May 2017
Volume 58, Issue 5
Open Access
Glaucoma  |   May 2017
The Characteristics of Deep Optic Nerve Head Morphology in Myopic Normal Tension Glaucoma
Author Affiliations & Notes
  • Jong Chul Han
    Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • Eun Jung Lee
    Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • Si Bum Kim
    Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • Changwon Kee
    Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • Correspondence: Changwon Kee, Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135–710, Korea; ckee@skku.edu
Investigative Ophthalmology & Visual Science May 2017, Vol.58, 2695-2704. doi:10.1167/iovs.17-21791
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      Jong Chul Han, Eun Jung Lee, Si Bum Kim, Changwon Kee; The Characteristics of Deep Optic Nerve Head Morphology in Myopic Normal Tension Glaucoma. Invest. Ophthalmol. Vis. Sci. 2017;58(5):2695-2704. doi: 10.1167/iovs.17-21791.

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

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Abstract

Purpose: To investigate the relationship between axial length (AL) and deep optic nerve head (ONH) structure and to evaluate the characteristics of deep ONH structures in myopic normal tension glaucoma (NTG).

Methods: The following parameters were assessed using spectral-domain optical coherence tomography (SD-OCT): externally oblique border tissue (EOBT) length, ONH tilt angle, optic canal (OC) obliqueness, and β-zone peripapillary atrophy (PPA). In addition, the angular location of the maximal value of each parameter and retinal nerve fiber layer (RNFL) defect were measured using infrared and red-free photos.

Results: A total of 74 myopic NTG eyes and 67 myopic control eyes with a spherical equivalent < −0.5 diopters from 141 subjects were included. AL was correlated with the maximal values of EOBT length, ONH tilt angle, OC obliqueness, and β-zone PPA (P < 0.001, P = 0.003, P < 0.001, and P < 0.001, respectively). Multivariate logistic regression analysis revealed that temporally located maximal values of EOBT length, ONH tilt angle, and OC obliqueness were associated with the presence of myopic NTG (P = 0.014, P = 0.016, and P = 0.030, respectively). In myopic NTGs, RNFL defect locations were consistent with the locations of maximal values of EOBT length, ONH tilt angle, OC obliqueness, and β-zone PPA (P < 0.001, P < 0.001, P < 0.001, and P = 0.003, respectively).

Conclusions: Temporalized angular locations of deep ONH parameters were associated with the presence of NTG in myopia. In myopic NTGs, the locations of deep ONH parameters were consistent with the locations of RNFL defect.

