- Email: [email protected]
Myopic Maculopathy Imaged by Optical Coherence Tomography
Myopic Maculopathy Imaged by Optical Coherence Tomography The Beijing Eye Study Qi Sheng You, MD,1 Xiao Yan Peng, MD, PhD,1 Liang Xu, MD,1 Chang Xi Chen,1 Ya Xing Wang, MD,1 Jost B. Jonas, MD1,2 Purpose: To examine the features of myopia-related optical coherence tomography (OCT) findings in a population-based setting. Design: Population-based study. Participants: The Beijing Eye Study 2011 included 3468 subjects with an age of 50 years or more. Methods: The participants underwent a detailed ophthalmic examination including OCT with enhanced depth imaging of the macula. Main Outcome Measures: Optical coherence tomography features of the macula in highly myopic eyes defined by a refractive error of 6 diopters or less or an axial length of 26.5 mm or more. Results: Readable OCT images were available for 6530 eyes (94.5%) of 3278 participants. The most common change in the macula was maculoschisis (0.80.1%), followed by incomplete posterior vitreous detachment (0.70.1%), disruption of the photoreceptor inner segment/outer segment interface (0.60.1%), epiretinal membranes (0.60.1%), macular defects in Bruch’s membrane (0.30.1%), clumping of the retinal pigment epithelium (0.20.1%), vitreofoveal adhesion (0.20.1%), and macular holes in 2 eyes (0.10.1%). Prevalence of any myopic maculopathy per eye was 112 of 6530, or 1.710.16% (95% confidence interval [CI], 1.40e2.03). After adjustment for longer axial length (P<0.001; odds ratio [OR], 2.68; 95% CI, 1.97e3.64) and myopic refractive error (P<0.001; OR, 0.63; 95% CI, 0.55e0.73), presence of any myopic maculopathy was not significantly associated with any systemic variables (all P0.05), including biochemical blood examination and ocular parameters. Best-corrected visual acuity was associated significantly with the absence of a disruption of the photoreceptor inner segment/outer segment interface (P<0.001), epiretinal membranes (P<0.001), and macular holes (P<0.001) after adjustment for age and cylindrical refractive error. Conclusions: Based on OCT examination, the most common macular change in highly myopic eyes was maculoschisis, followed by incomplete posterior vitreous detachment, disruption of the photoreceptor inner segment/outer segment interface, epiretinal membranes, macular defects in Bruch’s membrane, clumping of the retinal pigment epithelium, vitreofoveal adhesion, and macular holes. The most important macular changes with a negative effect on best-corrected visual acuity were a disruption of the photoreceptor inner segment/outer segment interface and epiretinal membranes. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;-:1e5 ª 2013 by the American Academy of Ophthalmology.
Myopic retinopathy is characterized by changes in the macular region, including staphylomata, lacquer cracks, Fuchs’ spot, chorioretinal atrophy, and secondary defects in Bruch’s membrane.1e4 It has been recognized as one of the leading causes of irreversible visual impairment and blindness worldwide. It was the second most common cause of low vision and blindness in the Handan Eye Study and Beijing Eye Study in mainland China and in the Shihpai Eye Study in Taiwan, and the second most common cause of blindness and third most common cause of low vision in the Tajimi Study in Japan.5e8 In white populations in Western countries and in Hispanics, myopic retinopathy was the second to fourth most frequent cause of blindness.9e12 Because the myopic shift in the metropolitan regions at the Pacific rim so far has affected mostly the relatively 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
young generations in which the vision-reducing effect of pathologic myopia has not yet become fully effective, it can be expected that the role of myopic retinopathy as a cause of visual impairment and blindness will increase in the near future.13,14 Previous studies have addressed the prevalence, incidence, and natural course of myopic retinopathy in population-based studies using fundus photographs, and studies have addressed the histologic features of myopic maculopathy.2,4,15e21 Spectral-domain optical coherence tomography (OCT) has further expanded the panoply of diagnostic procedures to examine the myopic macula.22,23 Because there have been no data available on the prevalence of OCT-defined changes in myopic maculopathy and because, in particular, there have been no OCT-based studies on the highly myopic macula considering new ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.06.013
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Ophthalmology Volume -, Number -, Month 2013 findings of the histologic features of myopic maculopathy, we performed this study. We investigated the frequency of OCT abnormalities in the macular region of highly myopic eyes, defined as a myopic refractive error of more than 6 diopters (D) or an axial length of more than 26.5 mm, and examined their associations with other ocular and systemic parameters. The findings may be helpful for the OCT-based definition and differentiation of highly myopic changes in the macula, increase the knowledge about the prevalence of these detailed changes in the general population, and give hints for risk factors by analyzing factors associated with the myopic maculopathy.
