Distribution of Optic Disc Parameters Measured by OCT: Findings from a Population-Based Study of 6-Year-Old Australian Children

Home , Optic disc

Son C. Huynh,1 Xiu Ying Wang,1,2 Elena Rochtchina,1 Jonathan G. Crowston,3 and Paul Mitchell1,2

PURPOSE. To study the distribution of optic disc, cup, and were demonstrated for most parameters. (Invest Ophthalmol neural rim size by ocular and demographic variables in a Vis Sci. 2006;47:3276–3285) DOI:10.1167/iovs.06-0072 population-based sample of 6-year-old children. METHODS. The Sydney Childhood Eye Study examined 1765 of lthough qualitative assessment of the optic nerve head is 2238 eligible 6-year-old children (78.9%) from 34 randomly Aimportant in diagnosis of optic neuropathy, a knowledge selected Sydney schools during 2003 to 2004. Comprehensive of how optic disc parameters vary with disc size and other standardized eye examination included cycloplegic autorefrac- ocular and demographic parameters in the general population tion, optical biometry and “fast optic disc” scans performed is valuable in differentiating healthy from diseased nerves and using optical coherence tomography. for identifying optic discs at risk of disease. This is particularly important in children because the associated vision loss can RESULTS. Scans of adequate quality were available for 1309 adversely influence their overall development.1 children (75% of participants), with 70% aged 6 years; 50.9% Although normative data on macular thickness in a large were boys. Mean (Ϯ SD) horizontal and vertical disc diameter 2 Ϯ Ϯ sample of 6-year-old children were recently reported, child- and disc area was 1.53 0.21 mm, 1.79 0.28 mm, and hood normative data on optic disc parameters are limited3 and Ϯ 2 2.20 0.39 mm , respectively. Corresponding cup dimensions to our knowledge, there have been no population-based re- Ϯ Ϯ Ϯ 2 were 0.70 0.28 mm, 0.73 0.27 mm, and 0.48 0.32 mm . ports. Further, optic nerve head differences between white A definable optic cup was absent in 7.4%, 87% of whom were and East Asian children have not previously been examined, Ϯ European white. Cup-to-disc diameter ratios were 0.46 0.16 and few studies have controlled for the influence of disc size Ϯ horizontally and 0.42 0.15 vertically, whereas cup-to-disc on measures of neural content.4,5 area ratio was 0.22 Ϯ 0.13. Mean Ϯ SD neural rim area was Optical coherence tomography (OCT) is a promising new 2 1.76 Ϯ 0.44 mm and increased with disc size (Pearson corre- technology that allows rapid and reproducible measurement of lation ϭ 0.68, P Ͻ 0.0001). Horizontal and vertical average the retina and optic nerve head.6 OCT has already been incor- nerve widths were 0.36 Ϯ 0.05 and 0.28 Ϯ 0.05 mm, respec- porated into the management of conditions such as glaucoma, tively. In analyses adjusting for potential confounders, disc area macular edema caused by diabetic retinopathy or uveitis, and Ͻ increased significantly with axial length (Ptrend 0.0001) and other macular diseases, including age-related macular degener- ϭ 7,8 refraction (Ptrend 0.02). Rim area increased only with axial ation and central serous chorioretinopathy. The potential ϭ length (Ptrend 0.01). There were no gender differences, usefulness of this instrument in juvenile glaucoma was recently except for average nerve width, marginally greater in boys. demonstrated.9 Most disc and cup dimensions were significantly larger in In the present study, we sought to establish a normative East-Asian than European white and Middle Eastern children. database of optic disc, cup, and neural rim parameters and to CONCLUSIONS. Disc, cup, and neural rim parameters were gen- examine their variation with refraction, axial length, gender, erally normally distributed in this young population. Axial and ethnicity, in a population-based sample of young (predom- length appeared to be a stronger determinant of disc and rim inantly 6-year-old) children. size than refraction. Some ethnic but not gender differences METHODS

From the 1Centre for Vision Research, Department of Ophthal- Study Population mology and the Westmead Millennium Institute, University of Sydney, The Sydney Childhood Eye Study comprises population-based surveys 2 Sydney, Australia; the Vision Co-operative Research Centre, School of designed to examine childhood eye conditions across a range of ages. Optometry, University of New South Wales, Sydney, Australia; and the This article describes data from the Sydney Myopia Study component, 3Hamilton Glaucoma Center, University of California-San Diego, La Jolla, California. which examined school children resident in the metropolitan area of Supported by Australian National Health and Medical Research Sydney, Australia, from 2003 to 2004. The study was approved by the Council Grant 253732, the Westmead Millennium Institute, University Human Research Ethics Committee, University of Sydney and the of Sydney, and the Vision Cooperative Research Centre, University of Department of Education and Training, New South Wales, Australia. It New South Wales, Sydney, Australia. was conducted in accordance with the tenets of the Declaration of Submitted for publication January 24, 2006; revised March 18, Helsinki. We obtained informed written consent from at least one 2006; accepted June 1, 2006. parent of each child, as well as verbal assent from each child. The study Disclosure: S.C. Huynh, None; X.Y. Wang, None; E. Rocht- protocol adhered to the guidelines set forth in the Declaration of china, None; J.G. Crowston, None; P. Mitchell, none. Helsinki. The publication costs of this article were defrayed in part by page 10,11 charge payment. This article must therefore be marked “advertise- Detailed study methods have been described elsewhere. In ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. brief, 34 primary schools in Sydney were identified through random Corresponding author: Paul Mitchell, Centre for Vision Research, stratified sampling. Stratification of the city was based on socioeco- Department of Ophthalmology, Westmead Hospital, Hawkesbury Road, nomic status data from the Australian Bureau of Statistics 2001 national Westmead NSW 2145, Australia; [email protected]. census. A proportional mix of public and private or religious schools

