Glaucoma-Diagnostic Ability of Ganglion Cell-Inner Plexiform Layer Thickness Difference Across Temporal Raphe in Highly Myopic Eyes

Abstract

Purpose: To evaluate the glaucoma-diagnostic ability of the ganglion cell-inner plexiform layer (GCIPL) thickness difference across the temporal raphe in highly myopic eyes.

Methods: We consecutively enrolled a total of 195 highly myopic eyes (axial length [AL] >26.5 mm) of 195 subjects: 93 glaucoma patients along with and 102 nonglaucomatous subjects. Cirrus high-definition optical coherence tomography (OCT) was employed to scan all of the subjects' macular and optic discs. Using a MATLAB-based customized program (the GCIPL hemifield test), a positive test result was automatically declared if the following two conditions were met: (1) the horizontal line is detected for longer than one-half of the distance from the temporal inner elliptical annulus to the outer elliptical annulus, and (2) the average GCIPL thickness difference within 10 pixels of the reference line, both above and below, is 5 μm or more. The glaucoma-diagnostic ability was computed using the area under the receiver operating characteristic curve (AUC).

Results: Among the glaucomatous eyes, GCIPL hemifield test positivity was shown in 92.5% (86 of 93), significantly higher than that for the nonglaucomatous eyes (4.90%, 5 of 102; P <0.001). The value of AUC for the GCIPL hemifield test was excellent (0.938; sensitivity 92.50%, specificity 95.10%) and was the best compared with those for any of OCT parameters.

Conclusions: In highly myopic eyes, determination of the presence or absence of GCIPL thickness difference across the temporal raphe via OCT macula scan can be a useful means of distinguishing the glaucomatous damage.

Evaluation of retinal nerve fiber layer (RNFL) thinning is crucial to successful glaucoma management.^1–3 With an improved examination modality (i.e., spectral-domain optical coherence tomography [OCT]), it has become feasible to reproducibly measure the circumpapillary RNFL thickness as well as to serially monitor its change.^4–7 However, in highly myopic eyes, circumpapillary RNFL measurement is not always reliable, because the disc-margin definition algorithm in the optic disc cube protocol can be influenced by optic disc variation such as tilting, oval configuration, and peripapillary atrophy.^8,9 Furthermore, a 3.46-mm diameter scan circle is used routinely to assess RNFL thickness even in large-sized or tiled discs of highly myopic eyes.^10–12 

Macular ganglion cell-inner plexiform layer (GCIPL) thickness is a parameter that reflects the thickness of glaucoma-affected retinal ganglion cell (RGC) bodies and their axons.¹³ High-definition (HD)-OCT (Cirrus; Carl Zeiss Meditec, Dublin, CA, USA) provides the ganglion cell analysis (GCA) algorithm for macular GCIPL thickness measurement.¹⁴ And as the macular region is free from optic disc variation, macular GCIPL thickness measurement has been utilized as a good glaucoma-discrimination tool for highly myopic eyes.¹⁵ 

In clinical practice, there are a number of challenging high-myopia cases that render determination of the presence or absence of glaucomatous damage difficult. For instance, in the case presented in Figure 1, there was no evidence on the disc photograph, RNFL photograph, RNFL deviation map, or RNFL thickness map warranting suspicion of structural glaucomatous damage. Nonetheless, definite glaucomatous visual-field defect was present in the superior hemifield. Interestingly in this regard, the GCIPL thickness map clearly indicated the glaucomatous damage: macular GCIPL thinning in the corresponding area with a horizontally demarcated line at the temporal macula (see the red arrow in Fig. 1F). These findings imply that GCA algorithm can be useful for discrimination of glaucomatous structural loss in highly myopic eyes. 

Figure 1

 

Case of highly myopic eye (axial length 26.82 mm, spherical equivalent −7.25 D) presenting difficulty in distinguishing presence of glaucomatous damage by (A) disc photograph, (B) RNFL photograph, (C) RNFL deviation map, (D) and RNFL thickness map. Interestingly, the (F, G) GCIPL deviation map and thickness map indicated structural glaucomatous damage (i.e., inferior macular GCIPL thinning) (E, F). Additionally, the GCIPL thickness map showed a horizontally demarcated line in the (G) temporal macular area (red arrow on F). Definite functional glaucomatous defect shown in (H) corresponding visual field (i.e., superior hemifield) (G).