Patients and Methods The Beijing Eye Study 2011 is a population-based, cross-sectional study in Northern China and has been described in detail previously.5,16,24 The Medical Ethics Committee of the Beijing Tongren Hospital approved the study protocol, and all participants gave informed consent. The only eligibility criterion for inclusion into the study was an age of 50 years or more. Of a total eligible population of 4403 individuals, 3468 (1963 women; 56.6%) participated (response rate, 78.8%). The study was divided into a rural part (1633 subjects [47.1%]; 943 women [57.7%]) and an urban part (1835 subjects [52.9%]; 1020 women [55.6%]). The mean age was 64.69.8 years (median, 64 years; range, 50e93 years). All study participants underwent an interview with standardized questions regarding their family status, level of education, physical activity, and known major systemic diseases. Body height and weight were recorded. Blood pressure was measured, and fasting blood samples were examined for the concentration of blood lipids, glucose, glycosylated hemoglobin, creatinine, and C-reactive protein. The ophthalmic examination included measurement of presenting visual acuity, uncorrected visual acuity, and best-corrected visual acuity; tonometry; slit-lamp examination of the anterior and posterior segments of the eye; and digital photography the cornea, lens, macula, and optic disc (fundus camera type CR6-45NM; Canon, Inc., Tokyo, Japan). Pseudoexfoliation of the lens was searched for by slit-lamp biomicroscopy after medical pupillary dilatation. Spectral-domain OCT (wavelength, 870 nm; Spectralis; Heidelberg
Engineering Co., Heidelberg, Germany) with the enhanced depth imaging mode was performed after pupil dilation.23,24 Thirty-one sections were obtained, which covered a 30 30 large rectangle centered onto the fovea. Using the enhanced depth imaging mode, 7 additional sections (each comprising 100 averaged scans) were obtained in a 530 large rectangle centered onto the fovea. Biometry for measurement of the anterior corneal curvature, central corneal thickness, anterior chamber depth, lens thickness, and axial length (optical low-coherence reflectometry; Lensstar 900 Optical Biometer; Haag-Streit, Koeniz, Switzerland) was carried out in the right eyes of the study participants. Using fundus photographs, we also assessed the presence of retinal vein occlusions, diabetic retinopathy, and glaucomatous optic neuropathy, as defined and described in detail previously.25,26 All OCT sections of all highly myopic eyes, defined as a myopic refractive error of more than 6 D or an axial length of more than 26.5 mm, were examined for epiretinal membranes, vitreofoveal adhesion, incomplete posterior vitreous detachment, retinoschisis, macular holes, disruption of the photoreceptor inner segment/outer segment interface, changes in Bruch’s membrane such as disruption, and clumping of the retinal pigment epithelium (Fig 1). Presence of staphylomata was not examined because an enlargement of emissary openings within a region with macular atrophy, sometimes accompanied by a dehiscence of the entire scleral thickness, could be mistaken as a localized staphyloma. It thus was difficult to detect staphyloma by OCT. We additionally measured the thickness of the retina and choroid in the section running through the center of the fovea. Subfoveal choroidal thickness was defined as the vertical distance from the hyperreflective line of the Bruch’s membrane to the hyperreflective line of the inner surface of the sclera. All measurements were performed using the Heidelberg Eye Explorer software (version 5.3.3.0; Heidelberg Engineering Co.). The images were obtained by a technician (C.X.C.) and the images were examined by a retinal specialist (X.Y.P.) and retinal fellow (Q.S.Y.). In case of doubt, the images were reexamined by a panel of ophthalmologists (Q.S.Y., J.B.J., X.Y.P., and L.X.).
Statistical Analysis Statistical analysis was performed using a commercially available statistical software package (SPSS for Windows, version 20.0;
Figure 1. Optical coherence tomography images showing myopic macular changes in highly myopic eyes from the Beijing Eye Study 2011: (A) macular schisis, (B) macular hole, (C) disruption of the photoreceptor inner segment/outer segment interface (white arrow), and (D) disruption of Bruch’s membrane with collateral atrophy of the retinal pigment epithelium (between 2 white arrows).
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IBM/SPSS, Chicago, IL). In a first step, we examined the prevalence (presented as mean standard error) of each macular change. The mean values of other parameters were expressed as mean standard deviation. In a second step, we examined associations between the prevalence of OCT-defined myopic macular lesions and other ocular and systemic parameters in univariate analysis. In a third step, we performed a binary regression analysis, with the presence of a myopic macular lesion as a dependent parameter and those parameters that were associated significantly with myopic maculopathy as independent parameters. From the list of independent parameters, we dropped step by step those with the highest P value, until eventually all independent parameters showed a statistically significant association with the presence of myopic maculopathy. Odds ratios (ORs) and 95% confidence intervals (CIs) were presented. All P values were 2-sided and were considered statistically significant when they were less than 0.05.