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was included. All children in the first grade of school (mostly aged 6 drop. The median of five refractions automatically performed by the years) were eligible. instrument was used for analyses. Mydriatic retinal photography was also performed to detect any retinal conditions. Demographic Data Demographic data were obtained from a comprehensive questionnaire OCT Measurements sent to the parents of the children. The child’s ethnicity was deter- Optic disc parameters were measured through dilated pupils using an mined from the ethnicity and country of birth of both parents. Ethnic optical coherence tomographer (StratusOCT, software v.4.0.4; Carl groups represented were white (European), East Asian, Indian, Paki- Zeiss Meditec, Inc., Dublin, CA), which used PCI (wavelength 820 nm) stani, Sri Lankan, African, Melanesian-Polynesian, Middle Eastern, in- to obtain high-resolution (Ͻ10 ␮m) cross-sectional images of the optic digenous Australian, South American, and mixed. disc.13 Measurements were performed using the fast optic disc scanning protocol, which acquired the full scan in 1.92 seconds. Each scan Ocular Examination consisted of six 4-mm line scans radially arranged and centered on the Axial length was measured before cycloplegia with an optical biometer optic disc. Each line scan was sampled at 128 points (A-scans), giving (IOLMaster; Carl Zeiss Meditec, Inc., Jena, Germany) that used dual- a total of 768 A-scans for the whole optic nerve head. Three fast optic beam partial coherence interferometry (PCI).12 In this instrument, low disc scans were performed successively without making changes to coherence laser light (wavelength 780 nm) emitted by a superlumines- scan placement, and the measurements were averaged before analysis. cent diode is passed through a Michelson interferometer where it is Peripapillary retinal nerve fiber layer (RNFL) average thickness was split into two beams, a reference beam and a second beam directed also measured, to examine its relationship with optic disc size. The fast into the eye. The echo time delay between the reference beam and the RNFL thickness (3.4) scanning protocol was used, which consists of second beam, which reflected back from the retinal pigment epithe- 256 A-scans along a circular scan path, with a radius of 1.73 mm. The lium (RPE), was used to calculate axial length. The average of five such average of three scans was used in the analyses. More than 90% of measurements was used in the analysis. scans were performed by a single experienced operator. An internal After instillation of amethocaine 1% (1 drop) to anesthetize the fixation target was used in all scans, with scan placement continuously cornea, cycloplegia was induced by instilling cyclopentolate 1% and monitored using an infrared-sensitive video camera (Fig. 1A). Scans tropicamide 1% (2 drops each) separated by 5 minutes. Phenylephrine were only accepted if they were complete, free of artifacts, and had 2.5% was also instilled in a small proportion of children to achieve signal strengths of at least 5. adequate mydriasis (Ն6 mm). Autorefraction (RK-F1 autorefractor; The optic disc margin was automatically defined by the instrument Canon, Tokyo, Japan) was performed 25 to 30 minutes after the last as the termination of the RPE at the optic nerve head (Fig. 1C).

FIGURE 1. (A) Infrared-sensitive video view of the right optic disc and scan pattern. The scan pattern consists of 4-mm long intersecting scan lines that are approximately centered on the optic disc. (B) Topographic map showing disc reference points (red circles), the disc margin (red contour), cup margin (green contour), and scan lines (blue and yellow). (C) Proﬁle of the optic nerve head along the vertical meridian showing optic disc reference points at the termination of the retinal pigment epithelium (blue circles), disc line (blue line), cup reference plane (red dotted line) 150 ␮m anterior to the disc line, nerve width (yellow lines), and rim area (vertical cross-section; red-shaded area).