Deep optic nerve head (ONH) structures, such as the parapapillary sclera, scleral canal wall, and lamina cribrosa (LC), have been regarded as important factors in glaucoma pathogenesis.1,2 Intraocular pressure (IOP),3,4 the most important factor in glaucoma, generates load on ONH tissues at all levels of IOP that is presumed to damage retinal ganglion cell axons through IOP-related and non–IOP-related mechanisms that remain unclear. 
Although there have been controversies, in myopic eyes, locations of β-zone parapapillary atrophy (PPA)5,6 and optic disc tilt direction79 have been reported to predict retinal nerve fiber layer (RNFL) defects in glaucoma eyes. Previous studies indicated that these associations are in part attributable to ONH morphologic differences related to myopic elongation. However, when ONH surface changes, such as PPA or disc tilt, are subtle, it can be difficult to evaluate the ONH morphologic characteristics. 
The advent of optical coherence tomography (OCT) has enabled the observation of deep ONH structure. Several reports demonstrated the clinical importance of evaluating deep ONH structures, including Bruch's membrane opening (BMO) and border tissues.1012 Reis et al.11 reported that the clinically observed disc margin is not consistent with deep ONH disc margin measured on OCT. They demonstrated that the clinically visible margin of the ONH consists of deep ONH structures such as Bruch's membrane (BM) or the border tissue of Elschnig. 
Although IOP-related stress and strain likely contribute to neuropathy in glaucoma that occurs at normal IOP levels and/or in the setting of myopia, we hypothesize that non–IOP-related factors, such as deep ONH geometric characteristics, may also make important contributions to the susceptibility of axons and connective tissues to normal IOP. To test this hypothesis, we defined several parameters based on deep ONH structures, such as the BMO and border tissue configurations. To determine whether these parameters are associated with axial elongation, we investigated changes in the extent and the angular location of deep ONH parameters according to axial elongation. In addition, we investigated whether deep ONH morphologic characteristics can affect the presence of myopic normal tension glaucoma (NTG) and whether deep ONH parameters show spatial correlation with RNFL defects in myopic NTG eyes. 
Methods
This was a cross-sectional observational study. Candidates for this study were patients with myopic eyes with less than −0.5 diopters (D), with or without NTG, who visited Samsung Medical Center (Seoul, South Korea) for their first ophthalmic examination between January 2015 and March 2016. This study followed all guidelines for experimental investigation in human subjects, was approved by the Samsung Medical Center Institutional Board, and adhered to the tenets of the Declaration of Helsinki. 
Each participant underwent a comprehensive ophthalmic examination, including slit-lamp biomicroscopy, Goldmann applanation tonometry, manifest refraction, gonioscopic examination, dilated stereoscopic examination of the ONH, color and red-free fundus photography (TRC-50DX; Topcon Medical Systems, Inc., Oakland, NJ, USA), automated perimetry using a central 30-2 Humphrey Field Analyzer (HFA model 640; Humphrey Instruments, Inc., San Leandro, CA, USA) with the Swedish interactive threshold algorithm standard, axial length (AL) measurement (IOL master; Carl Zeiss Meditec, Jena, Germany), and ultrasound pachymetry (Tomey SP-3000; Tomey Ltd., Nagoya, Japan). The extent of visual field (VF) defect was measured using mean deviation (MD), pattern standard deviation (PSD), and visual field index (VFI). Reliable VF analysis was defined as a false-negative rate <15%, a false-positive rate <15%, and fixation loss <20%. IOPs were measured at the first and second visit without IOP-lowering medications. Average IOP values were used in the analyses. 
The following criteria were required for the diagnosis of NTG. First, glaucomatous optic disc changes, such as increased cupping (vertical cup-to-disc ratio >0.7), diffuse or focal neural rim thinning, disc hemorrhage, or RNFL defects at the time of diagnosis. Second, glaucomatous VF defects positive by more than one reliable test for at least two of the following three criteria: (1) a cluster of three points with a probability less than 5% on the pattern deviation map in at least one hemifield, including at least one point with a probability less than 1% or a cluster of two points with a probability less than 1%; (2) a glaucoma hemifield test result outside the normal limits; or (3) a PSD of 95% outside the normal limits. Third, an open angle on gonioscopic examination confirmed to have no identified causes of secondary glaucoma present. Fourth, the IOP ≤21 mm Hg at each of the two visits. 
Normal healthy eyes with a best-corrected visual acuity ≥20/40, open angles on gonioscopic examination, and without glaucomatous optic disc or VF changes and with an IOP ≤21 mm Hg were used as controls. 
Exclusion criteria included eyes with media opacities, such as a corneal or vitreous opacity, cataract, and systemic disease or ocular diseases that could affect VF test results. Only one randomly selected eye per patient was analyzed in the present study. 
Enhanced Depth Imaging OCT
Enhanced depth imaging spectral-domain OCT (EDI SD-OCT) (Heidelberg Engineering, Heidelberg, Germany) was used to measure deep ONH parameters. The device was pushed closer to the eye to move the zero-reference plane to the posterior, which enhanced the images of the deeper structures and created an inverted image, with the inner portions of the retina shown facing downward. Scans were performed in automatic real-time mode, which uses multiple line acquisition to reduce noise. EDI scans were obtained using 48 radial-line B-scans (each at an angle of 3.75°) centered on the optic disc. Each EDI scan included an average of 20 OCT frames; every other section (24 radial EDI scans in total) was selected, as previously reported.13 OCT machine scaling was adjusted into 1:1 μm before measurement. If the scan section contained a poor-quality OCT image that did not offer interpretable information with respect to BMO or border tissue due to prelaminar tissue or overlying vessels, the next image was used. If more than 3 of the 24 radial scans were unrecognizable, the eye was excluded. 
Measurement of Parameters Associated With Axial Elongation
EDI SD-OCT was used to measure the relationships between deep ONH structures and axial elongation. In our preliminary data, deep ONH structures varied with axial elongation as follows: first, axial elongation accompanied by longer border tissue extended externally. With myopic changes, the border tissue of Elschnig was extended externally and was easily observed on OCT. Reis et al.11 defined this type of border tissue as externally oblique border tissue (EOBT). EOBT length was defined as the length between the end points of the EOBT tissue. Second, axial elongation was associated with a greater ONH tilt angle. ONH tilt angle was defined as the angle between the BMO plane and the optic canal (OC) plane.14 The BMO plane was defined as the line connecting both BMOs. The OC plane was defined as the line connecting the nasal BMO and the innermost margin of the EOBT. AL and ONH tilt angle have previously been shown to be correlated.15 Third, axial elongation was likely to be associated with a greater degree of OC obliqueness. OC obliqueness was defined as the angle formed by a vertical line and the EOBT (Fig. 1). To compare these parameters with a known AL-related parameter, the β-zone PPA was also measured. The β-zone PPA was defined as the region of chorioretinal atrophy with both visible sclera and choroidal vessels adjacent to the ONH as observed in the red-free image. The size of β-zone PPA was defined as the distance between the point on the temporal β-zone PPA margin and ONH margin. The maximum values of these parameters were used as deep ONH parameters in all analyses. 
Figure 1
 
