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Characteristics of Optic Disc Rotation in Myopic Eyes
Characteristics of Optic Disc Rotation in Myopic Eyes Mi Sun Sung, MD,1 Yeon Soo Kang, MD,1 Hwan Heo, MD,1 Sang Woo Park, MD, PhD1,2 Purpose: To investigate the characteristics of optic disc rotation and ocular parameters affecting optic disc rotation in healthy myopic eyes. Design: Cross-sectional, comparative study. Participants: A total of 220 participants with healthy myopic eyes. Methods: Spherical equivalent (SE) refractive error, axial length, central corneal thickness, and intraocular pressure (IOP) were evaluated. Optic disc tilt ratio, degree of optic disc rotation, and area of b-zone parapapillary atrophy (PPA) were measured. Optic nerve head (ONH) parameters and thickness of the peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell-inner plexiform layer (mGCIPL) were measured using Cirrus optical coherence tomography (Carl Zeiss Meditec Inc., Dublin, CA). Subjects were divided into 2 groups, group 1 with superior rotation and group 2 with inferior rotation of the optic disc, and various parameters were compared. Linear regression analysis was performed to evaluate the relationships between the degree of optic disc rotation and several parameters. Main Outcome Measures: Degree of optic disc rotation. Results: Among 220 eyes, 147 showed superior rotation of the optic disc and 73 showed inferior rotation. The mean tilt ratio and rotation degree were 1.16 and 19.51 , respectively, in group 1 and 1.20 and 28.93 , respectively, in group 2, showing significant differences between the groups (P ¼ 0.028 and P ¼ 0.035, respectively). There were also significant between-group differences in IOP (15.59 vs. 16.34 mmHg), SE refractive error (4.05 vs. 5.66 diopters [D]), axial length (25.51 vs. 26.26 mm), and area of b-zone PPA (0.32 vs. 0.70 mm2). Overall, a multivariate linear regression analysis showed that IOP, axial length, and area of b-zone PPA were significant parameters related to the degree of optic disc rotation (P ¼ 0.011, P ¼ 0.043, and P ¼ 0.030, respectively). Group 2 showed thinner pRNFL and mGCIPL thickness in general compared with group 1. Conclusions: In healthy myopic eyes, superior rotation of the optic disc was more prevalent than inferior rotation. As the optic disc rotates inferiorly, there was a significant positive correlation with IOP, axial length, and area of the b-zone PPA. Conversely, a significant negative correlation with pRNFL and mGCIPL thickness was observed. Ophthalmology 2015;-:1e8 ª 2015 by the American Academy of Ophthalmology. Supplemental material is available at www.aaojournal.org.
Myopia is a common ocular condition and continues to increase in prevalence, particularly in Asian populations.1e3 Because axial elongation in the myopic eye is associated with posterior scleral remodeling, myopic eyes demonstrate various characteristic features of the optic nerve head (ONH), including marked parapapillary atrophy (PPA), shallow disc cupping, a macrodisc with an abnormal elongation, optic disc tilt, and torsion.4e9 Recently, these morphologic features of the optic disc have become candidates for the explanation of the high prevalence of glaucoma in myopic eyes. Among them, optic disc torsion has been recognized as a new area of concern. It has been reported that optic disc torsion was highly prevalent in Asian populations and associated with visual field (VF) defects.9e13 Park et al10 reported that the direction of optic disc torsion was a strong predictor of VF defect location in normal-tension glaucoma (NTG). Likewise, Lee et al12 found a significant correlation between the amount of optic disc torsion and the VF defect severity based on the mean deviation in young myopic eyes. 2015 by the American Academy of Ophthalmology Published by Elsevier Inc.
Traditionally, torsion has been a term used to describe the rotation of the optic disc. Because the optic nerve extends from the optic disc to the chiasm, rotation of the optic disc, which is 1 end of the optic nerve, may result in optic nerve twisting. Until now, however, none of the studies have demonstrated actual twisting of the optic nerve in eyes with optic disc torsion. Moreover, Lee et al14 recently suggested that optic disc torsion is another form of optic disc tilt centered on the oblique axis. Therefore, we used the term “optic disc rotation,” which only describes the anatomic variation of the optic disc and retinal vessels, rather than the term “optic disc torsion” in this study. To date, most studies have focused on optic disc rotation in glaucomatous eyes,9e13 and few have reported on the features of optic disc rotation in healthy subjects. Thus, the aim of this study was to characterize optic disc rotation and evaluate ocular parameters affecting optic disc rotation in healthy myopic eyes. http://dx.doi.org/10.1016/j.ophtha.2015.10.018 ISSN 0161-6420/15
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Methods Subjects The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board of the Chonnam National University Hospital. The participants were informed about the study objectives, and signed informed consent was obtained from all participants. Healthy volunteers were prospectively and consecutively recruited from February to August 2014. The subjects were selected from students attending the Chonnam National University Medical School. All subjects underwent complete ophthalmic examination including measurement of best-corrected visual acuity, intraocular pressure (IOP) by Goldmann applanation tonometry, manifest refraction, slit-lamp examination, anterior chamber angle examination by gonioscopy, ONH and retinal nerve fiber layer (RNFL) examination by color stereoscopic disc photography and red-free RNFL fundus photography, and the Swedish Interactive Threshold Algorithm standard 30-2 perimetry with a Humphrey Field Analyzer (Carl Zeiss Meditec Inc., Dublin, CA). All IOP measurements were made between 5:00 and 7:00 PM. Axial length, central corneal thickness, and anterior chamber depth were measured by optical low-coherence reflectometry (Lenstar; HaagStreit AG, Koeniz, Switzerland). A detailed medical history was also recorded for each subject. The following inclusion criteria were used: healthy subjects aged between 20 and 40 years, a spherical equivalent (SE) refractive error between 9.0 and 0.5 diopters (D), astigmatism within 2 D, best-corrected visual acuity 20/25, IOP 21 mmHg, normal anterior chamber angles, nonglaucomatous ONHs on stereoscopic photographs (an intact neuroretinal rim without peripapillary hemorrhage, thinning, or localized pallor), absence of any RNFL abnormalities on red-free fundus photographs, and normal VF results in both eyes. Because myopic refractive error can be affected by lenticular changes, and aging may increase the incidence of glaucoma, we excluded subjects older than 40 years of age. To increase the yield of healthy myopic eyes, we also excluded extremely highly myopic eyes with an SE <9.0 D, because it is known that various pathologic changes on the myopic fundus, such as staphyloma, lacquer cracks, and so forth, increase in prevalence with increasing myopic refractive error. Normal VF presentation was defined as a glaucoma hemifield test result within normal limits, as well as mean and pattern standard deviation values associated with probabilities of normality greater than 5%. Some eyes had an enlarged blind spot associated with a large area of PPA, and such eyes were also included in this study. Patients with a family history of glaucoma in a first-degree relative, history of intraocular or refractive surgery, pathologic myopia (patch chorioretinal atrophy, lacquer crack lesions, intrachoroidal cavitations, choroidal neovascularization), other evidence of retinal pathology, or opaque media were excluded. Eligibility was determined by 2 glaucoma specialists (M.S.S. and S.W.P.), who evaluated optic disc appearance on stereoscopic disc photographs and RNFL defects on red-free fundus photographs. Evaluators were masked to all other patient and ocular data, and an eye was excluded from study analyses if a consensus could not be reached. The right eye was selected for the analyses.
Optical Coherence Tomography Imaging The ONH, peripapillary RNFL (pRNFL), and macular ganglion cell-inner plexiform layer (mGCIPL) parameters were measured using a Cirrus high-definition optical coherence tomography (HD-OCT) device (Carl Zeiss Meditec). All measurements were
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performed by the same examiner who was experienced in taking OCT images. The Optic Disc Cube 200200 protocol provides the results obtained from 200 horizontal B-scans (200 A-scans per B-scan) and measures pRNFL thickness in a cube of 662 mm. The average pRNFL thickness was measured within a 3.46-mmediameter circle, the center of which was manually positioned at the optic disc center. Quadrant pRNFL thickness values were used in our analysis. The Macular Cube 200200 protocol provides the results obtained from 200 horizontal B-scans (200 A-scans per B-scan) over 1024 samplings within a cube (662 mm) centered at the fovea. The ganglion cell analysis algorithm in the 6.0 software version of Cirrus HD-OCT reports the combined thickness of the retinal ganglion cell and inner plexiform layers by identifying the outer boundaries of the RNFL and the inner plexiform layer. The average, minimum (lowest mGCIPL thickness over a single meridian crossing the annulus), and 6 sectoral (superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal) mGCIPL thicknesses were measured within a 14.13-mm2 elliptical annulus area (vertical inner and outer radii of 0.5 mm and 2.0 mm, respectively; horizontal inner and outer radii of 0.6 and 2.4 mm, respectively) centered on the fovea within the cube. Subjects with any abnormalities (including an extremely large PPA) in the circumpapillary region that affected the scan ring where the OCT RNFL thickness measurements were obtained were excluded.