Our group recently introduced a MATLAB-based computer program (the GCIPL hemifield test) for automated detection of GCIPL thickness difference across the temporal raphe and discrimination, thereby, of early-glaucomatous change in eyes with an spherical equivalent (SE) > −6 diopters (D) and <3 D.¹⁶ As glaucomatous structural loss temporal to the macula is often, for well-known anatomic reasons, asymmetric,^17–20 observation of the step-like configuration of the GCIPL thickness near the temporal raphe was effective for discrimination of early-glaucomatous structural loss.¹⁶ Thus prompted, the present study was undertaken to evaluate the glaucoma detection ability of the GCIPL hemifield test in eyes with high myopia (axial length [AL] >26.5 mm). 

Methods

This study was approved by the Seoul National University Hospital Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. 

Study Subjects

Highly myopic eyes with glaucoma along with highly myopic eyes without glaucoma examined at the Glaucoma Clinic of Seoul National University Hospital between January 2011 and January 2016 were consecutively enrolled on the basis of a retrospective medical-record review. All subjects underwent a complete ophthalmic examination, including visual acuity assessment; refraction; slit-lamp biomicroscopy; gonioscopy; Goldmann applanation tonometry (Haag-Streit, Koniz, Switzerland); and dilated stereoscopic examination of the optic disc. They also underwent central corneal thickness (CCT) measurement (Orbscan 73 II; Bausch & Lomb Surgical, Rochester, NY, USA); AL measurement (Axis II PR; Quantel Medical, Inc., Bozeman, MT, USA); digital color stereo disc photography; red-free RNFL photography; optic nerve head (ONH) and macular imaging by HD-OCT (Cirrus; Carl Zeiss Meditec) and a central 30-2 threshold test of the Humphrey visual field (HVF, HFA II; Humphrey Instruments, Inc., Dublin, CA, USA). 

For inclusion, individuals were required to have an AL >26.5 mm and a normal open anterior chamber angle. Individuals were excluded from further analysis based on the following criteria: (1) the existence of a secondary cause of glaucomatous optic neuropathy; (2) a history of intraocular surgery (except cataract surgery) or retinal laser photocoagulation; and (3) any neurologic or systemic diseases that could affect retinal or visual-field results. One eye was randomly selected if both were found to be eligible. 

All stereo disc photographs were examined for a glaucomatous optic disc appearance by two experienced, masked examiners (YYK, KHP) working independently of each other. At the time of the evaluation, neither examiner was aware of the perimetric findings or of any other clinical data. We differentiated between the absolute and relative criteria for diagnosis of glaucomatous optic disc described previously by Jonas et al.²¹ The absolute criteria include a notch in the neuroretinal rim in the temporal inferior disc region or temporal superior disc region, localized RNFL defects that cannot be explained by any cause other than glaucoma, and an abnormally large cup size as compared with the optic disc size. The relative criteria were a neuroretinal rim markedly narrower in the inferior disc region than in the superior disc region, even if the smallest neuroretinal rim part was located in the temporal horizontal disc region; a diffuse decrease in the visibility of the RNFL (particularly in eyes with small discs), if there were no other reasons other than glaucoma for the loss; and an optic disc hemorrhage, if there were no other causes for disc hemorrhages. If none of the absolute criteria were positive, at least two of the relative criteria had to be fulfilled. 

Glaucomatous visual-field defect was defined as (1) a cluster of 3 points with probabilities less than 5% in at least 1 hemifield on the pattern deviation map, including at least 1 point with a probability less than 1% or a cluster of 2 points with a probability less than 1%; (2) glaucomatous Hemifield test results outside of the normal limits; or (3) a pattern standard deviation (PSD) beyond 95% of the normal limits, as confirmed by at least two reliable examinations (false-positive/negatives <15%, fixation losses <15%). Visual-field defects located in the central visual field that were correspondent with myopic macular change were not considered. 

Eyes were diagnosed as highly myopic glaucoma if the following two conditions were met: glaucomatous-type optic disc appearance and the presence of glaucomatous visual-field defect. The highly myopic controls without glaucoma had an IOP ≤ 21 mm Hg, no IOP-elevation history, no glaucomatous-type optic disc appearance, and the absence of glaucomatous visual-field defects. 

