ORIGINAL ARTICLE

Corneal Asymmetry Analysis by Pentacam Scheimpflug Tomography for Keratoconus Diagnosis Jonatán D. Galletti, MD; Pablo R. Ruiseñor Vázquez, MD; Natalia Minguez, MD; Marianella Delrivo, MD; Fernando Fuentes Bonthoux, MD; Tomás Pförtner, PhD; Jeremías G. Galletti, MD, PhD ABSTRACT PURPOSE: To evaluate intereye corneal asymmetry in Pentacam (Oculus Optikgeräte GmbH, Wetzlar, Germany) indices as a diagnostic method between normal patients and patients with keratoconus. METHODS: A retrospective, observational case series of 177 healthy, 44 indeterminate, and 121 patients with keratoconus classified by Pentacam ectasia detection indices, randomized to analysis and validation datasets. Intereye asymmetry in 20 Scheimpflug tomography corneal descriptors was calculated and compared to develop diagnostic models. RESULTS: Intereye asymmetry was not correlated with anisometropia in healthy controls but was correlated with the ectasia grade of the worse eye in patients with keratoconus. Patients with keratoconus had significantly greater intereye asymmetry in all descriptors except for relational thickness indices. Intereye asymmetry in front elevation at the thinnest corneal location afforded the single highest diagnostic performance (71% sensitivity and 85% specificity), whereas the best multivariate model combining intereye asymmetry in anterior and posterior keratometry, corneal thickness, and front and back elevation at the thinnest point provided 65% sensitivity and 97% specificity. Multivariate models upheld their performance in the validation dataset. Most (more than 90%) indeterminate patients, according to conventional Pentacam analysis, showed within-normal-range corneal asymmetry. CONCLUSIONS: Healthy corneas are markedly symmetric irrespective of anisometropia, but corneal asymmetry analysis does not provide sufficient sensitivity to be used alone for detecting keratoconus. However, its remarkable specificity suggests that it could be used combined with conventional single cornea Pentacam analysis to reduce the false-positive rate or in dubious cases. [J Refract Surg. 2015;31(2):116-123.]

D

etection of early keratoconus signs constitutes a key aspect of preoperative screening for corneal refractive surgery and, in addition to rigorous biomicroscopy examination, there are numerous technologies to assist the clinician in this task. Most diagnostic options focus on the typical ectatic corneal changes, such as abnormal anterior and posterior curvature,1 localized thinning,2 focally decreased epithelial thickness,3 and biomechanical instability.4,5 But because none of these methods provide absolute sensitivity and specificity, especially when dealing with truly subclinical cases (eyes with unremarkable slit-lamp and topography findings that develop ectatic changes in time), there is still a need for improvement of current diagnostic models. Asymmetrical progression is a well-characterized feature of keratoconus.6,7 Previous studies have explored in depth the intereye difference in corneal shape in patients with keratoconus,7-10 but to the best of our knowledge, there are no established diagnostic models for clinical use based on this specific feature of the disease. Because normal corneas are markedly symmetric,11-14 the possibility of detecting early ectatic changes by evaluating intereye differences is attractive. In addition, most corneal descriptors show significant overlap between healthy and subclinical keratoconic eyes,1,15 hence the prospect of increasing sensitivity by also evaluating their asymmetry. The Pentacam HR Scheimpflug tomography system (Oculus Optikgeräte GmbH, Wetzlar, Germany) has gained wide acceptance in clinical practice for keratoconus screening because it provides several corneal descriptors and diagnostic From ECOS (Clinical Ocular Studies) Laboratory, Buenos Aires, Argentina (JDG, PRRV, NM, MD, FFB, TP, JGG); the Department of Ophthalmology, Hospital de Clínicas José de San Martín, University of Buenos Aires, Argentina (JDG, PRRV, NM); and the Institute of Experimental Medicine, National Academy of Medicine/CONICET, Buenos Aires, Argentina (JGG). Submitted: July 27, 2014; Accepted: November 19, 2014 The authors have no financial or proprietary interest in the materials presented herein. Correspondence: Jeremías G. Galletti, MD, PhD, ECOS (Clinical Ocular Studies) Laboratory, (1119) Pueyrredón 1716 7 B, Buenos Aires, Argentina. E-mail: [email protected] doi:10.3928/1081597X-20150122-07