Measurements of Optic Disc Tilt, Rotation, and Parapapillary Atrophy Area Digital retinal photographs centered on the optic disc and macula were obtained using standard settings with a nonmydriatic retinal camera (Canon, Tokyo, Japan). Each photograph was exported to a desktop computer as a TIFF image file. Using public-domain Javabased image processing software developed by the National Institutes of Health (ImageJ, version 1.4.1; Wayne Rasband; National Institutes of Health, Rockville, MD), the optic disc tilt, rotation, and area of b-zone PPA were measured by 2 independent examiners. Average data were used in the final analysis. The definition of optic disc tilt and its measurement have been described.10e13 Briefly, optic disc tilt was measured as the tilt ratio, defined as the ratio between the longest and shortest diameters of the optic disc. Optic discs were classified as tilted in those with tilt ratios exceeding 1.30. Optic disc rotation was defined as the deviation of the long axis of the optic disc from the reference line, 90 from a horizontal line connecting the fovea and the center of the optic disc. The angle between the long axis of the optic disc and the reference line was termed the “degree of rotation.” The optic disc was classified as having significant rotation when the degree of rotation exceeded 15 . All eyes were divided into 2 groups according to the direction of optic disc rotation. Eyes with superior rotation of the optic discs were defined as group 1, and eyes with inferior rotation of the optic discs were defined as group 2. Because all eyes included in the analysis were right eyes, superior rotation indicated clockwise rotation of the optic disc and inferior rotation indicated counterclockwise rotation of the optic disc. Superior rotation was presented as a negative value, and inferior rotation was presented as a positive value. The presence of the b-zone PPA was defined as marked atrophy of the retinal pigment epithelium and a horizontal width of the choriocapillaris apparently larger than the diameter of the major retinal vein at the optic disc edge. The areas of b-zone PPA (an inner crescent of chorioretinal atrophy with visible sclera and choroidal vessels) were determined as the total number of pixels using the ImageJ software in a circumferential pattern. Combined with the magnification factor of 1.4 of the fundus camera, the total magnification by the camera and ImageJ system was
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calculated. We converted the area of b-zone PPA from pixels to millimeters squared. The area was corrected by using Littmann’s formula for each axial length.15 The anterior corneal curvature radius was set at 7.8 mm, which is the reported mean for white and Chinese persons.16
Statistical Analysis SPSS version 18.0 (SPSS Inc., Chicago, IL) was used for all statistical analyses. Agreement on the optic disc tilt ratio, degree of rotation, and area of b-zone PPA between 2 observers was assessed using the BlandeAltman method, which plots their means against their differences.17 The limits of agreement were defined as the mean differences of 2 measurements 1.96 standard deviation of the difference. The normality of distribution was verified using the ShapiroeWilk normality test. Baseline characteristics were reported in counts and proportions or mean standard deviation values as appropriate. Groups were compared using the chisquare test, independent t test, or ManneWhitney U test as appropriate. The comparison of the degree of optic disc rotation between groups 1 and 2 was done with the unsigned value. Because there were significant differences in the SE refractive error and axial length between the 2 groups, an analysis of covariance model with the SE refractive error and axial length as covariates was used to compare the pRNFL and mGCIPL thickness between the groups. Univariate and multivariate linear regression analyses were used to identify explanatory variables with a statistically significant contribution to optic disc rotation. Parameters with P values <0.1 in the univariate analysis were included in the multivariate models. In addition, linear regressions were used to search for correlations between the degree of optic disc rotation and the pRNFL and mGCIPL thickness, introducing age and axial length as covariates. The coefficient of determination (R2) and adjusted R2 in the linear regression were reported. Statistical significance was considered at P < 0.05.
Results During the enrollment period, 235 subjects were evaluated. Of these, 7 subjects were excluded because of prior refractive surgery, 5 subjects were excluded because of VF defects or glaucomatous ONH changes, and 3 subjects were excluded because of other retinal pathologic features. Subsequently, 220 eligible subjects were included in the analyses. The interobserver agreement in the measurements of the tilt ratio, degree of rotation, and area of bzone PPA for all subjects are represented in BlandeAltman plots, showing no systemic differences in their measurements (Fig 1, available at www.aaojournal.org). Characteristics of the included subjects are presented in Table 1. The mean age was 27.946.67 years, 125 subjects were male, and 95 subjects were female. The mean SE refractive error and axial length were 4.582.66 D and 25.761.47 mm, respectively. An SE refractive error less than 6 D (the definition of high myopia) was found in 65 participants. The distribution of the degree of optic disc rotation was fairly normal, although right-skewed (Fig 2). As shown in Table 2, there were no significant differences between the groups in age, sex, central corneal thickness, anterior chamber depth, or the optic disc parameters measured using Cirrus HD-OCT. In contrast, group 2 showed more myopic SE refractive error, higher IOP, and longer axial length compared with group 1 (P < 0.001, P ¼ 0.043, and P < 0.001, respectively). With regard to ONH morphology, we found that group 2 had greater disc tilt and degree of rotation, higher occurrence of a b-zone PPA, and a
Table 1. Demographic Characteristics of Subjects Variables
Description
No. Age (yrs) Sex (male/female) no % SE refractive error (D) IOP (mmHg) Axial length (mm) Central corneal thickness (mm) Anterior chamber depth (mm) Rim area (mm2) Disc area (mm2) Average CDR Vertical CDR Cup volume (mm3) Optic disc tilt Tilted disc/disc without tilt, no (%) Tilt ratio Optic disc rotation Superior/inferior Significant/insignificant Rotation degree ( ) b-zone PPA Presence/absence, no (%) Area of b-zone PPA (mm2)
220 27.946.67 125 (56.82%)/95 (43.18%) 4.582.66 15.842.60 25.761.47 551.2735.71 3.140.25 1.240.29 1.860.50 0.540.19 0.500.19 0.270.27 40 (18.18%)/180 (81.82%) 1.170.13 147 (66.82%)/73 (33.18%) 126 (57.27%)/94 (42.73%) 3.4430.35 124 (56.36%)/96 (43.64%) 0.440.62
Data are mean standard deviation unless otherwise indicated. CDR ¼ cup-to-disc ratio; D ¼ diopters; IOP ¼ intraocular pressure; PPA ¼ parapapillary atrophy; SE ¼ spherical equivalent.
larger area of b-zone PPA when compared with group 1 (P ¼ 0.028, P ¼ 0.035, P < 0.001, and P < 0.001, respectively). Table 3 shows the relationships between the degree of optic disc rotation and various parameters. A univariate regression analysis revealed a significant correlation of the degree of optic disc rotation with age (b ¼ 0.146; P ¼ 0.030), SE refractive error (b ¼ 0.336; P < 0.001), IOP (b ¼ 0.238; P < 0.001), axial length (b ¼ 0.282; P < 0.001), and area of b-zone PPA (b ¼ 0.265; P < 0.001). By using multivariate regression modeling, the IOP (b ¼ 0.234; P ¼ 0.011), axial length (b ¼ 0.222; P ¼ 0.043), and area of b-zone PPA (b ¼ 0.226; P ¼ 0.030) were significant predictors of the degree of rotation. Because the SE refractive error and axial length strongly correlated with each other (r ¼ 0.818; P < 0.001), it would not be adequate to use both as explanatory variables in the multivariate regression model. We adopted axial length as an explanatory variable, because it is known that axial elongation is related to the mechanism of the myopic optic disc. The combination of these 3 variables yielded an R2 of 0.284 and an adjusted R2 of 0.245 (P < 0.001). Figure 3 shows the correlation between the degree of optic disc rotation and the IOP, axial length, and area of b-zone PPA. In a subgroup analysis according to the direction of optic disc rotation, the statistical significance of the relationship between the degree of optic disc rotation and the IOP, axial length, and area of b-zone PPA were similarly maintained in group 2 (P < 0.001; P ¼ 0.040, and P ¼ 0.042, respectively). The combination of these variables yielded an R2 of 0.333 and an adjusted R2 of 0.304 (P < 0.001). In contrast, we found no significant parameters associated with the degree of optic disc rotation in group 1 (Table 4, available at www.aaojournal.org).
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Figure 2. Histogram showing the distribution of the degree of optic disc rotation in myopic eyes.
After controlling for the SE refractive error and axial length, superior and inferior pRNFL thickness and minimum and inferonasal mGCIPL thickness were found to be significantly thinner in group 2 when compared with group 1. In a linear regression analysis with age and axial length as covariates, a significant negative correlation was observed between the degree of optic disc rotation and the following thickness parameters: superior pRNFL (b ¼ 0.226; P ¼ 0.016), inferior pRNFL (b ¼ 0.243; P ¼ 0.012), minimum mGCIPL (b ¼ 0.223; P ¼ 0.018), and inferonasal mGCIPL thickness (b ¼ 0.234; P ¼ 0.016) (Table 5).
