May 2019
Volume 60, Issue 6
Open Access
Glaucoma  |   May 2019
Impact of Posterior Sclera on Glaucoma Progression in Treated Myopic Normal-Tension Glaucoma Using Reconstructed Optical Coherence Tomographic Images
Author Affiliations & Notes
  • Yong Chan Kim
    Department of Ophthalmology, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Republic of Korea
  • Yong Ho Koo
    Department of Ophthalmology, College of Medicine, Chuncheon Sacred Heart Hospital, Hallym University, Chuncheon-si, Gangwon-do, Republic of Korea
  • Kyoung In Jung
    Department of Ophthalmology, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea
  • Chan Kee Park
    Department of Ophthalmology, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea
  • Correspondence: Chan Kee Park, Department of Ophthalmology, College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, 222, Banpo-daero Seocho-gu, Seoul 06591, Republic of Korea; ckpark@catholic.ac.kr
Investigative Ophthalmology & Visual Science May 2019, Vol.60, 2198-2207. doi:https://doi.org/10.1167/iovs.19-26794
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      Yong Chan Kim, Yong Ho Koo, Kyoung In Jung, Chan Kee Park; Impact of Posterior Sclera on Glaucoma Progression in Treated Myopic Normal-Tension Glaucoma Using Reconstructed Optical Coherence Tomographic Images. Invest. Ophthalmol. Vis. Sci. 2019;60(6):2198-2207. doi: https://doi.org/10.1167/iovs.19-26794.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To investigate factors associated with visual field (VF) progression in treated myopic normal-tension glaucoma (NTG) using a novel posterior sclera reconstruction method involving swept-source optical coherence tomography (OCT).

Methods: Fifty-six myopic patients on ocular hypotensive therapy with the diagnose NTG had five or more VF tests during a period of 72.63 ± 20.46 months in clinical follow-up. Glaucomatous VF progression was decided by the standards of Early Manifest Glaucoma Trial criteria. Coronally reconstructed OCT images were used to obtain the position of the deepest point of the eye (DPE), and parameterized the distance (Disc-DPE distance), depth (Disc–DPE depth) and angle (Disc-DPE angle) of the posterior sclera. The Cox proportional hazards model and Kaplan-Meier curves were used to determine the risk factors for VF progression.

Results: Among 56 eyes, 28 showed VF progression. Eyes with progression had significantly different distance, depth, and angle of the DPE position (P = 0.049, P = 0.032, and P = 0.006, respectively). A multivariate Cox proportional hazard model revealed that the vertical tilt angle (hazard ratio [HR] 0.835, P = 0.026) and the DPE positioned temporal to fovea (HR 4.314, P = 0.001) were associated with VF progression. Among eyes with DPE positioned temporal to fovea, in addition to percentage reduction in IOP from baseline (HR 0.915, P = 0.012), shorter axial length (HR 0.542, P = 0.044) was found to be associated with VF progression.

Conclusions: Eyes with a particular posterior sclera structure are at increased risk for glaucoma progression in treated myopic NTG patients. This finding highlights the significance of investigating posterior sclera structure and its relevance to initiate or augment treatment for myopic glaucoma patients.