Morphologic differences in deep ONH structures according to AL. Three deep ONH structures were measured: EOBT length, defined as the length between the end points of EOBT tissue (yellow line); ONH tilt angle, defined as the angle between BMO plane (red line) and OC plane (red dotted line). BMO plane (red line) was the line connecting both BMO and the OC plane (red dotted line) was defined as the line connecting the nasal BMO and the innermost margin of the EOBT; and OC obliqueness, defined as the angle made by a vertical line (yellow dotted line) and EOBT (yellow line). Images are shown of a representative eye with an AL of 25.54 mm (A, C, E) showing a longer EOBT length, larger ONH tilt angle, and larger degree of OC obliqueness than a representative eye with an AL of 23.83 mm (B, D, F).
Figure 1
 
Morphologic differences in deep ONH structures according to AL. Three deep ONH structures were measured: EOBT length, defined as the length between the end points of EOBT tissue (yellow line); ONH tilt angle, defined as the angle between BMO plane (red line) and OC plane (red dotted line). BMO plane (red line) was the line connecting both BMO and the OC plane (red dotted line) was defined as the line connecting the nasal BMO and the innermost margin of the EOBT; and OC obliqueness, defined as the angle made by a vertical line (yellow dotted line) and EOBT (yellow line). Images are shown of a representative eye with an AL of 25.54 mm (A, C, E) showing a longer EOBT length, larger ONH tilt angle, and larger degree of OC obliqueness than a representative eye with an AL of 23.83 mm (B, D, F).
In addition, we also defined eyes with disc tilt as eyes with a tilt ratio (long axis/short axis) greater than 1.3.16 
Measurement of the Angular Location of Parameters Associated With Axial Elongation and RNFL Defects
The angular location of deep ONH parameters was measured via infrared (IR) photography, which was included in SD-OCT. Because the fovea was not included or recognized in some IR photos, we aligned the IR photos and red-free fundus photos using Photoshop CS5 (Adobe Systems, Inc., San Jose, CA, USA). The line connecting the center of the BMO and the fovea was defined as the foveal-BMO (FoBMO) axis (Fig. 2A).13 The angular location of each deep ONH parameter was defined as the angle between the parameter location and the FoBMO axis (Fig. 2B). The angular location of PPA was defined as the direction of the maximal extent of PPA from the FoBMO axis (Fig. 2C). To measure the angular location of RNFL defects, each angular location of RNFL defect margin was measured. The angle between the FoBMO axis and the mean angular location of the RNFL margin was regarded as the angular location of the RNFL defect (Fig. 2D). If the angular location of each parameter was below the FoBMO axis, the location was assigned a positive value. Otherwise, the location of each parameter was assigned a negative value. For myopic eyes with NTG, only cases with a single RNFL defect were analyzed to evaluate the associations between RNFL defect location and parameter locations. The extent and angular location of each parameter were assessed by two investigators (EJL and SBK) in a masked fashion using built-in SD-OCT software. The averages of the two investigators were used in the final analysis. 
Figure 2
 
Measurement of angular locations of the parameters. (A) BMOs were measured from IR photos obtained by SD-OCT (yellow dotted circle). For cases in which the center of the macula was difficult to detect in the IR photo, the IR photo was aligned to a red-free fundus photo as a reference. The FoBMO axis was defined as the line connecting the center of the BMO and the fovea. This axis was used as the measurement reference for the angular locations of all parameters (yellow line). (B) The angular locations of the maximum values of each deep ONH parameter (EOBT, ONH tilt angle, and OC obliqueness) were measured (green arrow). (C) The angular location of β-zone PPA was defined as the direction of maximal PPA from the FoBMO axis (blue arrow). (D) To measure RNFL defects, each angular location of the RNFL defect margin (white line) was drawn. The angle between the FoBMO and the average angular location of each RNFL defect margin was defined as the angular location of the RNFL defect (red arrow).
Figure 2
 
