- Email: [email protected]
Therapeutic effect of atropine 1% in children with low myopia
Major Article Therapeutic effect of atropine 1% in children with low myopia Shu Yi, MM,a Yuanshuai Huang, MD,b Shi-Zhi Yu, MB,a Xi-Jia Chen, MB,a Hong Yi, MB,a and Xiao-Li Zeng, MBa PURPOSE
To evaluate the efficacy of topical atropine 1% in promoting unaided visual acuity, reducing myopia, and slowing the progression of ocular axial elongation in Chinese children with low myopia.
METHODS
Children with low myopia were randomly assigned to one of two groups, receiving either atropine 1% (treatment group) or placebo eyedrops (control group) once nightly for 1 year. After instillation of 3 drops of cyclopentolate 1%, unaided visual acuity, cycloplegic refraction, and ocular axial length were tested and recorded at baseline (2 weeks after atropine or vehicle eyedrops), 3 months, 6 months, 9 months, and 1 year.
RESULTS
A total of 132 children 7-12 years of age with a refractive error of spherical equivalent 0.50 D to 2.00 were included. After 1 year, the mean unaided visual acuity in the treatment group was 0.31 0.16 logMAR; in the control group, 0.66 0.15 logMAR, (P \ 0.0001). After treatment for 1 year, there was a decrease of 0.32 0.22 D from baseline in the treatment group and an increase of 0.85 0.31 D in the control group (P \ 0.0001). The axial elongation in the treatment group was 0.03 0.07 mm; in the control group, 0.32 0.15 mm (P \ 0.0001).
CONCLUSIONS
In this study cohort, topical atropine1% reduced the degree of low myopia and slowed the progression of ocular axial elongation in children. ( J AAPOS 2015;-:1-5)
T
he prevalence of myopia in China is increasing and has become an important public health problem.1-3 In China, the prevalence of all myopia is 27% in primary school students and as high as 73% in high-school students. Studies have shown that myopia progresses faster in children when myopia occurs at a younger age.4-6 Early-onset myopia in childhood is associated with high myopia (. 6 D) in adult life.7 High myopia is associated with increased risk of several ocular diseases, including retinal break, retinal detachment, macular degeneration, choroidal neovascularization, and glaucoma, which adversely affect vision and are often irreversible.8-11 Recent clinical trials using progressive addition lenses or rigid gas-permeable contact lenses to halt or slow progression of myopia have had disappointing results or positive results of marginal clinical significance.12-14 To date, only topical atropine, a nonselective muscarinic antagonist, has been demonstrated through randomized
Author affiliations: aThe Third People’s Hospital of Chongqing City, China; bThe Affiliated Hospital of Luzhou Medical College, China Submitted August 23, 2014. Revision accepted April 26, 2015. Correspondence: Xiao-Li Zeng, MB, 104# Piba Shan Zheng Jie, Yuzhong Qu, Chongqing China, 400014 (email: [email protected]). Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.04.006
Journal of AAPOS
trials to have some clinical effect on the progression of myopia.15-17 However, the participants of these atropine studies were children with refractive error of spherical equivalent between 1.00 D and 6.00 D. There are few reports of medical interventions to prevent or reduce the progression of low myopia. The purpose of this study was to evaluate whether topical atropine administered over a period of 1 year can reduce the degree of low myopia in children.