Open-angle glaucoma (OAG) is a chronic, progressive optic neuropathy with a characteristic appearance of the optic nerve and associated visual field (VF) defects.1 Even in patients with treated OAG, the prognosis of glaucoma varies significantly, with some leading to blindness.2,3 Thus, the importance of identifying patients at risk of rapid progression is critical, determining who needs augmented treatment to prevent blindness. Many reports have addressed the issue of prognostic factors for glaucomatous VF progression.4,5 Outcomes on many studies of prognostic factors judged patients with systemic diseases including diabetes mellitus, cardiac diseases or with IOP exceeding normal range.69 However, the conditions have shifted due to the major increase in prevalence rates of myopia, which has become a problem in East Asia where most of the population is nearsighted.1012 Axial myopia involves scleral thinning and collagen fibril alteration, which is likely to contribute to the weakened biomechanical properties of the sclera.13,14 Therefore, morphologic features involving in a myopic shift should be investigated as a possible risk factor, in addition to systemic factors and IOP.15 
β-Zone peripapillary atrophy (PPA) was reported to be associated with the location and progression of VF defects in patients with myopic primary OAG.1618 The direction of the optic disc torsion was identified to be associated with the progression of glaucoma.19 However, myopia involves not only the optic nerve head (ONH), but the entire posterior sclera, which contains ONH and macula. ONH and macula are the main target sites for glaucomatous damage, so investigating the changes in posterior sclera may be necessary to establish the pathogenesis of glaucoma.20 Hence, our group recently proposed a novel method to represent geometrical information of the posterior sclera by parametrizing the deepest point of the eyeball (DPE) in three-dimensional coordinates.2123 This method uses reconstructed serial coronal sections provided by swept-source optical coherence tomography (SSOCT) and obtains anterior-posterior depth (z-axis in Cartesian coordinates) in relation to the two-dimensional coordinate (x-y plane) information of the posterior pole. This study was designed to investigate the factors associated with VF progression in treated myopic normal-tension glaucoma (NTG) and to determine the relationship with posterior sclera structure, which is one of the most important characteristics of myopic eyes. 
Methods
This study was approved by The Catholic University of Korea institutional review board and adhered to the tenets of the Declaration of Helsinki. All of the participants provided written informed consent. 
Study Participants
Patients who had first been examined between January 2009 and December 2012 at Seoul Saint Mary's Hospital Glaucoma Clinic were considered as study participants. All subjects underwent a complete ophthalmic examination at baseline: visual acuity assessment, refraction, slit lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry (Haag-Streit), dilated funduscopic examination, standard automated perimetry (Humphrey VF Analyzer; 30–2 Swedish Interactive Threshold Algorithm; Carl Zeiss Meditec, Inc., Dublin, CA, USA), central corneal thickness by ultrasound pachymetry (Tomey Corporation, Nagoya, Japan), axial length with ocular biometry (IOLMaster; Carl Zeiss Meditec, Inc.), stereo disc photography and red-free retinal nerve fiber layer (RNFL) photography (Canon, Tokyo, Japan). Patients who followed up for more than 4 years at 6- to 12-month intervals and had five or more reliable VF examinations were included in this study by a retrospective medical record review in September 2018. Additionally, they were subjected to three-dimensional, volumetric scans using SSOCT (DRIOCT Triton; Topcon Corporation, Tokyo, Japan) at their visit in 2017 to 2018. 
The diagnosis of NTG was based on the following criteria: typical glaucomatous optic neuropathy disc changes (such as localized or diffuse rim thinning, disc hemorrhage, and notch in the rim) as seen on stereo disc photography; typical glaucomatous RNFL changes as seen on either stereo disc photography or red-free RNFL images; corresponding glaucomatous VF loss; open anterior chamber angles (>180° visible pigmented posterior trabecular meshwork on nonindentation gonioscopy in primary position); and normal untreated IOP level (≤21 mm Hg). Glaucomatous VF defect diagnoses were made based on the following criteria: glaucoma hemifield test outside normal limits results or the presence of at least three contiguous test points within the same hemifield on the pattern deviation plot at P value less than 5% with at least one of these points less than 1%, confirmed by two consecutive reliable tests (fixation loss rate ≤20% as well as false-positive and false-negative error rates ≤15%). 
Patients were excluded from the study when they met one or more of the following criteria: best-corrected visual acuity less than 20/40; an emmetropic or hyperopic eye with the axial length les than 24.0 mm and spherical equivalent exceeding 0 diopters; a history or evidence of optic neuropathies other than glaucoma or congenital anomalies of the optic disc; signs of pathologic myopia including myopic choroidal neovascularization, lacquer crack, angioid streaks; extremely myopic eyes with an axial length >30 mm or evident posterior staphyloma; history of ocular surgery (other than uncomplicated cataract surgery); any other systemic or ocular pathology known to affect the optic disc, RNFL, or VF (e.g., retinal vascular occlusive disease, diabetic retinopathy, hypertensive retinopathy, uveitis, previous or current use of systemic or topical steroids); and eyes with poor image quality of the OCT scan that was not delineated clearly. Eligibility was determined by two glaucoma specialists (YCK and KIJ), who evaluated the optic disc appearance using stereoscopic disc photography, RNFL defects based on red-free fundus photography, and the results of VF examinations. Both evaluators were masked to all patient systemic and ocular data. Eyes were excluded from the study analyses if a consensus was not reached. When both eyes were eligible, one eye was selected randomly in each subject for data analysis. 
Measurement of IOP
Goldmann applanation tonometry was used to measure IOP at the baseline (before initiation of topical antiglaucoma medication) and at every follow-up visit thereafter. On diagnosis, patients received topical ocular hypotensive medications with the treatment target matched to 20% reduction from baseline IOP. When this was not accomplished, further treatment decisions were made by the treating physician. Mean follow-up IOP was calculated by averaging all IOP measurements during the follow-up period before detection of the VF progression, and IOP fluctuation was defined as the SD of this value. The rate of IOP reduction was calculated as the percentage of difference between the baseline and mean follow-up IOP values. 
Investigation of Posterior Sclera Structure
The posterior sclera was analyzed using the reconstructed images of the Topcon DRIOCT triton scan with a novel method described previously.21 In brief, the scanning protocol consisted of 256 B-scans centered on the fovea, providing the image of the posterior segment 12 mm horizontally and 9 mm vertically. The system software reconstructs the 2.6 mm of the posterior segment of the eyeball with 1000 consecutive coronal images from the anterior to the posterior. It also provides precise point-to-point correlation between the individual reconstructed OCT images with the fundus photographic images. The Bruch membrane opening (BMO) has recently been proposed as an anatomic landmark from which neuroretinal measurements can be made and the BMO is not likely to change substantially with glaucoma progression.24,25 Also, the Bruch membrane (BM) appears as a hyperreflective round plane with the inhomogeneous hyporeflective choroid surrounding in the reconstructed images, which makes the BM a prominent landmark to locate. This landmark is designated as the DPE. Specifically, the DPE was the deepest and the most posterior BM/choroid interface in the anteroposterior axis that showed no vitreous cavity at its center, and also with the least amount of the BM shown inside the choroid tissue (Fig. 1). 
Figure 1
 
A conceptual diagram of the reconstructed coronal sections in the anteroposterior axis (AC). At the DPE of the anteroposterior axis, the BM appears as a hyperreflective round plane and the choroid surrounds the round plane as a round, inhomogeneous, hyporeflective figure with indistinct boundary. The location of the DPE was the center of hyperreflective round plane, which is the tiny blue circle inside the blue plane (C). The Disc-DPE distance was quantified as the lineal distance from the optic disc center to the DPE measured along the same en face image as the DPE (C). The Disc-DPE depth was calculated by counting the number of coronal sections from the interface of the DPE to the interface of the optic disc center (D, E).
Figure 1
 
