keratoconus patients Orkun Muftuoglu, MD, Orhan Ayar, MD, Kemal Ozulken, MD, Erhan Ozyol, MD, Arsen Akıncı, MD
PURPOSE: To evaluate posterior corneal elevation and back difference corneal elevation in patients with keratoconus in 1 eye and forme fruste keratoconus in the fellow eye. SETTING: Kudret Eye Hospital, Ankara, Turkey. DESIGN: Case-control study. METHODS: This study retrospectively reviewed patients with keratoconus in 1 eye and forme fruste keratoconus in the fellow eye and eyes of normal subjects. All subjects were evaluated with a rotating Scheimpflug imaging system (Pentacam), including sagittal and tangential anterior curve analysis, keratometry, and posterior elevation. The back difference elevation values were extrapolated from the difference maps of the Belin-Ambrosio enhanced ectasia display of the Scheimpflug system. The receiver operating characteristic (ROC) curves were analyzed to evaluate the sensitivity and specificity of the parameters. RESULTS: The corneal power, pachymetric progression index, and posterior corneal elevation (posterior elevation and back difference elevation) measurements were statistically significantly higher in eyes with keratoconus or forme fruste keratoconus than in eyes of normal control subjects (P<.05). Using ROC analysis, the area under the curve values of mean keratometry, steepest point on the tangential curve, minimum corneal thickness, pachymetric progression index, Ambrosio’s relational thickness, posterior elevation, and back difference elevation to distinguish forme fruste keratoconus from control subjects were 0.51, 0.84, 0.65, 0.81, 0.72, 0.68, and 0.76, respectively. CONCLUSIONS: Back difference elevation was better than posterior elevation in diagnosing forme fruste keratoconus. However, as sole parameters, both had limited sensitivity and specificity to differentiate between forme fruste keratoconus eyes and normal control eyes. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2013; -:-–- Q 2013 ASCRS and ESCRS
Keratoconus is a progressive corneal ectatic disorder that may have an extremely variable expression at earlier stages, with subtle signs and borderline abnormal features that are difficult to establish with certainity.1–3 Various terms have been proposed to describe early keratoconus. The term forme fruste keratoconus was proposed for corneas that have subtle topographic characteristics that do not reach the threshold of keratoconus suspect.1–3 Keratoconus is usually a bilateral condition but can be asymmetric.4 Previous studies5–7 report that patients with unilateral keratoconus will eventually develop keratoconus in the fellow eye with the same Q 2013 ASCRS and ESCRS Published by Elsevier Inc.
genetic makeup. Thus, the fellow eye of patients with unilateral keratoconus has the earliest and mildest form of the disease, corresponding to the proposed definition of forme fruste keratoconus.6–8 Long-term studies9,10 found laser in situ keratomileusis (LASIK) to be a safe and effective procedure to correct refractive errors. However, iatrogenic corneal ectasia remains a rare but feared complication of this procedure, and undiagnosed forme fruste keratoconus is reported to be a main reason for corneal ectasia after LASIK.4,10,11 Although corneal topography has been used to rule out the possibility of forme fruste 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2013.03.023
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keratoconus before LASIK,1,12,13 recent studies14–17 suggest that screening the posterior elevation may also be important in the diagnosis of early ectatic diseases. Recently, a new elevation-based screening software imaging system was introduced with the aim of identifying patients who may have early keratoconus that may progress to ectasia after LASIK.A The purpose of this study was to evaluate posterior elevation and back difference elevation and compare them with topographic and pachymetric findings in patients with keratoconus in 1 eye and forme fruste keratoconus in the fellow eye. PATIENTS AND METHODS This case series and study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee, Kudret Eye Hospital, Ankara, Turkey. Patients examined at the Kudret Eye Hospital were retrospectively enrolled. All patients included in the study provided informed consent. Clinical keratoconus was defined as findings characteristic of keratoconus (eg, corneal topography with asymmetric bow-tie pattern with or without skewed axes) and at least 1 keratoconus sign (eg, stromal thinning, conical protrusion of the cornea at the apex, Fleischer ring, Vogt striae, or anterior stromal scar) on slitlamp examination. Patients in whom clinical keratoconus was diagnosed in 1 eye (Group A) and whose fellow eye had no slitlamp or significant topography finding that would lead to a diagnosis of clinical keratoconus (Group B) were included in the study. The Amsler-Krumeich classification was used to grade the keratoconus. Control cases (Group C) were selected from a database of consecutive candidates for refractive surgery with normal corneas and myopia or myopic astigmatism (sphere !6.00 diopters [D]; cylinder !3.00 D). Eyes were considered normal if they had no ocular pathology, no previous ocular surgery, and no irregular corneal pattern. Of the consecutively numbered control cases, 1 eye of each patient (right eye for single numbers and left eye for even numbers) was evaluated. Exclusion criteria were a history of corneal surgery or contact lens wear, significant corneal scarring, and significant ophthalmic disease that may potentially affect the outcomes. All eyes had a comprehensive ocular examination. This included rotating Scheimpflug corneal tomography (Pentacam, software version 6.03r19, Oculus Optikger€ate GmbH).
Submitted: December 5, 2012. Final revision submitted: March 2, 2013. Accepted: March 9, 2013. From the Department of Ophthalmology (Muftuoglu), Medipol University, Istanbul, Kudret Eye Hospital (Ayar, Ozulken, Akıncı), € Ankara, and Unye Devlet Hastanesi (Ozyol), Ordu, Turkey. Corresponding author: Orkun Muftuoglu, MD, Department of Ophthalmology, Medipol University, Medipol Mega Universite Hastanesi, Goz Hastalıkları, TEM Otoyolu Number: 1, Bagcilar; 34214, Istanbul, Turkey. E-mail: [email protected].
Two patients with clinical keratoconus were using rigid gas-permeable contact lenses; all patients were asked to discontinue contact lens use at least 4 weeks before the topographic examination. During the Scheimpflug tomography examination, the patient was positioned at the instrument with proper placement on the chinrest and forehead strap. The patient was asked to blink a few times and to open both eyes and stare at the fixation target. After proper alignment was obtained, the automatic-release mode started the scan; 25 single Scheimpflug images of each eye were captured within 2 seconds. Only cases with acceptable-quality images were included in the study. Each eye was required to have a corneal map with at least 9.0 mm of corneal coverage and no extrapolated data. The sagittal curvature and tangential curvature maps were evaluated, and the map patterns were noted. The following anterior and posterior corneal surface parameters were evaluated with the Scheimpflug system: corneal dioptric power in the flattest meridian in the 3.0 mm central zone (flat keratometry [K] value), corneal dioptric power in the steepest meridian in the 3.0 mm central zone (steep K value), and mean corneal power in the 3.0 mm zone (mean K value). The inferior–superior (I–S) dioptric asymmetry value on the sagittal I–S and tangential I–S curvature maps was calculated by subtracting the superior mean value of 3 data points (slightly different than the mean reported by Rabinowitz18) 3.0 mm from the center of the cornea at 30-degree intervals (60 degrees, 90 degrees, and 120 degrees) from the mean value of the 3 corresponding data points along the inferior cornea (240 degrees, 270 degrees, and 300 degrees). The value of the steepest point (steepest K) on the sagittal steepest and tangential steepest curvature maps was determined manually by moving the cursor on the map. The central corneal thickness (CCT) at the apex (geometric center of the examination), the minimum corneal thickness