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Corneal Asymmetry Analysis for Keratoconus Diagnosis/Galletti et al

models that have been previously described.2,15-21 We have recently shown that although testing with this device can diagnose many eyes with subclinical keratoconus, a significant fraction of cases could still go undetected and the false-positive rate could be an issue.15 Remarkably, corneal asymmetry is not considered by the Pentacam software for keratoconus detection or, to the best of our knowledge, by any other Scheimpflug device approved for clinical use. In this study, we evaluated corneal asymmetry in healthy patients and patients with keratoconus to explore its applicability to disease detection in the clinical setting. We separately evaluated the sensitivity and specificity of single parameter cutoff values for corneal asymmetry, and looked at how combinations of these new corneal descriptors compared to the Pentacam’s already established corneal indices. PATIENTS AND METHODS This study was a retrospective, observational case series. The research protocol followed the tenets of the Declaration of Helsinki and was approved by the Hospital de Clínicas ethics committee. The records of patients who had been referred for spectacle or contact lens prescription or keratoconus diagnosis and examined at ECOS Laboratory between March and November 2013 were reviewed. Exclusion criteria were the following: previous eye surgery or trauma, corneal scarring, any eye disease other than keratoconus, and chronic use of topical medication. Patients were asked to cease contact lens wear at least 3 weeks before examination. All patients were examined at ECOS Laboratory by three trained ophthalmologists (JDG, PPRV, and MD). Each patient underwent slit-lamp examination, Pentacam HR Scheimpflug tomography, and Placido disk topography and aberrometry (iTrace, software version 4.2.1; Tracey Technologies, Houston, TX). Patients were told to blink before the examinations and only reliable studies were included. Topographic examinations with artifacts or irregularities were discarded, whereas for the Pentacam, only acquisitions with acceptable quality (as defined by the manufacturer) were included (25 images in 2 seconds). One examination per eye was analyzed and data of both eyes were recorded. Average corneal power and higher-order aberrations of the corneal 5-mm central surface were provided by the iTrace software, and refractive spherical equivalent and cylinder. Anisometropia was defined as an intereye difference 1 diopter (D) or greater in either variable. The following Pentacam descriptors were analyzed: flat, steep, and mean anterior keratometry, mean posterior keratometry, central, apex, and Journal of Refractive Surgery • Vol. 31, No. 2, 2015

thinnest corneal thickness, corneal thickness progression indices (minimum, average, and maximum), anterior and posterior elevation at thinnest corneal location, Ambrosio’s relational thickness indices (average and maximum), and the normalized indices deviation of normality of the front elevation, deviation of normality of the back elevation, deviation of normality of corneal thickness progression, deviation of normality of corneal thinnest point, deviation of normality of relational thickness, and overall deviation of normality. The methodology has been disclosed by the manufacturer for some but not all of these indices.2,19,22,23 Patients were classified solely by their Pentacam findings into one of three categories. The most sensitive ectasia detection indices according to previous reports were considered.2,15 Healthy controls consisted of patients with unremarkable Scheimpflug tomography in both eyes, defined as showing normal values (less than 1.6) in the standardized indices (back elevation, corneal thickness progression, relational thickness, and overall indices) and for the Ambrosio’s maximum relational thickness index (339 or greater). Patients with at least one abnormal value in any of the aforementioned indices (2.6 or greater for the standardized index or maximum relational thickness less than 339) were diagnosed as having keratoconus. Patients with suspicious values in one or both eyes for any of the standardized indices (1.6 or greater and less than 2.6) were included in a separate, indeterminate group. It should be noted that the latter group does not correspond to the keratoconus suspect category usually found in the literature, but to a relatively common situation when screening patients with Pentacam HR Scheimpflug tomography.15 In a previous study, we showed that approximately 20% of normal eyes and 20% of subclinical keratoconic corneas have suspicious values (1.6 or greater and less than 2.6) for the Pentacam’s standardized indices.15 These eyes cannot be considered keratoconic due to insufficient findings, but the possibility of subclinical ectasia cannot be ruled out. We did not include the indeterminate group in the analysis and only examined the performance of the diagnostic models in this sample for exploratory purposes. Two datasets (analysis and validation) with two groups each were compiled by random 2:1 allocation of healthy patients and patients with keratoconus. The Keratoconus Severity Score was used for keratoconus grading,24 which is based on average corneal power and corneal higher-order aberrations obtained from Placido topography. The Keratoconus Severity Score scale includes scores of 0 (unaffected, normal topography), 1 (unaffected, atypical topography), 2 (suspect), 3 (mild 117