Cirrus High-Definition Optical Coherence Tomography Measurement

Optic-disc (optic disc cube 200 × 200 protocol) and macular scans (macular cube, 512 × 128 protocol) using HD-OCT software (Cirrus, version 6.0; Carl Zeiss Meditec) for RNFL and GCIPL thickness measurements, respectively, were carried out. Poor-quality images showing eye motion, blinking artifacts or poor centration were discarded by the examiner, and those with a signal strength <7 were excluded from the study. The circumpapillary RNFL thicknesses were measured overall, in each of the four quadrants and in each of the 12 o'clock-hour sectors. The average, minimum, and six sectorial (superotemporal, superior, superonasal, inferonasal, inferior, inferotemporal) GCIPL thicknesses in an elliptical annulus were measured in the macular cube scan mode.^22,23 

GCIPL Hemifield Test

For automated detection of GCIPL thickness difference across the temporal raphe, the GCIPL hemifield test, a customized software (MATLAB, version 2013a; MathWorks, Inc., Natick, MA, USA), was employed, as described previously (Fig. 2).¹⁶ Briefly, the GCIPL hemifield test automatically extracted, from the GCIPL thickness map, a 32-bit color-scale image of an elliptical annulus of 2.0-mm vertical outer radius and 2.4-mm horizontal outer radius. Then, it employed the Hough transform algorithm for automated image–processing-based line detection on the GCIPL thickness map. Hough transform is a technique widely utilized in the image processing field for detection of lines according to their parametric representation. Generally in Hough transform implementation, the threshold is selected heuristically. Setting the threshold too low or too high can give rise to false positivity or misdetection, respectively, for a given shape. According to the set threshold, the small gaps in line segments were determined to be automatically filled or not. Then, the endpoints of the line segments corresponding to the peaks in the Hough transform were found. Subsequent image processing for detection of color values was conducted only in cases where horizontal reference lines longer than one-half the distance from the temporal inner elliptical annulus to the outer elliptical annulus were successfully detected. The red, green, and blue (RGB) color values of the pixels above and below the detected line dividing the superior and inferior hemifields were determined and subsequently converted to GCIPL thicknesses based on the GCIPL thickness map's reference color bar. 

Figure 2

 

Schematic representation of GCIPL hemifield test for automated detection of hemifield difference across temporal raphe on HD OCT (Carl Zeiss Meditec) GCIPL thickness map. (A) The hemifield test of GCIPL automatically extracted, from a GCIPL thickness map, a 32-bit color-scale image of an elliptical annulus of 2.0 mm vertical outer radius and a 2.4 mm horizontal radius. (B, C) The reference line (red dashed line), running from the temporal inner elliptical annulus to the outer elliptical annulus and dividing the superior and inferior hemifields, was detected using a computer program. (C) The average RGB color values of 10 pixels both above and below the (black dashed line) reference line were calculated and automatically converted to GCIPL thicknesses based on the GCIPL thickness map's reference color bar. (D) The glaucoma hemifield test on a left eye showed a positive result, because both of the following two conditions were met: (1) the reference line (a red horizontal line dividing the superior and inferior hemifields) is detected for longer than one-half of the distance from the temporal inner elliptical annulus to the outer elliptical annulus; and (2) the average GCIPL thickness difference within 10 pixels of the reference line, both above and below, is 5 μm or over.

The optimal cutoff values for classifying cases as positive or negative were evaluated by reference to the areas under the receiver operating characteristic curves (AUCs). A positive (i.e., “outside normal limits”) GCIPL hemifield test was declared if the following two conditions were met: (1) the reference line (a horizontal line dividing the superior and inferior hemifields) is detected for longer than one-half of the distance from the temporal inner elliptical annulus to the outer elliptical annulus; and (2) the average GCIPL thickness difference within 10 pixels of the reference line, both above and below, is 5 μm or over. 

Statistical Analysis

For the healthy and glaucoma groups, the age and SE of refractive error differences were obtained using independent t-tests; sex differences were computed using χ² tests. The glaucoma-diagnostic abilities were compared on the basis of the computed area under the AUC values. The sensitivities and specificities were calculated according to the optimal cutoff point, which was set as the maximum of the Youden index (obtained as J = max [sensitivity + specificity − 1]). Statistical analyses were performed with statistical software (SPSS version 19; SPSS, Inc., Chicago, IL, USA) and the AUC comparisons with statistical software (MedCalc14.12; MedCalc Software, Mariakerke, Belgium). Values of P less than 0.05 were considered statistically significant. The data ranges were recorded as mean ± standard deviations. 