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Opposite points across the optic disc were joined by a disc line. A the sample size was large. Differences between children with and constant reference plane 150 ␮m anterior to the disc line was used to without OCT performed were examined using ␹2 tests for categorical define the edges of the optic cup. Variables examined included hori- variables, and two-sample Student’s t-test for continuous variables. zontal and vertical cup and disc diameters, cup and disc areas, and Effects of axial length and refraction on measures were examined in an cup-to-disc diameter, and area ratios. We also calculated in each child analysis of trend, whereas gender and ethnic differences were exam- a shape factor, which is the ratio of vertical-to-horizontal disc and cup ined using mixed models and generalized estimating equations, with diameters. The nerve width (nerve fiber layer thickness at the disc) was adjustment for multiple variables. the shortest distance from the disc margin (termination of RPE) to the internal limiting membrane. The average nerve width was calculated by the instrument as the average of two nerve widths on opposite sides RESULTS of the disc. Measures of neural rim area included rim area and hori- Population Characteristics zontal integrated rim width. Rim area was defined as the difference between disc and cup areas. Horizontal integrated rim width was a There were 2238 eligible children, of whom 1765 (78.9%) product of the disc circumference and average nerve width. Rim area consented to the study. Twenty-five children were absent from (vertical cross-section) was the area bounded by the disc line, a line school during the examination period, and 431 had scans with perpendicular to the disc line, and the nerve fiber layer surface. low signal strength, leaving data available for 1309 children Vertical integrated rim area measured nerve fiber layer volume and was (75% of those examined). These children were predominantly obtained by multiplying the rim area (vertical cross-section) by the disc European white (n ϭ 866, 66.2%), East Asian (n ϭ 197, 15.1%), circumference. and Middle Eastern (n ϭ 53, 4.1%). The remaining 193 (14.7%) children were from six other ethnic groups whose numbers Correction for Magnification were too small for their data to be meaningful. There was a slightly higher ratio of European white to East Asian and Middle Scans were performed without entering axial length and refraction Eastern children among those who had scan data available. data, for consistency with usual clinical practice. Transverse disc mea- There were no significant differences between the two OCT surements, however, were affected by magnification when the axial groups for the categorical variables of age and gender, nor for length and refraction of the eye being scanned were different from the the continuous variables of spherical equivalent, axial length, default values of 24.46 mm and 0.0 D, respectively (personal commu- logarithm of the minimum angle of resolution acuity, height, nication, Alan Kirschbaum, Carl Zeiss Meditec, Inc., 2006). The mag- weight, and body mass index (Table 1). nification of this instrument is given by: Distribution h0 h ϭ , 1 ϩ ͑0.018 ϫ D ϩ 0.002 ϫ D ͒ The overall distributions of optic disc, optic cup, and neural axial refraction rim parameters are shown in Figure 2 and Table 2. Horizontal and vertical disc diameter and disc area were normally distrib- where h and h are uncorrected and corrected transverse lengths, 0 uted, with mean Ϯ standard deviations of 1.53 Ϯ 0.21 mm, respectively. The same correction was used for areas with one axial 1.79 Ϯ 0.28 mm, and 2.20 Ϯ 0.39 mm2, respectively. Disc size dimension. For transverse areas and for volumes, the denominator varied by approximately fourfold between the largest and the was squared. D and D are changes in magnification due to axial refraction smallest discs. The mean disc shape was vertically oval with a differences from default values of axial length (L) and refraction (D ), error shape factor of 1.2 Ϯ 0.2 (range, 0.4–2.8). In 17.0% of the respectively, where D ϭ (24.46 Ϫ L)/0.42 and D ϭ (D Ϫ axial refraction error children, the optic disc was horizontally oval (shape factor, D ). axial Ͻ1.0). The optic cup could not be defined in 97 children (7.4% of Statistical Analysis those with scans). Among these, 87% were European white, 2% Analyses were performed for right eyes on computer (Statistical Anal- were East Asian, and 4% were Middle Eastern in background. ysis System software, ver .9.1; SAS Institute, Cary, NC). We used the They were slightly older (by 6 weeks, P ϭ 0.01) than the Kolmogorov-Smirnov test to check for normality of distributions since children with definable optic cups. There were no significant

TABLE 1. Characteristics of Children with and without OCT Scans of the Optic Disc (24.8%)

Children with OCT Children without OCT P (431 ؍ Performed (n (1309 ؍ Variables Performed (n

Age (y) n (%) Ͻ6 51 (3.0) 13 (3.9) 0.4 6–Ͻ7 912 (69.7) 318 (73.8) 7ϩ 346 (26.4) 100 (23.2) Gender (boys) n (%) 666 (50.9) 215 (49.9) 0.7 Ethnicity* n (%) European white 866 (66.2) 242 (56.2) Ͻ0.0001 East Asian 197 (15.1) 102 (23.7) Middle Eastern 53 (4.1) 30 (7.0) Spherical equivalent (D)† 1.28 (0.02) 1.24 (0.05) 0.5 Axial length (mm) 22.61 (0.02) 22.6 (0.04) Ͼ0.9 LogMAR acuity (letters) 49.8 (0.1) 49.7 (0.2) 0.5 Height (cm) 120.7 (0.2) 120.3 (0.3) 0.3 Weight (kg) 23.7 (0.1) 23.6 (0.2) 0.8 Body mass index (kg/m2) 16.2 (0.06) 16.2 (0.1) 0.7

* Data for other ethnic groups not presented due to small numbers. † Remaining data are the mean Ϯ SE.

