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Corneal Topographic and Tomographic Analysis of Fellow Eyes in Unilateral Keratoconus Patients Using Pentacam
Corneal Topographic and Tomographic Analysis of Fellow Eyes in Unilateral Keratoconus Patients Using Pentacam GI HYUN BAE, JAE RYUNG KIM, CHI HOON KIM, DONG HUI LIM, EUI SANG CHUNG, AND TAE-YOUNG CHUNG PURPOSE:
To evaluate topographic and tomographic changes in fellow eyes in unilateral keratoconus (KCN) patients by comparing them with normal eyes. DESIGN: Retrospective comparative case series. METHODS: Fourteen eyes of 14 patients with unilateral KCN and 34 eyes of 34 refractive surgery candidates were divided into 3 diagnostic groups using a Pentacam rotating Scheimpflug camera: advanced KCN eyes of unilateral KCN (KCN group, 14 eyes), normal fellow eyes of unilateral KCN (fellow eye group, 14 eyes), and refractive surgery candidates (normal group, 34 eyes). Topographic and tomographic parameters, which were obtained from Pentacam using sagittal curvature, elevation, and corneal thickness maps, were compared among the 3 groups. Receiver operating characteristic (ROC) curves were used to identify cutoff points in discriminating between fellow and normal eyes. RESULTS: Keratometric asymmetry, topometric indices, and elevation differences (maximum L minimum) on both the anterior and posterior surfaces were statistically different (P < .05). On ROC curve analysis, keratometric asymmetry and topometric index were best at discriminating fellow eyes from normal, followed by elevation differences (maximum L minimum) on the posterior and anterior cornea surface. CONCLUSIONS: Fellow eyes in unilateral KCN showed differences in several parameters that were not detectable with the Pentacam detection program, when compared with normal. However, each single parameter alone is not sufficient to detect early changes; thus, elevation indices as well as indices of anterior curvature should be considered together. (Am J Ophthalmol 2014;157: 103–109. Ó 2014 by Elsevier Inc. All rights reserved.)
Accepted for publication Aug 13, 2013. From the Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (G.H.B., J.R.K., C.H.K., D.H.L., E.S.C., T.Y.C.); Department of Ophthalmology, Sahmyook Medical Center, Seoul, South Korea (G.H.B.); and Chungju St. Mary’s Eye Clinic, Chungju, South Korea (C.H.K.). Inquiries to Tae-Young Chung, Associate Professor, Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Irwon-Dong, Kangnam-Ku, Seoul 135-710, South Korea; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.08.014
Ó
2014 BY
C
ORNEAL ECTASIA IS ONE OF THE MOST SERIOUS
complications of refractive surgery. Risk factors identified for post–laser in situ keratomileusis (LASIK) ectasia include high myopia, low residual stromal bed thickness, and defined topographic abnormalities such as keratoconus (KCN) and pellucid marginal corneal degeneration.1–5 Although the majority of these risk factors are identifiable preoperatively, missed preoperative topographic abnormalities are a major independent risk factor.6 As a result, detection of early KCN in the preclinical stage is very important for preventing post-LASIK ectasia. Advanced KCN can be diagnosed with typical biomicroscopic, retinoscopic, and topographic findings. However, detection of the disease in the preclinical stage is difficult. Several terms have been employed to describe the preclinical stages of the KCN condition, including subclinical keratoconus, keratoconus suspect (KCS), and forme fruste keratoconus (FFKC).7–10 The term KCS was reserved for the cornea with some anterior topographic changes of KCN but without evidence of clinical KCN in either eye. The term FFKC was first described by Amsler8 as an incomplete, abortive, or unusual form of a syndrome of disease, meaning corneas that have subtle topographic characteristics that do not reach the threshold of keratoconus suspect. However, because of the ambiguity of definition and significant overlap between these designations, there are no definitive criteria to help discriminate subclinical KCN from normal. Placido disk–based topography had been the most sensitive method to detect KCN, and several indices and artificial intelligence methods have been developed to help diagnose subclinical KCN.11–15 With recent advances in Orbscan slit-scanning topography (Bausch & Lomb, Rochester, New York, USA) and the Pentacam rotating Scheimpflug camera (Oculus, Wetzlar, Germany), anterior and posterior corneal elevation and pachymetric maps provide useful data to discriminate subclinical KCN from normal.6,10,16–24 Recent studies have found that pachymetric progression and elevation data can help to identify subclinical KCN not detected by Placido disk–based topography.25,26 Ambrosio and associates26 proposed new tomographicderived pachymetric parameters, such as relation thickness, which were better able to differentiate normal and keratoconic corneas. This suggests that several tomographic data from elevation and pachymetric values could be more sensitive to detect subclinical KCN before changes of anterior curvature in Placido disk–based topography. Several studies
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described topographic and tomographic differences between subclinical KCN and normal controls, which were not detectable using Placido disk–based topography.10,22,23 But there has not been any report about the subclinical KCN with normal elevation and pachymetric-derived parameters. The purpose of this study was to investigate the characteristics of the subtle changes in subclinical KCN and compare it with normal. Previous research indicates that true unilateral KCN is very rare, and that the normal fellow eye is also thought to have subclinical KCN.27 Thus, the normal fellow eye in unilateral KCN may be the ideal model for the mildest form of subclinical KCN. In the present study, normal fellow eyes in unilateral KCN patients were considered as the mildest form of subclinical KCN and topographic and tomographic parameters were analyzed using Pentacam.
SUBJECTS AND METHODS SUBJECTS:
This study included patients with unilateral KCN diagnosed by Pentacam and candidates for refractive surgery with normal corneas. Clinical records of 48 patients (62 eyes) seen at the Samsung Medical Center between January 2009 and March 2011 were retrospectively analyzed. The study protocol was reviewed and approved by the Sungkyunkwan University Institutional Review Board, and a waiver of informed consent was granted because of the low risk of this research. The tenets of the Declaration of Helsinki were followed for all study procedures. The study subjects were divided into 3 groups: advanced KCN eyes of unilateral KCN patients (KCN group, 14 eyes), normal fellow eyes of unilateral KCN patients (fellow eye group, 14 eyes), and refractive surgery candidates (normal group, 34 eyes). Eyes were diagnosed as KCN on the basis of Pentacam rotating Scheimpflug camera–derived topographic/tomographic parameters and criteria used in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study.28 Patients who had advanced KCN in 1 eye and a normal fellow eye were considered unilateral KCN. In this study, fellow eyes in unilateral KCN should not only be clinically normal but also satisfy all of the following criteria determined by the Pentacam: normal index of topographic keratoconus classification (use of keratometric values on the anterior corneal surface to detect ectatic changes) and final D value <1.6 SD from the Belin/Ambro´sio Enhanced Ectasia Display II. Normal control patients were candidates for refractive surgery with clinically normal corneas and topographic/tomographic values that were within normal limits determined by the Pentacam. All normal control patients underwent uncomplicated refractive surgery (femto-LASIK or laser-assisted subepithelial keratectomy) and had a 2-year follow-up without any evidence of ectatic corneal changes. In the normal group, only left eyes were used in the study analysis. 104