Results

Study Subjects

On the basis of a medical record review, we recruited, for the present study, 93 highly myopic eyes of 93 glaucoma patients along with 102 highly myopic eyes of 102 nonglaucomatous subjects, which fulfilled the eligibility criteria. The study population's clinical characteristics are provided in Table 1. The mean age of the glaucomatous subjects (n = 93) was 49.05 ± 11.8 years (32–65); 51 were men (54.8%) and 42 were women (45.2%). The mean age of the nonglaucomatous subjects (n = 102) was 46.28 ± 13.0 years (30–68); 60 were men (58.8%) and 42 were women (41.2%). The glaucomatous subjects ranged, in AL from 26.51 to 33.52 mm (28.79 ± 1.97 mm), in SE of refractive error from −13.75 to −7.50 D (−11.97 ± 2.31 D), and in MD from −12.79 to −3.53 dB (−7.05 ± 3.12 dB). The nonglaucomatous subjects ranged, in AL from 26.53 to 33.07 mm (29.01 ± 2.21 mm), in SE of refractive error from −14.25 to −6.50 D (−11.75 ± 2.70 D), and in MD from −1.89 to 2.55 dB (−0.29 ± 1.25 dB). The differences in age, sex, AL, SE, IOP, and central corneal thickness between the glaucomatous and nonglaucomatous eyes were not statistically significant. 

Table 1

 

Clinical Characteristics of Study Participants With High Myopia

 

Cirrus High-Definition OCT Index

Table 2 shows that all of circumpapillary RNFL parameters (i.e., average, superior, nasal, inferior, temporal RNFL thickness and absolute difference of circumpapillary RNFL thickness between the superior and inferior quadrants) and the GCA parameters (i.e., average, minimum, superotemporal, superior, superonasal, inferonasal, inferior, inferotemporal GCIPL thickness and absolute difference of GCIPL thickness between the superotemporal and inferotemporal sectors) were lower in the glaucomatous than in the nonglaucomatous eyes. However, statistically significant differences were shown only in superior RNFL thickness (P < 0.001); inferior RNFL thickness (P = 0.008); superior-inferior difference of circumpapillary RNFL thickness (P < 0.001); average GCIPL thickness (P = 0.005); minimum GCIPL thickness (P = 0.001); inferior GCIPL thickness (P = 0.041); inferotemporal GCIPL thickness (P <0.001); and superior-inferior difference of GCIPL thickness (P = 0.042). 

Table 2

 

Circumpapillary RNFL and Macular GCIPL Thickness Obtained Using Cirrus HD OCT

 

Diagnostic Ability of GCIPL Hemifield Test

Among the glaucomatous eyes, GCIPL hemifield test positivity was shown in 92.5% (86/93), significantly higher than that for the nonglaucomatous eyes (4.90%, 5/102; P < 0.001). The AUC value for the GCIPL hemifield test was excellent (0.938; sensitivity 92.50%, specificity 95.10%) and was the best compared with those for any of OCT parameters: 0.784 (sensitivity 80.50%, specificity 76.05%) of average RNFL thickness, 0.775 (sensitivity 78.25%, specificity 80.21%) of average GCIPL thickness, 0.818 (sensitivity 81.00%, specificity 79.33%) of minimum GCIPL thickness, and 0.814 (sensitivity 79.21%, specificity 82.50%) of inferotemporal GCIPL thickness (all P < 0.001, when comparing the AUC values between each parameter and the GCIPL hemifield test; Table 3, Fig. 3). 

Table 3

 

Areas Under the Receiver Operating Characteristic Curve of GCIPL Hemifield Test and Cirrus HD OCT Parameters (95% Confidence Interval)

 

Figure 3

 

Areas under receiver operating characteristic curves discriminating glaucomatous eyes from nonglaucomatous eyes in highly myopic subjects. The value of AUC for the GCIPL hemifield test was excellent (0.938; sensitivity 92.50%, specificity 95.10%); moreover, it was significantly higher than that of the average RNFL thickness (0.784; sensitivity 80.50%, specificity 76.05%); average GCIPL thickness (0.775; sensitivity 78.25%, specificity 80.21%); minimum GCIPL thickness (0.818; sensitivity 81.00%, specificity 79.33%); and inferotemporal GCIPL thickness (0.814; sensitivity 79.21%, specificity 82.50%; all P < 0.001, when comparing the AUC values between each parameter and the GCIPL hemifield test).