A conceptual diagram of the reconstructed coronal sections in the anteroposterior axis (AC). At the DPE of the anteroposterior axis, the BM appears as a hyperreflective round plane and the choroid surrounds the round plane as a round, inhomogeneous, hyporeflective figure with indistinct boundary. The location of the DPE was the center of hyperreflective round plane, which is the tiny blue circle inside the blue plane (C). The Disc-DPE distance was quantified as the lineal distance from the optic disc center to the DPE measured along the same en face image as the DPE (C). The Disc-DPE depth was calculated by counting the number of coronal sections from the interface of the DPE to the interface of the optic disc center (D, E).
The DPE position was measured by means of the amount distance from the optic disc center (the SSOCT software indicates the center of the optic disc as a green cross based on the margin of BM as a default), the amount of angular position from the horizontal line crossing the OCT-defined optic disc center, and the amount of anteroposterior depth from the optic disc center. First, the Disc-DPE distance was quantified as the lineal distance from the optic disc center to the DPE measured along the same en face image as the DPE. Second, the Disc-DPE angle was measured as the angle from the horizontal meridian crossing the OCT-defined optic disc center to the linear line from the OCT-defined optic disc center to the DPE center. Third, the Disc-DPE depth was calculated by counting the number of coronal sections from the interface of the DPE to the interface of the optic disc center and converting the number of sections into micrometers by assuming a depth of 2.6 μm for each coronal section. Two observers (YCK and YHG) measured the parameters manually using the inbuilt intrinsic caliper function of the Topcon Triton software in a blinded fashion (Fig. 1). 
The position of the DPE was further categorized with respect to the relative location from the fovea. An imaginary vertical line crossing the fovea was established as the reference line. An eye with the DPE center positioned temporal from the reference line was designated as the DPE temporal to fovea (temporal DPE) as shown in Figures 2A, 2C, and 2E. An eye with the DPE center positioned nasal from the reference line was designated as the DPE nasal to fovea (nasal DPE) as shown in Figures 2B, 2D, and 2F. 
Figure 2
 
Representative case of characteristic posterior sclera geometry of the progressed eye (A, C, E) and the stable eye (B, D, F). Fundus photographs (superior), reconstructed coronal image of the DPE (middle), and horizontal scan of the OCT (inferior) depicting both eyes of subject. The vertical purple line was the reference line of the DPE position.
Figure 2
 
Representative case of characteristic posterior sclera geometry of the progressed eye (A, C, E) and the stable eye (B, D, F). Fundus photographs (superior), reconstructed coronal image of the DPE (middle), and horizontal scan of the OCT (inferior) depicting both eyes of subject. The vertical purple line was the reference line of the DPE position.
Measurement of ONH
The ONH configuration was quantified by measuring the degree of optic disc tilt from the SSOCT horizontal and vertical cross-sectional images. The measurement procedure has been described in detail elsewhere.26 In brief, the disc photographs acquired simultaneously by the DRIOCT were overlapped to the horizontal scan of the OCT. The two glaucoma specialists (YCK and KIJ) marked the nasal and the temporal clinical disc margin points at the fundus photographic images, which automatically marks the equivalent points at the horizontal scan of the OCT due to the precise point-to-point correlation of intrinsic software. A line connecting the two points marking the clinical disc margin on the cross-sectional images was defined as the ONH plane. A line connecting the inner tips of BM on each side of the ONH plane on the cross-sectional images was drawn as the reference plane. Degree of tilt was defined as the angle between the reference plane and the ONH plane. Angle measurements were performed by two observers (YCK and YHG) with the built-in caliper of the software. A positive degree of horizontal tilt indicated a temporal tilt, and a negative value indicated a nasal tilt. The degree of vertical tilt was also measured from a vertical cross-sectional image in the same way as described above. A positive degree of tilt indicated an inferior tilt, and a negative value indicated a superior tilt. 
The optic disc was defined as torsioned when the axis of the maximum optic disc diameter was not aligned with the vertical meridian, similar to the Blue Mountains study.27 The vertical meridian was considered a vertical line 90 degrees from a line connecting the fovea to the center of the disc. A positive torsion value indicated counterclockwise torsion in the right eye format, and a negative value indicated clockwise torsion in the right eye format.28 
Assessment of Functional Progression
Follow-up VF tests were performed at 6- to 12-month intervals. The one of first two VF results were excluded to minimize learning effects. A reliable VF was required to have a fixation loss <20% and a false-negative and false-positive rate <15%. The average values from the first two reliable fields were used for baseline mean deviation (MD), pattern SD (PSD), and mean of the entire numeric total deviation (TD) values. 
Early Manifest Glaucoma Trial criteria were used to confirm VF progression during follow-up.29 The baseline VF measurement was compared with those of subsequent tests using glaucoma change probability maps (Humphrey Field Analyzer) based on pattern deviation. If a statistically significant deterioration (P < 0.05) in the three noncontiguous locations on pattern deviation change probability maps have occurred, a functional progression of glaucoma is considered. If the equivalent deterioration is confirmed on two consecutive tests, the progression was confirmed. The VF progression rate was evaluated reference to the MD, PSD, and TD slope between the stable group and the progression group. 
Measurement Reproducibility
The position of the DPE is highly reproducible as long as proper fixation is achieved. The most effective way to ensure that the fixation is achieved in the scan is to verify the reproducibility of the biomarkers. Twenty eyes underwent intraclass correlation test on two separate scans. The analysis was based on 20 independent cases of intervisit reproducibility conducted twice on different days by two authors (YCK and YHK). The intraclass correlation coefficients were determined by two-way mixed effect model.30 Intraclass correlation scores over 0.75 are considered excellent (Supplementary Table S1).31 The reproducibility is excellent because the DPE position is accountable whenever the visual axis is fixed at the same target on each scan. Also, SSOCT has real-time eye tracking that has been known to eliminate eye motion and minimize artifacts by fixating on the fovea on each scan. Thus, like any other structures of the fundus photograph, DPE position is reproducible as long as the proper fixation is achieved. 
Statistical Analysis
Baseline characteristics were reported in mean ± SD values. The normally distributed data between the two groups were compared by independent t-test and the categorical data were analyzed by χ2 test or Mann-Whitney test as appropriate. Hazard ratios (HRs) with 95% confidence intervals were calculated using univariate and multivariate Cox proportional regression models to identify the risk factors predictive of VF progression in myopic NTG subjects. Variables with P < 0.10 in the univariate model were entered in a multivariate model. A Cox proportional hazards multivariate model was performed using a backward elimination approach based on likelihood ratios. A Kaplan-Meier survival analysis and log-rank test was used to compare the cumulative probability of functional progression between groups, stratified by significantly associated factors. The first time that functional deterioration was found was regarded as the end point in survival analyses. A P value less than 0.05 was considered statistically significant. To estimate the average rate of VF change, the global MD, PSD, and TD slope were obtained. Because the data from the same patient were correlated with each other, linear mixed-effects model analysis was used. Linear mixed-effects models also can manage data sets with high variation in examination times. The regression coefficients of the time course of MD, PSD, and TD were determined, and the progression rates were compared between the two groups. The statistical analysis was performed using the SPSS statistical package, version 22.0 (IBM Corp., Chicago, IL, USA). Statistical significance was defined as a P value less than 0.05. 
Results
Among the 221 myopic NTG patients who underwent the three-dimensional, volumetric scans of the OCT, 20 were excluded owing to a diffuse thinning of the circumpapillary RNFL with a noncorresponding VF defect. A total of 123 eyes had four or fewer consecutive VF tests and were excluded. Twenty-two eyes had inadequate image quality of the OCT scan. Finally, a total of 56 eyes were included in the analysis. The progression was confirmed in 28 eyes and the other 28 eyes were stable. 
Demographics and ocular characteristics of each group are compared in Table 1. The mean age was 46.75 ± 11.24 years in the stable group and 47.00 ± 10.83 years in the progression group, which was not significantly different (P = 0.933). The follow-up duration of each group was 69.42 ± 19.14 months and 75.85 ± 21.67 months, respectively (P = 0.245). The comparison of ocular characteristics, including axial length, baseline IOP, mean follow-up IOP, IOP fluctuation, and IOP reduction from baseline were insignificant as well (P = 0.070, P = 0.674, P = 0.104, P = 0.430, and P = 0.405, respectively). The comparison of baseline VF examination values, including MD, PSD, TD, and abnormal hemifield TD also were nonsignificant (P = 0.484, P = 0.278, P = 0.496, and P = 0.437, respectively). The RNFL thickness compared in each of its sectors was also insignificant. However, the vertical tilt of the progression group was significantly smaller (P = 0.002) and every factor of the posterior sclera structure of the progression group was different, showing a longer Disc-DPE distance, deeper Disc-DPE depth, and smaller Disc-DPE angle (P = 0.049, P = 0.032, and P = 0.006, respectively). When subjects were further classified with respect to DPE position in each group, only three were classified as DPE positioned temporal to fovea in the stable group (10.71%), but 14 were classified as DPE positioned temporal to fovea in the progression group (50%) (P = 0.001). 
Table 1
 