Corneal Asymmetry Analysis for Keratoconus Diagnosis/Galletti et al

keratoconus), 4 (moderate keratoconus), and 5 (severe keratoconus).24 Intereye asymmetry of each parameter was calculated as the absolute value of the difference between fellow eyes to ease interpretation. The normality of the data was assessed by the Kolmogorov–Smirnov test and then either parametric or non-parametric comparison tests were performed accordingly. Receiver operating characteristic curves were used to calculate sensitivity, specificity, and area under the curve of each parameter. Optimal cutoff points were derived from the receiver-operating characteristic curves as the value closest to the perfect classification point.4 A composite asymmetry score was created by examining five corneal descriptors (anterior and posterior keratometry, thinnest corneal thickness, and front and back elevation at thinnest corneal location) according to their optimal cutoff points, as previously described. To calculate the composite score, which ranged from 0 to 5, the number of positive asymmetry descriptors was counted for each patient. In addition, logistic regression with all variables entered at once was used to obtain the best combination of these five descriptors. The resulting logistic function was applied with a 0.5 cutoff: logit = 0.210 3 mean anterior keratometry 1 5.546 3 mean posterior keratometry 1 0.015 3 thinnest corneal thickness 1 0.539 3 front elevation at thinnest location 1 0.116 3 back elevation at thinnest location – 2.541. All data were recorded and sorted using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA). Statistical analysis was performed with Prism 5 (GraphPad Software, La Jolla, CA) and SPSS version 17 software (SPSS, Inc., Chicago, IL). A P value of less than .05 was considered statistically significant. Data are shown as mean ± standard deviation unless otherwise stated. RESULTS Demographics and Corneal Intereye Asymmetry The analysis dataset consisted of a control group of 115 patients (mean age: 32 ± 8 years, 59 [51%] female) and a keratoconus group of 75 patients (mean age: 32 ± 10 years, 37 [49%] female), whereas the validation dataset included a control group of 62 patients (mean age: 33 ± 10 years, [56%] female) and a keratoconus group of 46 patients (mean age: 34 ± 11 years, [41%] female). The indeterminate group comprised 44 patients (mean age: 33 ± 8 years, 28 [64%] female). For each group, corneal descriptors per eye are summarized in Table 1 and the proportion of patients with abnormal ectasia detection indices in neither, one, or both eyes is shown in Table A (available in the online version of 118

this article). Intereye asymmetry for each of the analyzed variables is summarized in Table B (available in the online version of this article) and depicted for some descriptors in Figure 1. Compared with control patients, median values for intereye asymmetry were significantly greater (P < .001) in patients with keratoconus for every variable except for standardized relational thickness and maximum relational thickness. Anisometropia and Corneal Intereye Asymmetry In the control group, 42 (37%) patients (17 males, 41%) had spherical equivalent anisometropia of 1 D or greater and 32 (28%) patients (16 [50%] males) had cylindrical anisometropia of 1 D or greater. When comparing the spherical equivalent of patients with anisometropia and those without, median intereye difference was significantly greater only in the overall standardized deviation index (0.15 vs 0.29, P = .002). When comparing the cylinder of patients with anisometropia and those without, median intereye difference was significantly greater only in steepest anterior keratometry (0.3 vs 0.5, P = .04). In this group, spherical equivalent anisometropia was only significantly correlated with intereye asymmetry in average corneal thickness progression (r = 0.205, P = .028) and the overall standardized deviation index (r = 0.218, P = .02), whereas cylindrical anisometropia was only significantly correlated with intereye asymmetry in steep anterior keratometry (r = 0.290, P = .002). Keratoconus Grade and Corneal Intereye Asymmetry In the keratoconus group, the steepest (of both eyes) mean anterior keratometry was positively correlated with the intereye asymmetry in all variables but refractive cylinder, back elevation at the thinnest corneal point, and relational thickness indices. The highest Keratoconus Severity Score of both eyes was also positively correlated with the intereye asymmetry in all variables but relational thickness indices. Diagnostic Performance of Intereye Asymmetry The diagnostic performance of intereye asymmetry in each variable for differentiating between control patients and patients with keratoconus is shown in Table 2. The best variables describing anterior and posterior curvature and the potentially ectatic corneal region (thickness and anterior and posterior elevation at the thinnest corneal location) were evaluated together as multivariate intereye asymmetry. The combined score of intereye asymmetry in mean anterior (positive if 0.3 D or greater) and posterior (positive if 0.1 D or greater) keratometry, and corneal thickness (positive if Copyright © SLACK Incorporated

Journal of Refractive Surgery • Vol. 31, No. 2, 2015

– – 6 (13%) 2 (4%) – – 4 (5%) 4 (5%) – – KSS 5

OD = right eye; OS = left eye; K = keratometry; KSS = Keratoconus Severity Score a Data are given as mean ± standard deviation.