Subjects and Methods Patients seen at the Third People’s Hospital of Chongqing City, Chongqing, China, between January 2012 and October 2012 were recruited. Inclusion criteria were as follows: (1) spherical equivalent of refractive status range of 0.50 to 2.00 D in both eyes as measured by cycloplegic autorefraction; (2) normal binocular function and stereopsis; (3) normal intraocular pressure (IOP) of\21 mm Hg; (4) willingness and ability to tolerate cycloplegia and mydriasis. Patients meeting any of the following criteria were excluded: (1) astigmatism . 1.00 D; (2) children with other combined ocular diseases, such as amblyopia, strabismus, congenital cataract, glaucoma, corneal scar, optic neuropathy, traumatic ocular injury, uveitis, or ocular tumor; (3) history of any ocular surgery; (4) any systemic diseases or conditions that could affect visual function and development, including diabetes mellitus and/or chromosome anomaly; (5) previous or current use of contact lenses, bifocals, progressive addition lenses,
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or other forms of treatment (including atropine) for myopia. Power analysis was performed to justify the number of patients enrolled in the study. Every child gave assent, and written informed consent was obtained from their parents or legal guardians after thorough explanation of the nature and risks of the study before enrollment. Overall study performance and child safety were reviewed and approved by the independent institutional data and safety monitoring committee. This randomized and placebo-controlled trial study was performed according to the guidelines from Ethics Committee of Chongqing Medical University, which abides by the Helsinki Declaration on ethical principles for medical research involving human subjects. Participants were randomized to one of two groups, receiving either atropine 1% (treatment group) or vehicle eyedrops (control group) once nightly for 1 year in both eyes. The vehicle eyedrops (Tears Naturale Free; Alcon, Fort Worth, TX) consisted of hypromellose 2910, dextran 70, and glycerol. Trial medications were prepacked so that bottles were prelabeled with subject number and of similar appearance. After assessment at the time of recruitment, children were reassessed 2 weeks after starting atropine or vehicle eyedrops (baseline) and then at 3, 6, 9, and 12 months. At each visit, subjects were given 3 drops of cyclopentolate 1% at 5 minute intervals 30 minutes before examinations. Unaided distance visual acuity was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart and converted to logarithm of the minimum angle of resolution (logMAR). The spherical equivalent of refractive status was obtained by autorefractor (KR-7000/8100; Topcon, Tokyo, Japan). Five readings, all of which had to be \0.25 D apart, were obtained and averaged. After cycloplegic refraction, axial length was measured by contact A-scan ultrasonography using the Nidek US-800 EchoScan (Nidek Co. Ltd, Tokyo, Japan). Six readings, with a maximum– minimum deviation of #0.10 mm were taken and averaged. Adverse events of atropine use were recorded based on interrogation and examination. Best-corrected visual acuities were obtained using the ETDRS chart, and IOPs were obtained via noncontact tonometry. Ophthalmoscopy, slit-lamp biomicroscopy, and fundus examination with optical coherence tomography were also performed. To minimize observational bias, both pupils of every child were dilated fully and checked by nurses before being examined by the study investigators, who were kept masked to the assigned trial medications. To aid compliance with the trial medications, each child was given a small calendar to tick off the days when the eyedrops were used. Children were also offered photochromatic glasses (which darken on exposure to ultraviolet or sunlight) if they experienced glare or their parents were worried about excessive light exposure, or progressive glasses (reading add) if children experienced difficulty with near vision. Because a hyperopic shift may occur after atropine administration, myopic progression was calculated from the baseline, after children had been on the trial medication for 2 weeks.
Statistical Analysis The data of the right eye were used for further statistical analysis. All statistical analyses were based on the intention-to-treat prin-
Table 1. Baseline demographic characteristics Characteristic
Treatment group (n 5 68)
Control group (n 5 64)
P value
Male/female Age Unaided VA Initial SER, D Axial length
30/38 9.91 1.36 0.43 0.11 1.23 0.32 23.75 0.12
35/29 9.72 1.40 0.40 0.10 1.15 0.30 23.72 0.12
0.23 0.42 0.34 0.27 0.43
D, diopter; SER, spherical equivalent refraction; VA, visual acuity.
FIG 1. Mean distance unaided visual acuity change from baseline. ciple and performed using SAS software version 9.13 (Cary, NC). For continuous variables, such as unaided visual acuity, spherical equivalent refraction and axial length, analysis of variance of repeated measure data was used to determine the statistical significance of the between-group differences. The c2 test was used to compare the categorical variables.
Results Between January 2012 and October 2012, 140 children were enrolled in the study, with equal randomization for the treatment and the control groups. A total of 132 subjects completed this 1-year study; 8 subjects withdrew on their own accord: 6 (8%) from the treatment group and 2 (3%) from the control group (P 5 0.31). At baseline, there were no significant differences between the groups in mean age, sex, unaided visual acuity, refractive status, and axial length (Table 1). After 1 year, mean distance unaided visual acuity (logMAR) in the treatment group was 0.31 0.16 and in the control group, 0.66 0.15 (P \ 0.0001; Figure 1). Mean myopia in the treatment group was 0.91 0.45 D, but in the control group it was 2.00 0.54 D (P \ 0.0001; Figure 2). The mean progression of myopia in the control group was 0.85 0.31 D. In the atropine group there was a reduction of myopia by 0.32 0.22 D. After 1 year, the mean axial length in the treatment group was 23.71 0.15 mm; in the control group, 24.05 0.33 mm (P \ 0.0001; Figure 3). The mean axial elongation in the control group was 0.32 0.15 mm, but in the treatment group the axial length remained unchanged compared to baseline
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FIG 3. Mean axial length change from baseline. FIG 2. Mean spherical equivalent change from baseline.