Demographics and Clinical Characteristics of Subjects With Stable and Progressed VF
Table 1
 
Demographics and Clinical Characteristics of Subjects With Stable and Progressed VF
A list of factors for VF progression considered in the Cox proportional hazard model is provided in Table 2. Degree of vertical tilt angle, degree of disc torsion, amount of Disc-DPE distance, amount of Disc-DPE depth, degree of Disc-DPE angle, and DPE position temporal to fovea were each found to be associated with VF progression (P < 0.10) in univariate analyses. Percentage reduction of IOP from the baseline, IOP fluctuation, and baseline severity of VF defects was not considered to be associated with an increased risk of functional progression in myopic NTG patients. Multivariate analysis showed that degree of vertical tilt (HR 0.835; P = 0.026), DPE position temporal to fovea (HR 4.314; P = 0.001) were significant independent prognostic factors for patients with myopic NTG. 
Table 2
 
Cox Proportional Hazards Univariate and Multivariate Analysis on the Association Between Each Variable and the HRs of VF Progression
Table 2
 
Cox Proportional Hazards Univariate and Multivariate Analysis on the Association Between Each Variable and the HRs of VF Progression
When the subjects were reclassified according to DPE position, 39 were categorized as eyes with DPE positioned nasal to fovea (nasal DPE) and 17 were categorized as eyes with DPE positioned temporal to fovea (temporal DPE). Age at diagnosis, axial length, central corneal thickness, all IOP-related parameters, all baseline VF examination-related factors, and all ONH-related factors were not significantly different between the two groups (all P > 0.05). However, when comparing the global rate of progression, the temporal DPE group had more patients who reached a progression end point (82.35%) than the nasal group (35.89%), had more eyes with fast progression rates (P = 0.024), and had fewer eyes with slow progression rates (P = 0.017). The rates of deterioration in the global PSD slope were significantly steep in temporal DPE group than nasal DPE group (0.17 ± 0.06 dB/year versus 0.02 ± 0.06 dB/year; P = 0.01) (Table 3). Kaplan-Meier survival analysis for VF progression showed a statistically significant difference in the cumulative probability of survival between the temporal DPE group and the nasal DPE group, with a better survival probability in the eyes with nasal DPE group (P = 0.002, log-rank test) (Fig. 3). Figure 4 shows a scatterplot of the relationship between the Disc-DPE distance and MD slope (R = −0.362, P = 0.006). 
Table 3
 