– – 2 (4%) 3 (7%) – – 7 (9%) 5 (6%) – KSS 4





– –

– 8 (17%)

4 (9%) 9 (20%)

8 (17%) –

1 (2%) 1 (2%)

– 13 (17%)

6 (8%) 6 (8%)

14 (19%) – KSS 3



– KSS 2

1 (1%)



44 (100%) 43 (98%)

1 (2%) 7 (15%)

19 (41%) 19 (41%)

5 (11%) –

61 (98%) 61 (98%)

– 4 (5%)

41 (55%) 41 (55%)

5 (7%) 1 (1%) – KSS 1

113 (98%) 115 (100%) KSS 0

8±4 8±4 37 ± 34 38 ± 36 4±3 4±3 27 ± 26 27 ± 26 3±3 3±4 Back elevation at thinnest point

525 ± 29

5±2 5±2

529 ± 29 464 ± 53

17 ± 16 17 ± 18

468 ± 43 542 ± 33

2±2 2±1

541 ± 32 479 ± 40

12 ± 12 13 ± 13

481 ± 39 532 ± 29

2±2 2±2

535 ± 29 Thinnest corneal thickness

Front elevation at thinnest point

528 ± 30

-6.5 ± 0.3 -6.6 ± 0.3

532 ± 30 483 ± 45

-6.7 ± 0.8 -6.6 ± 0.6

489 ± 38 545 ± 33

-6.3 ± 0.3 -6.2 ± 0.25

544 ± 32 493 ± 35

-6.8 ± 0.8 -6.7 ± 0.5

495 ± 32 535 ± 30 538 ± 30 Central corneal thickness

-6.3 ± 0.2 -6.3 ± 0.2 Mean posterior K

OS OD

45.0 ± 1.6 46.5 ± 4.6

OS OD

46.1 ± 2.8 43.8 ± 1.6

OS OD

43.7 ± 1.6 46.5 ± 3.7

OS OD

46.3 ± 2.43 44.1 ± 1.4

OS OD

44.1 ± 1.4 Mean anterior K

Parameter

Keratoconus (n = 46) Control (n = 62) Keratoconus (n = 75) Control (n = 115)

Validation Dataset (n = 108) Analysis Dataset (n = 190)

Corneal Descriptors in Control, Keratoconus, and Indeterminate Groupsa

DISCUSSION In this study, we observed little corneal asymmetry in normal patients, in agreement with previous reports.9,12,13 Remarkably, mean intereye differences for most corneal descriptors were not greater in anisometropic eyes in the control group, suggesting that both corneas in normal patients tend to develop symmetrically despite differences in total refraction. Mean spherical anisometropia in the control group (1.09 ± 1.34 D) was greater than in other reports (0.63 ± 1.02 D),9,10 and yet we could only detect a correlation between this variable and the intereye difference for average corneal thickness progression and the overall standardized deviation index in this group.

TABLE 1

Intereye Asymmetry in the Validation Dataset and the Indeterminate Group In the validation dataset, the combined score of intereye asymmetry with a value of 3 or greater positive criteria cutoff provided 0.67 sensitivity and 0.89 specificity, whereas the logistic regression function yielded 0.72 sensitivity and 0.94 specificity. Five patients (8%) in the control group had an intereye asymmetry score of 3 and 2 patients (3%) had a score of 5. The combined intereye asymmetry score distribution in the indeterminate group was as follows: 14 (32%) patients with a score of 0, 15 (34%) with a score of 1, 10 (22%) with a score of 2, 3 (7%) with a score of 3, and 2 (5%) with a score of 4. The logistic regression function classified 3 (7%) patients as abnormal. The distribution of intereye asymmetry scores in both datasets combined is represented in Figure 2 and summarized in Table 3.

Indeterminate (n = 44)

12 µm or greater) and front (positive if 2 µm or greater) and back (positive if 5 µm or greater) elevation at the thinnest corneal point had an area under the receiver-operating characteristic curve of 0.85 (95% confidence interval: 0.80 to 0.90): a value of 2 or greater positive criteria cutoff provided 0.82 sensitivity and 0.70 specificity, whereas a value of 3 or greater positive criteria cutoff afforded 0.67 sensitivity and 0.92 specificity. A logistic regression approach combining the intereye asymmetry in the aforementioned five variables had 0.65 sensitivity and 0.97 specificity, with an area under the receiver-operating characteristic curve of 0.86 (95% confidence interval: 0.80 to 0.92).