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FIGURE 2. Frequency distribution of magniﬁcation-corrected (A) optic disc horizontal and vertical diameters; (B) optic cup horizontal and vertical diameters; and (C) optic disc, cup, and rim areas.

differences, however, in gender distribution, spherical equiva- CI, 0.30–1.48), and rim area was 2.93 mm2 (95% CI, 2.36– lent, and axial length. When these children were included in 3.51). the analysis, mean Ϯ SD horizontal and vertical cup diameter Peripapillary RNFL average thickness was also positively Ϯ Ϯ Ͻ and cup area were 0.65 0.32 mm, 0.68 0.32 mm, and associated with optic disc area (Ptrend 0.0001). Mean RNFL 0.44 Ϯ 0.33 mm2, respectively. Optic cup diameter (horizontal average thickness increased from 99.4 ␮m (95% CI, 98.1–100.7 and vertical) and area with these children excluded are pre- ␮m) to 109.4 ␮m (95% CI, 108.0–110.8 ␮m) from the lowest sented in Table 2. Cup diameter and area varied 30- to 300-fold, (mean, 1.70 mm2) to highest (mean, 2.76 mm2) quintile of respectively, between the smallest and largest cup, whereas optic disc area. cup volume varied 1700-fold. Horizontal and vertical cup di- The average nerve width was greater along the vertical ameters were normally distributed in these children. The dis- (0.36 Ϯ 0.05 mm) than the horizontal meridian (0.28 Ϯ 0.05 tribution of cup area and volume was slightly positively mm). There were similar findings for the rim area (vertical skewed. Mean cup shape was almost circular with a shape cross-section), which was greater for the vertical (0.32 Ϯ 0.19 factor of 1.1 Ϯ 0.2 (range, 0.3–3.6). In 35.6% of children, the 2 2 mm ) than horizontal meridian (0.19 Ϯ 0.13 mm ). optic cup was horizontally oval (shape factor, Ͻ1.0). Effects of axial length and refraction were examined in Cup-to-disc diameter and area ratios were normally distrib- multivariate analyses adjusting for age, gender, ethnicity, and uted. Horizontal (0.46 Ϯ 0.16) and vertical (0.42 Ϯ 0.15) cluster sampling. Optic disc area increased significantly with cup-to-disc diameter ratios were similar to each other. Cup-to- Ͻ axial length (Ptrend 0.0001; Fig. 4A). For the lowest quintile disc diameter ratio varied 30-fold with a maximum ratio of 0.90 2 horizontally. of axial length (mean 21.63 mm), mean disc area was 2.09 mm (95% CI, 2.03–2.14), whereas for the highest quintile (mean Neural rim area was normally distributed, with similar re- 2 sults between rim area (1.76 Ϯ 0.44 mm2) and horizontal 23.54 mm), mean disc area was 2.29 mm (95% CI, 2.23–2.34). 2 ϭ integrated rim width (1.71 Ϯ 0.30 mm ). There were signifi- Rim area was positively associated with axial length (Ptrend 2 cant correlations (r) of optic disc area with rim (r ϭ 0.68, P Ͻ 0.01). Mean rim area was 1.68 mm (95% CI, 1.62–1.74) and 2 0.0001) and cup area (r ϭ 0.39, P Ͻ 0.0001). Cup and rim areas 1.74 mm (95% CI, 1.68–1.81), for the lowest and highest for specific optic disc sizes are shown in Figure 3. For the quintiles of axial length, respectively. After further adjusting smallest mean optic disc area (1.4 mm2), mean cup area was for disc area, rim area became negatively associated with axial 0.25 mm2 (95% confidence interval [CI] 0.17–0.33 mm2), and length. Mean rim area was 1.77 mm2 (95% CI, 1.73–1.81) and rim area was 1.19 mm2 (95% CI, 1.10–1.27). For the largest 1.67 mm2 (95% CI, 1.62–1.72) for the lowest and highest mean optic disc area (3.4 mm2), cup area was 0.89 mm2 (95% quintiles of axial length, respectively.

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TABLE 2. Overall Distribution of Optic Nerve Head Parameters in Right Eyes

K-S

Mean (SD) Median Range Kurtosis Skew D Statistic P

Horizontal disc diameter (mm) 1.53 (0.21) 1.52 0.62–2.63 1.7 0.6 0.04 Ͻ0.01 Vertical disc diameter (mm) 1.79 (0.28) 1.78 0.61–2.72 0.8 0.0 0.03 Ͻ0.01 Disc area (mm2) 2.20 (0.39) 2.18 1.09–4.27 1.5 0.7 0.04 Ͻ0.01 Horizontal cup diameter (mm)* 0.70 (0.28) 0.69 0.03–1.74 0.3 0.4 0.04 Ͻ0.01 Vertical cup diameter (mm)* 0.73 (0.27) 0.72 0.06–1.71 0.1 0.2 0.02 Ͼ0.15 Cup area (mm2)* 0.48 (0.32) 0.42 0.007–2.22 2.4 1.3 0.09 Ͻ0.01 Cup volume (mm3)* 0.06 (0.07) 0.04 0.0003–0.52 7.1 2.3 0.2 Ͻ0.01 Horizontal cup-to-disc ratio* 0.46 (0.16) 0.46 0.03–0.90 Ϫ0.2 Ϫ0.1 0.02 0.08 Vertical cup-to-disc ratio* 0.42 (0.15) 0.42 0.03–0.84 Ϫ0.3 Ϫ0.1 0.02 Ͼ0.2 Cup-to-disc area ratio* 0.22 (0.13) 0.20 0.002–0.72 0.3 0.7 0.06 Ͻ0.01 Rim area (mm2) 1.76 (0.44) 1.70 0.73–4.16 1.6 0.8 0.06 Ͻ0.01 Horizontal integrated rim width (mm2) 1.71 (0.30) 1.68 0.93–3.08 0.8 0.6 0.05 Ͻ0.01 Average nerve width (mm) Horizontal 0.28 (0.05) 0.28 0.09–0.53 1.0 0.2 0.02 0.09 Vertical 0.36 (0.05) 0.36 0.04–0.65 2.7 0.0 0.04 Ͻ0.01 Overall 0.32 (0.04) 0.32 0.17–0.48 0.2 0.2 0.03 Ͻ0.01 Rim area (vertical cross-section) (mm2) Horizontal 0.19 (0.13) 0.16 0.002–0.91 2.6 1.3 0.09 Ͻ0.01 Vertical 0.32 (0.19) 0.28 0.0009–1.33 2.5 1.3 0.09 Ͻ0.01 Vertical integrated rim area (mm3) 0.68 (0.43) 0.57 0.07–3.09 3.9 1.6 0.1 Ͻ0.01

