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To detect abnormal corneal thinning in keratoconus using pachymetry maps measured by high-speed anterior segment optical coherence tomography (OCT).
Cross-sectional observational study.
Thirty-seven keratoconic eyes from 21 subjects and 36 eyes from 18 normal subjects.
The OCT system operated at a 1.3 μm wavelength with a scan rate of 2000 axial scans per second. A pachymetry scan pattern (8 radials, 128 axial scans each; 10 mm diameter) centered at the corneal vertex was used to map the corneal thickness. The pachymetry map was divided into zones by octants and annular rings. Five pachymetric parameters were calculated from the region inside the 5 mm diameter: minimum, minimum–median, inferior–superior (I-S), inferotemporal–superonasal (IT-SN), and the vertical location of the thinnest cornea. The 1-percentile value of the normal group was used to define the diagnostic cutoff. Placido-ring–based corneal topography was obtained for comparison.
The OCT pachymetric parameters and a quantitative topographic keratoconus index (keratometry, I-S, astigmatism, and skew percentage [KISA%]) were used for keratoconus diagnosis. Diagnostic performance was assessed by the area under the receiver operating characteristic (AROC) curve.
Keratoconic corneas were thinner. The pachymetric minimum averaged 452.6±60.9 μm in keratoconic eyes versus 546±23.7 μm in normal eyes. The 1-percentile cutoff was 491.6 μm. The thinnest location was inferiorly displaced in keratoconus (−805±749 μm vs −118±260 μm ; cutoff, −716 μm). The thinning was focal (minimum–median: −95.2±41.1 μm vs −45±7.7 μm ; cutoff, −62.6 μm). Keratoconic maps were more asymmetric (I-S, −44.8±28.7 μm vs −9.9±9.3 μm ; cutoff, −31.3 μm ; and IT-SN, −63±35.7 μm vs −22±11.4 μm ; cutoff, −48.2 μm). Keratoconic eyes had a higher KISA% index (2641±5024 vs 21±19). All differences were statistically significant (t test, P<0.0001). Applying the diagnostic criteria of any 1 OCT pachymetric parameter below the keratoconus cutoff yielded an AROC of 0.99, which was marginally better (P= .09) than the KISA% topographic index (AROC, 0.91).
Optical coherence tomography pachymetry maps accurately detected the characteristic abnormal corneal thinning in keratoconic eyes. This method was at least as sensitive and specific as the topographic KISA.
Proprietary or commercial disclosure may be found after the references.
Keratoconus is a bilateral progressive ectatic corneal disease characterized by thinning and apical protrusion.1,2 The clinical diagnosis of moderate to advanced keratoconus is not difficult because of the characteristic topographic pattern and the classic clinical signs.2 However, diagnosing early keratoconus in patients with normal best spectacle-corrected visual acuity and minimum or no clinical signs can be challenging.3 This identification is especially important in preoperative screening for laser refractive surgeries because undetected corneal ectatic disorders can result in accelerated, progressive keratoectasia and unpredictable outcomes after LASIK and photorefractive keratectomy.1,4-8
Currently, Placido-disk–based corneal topography is regarded as the most sensitive measurement for detecting ectatic corneal disorders such as keratoconus and pellucid marginal degeneration.9-13 Topographic analyses have revealed characteristic features of these diseases before biomicroscopic signs or symptoms.14,15 Normal, suspicious, and abnormal topography patterns of these diseases had been classified.8,16 Quantitative topographic indices, such as the Rabinowitz–McDonnell index,17 the keratoconus prediction index,18 the Z3 index,19 the keratometry, inferior-superior (I-S), astigmatism, and skew percentage (KISA%) index,20 and the mean curvature,21,22 have been developed to help diagnose keratoconus, and these indices are highly sensitive for keratoconus detection.2,20,23,24 However, topography screening methods have shortcomings. First, satisfactory topography maps may not available owing to cornea irregularity or tear film breakup. Second, topography may not detect all patients at risk for keratectasia; Randleman et al8 reported a meta-analysis in which 27% of 93 postrefractive surgery ectasia cases had normal preoperative topography, and 22% have an equivocal pattern (asymmetric bowtie). The asymmetric bowtie pattern is overrepresented in fellow eyes and relative eyes of keratoconus, but also occurs in normal eyes.25 Third, it is difficult for these topography-based methods to distinguish keratoconus from contact lens–induced warpage, subepithelial deposits or scarring, uneven tear film, lid artifact, or other causes of corneal distortion.26-28 These causes of topographic distortion may cause a false-positive diagnosis of keratoconus or mask a true diagnosis of keratoconus.
