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1From the Singapore Eye Research Institute, Republic of Singapore; the 2Department of Community, Occupational and Family Medicine, National University of Singapore, Republic of Singapore; 3The Institute of Ophthalmology, London, United Kingdom; the 4Singapore National Eye Center, Republic of Singapore; the 5Department of Ophthalmology, National University Hospital, Republic of Singapore; the 6University of Sydney, Center for Vision Research, Westmead Millennium Institute, Westmead, New South Wales, Australia; and the 7Center for Eye Research Australia, University of Melbourne, Melbourne, Australia.
| Abstract |
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METHODS. A total of 104 Chinese school children (51 girls and 53 boys) 11 to 12 years of age were randomly selected from one school during the 2005 examination in the Singapore Cohort Study of the Risk Factors for Myopia (SCORM). Cycloplegic autorefraction was performed to obtain refraction (defined as spherical equivalent [SE]) and ultrasound biometry performed to obtain the AL. Macular volume and thickness were then measured (StratusOCT3; Carl Zeiss Meditec, Dublin, CA).
RESULTS. Children with moderate myopia (SE at least 3.0 D) tended to have smaller total macular volume and thinner quadrant-specific macular thickness (except in the inferior and superior inner quadrants), followed by children with low myopia (0.5
SE < 3.0 D), compared with children with no myopia (SE > 0.5 D). Total macular volume was positively associated with SE (ß = 1.58, 95% CI, 0.84 to 2.32, standardized ß = 0.14, P < 0.001) and negatively associated with AL (ß = 1.20, 95% CI, 1.62 to 0.79, standardized ß = 0.45, P < 0.001) in multiple linear regression models controlling for age and gender.
CONCLUSIONS. In children, increasing axial myopia was associated with reduced macular volume and thickness. These findings suggest that early anatomic changes may be present in the retinas of children with axial myopia.
Few studies have evaluated possible structural retinal changes in individuals with low to moderate myopia without evidence of clinically overt retinal disease. In adults, studies based on the use of optical coherence tomography (OCT) to detect subtle macular changes have shown inconsistent results.7 8 In two Asian adult OCT studies in Japan and Singapore, the average macular retinal thickness did not vary with refraction.9 10 However, in the Singapore study, minimum (foveal) macular thickness was greater in adults with longer axial lengths (ALs), whereas the parafoveal macular layers in the superior and inferior quadrants were thinner. Macular thickness of the nasal and superior quadrants were greater than the temporal and inferior parts.9 10
There are few studies in children in which early macular anatomic features have been examined in myopic eyes. In a study using OCT among Polish adolescents 14 to 18 years of age, macular thickness decreased with increasing myopic refraction, with a mean macular retinal thickness of 231.0 µm in eyes with low myopia, 218.0 µm in moderate myopia, and 178.0 µm in high myopia.11
To our knowledge, however, there are no reports of the correlations of OCT-defined parameters with ocular biometry in children. The purpose of this study was to investigate the associations of OCT measurements of macular volume and macular thickness with refractive error and AL in Singaporean children.
| Methods |
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This cohort was examined yearly. During the 2005 (fourth year) examination, 104 Chinese children randomly selected from 561 children in the Western school who were in grades 5 and 6 (ages 11 and 12 years) had OCT measurements. The mean age of this sample was 11.5 ± 0.5 years (51 girls and 53 boys). The mean spherical equivalent (SE) refraction was 1.38 ± 1.58 D (range, 4.5 to +1.10). Comparison of this random sample with those not selected for this study showed that it was similar by age (P = 0.42) and gender (P = 0.91), but the mean SE of this group was less myopic (1.38 D vs. 2.20 D) and they had shorter ALs (23.87 mm vs. 24.23 mm) compared with those not selected.
This research followed the tenets of the Declaration of Helsinki. Informed written consent was obtained from parents of each subject, and each procedure was performed with the subjects consent. The study was approved by the ethics committee of the Singapore Eye Research Institute.
Eye Examinations
All children had a standardized examination as follows. Cycloplegic refraction was performed after instillation of 3 drops of 1% cyclopentolate 5 minutes apart. At least 30 minutes after the last drop, five consecutive refraction and keratometry readings were obtained with one of two calibrated autokeratorefractometers (model RK5; Canon, Inc. Ltd., Tochigiken, Japan). AL measurements were obtained using one of two contact ultrasound biometry machines (Echoscan model US-800, probe frequency of 10 mHz; Nidek Co., Ltd., Tokyo, Japan), after 1 drop of 0.5% proparacaine was administered. The average of six measurements was taken if the standard deviation was <0.12 mm. If the standard deviation was
0.12 mm, the data were not included, and the measurements were repeated until the standard deviation reached <0.12 mm.