Measurement of angular locations of the parameters. (A) BMOs were measured from IR photos obtained by SD-OCT (yellow dotted circle). For cases in which the center of the macula was difficult to detect in the IR photo, the IR photo was aligned to a red-free fundus photo as a reference. The FoBMO axis was defined as the line connecting the center of the BMO and the fovea. This axis was used as the measurement reference for the angular locations of all parameters (yellow line). (B) The angular locations of the maximum values of each deep ONH parameter (EOBT, ONH tilt angle, and OC obliqueness) were measured (green arrow). (C) The angular location of β-zone PPA was defined as the direction of maximal PPA from the FoBMO axis (blue arrow). (D) To measure RNFL defects, each angular location of the RNFL defect margin (white line) was drawn. The angle between the FoBMO and the average angular location of each RNFL defect margin was defined as the angular location of the RNFL defect (red arrow).
Statistical Analysis
The Mann-Whitney U test for continuous variables and χ2 test for categorical variables were used for comparisons between myopic eyes with versus without NTG. The intraobserver and interobserver reproducibility of each parameter were assessed by calculating the intraclass correlation coefficient (ICC). Twenty measurements of each parameter in 20 randomly selected subjects were used for this analysis. One investigator (SBK) measured the data twice at 1-week intervals for intraobserver reproducibility and two investigators (EJL and SBK) measured the data for interobserver reproducibility. 
Correlations between the parameters and AL and correlations among the parameters were evaluated by Pearson's correlation approach. The correlation coefficient (R) was also calculated. The Brown-Forsythe test was performed to assess the equality of distribution of the parameters. 
To investigate which factors were associated with the presence of NTG in myopic eyes, logistic regression analysis was performed using univariate and multivariate analysis. Factors with P < 0.2 on the univariate analysis were included in multivariate analysis. However, there were correlations among EOBT, ONH tilt angle, and OC obliqueness; we used three multivariate analysis models to divide these parameters in different models. The Mann-Whitney U test was used to compare the factors between the inferior versus superior RNFL defect groups in myopic eyes with NTG. 
Results
Baseline Characteristics
A total of 160 eyes from 160 enrolled patients were analyzed. Only eyes for which EOBT, ONH tilt angle, OC obliqueness, and beta-zone PPA could be measured were included in the analysis. Seven eyes (4.4%) were excluded because parameter measurements could not be made; this was due to the exclusive presence of internally oblique border tissues throughout the ONH. Twelve eyes (7.5%) were excluded because of poor imaging quality that did not allow visualization of deep structures such as BMO or border tissue. In total, 141 eyes from 141 patients were included in the analysis. Of these 141 eyes, 67 eyes were myopic control eyes and 74 eyes were myopic NTG eyes. No differences were found in age, sex, baseline IOP, spherical equivalent, AL, and central corneal thickness between myopic eyes with versus without NTG. VF parameters, such as MD, PSD, VFI, and average RNFL thickness, were significantly different between myopic eyes with versus without NTG (P < 0.001 for all four parameters). The clinical characteristics of the participants are compared in Table 1. Intraobserver and interobserver ICCs showed good agreement for the assessment of the extent and the angular location of the parameters (Table 2). 
Table 1
 
Baseline Characteristics
Table 1
 
Baseline Characteristics
Table 2
 
Intraobserver and Interobserver Reproducibility of Measurements
Table 2
 
Intraobserver and Interobserver Reproducibility of Measurements
The Extent and the Location of Deep ONH Parameters According to AL
The parameters of the 141 included eyes were analyzed. The extent of deep ONH parameters and maximal β-zone PPA were significantly correlated with AL (R = 0.61, P < 0.001 for maximal EOBT length; R = 0.25, P = 0.003 for maximal ONH tilt angle; R = 0.35, P < 0.001 for maximal OC obliqueness; and R = 0.55, P < 0.001 for maximal PPA length, respectively) (Fig. 3). 
Figure 3
 
Pearson's correlation plots showing correlations between AL and maximal EOBT length (A), maximal ONH tilt angle (B), maximal OC obliqueness (C), and β-zone PPA (D). All parameters demonstrated significant correlation with AL.
Figure 3
 
Pearson's correlation plots showing correlations between AL and maximal EOBT length (A), maximal ONH tilt angle (B), maximal OC obliqueness (C), and β-zone PPA (D). All parameters demonstrated significant correlation with AL.
The angular locations of the parameters are shown in Figure 4. As maximal β-zone PPA, the angular locations of maximal EOBT length, maximal ONH tilt angle, and maximal OC obliqueness were mainly positioned at the inferotemporal area of the ONH. AL was divided into two groups (AL ≥26 mm and AL <26 mm) according to the median value of included eyes. In eyes with an AL ≥26 mm, the parameters showed narrower distributions than in eyes with AL <26 mm (P = 0.009 for maximal EOBT; P = 0.046 for maximal ONH tilt angle; P = 0.003 for maximal OC obliqueness; P = 0.191 for maximal β-zone PPA, respectively). Significant correlations were observed among the extent of the parameters and their angular location (Table 3). 
Figure 4
 