Corneal thinning is a key pathologic feature of keratoconus1; therefore, a keratoconus diagnosis based on corneal thickness measurement may offer additional information not available on topography.3,29 Corneal thickness has been proposed to be a useful parameter for the clinical identification of keratoconus.30-34 Studies using ultrasound or slit-scanning technologies have found that the difference (or ratio) between the peripheral and the thinnest (or central) corneal thickness was significantly greater in eyes with keratoconus than in normal eyes.3,35-38 However, to the best of our knowledge, corneal focal thinning and asymmetric thinning have not been evaluated together to detect corneal abnormality in keratoconus.
Optical coherence tomography (OCT) has micron-level high resolution and can accurately map the corneal thickness of normal, postoperative, and opacified corneas.39-41 In this study, we developed a keratoconus screening method using a high-speed anterior segment OCT prototype. We compared the OCT pachymetry-based method with a topography-based KISA% method for categorized diagnosis of keratoconus.
Thirty-seven keratoconic eyes of 21 patients (12 men and 9 women) were recruited for this cross-sectional observational study at the Cleveland Clinic Cole Eye Institute, Cleveland, Ohio. Thirty-six eyes of 18 normal subjects (10 men and 8 women) were also included as a control group. This study followed the tenants of the Declaration of Helsinki, was in accord with the Health Insurance Portability and Accountability Act of 1996, and was approved by the Institutional Review Board of Cleveland Clinic. Written informed consent was obtained from all the subjects.
Keratoconic eyes included in this study were diagnosed clinically; each had ≥1 clinical sign other than the topographic appearance of the map, including slit lamp findings of Munson’s sign, hydrops, Vogt’s striae, Fleischer’s ring, apical scar, apical thinning, or Rizutti’s sign. None of the eyes had signs or history of other cornea disease, and none had undergone previous ocular surgery.
The OCT pachymetry map scans (Fig 1) were acquired with a high-speed anterior segment OCT prototype (Carl Zeiss Meditec Inc., Dublin, CA) as previous described.39 Each eye was scanned 3 times within a single visit and the pachymetry maps were calculated. The maps (Fig 2) were divided into zones by octants: superior (S), superotemporal (ST), temporal (T), inferotemporal (IT), inferior (I), inferonasal (IN), nasal (N), superonasal (SN), and annular rings (2, 5, 7, and 10 mm diameters).
We constructed several diagnostic parameters from the OCT pachymetric map with the aim of capturing the focal and asymmetric nature of keratoconic corneal thinning. The parameters were calculated from the central 5 mm diameter of the pachymetry map. The octant values were averaged in the 2- to 5-mm diameter zone. The 5 pachymetric diagnostic parameters were as follows:
Focal thinning was captured by the minimum–median and minimum parameters. Asymmetric thinning was captured by the I-S and IT-SN parameters, and by the vertical location of the minimum.
Topography maps of the corneas were obtained with a Placido-ring corneal topography system (Atlas 995, Carl Zeiss Meditec). The average keratometry reading (Sim-K) was calculated by taking the average of the flat K and steep K readings from Atlas. The KISA% index was calculated using a previously published method for all subjects.20 The published threshold value for a classification keratoconus is KISA% > 100.42
The repeatability of the OCT pachymetry map was evaluated by the root-mean-square deviation from the average corneal thickness map. The repeatability of each OCT pachymetric parameter was calculated by pooled standard deviation (SD) of repeated measurements.43 The mean value ± SD of each pachymetric parameter was calculated for both the keratoconus and normal groups. The normality of the OCT diagnostic parameters was confirmed by a Kolmogorov–Smirnov test on the dataset, in which 1 eye was randomly selected from each normal subject. The generalized estimating equation44 was used to account for the inter-eye correlation in the variance of t test.
The 1-percentile value (mean – 2.33 SD) of the normal group was used to define the cutoff value of each pachymetry parameter. Two criteria, “1 abnormal” or “2 abnormal,” were used to screen keratoconus. With the “1 abnormal” criterion, if any of the pachymetric parameter values exceeded the cutoff value, the eye was considered to be keratoconic. Similarly, with the “2 abnormal” criterion, if any 2 of the parameters were abnormal, the eye was keratoconic.