45.0 ± 1.7

Corneal Asymmetry Analysis for Keratoconus Diagnosis/Galletti et al

119

Corneal Asymmetry Analysis for Keratoconus Diagnosis/Galletti et al

Figure 1. Intereye corneal asymmetry in control patients and patients with keratoconus. Whisker-box plots of intereye asymmetry of mean anterior keratometry (Mean ant. K), mean posterior keratometry (Mean post. K), thinnest pachymetry (Thinnest pach.), and front and back elevation at thinnest corneal location in control patients (n =177, green boxes) and patients with keratoconus (n = 121, red boxes) . *** = statistically significant difference (P < .001) in median values between groups according to Mann–Whitney U test.

TABLE 2

Diagnostic Performance of Intereye Asymmetry in Individual Corneal Descriptors for Keratoconus Parameter

AROC (95% CI)

Cutoff

Sensitivity (%)

Specificity (%)

Flat anterior keratometry

0.73 (0.66 to 0.81)

≥ 0.4

66.7

66.1

Steep anterior keratometry

0.77 (0.69 to 0.85)

≥ 0.8

62.5

88.4

Mean anterior keratometry

0.74 (0.66 to 0.83)

≥ 0.3

66.7

78.6

Mean posterior keratometry

0.77 (0.70 to 0.85)

≥ 0.1

61.1

79.5

Central corneal thickness

0.75 (0.68 to 0.82)

≥ 10

68.1

76.8

Apex corneal thickness

0.76 (0.69 to 0.83)

≥9

73.6

70.5

Thinnest corneal thickness

0.78 (0.71 to 0.85)

≥ 12

65.3

79.5

Minimum pachymetric progression index

0.76 (0.68 to 0.84)

≥ 0.10

68.1

76.8

Average pachymetric progression index

0.78 (0.70 to 0.85)

≥ 0.08

66.7

77.7

Maximum pachymetric progression index

0.76 (0.68 to 0.84)

≥ 0.23

61.1

87.5

Front elevation at thinnest point

0.82 (0.75 to 0.89)

≥2

70.8

84.8

Back elevation at thinnest point

0.79 (0.72 to 0.86)

≥5

59.7

92.0

Deviation of front elevation

0.79 (0.72 to 0.87)

≥ 0.93

66.7

87.5

Deviation of back elevation

0.78 (0.70 to 0.86)

≥ 0.79

65.3

89.3

Deviation of pachymetric progression

0.79 (0.71 to 0.86)

≥ 0.49

70.8

75.9

Deviation of corneal thickness

0.82 (0.75 to 0.88)

≥ 0.36

69.4

83.0

Deviation of relational thickness

0.51 (0.42 to 0.60)

≥ 0.40

52.8

48.2

Overall deviation

0.82 (0.76 to 0.89)

≥ 0.47

69.4

87.5

Average ART

0.66 (0.58 to 0.75)

≥ 33

59.7

63.4

Maximum ART

0.53 (0.43 to 0.62)

≥ 66

41.7

69.6

AROC = area under receiver-operating characteristic curve; CI = confidence interval; ART = Ambrosio’s relational thickness

Cylindrical anisometropia in the control group was also greater than in previous studies (0.33 ± 0.44 D)9,10 and nonetheless only correlated to intereye difference in steepest anterior keratometry. These findings support the notion that, in healthy patients, both corneas are mirrored in shape to a high extent and that this aspect could be exploited for early keratoconus diagnosis. The intereye difference in standardized and maximum relational thickness indices was not greater in patients with keratoconus than in control patients, a finding that underscores the reported high sensitivity of the 120

relational thickness indices for early ectatic changes.2 Although to a different grade, both eyes are thought to be affected in patients with keratoconus.25 Therefore, an early marker of disease would be expected to be altered in both eyes and not show considerable difference between eyes, in contrast to a late marker, which would more likely exhibit greater intereye difference from the change in the worse eye and lack thereof in the better eye. This hypothesis is supported by the proportion of patients with keratoconus with normal values in both eyes for Ambrosio’s relational thickness Copyright © SLACK Incorporated

Corneal Asymmetry Analysis for Keratoconus Diagnosis/Galletti et al

Figure 2. Intereye corneal asymmetry score distribution in control patients, patients with keratoconus, and indeterminate patients. Histograms of combined intereye corneal asymmetry score in control patients (n = 177), patients with keratoconus (n = 121), and indeterminate patients (n = 44).