Frequency distribution of each deep ONH parameter according to the meridian clock. The eyes were divided into two groups arbitrarily based on median AL value, with a cutoff of 26 mm. No statistically significant differences in the averages were observed between the two groups for any parameter. Most deep ONH parameters (maximal values) were positioned in the inferotemporal direction. In eyes with an AL ≥26 mm, the distribution was narrower than with an AL <26 mm.
Figure 4
 
Frequency distribution of each deep ONH parameter according to the meridian clock. The eyes were divided into two groups arbitrarily based on median AL value, with a cutoff of 26 mm. No statistically significant differences in the averages were observed between the two groups for any parameter. Most deep ONH parameters (maximal values) were positioned in the inferotemporal direction. In eyes with an AL ≥26 mm, the distribution was narrower than with an AL <26 mm.
Table 3
 
Correlations Among Deep ONH Parameters and β-Zone PPA
Table 3
 
Correlations Among Deep ONH Parameters and β-Zone PPA
Comparison of the Extent and Location of Deep ONH Parameters in Myopic NTG Eyes Versus Myopic Control Eyes
Regarding deep ONH parameter extent, myopic NTG eyes only showed significantly greater maximal ONH tilt angle compared with myopic control eyes (P = 0.03). Regarding deep ONH parameter angular location, myopic NTG eyes demonstrated more temporalized location distributions of maximal EOBT, maximal ONH tilt, and maximal OC obliqueness compared with myopic controls (P = 0.01; P = 0.01; P = 0.03, respectively) (Table 4). Univariate logistic regression analysis revealed a significant association between the presence of myopic NTG and maximal ONH tilt angle (P = 0.042) and the temporalized locations of maximal EOBT, maximal ONH tilt angle, and maximal OC obliqueness (P = 0.008; P = 0.013; P = 0.029, respectively). In multivariate analysis, temporalized locations of maximal EOBT, maximal ONH tilt, and maximal OC obliqueness were significantly associated with the presence of myopic NTG (P = 0.014; P = 0.016; P = 0.030, respectively) (Table 5). 
Table 4
 
Comparison of Deep ONH Parameters on OCT
Table 4
 
Comparison of Deep ONH Parameters on OCT
Table 5
 
Logistic Regression Analysis: Parameters Associated With the Presence of Myopic NTG
Table 5
 
Logistic Regression Analysis: Parameters Associated With the Presence of Myopic NTG
Of the myopic NTG eyes, 56 NTG eyes with one dominant RNFL defect were selected. According to the direction of the RNFL defect, each eye was classified into either the inferior RNFL defect group (n = 44) or the superior RNFL defect group (n = 12). The angular locations of deep ONH parameters were consistent with RNFL defect locations (Table 6). 
Table 6
 
Comparison of Inferior and Superior RNFL Defects
Table 6
 
Comparison of Inferior and Superior RNFL Defects
Discussion
The present study introduced parameters for measuring deep ONH structural morphologic characteristics. The major findings of the study are as follows. First, the parameters seem to reflect ONH morphologic differences with axial elongation. Longer AL was associated with greater deep ONH parameter values. In addition, these parameters were concentrated in the ONH inferotemporal area, as β-zone PPA, which is known to be related to increased AL.1719 Second, the locations of deep ONH parameters were associated with glaucomatous defects in myopic eyes. Temporalized angular locations of deep ONH parameters were associated with the presence of NTG in myopia. Furthermore, the location of deep ONH parameters was consistent with that of RNFL defects in myopic NTG eyes (Fig. 5). 
Figure 5
 
Images from a representative case. A 61-year-old male with myopic NTG with an IOP <21 mm Hg without medication. The AL was 25.21 mm. Rim notching and thinning existed at the inferior ONH area. The RNFL defect (red line) was 45.3° from the FoBMO axis (yellow line). All the maximum values of deep ONH parameters were located approximately 26.5° (green arrow) (A). B-scan sections at approximately −26.5° (B), at the FoBMO axis (C), and at the location of the maximum values of the parameters (D), are shown. The B-scan at an inferotemporal location (D) demonstrates greater deep ONH morphologic changes, such as externally extended BMO (white arrowhead) and elongated and elevated EOBT (white arrow) compared with those at the FoBMO axis (C) and at the counterpart location (B).
Figure 5
 