None of the patients had a history of previous ocular surgery or trauma, and they were asked to stop wearing contact lenses for at least 3 weeks for rigid contact lenses and 1 week for soft contact lenses prior to examination. KCN subjects with corneal scarring significant enough to disturb Pentacam evaluation were excluded from this study. PROCEDURE:
All subjects underwent a clinical, topographic, and tomographic evaluation. Clinical examinations included slit-lamp biomicroscopy, retinoscopy, and fundus examination. Topographic and tomographic examinations were performed using the Pentacam rotating Scheimpflug camera (Oculus, Wetzlar, Germany). The sagittal curvature, anterior elevation, posterior elevation, corneal thickness, and Belin/Ambro´sio Enhanced Ectasia Display II were evaluated. Elevation data were taken from a fixed 8.0-mm zone (best fit sphere [BFS] set to Manual, Float, Sphere, Diameter ¼ 8.0 mm) centered on the corneal apex. The following data were analyzed in Pentacam: (1) keratometric values: flat keratometry (K1), steep keratometry (K2), and mean keratometry (Km) for the central 3.0 mm of the cornea; (2) keratometric asymmetry: inferior-superior asymmetry at 4 and 6 mm (4 mm I-S and 6 mm I-S), superotemporal-inferonasal asymmetry at 4 and 6 mm (4 mm ST-IN and 6 mm ST-IN), and superonasal-inferotemporal asymmetry at 4 and 6 mm (4 mm SN-IT and 6 mm SN-IT) radius ring of the cornea (Figure); (3) topometric indices in an 8-mm zone, which were derived via Placido disk–based data: index of surface variance, index of vertical asymmetry, keratoconus-index, center keratoconus-index, index of height asymmetry, index of height decentration, and radii minimum; (4) elevation values: diameter of BFS, elevations (maximum and minimum), elevation differences (maximum minimum) on anterior and posterior cornea in the central 2.0-mm zone; (5) corneal thickness: corneal thickness at the apex and at the thinnest point; (6) Belin/Ambro´sio Enhanced Ectasia Display II: D values representing the front surface (Df), back surface (Db), pachymetric progression (Dp), thinnest point (Dt), thinnest point displacement (Dy), and final (D), pachymetric progression indices: pachymetric progression indices (maximum, minimum, and average); (7) Ambro´sio’s relational thickness values calculated by the following formula:26 Ambro´sio’s relational thickness maximum ¼ thinnest pachymetry/pachymetric progression index maximum and Ambro´sio’s relational thickness average ¼ thinnest pachymetry/pachymetric progression index average. STATISTICAL ANALYSIS:
The normality of all data samples was first checked using the Shapiro-Wilk test. When parametric analysis was possible, paired t tests for paired data or Student t tests for unpaired data with Bonferroni correction were used to compare groups (KCN, fellow eye, and normal). When parametric analysis was not
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the unilateral KCN group and 13:21 in the normal group, respectively. There were significantly more men in the unilateral KCN than in the normal (P < .001). The mean age was 25.08 6 6.39 (range: 18–43) years in the unilateral KCN and 28.00 6 5.93 (range: 19–41) years in the normal, which was not statistically different. KCN VS FELLOW EYE:
There were significant differences between the KCN and fellow eye in all measured parameters (Table 1).
KCN VS NORMAL:
There were significant differences between the KCN and normal group in almost all measured parameters except for BFS in anterior/posterior cornea and Dy value in Belin/Ambro´sio Enhanced Ectasia Display (Table 1).
NORMAL VS FELLOW EYE:
FIGURE. Anterior axial topographic map of a fellow eye in unilateral keratoconus. Asymmetry in inferior-superior, superotemporal-inferonasal regions, and superonasalinferotemporal regions were calculated by subtraction of the dioptric power in each direction.
possible, Wilcoxon signed rank tests for paired data and Mann-Whitney U tests for unpaired data were used. Null hypotheses of no difference were rejected if P values were less than .05, and statistical calculations used PASW (PASW, version 17.0 for Windows; SPSS, Chicago, Illinois, USA). The receiver operating characteristic (ROC) curve was analyzed for parameters that were different between cases of fellow eye and normal groups. Cutoff values were determined as the maximized sum of sensitivity and specificity. Internal validation was evaluated by the bootstrap method. A single dataset with the same sample size as the original dataset was generated with replacement by using the Proc Survey select procedure from SAS software, version 9.1.3 (SAS Institute Inc, Cary, North Carolina, USA), and the cutoff values of the corneal parameters were determined given the results from this dataset. This procedure was repeated 1000 times, and 95% confidence intervals were developed from these cutoff values using the 2.5th and the 97.5th percentiles. Statistical analyses were performed using SAS software, version 9.1.3 (SAS Institute Inc).
RESULTS
Table 1 shows the difference between the fellow eye and normal group. There were no significant differences between the fellow eye and normal group for K1, K2, or Km. However, 4 mm I-S and 4 mm ST-IN differed significantly between the fellow eye and normal group (P ¼ .002 and P ¼ .002). And index of vertical asymmetry and index of height decentration were statistically significantly different (P ¼ .023 and P ¼ .007). In the elevation map, there were no differences in BFS or elevation Max and Min, but the elevation differences (Max Min) from the anterior and posterior cornea in the central 2.0-mm zone showed significant differences between the 2 groups (P ¼ .031 and P ¼ .033). In terms of corneal thickness and Belin/Ambro´sio Enhanced Ectasia Display, there were no significant differences between the 2 groups, including corneal thickness both at apex and at thinnest point, D values, pachymetric progression indices, and Ambro´sio’s relational thickness. Table 2 reports the results of the ROC curve analysis for the fellow eye vs the normal group. In discriminating the fellow eye from the normal group, 4 mm ST-IN (area under curve [AUC] ¼ 0.809) and 4 mm I-S (AUC ¼ 0.799) showed the highest AUCs, followed by index of height decentration, posterior elevation difference, anterior elevation difference, and index of vertical asymmetry. The cutoff points derived from the ROC curve analysis were 0.8 diopters for 4 mm ST-IN, 1.2 diopters for 4 mm I-S, 0.008 for index of height decentration, 11.1 mm for posterior elevation, 5.5 mm for anterior elevation difference, and 0.16 for index of vertical asymmetry.