For the subgroup analysis according to the stages of glaucoma, study subjects were divided into two groups: the group with early glaucoma (n = 43; HVF mean deviation [MD] better than −6 dB) and the group with moderate-to-advanced glaucoma (n = 50; HVF MD worsen than −6 dB). Among the group with early glaucoma, the GCIPL hemifield test positivity was shown in 93.0% (40/43) and the AUC value for the GCIPL hemifield test was excellent (0.941; sensitivity 95.10%, specificity 93.00%). Among the group with moderate-to-advanced glaucoma, GCIPL hemifield test positivity was shown in 92.0% (46/50) and the AUC value for the GCIPL hemifield test was excellent as well (0.935; sensitivity 95.10%, specificity 92.00%). There was no significant difference in the AUC values between two groups (P = 0.207). Figure 4 shows a representative case of highly myopic patient included in this study, which demonstrated the positive the GCIPL hemifield test in a left eye (AL 27.72 mm, SE −8.25 D, HVF MD −2.82 dB). 

Figure 4

 

Example of a highly myopic patient. (A–E) Right eye (AL 27.93 mm, SE −8.75 D, HVF mean deviation −0.23 dB). (F–J) Left eye (AL 27.72 mm, SE −8.25 D, HVF mean deviation −2.82 dB). In the left eye, a horizontally demarcated line at the (H) temporal macula (red arrows) was shown in GCIPL thickness map and was consistent with the superior defect on the (J) HVF pattern deviation map. Therefore, the diagnosed of glaucoma was made. In the right eye, however, a horizontally demarcated line was not shown in the (C) GCIPL thickness map and was consistent with the absence of scotoma on the (E) HVF pattern deviation map.

Factors Associated With the False Positive or False Negative Results of GCIPL Hemifield Test

Table 4 revealed the factors associated with the false negative result of the GCIPL hemifield test in eyes with highly myopic glaucoma. Univariate analysis showed that the false negative result of the GCIPL Hemifield Test was associated with longer AL (P = 0.09) and thinner average GCIPL thickness (P = 0.04). However, in a multivariate binary logistic regression analysis that included all parameters for which the P value of the association with the false negative result of the GCIPL hemifield test was ≤0.10 in the univariate analysis, any parameters showed a significant association with the false negative result of the GCIPL hemifield test. Table 5 revealed the factors associated with the false positive result of the GCIPL Hemifield Test in highly myopic eyes without glaucoma. Univariate analysis showed that the false positive result of the GCIPL hemifield test was associated with older age (P = 0.07), longer AL (P = 0.08), and lower SE (P = 0.07). However, in a multivariate binary logistic regression analysis, any parameters showed a significant association. 

Table 4

 

Univariate and Multivariate Linear Regression Analysis With False Negative Result of the GCIPL Hemifield Test

 

Table 5

 

Univariate and Multivariate Linear Regression Analysis With False Positive Result of the GCIPL Hemifield Test

 

Discussion

This paper introduces a computer program (MathWorks) for automated detection of GCIPL thickness difference across the temporal raphe and thus, discrimination of glaucomatous structural loss in highly myopic eyes. We found the GCIPL hemifield test showed significant efficacy in assessment of the presence or absence of glaucomatous structural loss in highly myopic eyes. 

High myopia is characterized by an elongation of the globe, predominantly at the posterior pole.²⁴ Accordingly, it has long been known as a risk factor for development of glaucomatous optic neuropathy, myopic retinopathy, and rhegmatogenous retinal detachment.^25–27 The underlying pathogeneses of increased glaucoma susceptibility in highly myopic eyes are thought to be associated with the following secondary ONH changes: (1) thinning of the lamina cribrosa and resulting steepening of the pressure gradient across the lamina cribrosa;²⁸ and (2) elongation and thinning of the peripapillary scleral flange, which is the biomechanical anchor of the lamina cribrosa.^29–34 