Images from a representative case. A 61-year-old male with myopic NTG with an IOP <21 mm Hg without medication. The AL was 25.21 mm. Rim notching and thinning existed at the inferior ONH area. The RNFL defect (red line) was 45.3° from the FoBMO axis (yellow line). All the maximum values of deep ONH parameters were located approximately 26.5° (green arrow) (A). B-scan sections at approximately −26.5° (B), at the FoBMO axis (C), and at the location of the maximum values of the parameters (D), are shown. The B-scan at an inferotemporal location (D) demonstrates greater deep ONH morphologic changes, such as externally extended BMO (white arrowhead) and elongated and elevated EOBT (white arrow) compared with those at the FoBMO axis (C) and at the counterpart location (B).
One strength of investigating deep ONH structure is that it reveals detailed information about deep ONH, including BMO, border tissue, and LC. Deep ONH morphologic characteristics may reflect deep ONH geometric changes that arise from the combination effects of material properties of the ONH and stretching around ONH structures that occurs during eyeball development. IOP is the most important factor associated with glaucoma; however, in myopic NTG, non–IOP-related ONH morphologic characteristics are also likely to play a role in glaucoma pathogenesis.1,20 However, few parameters that indicate the extent and location of ONH morphologic changes with axial elongation have been introduced. β-zone PPA and optic disc tilt (based on ONH surface morphology) have been used as biomarkers that indicate the direction of ONH morphologic characteristics.5,6,8,9 However, parameters such as PPA and optic disc tilt can be used only in myopic eyes with definite PPA or disc tilt. This was a limitation of previous studies in that their results could not be applied to glaucoma without definite PPA or disc tilt. Because all eyes experience axial elongation, ONH morphologic characteristics may be involved in the pathogenesis of most types of glaucoma; however, assessing the degree of involvement is difficult. In the present study, the inclusion criteria for myopia were not strict (i.e., eyes with a spherical equivalent < −0.5 were included). As a result, approximately half of the included eyes had a nontilted ONH surface morphology. 
Deep ONH parameters such as maximal EOBT length, maximal ONH tilt angle, and maximal OC obliqueness are mainly defined by border tissue configurations and BMO. We hypothesized that changes in border tissue configuration and BMO reflect deep ONH morphologic changes with axial elongation, and that these changes are associated with AL. Here we observed significant correlations between the extents of deep ONH parameters and AL. Deep ONH parameters mostly distributed in the inferotemporal ONH area and the distribution of each parameter was narrower in eyes with AL ≥26 mm than in eyes with AL <26 mm. Furthermore, the extent and location of deep ONH parameters were correlated with maximal β-zone PPA, which has also been shown to be associated with AL.17,21,22 
In the present study, the angular locations of deep ONH parameters were temporalized in myopic NTG eyes. We elucidated that the temporal locations of deep ONH parameters represent greater structural changes with axial elongation as larger extent of deep ONH structural changes. In previous studies of OCT findings, myopic eyes showed temporalized RNFL distributions.23 Temporalized RNFL distribution can be attributed to peripapillary scleral expansion with axial elongation.24 Temporalized scleral changes may lead the maximally extended BM and border tissue to the temporal direction. Thus, our results demonstrate that greater maximal deep ONH changes might be associated with NTG in myopic eyes. Interestingly, multivariate analysis, including AL, revealed that temporalized deep ONH parameters were independently associated with the presence of myopic NTG. Deep ONH structural characteristics are likely to be independent risk factors in myopic NTG. 
Previous studies have demonstrated that ONH morphology, such as PPA and disc tilt, are associated with glaucoma.6,7,9,2527 Using OCT, Reis et al.11 first reported different features of deep ONH structures, such as border tissue geometric changes and BMO according to the location. In a previous study, EOBTs were found most frequently at the inferotemporal ONH area in both glaucoma and normal eyes; however, inferotemporal EOBTs were more common in glaucoma eyes than healthy controls. The present study showed consistent results with the previous study. In the present study, most eyes had maximum EOBT in the inferotemporal ONH area, irrespective of the presence of glaucoma. In addition, more temporalized EOBT locations were found in myopic NTG eyes compared with myopic control eyes. The clinical significance of temporalized EOBT locations may be in line with that of frequent presence of EOBT in the inferotemporal area in that those results indicate the clinical importance of deep ONH characteristics in glaucoma pathogenesis. 
In previous studies, Kim et al.28 defined PPA using BMO and border tissue locations on OCT and observed related factors with PPA with and without BM. They concluded that PPA without BM may be associated with AL. However, in further studies, PPA without BM was not associated with glaucoma progression.29,30 Direct comparisons of the present study results with the previous study results is not likely possible due to different study design. In addition, it is possible that the risk factors associated with the glaucoma prevalence can be different from those of glaucoma progression. In our previous study, we demonstrated that glaucomatous VF progression pattern can vary according to the ONH surface tilt morphology.22 Further prospective studies will be needed to understand the relationship between ONH structure and prevalence and progression in glaucoma. 
In the present study, maximum parameter values rather than average parameter values were used for all analyses. In the previous study, Vianna et al.31 analyzed average values of OC obliqueness in all directions and did not find any differences between myopic NTG eyes and myopic control eyes. We speculated that maximal deep ONH structural changes may be more relevant to induction of glaucomatous damage than the average value, especially in myopic NTG. Even if one eye exhibits high average ONH changes, it may not have a glaucomatous defect if RNFL stress does not exceed the threshold throughout the ONH. However, even if one eye has lower average ONH changes than other eyes, it can have a glaucomatous defect if RNFL stress exceeds the threshold at the location of maximum ONH change. This hypothesis is supported by our findings that the locations of the maximum ONH parameters were consistent with the location of RNFL defects in myopic NTG eyes. 
This study has several limitations. First, the present study included a small number of cases. Thus, some parameters did not reach statistical significance. Because all parameters were correlated with each other, the clinical implications of the parameters appear to be similar, even though some parameters did not show statistical significance. Second, this study has a retrospective design. Thus, this study cannot offer information related to causal relationships and deep ONH morphology could result from glaucomatous defect in myopic eyes. However, considering that myopic control eyes had a similar distribution of deep ONH morphology like myopic NTG eyes, we speculated that deep ONH features may be the cause rather than the outcome of glaucomatous defects in myopic eyes. Third, the present study had wide inclusion criteria for myopia (less than −0.5 D). For now, there is no consensus regarding the cutoff values for AL or spherical equivalent that represent clinically significant myopia. In our study, we chose −0.5 D as the cutoff value for myopia because mild myopic eyes also demonstrated deep ONH changes according to AL. Fourth, other risk factors, such as ocular perfusion pressure and low blood pressure, were not analyzed as covariates. Because glaucoma can be caused by multiple risk factors, these factors might have influenced the results. 
In conclusion, we proposed parameters that could potentially be used as biomarkers representing deep ONH features with axial elongation. In myopic eyes, temporalized angular locations of the parameters were associated with the presence of NTG. Moreover, deep ONH parameter locations exhibited spatial correlation with RNFL defects in myopic NTG eyes. 
Acknowledgments
Disclosure: J.C. Han, None; E.J. Lee, None; S.B. Kim, None; C. Kee, None 
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Figure 1
 