Receiver operating characteristic (ROC) curve analyses were performed to compare the diagnostic performance of OCT pachymetry and KISA%. The ROC curves of the “1 abnormal” and “2 abnormal” criteria were generated by “composite scores” based on the standardized deviation of the 5 pachymetric diagnostic parameters. The ROC curve generated by the composite scores had been used in other ophthalmology studies.45 The composite scores for “1 abnormal” and “2 abnormal” criteria were calculated as follows: The mean and SD of the normal group were denoted by meanN and SDN. Then the standardized deviation of a OCT pachymetry parameter value (denoted by OCTscore) was defined by:
The composite score of the “1 abnormal” criterion was the most negative among the 5 standardized deviations (the parameters were defined so that more negative values are indicative of keratoconus). The composite score of the “2 abnormal” criterion was the second lowest of 5 standardized deviations. Moreover, the AROC values were computed based on the formula in Obuchowski46 extending the nonparametric method of Delong et al47 to clustered data. The standard error of sensitivity and specificity was computed based on the formula for clustered binary data derived by Rao and Scott.48 The same method was already used in previous studies in ophthalmology45,49 to handle the intereye correlation appropriately.
We set the level of significance at P<0.05. The AROC, sensitivity, and specificity analyses were performed with MATLAB 7.0 (The MathWorks, Inc., Natick, MA) and the other analyses were done in SAS 9.1 (SAS Institute Inc., Cary, NC).
Keratoconus cases had an average spherical error of −8.0±6.1 diopters (D; mean ± SD; range −22.5 to 0). The average astigmatism in these eyes was 3.2±2.2 D (range, 0–7.0). The average keratometry reading (Sim-K) was 49.2±5.2 D (range, 40.8–60.9). For the normal group, the mean spherical error was −3.7±2.2 D (range, −8.75 to 1.25). The mean astigmatism was 0.8±0.7 D (range, 0–2.75). The average recorded keratometry reading was 43±1.4 D (range, 41–47).
The repeatability of the OCT pachymetry map inside the central 5-mm zone was 3.0 μm for the normal eyes and 5.0 μm for the keratoconic eyes. The repeatability of the individual OCT pachymetric parameters are given in Table 1. In general, the parameters were more reproducible in normal eyes than in keratoconic eyes. The I-S and the IT-SN asymmetric parameters were more repeatable in the 2- to 5-mm diameter zone than in the outer zones (>5 mm).
The average OCT pachymetric measurements are listed in Table 2. The pachymetric parameters of the keratoconus eyes were all significantly smaller than those of the normal eyes (P<0.0001 by 2-sided generalized estimating equation t test).
The 1-percentile cutoff values for the OCT pachymetric diagnostic parameters are listed in Table 3. The cutoff values were 491.6 μm for minimum; −62.6 μm for minimum–median; −31.3 μm for I-S; −48.2 μm for IT-SN; and −716 μm for the vertical location of the thinnest corneal region.
The sensitivity, specificity, and AROC of the individual OCT parameters are listed in Table 4. All OCT parameters had good diagnostic power to detect keratoconus eyes with AROC (0.868–0.954) and good sensitivities (0.622–0.757) at the 1-percentile cutoff. The minimum parameter has the best AROC (0.954); however, there is no statistical difference among the 5 parameters. The minimum–median parameter had the second highest AROC (0.929) and the best sensitivity (0.757).
The KISA% indices were 2641±5024 for the keratoconus group and 21±19 for the normal group. The cutoff value of the KISA% was 100, reflecting a previously published method.42
The sensitivity and the specificity of the OCT method and KISA% methods are compared in Table 5. The ROC curves of the OCT keratoconus screening method with the “1 abnormal” rule and the KISA% method are plotted in Figure 3. Both methods provided excellent discrimination between normal and keratoconic eyes. The AROC was 0.99±0.01 for the OCT method and 0.91±0.05 for the KISA% method. The difference between the AROC values was not statistically significant (P= 0.09).