In patients with high myopia, glaucoma assessment is challenging, because precise measurement of the neuroretinal rim is difficult due to decreased spatial and color contrast between the neuroretinal rim and optic cup. Also, highly myopic eyes tend to have thinner RNFL than the normal population and, resultantly, the diagnostic accuracy of circumpapillary RNFL measurement reported to be decreased significantly.^35–40 Furthermore, circumpapillary RNFL measurement can be influenced by AL^35,36,38 and optic disc variations such as tilting, oval configuration, and peripapillary atrophy.^8,9 

Macular GCIPL or ganglion-cell complex thickness, which reflects the thickness of glaucoma-affected RGC bodies and their axons,^15,40,41 have been known to offer superior glaucoma detection ability compared with circumpapillary RNFL thickness for highly myopic patients.^15,40,41 However, highly myopic patients have been reported to have different topographic profiles from those of nonmyopic subjects, as well as thinner parafoveal and perifoveal thicknesses.^42,43 Therefore, imaging and classification of glaucoma in highly myopic eyes remains a challenge, even with OCT instruments. 

Several diagnostic tools have been used for discrimination of glaucoma in highly myopic patients; however, more objective evaluation is preferred. Hence, the present study introduced the GCIPL hemifield test for discrimination of glaucoma in highly myopic patients. Our results confirmed that the GCIPL hemifield test provides a superior diagnostic ability for discriminating between glaucomatous and nonglaucomatous eyes in highly myopic patients. Even in highly myopic glaucomatous eyes in which discriminating the glaucomatous structural damage from myopic change is difficult, there was an apparent hemifield difference across the temporal raphe on GCIPL thickness maps. This indicates that even if ONH variation interferes with the evaluation of ONH deformation and/or circumpapillary RNFL thickness, detectable hemifield difference across the temporal raphe on GCIPL thickness maps can be evident. Therefore, the GCIPL hemifield test can be utilized as a marker of clinical abnormalities of the ganglion cell layer in these eyes. This is particularly important because such clinical abnormalities can provide physicians with clear clues to the correct decision on the initiation of subsequent glaucoma management and monitoring. 

In this study, we defined the cutoff value for high myopia as an AL >26.5 mm. Indeed, the values of SE or AL at which optic disc size and parapapillary atrophy markedly increase are known to be < −8.00 D and >26.5 mm,^21,29,44,45 respectively, beyond which the prevalence of myopic retinopathy and glaucomatous optic neuropathy steeply increases.^25,26 This study had not applied SE of refractive error as the cutoff value, because more subjects with refractive myopia rather than axial myopia would have been preferentially enrolled. 

Several points need to be considered when interpreting the results of the current study. First, the GCIPL hemifield test program is intended specifically for use in glaucoma diagnostics and is ineffective for other types of diagnosis such as differential diagnosis. Certainly, the GCIPL hemifield test will have to be further developed for better efficacy in assessment of the presence or absence of glaucomatous structural loss and diagnosis of glaucoma. Second, because the GCIPL hemifield test uses arbitrary cutoff values for classifying cases as positive or negative, there might be a potential risk of misdiagnosis, especially in cases of borderline values. Examples would be a value showing the reference line less than one-half of the distance from the temporal inner elliptical annulus to the outer elliptical annulus or an average GCIPL thickness difference of 5 μm within 10 pixels of the reference line. Third, we need to compare the glaucoma-diagnostic abilities among the various asymmetry analyses (including Spectralis OCT posterior pole asymmetry analysis¹⁹). Fourth, we studied a group of mostly highly myopic normal-baseline-IOP POAG eyes (91.8% of the subjects had a baseline IOP ≤ 21 mm Hg), thus our results might not be applicable to other POAG populations. Fifth, because highly myopic eyes manifest structural change that mimics glaucoma, it can be difficult to discriminate early glaucomatous damage from myopic change. Therefore, highly myopic glaucoma suspect, even in those who show GCIPL hemifield test positivity, has to be observed longitudinally. 

In conclusion, in highly myopic eyes. the GCIPL hemifield test showed significant efficacy in assessment of the presence or absence of glaucomatous structural loss. Examining the macula carefully for the GCIPL thickness difference across the temporal raphe could provide the helpful new approaches to glaucoma diagnosis in highly myopic eyes. 

Acknowledgments

Disclosure: Y.K. Kim, None; B.W. Yoo, None; J.W. Jeoung, None; H.C. Kim, None; H.J. Kim None; K.H. Park None