Discussion It has been well documented that a large percentage of myopic optic discs are tilted and rotated with a PPA, and
that these morphologic changes may be correlated with VF defects in patients with myopia. Tay et al5 reported that optic disc ovality (an index of tilt) was significantly correlated with greater myopia and VF defects. Likewise, the b-zone PPA has been shown to be associated with glaucomatous damage to the ONH, as well as VF defects, in patients with myopia.18 In regard to optic disc rotation, the results of recent studies demonstrated a significant association between the degree or direction of optic disc rotation and the VF defects in myopic eyes.10e13 Although the relationship between the optic disc tilt or PPA and myopia has been reported in epidemiologic studies,6e8 the relationship between optic disc rotation and myopia remains questionable; most of the aforementioned previous studies focused on specific subpopulations of myopic patients with NTG or glaucomatous-appearing VF changes.10e14 Therefore, we described the characteristics of optic disc rotation in consecutively recruited healthy myopic subjects in this study. Traditionally, the amount of optic disc rotation over 15 has been defined as the optic disc rotation, because it had been shown that the longest diameter of the ONH usually falls within 15 of the vertical meridian. However, optic disc rotation is a subjective interpretation, and thus far there has been no strict definition of a “rotated optic disc”. The Tanjong Pagar Study demonstrated that approximately two thirds of the normal population (64.7%) had rotated optic discs.8 Therefore, we have considered all optic discs with a
Table 2. Comparison of Subject Characteristics According to the Direction of Optic Disc Rotation in Healthy Myopic Eyes Variables
Group 1 (n[147)
Group 2 (n[73)
P Value
Age (yrs) Sex (male/female) SE refractive error (D) IOP (mmHg) Axial length (mm) Central corneal thickness (mm) Anterior chamber depth (mm) Rim area (mm2) Disc area (mm2) Average CDR Vertical CDR Cup volume (mm3) Optic disc tilt Tilted disc/disc without tilt Tilt ratio Optic disc rotation Significant/insignificant Rotation ( ) b-zone PPA Presence/absence Area of b-zone PPA (mm2)
27.376.62 87/60 4.052.47 15.592.54 25.511.35 548.6033.10 3.160.22 1.270.27 1.910.50 0.550.19 0.510.18 0.290.28
29.106.67 38/35 5.662.71 16.342.66 26.261.58 555.9539.88 3.110.31 1.190.31 1.730.50 0.510.21 0.480.20 0.210.23
0.070* 0.386y <0.001* 0.043* <0.001* 0.295* 0.413* 0.201* 0.125* 0.360* 0.506* 0.158*
21/126 1.160.14
19/54 1.200.17
0.041y 0.028*
44/29 28.9326.55
0.565y 0.035z,x
82/65 19.5115.83 67/80 0.320.51
57/16 0.700.73
CDR ¼ cup-to-disc ratio; D ¼ diopters; IOP ¼ intraocular pressure; PPA ¼ parapapillary atrophy; SE ¼ spherical equivalent. Group 1 indicates eyes with superior rotation of the optic disc, and group 2 indicates eyes with inferior rotation of the optic disc. Factors with statistical significance are shown in boldface. *Independent t test. y Chi-square test. z ManneWhitney U test. x The comparison was done with the unsigned value.
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<0.001y <0.001z
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Table 3. Linear Regression Analysis to Determine the Correlation between Variables and the Degree of Optic Disc Rotation Univariate Analysis
Multivariate Analysis*
Variables
B
b
P Value
Age (yrs) Female (vs. male) SE refractive error (D) IOP (mmHg) Axial length (mm) Central corneal thickness (mm) Anterior chamber depth (mm) Rim area (mm2) Disc area (mm2) Average CDR Vertical CDR Cup volume (mm3) Optic disc tilt ratio Area of b-zone PPA (mm2)
0.665 3.437 3.836 2.784 5.812 0.059 5.016 12.306 11.524 2.238 1.105 10.431 23.810 12.935
0.146 0.056 0.336 0.238 0.282 0.068 0.041 0.117 0.178 0.014 0.007 0.093 0.105 0.265
0.030 0.407 <0.001 <0.001 <0.001 0.459 0.658 0.249 0.078 0.887 0.946 0.358 0.121 <0.001
B
b
P Value
0.633
0.172
0.063
2.645 4.340
0.234 0.222
0.011 0.043
4.760
0.074
0.429
12.508
0.226
0.030
B ¼ unstandardized coefficient; b ¼ standardized coefficient; CDR ¼ cup-to-disc ratio; D ¼ diopters; IOP ¼ intraocular pressure; PPA ¼ parapapillary atrophy; SE ¼ spherical equivalent. Factors with statistical significance are shown in boldface. *Only variables with a P value <0.10 in the univariate analysis were included in the multivariate model.
degree of rotation of >0 as rotated optic discs, and optic discs with degrees of rotation >15 were defined as “significantly” rotated. By using these definitions, the prevalence of significant optic disc rotation was 57.27%, consistent with the observations from the Tanjong Pagar Study.8 In regard to the direction of optic disc rotation, Park et al13 recently reported that inferior rotation of the optic disc was observed in 76.7% of glaucomatous eyes. In addition, the same group found that the inferior rotation was prevalent in primary open-angle glaucoma and NTG (89.7% and 66.7%, respectively).11 In contrast, we found that superior rotation was more prevalent than inferior rotation in myopic subjects who were otherwise
ophthalmologically normal. This finding was partially commensurate with that of Lee et al.19 Although their subjects were not all myopic and their definition of optic disc rotation differed from ours, the prevalence of superior rotation was higher than that of inferior rotation among the consecutively enrolled healthy eyes. The results of 2 previous studies have shown a significant positive correlation between the degree of optic disc rotation and the tilt ratio.13,20 However, the correlation between the degree of optic disc rotation and the tilt ratio did not reach the level of statistical significance in the current study (P ¼ 0.121). This discrepancy may be due to the different populations studied; the 2 previous studies included in patients with glaucoma who were less myopic.
Figure 3. Scatterplots showing relationships between (A) degree of optic disc rotation and intraocular pressure (IOP), (B) axial length, and (C) area of b-zone parapapillary atrophy (PPA).
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Ophthalmology Volume -, Number -, Month 2015 Table 5. Comparison of Peripapillary Retinal Nerve Fiber Layer and Macular Ganglion CelleInner Plexiform Layer Thickness According to the Direction of Optic Disc Rotation and Linear Regression between Thickness Parameters and Degree of Optic Disc Rotation in Healthy Myopic Eyes Degree of Optic Disc Rotation Parameters pRNFL thickness, mm Average Superior Inferior Nasal Temporal mGCIPL thickness, mm Minimum Average Superonasal Superior Superotemporal Inferotemporal Inferior Inferonasal
Group 1
Group 2
P Value*
P Valuey
B
b
P Valuez
97.969.42 123.8015.22 125.3015.18 64.3611.16 78.2917.35
93.1410.13 111.5519.66 113.4114.88 60.8610.61 83.3114.33
0.026 0.001 0.001 0.154 0.236
0.121 0.015 0.046 0.512 0.597
0.396 0.390 0.435 0.082 0.139
0.129 0.226 0.243 0.030 0.088
0.170 0.016 0.012 0.756 0.366
81.265.10 83.265.31 85.306.24 84.265.63 82.645.70 82.916.28 80.516.25 83.495.56
77.075.47 79.765.26 81.625.91 81.076.41 80.626.16 81.217.50 77.036.63 78.975.77
<0.001 0.003 0.008 0.016 0.120 0.248 0.015 <0.001
0.011 0.083 0.111 0.207 0.413 0.743 0.215 0.029
1.224 0.824 0.369 0.222 0.417 0.047 0.679 1.185
0.223 0.150 0.078 0.044 0.081 0.010 0.147 0.234
0.018 0.119 0.418 0.646 0.387 0.912 0.130 0.016
B ¼ unstandardized coefficient; b ¼ standardized coefficient; mGCIPL ¼ macular ganglion celleinner plexiform layer; pRNFL ¼ peripapillary retinal nerve fiber layer. Group 1 indicates eyes with superior rotation of the optic disc, and group 2 indicates eyes with inferior rotation of the optic disc. Factors with statistical significance are shown in boldface. *Value for independent t test. y Value for analysis of covariance after controlling for SE refractive error and axial length. z Value for multiple linear regression with age and axial length as covariates.