Case 1 (Fig 4A) was an keratoconic eye with Munson’s sign, Vogt’s striae, Fleisher’s ring, apical scar, apical thinning, and Rizutti’s sign. The topographic KISA% value was calculated to be 49 647. The OCT pachymetric parameters were: minimum–median = −161.6 μm; I-S = −60.8 μm; IT-SN = −104 μm; minimum = 380.1 μm; and vertical location of the minimum = −921 μm. All the parameters exceeded the keratoconus thresholds. Both topographic and OCT pachymetric analysis accurately classified this eye as keratoconic. In contrast with the loss of data in the topography map, OCT was able to measure the pachymetry map over a wide area of central cornea.
Case 2 (Fig 4B) was an keratoconic eye with Munson’s sign and Rizutti’s sign. The topographic KISA% value was 9. The OCT pachymetric parameters were as follows: minimum-median = −37.3 μm; I-S = −42 μm; IT-SN = −37.3 μm; minimum = 496.9 μm; and vertical location of the minimum = −1470 μm. The KISA% method misclassified this eye as normal. The OCT pachymetric analysis accurately identified the eye as keratoconic, based on 2 abnormal parameters: I-S and the vertical location of the minimum. Inspection of the topography map indicated a skewed and asymmetric bow-tie astigmatism pattern that could be due to keratoconus. However, the skew and asymmetry were not picked up by automated topography analysis (I-S and skewed radial axis were normal) because of masking by what seems to be an upper lid artifact.
Case 3 (Fig 4C) was a keratoconic eye with Munson’s and Rizutti’s signs. The KISA% value was 23. The OCT pachymetric parameters were as follows: minimum-median = −84.3 μm (below the cutoff of −63 μm); I-S = −25 μm; IT-SN = −29.4 μm; minimum = 429.9 μm (below the cutoff of 492 μm); and vertical location of the minimum = −2503 μm (below the cutoff of −716 μm). The KISA% index misclassified this eye as normal. The OCT pachymetric analysis accurately identified the eye as keratoconic, based on 3 abnormal parameters: minimum–median, minimum, and the vertical location of the minimum. Inspection of the topography map showed possible asymmetry in the bow-tie astigmatism pattern that could indicate keratoconic inferotemporal steepening. However, this possibility was difficult to assess, owing to irregular variations in the inferotemporal region of the topography map that might be due to an irregular poor tear film. The asymmetry was not picked up by automated topography analysis (I-S was within normal limits).
The OCT pachymetry maps are highly repeatable: Our study showed a pooled root-mean-square repeatability of 3 μm (normal) or 5 μm (keratoconus). We applied keratoconus analysis to the central 5-mm area of the OCT pachymetry maps, because we had previously found the repeatability to be better in the 0- to 5-mm diameter zones than in larger diameter zones.39 This was confirmed for keratoconus parameter calculations (I-S and IT-SN) in this study (Table 1). Another rationale for applying the analysis to the central 5-mm region is that the cone peak of a keratoconic eye is most likely located inside this region.22
Minimum (or central) corneal thickness is the most frequently cited pachymetric parameter to evaluate keratoconus. Rabinowitz et al,33 Pflugfelder et al,3 and several other research groups29,31,32,34 reported that keratoconic corneas were significantly thinner than normal corneas (Table 6). Minimum corneal thickness was the best parameter in our study (highest AROC value, 0.954). However, a low “minimum corneal thickness” value could also be due to generalized corneal thinning, focal thinning, or both; it might not specifically indicate keratoconus. Binder’s study50 showed that a thin cornea may not necessary lead to ectasia after refractive surgeries. Furthermore, the normal corneal thickness range has a wide distribution: The average central corneal thickness of normal eyes is 536±31 μm (median ± SD), as determined by a metaanalysis.51 The smaller population SD of 23.7 μm found in our study might be due to the relatively small sample size; the 492-μm cutoff value derived from our normal reference data might be too high and might result in lower specificity when applied to larger populations. In the future, larger studies will more firmly establish the diagnostic cutoff values and diagnostic performance of OCT pachymetric map analysis.
Focal corneal thinning is possibly a more specific indicator of keratoconus.2 We designed a new parameter—“minimum–median”—to detect focal thinning. The AROC of this difference parameter was not higher than the minimum, but we considered these 2 parameters to be complementary, because they measured different aspects of corneal thinning (focal and general).