The OCT measurements (StratusOCT3; Carl Zeiss Meditec, Dublin, CA) were performed in a dim room after cycloplegia. The pupils were dilated to at least 5 mm diameter before the measurements. The measurements of AL and refractive error were entered into the OCT software. The OCT examination was performed by the same ophthalmologist (AF) and analyzed (ver. 4.1 software; Carl Zeiss Meditec, Dublin, CA). Scans were performed using the Fast Macular Thickness protocol and were repeated six times until three good-quality horizontal and three good-quality vertical scans were achieved for each child. Twenty-three parameters were measured by the Fast Macular Thickness scan protocol: the volume and average retinal thickness of the macula, the thickness of four quadrants of the inner and outer macula in the parafoveal area; the minimum macular thickness in the foveal area; and ratios of superiorinferior outer macular thickness and temporalnasal inner and outer macular thickness by horizontal and vertical 6-mm scans centered against the point of fixation of each eye.
Definitions and Data Analysis
Spherical equivalent was defined as spherical power plus half-negative cylinder power. Myopia was defined as an SE of at least 0.5 D. Levels of myopia included low myopia, defined as SE
0.5 D and > 3 D, and moderate myopia, defined as SE of at least 3 D.12 The OCT measurements of macular volume and macular thickness were normally distributed. The ANOVA procedure was used to compare the differences in OCT parameters among groups of children with no myopia, low myopia, and moderate myopia and among groups with AL in the highest, middle, and lowest tertiles. Multiple linear regression models were conducted with OCT parameters as the dependent variable, with SE, AL, age, and gender as the covariates. All data were analyzed with statistical software (SPSS ver. 12.0; SPSS Inc., Chicago, IL), and statistical significance was assumed at P < 0.05. However, for multiple comparisons among the 23 parameters measured by the OCT Fast Macular Thickness scan protocol, a Bonferroni correction was applied with resultant significance of P< 0.0022.
| Results |
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The average total macular volume, average foveal volume, overall average macula thickness (overall), and foveal minimum thickness, were 6.65 ± 0.39 mm3 (median, 6.57; range, 5.997.67), 0.15 ± 0.01 mm3, 171.4 ± 35.8 µm (median, 169.8; range, 101.3241.3), and 157.0 ± 19.2 µm (median, 155.8; range, 122.0208.7), respectively. The boys had higher foveal minimum thickness (162.1 ± 17.5 µm vs. 151.4 ± 19.6 µm) than did the girls. Inner and outer macular thicknesses were significantly positively correlated with inner and outer macular volume in all quadrants (linear regression, P < 0.001). The average inner macular thicknesses of the superior, inferior, temporal, and nasal quadrants were 271.4 ± 14.3, 261.8 ± 13.2, 255.4 ± 13.4, and 266.2 ± 16.2 µm, respectively, and the average outer macular thicknesses were 234.5 ± 13.2, 230.2 ± 14.1, 214.6 ± 13.5, and 254.6 ± 14.9 µm, respectively.
Comparisons of differences in macular volume and thickness among the children with moderate myopia, low myopia, and no myopia are shown in Table 1 . The children with moderate and mild myopia had significantly lower total macular volume and superior inner, temporal inner, nasal inner, temporal outer, nasal outer, and inferior outer macular volumes than did the children with no myopia. The children with moderate and mild myopia also had higher minimum macular thickness and lower quadrant-specific macular thickness (except inferior inner) than did those with low myopia and no myopia. After the application of the Bonferroni correction for multiple comparisons, only the differences in total macular volume, temporal outer, nasal outer, and inferior outer macular volumes and macular thicknesses remained statistically significant among the three groups.
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Figure 1 depicts scatterplots of SE with selected OCT measurements, and Figure 2 depicts scatterplots of AL with selected OCT measurements. The Pearson correlation coefficients were 0.44 for total macular volume and SE, 0.07 for average macular thickness versus SE, and 0.26 for minimum macular thickness versus SE. The Pearson correlation coefficients were 0.48 for total macular volume and AL, 0.02 for average macular thickness versus AL, and 0.30 for minimum macular thickness versus AL.
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| Discussion |
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One of the key findings of our study is that three-dimensional OCT macular measurement parameters such as total macular volume and outer and inner macular volume decreased with more myopic refraction and increasing AL. The difference in total macular volume among the nonmyopic, low myopic, and high myopic children was small but statistically significant (6.84 ± 0.37 mm3 vs. 6.56 ± 0.37 mm3 vs. 6.48 ± 0.32 mm3, P = 0.0002). To our knowledge, there have been no previous reports regarding differences in macular volume measured by OCT between myopic and nonmyopic subjects. Hess et al. 14 showed that macular volume was smaller in glaucomatous (6.57 ± 0.85 mm3) than in normal (7.01 ± 0.42 mm3) eyes in white children (P < 0.001).
The two-dimensional OCT measurements of macular thickness and its correlation with myopia in our study are in agreement with previous reports.9 10 Our findings should be compared with findings from a recent OCT study in a Singaporean adult population.10 Both studies show that the thickest point at the parafoveal region decreased with myopia, whereas foveal thickness increased. The reduction in the difference in thickness between the foveal pit and parafoveal crest with increasing myopic refraction in adults10 was also observed in our study.