In addition, our method of tilt measurement also may have contributed to the aforementioned discrepancy. The 2 previous studies measured the degree of the actual optic disc tilt, whereas the optic disc ovality index was used to assess optic disc tilt in this study. Although the ovality index has been widely used as a surrogate measure of optic disc tilt,5,8,21 it is the result of the measurement of flat projections and therefore is affected not only by optic disc tilt but also by optic disc shape. This finding requires reexamination to identify the relationship between the real optic disc tilt and the rotation in healthy myopic eyes. Whether there are different clinical characteristics according to the direction of optic disc rotation remains an open question. Of note, we found that there were significantly different characteristics between groups in this study. Eyes with inferior rotation of the optic disc showed more myopic SE refractive error, higher IOP, longer axial length, greater amounts of tilt and rotation, higher occurrence of a b-zone PPA, and larger area of b-zone PPA when compared with eyes with superior rotation of the optic disc. Because it is well known that myopia, higher IOP, and b-zone PPA are associated with glaucoma prevalence, our findings may help to explain some of the reasons why inferior rotation, compared with superior rotation, is more prevalent among glaucomatous eyes. In the linear regression analysis, we found that a greater inferior rotation was significantly correlated with longer axial length, higher IOP, and larger area of b-zone PPA (P ¼ 0.043, P ¼ 0.011, and P ¼ 0.030, respectively). The association between the optic disc rotation and the axial
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length is a well-known finding,11,20 and our study results confirmed this association. Choi et al20 found that greater inferior rotation of the optic disc was significantly correlated with longer axial length. Park et al11 also reported that axial length was an important factor related to the degree of optic disc rotation in subjects with NTG. These findings led to the speculation that optic disc rotation may occur as a result of the axial elongation of the eyeball. As axial length increases, posterior scleral changes occur, especially at the posterior pole near the ONH, and such changes may result in morphologic changes of the optic disc. This may be explained by positive correlation between the degree of optic disc rotation and the area of b-zone PPA for this reason. In terms of IOP, there was a significant positive correlation between the IOP and the degree of optic disc rotation (P < 0.001). We hypothesized that IOP may result in additional stress on the posterior sclera during axial elongation and therefore affect the development of optic disc rotation. Although all subjects in this study had normal IOP, the stretching of the sclera with changes in IOP is dependent on the rigidity and elasticity of the sclera. Therefore, a certain level of IOP may play a role in the morphologic changes observed in the myopic ONH. We should note the fact that even the normal range of IOP is an important causative risk factor for NTG.22 Nevertheless, we cannot be certain whether the inferior rotation of the optic disc in myopic eyes could be prevented by reducing IOP. This question opens interesting avenues for future studies of the role of IOP lowering in the prevention of optic disc rotation in myopic eyes.
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Optic Disc Rotation in Myopic Eyes
Of note, measurements of pRNFL and mGCIPL thickness showed that all parameters, with the exception of temporal pRNFL thickness, were thinner in group 2. To exclude the effect of myopia on inner retinal thickness measurements, we controlled for both the SE refractive error and the axial length, and found statistically significant differences in the superior and inferior pRNFL thickness and minimum and inferonasal mGCIPL thickness between groups. These parameters showed a significant correlation with the degree of optic disc rotation in a linear regression with age and axial length as covariates. In regard to the superior pRNFL thickness, our result is consistent with previous studies.19,23 Lee et al19 showed that inferior rotation of the optic disc resulted in temporalization of the superior peak in pRNFL thickness, and because of RNFL bundle shifting, temporal pRNFL thickness had a tendency to be thicker and superior pRNFL thickness had a tendency to be thinner. Hwang et al23 also reported similar distribution patterns of pRNFL in eyes with optic disc rotation. However, thinning of the inferior pRNFL, minimum mGCIPL, and inferonasal mGCIPL thickness in group 2 cannot be explained by pRNFL bundle shifting, suggesting a different constitutional anatomic feature between the groups. It has been suggested that optic disc rotation may twist the axonal fibers and thereby exert mechanical stress on them, leading to retinal nerve fiber loss.10e13 Superior rotation could place stress on the superior axons, and inferior rotation could place stress on the inferior axons. We speculate that such stress might be due to the thinning of inferior pRNFL, minimum mGCIPL, and inferonasal mGCIPL thickness in group 2, although we could not find thinning of superior pRNFL thickness in eyes with superior rotation of the optic disc. Another suggestion to explain our results is that the difference in choroidal thickness may affect the difference in the amount of axonal distortion between the superior and inferior bundles. It has been reported that choroidal thinning leads to reduced choroidal circulation, which in turn may cause a circulatory problem in the prelaminar region.24,25 Gupta et al26 and Li et al27 recently showed that the inferior peripapillary choroid is thinner than the superior quadrant. Thus, we hypothesized that these anatomic differences in choroidal thickness may make the inferior bundle more vulnerable to the mechanical stress during the development of optic disc rotation. From the subgroup analysis conducted according to the direction of the optic disc rotation, axial length was not shown to be significantly correlated with the degree of optic disc rotation in group 1. If axial elongation was responsible for the development of superior rotation, greater superior rotation would also be associated with longer axial length. However, this was not the case in this study. In addition, IOP did not correlate significantly with the degree of optic disc rotation in group 1 (P ¼ 0.566). Although our study provided an overall assessment of the characteristics of optic disc rotation, additional studies will be required to elucidate the characteristics of superior rotation.
Study Limitations The results reported should be interpreted in the context of study limitations. First, this study was not population based. Because aging increases the incidence of glaucoma, we excluded subjects older than 40 years of age. Because the participants’ age distribution was biased toward those aged 20 to 30 years, our results may not be representative of the entire myopic population. Second, only single-point measurements of IOP were included in our study. Therefore, potential fluctuations during the day were not considered. Third, our study was cross-sectional, and therefore the changes in optic disc rotation and various parameters could not be documented. Thus, we are uncertain as to whether inferior rotation of the optic disc predisposes to the development of a VF defect or glaucoma. Further prospective, longitudinal studies may better delineate the evolution of glaucoma in myopic eyes with optic disc rotation. In summary, we have investigated the characteristics of optic disc rotation in myopic eyes and found that superior rotation was more prevalent than inferior rotation. Eyes with greater inferior rotation of the optic disc showed a significant association with longer axial length, higher IOP, larger area of b-zone PPA, and constitutional anatomic changes, such as reduced pRNFL and mGCIPL thickness. The role of IOP in optic disc rotation and the relationship between optic disc rotation and development of glaucoma deserve further investigation.
References 1. Sperduto RD, Seigel D, Roberts J, Rowland M. Prevalence of myopia in the United States. Arch Ophthalmol 1983;101: 405–7. 2. Wong TY, Foster PJ, Hee J, et al. Prevalence and risk factors for refractive errors in adult Chinese in Singapore. Invest Ophthalmol Vis Sci 2000;41:2486–94. 3. Sawada A, Tomidokoro A, Araie M, et al. Refractive errors in an elderly Japanese population: the Tajimi study. Ophthalmology 2008;115:363–70. 4. McBrien NA, Gentle A. Role of the sclera in the development and pathological complications of myopia. Prog Retin Eye Res 2003;22:307–38. 5. Tay E, Seah SK, Chan SP, et al. Optic disk ovality as an index of tilt and its relationship to myopia and perimetry. Am J Ophthalmol 2005;139:247–52. 6. Vongphanit J, Mitchell P, Wang JJ. Population prevalence of tilted optic disks and the relationship of this sign to refractive error. Am J Ophthalmol 2002;133:679–85. 7. Jonas JB, Gusek GC, Naumann GO. Optic disk morphometry in high myopia. Graefes Arch Clin Exp Ophthalmol 1988;226: 587–90. 8. 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;127:894–9. 9. Samarawickrama C, Mitchell P, Tong L, et al. Myopia-related optic disc and retinal changes in adolescent children from Singapore. Ophthalmology 2011;118:2050–7. 10. Park HY, Lee K, Park CK. Optic disc torsion direction predicts the location of glaucomatous damage in normal-tension
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11. 12.
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16. 17. 18.
glaucoma patients with myopia. Ophthalmology 2012;119: 1844–51. Park HY, Lee KI, Lee K, et al. Torsion of the optic nerve head is a prominent feature of normal-tension glaucoma. Invest Ophthalmol Vis Sci 2014;56:156–63. Lee KS, Lee JR, Kook MS. Optic disc torsion presenting as unilateral glaucomatous-appearing visual field defect in young myopic Korean eyes. Ophthalmology 2014;121: 1013–9. Park HY, Choi SI, Choi JA, Park CK. Disc torsion and vertical disc tilt are related to subfoveal scleral thickness in open-angle glaucoma patients with myopia. Invest Ophthalmol Vis Sci 2015;56:4927–35. Lee KM, Lee EJ, Kim TW. Lamina cribrosa configuration in tilted optic discs with different tilt axes: a new hypothesis regarding optic disc tilt and torsion. Invest Ophthalmol Vis Sci 2015;56:2958–67. Bennett AG, Rudnicka AR, Edgar DF. Improvements on Littmann’s method of determining the size of retinal features by fundus photography. Graefes Arch Clin Exp Ophthalmol 1994;232:361–7. Cheung SW, Cho P, Douthwaite W. Corneal shape of Hong Kong-Chinese. Ophthalmic Physiol Opt 2000;20:119–25. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307–10. Park KH, Tomita G, Liou SY, Kitazawa Y. Correlation between peripapillary atrophy and optic nerve damage in normaltension glaucoma. Ophthalmology 1996;103:1899–906.