max index, which was the lowest among the surveyed Pentacam metrics in this study (Table A). But despite the observed corneal asymmetry for most descriptors in patients with keratoconus, none of them provided adequate sensitivity and specificity when considered alone. Our findings are in agreement with Henríquez et al.,10 who reported high specificity but less sensitivity for these descriptors. Nevertheless, the high specificity of some variables could serve for readily detecting abnormal patients, which can be interpreted from Table B; it is unlikely (less than 5%) that a healthy patient would exhibit a difference greater than 0.6 D in anterior mean keratometry, greater than 0.1 D in posterior mean keratometry, greater than 5 µm in posterior elevation at the thinnest corneal point, or greater than 20 µm in central apex of thinnest corneal thickness. To improve overall performance, we analyzed combinations of corneal descriptors as diagnostic models. Both the combined score and the logistic function described in the Results section showed remarkably high specificity but moderate sensitivity, and the performance of both models was almost equivalent. However, the combined score is much simpler and could be readily assessed by the clinician without additional computation (Table 3). The false-positive rate of either model was considerably better than what we previously observed for the multivariate metric provided by the Pentacam software (overall standardized deviation index), but the sensitivity of the latter was higher.15 Although an actual comparison in the same patient sample between Placido topography and Scheimpflug tomography is lacking in the literature, the reported sensitivity in different studies for advanced topographic analysis is better than that of our intereye corneal asymmetry models.26,27 Of note, the diagnostic performance of these models was evaluated on different samples, and thus these observations Journal of Refractive Surgery • Vol. 31, No. 2, 2015

TABLE 3

Summary of Intereye Corneal Asymmetry Scorea Scoring Criteria

Positive (+1 point) if Intereye Difference

Mean anterior keratometry

≥ 0.3 diopters

Mean posterior keratometry

≥ 0.1 diopters

Thinnest pachymetry

≥ 12 µm

Front elevation at thinnest location

≥ 2 µm

Front elevation at thinnest location

≥ 5 µm

Score of 3 is observed in up to 6% to 11% of healthy patients, whereas a score of 4 is found in less than 4% of patients without keratoconus. A score of 5 should be considered highly abnormal (1% or less of non-keratoconic patients). a

cannot be generalized to other patient populations without proper validation. Nevertheless, our findings suggest that corneal asymmetry analysis should be applied to indeterminate cases in combination with corneal tomography and/or topography because its low sensitivity is not sufficient to warrant its use as the sole method for keratoconus detection. In other words, the high specificity of corneal asymmetry implies that an abnormal score should be considered a strong indicator of ectatic disease even if other corneal indices are within the normal range, whereas a normal score does not imply the absence of disease. Only 2 (3%) of 62 patients who were selected in the control group by their unremarkable single cornea analysis with Pentacam Scheimpflug tomography in both eyes had exceedingly high intereye corneal asymmetry, a proportion consistent with the keratoconus prevalence reported elsewhere. Figure A (available in the online version of this article) shows two representative cases from the control group that had three or more positive asymmetry criteria and remarkably 121

Corneal Asymmetry Analysis for Keratoconus Diagnosis/Galletti et al

also exhibited abnormal biomechanical profiles when tested with the Ocular Response Analyzer (Reichert, Inc., Buffalo, NY), a finding that characterizes early ectatic changes.4,5 Within the indeterminate group, which consisted of 44 patients who had one or more keratoconus detection indices with a suspicious value but insufficient to be classified as diseased, 3 (7%) to 5 (12%) patients showed abnormal intereye corneal asymmetry, depending on the diagnostic model employed. This finding exemplifies the conundrum faced by clinicians when dealing with real-world patients because there is a considerable fraction of patients who exhibit inconclusive findings even by Scheimpflug tomography.15 In this way, corneal asymmetry could serve to identify those patients with ectatic changes from those more likely to represent false-positives that arise from any screening technique with high sensitivity. Figures B-C (available in the online version of this article) show representative cases from the indeterminate group that exhibited normal and abnormal corneal asymmetry, respectively, which could represent false-positives and true positives, respectively. Biomechanical data from these patients were also available and were consistent with the asymmetry analysis. These examples lend credit to the potential role of corneal asymmetry assessment in early keratoconus detection but are not in any way conclusive. Therefore, the predictive value of the proposed models must be prospectively validated. There are limitations to this study. We relied on only one high-quality examination per eye to calculate corneal asymmetry and some studies have suggested that the Pentacam’s precision can be improved by averaging repeated measurements.16,17 In addition, the elevation data obtained by this device do not necessarily match that generated by other Scheimpflug devices,28 and therefore the reported diagnostic models might only apply to the Pentacam. We hypothesize that calculating intereye differences in measurements might compensate for interdevice differences, but nonetheless the diagnostic value of corneal asymmetry should be validated with other Scheimpflug tomography systems. Our results highlight the potential role of corneal asymmetry analysis for keratoconus screening. On the one hand, we derived single cutoff values for intereye asymmetry in some commonly assessed corneal descriptors, which could be readily applied to clinical practice and perhaps extended to other Scheimpflug devices. On the other hand, we showed that either a combined score or multivariate analysis of corneal asymmetry provides high specificity, which complements the already established keratoconus detection indices and thus could serve to analyze dubious cases. 122