DISCUSSION THE AIM OF THE PRESENT STUDY WAS TO CHARACTERIZE
FOURTEEN EYES OF 14 UNILATERAL KCN PATIENTS AND 34
eyes of 34 normal refractive surgery candidates were analyzed. The ratio of male to female patients was 13:1 in VOL. 157, NO. 1
subtle morphologic changes of the fellow eye that are missed using the currently available Pentacam detection program. Compared with Placido disk–based topography,
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TABLE 1. Comparison of Keratometric, Pachymetric, and Elevation Parameters, as Well as Topometric Indices in Keratoconus, Fellow Eye, and Normal Groups KCN (14 Eyes)
Fellow Eye (14 Eyes)
Normal (34 Eyes)
KCN vs Fellow Eye KCN vs Normal Normal vs Fellow Eye
Mean 6 SD
P Value
Keratometry of anterior surface K1 (D) K2 (D)
45.26 6 4.22 50.47 6 8.45
42.20 6 1.08 43.40 6 1.36
42.57 6 1.65 43.90 6 1.49
.020a .001c
.036b <.001d
.365b .268b
Km (D) 4 mm I-S (D)
47.53 6 5.01 12.05 6 5.28
42.79 6 1.20 1.68 6 1.20
43.21 6 1.52 0.65 6 0.55
.003a <.001a
.007b <.001d
.318b .002d
4 mm ST-IN(D) 4 mm SN-IT(D)
6.41 6 4.53 11.08 6 4.91
1.09 6 0.64 0.86 6 0.61
0.50 6 0.41 0.58 6 0.53
.002c <.001a
<.001d <.001d
.002d .182d
6 mm I-S(D) 6 mm ST-IN(D)
8.93 6 4.26 4.55 6 4.35
1.42 6 1.20 0.79 6 0.72
0.78 6 0.59 0.55 6 0.36
.002c .009c
<.001d <.001d
.908d 1.0d
6 mm SN-IT(D) Topometric index
8.30 6 3.34
0.92 6 0.67
0.74 6 0.45
<.001a
<.001b
1.0b
103.29 6 44.85 1.12 6 0.42
20.07 6 7.11 0.18 6 0.08
17.88 6 4.48 0.12 6 0.04
<.001a <.001c
<.001d <.001d
.539d .023b
1.23 6 0.13 1.11 6 0.18
1.03 6 0.03 1.00 6 0.01
1.02 6 0.02 1.01 6 0.01
<.001a .005c
<.001b .003d
.092d .251d
37.47 6 24.84 0.09 6 0.04
5.72 6 4.27 0.01 6 0.00
3.48 6 3.39 0.01 6 0.00
<.001a <.001a
<.001d <.001d
.066d .007d
5.95 6 1.02
7.56 6 0.33
7.59 6 0.28
<.001a
<.001b
.807b
Index of surface variance Index of vertical asymmetry Keratoconus index Central keratoconus index Index of height asymmetry Index of height decentration Radii minimum Anterior elevation
7.91 6 0.41
7.90 6 0.28
.013c
.067b
.468d
Elevation Max (mm) Elevation Min (mm)
32.86 6 14.69 8.21 6 10.57
5.07 6 2.95 1.36 6 2.17
3.32 6 1.15 0.56 6 1.28
<.001a .035c
<.001d <.001d
.195d .156d
Elevation difference (Max L Min) (mm)
41.07 6 16.85
6.43 6 3.84
3.88 6 1.55
<.001a
<.001b
.031d
BFS (mm)
Posterior elevation BFS (mm)
7.69 6 0.37
6.51 6 0.25
6.40 6 0.26
.003a
.198b
.185b
56.14 6 28.70 13.71 6 17.40
8.71 6 4.76 -2.93 6 3.63
5.77 6 2.49 1.21 6 2.38
<.001a .039c
<.001d .010d
.161d .357b
69.86 6 37.18
11.64 6 5.89
6.97 6 3.35
<.001c
<.001b
.033d
511.14 6 50.15 478.93 6 58.37
535.29 6 26.37 533.07 6 25.58
549.06 6 30.24 546.35 6 30.06
.017c .001c
.017b .001b
.127b .132b
2.99 6 1.57
1.21 6 0.16
1.23 6 0.17
.005c
<.001d
1.0b
Min Ave
1.66 6 0.89 2.10 6 0.95
0.74 6 0.09 1.00 6 0.12
0.76 6 0.12 1.02 6 0.12
c
.007 .005c
<.001 <.001d
1.0d 1.0d
D value Df
12.30 6 6.87
0.54 6 0.64
0.19 6 0.88
.001a
<.001b
Db Dp
9.54 6 7.56 8.07 6 6.37
0.03 6 0.80 0.65 6 0.83
0.15 6 0.87 0.76 6 0.70
.004a .001c
.004b <.001d
Dt Dy
1.60 6 1.47 1.39 6 1.00
0.15 6 0.71 0.37 6 0.82
0.19 6 0.81 0.74 6 0.85
.002a .010a
.005b .322b
9.65 6 5.74
1.03 6 0.57
1.04 6 0.54
.001a
<.001d
1.0d
204.15 6 90.82 281.13 6 121.30
450.46 6 76.57 540.87 6 75.12
452.97 6 69.49 541.98 6 67.67
<.001a <.001a
<.001b <.001b
1.0d 1.0b
Elevation Max (mm) Elevation Min (mm) Elevation difference (Max L Min) (mm) Corneal thickness Apex (mm) Thinnest (mm) Pachymetric progression index Max
Final D Ambro´sio’s relational thickness Max Ave
6.29 6 0.29
d
.787b 1.0b 1.0b .950b 1.0b
Ave ¼ average; BFS ¼ diameter of best fit sphere in 8.0-mm area; I-S ¼ inferior-superior asymmetry; K1 ¼ corneal dioptric power in the flattest meridian for the 3-mm central zone; K2 ¼ corneal dioptric power in the steepest meridian for the 3-mm central zone; KCN ¼ keratoconus; Km ¼ mean corneal power in the 3-mm zone; Max ¼ maximum; Min ¼ minimum; SN-IT ¼ superonasal-inferotemporal asymmetry; ST-IN ¼ superotemporal-inferonasal asymmetry. Bold indicates significant results. a Paired t test with Bonferroni correction. b t test with Bonferroni correction. c Wilcoxon signed rank test with Bonferroni correction. d Mann-Whitney U test with Bonferroni correction.
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TABLE 2. Cutoffs for the Total Area Under the Receiver Operating Characteristic Curve and Sensitivity and Specificity for the Parameters Used to Discriminate Between Fellow Eye in Unilateral Keratoconus and Normal Groups
Anterior elevation difference (Max Min) (mm) Posterior elevation difference (Max – Min) (mm) Index of vertical asymmetry Index of height decentration 4 mm I-S (D) 4 mm ST-IN (D)
AUC
Cutoff Value
Sensitivity
Specificity
P Value
95% Confidence Interval
0.734 0.735 0.733 0.748 0.799 0.809
> _5.5 > _11.1 > _0.16 > _0.008 > _1.2 > _0.8
50.00 57.14 71.43 71.43 85.71 57.14
85.29 88.24 61.76 85.29 73.53 91.18
.024b .002b .036a <.001b <.001a <.001b
(3, 9) (6, 15) (0.11, 0.27) (0.006, 0.009) (0.9, 1.5) (0.4, 1.1)
AUC ¼ area under curve; I-S ¼ inferior-superior asymmetry; Max ¼ maximum; Min ¼ minimum; ST-IN ¼ superotemporal-inferonasal asymmetry. a 2 x test. b Fisher exact test.
Pentacam is believed to be a more sensitive device for detecting the early form of keratoconus using various parameters, such as corneal thickness spatial profile, the percentage of thickness increase, and Belin/Ambro´sio Enhanced Ectasia Display.16,19,25,26,29 In the present study, fellow eyes of unilateral KCN showed normal values with respect to not only topographic but also tomographic parameters in Pentacam. These results differ from previous studies, which reported the importance of posterior elevation change in early stages of KCN. This may be explained by the fact that fellow eye in our study was defined as the mildest form, with normal elevation and pachymetric values including the final D value in Belin/Ambro´sio Enhanced Ectasia Display. However, anterior and posterior elevation differences (Max Min) differed significantly in the fellow eye compared with the normal group, suggesting new elevation criteria for the future. Some parameters for asymmetry of the anterior curvature (4 mm I-S and 4 mm ST-IN) and topometric indices (index of vertical asymmetry and index of height decentration) differed significantly between the fellow eye and the normal group, emphasizing the importance of the anterior curvature changes in subclinical KCN detection. Despite many studies comparing subclinical KCN from normal controls using unilateral KCN patients, most reports are from unilateral KCN with some abnormalities in the topography. However, there has been no paper studying the fellow eyes of unilateral KCN that were restricted with normal findings in the Pentacam detection program, including topometric indices that reflect anterior corneal surface and tomographic parameters in Belin/Ambro´sio Enhanced Ectasia Display. The importance of our study cannot be overemphasized, since we analyzed the difference between fellow eyes in unilateral KCN that showed normal topographic/tomographic values and normal controls. Saad and Gatinel10 defined FFKC as the contralateral eye of unilateral KCN without any ectatic changes clinically or topographically using Placido disk–based topogVOL. 157, NO. 1
raphy (Corneal Navigator OPD-Scan). They compared characteristics of FFKC and normal groups using Orbscan IIz and found that 3- and 5-mm irregularities are significantly more common in the FFKC than in the normal group. We report similar findings, in that keratometric asymmetry and topometric indices derived from Placido disk–based data were higher in fellow eyes. In discrimination analysis, they suggested that Placido disk–based indices are not sufficient to detect the earliest form of KCN, and that the posterior elevation and corneal thickness indices may be the most useful parameters to discriminate between FFKC and normal groups. Our results did not corroborate these findings, as we found that indices from the anterior curvature data, such as keratometric asymmetry and topometric indices, showed a higher discriminative ability than elevation and pachymetric parameters. This discrepancy might be explained by differences in the definition of the study groups (FFKC vs fellow eye) between the 2 studies. Fellow eye in the present study is defined to be normal not only in the anterior curvature but also in the elevation and pachymetric maps, including the normal eyes using the Belin/Ambro´sio Enhanced Ectasia Display. Ucakhan and associates22 evaluated Pentacam parameters in subclinical KCN compared with normal eyes. They defined subclinical KCN as the fellow eye of KCN, which had a normal-appearing cornea on clinical examination and inferior-superior asymmetry and/or bow-tie pattern with skewed radial axes, as detected on tangential Placido disk–based videokeratographs (CSO EyeTop, Florence, Italy). They found that corneal thickness distribution indices and posterior elevation are more helpful than anterior curvature data in identifying eyes with subclinical KCN. On the contrary, in our findings, anterior curvature data contribute less in detecting early forms of subclinical KCN, likely because of differing definitions as previously mentioned. Additionally, they also evaluated the anterior/ posterior elevation depression difference and suggested that posterior elevation difference is the strongest discriminating factor, followed by anterior elevation depression