at the thinnest point, the difference between the CCT and minimum corneal thickness, and the distance between the CCT and minimum corneal thickness were recorded. The average progression index is calculated as the progression value at the different rings, referenced to the mean curve. The minimum pachymetric progression index and maximum pachymetric progression index values and the axis were recorded with the pachymetric progression index average. The Ambr osio relational thickness was calculated by the following formulas: average Ambr osio relational thickness Z minimum corneal thickness/average pachymetric progression index; Ambr osio relational thickness minimum Z minimum corneal thickness/minimum pachymetric progression index; Ambr osio relational thickness maximum Z minimum corneal thickness/maximum pachymetric progression index.19 Corneal volume was also determined. The posterior elevation maps were evaluated and posterior corneal elevation values from the corneal apex analyzed. Elevation was measured in a standardized fashion relative to a reference best-fit sphere (BFS) calculated at a fixed optical zone of 9.0 mm, as previously described.20 The back difference posterior elevation values were extrapolated from the difference maps of the Belin-Ambrosi o enhanced ectasia display of Pentacam device.A Different than the standard elevation maps, the reference surface is the enhanced BFS rather than the standard BFS for the exclusion maps. In these maps, the BFS is calculated using all raw elevation data located outside a 4.0 mm circle centered on the thinnest point of the cornea. This area of excluded data is called the exclusion zone, and the map is an exclusion
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Table 1. Comparison of Scheimpflug parameters between keratoconus, forme fruste keratoconus, and control groups. P Value*
Ks (D) Mean G SD Range Kf (D) Mean G SD Range Km (D) Mean G SD Range I/S-S Mean G SD Range Ssteepest (D) Mean G SD Range I/S-T Mean G SD Range Tsteepest (D) Mean G SD Range CTmin (mm) Mean G SD Range CCT (mm) Mean G SD Range CT-diff (mm) Mean G SD Range Dist CCT-CTmin (mm) Mean G SD Range CV (mm3) Mean G SD Range PPIavg Mean G SD Range PPImin Mean G SD Range PPImax Mean G SD Range ARTavg Mean G SD Range ARTmin Mean G SD Range
KCN
FFKC (Fellow Eyes)
Controls
KC vs Control
FFKC vs Control
48.68 G 3.48 43.40, 57.10
44.39 G 1.56 40.50, 47.10
42.86 G 1.41 39.70, 45.90
!.001
!.001
45.47 G 4.06 41.00, 62.30
43.37 G 1.27 40.90, 46.10
43.87 G 1.38 41.00, 47.30
!.001
.119
47.07 G 3.57 42.20, 59.70
43.88 G 1.38 40.70, 46.60
43.37 G 1.33 40.70, 46.40
!.001
.089
0.67 G 0.91 1.40, 2.33
0.10 G 0.52 1.20, 1.20
!.001
.001
51.48 G 4.89 44.50, 67.80
45.03 G 1.47 41.30, 47.40
44.05 G 1.36 41.20, 47.60
!.001
.003
5.14 G 3.45 2.43, 10.67
0.78 G 0.81 1.00, 2.20
0.22 G 0.55 1.13, 1.27
!.001
.001
52.70 G 4.87 44.80, 63.50
45.46 G 1.7 42.00, 49.00
44.36 G 1.47 41.50, 48.00
!.001
.003
468 G 30 405, 513
494 G 35 435, 566
546 G 31 487, 611
!.001
!.001
480 G 31 421, 537
500 G 34 440, 569
549 G 31 491, 615
!.001
!.001
12.57 G 8.33 2.00, 42.00
5.86 G 4.12 1.00, 16.00
3.11 G 1.83 0.00, 9.00
!.001
.001
0.83 G 0.26 0.31, 1.33
0.80 G 0.23 0.33, 1.24
0.68 G 0.22 0.07, 1.30
!.001 !.001
.003 .003
57.79 G 3.71 48.70, 65.50
57.94 G 3.68 50.00, 64.80
60.82 G 3.32 54.20, 69.70
.882 .882
.001 .001
1.97 G 0.51 1.29, 3.19
1.16 G 0.22 0.81, 1.65
0.88 G 0.13 0.52, 1.21
!.001 !.001
!.001 !.001
1.47 G 0.54 0.67, 3.14
0.80 G 0.18 0.50, 1.30
0.57 G 0.13 0.31, 1.01
!.001
!.001
2.58 G 0.68 1.64, 4.36
1.55 G 0.28 1.03, 2.20
1.15 G 0.17 0.71, 1.60
!.001
!.001
253 G 70 151, 392
442 G 105 290, 682
633 G 108 424, 1035
!.001
!.001
361 G 137 130, 721
649 G 160 385, 1011
1003 G 248 505, 1735
!.001
!.001
4.36 G 4.87 10.60, 13.27
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Table 1. (Cont.) P Value*
ARTmax Mean G SD Range PE (mm) Mean G SD Range BDE (mm) Mean G SD Range
KCN
FFKC (Fellow Eyes)
Controls
KC vs Control
FFKC vs Control
192 G 49 111, 313
334 G 77 230, 523
488 G 91 321, 818
!.001
!.001
45.79 G 21.10 12.00, 95.00
10.32 G 7.02 2.00, 28.00
6.87 G 2.14 3.00, 15.00
!.001
.033
42.50 G 20.51 8.00, 105.00
16.43 G 5.96 8.00, 32.00
10.15 G 4.76 0.00, 23.00
!.001
!.001
ART Z Ambrosi o relational thickness; avg Z average; BDE Z back difference elevation on Belin-Ambrosi o display of Scheimpflug device; CCT Z central corneal thickness; CT-diff Z difference between central corneal thickness and minimum corneal thickness; Ctmin Z minimum corneal thickness; CV Z corneal volume; Dist CCT-Ctmin Z distance between central corneal thickness and minimum corneal thickness; FFKC Z forme fruste keratoconus; I/S-S Z inferior/ superior sagittal; I/S-T Z inferior/superior tangential; KCN Z keratoconus; Kf Z flat keratometry; Km Z mean keratometry; Ks Z steep keratometry; max Z maximum; min Z minimum; PE Z posterior corneal elevation; PPI Z pachymetric progression index; Ssteepest Z steepest keratometry on sagittal curvature map; Tsteepest Z steepest keratometry on tangential curvature map *Mann-Whitney U test
map. The location of the exclusion zone is indicated by a 4.0 mm red circle. The difference maps (posterior and back) show the relative change in elevation from the baseline elevation map to the exclusion map, in which each point corresponds to the amount of elevation change that occurs between the baseline elevation map and the exclusion map.A Statistical analysis was performed using SPSS software (version 11.0, SPSS, Inc.). The data were not normally distributed; therefore, the nonparametric Mann-Whitney U test (Wilcoxon rank-sum test) was used to compare each parameter between 2 groups. Receiver operating characteristic (ROC) curves were used to determine the overall predictive accuracy of the test parameters as described by the area under the curve (AUC) and to calculate the sensitivity and specificity of the parameters. A P value less than 0.05 was considered statistically significant.
RESULTS Group A (clinical keratoconus) and Group B (forme fruste keratoconus, fellow eye) comprised 28 patients each. Group C (control cases) comprised 82 eyes of 82 subjects. The mean age was 26.7 years G 7.8 (SD) (range 13.0 to 51.0 years) in keratoconus patients and 29.8 G 7.2 years (range 19.0 to 53.0 years) in controls. There was no significant difference in age between the 2 groups (PZ.066). According to the KrumeichAmsler classification of the severity of keratoconus in Group A, 1 eye (3.6%) was classified as grade IV, 6 eyes (21.4%) were classified as grade II, and 21 eyes (75.0%) were classified as grade I. Topography In Group B, on the sagittal curvature map, 16 eyes (57.1%) had inferior or inferotemporal steepening (12 eyes with significant inferior steepening; 4 eyes with
mild inferior steepening), 6 eyes (21.4%) had skewed axes (2 also had inferior steepening), 4 eyes (14.3%) had bow-tie pattern (1 steep, 1 normal), and 2 eyes (7.1%) were normal. On the tangential curvature map, 18 eyes (64.3%) had the oil-droplet sign (12 eyes inferior, 2 eyes central, and 4 eyes mild), 1 eye (3.6%) had central steepening, 2 eyes (7.1%) had inferior steepening, 1 eye (3.6%) had superior steepening, and 6 eyes (21.4%) had bow-tie pattern (2 eyes with inferior asymmetric steepening, 2 eyes with superior asymmetric steepening). Rotating Scheimpflug Imaging Table 1 shows the mean keratometric, pachymetric, and posterior elevation parameters in all groups. All parameters were significantly different between Group B and Group C (P!.05). Also, all parameters except the flat K value and mean K value were significantly different between Group B and Group C (P!.05). The corneal power (steep K value, flat K value, mean K value), keratometric parameters (I–S sagittal, sagittal steepest, I–S tangential, tangential steepest), pachymetric progression index (mean, minimum, maximum), and posterior corneal elevation and back distance elevation measurements were statistically significantly higher, whereas the corneal thickness (minimum corneal thickness, CCT, difference between CCT and minimum corneal thickness, and distance between CCT and minimum corneal thickness) and Ambr osio relational thickness (mean, minimum, maximum) measurements were significantly lower in Group A and Group B than in Group C (P!.05).