n ϭ 1309. * Excludes 97 children (7.4%) with no deﬁnable optic cup. K-S, Kolmogorov-Smirnov test for normality.

There was a weak association between optic disc area and Ethnicity-specific distributions of optic disc and cup param- ϭ spherical equivalent (SE, Ptrend 0.02; Fig. 4B), with only a eters, adjusted for age, gender, axial length, and cluster sam- marginal decrease in mean disc area (2.20 mm2; 95% CI, 2.15– pling, are detailed in Table 4. There were no significant differ- 2.24 versus 2.12 mm2, 95% CI 2.05–2.19) between the lowest ences between the Middle Eastern and the European white (mean SE, ϩ0.32 D) and highest (mean SE, ϩ2.45 D) quintile of children. With the exception of vertical disc diameter, all disc spherical equivalent. There were no significant associations of and cup dimensions were significantly larger in the East Asian ϭ rim area with refraction (Ptrend 0.9). After including disc area than in the European white children. Mean disc area was in this model, rim area increased significantly with more hy- approximately 4% larger, whereas mean cup area and mean ϭ peropic refraction (Ptrend 0.008). Mean rim area was 1.67 cup-to-disc area ratio was approximately 60% larger. Measures mm2 (95% CI, 1.63–1.71) and 1.74 mm2 (95% CI, 1.70–1.78) of neural rim were correspondingly lower in the East Asian for the lowest and highest quintiles, respectively. children, with mean rim area being approximately 10% smaller Optic disc and cup parameters by gender, adjusted for age, and average nerve width being 7% and 16% lower for the ethnicity, axial length, and cluster-sampling, are presented in vertical and horizontal meridians, respectively. Vertical inte- Table 3. There were generally no gender differences in disc or grated rim area and rim area (vertical cross-section) were also cup parameters, except for horizontal and vertical average lower in the East Asian children. After further adjustment for nerve width, measurements of which were slightly larger in the differences in disc area, rim area remained significantly larger boys than in the girls. Rim area remained nonsignificantly (P Ͻ 0.0001) in the European white (1.81 mm2; 95% CI, different between boys and girls even after adjustment for 1.79–1.83) than the East Asian (1.55 mm2; 95% CI, 1.49–1.60) optic disc area (P ϭ 0.4). children, but was similar to that in the Middle Eastern children (mean 1.81 mm2; 95% CI, 1.73–1.89).

DISCUSSION In this report, we have provided population norms for optic nerve head parameters in young children, most of whom were aged 6 years. Most parameters were normally distributed. Mean optic disc and cup shape were vertically oval, with large proportions having horizontally oval discs and cups. There was an association of increasing disc area with increasing cup area, neural rim area and RNFL thickness. Average nerve width and rim area (vertical cross-section) were greater along the vertical than horizontal meridians. Axial length was a significant determinant of disc and neural rim area. The East Asian children had larger discs but smaller neural rim areas than did the European white children. In comparing these results with other studies, it should be noted that optic disc and cup parameters were defined by the FIGURE 3. Plot showing the relationship of rim and cup areas with OCT, which uses different reference points from other exam- optic disc area. Error bars, 95% CI. Optic disc, cup, and rim areas were ination methods, including retinal photography, scanning laser corrected for magnification. polarimetry, and confocal scanning laser ophthalmoscopy

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FIGURE 4. Plots showing the relationship of magniﬁcation-corrected optic disc and rim area with (A) axial length and (B) spherical equivalent refraction. Association with disc area was adjusted for age, gender, ethnicity and cluster sampling, whereas the association with rim area was additionally adjusted for optic disc area. Error bars are 95% CI. The mean and range (in parentheses) of axial length (AL; mm) and spherical equivalent (SE; diopters) for each quintile were (1) AL: 21.63 (19.64–22.04); SE: 0.32 (Ϫ4.88–0.75); (2) AL: 22.26 (22.04–22.44); SE: 0.94 (0.76–1.08); (3) AL: 22.62 (22.44–22.78); SE: 1.20 (1.08–1.27); (4) AL: 22.99 (22.78–23.17); SE: 1.47 (1.27–1.66); and (5) AL: 23.54 (23.17–25.35); SE: 2.45 (1.66–8.58).