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difference. This is similar to the results of the present study, in which anterior/posterior elevation differences (Max Min) were important factors in discriminating between fellow eye and normal. Recently, Wei and associates23 described the normal fellow eyes of unilateral KCN without any clinical or topographic signs of KCN. They considered not only the anterior curvature but also elevation and pachymetric indices to detect abnormalities in normal fellow eyes with a Tomey keratoconus screening system (Topographic Modeling System, Tomey TMS-2N; Tomey Corp, Nagoya, Japan) and Orbscan II. According to their results, statistically significant differences were found only in a 3-mm irregularity between fellow eyes and control eyes. ROC curve analysis showed that 3- and 5-mm irregularities allow for discrimination between fellow eyes and controls (AUC ¼ 0.860, 0.772, respectively). Similarly, we also found that the anterior curvature made an important contribution to the detection of subtle corneal changes in fellow eyes. Although Wei and associates described useful parameters for detecting subtle ectatic changes that are not detectable even in elevation-based topography, the sample size (5 unilateral keratoconus cases) is too small to provide conclusive results. The current study, on the other hand, has a larger sample size and has more parameters for discrimination (anterior/posterior elevation difference, keratometry asymmetry, and topometric indices). On ROC analysis, keratometric asymmetry (4 mm ST-IN, 4 mm I-S) show strong discriminative abilities and anterior/posterior elevation differences also have moderate discriminative ability regarding subtle changes in fellow eyes. Previously, corneal thickness of thinnest point, corneal thickness spatial profile, and percentage of thickness increase were known as good discriminative indices between KCN and normal.23 Saad and Gatinel10 also reported that corneal thickness and percentage of thickness increase are significantly different between FFKC and normal. In this study, however, corneal thickness and pachymetric progression indices were not different between fellow and normal groups. This may result from the difference in the definition of the study groups between the 2 studies. Recently Ambro´sio’s relational thickness
values were introduced, which were shown to be better than single-point pachymetric parameters for discriminating normal eyes and keratoconus.26 On the other hand, Ambro´sio’s relational thickness values showed no difference between fellow and normal groups in our study. Further evaluation should be required to come up with a definite conclusion. The cutoff values described in our results could be useful in detecting very mild corneal changes. However, these data should be interpreted with caution, as the relatively small sample size does not allow us to conclude that a single parameter taken alone is sufficient to distinguish a normal control from mildest form of subclinical KCN. We included the unilateral KCN patients diagnosed by the Pentacam and intended to compare the normal fellow eyes with the normal controls to investigate the earliest changes in subclinical KCN eyes. Pentacam was selected as the study device because of relatively high sensitivity in subclinical KCN detection using various programs, such as topographic (topometric indices) and tomographic (elevation, pachymetry and Belin/Ambro´sio Enhanced Ectasia Display) values. However, Pentacam emphasizes the elevation values, then the curvature values in subclinical KCN detection and considers eyes with abnormal I-S ratio and normal elevation values as normal (displaced corneal apex).24 After all, this may be the reason for the relatively strong discriminative ability of keratometric asymmetry in detecting early subclinical KCN in this study, which could be one of the limitations of this study. In conclusion, we propose several parameters for early detection of subclinical KCN that are not detectable using the current Pentacam detection program. Keratometric asymmetry (4 mm ST-IN, 4 mm I-S), some topometric indices, and anterior/posterior elevation difference (Max Min) may be useful in detecting the earliest form of subclinical KCN. Although current suggestions focus on the importance of the posterior elevation for early KCN detection, the importance of detecting subtle changes in the anterior corneal surfaces (including keratometric asymmetry and surface irregularities) along with the clinical signs cannot be overemphasized.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. All authors indicate no funding support, and they have no financial or proprietary disclosures in any materials or methods described herein. Contributions of authors: involved in conception and design (G.B., C.K., E.C., T.C.) and conduct of the study (G.B., C.K., E.C., T.C.); collection, management, and interpretation of data (G.B., C.K., J.K., D.L., T.C.); data analysis (G.B., C.K., T.C.); and preparation, review, and approval of the manuscript (G.B., D.L., E.C., T.C.).
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4. Randleman JB, Trattler WB, Stulting RD. Validation of the Ectasia Risk Score System for preoperative laser in situ keratomileusis screening. Am J Ophthalmol 2008;145(5): 813–818. 5. Randleman JB, Woodward M, Lynn MJ, Stulting RD. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology 2008;115(1):37–50. 6. Klein SR, Epstein RJ, Randleman JB, Stulting RD. Corneal ectasia after laser in situ keratomileusis in patients without apparent preoperative risk factors. Cornea 2006;25(4): 388–403. 7. Gatinel D, Saad A. The challenges of the detection of subclinical keratoconus at its earliest stage. Int J Keratoco Ectatic Corneal Dis 2012;1:36–43. 8. Amsler M. The ‘‘forme fruste’’ of keratoconus. Wien Klin Wochenschr 1961;73:842–843. 9. Klyce SD. Chasing the suspect: keratoconus. Br J Ophthalmol 2009;93(7):845–847. 10. Saad A, Gatinel D. Topographic and tomographic properties of forme fruste keratoconus corneas. Invest Ophthalmol Vis Sci 2010;51(11):5546–5555. 11. Rabinowitz YS. Videokeratographic indices to aid in screening for keratoconus. J Refract Surg 1995;11(5):371–379. 12. Maeda N, Klyce SD, Smolek MK, Thompson HW. Automated keratoconus screening with corneal topography analysis. Invest Ophthalmol Vis Sci 1994;35(6):2749–2757. 13. Rabinowitz YS, Rasheed K. KISA% index: a quantitative videokeratography algorithm embodying minimal topographic criteria for diagnosing keratoconus. J Cataract Refract Surg 1999;25(10):1327–1335. 14. Smolek MK, Klyce SD. Current keratoconus detection methods compared with a neural network approach. Invest Ophthalmol Vis Sci 1997;38(11):2290–2299. 15. Klyce SD, Karon MD, Smolek MK. Screening patients with the corneal navigator. J Refract Surg 2005;21(5 Suppl): S617–S622. 16. de Sanctis U, Loiacono C, Richiardi L, Turco D, Mutani B, Grignolo FM. Sensitivity and specificity of posterior corneal elevation measured by Pentacam in discriminating keratoconus/subclinical keratoconus. Ophthalmology 2008;115(9): 1534–1539. 17. Fontes BM, Ambrosio R Jr, Salomao M, Velarde GC, Nose W. Biomechanical and tomographic analysis of unilateral keratoconus. J Refract Surg 2010;26(9):677–681.