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Posterior Elevation Findings Figure 1 shows a scatterplot of the distribution of the mean K value versus posterior elevation and the mean K value versus back difference elevation in all 3 groups. Figure 2 shows samples from Group A and fellow eyes in Group B. Receiver Operating Characteristic Curve Analysis Table 2 shows the results of the ROC curve analysis AUC, standard error, 95% confidence intervals, significance level, best cutoff point, and sensitivity and specificity of best cutoff points for each parameter tested in Group A versus Group C. Table 3 shows these results in Group B versus Group C. In discriminating keratoconus from control eyes, almost all parameters had
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a high AUC; however, pachymetric parameters (Ambr osio relational thickness and pachymetric progression index) had the highest AUC. In discriminating Group B from Group C, the topographic parameters (tangential steepest, I–S tangential, sagittal steepest, I–S sagittal) and pachymetric progression index (mean, maximum, and minimum) levels had the highest AUC. DISCUSSION There is still a discussion in the literature that posterior elevation is one of the earliest signs of an ectatic disease.14–16,20 Using the Pentacam system, de Sanctis et al.14 found high AUC levels of posterior elevation to diagnose keratoconus and subclinical keratoconus (0.99 and 0.93, respectively). Similarly, Uc¸akhan
Figure 1. Distribution of mean K value versus posterior corneal elevation in eyes with forme fruste keratoconus (fellow eyes), eyes with keratoconus, and control eyes (A) and forme fruste keratoconus eyes and controls eyes (B). Distribution of mean K value versus back difference posterior elevation in eyes with forme fruste keratoconus, eyes with keratoconus, and control eyes (C) and in eyes with forme fruste keratoconus and control eye (D) (FFKCN Z forme fruste keratoconus; KCN Z keratoconus). J CATARACT REFRACT SURG - VOL -, - 2013
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Figure 2. Samples of rotating Scheimpflug imaging and Belin-Ambrosi o display scans of patients with keratoconus and the fellow eye with forme fruste keratoconus. For each scan, sagittal curve map (upper left), tangential curve map (upper right), corneal thickness map (middle left), posterior corneal elevation map (middle right), front difference map (bottom left), and back difference map (bottom right) are given. Note that there is inferior steepening on sagittal curve maps, particularly on tangential maps; however, there is no significant posterior corneal elevation or back difference corneal elevation in forme fruste keratoconus (fellow) eyes in Cases 1 and 2. There is slight or no change on sagittal or tangential curve maps and no significant posterior corneal elevation; however, there is significant elevation on the back difference map, suggesting early ectatic disease in the fellow (forme fruste keratoconus) eye in Case 3. There is inferior steepening on sagittal curve maps and tangential maps and significant elevation on posterior corneal and back difference maps, indicating ectatic disease in the fellow eye in Case 4 (FFKCN Z forme fruste keratoconus).
et al.15 found a good AUC (0.94) of posterior elevation to discriminate keratoconus eyes from normal eyes; however, they found a relatively lower AUC value (0.78) to distinguish between subclinical keratoconus eyes and normal eyes. In accordance with previous reports, the ROC analysis in our study showed a good AUC level of posterior elevation (0.97) to discriminate keratoconus eyes from normal eyes. However, the AUC level of posterior elevation to distinguish between forme fruste keratoconus eyes and normal eyes in our study was lower (0.68) than in previous reports. Previous studies14–16,21 found a best cutoff level between 20.0 mm and 26.5 mm of posterior elevation to differentiate keratoconus eyes from normal eyes and between 15.5 mm and 29.0 mm to differentiate forme fruste keratoconus eyes from normal eyes. We found a best cutoff level of 19.2 mm for posterior elevation
to discriminate keratoconus eyes from normal eyes and 14.7 mm to discriminate forme fruste keratoconus eyes from normal eyes. The best cutoff levels in our study were also lower than in previous reports, which may be explained by the different study designs and populations. Our group of forme fruste keratoconus eyes comprised fellow eyes of unilateral keratoconus patients regardless of topography, whereas other studies14–16,20 included only Placido topography–positive subclinical keratoconus patients. Therefore, our group may represent an earlier stage of keratoconus then those reported in other studies and may explain the lower levels of AUC and best cutoff value in forme fruste keratoconus eyes. In a recent multinational study of 555 normal control eyes, Feng et al.22 reported a median posterior elevation value measured on the thinnest points of
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Table 2. Receiver operating characteristic curve analysis for the keratoconus eyes versus normal eyes. Parameter
AUC
SE
95% CI
P Value
Cutoff
Sensitivity
Specificity
Ks Kf Km I/S-S Ssteepest I/S-T Tsteepest CTmin CCT CT-diff CV Dist CCT-CTmin PPIavg PPImin PPImax ARTavg ARTmin ARTmax PE BDE
0.912 0.721 0.894 0.921 0.963 0.953 0.969 0.897 0.811 0.885 0.376 0.760 0.976 0.957 0.980 0.989 0.968 0.991 0.949 0.938
0.021 0.070 0.041 0.072 0.020 0.058 0.018 0.019 0.035 0.038 0.056 0.062 0.010 0.010 0.009 0.002 0.004 0.003 0.004 0.009
0.745, 0.938 0.593, 0.819 0.833, 0.925 0.799, 0.993 0.933, 0.986 0.897, 0.987 0.944, 0.994 0.872, 0.924 0.779, 0.843 0.840, 0.921 0.306, 0.427 0.688, 0.832 0.963, 0.988 0.942, 0.968 0.970, 0.991 0.986, 0.995 0.971, 0.982 0.976, 0.998 0.924, 0.966 0.910, 0.952
!.001 .048 !.001 !.001 !.001 !.001 !.001 !.001 !.001 !.001 .124 .008 !.001 !.001 !.001 !.001 !.001 !.001 !.001 !.001
45.95 44.45 45.2 1.25 46.45 1.31 47.85 489 494 5.87 NA 0.74 1.29 0.93 1.69 407 607 301 12.11 17.95
0.91 0.71 0.87 0.92 0.93 0.94 0.95 0.90 0.82 0.87 NA 0.75 0.95 0.92 0.95 0.98 0.95 0.99 0.94 0.93
0.79 0.65 0.71 0.92 0.86 0.90 0.92 0.79 0.71 0.78 NA 0.71 0.91 0.90 0.92 0.94 0.92 0.95 0.93 0.91
ART Z Ambrosi o relational thickness; AUC Z area under curve; avg Z average; BDEZ back difference elevation; CCT Z central corneal thickness; CI Z confidence interval; CT-diff Z difference between central corneal thickness and minimum corneal thickness; CTmin Z minimum corneal thickness; CV Z corneal volume; Dist CCT-Ctmin Z distance between central corneal thickness and minimum corneal thickness; I/S-S Z inferior/superior (sagittal); I/S-T Z inferior/ superior (tangential); Kf Z flat keratometry; Km Z mean keratometry; Ks Z steep keratometry; max Z maximum; min Z minimum; NA Z not analyzed because there was no significant difference; PE Z posterior corneal elevation; PPI Z pachymetric progression index; SE Z standard error; Ssteepest Z steepest keratometry on sagittal curvature map; Tsteepest Z steepest keratometry on tangential curvature map
3.0 mm (interquartile range, 3.0), which was lower than the mean posterior elevation value in normal eyes reported in previous studies comparing forme fruste keratoconus eyes and normal eyes.14–16,20 The mean posterior elevation of normal controls in our study (6.87 mm) was much closer but still slightly higher than that reported by Feng et al.22 Khachikian and Belin23 suggest that the posterior elevation measurements taken as the maximum value above the BFS within the central 5.0 mm may incorporate astigmatic elevation into the calculation of the average normal elevation, which may artificially inflate normal elevation measurements. More studies are needed to assess the reliability and repeatability of elevation measurements. The rotating Scheimpflug device we used measures posterior elevation by fitting the best-possible sphere to the posterior cornea, which could miss small protrusions on the posterior cornea, such as the ones that can be seen with early keratoconus. To overcome this problem, a new screening tool of the rotating Scheimpflug devicedthe back difference elevationdwas introduced. This software creates a difference map that shows the relative change in elevation from the baseline elevation map to the exclusion map (formed by an exclusion zone of
4.0 mm centered on the thinnest point of the cornea) to identify the posterior elevation. The manufacturer claims that a back difference elevation greater than 20 mm is suggestive of ectatic disease and a change between 10 mm and 20 mm is in the suspect zone.A In our study, we found a best cutoff level of 17.2 mm for the back difference elevation to discriminate between keratoconus eyes and normal eyes and 13.2 mm to discriminate between forme fruste keratoconus eyes and normal eyes. In our study, we found that back difference elevation (0.75 mm) was better than posterior elevation (0.68 mm) in discriminating forme fruste keratoconus eyes from normal control eyes. This may imply that back difference elevation can be a better screening parameter than posterior elevation for early detection of ectatic diseases. However, significant overlaps in posterior elevation and back difference elevation levels between forme fruste keratoconus eyes and control eyes were noted (Figure 1). Clinically, the best cutoff levels found by previous reports or in our study would miss many cases of forme fruste keratoconus. This suggests that as sole parameters, back difference elevation and posterior elevation have limited sensitivity and specificity to diagnose very early keratoconus. To our knowledge, we are unaware of