AUTHOR CONTRIBUTIONS Study concept and design (JDG, FFB, TP, JGG); data collection (JDG, PRRV, NM, MD); analysis and interpretation of data (JDG, PRRV, NM, JGG); drafting of the manuscript (JDG, JGG); critical revision of the manuscript (PRRV, NM, MD, FFB, TP)

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assessment. J Refract Surg. 2009;25:534-538. 19. Ambrósio R, Alonso RS, Luz A, Coca Velarde LG. Cornealthickness spatial profile and corneal-volume distribution: tomographic indices to detect keratoconus. J Cataract Refract Surg. 2006;32:1851-1859. 20. Delrivo M, Ruiseñor Vázquez PR, Galletti JD, et al. Agreement between Placido topography and Scheimpflug tomography for corneal astigmatism assessment. J Refract Surg. 2014;30:4953.

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Journal of Refractive Surgery • Vol. 31, No. 2, 2015

123

TABLE A

Pentacam Ectasia Indices in Both Eyesa Analysis Dataset (n = 190) Control Patients (n = 115) Which Eyes Were Abnormal? Parameter PPIave

Validation Dataset (n = 108)

Patients With Keratoconus (n = 75) Which Eyes Were Abnormal?

Control Patients (n = 62) Which Eyes Were Abnormal?

Patients With Keratoconus (n = 46) Which Eyes Were Abnormal?

Indeterminate Group (n = 44) Which Eyes Were Abnormal?

Neither

One

Both

Neither

One

Both

Neither

One

Both

Neither

One

Both

Neither

One

Both

83.5

11.3

5.2

12.0

14.7

73.3

87.1

8.1

4.8

15.2

6.5

78.3

38.6

15.9

45.5

ARTmax

100





5.3

38.7

56.0

100





6.5

21.7

71.7

100





Df

91.3

5.2

3.5

34.7

28.0

37.3

86.9

11.5

1.6

26.1

15.2

58.7

50.0

15.9

34.1

Db

100





45.9

18.9

35.1

100





32.6

8.7

58.7

81.8

13.6

4.5

Dp

100





25.3

21.3

53.3

100





15.2

19.6

65.2

65.9

29.5

4.5

Dt

94.8

1.7

3.5

32.0

22.7

45.3

91.9

3.2

4.8

21.7

23.9

54.3

90.9

4.5

4.5

Da

100





32.9

23.3

43.8

100





19.6

15.2

65.2

100





D

100





9.5

18.9

71.6

100





8.7

13.0

78.3

15.9

38.6

45.5

PPIave = average pachymetric progression; ARTmax = Ambrosio’s maximum relational thickness; Df = standardized front deviation; Db = standardized back deviation; Dp = standardized pachymetric progression deviation; Dt = standardized thickness deviation; Da = standardized relational thickness deviation; D = standardized overall deviation a Results are shown in percentage form. Each index was analyzed with the cutoff values described in Methods: PPIave > 1.06, ARTmax < 339 and any of the standardized D indices > 1.6 were considered abnormal. It should be noted that ARTmax, Db, Dp, Da and D indices were used for classifying patients; therefore the 100% proportion of normal values in both eyes of control and indeterminate patients is meaningless, and it is shown only for consistency. The Pentacam is manufactured by Oculus Optikgeräte GmbH, Wetzlar, Germany.