Results Of the 3468 subjects, readable OCT images of the macula were available for 6530 eyes (94.5%) of 3278 participants (1844 women; 56.3%). The mean age was 64.39.6 years (median, 63 years; range, 50e93 years); the mean axial length was 23.21.13 mm (median, 23.1 mm; range, 18.96e30.88 mm); and the mean refractive error (spherical equivalent) was 0.182.04 D (median, 0.25 D; range, 22.0 to þ7.50 D). For 192 eyes (5.5%), OCT images either had not been obtained or the images could not be examined because of vitreous clouding or cataract. The subjects without OCT examinations of their macula, compared with the subjects with macula OCT examinations, were significantly older (70.111.2 vs. 64.39.6 years; P<0.001; 95% CI, 4.15e7.39). Both groups did not vary significantly with regard to sex (P ¼ 0.12) or refractive error (P ¼ 0.29). High myopia, defined as a spherical equivalent of less than 8.0 D or an axial length longer than 26.5 mm, was present in 126 eyes (1.90.2%) of 72 participants (2.20.3%; 95% CI, 1.7e2.7). Of these 6530 eyes with readable OCT images of the macula, 164 eyes (101 subjects) had a refractive error of 6 D or less or an axial length of 26.5 mm or more. The mean age of these highly myopic study participants was 65.18.7 years, and the mean refractive error was 8.374.51 D. The most common change in the macula was a maculoschisis, found in 54 eyes (0.8% of the entire study population), followed by an incomplete posterior vitreous detachment in 46 eyes (0.7%), disruption of the photoreceptor inner segment/outer segment interface in 39 eyes (0.6%), epiretinal membranes in 38 eyes (0.6%), macular defects in Bruch’s membrane in 24 eyes (0.3%), clumping of the retinal pigment epithelium in 11 eyes (0.2%), vitreofoveal adhesion in 10 eyes (0.2%), and macular holes in 2 eyes (0.1%; Table 1). Prevalence of any myopic maculopathy per eye was 112 cases in 6530 eyes, or 1.710.16% (95% CI, 1.40e2.03). Within the highly myopic group, the prevalence of any maculopathy per eye was 112 cases in 164 eyes, or 68.33.6 cases (95% CI, 61.5e75.9), with the highest prevalences for maculoschisis (32.9%), incomplete posterior vitreous detachment (28.0%), and disruption of the photoreceptor inner segment/outer segment interface (23.8%; Table 1). In univariate analysis, the prevalence of any myopic maculopathy was associated significantly with longer axial length (P<0.001), deeper anterior chamber depth (P<0.001), more myopic refractive error (P<0.001), higher corneal curvature/axial length ratio (P<0.001), thinner subfoveal choroidal thickness (P<0.001), larger b zone of parapapillary atrophy (P<0.001), lower best-corrected visual acuity (P<0.001), prevalence of
Table 1. Frequency of Myopic Macular Lesions as Detected by Optical Coherence Tomography in Highly Myopic Eyes in the Beijing Eye Study 2011
Lesion Retinoschisis Paravessel schisis Foveal and paravessel schisis Foveal schisis Incomplete posterior vitreous detachment Disruption of photoreceptor inner segment/outer segment interface Epiretinal membrane Macular defects in Bruch’s membrane Clumping of retinal pigment epithelium and signs of neovascular membranes Vitreofoveal adhesion Macular hole
No. (% per Eye) in the Highly Myopic Group (n [ 164)
No. (% per Eye) in the Total Study Population (n [ 6530)
54 (32.93.7) 37 (22.6) 11 (6.7)
54 (0.80.1) 37 (0.6) 11 (0.2)
6 (3.7) 46 (28.03.5)
5 (0.1) 24 (0.70.1)
39 (23.83.3)
30 (0.60.1)
38 (23.23.3) 24 (14.62.8)
38 (0.60.1) 24 (0.30.1)
11 (6.72.0)
11 (0.20.1)
10 (6.11.9) 2 (1.20.1)
10 (0.20.1) 2 (0.10.1)
glaucoma (P ¼ 0.004), higher cylindrical refractive error (P ¼ 0.03), and lower body mass index (P ¼ 0.005). It was not associated significantly with the systemic parameters of age (P ¼ 0.53), sex (P ¼ 0.77), body height (P ¼ 0.23), body weight (P ¼ 0.08), systolic blood pressure (P ¼ 0.10), diastolic blood pressure (P ¼ 0.22), blood concentration of glucose (P ¼ 0.62), glycosylated hemoglobin (P ¼ 0.39), creatinine (P ¼ 0.67), C-reactive protein (P ¼ 0.89), high-density lipoproteins (P ¼ 0.97), low-density lipoproteins (P ¼ 0.70), cholesterol (P ¼ 0.80), triglycerides (P ¼ 0.45), prevalence of diabetes mellitus (P ¼ 0.58), or cognitive function score (P ¼ 0.51), nor with the ocular parameters of central corneal thickness (P ¼ 0.63), lens thickness (P ¼ 0.052), presence of retinal vein occlusions (P ¼ 0.63), or intraocular pressure (P ¼ 0.23). The binary regression analysis included the presence of any myopic maculopathy as the dependent parameter and all those variables that were associated significantly with myopic maculopathy as independent parameters in the univariate analysis. After stepwise dropping of the presence of glaucoma (P ¼ 0.99), anterior chamber depth (P ¼ 0.80), area of parapapillary b zone (P ¼ 0.34), CC/AL ratio (P ¼ 0.86), body mass index (P ¼ 0.41), age (P ¼ 0.15), subfoveal choroidal thickness (P ¼ 0.28), and cylindrical refractive error (P ¼ 0.06), presence of myopic maculopathy was associated significantly with longer axial length (P<0.001; OR, 2.68; 95% CI, 1.97e3.64) and more myopic refractive error (P<0.001; OR, 0.63; 95% CI, 0.55e0.73). In a similar manner, myopic maculoschisis was associated with axial length (P<0.001; OR, 2.85; 95% CI, 1.89e4.30) and more myopic refractive error (P ¼ 0.009; OR, 0.80; 95% CI, 0.67e0.94), and presence of a disruption of the photoreceptor inner segment/outer segment interface was associated with longer axial length (P<0.001; OR, 4.87; 95% CI, 2.30e10.4). In a similar manner, we performed a multivariate regression analysis with best-corrected visual acuity (expressed in logarithm of the minimum angle of resolution units) as the dependent variable; age, axial length, refractive error, and cylindrical refractive error as parameters to be adjusted for; and the prevalence of all types of myopic maculopathy in the list of independent variables. As a first step, we removed refractive error from the list of independent
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Ophthalmology Volume -, Number -, Month 2013 parameters because its variance inflation factor in the analysis of collinearity was higher than 1.6. We then dropped axial length (P ¼ 0.36), presence of clumping of the retinal pigment epithelium (P ¼ 0.90), presence of maculoschisis (P ¼ 0.97), and macular defects in Bruch’s membrane (P ¼ 0.39) until eventually best-corrected visual acuity was significantly associated with the absence of a disruption of the photoreceptor inner segment/outer segment interface (P<0.001; standardized correlation coefficient b, 0.09), epiretinal membranes (P<0.001; b, 0.08), macular holes (P<0.001; b, 0.06), incomplete posterior vitreous detachment (P ¼ 0.002; b, 0.06), and presence of vitreofoveal adhesion (P ¼ 0.002) from the list and after adjustment for age and cylindrical refractive error.