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Table 3. Receiver operating characteristic curve analysis for the forme fruste keratoconus eyes versus normal eyes. Parameter
AUC
SE
95% CI
P Value
Cut-off
Sensitivity
Specificity
Ks Kf Km I/S-S Ssteepest I/S-T Tsteepest CTmin CCT CT-diff CV Dist CCT-CTmin PPIavg PPImin PPImax ARTavg ARTmin ARTmax PE BDE
0.709 0.401 0.508 0.794 0.811 0.821 0.855 0.652 0.601 0.703 0.195 0.688 0.806 0.795 0.813 0.722 0.714 0.739 0.683 0.755
0.053 0.062 0.062 0.048 0.058 0.064 0.060 0.041 0.042 0.064 0.072 0.060 0.042 0.042 0.039 0.040 0.035 0.036 0.071 0.043
0.634, 0.773 0.310, 0.482 0.387, 0.629 0.721, 0.857 0.738, 0.884 0.756, 0.906 0.781, 0.915 0.612, 0.701 0.553, 0.667 0.631, 0.773 0.103, 0.287 0.600, 0.776 0.734, 0.863 0.703, 0.857 0.761, 0.873 0.660, 0.786 0.675, 0.763 0.694, 0.799 0.543, 0.792 0.692, 0.860
!.001 .119 .089 !.001 !.001 !.001 !.001 .034 .053 .001 .582 .030 !.001 !.001 !.001 !.001 !.001 !.001 .021 !.001
44.45 NA NA 0.57 44.85 0.62 45.14 512 519 5.1 NA 0.72 0.98 0.62 1.32 487 691 372 9.17 14.41
0.70 NA NA 0.77 0.79 0.80 0.84 0.64 0.58 0.69 NA 0.64 0.77 0.76 0.78 0.72 0.70 0.73 0.67 0.74
0.61 NA NA 0.69 0.67 0.69 0.70 0.58 0.54 0.60 NA 0.59 0.65 0.64 0.65 0.60 0.61 0.63 0.59 0.65
ART Z Ambrosi o relational thickness; AUC Z area under curve; avg Z average; BDE Z back difference elevation on Belin-Ambrosi o display of Scheimpflug device; CI Z confidence intervals; CT-diff Z difference between central corneal thickness and minimum corneal thickness; CTmin Z minimum corneal thickness; CTT Z central corneal thickness; CV Z corneal volume; Dist CCT-Ctmin Z distance between CCT and Ctmin; I/S-S Z inferior/superior (sagittal); I/S-T Z inferior/superior (tangential); Kf Z flat keratometry; Km Z mean keratometry; Ks Z steep keratometry; max Z maximum; min Z minimum; NA Z not analyzed because there was no significant difference; PE Z posterior corneal elevation; PPI Z pachymetric progression index; SE Z standard error; Ssteepest Z steepest keratometry on sagittal curvature map; Tsteepest Z steepest keratometry on tangential curvature map
a published study of using back difference elevation to screen for keratoconus or forme fruste keratoconus. Thus, we cannot compare our results with those in other studies. Corneal topography remains the gold standard to evaluate ectatic diseases.5,12 Our study confirms the importance of manual evaluation of the topographic patterns. However, this analysis is subjective, requires experience and training, and has inherent limitations in using axial curvature to imply the shape of an abnormal cornea.24 Although we were not able to evaluate all topographic indices reported, our results suggest that topographic indices are useful but that they still may not have enough sensitivity and specificity to detect early ectatic diseases as sole parameters. In this study, we found that the minimum corneal thickness and the difference between CCT and the minimum corneal thickness had higher AUC levels than the CCT and may be clinically more meaningful. Similar to previous studies,15,18,25,26 we found that the corneal progression indices also had high predictive accuracies in discriminating keratoconic or forme fruste keratoconus eyes from normal eyes. Total or corneal wavefront aberrations27 and corneal biomechanical response28 were reported to be useful in the diagnosis of forme fruste keratoconus; however,
comparative studies would be needed to fully evaluate the efficacy of these parameters. To ideally evaluate the specificity and cutoff point of any parameter in discriminating keratoconus and forme fruste keratoconus using ROC analysis, the control group should consist of a relevant clinical population rather than of normal patients. Therefore, performance of any parameter might be overestimated in this study and also in any study with a limited number of control eyes.29,30 Further studies with a larger number of patients and greater number of controls are needed, in particular for the detection of a better cutoff level. Also, although keratoconus is an asymmetric progressive disorder that ultimately affects both eyes and has a strong genetic component,31,32 true unilateral keratoconus is possible, and the disease may not develop in the fellow eyes. Therefore, genetic and follow-up studies are needed to elucidate the risk for developing keratoconus in fellow eyes of unilateral keratoconus patients. In conclusion, the results in our study indicate that back difference elevation seems to be a better parameter than posterior elevation to diagnose early ectatic conditions. However, as sole parameters, posterior elevation and back difference elevation have limited sensitivity and specificity to diagnose very early
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keratoconus because of significant overlaps in posterior elevation and back difference elevation levels between forme fruste keratoconus eyes and control eyes. Our study also confirmed that evaluation of topography pattern, topographic indices, and pachymetric indices are useful in the diagnosis of forme fruste keratoconus. These results may suggest that rather than relying on a single parameter, comprehensive analysis of topography, pachymetric data, and posterior elevation seems to be important in diagnosing forme fruste keratoconus. Further studies with more patients are needed to fully validate the efficacy of our tools to diagnose early keratoconus. WHAT WAS KNOWN Posterior elevation can be used to diagnose keratoconus and forme fruste keratoconus.
10.
11. 12.
13.
14.
15.
16.
WHAT THIS PAPER ADDS Back difference elevation was better than posterior elevation in distinguishing between forme fruste keratoconus eyes and normal eyes. There may be overlaps in posterior elevation and back difference elevation levels between forme fruste keratoconus eyes and control eyes. It may not always be possible to diagnose forme fruste keratoconus using only posterior elevation or back difference elevation.
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17.
18. 19.
20.
1. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998; 42: 297–319. Available at: http://www.keratoconus.com/resources/ MajorCReview-Keratoconus.pdf. Accessed March 26, 2013 2. Saad A, Gatinel D. Topographic and tomographic properties of forme fruste keratoconus corneas. Invest Ophthalmol Vis Sci 2010; 51:5546–5555. Available at: http://www.iovs.org/ content/51/11/5546.full.pdf. Accessed March 26, 2013 3. Klyce SD. Chasing the suspect: keratoconus [editorial]. Br J Ophthalmol 2009; 93:845–847 4. Randleman JB, Woodward M, Lynn MJ, Stulting RD. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology 2008; 115:37–50 5. Rabinowitz YS, Nesburn AB, McDonnell PJ. Videokeratography of the fellow eye in unilateral keratoconus. Ophthalmology 1993; 100:181–186 6. Holland DR, Maeda N, Hannush SB, Riveroll LH, Green MT, Klyce SD, Wilson SE. Unilateral keratoconus; incidence and quantitative topographic analysis. Ophthalmology 1997; 104:1409–1413 7. Li X, Rabinowitz YS, Rasheed K, Yang H. Longitudinal study of the normal eyes in unilateral keratoconus patients. Ophthalmology 2004; 111:440–446 8. Klyce SD, Karon MD, Smolek MK. Screening patients with the corneal navigator. J Refract Surg 2005; 21:S617–S622 JL, Muftuoglu O, Ortiz D, Pe rez-Santonja JJ, Artola A, 9. Alio Ayala MJ, Garcia MJ, Castro de Luna G. Ten-year follow-up of
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laser in situ keratomileusis for myopia of up to 10 diopters. Am J Ophthalmol 2008; 145:46–54 JL, Muftuoglu O, Ortiz D, Pe rez-Santonja JJ, Artola A, Alio Ayala MJ, Garcia MJ, Castro de Luna G. Ten-year follow-up of laser in situ keratomileusis for high myopia. Am J Ophthalmol 2008; 145:55–64 Rabinowitz YS. Ectasia after laser in situ keratomileusis [special commentary]. Curr Opin Ophthalmol 2006; 17:421–426 Wilson SE, Klyce SD. Screening for corneal topographic abnormalities before refractive surgery. Ophthalmology 1994; 101: 147–152 Rabinowitz YS, Rasheed K. KISA% index: a quantitative videokeratography algorithm embodying minimal topographic criteria for diagnosing keratoconus. J Cataract Refract Surg 1999; 25:1327–1335; errata, 2000; 26:480 de Sanctis U, Loiacono C, Richiardi L, Turco D, Mutani B, Grignolo FM. Sensitivity and specificity of posterior elevation measured by Pentacam in discriminating keratoconus/subclinical keratoconus. Ophthalmology 2008; 115:1534–1539 € O, € Cetinkor V, Ozkan € Uc‚akhan O M, Kanpolat A. Evaluation of Scheimpflug imaging parameters in subclinical keratoconus, keratoconus, and normal eyes. J Cataract Refract Surg 2011; 37:1116–1124 Nilforoushan M-R, Speaker M, Marmor M, Abramson J, Tullo W, Morschauser D, Latkany R. Comparative evaluation of refractive surgery candidates with Placido topography, Orbscan II, Pentacam, and wavefront analysis. J Cataract Refract Surg 2008; 34:623–631 Chen D, Lam AKC. Intrasession and intersession repeatability of the Pentacam system on posterior corneal assessment in the normal human eye. J Cataract Refract Surg 2007; 33:448–454 Rabinowitz YS. Videokeratographic indices to aid in screening for keratoconus. J Refract Surg 1995; 11:371–379 R, Caiado ALC, Guerra FP, Louzada R, Roy AS, Ambrosio Luz A, Dupps WJ, Belin MW. Novel pachymetric parameters based on corneal tomography for diagnosing keratoconus. J Refract Surg 2011; 27:753–758 Belin MW, Khachikian SS. An introduction to understanding elevation-based topography: how elevation data are displayed – a review. Clin Exp Ophthalmol 2009; 37:14–29. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.14429071.2008.01821.x/pdf. Accessed March 26, 2013 Nagy ZZ. Evaluation of keratoltz K, Kova cs I, Taka cs A, Miha metric, pachymetric, and elevation parameters from keratoconic corneas with Pentacam. Cornea 2009; 28:976–980 sio R Jr, Grewal SPS, Yan W, Feng MT, Belin MW, Ambro Shaheen MS, Jordon CA, McGhee C, Maeda N, Neuhann TH, Dick HB, Steinmueller A. International values of corneal elevation in normal subjects by rotating Scheimpflug camera. J Cataract Refract Surg 2011; 37:1817–1821 Khachikian SS, Belin MW. Posterior elevation in keratoconus [letter]. Ophthalmology 2009; 116:816; reply by U de Sanctis, F Grignolo, 816–817 Belin MW, Khachikian SS. Keratoconus: it is hard to define, but. [editorial]. Am J Ophthalmol 2007; 143:500–503 R Jr, Alonso RS, Luz A, Coca Velarde LG. CornealAmbrosio thickness spatial profile and corneal-volume distribution: tomographic indices to detect keratoconus. J Cataract Refract Surg 2006; 32:1851–1859 € hren J, Kook D, Yoon G, Kohnen T. Detection of subclinical Bu keratoconus by using corneal anterior and posterior surface aberrations and thickness spatial profiles. Invest Ophthalmol Vis Sci 2010; 51:3424–3432. Available at: http://www.iovs.org/ content/51/7/3424.full.pdf. Accessed March 26, 2013
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27. Saad A, Gatinel D. Evaluation of total and corneal wavefront high order aberrations for the detection of forme fruste keratoconus. Invest Ophthalmol Vis Sci 2012; 53:2978–2992. Available at: http://www.iovs.org/content/53/6/2978.full.pdf. Accessed March 26, 2013 28. Schweitzer C, Roberts CJ, Mahmoud AM, Colin J, Maurice-Tison S, Kerautret J. Screening of forme fruste keratoconus with the Ocular Response Analyzer. Invest Ophthalmol Vis Sci 2010; 51:2403–2410. Available at: http://www.iovs.org/ content/51/5/2403.full.pdf. Accessed March 26, 2013 29. Motulsky H. Intuitive Biostatistics. New York, NY, Oxford University Press, 1995; 9–60 30. McClish DK. Analyzing a portion of the ROC curve. Med Decis Making 1989; 9:190–195 31. Edwards M, McGhee CNJ, Dean S. The genetics of keratoconus. Clin Exp Ophthalmol 2001; 29:345–351 32. Sugar J, Macsai MS. What causes keratoconus? Cornea 2012; 31:716–719
OTHER CITED MATERIAL A. Belin MW, Khachikian SS. Keratoconus / ectasia detection with enhanced ectasia the Oculus Pentacam: Belin/Ambrosio display. In: New Advances and Technology With Pentacam. Wetzlar, Germany, Oculus Optikgerate GmbH; 3–7. Available at: http://www.oculus.de/en/downloads/dyn/oculus/presse/158/ oculus_low_res.pdf. Accessed March 26, 2013
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First author: Orkun Muftuoglu, MD Department of Ophthalmology, Medipol University, Istanbul, Turkey
Posterior corneal elevation and back difference corneal elevation in diagnosing forme fruste keratoconus in the fellow eyes of unilateral keratoconus patients Orkun Muftuoglu, MD, Orhan Ayar, MD, Kemal Ozulken, MD, Erhan Ozyol, MD, Arsen Akıncı, MD
PURPOSE: To evaluate posterior corneal elevation and back difference corneal elevation in patients with keratoconus in 1 eye and forme fruste keratoconus in the fellow eye. SETTING: Kudret Eye Hospital, Ankara, Turkey. DESIGN: Case-control study. METHODS: This study retrospectively reviewed patients with keratoconus in 1 eye and forme fruste keratoconus in the fellow eye and eyes of normal subjects. All subjects were evaluated with a rotating Scheimpflug imaging system (Pentacam), including sagittal and tangential anterior curve analysis, keratometry, and posterior elevation. The back difference elevation values were extrapolated from the difference maps of the Belin-Ambrosio enhanced ectasia display of the Scheimpflug system. The receiver operating characteristic (ROC) curves were analyzed to evaluate the sensitivity and specificity of the parameters. RESULTS: The corneal power, pachymetric progression index, and posterior corneal elevation (posterior elevation and back difference elevation) measurements were statistically significantly higher in eyes with keratoconus or forme fruste keratoconus than in eyes of normal control subjects (P<.05). Using ROC analysis, the area under the curve values of mean keratometry, steepest point on the tangential curve, minimum corneal thickness, pachymetric progression index, Ambrosio’s relational thickness, posterior elevation, and back difference elevation to distinguish forme fruste keratoconus from control subjects were 0.51, 0.84, 0.65, 0.81, 0.72, 0.68, and 0.76, respectively. CONCLUSIONS: Back difference elevation was better than posterior elevation in diagnosing forme fruste keratoconus. However, as sole parameters, both had limited sensitivity and specificity to differentiate between forme fruste keratoconus eyes and normal control eyes. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2013; -:-–- Q 2013 ASCRS and ESCRS
Keratoconus is a progressive corneal ectatic disorder that may have an extremely variable expression at earlier stages, with subtle signs and borderline abnormal features that are difficult to establish with certainity.1–3 Various terms have been proposed to describe early keratoconus. The term forme fruste keratoconus was proposed for corneas that have subtle topographic characteristics that do not reach the threshold of keratoconus suspect.1–3 Keratoconus is usually a bilateral condition but can be asymmetric.4 Previous studies5–7 report that patients with unilateral keratoconus will eventually develop keratoconus in the fellow eye with the same Q 2013 ASCRS and ESCRS Published by Elsevier Inc.
genetic makeup. Thus, the fellow eye of patients with unilateral keratoconus has the earliest and mildest form of the disease, corresponding to the proposed definition of forme fruste keratoconus.6–8 Long-term studies9,10 found laser in situ keratomileusis (LASIK) to be a safe and effective procedure to correct refractive errors. However, iatrogenic corneal ectasia remains a rare but feared complication of this procedure, and undiagnosed forme fruste keratoconus is reported to be a main reason for corneal ectasia after LASIK.4,10,11 Although corneal topography has been used to rule out the possibility of forme fruste 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2013.03.023
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keratoconus before LASIK,1,12,13 recent studies14–17 suggest that screening the posterior elevation may also be important in the diagnosis of early ectatic diseases. Recently, a new elevation-based screening software imaging system was introduced with the aim of identifying patients who may have early keratoconus that may progress to ectasia after LASIK.A The purpose of this study was to evaluate posterior elevation and back difference elevation and compare them with topographic and pachymetric findings in patients with keratoconus in 1 eye and forme fruste keratoconus in the fellow eye. PATIENTS AND METHODS This case series and study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee, Kudret Eye Hospital, Ankara, Turkey. Patients examined at the Kudret Eye Hospital were retrospectively enrolled. All patients included in the study provided informed consent. Clinical keratoconus was defined as findings characteristic of keratoconus (eg, corneal topography with asymmetric bow-tie pattern with or without skewed axes) and at least 1 keratoconus sign (eg, stromal thinning, conical protrusion of the cornea at the apex, Fleischer ring, Vogt striae, or anterior stromal scar) on slitlamp examination. Patients in whom clinical keratoconus was diagnosed in 1 eye (Group A) and whose fellow eye had no slitlamp or significant topography finding that would lead to a diagnosis of clinical keratoconus (Group B) were included in the study. The Amsler-Krumeich classification was used to grade the keratoconus. Control cases (Group C) were selected from a database of consecutive candidates for refractive surgery with normal corneas and myopia or myopic astigmatism (sphere !6.00 diopters [D]; cylinder !3.00 D). Eyes were considered normal if they had no ocular pathology, no previous ocular surgery, and no irregular corneal pattern. Of the consecutively numbered control cases, 1 eye of each patient (right eye for single numbers and left eye for even numbers) was evaluated. Exclusion criteria were a history of corneal surgery or contact lens wear, significant corneal scarring, and significant ophthalmic disease that may potentially affect the outcomes. All eyes had a comprehensive ocular examination. This included rotating Scheimpflug corneal tomography (Pentacam, software version 6.03r19, Oculus Optikger€ate GmbH).