(CSLO). Optic disc reference points were defined using the sour3 examined stereo-photographs of 66 children aged 2 to 10 termination of the RPE at the disc, and the entire optic disc years and reported generally larger disc and neural rim areas margin was interpolated between these disc reference points. than we found (Table 5). Histologic measurements of disc size In scanning laser polarimetry and photographic methods, the in adult eyes16,17 are also generally larger, despite tissue shrink- optic disc margin is manually traced. The optic cup was also age by 13%16 to 21%17 caused by specimen fixation. Tong et defined using a fixed reference plane rather than the slope of al.27 reported horizontal and vertical cup-to-disc diameter and the retinal surface, so children with photographically shallow area ratios of 0.45, 0.38, and 0.19, respectively, in 8- to 13-year- cups that did not reach this reference plane would be classified old emmetropic East Asian children (n ϭ 100), although they as having no cup. Despite this, the use of a fixed reference did not use stereophotographs. These were similar to our plane is likely to reduce variability in measurement. Differ- findings in European white children, but were slightly smaller ences in optical magnification should also be considered. In than for our East Asian children. In contrast, Mansour3 re- small studies, measures of disc size using CSLO14 and of cup- ported average cup-to-disc diameter ratios that were consider- to-disc ratio using stereophotographs15 were both larger than ably smaller than those found in our sample (boys 0.30, girls when measured using OCT. 0.21, European white 0.15). Many studies have reported optic nerve head parameters in The greater average nerve width and rim area (vertical adults,4,5,16–26 but there have been few in children.3,27 Man- cross-section) along the vertical compared with the horizontal

TABLE 3. Gender-Speciﬁc Distribution of Optic Nerve Head Parameters

Boys Girls P (643 ؍ n) (666 ؍ n)

Horizontal disc diameter (mm) 1.54 (1.52–1.56) 1.53 (1.51–1.54) 0.4 Vertical disc diameter (mm) 1.77 (1.74–1.80) 1.77 (1.74–1.81) 0.7 Disc area (mm2) 2.18 (2.14–2.22) 2.19 (2.15–2.24) 0.6 Horizontal cup diameter (mm)* 0.72 (0.69–0.74) 0.74 (0.72–0.76) 0.1 Vertical cup diameter (mm)* 0.76 (0.73–0.78) 0.75 (0.73–0.78) 0.8 Cup area (mm2)* 0.51 (0.46–0.53) 0.49 (0.46–0.53) 0.3 Cup volume (mm3)* 0.07 (0.06–0.08) 0.06 (0.057–0.07) 0.09 Horizontal cup-to-disc ratio* 0.48 (0.47–0.50) 0.47 (0.45–0.48) 0.2 Vertical cup-to-disc ratio* 0.43 (0.42–0.45) 0.43 (0.41–0.44) 0.6 Cup-to-disc area ratio* 0.23 (0.22–0.24) 0.22 (0.21–0.24) 0.3 Rim area (mm2) 1.71 (1.66–1.76) 1.72 (1.67–1.76) 0.7 Horizontal integrated rim width (mm2) 1.69 (1.65–1.72) 1.66 (1.63–1.70) 0.1 Average nerve width (mm) Horizontal 0.274 (0.269–0.28) 0.267 (0.26–0.27) 0.01 Vertical 0.357 (0.351–0.363) 0.353 (0.347–0.358) 0.05 Overall 0.317 (0.312–0.321) 0.314 (0.309–0.319) 0.2 Rim area (vertical cross-section) (mm2) Horizontal 0.18 (0.17–0.19) 0.18 (0.17–0.19) 0.4 Vertical 0.31 (0.29–0.33) 0.30 (0.28–0.32) 0.08 Vertical integrated rim area (mm3) 0.65 (0.61–0.69) 0.63 (0.58–0.67) 0.2

Data are adjusted for age, ethnicity, axial length, and cluster sampling. Results presented are means (95% conﬁdence interval). * Excludes 97 children (7.4%) with no deﬁnable optic cup.

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TABLE 4. Ethnicity-Speciﬁc Distribution of Optic Nerve Head Parameters

European White East Asian Middle Eastern †P* P (53 ؍ n) (199 ؍ n) (866 ؍ n)