Discussion Applying spectral-domain OCT for the examination of the macula in our population-based study, we found that the most common macular change in highly myopic eyes was a maculoschisis, followed by incomplete posterior vitreous detachment, disruption of the photoreceptor inner segment/ outer segment interface, epiretinal membranes, macular defects in Bruch’s membrane, clumping of the retinal pigment epithelium, vitreofoveal adhesion, and macular holes. The prevalence of any myopic maculopathy was 1.710.16% (95% CI, 1.40e2.03) within the entire study population, and it was 68.33.6% (95% CI, 61.5e75.9) within the highly myopic group. In binary regression analysis, presence of any myopic maculopathy was associated significantly with longer axial length (P<0.001) and more myopic refractive error (P ¼ 0.001). After adjustment for axial length and refractive error, it was statistically independent of age, sex, body height, weight, body mass index, arterial blood pressure, diabetes mellitus, biochemical blood examination results, central corneal thickness, ocular biometric measures (except axial length), subfoveal choroidal thickness, retinal vein occlusion, and intraocular pressure. The most important macular changes with a negative effect on best-corrected visual acuity were a disruption of the photoreceptor inner segment/outer segment interface and epiretinal membranes. These results are in agreement with previous investigations in which the same morphologic elements of myopic maculopathy were described.27e31 Continuing the previous hospital-based studies of the highly myopic macula, our investigation delivered new data on the prevalence of OCTdefined highly myopic changes in the macula and their associations or nonassociations with other ocular or systemic parameters. Our study also confirms a recent histologic study in which macular defects of Bruch’s membrane were reported.21 In that investigation, the regions with macular Bruch’s membrane defects were free of retinal pigment epithelium cells and choriocapillaris, with the photoreceptor layer markedly diminished or rudimentary and the remaining choroid containing only few large choroidal vessels. The globe in these regions consisted of a markedly thinned sclera, some melanin-bearing cells on the inner surface of the sclera (lamina fusca sclerae), and remnants of the middle and inner layers of the retina. As in our study, the presence of a macular Bruch’s membrane defect was associated strongly with axial length. The
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macular Bruch’s membrane defect in the highly myopic macula may be regarded as a second hole in Bruch’s membrane, which has a primary or physiologic hole in the region of the optic nerve head. The macular Bruch’s membrane defect as described in our study and in the recent histologic study may be added to the panoply of the features of myopic retinopathy. As recently pointed out, these include the myopic Fuchs’ spot; scleral staphylomata and lacquer cracks in the macular region, g zone, and d zone of the parapapillary region; a secondarily enlarged macrodisc; and a marked stretching and thinning of the lamina cribrosa in association with increased susceptibility for glaucomatous optic neuropathy.21 The marked changes in Bruch’s membrane in the highly myopic eyes show the involvement of the choroid in the development of high myopia. Because choroidal thickness as the distance between Bruch’s membrane and the sclera decreases with increasing myopia, one may postulate that the changes in Bruch’s membrane are more marked than the changes in the sclera because otherwise the distance between the sclera and Bruch’s membrane would have enlarged. It theoretically could point to an active role of the growth and elongation of Bruch’s membrane in the process of emmetropization and development of myopia, as was discussed recently.21 Potential limitations of our study should be mentioned. First, as in any population-based study, the rate of nonparticipation or nonavailability of examination results can matter. In our study, readable OCT images of the macula were available for 94.5% of the participants, and the original participation rate of all eligible subjects was 78.8%. These figures may be sufficient to allow conclusions on the prevalence of disorders. Second, because fluorescein angiograms were not available, the macular schisis as diagnosed on the OCT images also might have represented macular edema. Third, the OCT technology could not distinguish between a completely attached vitreous body and a complete posterior vitreous detachment. All figures presented in this study therefore relate only to an incomplete posterior vitreous detachment. Strengths of our study are that it is the first population-based investigation of OCT-defined macular changes in highly myopic eyes and that a relatively new finding, the macular Bruch’s membrane defect, is described and confirmed. In conclusion, the most common macular change as examined by OCT in highly myopic eyes was a maculoschisis, followed by incomplete posterior vitreous detachment, disruption of the photoreceptor inner segment/ outer segment interface, epiretinal membranes, macular defects in Bruch’s membrane, clumping of the retinal pigment epithelium, vitreofoveal adhesion, and macular holes. The most important macular changes with a negative effect on best-corrected visual acuity were a disruption of the photoreceptor inner segment/outer segment interface and epiretinal membranes.
References 1. Curtin BJ. The posterior staphyloma of pathologic myopia. Trans Am Ophthalmol Soc 1977;75:67–86.
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2. Klein RM, Curtin BJ. Lacquer crack lesions in pathologic myopia. Am J Ophthalmol 1975;79:386–92. 3. Steidl SM, Pruett RC. Macular complications associated with posterior staphyloma. Am J Ophthalmol 1997;123:181–7. 4. Vongphanit J, Mitchell P, Wang JJ. Prevalence and progression of myopic retinopathy in an older population. Ophthalmology 2002;109:704–11. 5. Xu L, Wang Y, Li Y, et al. Causes of blindness and visual impairment in urban and rural areas in Beijing: the Beijing Eye Study. Ophthalmology 2006;113:1134–41. 6. Liang YB, Friedman DS, Wong TY, et al; Handan Eye Study Group. Prevalence and causes of low vision and blindness in a rural Chinese adult population: the Handan Eye Study. Ophthalmology 2008;115:1965–72. 7. Hsu WM, Cheng CY, Liu JH, et al. Prevalence and causes of visual impairment in an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology 2004;111:62–9. 8. Iwase A, Araie M, Tomidokoro A, et al; Tajimi Study Group. Prevalence and causes of low vision and blindness in a Japanese adult population: the Tajimi Study. Ophthalmology 2006;113:1354–62. 9. Klaver CC, Wolfs RC, Vingerling JR, et al. Age-specific prevalence and causes of blindness and visual impairment in an older population: the Rotterdam Study. Arch Ophthalmol 1988;116:653–8. 