Submitted: December 5, 2012. Final revision submitted: March 2, 2013. Accepted: March 9, 2013. From the Department of Ophthalmology (Muftuoglu), Medipol University, Istanbul, Kudret Eye Hospital (Ayar, Ozulken, Akıncı), € Ankara, and Unye Devlet Hastanesi (Ozyol), Ordu, Turkey. Corresponding author: Orkun Muftuoglu, MD, Department of Ophthalmology, Medipol University, Medipol Mega Universite Hastanesi, Goz Hastalıkları, TEM Otoyolu Number: 1, Bagcilar; 34214, Istanbul, Turkey. E-mail: [email protected].
Two patients with clinical keratoconus were using rigid gas-permeable contact lenses; all patients were asked to discontinue contact lens use at least 4 weeks before the topographic examination. During the Scheimpflug tomography examination, the patient was positioned at the instrument with proper placement on the chinrest and forehead strap. The patient was asked to blink a few times and to open both eyes and stare at the fixation target. After proper alignment was obtained, the automatic-release mode started the scan; 25 single Scheimpflug images of each eye were captured within 2 seconds. Only cases with acceptable-quality images were included in the study. Each eye was required to have a corneal map with at least 9.0 mm of corneal coverage and no extrapolated data. The sagittal curvature and tangential curvature maps were evaluated, and the map patterns were noted. The following anterior and posterior corneal surface parameters were evaluated with the Scheimpflug system: corneal dioptric power in the flattest meridian in the 3.0 mm central zone (flat keratometry [K] value), corneal dioptric power in the steepest meridian in the 3.0 mm central zone (steep K value), and mean corneal power in the 3.0 mm zone (mean K value). The inferior–superior (I–S) dioptric asymmetry value on the sagittal I–S and tangential I–S curvature maps was calculated by subtracting the superior mean value of 3 data points (slightly different than the mean reported by Rabinowitz18) 3.0 mm from the center of the cornea at 30-degree intervals (60 degrees, 90 degrees, and 120 degrees) from the mean value of the 3 corresponding data points along the inferior cornea (240 degrees, 270 degrees, and 300 degrees). The value of the steepest point (steepest K) on the sagittal steepest and tangential steepest curvature maps was determined manually by moving the cursor on the map. The central corneal thickness (CCT) at the apex (geometric center of the examination), the minimum corneal thickness at the thinnest point, the difference between the CCT and minimum corneal thickness, and the distance between the CCT and minimum corneal thickness were recorded. The average progression index is calculated as the progression value at the different rings, referenced to the mean curve. The minimum pachymetric progression index and maximum pachymetric progression index values and the axis were recorded with the pachymetric progression index average. The Ambr osio relational thickness was calculated by the following formulas: average Ambr osio relational thickness Z minimum corneal thickness/average pachymetric progression index; Ambr osio relational thickness minimum Z minimum corneal thickness/minimum pachymetric progression index; Ambr osio relational thickness maximum Z minimum corneal thickness/maximum pachymetric progression index.19 Corneal volume was also determined. The posterior elevation maps were evaluated and posterior corneal elevation values from the corneal apex analyzed. Elevation was measured in a standardized fashion relative to a reference best-fit sphere (BFS) calculated at a fixed optical zone of 9.0 mm, as previously described.20 The back difference posterior elevation values were extrapolated from the difference maps of the Belin-Ambrosi o enhanced ectasia display of Pentacam device.A Different than the standard elevation maps, the reference surface is the enhanced BFS rather than the standard BFS for the exclusion maps. In these maps, the BFS is calculated using all raw elevation data located outside a 4.0 mm circle centered on the thinnest point of the cornea. This area of excluded data is called the exclusion zone, and the map is an exclusion
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Table 1. Comparison of Scheimpflug parameters between keratoconus, forme fruste keratoconus, and control groups. P Value*
Ks (D) Mean G SD Range Kf (D) Mean G SD Range Km (D) Mean G SD Range I/S-S Mean G SD Range Ssteepest (D) Mean G SD Range I/S-T Mean G SD Range Tsteepest (D) Mean G SD Range CTmin (mm) Mean G SD Range CCT (mm) Mean G SD Range CT-diff (mm) Mean G SD Range Dist CCT-CTmin (mm) Mean G SD Range CV (mm3) Mean G SD Range PPIavg Mean G SD Range PPImin Mean G SD Range PPImax Mean G SD Range ARTavg Mean G SD Range ARTmin Mean G SD Range
KCN
FFKC (Fellow Eyes)
Controls
KC vs Control
FFKC vs Control
48.68 G 3.48 43.40, 57.10
44.39 G 1.56 40.50, 47.10
42.86 G 1.41 39.70, 45.90
!.001
!.001
45.47 G 4.06 41.00, 62.30
43.37 G 1.27 40.90, 46.10
43.87 G 1.38 41.00, 47.30
!.001
.119
47.07 G 3.57 42.20, 59.70
43.88 G 1.38 40.70, 46.60
43.37 G 1.33 40.70, 46.40
!.001
.089
0.67 G 0.91 1.40, 2.33
0.10 G 0.52 1.20, 1.20
!.001
.001
51.48 G 4.89 44.50, 67.80
45.03 G 1.47 41.30, 47.40
44.05 G 1.36 41.20, 47.60
!.001
.003
5.14 G 3.45 2.43, 10.67
0.78 G 0.81 1.00, 2.20
0.22 G 0.55 1.13, 1.27
!.001
.001
52.70 G 4.87 44.80, 63.50
45.46 G 1.7 42.00, 49.00
44.36 G 1.47 41.50, 48.00
!.001
.003
468 G 30 405, 513
494 G 35 435, 566
546 G 31 487, 611
!.001
!.001
480 G 31 421, 537
500 G 34 440, 569
549 G 31 491, 615
!.001
!.001
12.57 G 8.33 2.00, 42.00
5.86 G 4.12 1.00, 16.00
3.11 G 1.83 0.00, 9.00
!.001
.001
0.83 G 0.26 0.31, 1.33
0.80 G 0.23 0.33, 1.24
0.68 G 0.22 0.07, 1.30
!.001 !.001
.003 .003
57.79 G 3.71 48.70, 65.50
57.94 G 3.68 50.00, 64.80
60.82 G 3.32 54.20, 69.70
.882 .882
.001 .001
1.97 G 0.51 1.29, 3.19
1.16 G 0.22 0.81, 1.65
0.88 G 0.13 0.52, 1.21
!.001 !.001
!.001 !.001
1.47 G 0.54 0.67, 3.14
0.80 G 0.18 0.50, 1.30
0.57 G 0.13 0.31, 1.01
!.001
!.001
2.58 G 0.68 1.64, 4.36
1.55 G 0.28 1.03, 2.20
1.15 G 0.17 0.71, 1.60
!.001
!.001
253 G 70 151, 392
442 G 105 290, 682
633 G 108 424, 1035
!.001
!.001
361 G 137 130, 721
649 G 160 385, 1011
1003 G 248 505, 1735
!.001
!.001
4.36 G 4.87 10.60, 13.27
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Table 1. (Cont.) P Value*
ARTmax Mean G SD Range PE (mm) Mean G SD Range BDE (mm) Mean G SD Range
KCN
FFKC (Fellow Eyes)
Controls
KC vs Control
FFKC vs Control
192 G 49 111, 313
334 G 77 230, 523
488 G 91 321, 818
!.001
!.001
45.79 G 21.10 12.00, 95.00
10.32 G 7.02 2.00, 28.00
6.87 G 2.14 3.00, 15.00
!.001
.033
42.50 G 20.51 8.00, 105.00
16.43 G 5.96 8.00, 32.00
10.15 G 4.76 0.00, 23.00
!.001
!.001
ART Z Ambrosi o relational thickness; avg Z average; BDE Z back difference elevation on Belin-Ambrosi o display of Scheimpflug device; CCT Z central corneal thickness; CT-diff Z difference between central corneal thickness and minimum corneal thickness; Ctmin Z minimum corneal thickness; CV Z corneal volume; Dist CCT-Ctmin Z distance between central corneal thickness and minimum corneal thickness; FFKC Z forme fruste keratoconus; I/S-S Z inferior/ superior sagittal; I/S-T Z inferior/superior tangential; KCN Z keratoconus; Kf Z flat keratometry; Km Z mean keratometry; Ks Z steep keratometry; max Z maximum; min Z minimum; PE Z posterior corneal elevation; PPI Z pachymetric progression index; Ssteepest Z steepest keratometry on sagittal curvature map; Tsteepest Z steepest keratometry on tangential curvature map *Mann-Whitney U test
map. The location of the exclusion zone is indicated by a 4.0 mm red circle. The difference maps (posterior and back) show the relative change in elevation from the baseline elevation map to the exclusion map, in which each point corresponds to the amount of elevation change that occurs between the baseline elevation map and the exclusion map.A Statistical analysis was performed using SPSS software (version 11.0, SPSS, Inc.). The data were not normally distributed; therefore, the nonparametric Mann-Whitney U test (Wilcoxon rank-sum test) was used to compare each parameter between 2 groups. Receiver operating characteristic (ROC) curves were used to determine the overall predictive accuracy of the test parameters as described by the area under the curve (AUC) and to calculate the sensitivity and specificity of the parameters. A P value less than 0.05 was considered statistically significant.