An interesting observation in our study is that the minimum macular thickness at the foveal region increased, whereas overall macular thickness decreased with increasing myopic refraction and AL. This somewhat paradoxical finding is not easily explainable. Thinner maculae could be due to the stretching of a similar volume of retina over a larger area or a decreased number of photoreceptors. Even early chorioretinal atrophy in high myopia, which had been described in the posterior pole in eyes, has been associated with longer AL and increased retinal thinning with myopia.6 15 16 However, there were few highly myopic children in our study, and it would be surprising if chorioretinal atrophy were present in children with such small amounts of myopia. In contrast, the increased macular thickness in the foveal region may be related to other mechanisms. In a form-deprivation model of myopia of tree shrews,17 subfoveal blood-retinal barrier permeability in form-deprived myopic animals was significantly higher than in the control group. It is possible that the increase in minimum macular thickness (in the foveal area), which was associated with increasing myopic SE and AL in our study, may be due to pathologic subfoveal chorioretinal changes.18 An alternative explanation for the decreased macular crest thickness along with increased foveal thickness was suggested by Springer and Hendrickson in their experiments of macular modeling during a period of experimentally induced myopia progression in young animals. The absence of vasculature in the foveal area may lead to foveal pits that are very deformable in response to intraocular pressure, and ocular growth-induced retinal stretch may contribute to the formation of foveal pits in primates.19 20 21 The significance of these OCT findings may require further research.
The similar pattern of associations of OCT measurements with SE and AL in our study was, of course, related to the close correlation between SE and AL (Pearson coefficient = 0.6, P < 0.001),12 22 and indicates that the OCT findings reflect axial myopia. The standardized coefficient of AL was higher than that of SE (0.45 vs. 0.14) in the multiple linear regression model for the prediction of total macular volume. It is well known that more highly myopic eyes have longer AL, which is largely contributed by a greater vitreous chamber depth.23 Thus, AL possibly contributes to a relatively larger variation of total macular volume than does just the SE. The "stretch effect" from the elongation of AL in myopic progression may thus in part explain the reduction of macular retinal thickness and macular volume, aspects of an overall stretching process of ocular structures in both myopic human subjects and animal models.23 24
We did not find significant correlation between the absolute cylinder reading and the OCT measurements (both macular volume and macular thickness), indicating that the major factor affecting variations in OCT parameters is axial refraction. The overall average macular thickness did not show a significant relationship with refractive error. The measurements were not influenced by the refractive state of the eye. The counteracting effects of the decrease of parafoveal thickness and the increase of foveal thickness with increasing myopic SE and AL may explain the insignificant changes in overall average macular thickness in our study. It should be stated that magnification error may be present in transverse measurements in this StratusOCT study, as the manufacturer (Carl Zeiss Meditec, Inc.) did not control for error in the current version of the instrument. The StratusOCT does not provide correction of the actual scan itself. Future refinement of the instrument should include some estimation of this error introduced by refractive error. Despite this, OCT provided quantification of retinal thickness with the excellent reliability reported in previous studies.7 8 10 25 26 In one study, coefficients of variation of macular thickness measurements by OCT within the same subjects were 10%, decreasing to 9% when scans were repeated five times.26
Early macular changes such as peripapillary atrophy have been documented in young myopic children in an Asian country in which high myopia (SE at least 6 D) develops even in young children.12 To our knowledge, this is the first report of myopia-related variations in macular anatomy in young children determined by OCT measurement. Because high myopia has been reported to be associated with ocular disease including myopic macular degeneration, macular retinoschisis, and macular holes, the early identification of children with possible myopia-related macular changes is important.3 27 28 It has been shown that kinetics of cone pigments become abnormal preceding the loss of cone cells or chorioretinal degeneration in high myopia.28 It is uncertain whether there are any direct links between reductions in macular thickness and the subsequent onset of clinically significant macular disease.
The OCT is a commonly used method in the documentation of retinal diseases. It provides detailed measurements of the optic disc and retinal nerve fiber layer and the detection of decreased macular thickness may provide a sensitive method for the detection and monitoring of early glaucomatous tissue loss in the posterior pole.29 Our study shows that because macular thickness is influenced by the degree of refractive error, any interpretations of retinal changes should be made only after the refractive error of the individual is considered. Possible limitations of this study include the small number of children with high myopia, the unknown effect of the transverse magnification error, and the possible lack of generalizability of our study to other non-Asian or adult populations.
In summary, the myopic children in our study had reduced macular volumes and parafoveal thickness. The findings suggest that the three-dimensional OCT may serve as a useful tool in the evaluation of early macular changes in myopic children, although the ultimate clinical significances of these changes require further evaluation. Nonetheless, the degree of refractive error should be considered in all OCT assessments of macular changes in children with other eye diseases.
| Acknowledgements |
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| Footnotes |
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Submitted for publication October 24, 2005; revised December 29, 2005, and January 26, 2006; accepted April 26, 2006.
Disclosure: H.-D. Luo, None; G. Gazzard, None; A. Fong, None; T. Aung, None; S.T. Hoh, None; S.-C. Loon, None; P. Healey, None; D.T.H. Tan, None; T.-Y. Wong, None; S.-M. Saw, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C.
1734 solely to indicate this fact.
Corresponding author: Seang-Mei Saw, Associate Professor, Department of Community, Occupational and Family Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore; cofsawsm{at}nus.edu.sg.
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