Morphologic differences in deep ONH structures according to AL. Three deep ONH structures were measured: EOBT length, defined as the length between the end points of EOBT tissue (yellow line); ONH tilt angle, defined as the angle between BMO plane (red line) and OC plane (red dotted line). BMO plane (red line) was the line connecting both BMO and the OC plane (red dotted line) was defined as the line connecting the nasal BMO and the innermost margin of the EOBT; and OC obliqueness, defined as the angle made by a vertical line (yellow dotted line) and EOBT (yellow line). Images are shown of a representative eye with an AL of 25.54 mm (A, C, E) showing a longer EOBT length, larger ONH tilt angle, and larger degree of OC obliqueness than a representative eye with an AL of 23.83 mm (B, D, F).
Figure 1
 
Morphologic differences in deep ONH structures according to AL. Three deep ONH structures were measured: EOBT length, defined as the length between the end points of EOBT tissue (yellow line); ONH tilt angle, defined as the angle between BMO plane (red line) and OC plane (red dotted line). BMO plane (red line) was the line connecting both BMO and the OC plane (red dotted line) was defined as the line connecting the nasal BMO and the innermost margin of the EOBT; and OC obliqueness, defined as the angle made by a vertical line (yellow dotted line) and EOBT (yellow line). Images are shown of a representative eye with an AL of 25.54 mm (A, C, E) showing a longer EOBT length, larger ONH tilt angle, and larger degree of OC obliqueness than a representative eye with an AL of 23.83 mm (B, D, F).
Figure 2
 
Measurement of angular locations of the parameters. (A) BMOs were measured from IR photos obtained by SD-OCT (yellow dotted circle). For cases in which the center of the macula was difficult to detect in the IR photo, the IR photo was aligned to a red-free fundus photo as a reference. The FoBMO axis was defined as the line connecting the center of the BMO and the fovea. This axis was used as the measurement reference for the angular locations of all parameters (yellow line). (B) The angular locations of the maximum values of each deep ONH parameter (EOBT, ONH tilt angle, and OC obliqueness) were measured (green arrow). (C) The angular location of β-zone PPA was defined as the direction of maximal PPA from the FoBMO axis (blue arrow). (D) To measure RNFL defects, each angular location of the RNFL defect margin (white line) was drawn. The angle between the FoBMO and the average angular location of each RNFL defect margin was defined as the angular location of the RNFL defect (red arrow).
Figure 2
 