19. Lee KH, Kim CY, Kim NR. Variations of retinal nerve fiber layer thickness and ganglion cell-inner plexiform layer thickness according to the torsion direction of optic disc. Invest Ophthalmol Vis Sci 2014;55:1048–55. 20. Choi JA, Park HY, Shin HY, Park CK. Optic disc tilt direction determines the location of initial glaucomatous damage. Invest Ophthalmol Vis Sci 2014;55:4991–8. 21. Jonas JB, Kling F, Gründler AE. Optic disc shape, corneal astigmatism, and amblyopia. Ophthalmology 1997;104: 1934–7. 22. Anderson DR, Drance SM, Schulzer M; Collaborative Normal-Tension Glaucoma Study Group. Natural history of normal-tension glaucoma. Ophthalmology 2001;108:247–53. 23. Hwang YH, Yoo C, Kim YY. Characteristics of peripapillary retinal nerve fiber layer thickness in eyes with myopic optic disc tilt and rotation. J Glaucoma 2012;21:394–400. 24. Hayreh SS. Blood flow in the optic nerve head and factors that may influence it. Prog Retin Eye Res 2001;20:595–624. 25. Lieberman MF, Maumenee AE, Green WR. Histologic studies of the vasculature of the anterior optic nerve. Am J Ophthalmol 1976;82:405–23. 26. Gupta P, Cheung CY, Baskaran M, et al. Relationship between peripapillary choroid and retinal nerve fiber layer thickness in a population-based sample of non-glaucomatous eyes. Am J Ophthalmol 2015 Sep 17. pii: S0002-9394(15)00588-7. doi: 10.1016/j.ajo.2015.09.018. [Epub ahead of print]. 27. Li L, Bian A, Zhou Q, Mao J. Peripapillary choroidal thickness in both eyes of glaucoma patients with unilateral visual field loss. Am J Ophthalmol 2013;156:1277–84.
Footnotes and Financial Disclosures Originally received: May 22, 2015. Final revision: October 2, 2015. Accepted: October 12, 2015. Available online: ---.
Data collection: Sung, Kang, Heo, Park Obtained funding: Not applicable Manuscript no. 2015-832.
1
Department of Ophthalmology and Research Institute of Medical Sciences, Chonnam National University Medical School and Hospital, Gwangju, South Korea.
2
Center for Creative Biomedical Scientists, Chonnam National University, Gwangju, South Korea. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Author Contributions: Conception and design: Sung, Heo, Park Analysis and interpretation: Sung, Kang, Park
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Overall responsibility: Sung, Kang, Heo, Park Abbreviations and Acronyms: D ¼ diopters; HD-OCT ¼ high-definition optical coherence tomography; IOP ¼ intraocular pressure; mGCIPL ¼ macular ganglion cell inner plexiform layer; NTG ¼ normal-tension glaucoma; ONH ¼ optic nerve head; PPA ¼ parapapillary atrophy; pRNFL ¼ peripapillary retinal nerve fiber layer; RNFL ¼ retinal nerve fiber layer; SE ¼ spherical equivalent; VF ¼ visual field. Correspondence: Sang Woo Park, MD, PhD, Department of Ophthalmology and Research Institute of Medical Sciences, Chonnam National University Medical School and Hospital, 42 Jebong-ro, Dong-gu, Gwangju 501-757, South Korea. E-mail: [email protected].
Myopia is a common ocular condition and continues to increase in prevalence, particularly in Asian populations.1e3 Because axial elongation in the myopic eye is associated with posterior scleral remodeling, myopic eyes demonstrate various characteristic features of the optic nerve head (ONH), including marked parapapillary atrophy (PPA), shallow disc cupping, a macrodisc with an abnormal elongation, optic disc tilt, and torsion.4e9 Recently, these morphologic features of the optic disc have become candidates for the explanation of the high prevalence of glaucoma in myopic eyes. Among them, optic disc torsion has been recognized as a new area of concern. It has been reported that optic disc torsion was highly prevalent in Asian populations and associated with visual field (VF) defects.9e13 Park et al10 reported that the direction of optic disc torsion was a strong predictor of VF defect location in normal-tension glaucoma (NTG). Likewise, Lee et al12 found a significant correlation between the amount of optic disc torsion and the VF defect severity based on the mean deviation in young myopic eyes. 2015 by the American Academy of Ophthalmology Published by Elsevier Inc.
Traditionally, torsion has been a term used to describe the rotation of the optic disc. Because the optic nerve extends from the optic disc to the chiasm, rotation of the optic disc, which is 1 end of the optic nerve, may result in optic nerve twisting. Until now, however, none of the studies have demonstrated actual twisting of the optic nerve in eyes with optic disc torsion. Moreover, Lee et al14 recently suggested that optic disc torsion is another form of optic disc tilt centered on the oblique axis. Therefore, we used the term “optic disc rotation,” which only describes the anatomic variation of the optic disc and retinal vessels, rather than the term “optic disc torsion” in this study. To date, most studies have focused on optic disc rotation in glaucomatous eyes,9e13 and few have reported on the features of optic disc rotation in healthy subjects. Thus, the aim of this study was to characterize optic disc rotation and evaluate ocular parameters affecting optic disc rotation in healthy myopic eyes. http://dx.doi.org/10.1016/j.ophtha.2015.10.018 ISSN 0161-6420/15
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Methods Subjects The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board of the Chonnam National University Hospital. The participants were informed about the study objectives, and signed informed consent was obtained from all participants. Healthy volunteers were prospectively and consecutively recruited from February to August 2014. The subjects were selected from students attending the Chonnam National University Medical School. All subjects underwent complete ophthalmic examination including measurement of best-corrected visual acuity, intraocular pressure (IOP) by Goldmann applanation tonometry, manifest refraction, slit-lamp examination, anterior chamber angle examination by gonioscopy, ONH and retinal nerve fiber layer (RNFL) examination by color stereoscopic disc photography and red-free RNFL fundus photography, and the Swedish Interactive Threshold Algorithm standard 30-2 perimetry with a Humphrey Field Analyzer (Carl Zeiss Meditec Inc., Dublin, CA). All IOP measurements were made between 5:00 and 7:00 PM. Axial length, central corneal thickness, and anterior chamber depth were measured by optical low-coherence reflectometry (Lenstar; HaagStreit AG, Koeniz, Switzerland). A detailed medical history was also recorded for each subject. The following inclusion criteria were used: healthy subjects aged between 20 and 40 years, a spherical equivalent (SE) refractive error between 9.0 and 0.5 diopters (D), astigmatism within 2 D, best-corrected visual acuity 20/25, IOP 21 mmHg, normal anterior chamber angles, nonglaucomatous ONHs on stereoscopic photographs (an intact neuroretinal rim without peripapillary hemorrhage, thinning, or localized pallor), absence of any RNFL abnormalities on red-free fundus photographs, and normal VF results in both eyes. Because myopic refractive error can be affected by lenticular changes, and aging may increase the incidence of glaucoma, we excluded subjects older than 40 years of age. To increase the yield of healthy myopic eyes, we also excluded extremely highly myopic eyes with an SE <9.0 D, because it is known that various pathologic changes on the myopic fundus, such as staphyloma, lacquer cracks, and so forth, increase in prevalence with increasing myopic refractive error. Normal VF presentation was defined as a glaucoma hemifield test result within normal limits, as well as mean and pattern standard deviation values associated with probabilities of normality greater than 5%. Some eyes had an enlarged blind spot associated with a large area of PPA, and such eyes were also included in this study. Patients with a family history of glaucoma in a first-degree relative, history of intraocular or refractive surgery, pathologic myopia (patch chorioretinal atrophy, lacquer crack lesions, intrachoroidal cavitations, choroidal neovascularization), other evidence of retinal pathology, or opaque media were excluded. Eligibility was determined by 2 glaucoma specialists (M.S.S. and S.W.P.), who evaluated optic disc appearance on stereoscopic disc photographs and RNFL defects on red-free fundus photographs. Evaluators were masked to all other patient and ocular data, and an eye was excluded from study analyses if a consensus could not be reached. The right eye was selected for the analyses.