10. Cedrone C, Culasso F, Cesareo M, et al. Incidence of blindness and low vision in a sample population: the Priverno Eye Study, Italy. Ophthalmology 2003;110:584–8. 11. Buch H, Vinding T, La Cour M, et al. Prevalence and causes of visual impairment and blindness among 9980 Scandinavian adults: the Copenhagen City Eye Study. Ophthalmology 2004;111:53–61. 12. Cotter SA, Varma R, Ying-Lai M, et al; Los Angeles Latino Eye Study Group. Causes of low vision and blindness in adult Latinos: the Los Angeles Latino Eye Study. Ophthalmology 2006;113:1574–82. 13. He M, Zeng J, Liu Y, et al. Refractive error and visual impairment in urban children in southern China. Invest Ophthalmol Vis Sci 2004;45:793–9. 14. Morgan IG, Ohno-Matsui K, Saw SM. Myopia. Lancet 2012;379:1739–48. 15. Hayashi K, Ohno-Matsui K, Shimada N, et al. Long-term pattern of progression of myopic maculopathy: a natural history study. Ophthalmology 2010;117:1595–611. 16. Liu HH, Xu L, Wang YX, et al. Prevalence and progression of myopic retinopathy in Chinese adults: the Beijing Eye Study. Ophthalmology 2010;117:1763–8. 17. Gao LQ, Liu W, Liang YB, et al. Prevalence and characteristics of myopic retinopathy in a rural Chinese adult
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population: the Handan Eye Study. Arch Ophthalmol 2011;129:1199–204. Chen SJ, Cheng CY, Li AF, et al. Prevalence and associated risk factors of myopic maculopathy in elderly Chinese: the Shihpai Eye Study. Invest Ophthalmol Vis Sci 2012;53: 4868–73. Asakuma T, Yasuda M, Ninomiya T, et al. Prevalence and risk factors for myopic retinopathy in a Japanese population: the Hisayama Study. Ophthalmology 2012;119:1760–5. Grossniklaus HE, Green WR. Pathologic findings in pathologic myopia. Retina 1992;12:127–33. Jonas JB, Ohno-Matsui K, Spaide RF, et al. Macular Bruch’s membrane defects and axial length: associated with gamma zone and delta zone in parapapillary region. Invest Ophthalmol Vis Sci 2013;54:1295–302. Hee MR, Puliafito CA, Wong C, et al. Optical coherence tomography of macular holes. Ophthalmology 1995;102: 748–56. Spaide RF, Koizumi H, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. Wei WB, Xu L, Jonas JB, et al. Subfoveal choroidal thickness: the Beijing Eye Study. Ophthalmology 2013;120:175–80. Wang YX, Xu L, Yang H, Jonas JB. Prevalence of glaucoma in North China: the Beijing Eye Study. Am J Ophthalmol 2010;150:917–24. Liu W, Xu L, Jonas JB. Vein occlusion in Chinese subjects [letter]. Ophthalmology 2007;114:1795–6. Ohno-Matsui K, Akiba M, Modegi T, et al. Association between shape of sclera and myopic retinochoroidal lesions in patients with pathologic myopia. Invest Ophthalmol Vis Sci 2012;7(53):6046–61. Maruko I, Iida T, Sugano Y, et al. Morphologic analysis in pathologic myopia using high-penetration optical coherence tomography. Invest Ophthalmol Vis Sci 2012; 53:3834–8. Ohno-Matsui K, Akiba M, Moriyama M, et al. Intrachoroidal cavitation in macular area of eyes with pathologic myopia. Am J Ophthalmol 2012;154:382–93. Leveziel N, Caillaux V, Bastuji-Garin S, et al. Angiographic and optical coherence tomography characteristics of recent myopic choroidal neovascularization. Am J Ophthalmol 2013;155:913–9. Wang NK, Lai CC, Chou CL, et al. Choroidal thickness and biometric markers for the screening of lacquer cracks in patients with high myopia. PLoS One [serial online] 2013;8: e53660. Available at: http://www.plosone.org/article/info% 3Adoi%2F10.1371%2Fjournal.pone.0053660. Accessed May 27, 2013.
Footnotes and Financial Disclosures Originally received: February 26, 2013. Final revision: April 24, 2013. Accepted: June 6, 2013. Available online: ---.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2013-312.
1
Supported by the State Natural Sciences Fund, Beijing, China (grant no.: 81170890); and the Beijing Nova Program, Beijing, China (grant no.: 2010B032).
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Correspondence: Prof. Xiao Yan Peng, Prof. Liang Xu, Beijing Institute of Ophthalmology, 17 Hougou Lane, Chong Wen Men, 100005 Beijing, China. E-mail: [email protected].
Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing, China. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
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Myopic retinopathy is characterized by changes in the macular region, including staphylomata, lacquer cracks, Fuchs’ spot, chorioretinal atrophy, and secondary defects in Bruch’s membrane.1e4 It has been recognized as one of the leading causes of irreversible visual impairment and blindness worldwide. It was the second most common cause of low vision and blindness in the Handan Eye Study and Beijing Eye Study in mainland China and in the Shihpai Eye Study in Taiwan, and the second most common cause of blindness and third most common cause of low vision in the Tajimi Study in Japan.5e8 In white populations in Western countries and in Hispanics, myopic retinopathy was the second to fourth most frequent cause of blindness.9e12 Because the myopic shift in the metropolitan regions at the Pacific rim so far has affected mostly the relatively 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
young generations in which the vision-reducing effect of pathologic myopia has not yet become fully effective, it can be expected that the role of myopic retinopathy as a cause of visual impairment and blindness will increase in the near future.13,14 Previous studies have addressed the prevalence, incidence, and natural course of myopic retinopathy in population-based studies using fundus photographs, and studies have addressed the histologic features of myopic maculopathy.2,4,15e21 Spectral-domain optical coherence tomography (OCT) has further expanded the panoply of diagnostic procedures to examine the myopic macula.22,23 Because there have been no data available on the prevalence of OCT-defined changes in myopic maculopathy and because, in particular, there have been no OCT-based studies on the highly myopic macula considering new ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.06.013
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Ophthalmology Volume -, Number -, Month 2013 findings of the histologic features of myopic maculopathy, we performed this study. We investigated the frequency of OCT abnormalities in the macular region of highly myopic eyes, defined as a myopic refractive error of more than 6 diopters (D) or an axial length of more than 26.5 mm, and examined their associations with other ocular and systemic parameters. The findings may be helpful for the OCT-based definition and differentiation of highly myopic changes in the macula, increase the knowledge about the prevalence of these detailed changes in the general population, and give hints for risk factors by analyzing factors associated with the myopic maculopathy.