Measurement of angular locations of the parameters. (A) BMOs were measured from IR photos obtained by SD-OCT (yellow dotted circle). For cases in which the center of the macula was difficult to detect in the IR photo, the IR photo was aligned to a red-free fundus photo as a reference. The FoBMO axis was defined as the line connecting the center of the BMO and the fovea. This axis was used as the measurement reference for the angular locations of all parameters (yellow line). (B) The angular locations of the maximum values of each deep ONH parameter (EOBT, ONH tilt angle, and OC obliqueness) were measured (green arrow). (C) The angular location of β-zone PPA was defined as the direction of maximal PPA from the FoBMO axis (blue arrow). (D) To measure RNFL defects, each angular location of the RNFL defect margin (white line) was drawn. The angle between the FoBMO and the average angular location of each RNFL defect margin was defined as the angular location of the RNFL defect (red arrow).
Figure 3
 
Pearson's correlation plots showing correlations between AL and maximal EOBT length (A), maximal ONH tilt angle (B), maximal OC obliqueness (C), and β-zone PPA (D). All parameters demonstrated significant correlation with AL.
Figure 3
 
Pearson's correlation plots showing correlations between AL and maximal EOBT length (A), maximal ONH tilt angle (B), maximal OC obliqueness (C), and β-zone PPA (D). All parameters demonstrated significant correlation with AL.
Figure 4
 
Frequency distribution of each deep ONH parameter according to the meridian clock. The eyes were divided into two groups arbitrarily based on median AL value, with a cutoff of 26 mm. No statistically significant differences in the averages were observed between the two groups for any parameter. Most deep ONH parameters (maximal values) were positioned in the inferotemporal direction. In eyes with an AL ≥26 mm, the distribution was narrower than with an AL <26 mm.
Figure 4
 
Frequency distribution of each deep ONH parameter according to the meridian clock. The eyes were divided into two groups arbitrarily based on median AL value, with a cutoff of 26 mm. No statistically significant differences in the averages were observed between the two groups for any parameter. Most deep ONH parameters (maximal values) were positioned in the inferotemporal direction. In eyes with an AL ≥26 mm, the distribution was narrower than with an AL <26 mm.
Figure 5
 
Images from a representative case. A 61-year-old male with myopic NTG with an IOP <21 mm Hg without medication. The AL was 25.21 mm. Rim notching and thinning existed at the inferior ONH area. The RNFL defect (red line) was 45.3° from the FoBMO axis (yellow line). All the maximum values of deep ONH parameters were located approximately 26.5° (green arrow) (A). B-scan sections at approximately −26.5° (B), at the FoBMO axis (C), and at the location of the maximum values of the parameters (D), are shown. The B-scan at an inferotemporal location (D) demonstrates greater deep ONH morphologic changes, such as externally extended BMO (white arrowhead) and elongated and elevated EOBT (white arrow) compared with those at the FoBMO axis (C) and at the counterpart location (B).
Figure 5
 
Images from a representative case. A 61-year-old male with myopic NTG with an IOP <21 mm Hg without medication. The AL was 25.21 mm. Rim notching and thinning existed at the inferior ONH area. The RNFL defect (red line) was 45.3° from the FoBMO axis (yellow line). All the maximum values of deep ONH parameters were located approximately 26.5° (green arrow) (A). B-scan sections at approximately −26.5° (B), at the FoBMO axis (C), and at the location of the maximum values of the parameters (D), are shown. The B-scan at an inferotemporal location (D) demonstrates greater deep ONH morphologic changes, such as externally extended BMO (white arrowhead) and elongated and elevated EOBT (white arrow) compared with those at the FoBMO axis (C) and at the counterpart location (B).
Table 1
 
Baseline Characteristics
Table 1
 
Baseline Characteristics
Table 2
 
Intraobserver and Interobserver Reproducibility of Measurements
Table 2
 
Intraobserver and Interobserver Reproducibility of Measurements
Table 3
 
Correlations Among Deep ONH Parameters and β-Zone PPA
Table 3
 
Correlations Among Deep ONH Parameters and β-Zone PPA
Table 4
 
Comparison of Deep ONH Parameters on OCT
Table 4
 
Comparison of Deep ONH Parameters on OCT
Table 5
 
Logistic Regression Analysis: Parameters Associated With the Presence of Myopic NTG
Table 5
 
Logistic Regression Analysis: Parameters Associated With the Presence of Myopic NTG
Table 6
 
Comparison of Inferior and Superior RNFL Defects
Table 6
 
Comparison of Inferior and Superior RNFL Defects
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