RESULTS Group A (clinical keratoconus) and Group B (forme fruste keratoconus, fellow eye) comprised 28 patients each. Group C (control cases) comprised 82 eyes of 82 subjects. The mean age was 26.7 years G 7.8 (SD) (range 13.0 to 51.0 years) in keratoconus patients and 29.8 G 7.2 years (range 19.0 to 53.0 years) in controls. There was no significant difference in age between the 2 groups (PZ.066). According to the KrumeichAmsler classification of the severity of keratoconus in Group A, 1 eye (3.6%) was classified as grade IV, 6 eyes (21.4%) were classified as grade II, and 21 eyes (75.0%) were classified as grade I. Topography In Group B, on the sagittal curvature map, 16 eyes (57.1%) had inferior or inferotemporal steepening (12 eyes with significant inferior steepening; 4 eyes with
mild inferior steepening), 6 eyes (21.4%) had skewed axes (2 also had inferior steepening), 4 eyes (14.3%) had bow-tie pattern (1 steep, 1 normal), and 2 eyes (7.1%) were normal. On the tangential curvature map, 18 eyes (64.3%) had the oil-droplet sign (12 eyes inferior, 2 eyes central, and 4 eyes mild), 1 eye (3.6%) had central steepening, 2 eyes (7.1%) had inferior steepening, 1 eye (3.6%) had superior steepening, and 6 eyes (21.4%) had bow-tie pattern (2 eyes with inferior asymmetric steepening, 2 eyes with superior asymmetric steepening). Rotating Scheimpflug Imaging Table 1 shows the mean keratometric, pachymetric, and posterior elevation parameters in all groups. All parameters were significantly different between Group B and Group C (P!.05). Also, all parameters except the flat K value and mean K value were significantly different between Group B and Group C (P!.05). The corneal power (steep K value, flat K value, mean K value), keratometric parameters (I–S sagittal, sagittal steepest, I–S tangential, tangential steepest), pachymetric progression index (mean, minimum, maximum), and posterior corneal elevation and back distance elevation measurements were statistically significantly higher, whereas the corneal thickness (minimum corneal thickness, CCT, difference between CCT and minimum corneal thickness, and distance between CCT and minimum corneal thickness) and Ambr osio relational thickness (mean, minimum, maximum) measurements were significantly lower in Group A and Group B than in Group C (P!.05).
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Posterior Elevation Findings Figure 1 shows a scatterplot of the distribution of the mean K value versus posterior elevation and the mean K value versus back difference elevation in all 3 groups. Figure 2 shows samples from Group A and fellow eyes in Group B. Receiver Operating Characteristic Curve Analysis Table 2 shows the results of the ROC curve analysis AUC, standard error, 95% confidence intervals, significance level, best cutoff point, and sensitivity and specificity of best cutoff points for each parameter tested in Group A versus Group C. Table 3 shows these results in Group B versus Group C. In discriminating keratoconus from control eyes, almost all parameters had
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a high AUC; however, pachymetric parameters (Ambr osio relational thickness and pachymetric progression index) had the highest AUC. In discriminating Group B from Group C, the topographic parameters (tangential steepest, I–S tangential, sagittal steepest, I–S sagittal) and pachymetric progression index (mean, maximum, and minimum) levels had the highest AUC. DISCUSSION There is still a discussion in the literature that posterior elevation is one of the earliest signs of an ectatic disease.14–16,20 Using the Pentacam system, de Sanctis et al.14 found high AUC levels of posterior elevation to diagnose keratoconus and subclinical keratoconus (0.99 and 0.93, respectively). Similarly, Uc¸akhan
Figure 1. Distribution of mean K value versus posterior corneal elevation in eyes with forme fruste keratoconus (fellow eyes), eyes with keratoconus, and control eyes (A) and forme fruste keratoconus eyes and controls eyes (B). Distribution of mean K value versus back difference posterior elevation in eyes with forme fruste keratoconus, eyes with keratoconus, and control eyes (C) and in eyes with forme fruste keratoconus and control eye (D) (FFKCN Z forme fruste keratoconus; KCN Z keratoconus). J CATARACT REFRACT SURG - VOL -, - 2013
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CORNEAL BACK DIFFERENCE ELEVATION IN FORME FRUSTE KERATOCONUS
Figure 2. Samples of rotating Scheimpflug imaging and Belin-Ambrosi o display scans of patients with keratoconus and the fellow eye with forme fruste keratoconus. For each scan, sagittal curve map (upper left), tangential curve map (upper right), corneal thickness map (middle left), posterior corneal elevation map (middle right), front difference map (bottom left), and back difference map (bottom right) are given. Note that there is inferior steepening on sagittal curve maps, particularly on tangential maps; however, there is no significant posterior corneal elevation or back difference corneal elevation in forme fruste keratoconus (fellow) eyes in Cases 1 and 2. There is slight or no change on sagittal or tangential curve maps and no significant posterior corneal elevation; however, there is significant elevation on the back difference map, suggesting early ectatic disease in the fellow (forme fruste keratoconus) eye in Case 3. There is inferior steepening on sagittal curve maps and tangential maps and significant elevation on posterior corneal and back difference maps, indicating ectatic disease in the fellow eye in Case 4 (FFKCN Z forme fruste keratoconus).
et al.15 found a good AUC (0.94) of posterior elevation to discriminate keratoconus eyes from normal eyes; however, they found a relatively lower AUC value (0.78) to distinguish between subclinical keratoconus eyes and normal eyes. In accordance with previous reports, the ROC analysis in our study showed a good AUC level of posterior elevation (0.97) to discriminate keratoconus eyes from normal eyes. However, the AUC level of posterior elevation to distinguish between forme fruste keratoconus eyes and normal eyes in our study was lower (0.68) than in previous reports. Previous studies14–16,21 found a best cutoff level between 20.0 mm and 26.5 mm of posterior elevation to differentiate keratoconus eyes from normal eyes and between 15.5 mm and 29.0 mm to differentiate forme fruste keratoconus eyes from normal eyes. We found a best cutoff level of 19.2 mm for posterior elevation
to discriminate keratoconus eyes from normal eyes and 14.7 mm to discriminate forme fruste keratoconus eyes from normal eyes. The best cutoff levels in our study were also lower than in previous reports, which may be explained by the different study designs and populations. Our group of forme fruste keratoconus eyes comprised fellow eyes of unilateral keratoconus patients regardless of topography, whereas other studies14–16,20 included only Placido topography–positive subclinical keratoconus patients. Therefore, our group may represent an earlier stage of keratoconus then those reported in other studies and may explain the lower levels of AUC and best cutoff value in forme fruste keratoconus eyes. In a recent multinational study of 555 normal control eyes, Feng et al.22 reported a median posterior elevation value measured on the thinnest points of
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Table 2. Receiver operating characteristic curve analysis for the keratoconus eyes versus normal eyes. Parameter
AUC
SE
95% CI
P Value
Cutoff
Sensitivity
Specificity
Ks Kf Km I/S-S Ssteepest I/S-T Tsteepest CTmin CCT CT-diff CV Dist CCT-CTmin PPIavg PPImin PPImax ARTavg ARTmin ARTmax PE BDE
0.912 0.721 0.894 0.921 0.963 0.953 0.969 0.897 0.811 0.885 0.376 0.760 0.976 0.957 0.980 0.989 0.968 0.991 0.949 0.938
0.021 0.070 0.041 0.072 0.020 0.058 0.018 0.019 0.035 0.038 0.056 0.062 0.010 0.010 0.009 0.002 0.004 0.003 0.004 0.009
0.745, 0.938 0.593, 0.819 0.833, 0.925 0.799, 0.993 0.933, 0.986 0.897, 0.987 0.944, 0.994 0.872, 0.924 0.779, 0.843 0.840, 0.921 0.306, 0.427 0.688, 0.832 0.963, 0.988 0.942, 0.968 0.970, 0.991 0.986, 0.995 0.971, 0.982 0.976, 0.998 0.924, 0.966 0.910, 0.952
!.001 .048 !.001 !.001 !.001 !.001 !.001 !.001 !.001 !.001 .124 .008 !.001 !.001 !.001 !.001 !.001 !.001 !.001 !.001
45.95 44.45 45.2 1.25 46.45 1.31 47.85 489 494 5.87 NA 0.74 1.29 0.93 1.69 407 607 301 12.11 17.95
0.91 0.71 0.87 0.92 0.93 0.94 0.95 0.90 0.82 0.87 NA 0.75 0.95 0.92 0.95 0.98 0.95 0.99 0.94 0.93
0.79 0.65 0.71 0.92 0.86 0.90 0.92 0.79 0.71 0.78 NA 0.71 0.91 0.90 0.92 0.94 0.92 0.95 0.93 0.91
ART Z Ambrosi o relational thickness; AUC Z area under curve; avg Z average; BDEZ back difference elevation; CCT Z central corneal thickness; CI Z confidence interval; CT-diff Z difference between central corneal thickness and minimum corneal thickness; CTmin Z minimum corneal thickness; CV Z corneal volume; Dist CCT-Ctmin Z distance between central corneal thickness and minimum corneal thickness; I/S-S Z inferior/superior (sagittal); I/S-T Z inferior/ superior (tangential); Kf Z flat keratometry; Km Z mean keratometry; Ks Z steep keratometry; max Z maximum; min Z minimum; NA Z not analyzed because there was no significant difference; PE Z posterior corneal elevation; PPI Z pachymetric progression index; SE Z standard error; Ssteepest Z steepest keratometry on sagittal curvature map; Tsteepest Z steepest keratometry on tangential curvature map