Horizontal disc diameter (mm) 1.52 (1.51–1.54) 1.56 (1.53–1.59) 1.52 (1.48–1.56) 0.02 0.9 Vertical disc diameter (mm) 1.80 (1.78–1.81) 1.81 (1.78–1.84) 1.74 (1.67–1.82) 0.4 0.2 Disc area (mm2) 2.19 (2.16–2.22) 2.28 (2.24–2.32) 2.12 (2.01–2.22) Ͻ0.0001 0.2 Horizontal cup diameter (mm)‡ 0.66 (0.64–0.68) 0.88 (0.84–0.91) 0.67 (0.60–0.73) Ͻ0.0001 0.9 Vertical cup diameter (mm)‡ 0.63 (0.67–0.71) 0.88 (0.85–0.92) 0.69 (0.63–0.75) Ͻ0.0001 0.9 Cup area (mm2)‡ 0.42 (0.40–0.44) 0.68 (0.64–0.73) 0.41 (0.33–0.48) Ͻ0.0001 0.8 Cup volume (mm3)‡ 0.05 (0.045–0.053) 0.10 (0.09–0.12) 0.04 (0.03–0.06) Ͻ0.0001 0.5 Horizontal cup-to-disc ratio‡ 0.43 (0.42–0.44) 0.56 (0.54–0.58) 0.44 (0.40–0.48) Ͻ0.0001 0.9 Vertical cup-to-disc ratio‡ 0.39 (0.38–0.41) 0.49 (0.47–0.51) 0.40 (0.36–0.44) Ͻ0.0001 0.7 Cup-to-disc area ratio‡ 0.19 (0.185–0.20) 0.30 (0.28–0.32) 0.19 (0.16–0.23) Ͻ0.0001 0.97 Rim area (mm2) 1.80 (1.76–1.83) 1.62 (1.56–1.68) 1.74 (1.62–1.86) Ͻ0.0001 0.4 Horizontal integrated rim width (mm2) 1.74 (1.72–1.76) 1.58 (1.55–1.62) 1.72 (1.62–1.83) Ͻ0.0001 0.7 Average nerve width (mm) Horizontal 0.287 (0.284–0.290) 0.24 (0.234–0.246) 0.29 (0.27–0.30) Ͻ0.0001 0.9 Vertical 0.364 (0.360–0.368) 0.34 (0.332–0.347) 0.37 (0.35–0.38) Ͻ0.0001 0.9 Overall 0.328 (0.326–0.331) 0.292 (0.287–0.298) 0.33 (0.31–0.34) Ͻ0.0001 0.98 Rim area (vertical cross-section) (mm2) Horizontal 0.21 (0.20–0.22) 0.13 (0.11–0.14) 0.22 (0.19–0.25) Ͻ0.0001 0.4 Vertical 0.35 (0.34–0.37) 0.24 (0.22–0.26) 0.36 (0.30–0.41) Ͻ0.0001 0.9 Vertical integrated rim area (mm3) 0.74 (0.71–0.77) 0.48 (0.44–0.52) 0.74 (0.63–0.86) Ͻ0.0001 0.9

Data are adjusted for age, gender, axial length and cluster sampling. Results presented are the means (95% conﬁdence interval). * East Asian versus European white. † Middle Eastern versus European white. ‡ Excludes 97 children (7.4%) with no deﬁnable optic cup.

meridian is consistent with previous observations that the adults18,22,23,36 and children3 generally reported nonsignificant peripapillary nerve fiber layer is thicker in the superior and or only a weak association of disc and neural rim area with inferior regions than in the temporal or nasal regions.28,29 This refraction. Studies that found an association tended to report configuration also corresponds to regional differences in the slightly larger discs in myopic than nonmyopic eyes.25,35 Sev- size and number of nerve fibers in the optic disc.30 Histologic eral studies also found no significant association of refraction estimates of nerve fiber layer thickness at the disc margin in with cup-to-disc area27 and diameter27,37 ratios. Considered adult eyes were limited by small study samples.29,31 Dichtl et together, these findings indicate that eye size has a greater al.31 reported values of 313 ␮m superiorly, 397 ␮m inferiorly, influence on disc and neural rim area than does refraction. This 131 ␮m temporally, and 165 ␮m nasally. Varma et al.29 re- suggests that the observed increased risk of open-angle glau- ported corresponding values of 405, 376, 372, and 316 ␮m. coma in myopic adults38 could be related to the associated Because the number of nerve fibers decrease with age,16,32,33 increased eye size rather than myopia per se because axial our estimates would be lower than expected, although these length in myopic eyes is increased,11,39,40 and disc size has marked differences could in part be explained by the different been reported to be slightly larger in open-angle glaucoma.41,42 measurement techniques and the greater chance of selection This is only speculative, though, because most children in our bias in small non–population-based studies. The decreased re- study were hyperopic. flectance of nerve fibers at the optic disc resulting from their Our data showed a general lack of association of gender sloped orientation relative to the OCT scan beam13,34 may also with disc, cup, and neural rim parameters after adjusting for cause underestimation of this parameter. Another important potential confounders. Average nerve width was significantly consideration is that optic disc size significantly influences greater in the boys than in the girls, but these differences were other parameters, including peripapillary nerve fiber layer only marginal. The lack of association of gender with disc size thickness and vertical cup-to-disc diameter ratio,4 highlighting is consistent with previous reports in children3 and the importance of taking optic disc size into consideration adults.16,22,35,36 Several studies reported larger discs in adult when optic disc parameters are measured. males,17,18,23 including that of Ramrattan et al.,25 who reported In the present study, optic disc area increased and rim area data in more than 5000 predominantly white participants. decreased significantly with axial length. Chihara and Chi- Ramrattan et al.25 also reported slightly larger neural rim area hara,35 and Miglior et al.18 reported moderate positive corre- in men, but there were no gender differences in cup area and lations with disc (r ϭ 0.6) and rim areas (r ϭ 0.5). No corre- cup-to-disc ratios. Gender differences in ocular biometry or lation was reported with disc area by Quigley et al.17 and with height could have contributed to these inconsistent findings. rim area by Jonas and Gusek,36 although these studies were Further, gender differences may only become manifest at a limited by relatively small selected samples of eye bank eyes17 later age than that of this population sample. or clinic subjects.36 Optic disc area increased and rim area Numerous studies have found ethnic differences in disc and decreased only marginally with less hyperopic refractions, de- cup parameters. Most notably, persons of white background spite both being statistically significant. It should be noted, have been reported to have smaller discs than those of African- though, that our study sample was predominantly hyperopic, American,3,5,17,43 Asian,23 or Indian (South Asian)23 back- with a myopia (SE Յ Ϫ0.5 D) prevalence of only 1.4%.11 grounds. Cup area5 and cup-to-disc ratio3,19 are also smaller in Similar data derived from older children in whom the preva- white than African-American persons, although neural rim area lence of myopia is likely to be higher are needed to reach is not significantly different between these two ethnic definitive conclusions regarding the effect of myopia on disc groups.44 Differences between white and African-American and neural rim area. Previous studies conducted in children have not been examined in population-based studies.