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18. Johnson RD, Nguyen MT, Lee N, Hamilton DR. Corneal biomechanical properties in normal, forme fruste keratoconus, and manifest keratoconus after statistical correction for potentially confounding factors. Cornea 2011;30(5):516–523. 19. Pinero DP, Alio JL, Aleson A, Escaf Vergara M, Miranda M. Corneal volume, pachymetry, and correlation of anterior and posterior corneal shape in subclinical and different stages of clinical keratoconus. J Cataract Refract Surg 2010;36(5): 814–825. 20. Saad A, Lteif Y, Azan E, Gatinel D. Biomechanical properties of keratoconus suspect eyes. Invest Ophthalmol Vis Sci 2010; 51(6):2912–2916. 21. Schlegel Z, Hoang-Xuan T, Gatinel D. Comparison of and correlation between anterior and posterior corneal elevation maps in normal eyes and keratoconus-suspect eyes. J Cataract Refract Surg 2008;34(5):789–795. 22. Ucakhan OO, Cetinkor V, Ozkan M, Kanpolat A. Evaluation of Scheimpflug imaging parameters in subclinical keratoconus, keratoconus, and normal eyes. J Cataract Refract Surg 2011;37(6):1116–1124. 23. Wei RH, Zhao SZ, Lim L, Tan DT. Incidence and characteristics of unilateral keratoconus classified on corneal topography. J Refract Surg 2011;27(10):745–751. 24. Belin MW, Khachikian SS. An introduction to understanding elevation-based topography: how elevation data are displayed - a review. Clin Experiment Ophthalmol 2009; 37(1):14–29. 25. Ambrosio R Jr, Alonso RS, Luz A, Coca Velarde LG. Corneal-thickness spatial profile and corneal-volume distribution: tomographic indices to detect keratoconus. J Cataract Refract Surg 2006;32(11):1851–1859. 26. Ambrosio R Jr, Caiado AL, Guerra FP, et al. Novel pachymetric parameters based on corneal tomography for diagnosing keratoconus. J Refract Surg 2011;27(10):753–758. 27. Li X, Rabinowitz YS, Rasheed K, Yang H. Longitudinal study of the normal eyes in unilateral keratoconus patients. Ophthalmology 2004;111(3):440–446. 28. Zadnik K, Barr JT, Edrington TB, et al. Baseline findings in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study. Invest Ophthalmol Vis Sci 1998;39(13): 2537–2546. 29. Ambrosio R Jr, Nogueira LP, Caldas DL, et al. Evaluation of corneal shape and biomechanics before LASIK. Int Ophthalmol Clin 2011;51(2):11–38.
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Biosketch Gi Hyun, Bae, MD, received her medical degree from Ajou University School of Medicine, Suwon, South Korea in 2005. She completed her residency at Kangnam Sacred Heart Hospital, Hallym University, Seoul, South Korea in 2011, and clinical fellowship at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea between 2011-2012. She currently serves as an ophthalmologist at Sahmyook Medical center, Seoul, South Korea. Her research interests include Cornea, Cataract and Refractive surgery.
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To evaluate topographic and tomographic changes in fellow eyes in unilateral keratoconus (KCN) patients by comparing them with normal eyes. DESIGN: Retrospective comparative case series. METHODS: Fourteen eyes of 14 patients with unilateral KCN and 34 eyes of 34 refractive surgery candidates were divided into 3 diagnostic groups using a Pentacam rotating Scheimpflug camera: advanced KCN eyes of unilateral KCN (KCN group, 14 eyes), normal fellow eyes of unilateral KCN (fellow eye group, 14 eyes), and refractive surgery candidates (normal group, 34 eyes). Topographic and tomographic parameters, which were obtained from Pentacam using sagittal curvature, elevation, and corneal thickness maps, were compared among the 3 groups. Receiver operating characteristic (ROC) curves were used to identify cutoff points in discriminating between fellow and normal eyes. RESULTS: Keratometric asymmetry, topometric indices, and elevation differences (maximum L minimum) on both the anterior and posterior surfaces were statistically different (P < .05). On ROC curve analysis, keratometric asymmetry and topometric index were best at discriminating fellow eyes from normal, followed by elevation differences (maximum L minimum) on the posterior and anterior cornea surface. CONCLUSIONS: Fellow eyes in unilateral KCN showed differences in several parameters that were not detectable with the Pentacam detection program, when compared with normal. However, each single parameter alone is not sufficient to detect early changes; thus, elevation indices as well as indices of anterior curvature should be considered together. (Am J Ophthalmol 2014;157: 103–109. Ó 2014 by Elsevier Inc. All rights reserved.)
Accepted for publication Aug 13, 2013. From the Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (G.H.B., J.R.K., C.H.K., D.H.L., E.S.C., T.Y.C.); Department of Ophthalmology, Sahmyook Medical Center, Seoul, South Korea (G.H.B.); and Chungju St. Mary’s Eye Clinic, Chungju, South Korea (C.H.K.). Inquiries to Tae-Young Chung, Associate Professor, Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Irwon-Dong, Kangnam-Ku, Seoul 135-710, South Korea; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.08.014
Ó
2014 BY
C
ORNEAL ECTASIA IS ONE OF THE MOST SERIOUS
complications of refractive surgery. Risk factors identified for post–laser in situ keratomileusis (LASIK) ectasia include high myopia, low residual stromal bed thickness, and defined topographic abnormalities such as keratoconus (KCN) and pellucid marginal corneal degeneration.1–5 Although the majority of these risk factors are identifiable preoperatively, missed preoperative topographic abnormalities are a major independent risk factor.6 As a result, detection of early KCN in the preclinical stage is very important for preventing post-LASIK ectasia. Advanced KCN can be diagnosed with typical biomicroscopic, retinoscopic, and topographic findings. However, detection of the disease in the preclinical stage is difficult. Several terms have been employed to describe the preclinical stages of the KCN condition, including subclinical keratoconus, keratoconus suspect (KCS), and forme fruste keratoconus (FFKC).7–10 The term KCS was reserved for the cornea with some anterior topographic changes of KCN but without evidence of clinical KCN in either eye. The term FFKC was first described by Amsler8 as an incomplete, abortive, or unusual form of a syndrome of disease, meaning corneas that have subtle topographic characteristics that do not reach the threshold of keratoconus suspect. However, because of the ambiguity of definition and significant overlap between these designations, there are no definitive criteria to help discriminate subclinical KCN from normal. Placido disk–based topography had been the most sensitive method to detect KCN, and several indices and artificial intelligence methods have been developed to help diagnose subclinical KCN.11–15 With recent advances in Orbscan slit-scanning topography (Bausch & Lomb, Rochester, New York, USA) and the Pentacam rotating Scheimpflug camera (Oculus, Wetzlar, Germany), anterior and posterior corneal elevation and pachymetric maps provide useful data to discriminate subclinical KCN from normal.6,10,16–24 Recent studies have found that pachymetric progression and elevation data can help to identify subclinical KCN not detected by Placido disk–based topography.25,26 Ambrosio and associates26 proposed new tomographicderived pachymetric parameters, such as relation thickness, which were better able to differentiate normal and keratoconic corneas. This suggests that several tomographic data from elevation and pachymetric values could be more sensitive to detect subclinical KCN before changes of anterior curvature in Placido disk–based topography. Several studies
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RIGHTS RESERVED.
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described topographic and tomographic differences between subclinical KCN and normal controls, which were not detectable using Placido disk–based topography.10,22,23 But there has not been any report about the subclinical KCN with normal elevation and pachymetric-derived parameters. The purpose of this study was to investigate the characteristics of the subtle changes in subclinical KCN and compare it with normal. Previous research indicates that true unilateral KCN is very rare, and that the normal fellow eye is also thought to have subclinical KCN.27 Thus, the normal fellow eye in unilateral KCN may be the ideal model for the mildest form of subclinical KCN. In the present study, normal fellow eyes in unilateral KCN patients were considered as the mildest form of subclinical KCN and topographic and tomographic parameters were analyzed using Pentacam.