Demographics and Clinical Characteristics of Subjects With Myopic NTG Divided by the DPE Location Relative to Fovea
Table 3
 
Demographics and Clinical Characteristics of Subjects With Myopic NTG Divided by the DPE Location Relative to Fovea
Figure 3
 
Kaplan-Meier curves comparing the progression probability in subjects with myopic NTG. Log-rank test P = 0.002.
Figure 3
 
Kaplan-Meier curves comparing the progression probability in subjects with myopic NTG. Log-rank test P = 0.002.
Figure 4
 
Scatterplots showing the relationship between the Disc-DPE distance with MD slope and abnormal hemifield TD slope. Red dots indicate eyes with DPE temporal to fovea and blue dots indicate eyes with DPE nasal to fovea. Pearson's correlation coefficient were each R = −0.362, P = 0.006.
Figure 4
 
Scatterplots showing the relationship between the Disc-DPE distance with MD slope and abnormal hemifield TD slope. Red dots indicate eyes with DPE temporal to fovea and blue dots indicate eyes with DPE nasal to fovea. Pearson's correlation coefficient were each R = −0.362, P = 0.006.
A subgroup analysis with Cox proportional hazard analysis was also performed in the temporal DPE group. Among the eyes with DPE located temporal to fovea, axial length, IOP reduction from baseline, baseline severity of VF PSD, vertical tilt angle, and disc torsion degree were each found to be associated with VF progression (P < 0.10) in univariate analyses. In the multivariate analysis, shorter axial length (HR 0.542; P = 0.044) and less reduction of IOP from baseline (HR 0.915; P = 0.012) were significant independent factors for glaucoma progression in myopic NTG patients (Table 4). 
Table 4
 
Cox Proportional Hazards Univariate and Multivariate Analysis in Eyes That Have DPE Located Temporal to the Fovea
Table 4
 