Optical Coherence Tomography Imaging The ONH, peripapillary RNFL (pRNFL), and macular ganglion cell-inner plexiform layer (mGCIPL) parameters were measured using a Cirrus high-definition optical coherence tomography (HD-OCT) device (Carl Zeiss Meditec). All measurements were
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performed by the same examiner who was experienced in taking OCT images. The Optic Disc Cube 200200 protocol provides the results obtained from 200 horizontal B-scans (200 A-scans per B-scan) and measures pRNFL thickness in a cube of 662 mm. The average pRNFL thickness was measured within a 3.46-mmediameter circle, the center of which was manually positioned at the optic disc center. Quadrant pRNFL thickness values were used in our analysis. The Macular Cube 200200 protocol provides the results obtained from 200 horizontal B-scans (200 A-scans per B-scan) over 1024 samplings within a cube (662 mm) centered at the fovea. The ganglion cell analysis algorithm in the 6.0 software version of Cirrus HD-OCT reports the combined thickness of the retinal ganglion cell and inner plexiform layers by identifying the outer boundaries of the RNFL and the inner plexiform layer. The average, minimum (lowest mGCIPL thickness over a single meridian crossing the annulus), and 6 sectoral (superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal) mGCIPL thicknesses were measured within a 14.13-mm2 elliptical annulus area (vertical inner and outer radii of 0.5 mm and 2.0 mm, respectively; horizontal inner and outer radii of 0.6 and 2.4 mm, respectively) centered on the fovea within the cube. Subjects with any abnormalities (including an extremely large PPA) in the circumpapillary region that affected the scan ring where the OCT RNFL thickness measurements were obtained were excluded.
Measurements of Optic Disc Tilt, Rotation, and Parapapillary Atrophy Area Digital retinal photographs centered on the optic disc and macula were obtained using standard settings with a nonmydriatic retinal camera (Canon, Tokyo, Japan). Each photograph was exported to a desktop computer as a TIFF image file. Using public-domain Javabased image processing software developed by the National Institutes of Health (ImageJ, version 1.4.1; Wayne Rasband; National Institutes of Health, Rockville, MD), the optic disc tilt, rotation, and area of b-zone PPA were measured by 2 independent examiners. Average data were used in the final analysis. The definition of optic disc tilt and its measurement have been described.10e13 Briefly, optic disc tilt was measured as the tilt ratio, defined as the ratio between the longest and shortest diameters of the optic disc. Optic discs were classified as tilted in those with tilt ratios exceeding 1.30. Optic disc rotation was defined as the deviation of the long axis of the optic disc from the reference line, 90 from a horizontal line connecting the fovea and the center of the optic disc. The angle between the long axis of the optic disc and the reference line was termed the “degree of rotation.” The optic disc was classified as having significant rotation when the degree of rotation exceeded 15 . All eyes were divided into 2 groups according to the direction of optic disc rotation. Eyes with superior rotation of the optic discs were defined as group 1, and eyes with inferior rotation of the optic discs were defined as group 2. Because all eyes included in the analysis were right eyes, superior rotation indicated clockwise rotation of the optic disc and inferior rotation indicated counterclockwise rotation of the optic disc. Superior rotation was presented as a negative value, and inferior rotation was presented as a positive value. The presence of the b-zone PPA was defined as marked atrophy of the retinal pigment epithelium and a horizontal width of the choriocapillaris apparently larger than the diameter of the major retinal vein at the optic disc edge. The areas of b-zone PPA (an inner crescent of chorioretinal atrophy with visible sclera and choroidal vessels) were determined as the total number of pixels using the ImageJ software in a circumferential pattern. Combined with the magnification factor of 1.4 of the fundus camera, the total magnification by the camera and ImageJ system was
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Optic Disc Rotation in Myopic Eyes
calculated. We converted the area of b-zone PPA from pixels to millimeters squared. The area was corrected by using Littmann’s formula for each axial length.15 The anterior corneal curvature radius was set at 7.8 mm, which is the reported mean for white and Chinese persons.16
Statistical Analysis SPSS version 18.0 (SPSS Inc., Chicago, IL) was used for all statistical analyses. Agreement on the optic disc tilt ratio, degree of rotation, and area of b-zone PPA between 2 observers was assessed using the BlandeAltman method, which plots their means against their differences.17 The limits of agreement were defined as the mean differences of 2 measurements 1.96 standard deviation of the difference. The normality of distribution was verified using the ShapiroeWilk normality test. Baseline characteristics were reported in counts and proportions or mean standard deviation values as appropriate. Groups were compared using the chisquare test, independent t test, or ManneWhitney U test as appropriate. The comparison of the degree of optic disc rotation between groups 1 and 2 was done with the unsigned value. Because there were significant differences in the SE refractive error and axial length between the 2 groups, an analysis of covariance model with the SE refractive error and axial length as covariates was used to compare the pRNFL and mGCIPL thickness between the groups. Univariate and multivariate linear regression analyses were used to identify explanatory variables with a statistically significant contribution to optic disc rotation. Parameters with P values <0.1 in the univariate analysis were included in the multivariate models. In addition, linear regressions were used to search for correlations between the degree of optic disc rotation and the pRNFL and mGCIPL thickness, introducing age and axial length as covariates. The coefficient of determination (R2) and adjusted R2 in the linear regression were reported. Statistical significance was considered at P < 0.05.
Results During the enrollment period, 235 subjects were evaluated. Of these, 7 subjects were excluded because of prior refractive surgery, 5 subjects were excluded because of VF defects or glaucomatous ONH changes, and 3 subjects were excluded because of other retinal pathologic features. Subsequently, 220 eligible subjects were included in the analyses. The interobserver agreement in the measurements of the tilt ratio, degree of rotation, and area of bzone PPA for all subjects are represented in BlandeAltman plots, showing no systemic differences in their measurements (Fig 1, available at www.aaojournal.org). Characteristics of the included subjects are presented in Table 1. The mean age was 27.946.67 years, 125 subjects were male, and 95 subjects were female. The mean SE refractive error and axial length were 4.582.66 D and 25.761.47 mm, respectively. An SE refractive error less than 6 D (the definition of high myopia) was found in 65 participants. The distribution of the degree of optic disc rotation was fairly normal, although right-skewed (Fig 2). As shown in Table 2, there were no significant differences between the groups in age, sex, central corneal thickness, anterior chamber depth, or the optic disc parameters measured using Cirrus HD-OCT. In contrast, group 2 showed more myopic SE refractive error, higher IOP, and longer axial length compared with group 1 (P < 0.001, P ¼ 0.043, and P < 0.001, respectively). With regard to ONH morphology, we found that group 2 had greater disc tilt and degree of rotation, higher occurrence of a b-zone PPA, and a
Table 1. Demographic Characteristics of Subjects Variables
Description
No. Age (yrs) Sex (male/female) no % SE refractive error (D) IOP (mmHg) Axial length (mm) Central corneal thickness (mm) Anterior chamber depth (mm) Rim area (mm2) Disc area (mm2) Average CDR Vertical CDR Cup volume (mm3) Optic disc tilt Tilted disc/disc without tilt, no (%) Tilt ratio Optic disc rotation Superior/inferior Significant/insignificant Rotation degree ( ) b-zone PPA Presence/absence, no (%) Area of b-zone PPA (mm2)
220 27.946.67 125 (56.82%)/95 (43.18%) 4.582.66 15.842.60 25.761.47 551.2735.71 3.140.25 1.240.29 1.860.50 0.540.19 0.500.19 0.270.27 40 (18.18%)/180 (81.82%) 1.170.13 147 (66.82%)/73 (33.18%) 126 (57.27%)/94 (42.73%) 3.4430.35 124 (56.36%)/96 (43.64%) 0.440.62
Data are mean standard deviation unless otherwise indicated. CDR ¼ cup-to-disc ratio; D ¼ diopters; IOP ¼ intraocular pressure; PPA ¼ parapapillary atrophy; SE ¼ spherical equivalent.
larger area of b-zone PPA when compared with group 1 (P ¼ 0.028, P ¼ 0.035, P < 0.001, and P < 0.001, respectively). Table 3 shows the relationships between the degree of optic disc rotation and various parameters. A univariate regression analysis revealed a significant correlation of the degree of optic disc rotation with age (b ¼ 0.146; P ¼ 0.030), SE refractive error (b ¼ 0.336; P < 0.001), IOP (b ¼ 0.238; P < 0.001), axial length (b ¼ 0.282; P < 0.001), and area of b-zone PPA (b ¼ 0.265; P < 0.001). By using multivariate regression modeling, the IOP (b ¼ 0.234; P ¼ 0.011), axial length (b ¼ 0.222; P ¼ 0.043), and area of b-zone PPA (b ¼ 0.226; P ¼ 0.030) were significant predictors of the degree of rotation. Because the SE refractive error and axial length strongly correlated with each other (r ¼ 0.818; P < 0.001), it would not be adequate to use both as explanatory variables in the multivariate regression model. We adopted axial length as an explanatory variable, because it is known that axial elongation is related to the mechanism of the myopic optic disc. The combination of these 3 variables yielded an R2 of 0.284 and an adjusted R2 of 0.245 (P < 0.001). Figure 3 shows the correlation between the degree of optic disc rotation and the IOP, axial length, and area of b-zone PPA. In a subgroup analysis according to the direction of optic disc rotation, the statistical significance of the relationship between the degree of optic disc rotation and the IOP, axial length, and area of b-zone PPA were similarly maintained in group 2 (P < 0.001; P ¼ 0.040, and P ¼ 0.042, respectively). The combination of these variables yielded an R2 of 0.333 and an adjusted R2 of 0.304 (P < 0.001). In contrast, we found no significant parameters associated with the degree of optic disc rotation in group 1 (Table 4, available at www.aaojournal.org).