SUBJECTS AND METHODS SUBJECTS:
This study included patients with unilateral KCN diagnosed by Pentacam and candidates for refractive surgery with normal corneas. Clinical records of 48 patients (62 eyes) seen at the Samsung Medical Center between January 2009 and March 2011 were retrospectively analyzed. The study protocol was reviewed and approved by the Sungkyunkwan University Institutional Review Board, and a waiver of informed consent was granted because of the low risk of this research. The tenets of the Declaration of Helsinki were followed for all study procedures. The study subjects were divided into 3 groups: advanced KCN eyes of unilateral KCN patients (KCN group, 14 eyes), normal fellow eyes of unilateral KCN patients (fellow eye group, 14 eyes), and refractive surgery candidates (normal group, 34 eyes). Eyes were diagnosed as KCN on the basis of Pentacam rotating Scheimpflug camera–derived topographic/tomographic parameters and criteria used in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study.28 Patients who had advanced KCN in 1 eye and a normal fellow eye were considered unilateral KCN. In this study, fellow eyes in unilateral KCN should not only be clinically normal but also satisfy all of the following criteria determined by the Pentacam: normal index of topographic keratoconus classification (use of keratometric values on the anterior corneal surface to detect ectatic changes) and final D value <1.6 SD from the Belin/Ambro´sio Enhanced Ectasia Display II. Normal control patients were candidates for refractive surgery with clinically normal corneas and topographic/tomographic values that were within normal limits determined by the Pentacam. All normal control patients underwent uncomplicated refractive surgery (femto-LASIK or laser-assisted subepithelial keratectomy) and had a 2-year follow-up without any evidence of ectatic corneal changes. In the normal group, only left eyes were used in the study analysis. 104
None of the patients had a history of previous ocular surgery or trauma, and they were asked to stop wearing contact lenses for at least 3 weeks for rigid contact lenses and 1 week for soft contact lenses prior to examination. KCN subjects with corneal scarring significant enough to disturb Pentacam evaluation were excluded from this study. PROCEDURE:
All subjects underwent a clinical, topographic, and tomographic evaluation. Clinical examinations included slit-lamp biomicroscopy, retinoscopy, and fundus examination. Topographic and tomographic examinations were performed using the Pentacam rotating Scheimpflug camera (Oculus, Wetzlar, Germany). The sagittal curvature, anterior elevation, posterior elevation, corneal thickness, and Belin/Ambro´sio Enhanced Ectasia Display II were evaluated. Elevation data were taken from a fixed 8.0-mm zone (best fit sphere [BFS] set to Manual, Float, Sphere, Diameter ¼ 8.0 mm) centered on the corneal apex. The following data were analyzed in Pentacam: (1) keratometric values: flat keratometry (K1), steep keratometry (K2), and mean keratometry (Km) for the central 3.0 mm of the cornea; (2) keratometric asymmetry: inferior-superior asymmetry at 4 and 6 mm (4 mm I-S and 6 mm I-S), superotemporal-inferonasal asymmetry at 4 and 6 mm (4 mm ST-IN and 6 mm ST-IN), and superonasal-inferotemporal asymmetry at 4 and 6 mm (4 mm SN-IT and 6 mm SN-IT) radius ring of the cornea (Figure); (3) topometric indices in an 8-mm zone, which were derived via Placido disk–based data: index of surface variance, index of vertical asymmetry, keratoconus-index, center keratoconus-index, index of height asymmetry, index of height decentration, and radii minimum; (4) elevation values: diameter of BFS, elevations (maximum and minimum), elevation differences (maximum minimum) on anterior and posterior cornea in the central 2.0-mm zone; (5) corneal thickness: corneal thickness at the apex and at the thinnest point; (6) Belin/Ambro´sio Enhanced Ectasia Display II: D values representing the front surface (Df), back surface (Db), pachymetric progression (Dp), thinnest point (Dt), thinnest point displacement (Dy), and final (D), pachymetric progression indices: pachymetric progression indices (maximum, minimum, and average); (7) Ambro´sio’s relational thickness values calculated by the following formula:26 Ambro´sio’s relational thickness maximum ¼ thinnest pachymetry/pachymetric progression index maximum and Ambro´sio’s relational thickness average ¼ thinnest pachymetry/pachymetric progression index average. STATISTICAL ANALYSIS:
The normality of all data samples was first checked using the Shapiro-Wilk test. When parametric analysis was possible, paired t tests for paired data or Student t tests for unpaired data with Bonferroni correction were used to compare groups (KCN, fellow eye, and normal). When parametric analysis was not
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the unilateral KCN group and 13:21 in the normal group, respectively. There were significantly more men in the unilateral KCN than in the normal (P < .001). The mean age was 25.08 6 6.39 (range: 18–43) years in the unilateral KCN and 28.00 6 5.93 (range: 19–41) years in the normal, which was not statistically different. KCN VS FELLOW EYE:
There were significant differences between the KCN and fellow eye in all measured parameters (Table 1).
KCN VS NORMAL:
There were significant differences between the KCN and normal group in almost all measured parameters except for BFS in anterior/posterior cornea and Dy value in Belin/Ambro´sio Enhanced Ectasia Display (Table 1).
NORMAL VS FELLOW EYE:
FIGURE. Anterior axial topographic map of a fellow eye in unilateral keratoconus. Asymmetry in inferior-superior, superotemporal-inferonasal regions, and superonasalinferotemporal regions were calculated by subtraction of the dioptric power in each direction.
possible, Wilcoxon signed rank tests for paired data and Mann-Whitney U tests for unpaired data were used. Null hypotheses of no difference were rejected if P values were less than .05, and statistical calculations used PASW (PASW, version 17.0 for Windows; SPSS, Chicago, Illinois, USA). The receiver operating characteristic (ROC) curve was analyzed for parameters that were different between cases of fellow eye and normal groups. Cutoff values were determined as the maximized sum of sensitivity and specificity. Internal validation was evaluated by the bootstrap method. A single dataset with the same sample size as the original dataset was generated with replacement by using the Proc Survey select procedure from SAS software, version 9.1.3 (SAS Institute Inc, Cary, North Carolina, USA), and the cutoff values of the corneal parameters were determined given the results from this dataset. This procedure was repeated 1000 times, and 95% confidence intervals were developed from these cutoff values using the 2.5th and the 97.5th percentiles. Statistical analyses were performed using SAS software, version 9.1.3 (SAS Institute Inc).
RESULTS
Table 1 shows the difference between the fellow eye and normal group. There were no significant differences between the fellow eye and normal group for K1, K2, or Km. However, 4 mm I-S and 4 mm ST-IN differed significantly between the fellow eye and normal group (P ¼ .002 and P ¼ .002). And index of vertical asymmetry and index of height decentration were statistically significantly different (P ¼ .023 and P ¼ .007). In the elevation map, there were no differences in BFS or elevation Max and Min, but the elevation differences (Max Min) from the anterior and posterior cornea in the central 2.0-mm zone showed significant differences between the 2 groups (P ¼ .031 and P ¼ .033). In terms of corneal thickness and Belin/Ambro´sio Enhanced Ectasia Display, there were no significant differences between the 2 groups, including corneal thickness both at apex and at thinnest point, D values, pachymetric progression indices, and Ambro´sio’s relational thickness. Table 2 reports the results of the ROC curve analysis for the fellow eye vs the normal group. In discriminating the fellow eye from the normal group, 4 mm ST-IN (area under curve [AUC] ¼ 0.809) and 4 mm I-S (AUC ¼ 0.799) showed the highest AUCs, followed by index of height decentration, posterior elevation difference, anterior elevation difference, and index of vertical asymmetry. The cutoff points derived from the ROC curve analysis were 0.8 diopters for 4 mm ST-IN, 1.2 diopters for 4 mm I-S, 0.008 for index of height decentration, 11.1 mm for posterior elevation, 5.5 mm for anterior elevation difference, and 0.16 for index of vertical asymmetry.