Patients and Methods The Beijing Eye Study 2011 is a population-based, cross-sectional study in Northern China and has been described in detail previously.5,16,24 The Medical Ethics Committee of the Beijing Tongren Hospital approved the study protocol, and all participants gave informed consent. The only eligibility criterion for inclusion into the study was an age of 50 years or more. Of a total eligible population of 4403 individuals, 3468 (1963 women; 56.6%) participated (response rate, 78.8%). The study was divided into a rural part (1633 subjects [47.1%]; 943 women [57.7%]) and an urban part (1835 subjects [52.9%]; 1020 women [55.6%]). The mean age was 64.69.8 years (median, 64 years; range, 50e93 years). All study participants underwent an interview with standardized questions regarding their family status, level of education, physical activity, and known major systemic diseases. Body height and weight were recorded. Blood pressure was measured, and fasting blood samples were examined for the concentration of blood lipids, glucose, glycosylated hemoglobin, creatinine, and C-reactive protein. The ophthalmic examination included measurement of presenting visual acuity, uncorrected visual acuity, and best-corrected visual acuity; tonometry; slit-lamp examination of the anterior and posterior segments of the eye; and digital photography the cornea, lens, macula, and optic disc (fundus camera type CR6-45NM; Canon, Inc., Tokyo, Japan). Pseudoexfoliation of the lens was searched for by slit-lamp biomicroscopy after medical pupillary dilatation. Spectral-domain OCT (wavelength, 870 nm; Spectralis; Heidelberg
Engineering Co., Heidelberg, Germany) with the enhanced depth imaging mode was performed after pupil dilation.23,24 Thirty-one sections were obtained, which covered a 30 30 large rectangle centered onto the fovea. Using the enhanced depth imaging mode, 7 additional sections (each comprising 100 averaged scans) were obtained in a 530 large rectangle centered onto the fovea. Biometry for measurement of the anterior corneal curvature, central corneal thickness, anterior chamber depth, lens thickness, and axial length (optical low-coherence reflectometry; Lensstar 900 Optical Biometer; Haag-Streit, Koeniz, Switzerland) was carried out in the right eyes of the study participants. Using fundus photographs, we also assessed the presence of retinal vein occlusions, diabetic retinopathy, and glaucomatous optic neuropathy, as defined and described in detail previously.25,26 All OCT sections of all highly myopic eyes, defined as a myopic refractive error of more than 6 D or an axial length of more than 26.5 mm, were examined for epiretinal membranes, vitreofoveal adhesion, incomplete posterior vitreous detachment, retinoschisis, macular holes, disruption of the photoreceptor inner segment/outer segment interface, changes in Bruch’s membrane such as disruption, and clumping of the retinal pigment epithelium (Fig 1). Presence of staphylomata was not examined because an enlargement of emissary openings within a region with macular atrophy, sometimes accompanied by a dehiscence of the entire scleral thickness, could be mistaken as a localized staphyloma. It thus was difficult to detect staphyloma by OCT. We additionally measured the thickness of the retina and choroid in the section running through the center of the fovea. Subfoveal choroidal thickness was defined as the vertical distance from the hyperreflective line of the Bruch’s membrane to the hyperreflective line of the inner surface of the sclera. All measurements were performed using the Heidelberg Eye Explorer software (version 5.3.3.0; Heidelberg Engineering Co.). The images were obtained by a technician (C.X.C.) and the images were examined by a retinal specialist (X.Y.P.) and retinal fellow (Q.S.Y.). In case of doubt, the images were reexamined by a panel of ophthalmologists (Q.S.Y., J.B.J., X.Y.P., and L.X.).
Statistical Analysis Statistical analysis was performed using a commercially available statistical software package (SPSS for Windows, version 20.0;
Figure 1. Optical coherence tomography images showing myopic macular changes in highly myopic eyes from the Beijing Eye Study 2011: (A) macular schisis, (B) macular hole, (C) disruption of the photoreceptor inner segment/outer segment interface (white arrow), and (D) disruption of Bruch’s membrane with collateral atrophy of the retinal pigment epithelium (between 2 white arrows).
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IBM/SPSS, Chicago, IL). In a first step, we examined the prevalence (presented as mean standard error) of each macular change. The mean values of other parameters were expressed as mean standard deviation. In a second step, we examined associations between the prevalence of OCT-defined myopic macular lesions and other ocular and systemic parameters in univariate analysis. In a third step, we performed a binary regression analysis, with the presence of a myopic macular lesion as a dependent parameter and those parameters that were associated significantly with myopic maculopathy as independent parameters. From the list of independent parameters, we dropped step by step those with the highest P value, until eventually all independent parameters showed a statistically significant association with the presence of myopic maculopathy. Odds ratios (ORs) and 95% confidence intervals (CIs) were presented. All P values were 2-sided and were considered statistically significant when they were less than 0.05.