Cox Proportional Hazards Univariate and Multivariate Analysis in Eyes That Have DPE Located Temporal to the Fovea
Representative Case
Figure 2 shows fundus photographs (superior), reconstructed coronal image of the DPE (middle), and horizontal scan of the OCT (inferior) of a patient. The VF of the patient's right eye progressed (Figs. 2A, 2C, 2E) and the left eye was stable (Figs. 2B, 2D, 2F). The vertical purple line was the reference line of the DPE position. 
Discussion
In this study, we found that myopic NTG patients undergoing ocular hypotensive therapy have a different VF deterioration rate depending on different posterior sclera characteristics. Because myopia is closely associated with structural changes of the posterior sclera, the correlation between the posterior sclera structures with VF progression has its clinical significance. To the best of our knowledge, this is the first attempt to investigate the risks of the posterior sclera structure on the glaucomatous VF progression in a myopic subgroup. 
High IOP is a well-known risk factor for the progression of NTG.32,33 The importance of lowering IOP even in patients with NTG has been demonstrated by the Collaborative Normal Tension Glaucoma Study group, which claimed that a 30% reduction of baseline IOP reduced risk of disease progression.33 Kim et al.34 also demonstrated the importance of sufficient IOP reduction rather than absolute IOP values on reducing the risk of VF progression in preperimetric OAG. Our data also suggest that IOP reduction was a key risk in the subgroup with DPE located temporal to fovea; however, the percentage of IOP reduction from baseline was not a significant risk on VF progression in the analysis with entire subjects. This disparity may result from the faster VF deterioration rate in the subgroup with DPE located temporal to fovea, which would emphasize the association with IOP reduction percentage on VF progression. The DPE nasal to fovea subgroup rarely had progression and slow VF deterioration rate, which would dilute the association. Our group previously reported that the posterior sclera structure is different in myopes with NTG than in myopes without NTG, suggesting that with similar axial length, myopic eyes with NTG have different posterior sclera structure.22 Myopic eyes with glaucoma had characteristic tendency of posterior sclera featuring a deeper (larger Disc-DPE depth) and more distant DPE (larger Disc-DPE distance) position from the optic disc. This study further demonstrates the structure of posterior sclera not only correlates with the occurrence of glaucoma but also to the progression of glaucoma in myopic eyes. 
There were numerous attempts to find associations between visible ocular characteristics, including the optic disc tilt and optic disc torsion with glaucoma in the literature.16,35 Hosseini et al.26 reported that amount of optic disc tilt had correlation with VF loss, whereas another study suggested a protective role of optic disc tilt against glaucoma progression.36 Optic disc torsion was reported to be highly prevalent in NTG patients with myopia, whereas a population-based study described prominent optic disc torsion, such as tilted disc syndrome, was not associated with glaucoma.35,37 With opposing views, our data are consistent with the finding of Lee et al.,36 who demonstrated myopic glaucoma patients with small optic disc tilt ratio progressed faster than the large tilt group, who were followed over 4 years. Although this result is contrary to the conventional opinion, Doshi et al.38 also reported that young Chinese males with large tilted disc had a stable VF for up to 7 years. They interpreted that susceptible axons are limited in the tilted disc, whereas other remaining axons do not undergo further damage. This argument may be valid, but our study brought in new variables to the equation, which considers the all-around structural foundation of the optic disc and the axons crossing it. As supported by the Cox proportional hazard analysis, eyes with faster VF progression simultaneously have posterior sclera DPE at the temporal area and at the same time have small vertical tilt angle. An eye with a small vertical tilt angle would also have small disc torsion and have small Disc-DPE angle all at the same time because the location of the DPE (DPE angle) likely determines the optic disc torsion angle.21 There are three variables in the previous sentence, but all three variables (vertical tilt angle, disc torsion, Disc-DPE angle) are closely related statistically and structurally. Therefore, an eye vulnerable to faster VF deterioration has large Disc-DPE distance and simultaneously has small Disc-DPE angle. Small DPE angle means that the DPE is situated parallel to the horizontal line crossing the optic disc center area because the measurement is from the horizontal line crossing the optic disc center. We think that just by looking at the parameters of the ONH, its effectiveness as a diagnostic biomarker is greatly reduced, as shown in mixed results of clinical studies. To comprehend the action of the ONH using only the value of optic disc tilt and torsion seems a longshot, because it misses the most heavily changing part of the eye since birth, which is the posterior sclera. 
Our current observation that eyes with DPE positioned temporal to fovea are associated with worse clinical course may be explained from two different viewpoints. One possibility is that the unit or the scale of these changes is vastly different. Myopic eyes have an optic disc tilted or torsioned in micrometers, whereas posterior sclera grows in millimeters in the axial elongation process.39 Structural change of the posterior sclera is larger compared with the ONH, which would influence the biomechanics of the eye in a larger scale as well. In addition, measuring the variables with smaller scale would also be prone to error than larger scale. Another explanation for faster deterioration in eyes with temporal DPE is that their location of DPE may have undergone significant change than in eyes with DPE nasal to fovea. Our group previously examined the nonglaucomatous emmetropic eyes and found that DPE is located inferonasal to fovea in most cases (70.05%).21 However, the nonglaucomatous myopic eyes had DPE in the inferonasal area at only 43.2%, whereas glaucomatous myopic eyes had only 18.6% of their eyes.22 From these data, we speculate that in an ideal emmetropic eye, DPE is positioned somewhere between fovea and optic disc. We further assume that in a typical axial elongation process, the DPE migrates temporally and posteriorly simultaneously. When an exaggerated temporal migration of DPE occurs, impact on the ONH and lamina cribrosa would be severe. We found that this speculation is similar to the hypothesis on PPA pathogenesis. On this matter, Kim et al.40 suggested that PPA emerges from the migration of temporal peripapillary sclera toward the temporal side, which is an identical vector of posterior sclera migration in our supposition. The presence of PPA has been consistently connected with glaucoma and its progression, which is consistent with our data on temporal DPE position.4144 However, this is pure speculation and needs to be investigated in future prospective studies. 
A shorter axial length was a significant risk among eyes with temporal DPE. It is odd to say shorter axial length in myopic eyes is a risk of glaucoma progression, but eyes with shorter axial length would have to undergo excessive change partially in the area of posterior sclera. In shorter eyes with temporal DPE, changes in the axial elongation process would be concentrated in the posterior sclera, which would likely alter the protective biomechanical property of the ONH. In a previous study, level of myopia was not associated with glaucoma progression and was even a protective factor.45 In this regard, we suggest that the degree of myopia should not be assessed with the entire axial length or the refractive error, but with how the posterior sclera goes through its myopization process. We also suggest that the assessment of glaucoma progression with myopic eyes should be confined only to the posterior sclera and amount of its alteration. 