0 0 0

Central corneal thickness

Apex corneal thickness

Thinnest corneal thickness

0.00

Overall deviation

5

5

2

0.03

0.05

0.01

0.01

0.02

0.03

0

0

0.01

0.00

0.00

1

0

0

0.0

0.0

0.0

0.0

0.06

0.00

0.09

10

10

4

0.05

0.10

0.02

0.03

0.05

0.05

0

0

0.03

0.01

0.01

1

1

1

0.0

0.0

0.0

0.1

0.12

0.12

0.13

25

27

10

0.09

0.25

0.07

0.11

0.13

0.17

1

0

0.06

0.01

0.03

2

3

2

0.0

0.1

0.1

0.1

0.30

0.13

0.25

PPI = pachymetric progression index; ART = Ambrosio’s relational thickness

0

0.01

Deviation of relational thickness 0

0.01

Deviation of corneal thickness

Maximum ART

0.01

Deviation of pachymetric progression

Average ART

0.01

Deviation of back elevation

0 0.00

Back elevation at thinnest point

Deviation of front elevation

0

Front elevation at thinnest point

0.00

0.0

Mean posterior keratometry

Maximum PPI

0.0

Mean anterior keratometry

0.00

0.0

Steep anterior keratometry

0.00

0.0

Flat anterior keratometry

Average PPI

0.00

Spherical equivalent

Minimum PPI

0.00

Cylinder

1 0.00

Sphere

Parameter

47

24

0.17

0.43

0.17

0.26

0.34

0.47

1

1

0.11

0.04

0.06

6

6

6

0.1

0.2

0.3

0.2

0.69

0.50

0.62

50

71

44

0.35

0.66

0.31

0.49

0.60

0.74

3

1

0.17

0.07

0.10

10

10

9

0.1

0.3

0.6

0.4

1.19

1.00

1.50

75

102

77

0.54

0.94

0.46

0.79

0.85

1.02

4

2

0.26

0.11

0.14

17

15

15

0.1

0.5

0.9

0.6

2.75

1.75

3.32

90

Control (n = 115) (Percentile) 95

139

98

0.75

1.28

0.67

1.06

1.36

1.31

5

2

0.33

0.15

0.20

22

21

20

0.2

0.6

1.6

0.9

4.37

3.66

4.06

203

329

1.29

1.85

1.07

2.49

1.58

2.70

11

4

0.57

0.37

0.43

43

49

49

0.3

1.5

2.7

2.5

7.62

11.27

7.91

99

0

1

0.02

0.01

0.00

0.01

0.02

0.02

0

0

0.00

0.00

0.00

0

1

0

0.0

0.0

0.0

0.0

0.00

0.00

0.00

1

5

3

0.07

0.04

0.08

0.06

0.06

0.09

0

0

0.03

0.01

0.00

2

1

2

0.0

0.0

0.0

0.0

0.06

0.12

0.13

5

Intereye Asymmetry

6

10

0.12

0.05

0.11

0.14

0.09

0.10

1

0

0.05

0.02

0.02

3

2

3

0.0

0.0

0.1

0.1

0.13

0.13

0.25

10

16

20

0.31

0.14

0.26

0.34

0.42

0.65

2

1

0.12

0.05

0.07

8

7

7

0.1

0.2

0.3

0.3

0.51

0.50

0.62

25

47

40

1.28

0.42

0.54

1.09

1.36

1.78

9

5

0.41

0.16

0.16

16

13

11

0.2

0.6

1.4

0.6

1.50

1.63

1.25

50

138

125

3.70

1.08

1.22

4.47

5.07

5.74

22

9

0.99

0.66

0.51

28

27

20

0.6

2.9

3.8

2.3

3.69

2.88

3.37

75

226

220

7.16

1.77

2.03

7.95

8.48

10.23

36

17

2.15

1.17

1.06

49

46

35

1.2

5.3

6.6

5.0

8.68

5.22

5.50

90

Keratoconus (n = 75) (Percentile)

Intereye Asymmetry in Control Patients and Patients With Keratoconus

AQ5TABLE B

95

279

308

9.31

2.56

2.46

12.74

12.33

11.38

55

25

2.59

1.88

1.40

59

68

50

1.7

8.1

8.2

7.3

9.98

6.80

7.83

99

395

393

11.51

3.05

4.62

35.09

19.30

20.36

60

31

8.97

5.19

3.02

117

104

96

2.5

13.5

13.8

13.2

18.13

24.25

17.00

Figure A. Two representative cases from the control group that had three or more positive asymmetry criteria and remarkably also exhibited abnormal biomechanical profiles when tested with the Ocular Response Analyzer (Reichert, Inc., Buffalo, NY).

Figure B. Two representative cases from the indeterminate group that exhibited normal corneal asymmetry and that probably represent false positives. Biomechanical testing with the Ocular Response Analyzer (Reichert, Inc., Buffalo, NY) was unremarkable.

Figure C. Two representative cases from the indeterminate group that exhibited abnormal corneal asymmetry and that probably represent true positives. Biomechanical testing with the Ocular Response Analyzer (Reichert, Inc., Buffalo, NY) produced abnormal profiles.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

Corneal asymmetry analysis by pentacam scheimpflug tomography for keratoconus diagnosis.

To evaluate intereye corneal asymmetry in Pentacam (Oculus Optikgeräte GmbH, Wetzlar, Germany) indices as a diagnostic method between normal patients ...
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