In addition to focal thinning, Vinciguerra and Camesasca52 and Binder et al5 summarized that asymmetric and eccentric corneal thinning were also characteristics of keratoconus. To evaluate the asymmetry of the map, we calculated the difference between the average corneal thicknesses from all possible pairs of 4 opposite octants: I-S, IT-SN, T-N, and IN-ST. We found that only the I-S and IT-SN parameters yielded significant differences between the keratoconus and the normal groups (P<0.0001). The correlation coefficient between I-S and IT-SN was 0.74; therefore, we considered them to have some complementary information and used both octant differences as asymmetry parameters. To evaluate the eccentricity of the corneal thinning, we calculated 2 parameters: the distance from the thinnest corneal point to the corneal vertex, and the vertical location of the thinnest corneal point. We found that the vertical location of the thinnest corneal point had better discriminative power (AROC values, 0.92 vs 0.86), and we therefore selected it as the eccentricity parameter.
Our results suggested that the 5 OCT pachymetric diagnostic parameters we selected were highly complementary. The “1 abnormal” criterion improved the diagnosis power for keratoconus and provided an excellent combination of sensitivity (0.97) and specificity (0.97). And with “2 abnormal” criterion, the specificity of keratoconus diagnosis was very high (1.00). Of course, larger studies are necessary to validate our findings. Moreover, our study is a preliminary study consisting only of keratoconus cases that had been confirmed by clinical (slit lamp) signs. Therefore, the sensitivity of OCT in the detection of forme fruste keratoconus (those without clinical signs) has yet to be established.
An OCT pachymetry map analysis can provide decisive diagnostic information in cases where topography is ambiguous. In case 1, part of the topography map was loss might owing to poor corneal reflex. In contrast, OCT was able to provide pachymetry map over a wide area of central cornea. In cases 2 and 3, KISA% analysis identified the topography maps as within normal range, because asymmetry or skew in the bowtie astigmatism pattern were masked by irregularities that might be due to a lid artifact or tear film disturbance. Performance of OCT was not affected by these conditions. It is an important advantage that OCT can reliably map the corneal thickness of normal, postoperative, and opacified corneas.39-41
One limitation of the current OCT technology is that interpolation is used in the central 0.5- to 1.0-mm diameter and among the 8 radial scans. Thus, small areas of corneal thickness variation might be missed.39 Another limitation of the OCT system used in this study was that it was not fast enough to measure the corneal topography; therefore, it could not completely replace a Placido-ring topography system. In a previous study, we found the repeatability of anterior corneal power by this OCT system to be 0.79 D,53 significantly worse than the repeatability of standard keratometry (0.2 D) or Placido-ring topography (0.1 D).54 These findings suggested that the scan speed of 2000 a-scans/sec might not be sufficient to overcome the motion error for surface contour measurements. Thickness measurement was much more robust, because axial eye motion moved the anterior and posterior surface equally and had little effect on the thickness measurement. Therefore, we concentrated on pachymetry map analysis in this study. However, the speed limitation is not intrinsic to OCT; new Fourier-domain OCT technology is capable of >10-fold higher scan speeds.55 We are currently evaluating Fourier-domain OCT as a method to map both pachymetry and topography.
A commercially available OCT instrument similar in performance (wavelength, scan range, speed, signal) to the anterior segment OCT prototype used in this study, the Visante anterior segment OCT system (Carl Zeiss Meditec Inc.), was approved by the US Food and Drug Administration in October 2005. Thus, the keratoconus screening method presented in this study can now be applied by other researchers and clinicians. Because the Visante software uses different image processing algorithms and has a slightly different parameter output format, we are performing another study to confirm our findings using the commercial unit.
In summary, we showed that OCT pachymetry map-based analysis could detect abnormal corneal thinning in keratoconus eyes. We provide a set of 5 diagnostic parameters and cutoff values that performed well together in our small study.
The authors thank Dr William J. Dupps, Jr, for reviewing this manuscript and providing insightful suggestions. The authors thank Dr Mariana Avila for her assistance in this project.
Supported by NIH R01 EY018184, Carl Zeiss Meditec, Inc., NIH Core Grant EY03040.
Presented in part at: Association for Research in Vision and Ophthalmology (ARVO) annual meeting, May 9, 2007, Fort Lauderdale, Florida.
David Huang receives royalties from the Massachusetts Institute of Technology derived from an optical coherence tomography patent licensed to Carl Zeiss Meditec, Inc. (Dublin, CA). David Huang and Yan Li receive research grant support from Carl Zeiss Meditec Inc. The other authors do not have proprietary interest in the topic of this manuscript.