This study had several limitations. First, all study subjects were Asian, and the effects of posterior sclera structure on VF progression might be different in other study populations. Second, counting the number of coronal sections to estimate tissue depth is not an accurate measurement, but only an estimation. However, there is still no other way to measure the exact depth of the posterior sclera in vivo and our method is adequate to compare the different DPEs in various subjects. Third, VF tests were obtained at varied intervals from 6 to 12 months. Thus, a bias toward the patients who are more likely to show progression might have existed, because they might have checked VF tests at shorter intervals. Fourth, because of the retrospective nature of our study, we could not collect enough information about various potential factors for VF progression. Finally, the DPE position was stable only when participants' eyes were fixated on the scanning light. Nonetheless, every ocular imaging apparatus assumes that the subject is fixating on the scanning light. Therefore, like any other ocular parameters, such as the PPA, optic disc tilt, and optic disc torsion, the DPE position is reproducible as long as the proper fixation is achieved and is also unreproducible when a proper fixation is not achieved in the same manner as the PPA, optic disc tilt, and optic disc torsion. 
In conclusion, posterior sclera structure was a decisive factor of VF progression in myopic NTG patients undergoing ocular hypotensive therapy. A certain form of posterior sclera was associated with a significant progression of VF that had DPE positioned temporal to fovea. Among eyes with DPE positioned temporal to fovea, in addition to percentage reduction in IOP from baseline, shorter axial length was found to be associated with VF progression, which may indicate that the posterior sclera had undergone excessive change. The evaluation of posterior sclera structure may be taken into account when managing patients with myopic NTG. 
Acknowledgments
Supported by Hallym University Research Fund 2018 (HURF-2018-18). 
Disclosure: Y.C. Kim, None; Y.H. Koo, None; K.I. Jung, None; C.K. Park, None 
References
Kwon YH, Fingert JH, Kuehn MH, Alward WL. Primary open-angle glaucoma. N Engl J Med. 2009; 360: 1113–1124.
Hattenhauer MG, Johnson DH, Ing HH, et al. The probability of blindness from open-angle glaucoma. Ophthalmology. 1998; 105: 2099–2104.
Chen PP. Blindness in patients with treated open-angle glaucoma. Ophthalmology. 2003; 110: 726–733.
Heijl A, Leske MC, Bengtsson B, Bengtsson B, Hussein M; Early Manifest Glaucoma Trial Group. Measuring visual field progression in the Early Manifest Glaucoma Trial. Acta Ophthalmol Scand. 2003; 81: 286–293.
Kim J, Dally LG, Ederer F, et al. The Advanced Glaucoma Intervention Study (AGIS): 14. Distinguishing progression of glaucoma from visual field fluctuations. Ophthalmology. 2004; 111: 2109–2116.
Drance S, Anderson DR, Schulzer M; Collaborative Normal-Tension Glaucoma Study Group. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol. 2001; 131: 699–708.
Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002; 120: 1268–1279.
Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2003; 121: 48–56.
Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004; 111: 1627–1635.
Rose KA, Morgan IG, Smith W, Burlutsky G, Mitchell P, Saw SM. Myopia, lifestyle, and schooling in students of Chinese ethnicity in Singapore and Sydney. Arch Ophthalmol. 2008; 126: 527–530.
How AC, Tan GS, Chan YH, et al. Population prevalence of tilted and torted optic discs among an adult Chinese population in Singapore: the Tanjong Pagar Study. Arch Ophthalmol. 2009; 127: 894–899.
Rim TH, Kim SH, Lim KH, et al. Refractive errors in Koreans: The Korea National Health and Nutrition Examination Survey. 2008–2012. Korean J Ophthalmol. 2016; 30: 214–224.
McBrien NA, Cornell LM, Gentle A. Structural and ultrastructural changes to the sclera in a mammalian model of high myopia. Invest Ophthalmol Vis Sci. 2001; 42: 2179–2187.
Xu L, Wang Y, Wang S, Wang Y, Jonas JB. High myopia and glaucoma susceptibility the Beijing Eye Study. Ophthalmology. 2007; 114: 216–220.
Ernest PJ, Schouten JS, Beckers HJ, Hendrikse F, Prins MH, Webers CA. An evidence-based review of prognostic factors for glaucomatous visual field progression. Ophthalmology. 2013; 120: 512–519.
Teng CC, De Moraes CG, Prata TS, Tello C, Ritch R, Liebmann JM. Beta-zone parapapillary atrophy and the velocity of glaucoma progression. Ophthalmology. 2010; 117: 909–915.
Yamada H, Akagi T, Nakanishi H, et al. Microstructure of peripapillary atrophy and subsequent visual field progression in treated primary open-angle glaucoma. Ophthalmology. 2016; 123: 542–551.
Sawada Y, Hangai M, Ishikawa M, Yoshitomi T. Association of myopic deformation of optic disc with visual field progression in paired eyes with open-angle glaucoma. PLoS One. 2017; 12: e0170733.
Sung MS, Kang YS, Heo H, Park SW. Optic disc rotation as a clue for predicting visual field progression in myopic normal-tension glaucoma. Ophthalmology. 2016; 123: 1484–1493.
Anderson H. Ultrastructure of intraorbital portion of human and monkey optic nerve. Arch Ophthalmol. 1969; 82: 507–508.
Kim YC, Jung Y, Park HL, Park CK. The location of the deepest point of the eyeball determines the optic disc configuration. Sci Rep. 2017; 7: 5881.
Kim YC, Jung KI, Park HL, Park CK. Three-dimensional evaluation of posterior pole and optic nerve head in myopes with glaucoma. Sci Rep. 2017; 7: 18001.
Kim YC, Moon JS, Park HL, Park CK. Three dimensional evaluation of posterior pole and optic nerve head in tilted disc. Sci Rep. 2018; 8: 1121.
Strouthidis NG, Yang H, Fortune B, Downs JC, Burgoyne CF. Detection of optic nerve head neural canal opening within histomorphometric and spectral domain optical coherence tomography data sets. Invest Ophthalmol Vis Sci. 2009; 50: 214–223.
Chauhan BC, O'Leary N, Al-Mobarak FA, et al. Enhanced detection of open-angle glaucoma with an anatomically accurate optical coherence tomography-derived neuroretinal rim parameter. Ophthalmology. 2013; 120: 535–543.
Hosseini H, Nassiri N, Azarbod P, et al. Measurement of the optic disc vertical tilt angle with spectral-domain optical coherence tomography and influencing factors. Am J Ophthalmol. 2013; 156: 737–744.
Ong LS, Mitchell P, Healey PR, Cumming RG. Asymmetry in optic disc parameters: the Blue Mountains Eye Study. Invest Ophthalmol Vis Sci. 1999; 40: 849–857.
Park HY, Lee K, Park CK. Optic disc torsion direction predicts the location of glaucomatous damage in normal-tension glaucoma patients with myopia. Ophthalmology. 2012; 119: 1844–1851.
Leske MC, Heijl A, Hyman L, Bengtsson B. Early Manifest Glaucoma Trial: design and baseline data. Ophthalmology. 1999; 106: 2144–2153.
Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986; 1: 307–310.
Commenges D, Jacqmin H. The intraclass correlation coefficient: distribution-free definition and test. Biometrics. 1994; 50: 517–526.
Araie M, Sekine M, Suzuki Y, Koseki N. Factors contributing to the progression of visual field damage in eyes with normal-tension glaucoma. Ophthalmology. 1994; 101: 1440–1444.
Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998; 126: 487–497.
Kim KE, Jeoung JW, Kim DM, Ahn SJ, Park KH, Kim SH. Long-term follow-up in preperimetric open-angle glaucoma: progression rates and associated factors. Am J Ophthalmol. 2015; 159: 160–168.
Park HY, Lee KI, Lee K, Shin HY, Park CK. Torsion of the optic nerve head is a prominent feature of normal-tension glaucoma. Invest Ophthalmol Vis Sci. 2014; 56: 156–163.
Lee JE, Sung KR, Lee JY, Park JM. Implications of optic disc tilt in the progression of primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2015; 56: 6925–6931.
You QS, Xu L, Jonas JB. Tilted optic discs: The Beijing Eye Study. Eye (Lond). 2008; 22: 728–729.
Doshi A, Kreidl KO, Lombardi L, Sakamoto DK, Singh K. Nonprogressive glaucomatous cupping and visual field abnormalities in young Chinese males. Ophthalmology. 2007; 114: 472–479.
Chung HJ, Park CK. The distinct biometric features of high myopia compared to moderate myopia. Curr Eye Res. 2016; 41: 1580–1583.
Kim TW, Kim M, Weinreb RN, Woo SJ, Park KH, Hwang JM. Optic disc change with incipient myopia of childhood. Ophthalmology. 2012; 119: 21–26.e21 –23.
Primrose J. The incidence of the peripapillary halo glaucomatosus. Trans Ophthalmol Soc U K. 1970; 89: 585–587.
Wilensky JT, Kolker AE. Peripapillary changes in glaucoma. Am J Ophthalmol. 1976; 81: 341–345.
Jonas JB, Nguyen XN, Gusek GC, Naumann GO. Parapapillary chorioretinal atrophy in normal and glaucoma eyes. I. Morphometric data. Invest Ophthalmol Vis Sci. 1989; 30: 908–918.
Teng CC, De Moraes CG, Prata TS, et al. The region of largest beta-zone parapapillary atrophy area predicts the location of most rapid visual field progression. Ophthalmology. 2011; 118: 2409–2413.
Lee JY, Sung KR, Han S, Na JH. Effect of myopia on the progression of primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2015; 56: 1775–1781.
Figure 1
 