DISCUSSION THE AIM OF THE PRESENT STUDY WAS TO CHARACTERIZE
FOURTEEN EYES OF 14 UNILATERAL KCN PATIENTS AND 34
eyes of 34 normal refractive surgery candidates were analyzed. The ratio of male to female patients was 13:1 in VOL. 157, NO. 1
subtle morphologic changes of the fellow eye that are missed using the currently available Pentacam detection program. Compared with Placido disk–based topography,
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TABLE 1. Comparison of Keratometric, Pachymetric, and Elevation Parameters, as Well as Topometric Indices in Keratoconus, Fellow Eye, and Normal Groups KCN (14 Eyes)
Fellow Eye (14 Eyes)
Normal (34 Eyes)
KCN vs Fellow Eye KCN vs Normal Normal vs Fellow Eye
Mean 6 SD
P Value
Keratometry of anterior surface K1 (D) K2 (D)
45.26 6 4.22 50.47 6 8.45
42.20 6 1.08 43.40 6 1.36
42.57 6 1.65 43.90 6 1.49
.020a .001c
.036b <.001d
.365b .268b
Km (D) 4 mm I-S (D)
47.53 6 5.01 12.05 6 5.28
42.79 6 1.20 1.68 6 1.20
43.21 6 1.52 0.65 6 0.55
.003a <.001a
.007b <.001d
.318b .002d
4 mm ST-IN(D) 4 mm SN-IT(D)
6.41 6 4.53 11.08 6 4.91
1.09 6 0.64 0.86 6 0.61
0.50 6 0.41 0.58 6 0.53
.002c <.001a
<.001d <.001d
.002d .182d
6 mm I-S(D) 6 mm ST-IN(D)
8.93 6 4.26 4.55 6 4.35
1.42 6 1.20 0.79 6 0.72
0.78 6 0.59 0.55 6 0.36
.002c .009c
<.001d <.001d
.908d 1.0d
6 mm SN-IT(D) Topometric index
8.30 6 3.34
0.92 6 0.67
0.74 6 0.45
<.001a
<.001b
1.0b
103.29 6 44.85 1.12 6 0.42
20.07 6 7.11 0.18 6 0.08
17.88 6 4.48 0.12 6 0.04
<.001a <.001c
<.001d <.001d
.539d .023b
1.23 6 0.13 1.11 6 0.18
1.03 6 0.03 1.00 6 0.01
1.02 6 0.02 1.01 6 0.01
<.001a .005c
<.001b .003d
.092d .251d
37.47 6 24.84 0.09 6 0.04
5.72 6 4.27 0.01 6 0.00
3.48 6 3.39 0.01 6 0.00
<.001a <.001a
<.001d <.001d
.066d .007d
5.95 6 1.02
7.56 6 0.33
7.59 6 0.28
<.001a
<.001b
.807b
Index of surface variance Index of vertical asymmetry Keratoconus index Central keratoconus index Index of height asymmetry Index of height decentration Radii minimum Anterior elevation
7.91 6 0.41
7.90 6 0.28
.013c
.067b
.468d
Elevation Max (mm) Elevation Min (mm)
32.86 6 14.69 8.21 6 10.57
5.07 6 2.95 1.36 6 2.17
3.32 6 1.15 0.56 6 1.28
<.001a .035c
<.001d <.001d
.195d .156d
Elevation difference (Max L Min) (mm)
41.07 6 16.85
6.43 6 3.84
3.88 6 1.55
<.001a
<.001b
.031d
BFS (mm)
Posterior elevation BFS (mm)
7.69 6 0.37
6.51 6 0.25
6.40 6 0.26
.003a
.198b
.185b
56.14 6 28.70 13.71 6 17.40
8.71 6 4.76 -2.93 6 3.63
5.77 6 2.49 1.21 6 2.38
<.001a .039c
<.001d .010d
.161d .357b
69.86 6 37.18
11.64 6 5.89
6.97 6 3.35
<.001c
<.001b
.033d
511.14 6 50.15 478.93 6 58.37
535.29 6 26.37 533.07 6 25.58
549.06 6 30.24 546.35 6 30.06
.017c .001c
.017b .001b
.127b .132b
2.99 6 1.57
1.21 6 0.16
1.23 6 0.17
.005c
<.001d
1.0b
Min Ave
1.66 6 0.89 2.10 6 0.95
0.74 6 0.09 1.00 6 0.12
0.76 6 0.12 1.02 6 0.12
c
.007 .005c
<.001 <.001d
1.0d 1.0d
D value Df
12.30 6 6.87
0.54 6 0.64
0.19 6 0.88
.001a
<.001b
Db Dp
9.54 6 7.56 8.07 6 6.37
0.03 6 0.80 0.65 6 0.83
0.15 6 0.87 0.76 6 0.70
.004a .001c
.004b <.001d
Dt Dy
1.60 6 1.47 1.39 6 1.00
0.15 6 0.71 0.37 6 0.82
0.19 6 0.81 0.74 6 0.85
.002a .010a
.005b .322b
9.65 6 5.74
1.03 6 0.57
1.04 6 0.54
.001a
<.001d
1.0d
204.15 6 90.82 281.13 6 121.30
450.46 6 76.57 540.87 6 75.12
452.97 6 69.49 541.98 6 67.67
<.001a <.001a
<.001b <.001b
1.0d 1.0b
Elevation Max (mm) Elevation Min (mm) Elevation difference (Max L Min) (mm) Corneal thickness Apex (mm) Thinnest (mm) Pachymetric progression index Max
Final D Ambro´sio’s relational thickness Max Ave
6.29 6 0.29
d
.787b 1.0b 1.0b .950b 1.0b
Ave ¼ average; BFS ¼ diameter of best fit sphere in 8.0-mm area; I-S ¼ inferior-superior asymmetry; K1 ¼ corneal dioptric power in the flattest meridian for the 3-mm central zone; K2 ¼ corneal dioptric power in the steepest meridian for the 3-mm central zone; KCN ¼ keratoconus; Km ¼ mean corneal power in the 3-mm zone; Max ¼ maximum; Min ¼ minimum; SN-IT ¼ superonasal-inferotemporal asymmetry; ST-IN ¼ superotemporal-inferonasal asymmetry. Bold indicates significant results. a Paired t test with Bonferroni correction. b t test with Bonferroni correction. c Wilcoxon signed rank test with Bonferroni correction. d Mann-Whitney U test with Bonferroni correction.
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TABLE 2. Cutoffs for the Total Area Under the Receiver Operating Characteristic Curve and Sensitivity and Specificity for the Parameters Used to Discriminate Between Fellow Eye in Unilateral Keratoconus and Normal Groups
Anterior elevation difference (Max Min) (mm) Posterior elevation difference (Max – Min) (mm) Index of vertical asymmetry Index of height decentration 4 mm I-S (D) 4 mm ST-IN (D)
AUC
Cutoff Value
Sensitivity
Specificity
P Value
95% Confidence Interval
0.734 0.735 0.733 0.748 0.799 0.809
> _5.5 > _11.1 > _0.16 > _0.008 > _1.2 > _0.8
50.00 57.14 71.43 71.43 85.71 57.14
85.29 88.24 61.76 85.29 73.53 91.18
.024b .002b .036a <.001b <.001a <.001b
(3, 9) (6, 15) (0.11, 0.27) (0.006, 0.009) (0.9, 1.5) (0.4, 1.1)
AUC ¼ area under curve; I-S ¼ inferior-superior asymmetry; Max ¼ maximum; Min ¼ minimum; ST-IN ¼ superotemporal-inferonasal asymmetry. a 2 x test. b Fisher exact test.