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TABLE 5. Comparison of Optic Disc and Neural Rim Dimensions with Selected Studies

Disc

Age HDD VDD Area Rim Area Study Year N Subjects (y) Subgroup (mm) (mm) (mm2) (mm2)

Current study 2006 1309 Population-based 6–7 All 1.53 1.79 2.20 1.76 Boys 1.54 1.77 2.18 1.71 Girls 1.53 1.77 2.19 1.72 European white 1.52 1.80 2.19 1.80 East Asian 1.56 1.81 2.28 1.62 Middle Eastern 1.52 1.74 2.12 1.74 Histological studies Quigley et al.17 1990 60 Eye bank eyes 66.5* All 1.76 1.87 — — Male 1.81 1.89 — — Female 1.71 1.86 — — White 1.74 1.82 — — Black 1.79 1.96 — — Jonas et al.16 1992 56 Cornea donors 54.7* All — — 2.30 — Male — — 2.33 — Female — — 2.28 — Photographic studies Britton et al.20 1987 113 No information 20–81 — 1.57 1.66 2.10 1.65 Jonas et al.21 1988 88 SEϾϪ8D 42.5* — 1.79 1.97 2.89 2.26 Jonas et al.22 1988 319 Clinic subjects 42.7* — 1.76 1.92 2.69 1.97 Mansour23 1991 125 Volunteers 21–54 Male 1.93 2.03 3.09 — Female 1.83 2.00 2.89 — White 1.75 1.92 2.66 — Asian 1.98 2.06 3.22 — Mansour3 1992 66 Volunteers 2–10 Boys 1.82 2.03 2.93 2.50 SEϪ5Dtoϩ5 D Girls 1.78 1.99 2.81 2.54 White 1.76 1.91 2.53 2.53 Black 1.84 2.12 3.08 2.51 Miglior et al.18 1994 235 SE Ϫ8Dtoϩ4 D 52–54 Male — — 2.58† 2.16 Female — — 2.43 2.06 Healey et al.24 1997 3358 Population-based 49–97 White — 1.51 — — Ramrattan et al.25 1999 5114 Population-based 55ϩ White — — 2.42 1.85 Confocal Scanning Laser Ophthalmoscopy Wang et al.26 2000 114 SEϽϪ8 D 18.9* Asian 1.49 1.71 2.07 1.42 29 SEϾϪ3 D 21.4* Asian 1.47 1.68 1.98 1.20 Girkin et al.5 2005 53‡ Glaucoma study database 42.3* White — — 1.96 1.6 (normal subjects) 73§ 45.9* Black — — 2.14࿣ 1.6¶

HDD, horizontal disc diameter; VDD, vertical disc diameter. * Mean age. † Significant gender difference (P Ͻ 0.05). ‡ 97 eyes. § 146 eyes. ࿣ Significant difference between black and white subjects (P ϭ 0.02). ¶ No significant difference when adjusted for optic disc size differences between black and white subjects (P ϭ 0.06).

Our data are probably the first to report that children of ple measurements of the optic disc, nerve fiber layer, axial European white background have smaller disc and cup size, length, and refraction, were also performed to reduce measure- but larger neural rim area than children of East Asian origin, ment error, and optic disc dimensions were adjusted for the and that there were no significant differences between chil- magnification of the OCT. The sample also permitted exami- dren of European white and Middle Eastern origins. These nation of ethnic differences in parameters studied. An impor- ethnic differences in neural rim area concur with previous tant limitation was the exclusion of a significant proportion of findings of ethnic differences in peripapillary nerve fiber layer children who had scans with low signal strength. It is not clear thickness.33,45,46 Ethnic differences in these parameters prob- how this could have affected our results, although the inclu- ably have a stronger genetic than developmental basis, because sion of poor-quality scans would not be acceptable. The pre- they can be demonstrated in children as well as adults. If dominantly hyperopic refraction also limited our ability to increased disc size predisposes to glaucoma, and assuming that study the effects of myopia. ethnic differences in optic disc and optic cup parameters are In summary, in this OCT study of a large population of preserved with any growth of the optic nerve with age, then 6-year-old children, optic disc and neural rim parameters were these findings could also help explain observed differences in normally distributed. Disc and neural rim areas were slightly the prevalence of open-angle glaucoma between East Asian and smaller than found in adult studies. Average nerve width was white populations.47–49 greater along the vertical than horizontal meridian, consistent Strengths of this study include a large sample size, high with previously observed peripapillary distribution of nerve response rate, and standardized examination protocol. Multi- fiber layer thickness. Optic disc size was a significant determi-

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