A conceptual diagram of the reconstructed coronal sections in the anteroposterior axis (AC). At the DPE of the anteroposterior axis, the BM appears as a hyperreflective round plane and the choroid surrounds the round plane as a round, inhomogeneous, hyporeflective figure with indistinct boundary. The location of the DPE was the center of hyperreflective round plane, which is the tiny blue circle inside the blue plane (C). The Disc-DPE distance was quantified as the lineal distance from the optic disc center to the DPE measured along the same en face image as the DPE (C). The Disc-DPE depth was calculated by counting the number of coronal sections from the interface of the DPE to the interface of the optic disc center (D, E).
Figure 1
 
A conceptual diagram of the reconstructed coronal sections in the anteroposterior axis (AC). At the DPE of the anteroposterior axis, the BM appears as a hyperreflective round plane and the choroid surrounds the round plane as a round, inhomogeneous, hyporeflective figure with indistinct boundary. The location of the DPE was the center of hyperreflective round plane, which is the tiny blue circle inside the blue plane (C). The Disc-DPE distance was quantified as the lineal distance from the optic disc center to the DPE measured along the same en face image as the DPE (C). The Disc-DPE depth was calculated by counting the number of coronal sections from the interface of the DPE to the interface of the optic disc center (D, E).
Figure 2
 
Representative case of characteristic posterior sclera geometry of the progressed eye (A, C, E) and the stable eye (B, D, F). Fundus photographs (superior), reconstructed coronal image of the DPE (middle), and horizontal scan of the OCT (inferior) depicting both eyes of subject. The vertical purple line was the reference line of the DPE position.
Figure 2
 
Representative case of characteristic posterior sclera geometry of the progressed eye (A, C, E) and the stable eye (B, D, F). Fundus photographs (superior), reconstructed coronal image of the DPE (middle), and horizontal scan of the OCT (inferior) depicting both eyes of subject. The vertical purple line was the reference line of the DPE position.
Figure 3
 
Kaplan-Meier curves comparing the progression probability in subjects with myopic NTG. Log-rank test P = 0.002.
Figure 3
 
Kaplan-Meier curves comparing the progression probability in subjects with myopic NTG. Log-rank test P = 0.002.
Figure 4
 
Scatterplots showing the relationship between the Disc-DPE distance with MD slope and abnormal hemifield TD slope. Red dots indicate eyes with DPE temporal to fovea and blue dots indicate eyes with DPE nasal to fovea. Pearson's correlation coefficient were each R = −0.362, P = 0.006.
Figure 4
 
Scatterplots showing the relationship between the Disc-DPE distance with MD slope and abnormal hemifield TD slope. Red dots indicate eyes with DPE temporal to fovea and blue dots indicate eyes with DPE nasal to fovea. Pearson's correlation coefficient were each R = −0.362, P = 0.006.
Table 1
 
Demographics and Clinical Characteristics of Subjects With Stable and Progressed VF
Table 1
 
Demographics and Clinical Characteristics of Subjects With Stable and Progressed VF
Table 2
 
Cox Proportional Hazards Univariate and Multivariate Analysis on the Association Between Each Variable and the HRs of VF Progression
Table 2
 
Cox Proportional Hazards Univariate and Multivariate Analysis on the Association Between Each Variable and the HRs of VF Progression
Table 3
 
Demographics and Clinical Characteristics of Subjects With Myopic NTG Divided by the DPE Location Relative to Fovea
Table 3
 
Demographics and Clinical Characteristics of Subjects With Myopic NTG Divided by the DPE Location Relative to Fovea
Table 4
 
Cox Proportional Hazards Univariate and Multivariate Analysis in Eyes That Have DPE Located Temporal to the Fovea
Table 4
 
Cox Proportional Hazards Univariate and Multivariate Analysis in Eyes That Have DPE Located Temporal to the Fovea
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