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Figure 2. Histogram showing the distribution of the degree of optic disc rotation in myopic eyes.
After controlling for the SE refractive error and axial length, superior and inferior pRNFL thickness and minimum and inferonasal mGCIPL thickness were found to be significantly thinner in group 2 when compared with group 1. In a linear regression analysis with age and axial length as covariates, a significant negative correlation was observed between the degree of optic disc rotation and the following thickness parameters: superior pRNFL (b ¼ 0.226; P ¼ 0.016), inferior pRNFL (b ¼ 0.243; P ¼ 0.012), minimum mGCIPL (b ¼ 0.223; P ¼ 0.018), and inferonasal mGCIPL thickness (b ¼ 0.234; P ¼ 0.016) (Table 5).
Discussion It has been well documented that a large percentage of myopic optic discs are tilted and rotated with a PPA, and
that these morphologic changes may be correlated with VF defects in patients with myopia. Tay et al5 reported that optic disc ovality (an index of tilt) was significantly correlated with greater myopia and VF defects. Likewise, the b-zone PPA has been shown to be associated with glaucomatous damage to the ONH, as well as VF defects, in patients with myopia.18 In regard to optic disc rotation, the results of recent studies demonstrated a significant association between the degree or direction of optic disc rotation and the VF defects in myopic eyes.10e13 Although the relationship between the optic disc tilt or PPA and myopia has been reported in epidemiologic studies,6e8 the relationship between optic disc rotation and myopia remains questionable; most of the aforementioned previous studies focused on specific subpopulations of myopic patients with NTG or glaucomatous-appearing VF changes.10e14 Therefore, we described the characteristics of optic disc rotation in consecutively recruited healthy myopic subjects in this study. Traditionally, the amount of optic disc rotation over 15 has been defined as the optic disc rotation, because it had been shown that the longest diameter of the ONH usually falls within 15 of the vertical meridian. However, optic disc rotation is a subjective interpretation, and thus far there has been no strict definition of a “rotated optic disc”. The Tanjong Pagar Study demonstrated that approximately two thirds of the normal population (64.7%) had rotated optic discs.8 Therefore, we have considered all optic discs with a
Table 2. Comparison of Subject Characteristics According to the Direction of Optic Disc Rotation in Healthy Myopic Eyes Variables
Group 1 (n[147)
Group 2 (n[73)
P Value
Age (yrs) Sex (male/female) SE refractive error (D) IOP (mmHg) Axial length (mm) Central corneal thickness (mm) Anterior chamber depth (mm) Rim area (mm2) Disc area (mm2) Average CDR Vertical CDR Cup volume (mm3) Optic disc tilt Tilted disc/disc without tilt Tilt ratio Optic disc rotation Significant/insignificant Rotation ( ) b-zone PPA Presence/absence Area of b-zone PPA (mm2)
27.376.62 87/60 4.052.47 15.592.54 25.511.35 548.6033.10 3.160.22 1.270.27 1.910.50 0.550.19 0.510.18 0.290.28
29.106.67 38/35 5.662.71 16.342.66 26.261.58 555.9539.88 3.110.31 1.190.31 1.730.50 0.510.21 0.480.20 0.210.23
0.070* 0.386y <0.001* 0.043* <0.001* 0.295* 0.413* 0.201* 0.125* 0.360* 0.506* 0.158*
21/126 1.160.14
19/54 1.200.17
0.041y 0.028*
44/29 28.9326.55
0.565y 0.035z,x
82/65 19.5115.83 67/80 0.320.51
57/16 0.700.73
CDR ¼ cup-to-disc ratio; D ¼ diopters; IOP ¼ intraocular pressure; PPA ¼ parapapillary atrophy; SE ¼ spherical equivalent. Group 1 indicates eyes with superior rotation of the optic disc, and group 2 indicates eyes with inferior rotation of the optic disc. Factors with statistical significance are shown in boldface. *Independent t test. y Chi-square test. z ManneWhitney U test. x The comparison was done with the unsigned value.
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<0.001y <0.001z
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Table 3. Linear Regression Analysis to Determine the Correlation between Variables and the Degree of Optic Disc Rotation Univariate Analysis
Multivariate Analysis*
Variables
B
b
P Value
Age (yrs) Female (vs. male) SE refractive error (D) IOP (mmHg) Axial length (mm) Central corneal thickness (mm) Anterior chamber depth (mm) Rim area (mm2) Disc area (mm2) Average CDR Vertical CDR Cup volume (mm3) Optic disc tilt ratio Area of b-zone PPA (mm2)
0.665 3.437 3.836 2.784 5.812 0.059 5.016 12.306 11.524 2.238 1.105 10.431 23.810 12.935
0.146 0.056 0.336 0.238 0.282 0.068 0.041 0.117 0.178 0.014 0.007 0.093 0.105 0.265
0.030 0.407 <0.001 <0.001 <0.001 0.459 0.658 0.249 0.078 0.887 0.946 0.358 0.121 <0.001
B
b
P Value
0.633
0.172
0.063
2.645 4.340
0.234 0.222
0.011 0.043
4.760
0.074
0.429
12.508
0.226
0.030
B ¼ unstandardized coefficient; b ¼ standardized coefficient; CDR ¼ cup-to-disc ratio; D ¼ diopters; IOP ¼ intraocular pressure; PPA ¼ parapapillary atrophy; SE ¼ spherical equivalent. Factors with statistical significance are shown in boldface. *Only variables with a P value <0.10 in the univariate analysis were included in the multivariate model.
degree of rotation of >0 as rotated optic discs, and optic discs with degrees of rotation >15 were defined as “significantly” rotated. By using these definitions, the prevalence of significant optic disc rotation was 57.27%, consistent with the observations from the Tanjong Pagar Study.8 In regard to the direction of optic disc rotation, Park et al13 recently reported that inferior rotation of the optic disc was observed in 76.7% of glaucomatous eyes. In addition, the same group found that the inferior rotation was prevalent in primary open-angle glaucoma and NTG (89.7% and 66.7%, respectively).11 In contrast, we found that superior rotation was more prevalent than inferior rotation in myopic subjects who were otherwise
ophthalmologically normal. This finding was partially commensurate with that of Lee et al.19 Although their subjects were not all myopic and their definition of optic disc rotation differed from ours, the prevalence of superior rotation was higher than that of inferior rotation among the consecutively enrolled healthy eyes. The results of 2 previous studies have shown a significant positive correlation between the degree of optic disc rotation and the tilt ratio.13,20 However, the correlation between the degree of optic disc rotation and the tilt ratio did not reach the level of statistical significance in the current study (P ¼ 0.121). This discrepancy may be due to the different populations studied; the 2 previous studies included in patients with glaucoma who were less myopic.
Figure 3. Scatterplots showing relationships between (A) degree of optic disc rotation and intraocular pressure (IOP), (B) axial length, and (C) area of b-zone parapapillary atrophy (PPA).
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Ophthalmology Volume -, Number -, Month 2015 Table 5. Comparison of Peripapillary Retinal Nerve Fiber Layer and Macular Ganglion CelleInner Plexiform Layer Thickness According to the Direction of Optic Disc Rotation and Linear Regression between Thickness Parameters and Degree of Optic Disc Rotation in Healthy Myopic Eyes Degree of Optic Disc Rotation Parameters pRNFL thickness, mm Average Superior Inferior Nasal Temporal mGCIPL thickness, mm Minimum Average Superonasal Superior Superotemporal Inferotemporal Inferior Inferonasal
Group 1
Group 2
P Value*
P Valuey
B
b
P Valuez
97.969.42 123.8015.22 125.3015.18 64.3611.16 78.2917.35
93.1410.13 111.5519.66 113.4114.88 60.8610.61 83.3114.33
0.026 0.001 0.001 0.154 0.236
0.121 0.015 0.046 0.512 0.597
0.396 0.390 0.435 0.082 0.139
0.129 0.226 0.243 0.030 0.088
0.170 0.016 0.012 0.756 0.366
81.265.10 83.265.31 85.306.24 84.265.63 82.645.70 82.916.28 80.516.25 83.495.56
77.075.47 79.765.26 81.625.91 81.076.41 80.626.16 81.217.50 77.036.63 78.975.77
<0.001 0.003 0.008 0.016 0.120 0.248 0.015 <0.001
0.011 0.083 0.111 0.207 0.413 0.743 0.215 0.029
1.224 0.824 0.369 0.222 0.417 0.047 0.679 1.185
0.223 0.150 0.078 0.044 0.081 0.010 0.147 0.234
0.018 0.119 0.418 0.646 0.387 0.912 0.130 0.016
B ¼ unstandardized coefficient; b ¼ standardized coefficient; mGCIPL ¼ macular ganglion celleinner plexiform layer; pRNFL ¼ peripapillary retinal nerve fiber layer. Group 1 indicates eyes with superior rotation of the optic disc, and group 2 indicates eyes with inferior rotation of the optic disc. Factors with statistical significance are shown in boldface. *Value for independent t test. y Value for analysis of covariance after controlling for SE refractive error and axial length. z Value for multiple linear regression with age and axial length as covariates.