Results Of the 3468 subjects, readable OCT images of the macula were available for 6530 eyes (94.5%) of 3278 participants (1844 women; 56.3%). The mean age was 64.39.6 years (median, 63 years; range, 50e93 years); the mean axial length was 23.21.13 mm (median, 23.1 mm; range, 18.96e30.88 mm); and the mean refractive error (spherical equivalent) was 0.182.04 D (median, 0.25 D; range, 22.0 to þ7.50 D). For 192 eyes (5.5%), OCT images either had not been obtained or the images could not be examined because of vitreous clouding or cataract. The subjects without OCT examinations of their macula, compared with the subjects with macula OCT examinations, were significantly older (70.111.2 vs. 64.39.6 years; P<0.001; 95% CI, 4.15e7.39). Both groups did not vary significantly with regard to sex (P ¼ 0.12) or refractive error (P ¼ 0.29). High myopia, defined as a spherical equivalent of less than 8.0 D or an axial length longer than 26.5 mm, was present in 126 eyes (1.90.2%) of 72 participants (2.20.3%; 95% CI, 1.7e2.7). Of these 6530 eyes with readable OCT images of the macula, 164 eyes (101 subjects) had a refractive error of 6 D or less or an axial length of 26.5 mm or more. The mean age of these highly myopic study participants was 65.18.7 years, and the mean refractive error was 8.374.51 D. The most common change in the macula was a maculoschisis, found in 54 eyes (0.8% of the entire study population), followed by an incomplete posterior vitreous detachment in 46 eyes (0.7%), disruption of the photoreceptor inner segment/outer segment interface in 39 eyes (0.6%), epiretinal membranes in 38 eyes (0.6%), macular defects in Bruch’s membrane in 24 eyes (0.3%), clumping of the retinal pigment epithelium in 11 eyes (0.2%), vitreofoveal adhesion in 10 eyes (0.2%), and macular holes in 2 eyes (0.1%; Table 1). Prevalence of any myopic maculopathy per eye was 112 cases in 6530 eyes, or 1.710.16% (95% CI, 1.40e2.03). Within the highly myopic group, the prevalence of any maculopathy per eye was 112 cases in 164 eyes, or 68.33.6 cases (95% CI, 61.5e75.9), with the highest prevalences for maculoschisis (32.9%), incomplete posterior vitreous detachment (28.0%), and disruption of the photoreceptor inner segment/outer segment interface (23.8%; Table 1). In univariate analysis, the prevalence of any myopic maculopathy was associated significantly with longer axial length (P<0.001), deeper anterior chamber depth (P<0.001), more myopic refractive error (P<0.001), higher corneal curvature/axial length ratio (P<0.001), thinner subfoveal choroidal thickness (P<0.001), larger b zone of parapapillary atrophy (P<0.001), lower best-corrected visual acuity (P<0.001), prevalence of
Table 1. Frequency of Myopic Macular Lesions as Detected by Optical Coherence Tomography in Highly Myopic Eyes in the Beijing Eye Study 2011
Lesion Retinoschisis Paravessel schisis Foveal and paravessel schisis Foveal schisis Incomplete posterior vitreous detachment Disruption of photoreceptor inner segment/outer segment interface Epiretinal membrane Macular defects in Bruch’s membrane Clumping of retinal pigment epithelium and signs of neovascular membranes Vitreofoveal adhesion Macular hole
No. (% per Eye) in the Highly Myopic Group (n [ 164)
No. (% per Eye) in the Total Study Population (n [ 6530)
54 (32.93.7) 37 (22.6) 11 (6.7)
54 (0.80.1) 37 (0.6) 11 (0.2)
6 (3.7) 46 (28.03.5)
5 (0.1) 24 (0.70.1)
39 (23.83.3)
30 (0.60.1)
38 (23.23.3) 24 (14.62.8)
38 (0.60.1) 24 (0.30.1)
11 (6.72.0)
11 (0.20.1)
10 (6.11.9) 2 (1.20.1)
10 (0.20.1) 2 (0.10.1)
glaucoma (P ¼ 0.004), higher cylindrical refractive error (P ¼ 0.03), and lower body mass index (P ¼ 0.005). It was not associated significantly with the systemic parameters of age (P ¼ 0.53), sex (P ¼ 0.77), body height (P ¼ 0.23), body weight (P ¼ 0.08), systolic blood pressure (P ¼ 0.10), diastolic blood pressure (P ¼ 0.22), blood concentration of glucose (P ¼ 0.62), glycosylated hemoglobin (P ¼ 0.39), creatinine (P ¼ 0.67), C-reactive protein (P ¼ 0.89), high-density lipoproteins (P ¼ 0.97), low-density lipoproteins (P ¼ 0.70), cholesterol (P ¼ 0.80), triglycerides (P ¼ 0.45), prevalence of diabetes mellitus (P ¼ 0.58), or cognitive function score (P ¼ 0.51), nor with the ocular parameters of central corneal thickness (P ¼ 0.63), lens thickness (P ¼ 0.052), presence of retinal vein occlusions (P ¼ 0.63), or intraocular pressure (P ¼ 0.23). The binary regression analysis included the presence of any myopic maculopathy as the dependent parameter and all those variables that were associated significantly with myopic maculopathy as independent parameters in the univariate analysis. After stepwise dropping of the presence of glaucoma (P ¼ 0.99), anterior chamber depth (P ¼ 0.80), area of parapapillary b zone (P ¼ 0.34), CC/AL ratio (P ¼ 0.86), body mass index (P ¼ 0.41), age (P ¼ 0.15), subfoveal choroidal thickness (P ¼ 0.28), and cylindrical refractive error (P ¼ 0.06), presence of myopic maculopathy was associated significantly with longer axial length (P<0.001; OR, 2.68; 95% CI, 1.97e3.64) and more myopic refractive error (P<0.001; OR, 0.63; 95% CI, 0.55e0.73). In a similar manner, myopic maculoschisis was associated with axial length (P<0.001; OR, 2.85; 95% CI, 1.89e4.30) and more myopic refractive error (P ¼ 0.009; OR, 0.80; 95% CI, 0.67e0.94), and presence of a disruption of the photoreceptor inner segment/outer segment interface was associated with longer axial length (P<0.001; OR, 4.87; 95% CI, 2.30e10.4). In a similar manner, we performed a multivariate regression analysis with best-corrected visual acuity (expressed in logarithm of the minimum angle of resolution units) as the dependent variable; age, axial length, refractive error, and cylindrical refractive error as parameters to be adjusted for; and the prevalence of all types of myopic maculopathy in the list of independent variables. As a first step, we removed refractive error from the list of independent
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Ophthalmology Volume -, Number -, Month 2013 parameters because its variance inflation factor in the analysis of collinearity was higher than 1.6. We then dropped axial length (P ¼ 0.36), presence of clumping of the retinal pigment epithelium (P ¼ 0.90), presence of maculoschisis (P ¼ 0.97), and macular defects in Bruch’s membrane (P ¼ 0.39) until eventually best-corrected visual acuity was significantly associated with the absence of a disruption of the photoreceptor inner segment/outer segment interface (P<0.001; standardized correlation coefficient b, 0.09), epiretinal membranes (P<0.001; b, 0.08), macular holes (P<0.001; b, 0.06), incomplete posterior vitreous detachment (P ¼ 0.002; b, 0.06), and presence of vitreofoveal adhesion (P ¼ 0.002) from the list and after adjustment for age and cylindrical refractive error.