3.0 mm (interquartile range, 3.0), which was lower than the mean posterior elevation value in normal eyes reported in previous studies comparing forme fruste keratoconus eyes and normal eyes.14–16,20 The mean posterior elevation of normal controls in our study (6.87 mm) was much closer but still slightly higher than that reported by Feng et al.22 Khachikian and Belin23 suggest that the posterior elevation measurements taken as the maximum value above the BFS within the central 5.0 mm may incorporate astigmatic elevation into the calculation of the average normal elevation, which may artificially inflate normal elevation measurements. More studies are needed to assess the reliability and repeatability of elevation measurements. The rotating Scheimpflug device we used measures posterior elevation by fitting the best-possible sphere to the posterior cornea, which could miss small protrusions on the posterior cornea, such as the ones that can be seen with early keratoconus. To overcome this problem, a new screening tool of the rotating Scheimpflug devicedthe back difference elevationdwas introduced. This software creates a difference map that shows the relative change in elevation from the baseline elevation map to the exclusion map (formed by an exclusion zone of
4.0 mm centered on the thinnest point of the cornea) to identify the posterior elevation. The manufacturer claims that a back difference elevation greater than 20 mm is suggestive of ectatic disease and a change between 10 mm and 20 mm is in the suspect zone.A In our study, we found a best cutoff level of 17.2 mm for the back difference elevation to discriminate between keratoconus eyes and normal eyes and 13.2 mm to discriminate between forme fruste keratoconus eyes and normal eyes. In our study, we found that back difference elevation (0.75 mm) was better than posterior elevation (0.68 mm) in discriminating forme fruste keratoconus eyes from normal control eyes. This may imply that back difference elevation can be a better screening parameter than posterior elevation for early detection of ectatic diseases. However, significant overlaps in posterior elevation and back difference elevation levels between forme fruste keratoconus eyes and control eyes were noted (Figure 1). Clinically, the best cutoff levels found by previous reports or in our study would miss many cases of forme fruste keratoconus. This suggests that as sole parameters, back difference elevation and posterior elevation have limited sensitivity and specificity to diagnose very early keratoconus. To our knowledge, we are unaware of
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Table 3. Receiver operating characteristic curve analysis for the forme fruste keratoconus eyes versus normal eyes. Parameter
AUC
SE
95% CI
P Value
Cut-off
Sensitivity
Specificity
Ks Kf Km I/S-S Ssteepest I/S-T Tsteepest CTmin CCT CT-diff CV Dist CCT-CTmin PPIavg PPImin PPImax ARTavg ARTmin ARTmax PE BDE
0.709 0.401 0.508 0.794 0.811 0.821 0.855 0.652 0.601 0.703 0.195 0.688 0.806 0.795 0.813 0.722 0.714 0.739 0.683 0.755
0.053 0.062 0.062 0.048 0.058 0.064 0.060 0.041 0.042 0.064 0.072 0.060 0.042 0.042 0.039 0.040 0.035 0.036 0.071 0.043
0.634, 0.773 0.310, 0.482 0.387, 0.629 0.721, 0.857 0.738, 0.884 0.756, 0.906 0.781, 0.915 0.612, 0.701 0.553, 0.667 0.631, 0.773 0.103, 0.287 0.600, 0.776 0.734, 0.863 0.703, 0.857 0.761, 0.873 0.660, 0.786 0.675, 0.763 0.694, 0.799 0.543, 0.792 0.692, 0.860
!.001 .119 .089 !.001 !.001 !.001 !.001 .034 .053 .001 .582 .030 !.001 !.001 !.001 !.001 !.001 !.001 .021 !.001
44.45 NA NA 0.57 44.85 0.62 45.14 512 519 5.1 NA 0.72 0.98 0.62 1.32 487 691 372 9.17 14.41
0.70 NA NA 0.77 0.79 0.80 0.84 0.64 0.58 0.69 NA 0.64 0.77 0.76 0.78 0.72 0.70 0.73 0.67 0.74
0.61 NA NA 0.69 0.67 0.69 0.70 0.58 0.54 0.60 NA 0.59 0.65 0.64 0.65 0.60 0.61 0.63 0.59 0.65
ART Z Ambrosi o relational thickness; AUC Z area under curve; avg Z average; BDE Z back difference elevation on Belin-Ambrosi o display of Scheimpflug device; CI Z confidence intervals; CT-diff Z difference between central corneal thickness and minimum corneal thickness; CTmin Z minimum corneal thickness; CTT Z central corneal thickness; CV Z corneal volume; Dist CCT-Ctmin Z distance between CCT and Ctmin; I/S-S Z inferior/superior (sagittal); I/S-T Z inferior/superior (tangential); Kf Z flat keratometry; Km Z mean keratometry; Ks Z steep keratometry; max Z maximum; min Z minimum; NA Z not analyzed because there was no significant difference; PE Z posterior corneal elevation; PPI Z pachymetric progression index; SE Z standard error; Ssteepest Z steepest keratometry on sagittal curvature map; Tsteepest Z steepest keratometry on tangential curvature map
a published study of using back difference elevation to screen for keratoconus or forme fruste keratoconus. Thus, we cannot compare our results with those in other studies. Corneal topography remains the gold standard to evaluate ectatic diseases.5,12 Our study confirms the importance of manual evaluation of the topographic patterns. However, this analysis is subjective, requires experience and training, and has inherent limitations in using axial curvature to imply the shape of an abnormal cornea.24 Although we were not able to evaluate all topographic indices reported, our results suggest that topographic indices are useful but that they still may not have enough sensitivity and specificity to detect early ectatic diseases as sole parameters. In this study, we found that the minimum corneal thickness and the difference between CCT and the minimum corneal thickness had higher AUC levels than the CCT and may be clinically more meaningful. Similar to previous studies,15,18,25,26 we found that the corneal progression indices also had high predictive accuracies in discriminating keratoconic or forme fruste keratoconus eyes from normal eyes. Total or corneal wavefront aberrations27 and corneal biomechanical response28 were reported to be useful in the diagnosis of forme fruste keratoconus; however,
comparative studies would be needed to fully evaluate the efficacy of these parameters. To ideally evaluate the specificity and cutoff point of any parameter in discriminating keratoconus and forme fruste keratoconus using ROC analysis, the control group should consist of a relevant clinical population rather than of normal patients. Therefore, performance of any parameter might be overestimated in this study and also in any study with a limited number of control eyes.29,30 Further studies with a larger number of patients and greater number of controls are needed, in particular for the detection of a better cutoff level. Also, although keratoconus is an asymmetric progressive disorder that ultimately affects both eyes and has a strong genetic component,31,32 true unilateral keratoconus is possible, and the disease may not develop in the fellow eyes. Therefore, genetic and follow-up studies are needed to elucidate the risk for developing keratoconus in fellow eyes of unilateral keratoconus patients. In conclusion, the results in our study indicate that back difference elevation seems to be a better parameter than posterior elevation to diagnose early ectatic conditions. However, as sole parameters, posterior elevation and back difference elevation have limited sensitivity and specificity to diagnose very early
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keratoconus because of significant overlaps in posterior elevation and back difference elevation levels between forme fruste keratoconus eyes and control eyes. Our study also confirmed that evaluation of topography pattern, topographic indices, and pachymetric indices are useful in the diagnosis of forme fruste keratoconus. These results may suggest that rather than relying on a single parameter, comprehensive analysis of topography, pachymetric data, and posterior elevation seems to be important in diagnosing forme fruste keratoconus. Further studies with more patients are needed to fully validate the efficacy of our tools to diagnose early keratoconus. WHAT WAS KNOWN Posterior elevation can be used to diagnose keratoconus and forme fruste keratoconus.
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WHAT THIS PAPER ADDS Back difference elevation was better than posterior elevation in distinguishing between forme fruste keratoconus eyes and normal eyes. There may be overlaps in posterior elevation and back difference elevation levels between forme fruste keratoconus eyes and control eyes. It may not always be possible to diagnose forme fruste keratoconus using only posterior elevation or back difference elevation.
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First author: Orkun Muftuoglu, MD Department of Ophthalmology, Medipol University, Istanbul, Turkey