In addition, our method of tilt measurement also may have contributed to the aforementioned discrepancy. The 2 previous studies measured the degree of the actual optic disc tilt, whereas the optic disc ovality index was used to assess optic disc tilt in this study. Although the ovality index has been widely used as a surrogate measure of optic disc tilt,5,8,21 it is the result of the measurement of flat projections and therefore is affected not only by optic disc tilt but also by optic disc shape. This finding requires reexamination to identify the relationship between the real optic disc tilt and the rotation in healthy myopic eyes. Whether there are different clinical characteristics according to the direction of optic disc rotation remains an open question. Of note, we found that there were significantly different characteristics between groups in this study. Eyes with inferior rotation of the optic disc showed more myopic SE refractive error, higher IOP, longer axial length, greater amounts of tilt and rotation, higher occurrence of a b-zone PPA, and larger area of b-zone PPA when compared with eyes with superior rotation of the optic disc. Because it is well known that myopia, higher IOP, and b-zone PPA are associated with glaucoma prevalence, our findings may help to explain some of the reasons why inferior rotation, compared with superior rotation, is more prevalent among glaucomatous eyes. In the linear regression analysis, we found that a greater inferior rotation was significantly correlated with longer axial length, higher IOP, and larger area of b-zone PPA (P ¼ 0.043, P ¼ 0.011, and P ¼ 0.030, respectively). The association between the optic disc rotation and the axial
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length is a well-known finding,11,20 and our study results confirmed this association. Choi et al20 found that greater inferior rotation of the optic disc was significantly correlated with longer axial length. Park et al11 also reported that axial length was an important factor related to the degree of optic disc rotation in subjects with NTG. These findings led to the speculation that optic disc rotation may occur as a result of the axial elongation of the eyeball. As axial length increases, posterior scleral changes occur, especially at the posterior pole near the ONH, and such changes may result in morphologic changes of the optic disc. This may be explained by positive correlation between the degree of optic disc rotation and the area of b-zone PPA for this reason. In terms of IOP, there was a significant positive correlation between the IOP and the degree of optic disc rotation (P < 0.001). We hypothesized that IOP may result in additional stress on the posterior sclera during axial elongation and therefore affect the development of optic disc rotation. Although all subjects in this study had normal IOP, the stretching of the sclera with changes in IOP is dependent on the rigidity and elasticity of the sclera. Therefore, a certain level of IOP may play a role in the morphologic changes observed in the myopic ONH. We should note the fact that even the normal range of IOP is an important causative risk factor for NTG.22 Nevertheless, we cannot be certain whether the inferior rotation of the optic disc in myopic eyes could be prevented by reducing IOP. This question opens interesting avenues for future studies of the role of IOP lowering in the prevention of optic disc rotation in myopic eyes.
Sung et al
Optic Disc Rotation in Myopic Eyes
Of note, measurements of pRNFL and mGCIPL thickness showed that all parameters, with the exception of temporal pRNFL thickness, were thinner in group 2. To exclude the effect of myopia on inner retinal thickness measurements, we controlled for both the SE refractive error and the axial length, and found statistically significant differences in the superior and inferior pRNFL thickness and minimum and inferonasal mGCIPL thickness between groups. These parameters showed a significant correlation with the degree of optic disc rotation in a linear regression with age and axial length as covariates. In regard to the superior pRNFL thickness, our result is consistent with previous studies.19,23 Lee et al19 showed that inferior rotation of the optic disc resulted in temporalization of the superior peak in pRNFL thickness, and because of RNFL bundle shifting, temporal pRNFL thickness had a tendency to be thicker and superior pRNFL thickness had a tendency to be thinner. Hwang et al23 also reported similar distribution patterns of pRNFL in eyes with optic disc rotation. However, thinning of the inferior pRNFL, minimum mGCIPL, and inferonasal mGCIPL thickness in group 2 cannot be explained by pRNFL bundle shifting, suggesting a different constitutional anatomic feature between the groups. It has been suggested that optic disc rotation may twist the axonal fibers and thereby exert mechanical stress on them, leading to retinal nerve fiber loss.10e13 Superior rotation could place stress on the superior axons, and inferior rotation could place stress on the inferior axons. We speculate that such stress might be due to the thinning of inferior pRNFL, minimum mGCIPL, and inferonasal mGCIPL thickness in group 2, although we could not find thinning of superior pRNFL thickness in eyes with superior rotation of the optic disc. Another suggestion to explain our results is that the difference in choroidal thickness may affect the difference in the amount of axonal distortion between the superior and inferior bundles. It has been reported that choroidal thinning leads to reduced choroidal circulation, which in turn may cause a circulatory problem in the prelaminar region.24,25 Gupta et al26 and Li et al27 recently showed that the inferior peripapillary choroid is thinner than the superior quadrant. Thus, we hypothesized that these anatomic differences in choroidal thickness may make the inferior bundle more vulnerable to the mechanical stress during the development of optic disc rotation. From the subgroup analysis conducted according to the direction of the optic disc rotation, axial length was not shown to be significantly correlated with the degree of optic disc rotation in group 1. If axial elongation was responsible for the development of superior rotation, greater superior rotation would also be associated with longer axial length. However, this was not the case in this study. In addition, IOP did not correlate significantly with the degree of optic disc rotation in group 1 (P ¼ 0.566). Although our study provided an overall assessment of the characteristics of optic disc rotation, additional studies will be required to elucidate the characteristics of superior rotation.
Study Limitations The results reported should be interpreted in the context of study limitations. First, this study was not population based. Because aging increases the incidence of glaucoma, we excluded subjects older than 40 years of age. Because the participants’ age distribution was biased toward those aged 20 to 30 years, our results may not be representative of the entire myopic population. Second, only single-point measurements of IOP were included in our study. Therefore, potential fluctuations during the day were not considered. Third, our study was cross-sectional, and therefore the changes in optic disc rotation and various parameters could not be documented. Thus, we are uncertain as to whether inferior rotation of the optic disc predisposes to the development of a VF defect or glaucoma. Further prospective, longitudinal studies may better delineate the evolution of glaucoma in myopic eyes with optic disc rotation. In summary, we have investigated the characteristics of optic disc rotation in myopic eyes and found that superior rotation was more prevalent than inferior rotation. Eyes with greater inferior rotation of the optic disc showed a significant association with longer axial length, higher IOP, larger area of b-zone PPA, and constitutional anatomic changes, such as reduced pRNFL and mGCIPL thickness. The role of IOP in optic disc rotation and the relationship between optic disc rotation and development of glaucoma deserve further investigation.
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Footnotes and Financial Disclosures Originally received: May 22, 2015. Final revision: October 2, 2015. Accepted: October 12, 2015. Available online: ---.
Data collection: Sung, Kang, Heo, Park Obtained funding: Not applicable Manuscript no. 2015-832.
1
Department of Ophthalmology and Research Institute of Medical Sciences, Chonnam National University Medical School and Hospital, Gwangju, South Korea.
2
Center for Creative Biomedical Scientists, Chonnam National University, Gwangju, South Korea. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Author Contributions: Conception and design: Sung, Heo, Park Analysis and interpretation: Sung, Kang, Park
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Overall responsibility: Sung, Kang, Heo, Park Abbreviations and Acronyms: D ¼ diopters; HD-OCT ¼ high-definition optical coherence tomography; IOP ¼ intraocular pressure; mGCIPL ¼ macular ganglion cell inner plexiform layer; NTG ¼ normal-tension glaucoma; ONH ¼ optic nerve head; PPA ¼ parapapillary atrophy; pRNFL ¼ peripapillary retinal nerve fiber layer; RNFL ¼ retinal nerve fiber layer; SE ¼ spherical equivalent; VF ¼ visual field. Correspondence: Sang Woo Park, MD, PhD, Department of Ophthalmology and Research Institute of Medical Sciences, Chonnam National University Medical School and Hospital, 42 Jebong-ro, Dong-gu, Gwangju 501-757, South Korea. E-mail: [email protected].