Discussion Applying spectral-domain OCT for the examination of the macula in our population-based study, we found that the most common macular change in highly myopic eyes was a maculoschisis, followed by incomplete posterior vitreous detachment, disruption of the photoreceptor inner segment/ outer segment interface, epiretinal membranes, macular defects in Bruch’s membrane, clumping of the retinal pigment epithelium, vitreofoveal adhesion, and macular holes. The prevalence of any myopic maculopathy was 1.710.16% (95% CI, 1.40e2.03) within the entire study population, and it was 68.33.6% (95% CI, 61.5e75.9) within the highly myopic group. In binary regression analysis, presence of any myopic maculopathy was associated significantly with longer axial length (P<0.001) and more myopic refractive error (P ¼ 0.001). After adjustment for axial length and refractive error, it was statistically independent of age, sex, body height, weight, body mass index, arterial blood pressure, diabetes mellitus, biochemical blood examination results, central corneal thickness, ocular biometric measures (except axial length), subfoveal choroidal thickness, retinal vein occlusion, and intraocular pressure. The most important macular changes with a negative effect on best-corrected visual acuity were a disruption of the photoreceptor inner segment/outer segment interface and epiretinal membranes. These results are in agreement with previous investigations in which the same morphologic elements of myopic maculopathy were described.27e31 Continuing the previous hospital-based studies of the highly myopic macula, our investigation delivered new data on the prevalence of OCTdefined highly myopic changes in the macula and their associations or nonassociations with other ocular or systemic parameters. Our study also confirms a recent histologic study in which macular defects of Bruch’s membrane were reported.21 In that investigation, the regions with macular Bruch’s membrane defects were free of retinal pigment epithelium cells and choriocapillaris, with the photoreceptor layer markedly diminished or rudimentary and the remaining choroid containing only few large choroidal vessels. The globe in these regions consisted of a markedly thinned sclera, some melanin-bearing cells on the inner surface of the sclera (lamina fusca sclerae), and remnants of the middle and inner layers of the retina. As in our study, the presence of a macular Bruch’s membrane defect was associated strongly with axial length. The
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macular Bruch’s membrane defect in the highly myopic macula may be regarded as a second hole in Bruch’s membrane, which has a primary or physiologic hole in the region of the optic nerve head. The macular Bruch’s membrane defect as described in our study and in the recent histologic study may be added to the panoply of the features of myopic retinopathy. As recently pointed out, these include the myopic Fuchs’ spot; scleral staphylomata and lacquer cracks in the macular region, g zone, and d zone of the parapapillary region; a secondarily enlarged macrodisc; and a marked stretching and thinning of the lamina cribrosa in association with increased susceptibility for glaucomatous optic neuropathy.21 The marked changes in Bruch’s membrane in the highly myopic eyes show the involvement of the choroid in the development of high myopia. Because choroidal thickness as the distance between Bruch’s membrane and the sclera decreases with increasing myopia, one may postulate that the changes in Bruch’s membrane are more marked than the changes in the sclera because otherwise the distance between the sclera and Bruch’s membrane would have enlarged. It theoretically could point to an active role of the growth and elongation of Bruch’s membrane in the process of emmetropization and development of myopia, as was discussed recently.21 Potential limitations of our study should be mentioned. First, as in any population-based study, the rate of nonparticipation or nonavailability of examination results can matter. In our study, readable OCT images of the macula were available for 94.5% of the participants, and the original participation rate of all eligible subjects was 78.8%. These figures may be sufficient to allow conclusions on the prevalence of disorders. Second, because fluorescein angiograms were not available, the macular schisis as diagnosed on the OCT images also might have represented macular edema. Third, the OCT technology could not distinguish between a completely attached vitreous body and a complete posterior vitreous detachment. All figures presented in this study therefore relate only to an incomplete posterior vitreous detachment. Strengths of our study are that it is the first population-based investigation of OCT-defined macular changes in highly myopic eyes and that a relatively new finding, the macular Bruch’s membrane defect, is described and confirmed. In conclusion, the most common macular change as examined by OCT in highly myopic eyes was a maculoschisis, followed by incomplete posterior vitreous detachment, disruption of the photoreceptor inner segment/ outer segment interface, epiretinal membranes, macular defects in Bruch’s membrane, clumping of the retinal pigment epithelium, vitreofoveal adhesion, and macular holes. The most important macular changes with a negative effect on best-corrected visual acuity were a disruption of the photoreceptor inner segment/outer segment interface and epiretinal membranes.
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Footnotes and Financial Disclosures Originally received: February 26, 2013. Final revision: April 24, 2013. Accepted: June 6, 2013. Available online: ---.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2013-312.
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Supported by the State Natural Sciences Fund, Beijing, China (grant no.: 81170890); and the Beijing Nova Program, Beijing, China (grant no.: 2010B032).
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Correspondence: Prof. Xiao Yan Peng, Prof. Liang Xu, Beijing Institute of Ophthalmology, 17 Hougou Lane, Chong Wen Men, 100005 Beijing, China. E-mail: [email protected].
Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing, China. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
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