Pentacam is believed to be a more sensitive device for detecting the early form of keratoconus using various parameters, such as corneal thickness spatial profile, the percentage of thickness increase, and Belin/Ambro´sio Enhanced Ectasia Display.16,19,25,26,29 In the present study, fellow eyes of unilateral KCN showed normal values with respect to not only topographic but also tomographic parameters in Pentacam. These results differ from previous studies, which reported the importance of posterior elevation change in early stages of KCN. This may be explained by the fact that fellow eye in our study was defined as the mildest form, with normal elevation and pachymetric values including the final D value in Belin/Ambro´sio Enhanced Ectasia Display. However, anterior and posterior elevation differences (Max Min) differed significantly in the fellow eye compared with the normal group, suggesting new elevation criteria for the future. Some parameters for asymmetry of the anterior curvature (4 mm I-S and 4 mm ST-IN) and topometric indices (index of vertical asymmetry and index of height decentration) differed significantly between the fellow eye and the normal group, emphasizing the importance of the anterior curvature changes in subclinical KCN detection. Despite many studies comparing subclinical KCN from normal controls using unilateral KCN patients, most reports are from unilateral KCN with some abnormalities in the topography. However, there has been no paper studying the fellow eyes of unilateral KCN that were restricted with normal findings in the Pentacam detection program, including topometric indices that reflect anterior corneal surface and tomographic parameters in Belin/Ambro´sio Enhanced Ectasia Display. The importance of our study cannot be overemphasized, since we analyzed the difference between fellow eyes in unilateral KCN that showed normal topographic/tomographic values and normal controls. Saad and Gatinel10 defined FFKC as the contralateral eye of unilateral KCN without any ectatic changes clinically or topographically using Placido disk–based topogVOL. 157, NO. 1
raphy (Corneal Navigator OPD-Scan). They compared characteristics of FFKC and normal groups using Orbscan IIz and found that 3- and 5-mm irregularities are significantly more common in the FFKC than in the normal group. We report similar findings, in that keratometric asymmetry and topometric indices derived from Placido disk–based data were higher in fellow eyes. In discrimination analysis, they suggested that Placido disk–based indices are not sufficient to detect the earliest form of KCN, and that the posterior elevation and corneal thickness indices may be the most useful parameters to discriminate between FFKC and normal groups. Our results did not corroborate these findings, as we found that indices from the anterior curvature data, such as keratometric asymmetry and topometric indices, showed a higher discriminative ability than elevation and pachymetric parameters. This discrepancy might be explained by differences in the definition of the study groups (FFKC vs fellow eye) between the 2 studies. Fellow eye in the present study is defined to be normal not only in the anterior curvature but also in the elevation and pachymetric maps, including the normal eyes using the Belin/Ambro´sio Enhanced Ectasia Display. Ucakhan and associates22 evaluated Pentacam parameters in subclinical KCN compared with normal eyes. They defined subclinical KCN as the fellow eye of KCN, which had a normal-appearing cornea on clinical examination and inferior-superior asymmetry and/or bow-tie pattern with skewed radial axes, as detected on tangential Placido disk–based videokeratographs (CSO EyeTop, Florence, Italy). They found that corneal thickness distribution indices and posterior elevation are more helpful than anterior curvature data in identifying eyes with subclinical KCN. On the contrary, in our findings, anterior curvature data contribute less in detecting early forms of subclinical KCN, likely because of differing definitions as previously mentioned. Additionally, they also evaluated the anterior/ posterior elevation depression difference and suggested that posterior elevation difference is the strongest discriminating factor, followed by anterior elevation depression
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difference. This is similar to the results of the present study, in which anterior/posterior elevation differences (Max Min) were important factors in discriminating between fellow eye and normal. Recently, Wei and associates23 described the normal fellow eyes of unilateral KCN without any clinical or topographic signs of KCN. They considered not only the anterior curvature but also elevation and pachymetric indices to detect abnormalities in normal fellow eyes with a Tomey keratoconus screening system (Topographic Modeling System, Tomey TMS-2N; Tomey Corp, Nagoya, Japan) and Orbscan II. According to their results, statistically significant differences were found only in a 3-mm irregularity between fellow eyes and control eyes. ROC curve analysis showed that 3- and 5-mm irregularities allow for discrimination between fellow eyes and controls (AUC ¼ 0.860, 0.772, respectively). Similarly, we also found that the anterior curvature made an important contribution to the detection of subtle corneal changes in fellow eyes. Although Wei and associates described useful parameters for detecting subtle ectatic changes that are not detectable even in elevation-based topography, the sample size (5 unilateral keratoconus cases) is too small to provide conclusive results. The current study, on the other hand, has a larger sample size and has more parameters for discrimination (anterior/posterior elevation difference, keratometry asymmetry, and topometric indices). On ROC analysis, keratometric asymmetry (4 mm ST-IN, 4 mm I-S) show strong discriminative abilities and anterior/posterior elevation differences also have moderate discriminative ability regarding subtle changes in fellow eyes. Previously, corneal thickness of thinnest point, corneal thickness spatial profile, and percentage of thickness increase were known as good discriminative indices between KCN and normal.23 Saad and Gatinel10 also reported that corneal thickness and percentage of thickness increase are significantly different between FFKC and normal. In this study, however, corneal thickness and pachymetric progression indices were not different between fellow and normal groups. This may result from the difference in the definition of the study groups between the 2 studies. Recently Ambro´sio’s relational thickness
values were introduced, which were shown to be better than single-point pachymetric parameters for discriminating normal eyes and keratoconus.26 On the other hand, Ambro´sio’s relational thickness values showed no difference between fellow and normal groups in our study. Further evaluation should be required to come up with a definite conclusion. The cutoff values described in our results could be useful in detecting very mild corneal changes. However, these data should be interpreted with caution, as the relatively small sample size does not allow us to conclude that a single parameter taken alone is sufficient to distinguish a normal control from mildest form of subclinical KCN. We included the unilateral KCN patients diagnosed by the Pentacam and intended to compare the normal fellow eyes with the normal controls to investigate the earliest changes in subclinical KCN eyes. Pentacam was selected as the study device because of relatively high sensitivity in subclinical KCN detection using various programs, such as topographic (topometric indices) and tomographic (elevation, pachymetry and Belin/Ambro´sio Enhanced Ectasia Display) values. However, Pentacam emphasizes the elevation values, then the curvature values in subclinical KCN detection and considers eyes with abnormal I-S ratio and normal elevation values as normal (displaced corneal apex).24 After all, this may be the reason for the relatively strong discriminative ability of keratometric asymmetry in detecting early subclinical KCN in this study, which could be one of the limitations of this study. In conclusion, we propose several parameters for early detection of subclinical KCN that are not detectable using the current Pentacam detection program. Keratometric asymmetry (4 mm ST-IN, 4 mm I-S), some topometric indices, and anterior/posterior elevation difference (Max Min) may be useful in detecting the earliest form of subclinical KCN. Although current suggestions focus on the importance of the posterior elevation for early KCN detection, the importance of detecting subtle changes in the anterior corneal surfaces (including keratometric asymmetry and surface irregularities) along with the clinical signs cannot be overemphasized.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. All authors indicate no funding support, and they have no financial or proprietary disclosures in any materials or methods described herein. Contributions of authors: involved in conception and design (G.B., C.K., E.C., T.C.) and conduct of the study (G.B., C.K., E.C., T.C.); collection, management, and interpretation of data (G.B., C.K., J.K., D.L., T.C.); data analysis (G.B., C.K., T.C.); and preparation, review, and approval of the manuscript (G.B., D.L., E.C., T.C.).
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Biosketch Gi Hyun, Bae, MD, received her medical degree from Ajou University School of Medicine, Suwon, South Korea in 2005. She completed her residency at Kangnam Sacred Heart Hospital, Hallym University, Seoul, South Korea in 2011, and clinical fellowship at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea between 2011-2012. She currently serves as an ophthalmologist at Sahmyook Medical center, Seoul, South Korea. Her research interests include Cornea, Cataract and Refractive surgery.
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