( 0.03 0.07 mm, P 5 0.11). The difference between groups in myopia progression was 1.17 D (P \ 0.0001); in axial elongation, 0.35 mm (P \ 0.0001). No patients complained of itching and distention of eyes, ocular redness, or foreign body sensation, and so forth. During this trial, there was no deterioration in best-corrected visual acuity in either group. There were no changes observed in IOPs, crystalline lenses, optics disk, or macula following atropine administration.
Discussion Atropine is a nonspecific muscarinic receptor antagonist. To date, it is uncertain how atropine acts to retard progression of myopia and axial elongation, likely the cause of myopia.18 Initially, atropine was used based on the putative role of excessive accommodation in causing myopia. Subsequent studies have shown that atropine also inhibits myopia in animals (eg, chickens) that have no accommodative facility. Arumugam and McBrien19 hypothesized that atropine’s anti-myopia effect was based on a retinal site of action: muscarinic antagonist control of myopia is mediated via M1 and M4 muscarinic receptors. Muscarinic antagonist control of myopia has also been linked with the sclera.20 Unanswered questions remain as to the full signaling pathway by which atropine prevents axial myopia in humans and animal models. The prevention of myopia progression may reduce the threat of visual complications associated with high myopia in later life. Therefore, delaying the onset of myopia and initiating intervention to stop or retard myopia progression from childhood to adolescence are important goals. In the present study a once nightly instillation of atropine 1% achieved a reduction in the progression of low-level childhood myopia that was both statistically and clinically significant. A number of studies have evaluated the efficacy of atropine in preventing the progression of childhood myopia. To date, atropine eyedrops are still the only treatment demonstrated to have a consistent effect on the retardation of myopia progression.21-24 Although there have been multiple reports about the effect of atropine in the
Journal of AAPOS
treatment of myopia progression, most studies include moderate or high myopic or premyopic patients. To our knowledge, the present report is the first to show atropine 1% effectively retarding early myopia: 93% of patients in the treatment group had reduction in myopia and experienced an improvement in uncorrected distance visual acuity. In the present study, we chose to test myopia of 0.50 D to 2.00 D. After 1 year of atropine treatment, there was a reduction of myopia by 0.32 0.22 D. In the study by Fang and colleagues,22 although the participants’ spherical refraction was 0.31 0.45 D, there was a slight increase in the spherical refraction of atropine-treated subjects. We believe that the this result could be explained by the low concentration of atropine (0.025%)—perhaps too low to develop the full effect. To avoid the phenomenon of pseudomyopia, the baseline assessment took place 2 weeks after treatment began. The mild hyperopic shift after atropine treatment might be due to a stronger cycloplegic response and persistent inhibition of myopic shift by long-term atropine use. In our study, myopia declined in most cases, while there was no response to atropine in a few cases. Many factors might explain heterogeneous drug response, including genetics, environmental exposures, disease severity, amplitude of accommodation, and participation in outdoor activities.25-27 More studies are needed to elucidate this issue. After 1 year, uncorrected distance visual acuity in 35 patients among 68 in the atropine group was #0.3 (20/ 40). These patients should be able to see clearly without glasses for most tasks. In the control group, by contrast, all the patients would likely need spectacle correction for distance vision. In China, many parents do not want their children to wear glasses at the onset of myopia, and atropine could prove a good treatment for early myopia. No study of the effect of atropine on myopia has followed subjects for more than 5 years. Yet as children grow older, compliance with treatment declined, perhaps as a result of increased pressure to study. Spectacle correction may be required in such cases, but atropine treatment could reduce the degree of final myopia. Recently, Tong and colleagues16 reported that rebound myopia progression was noticed after 2 years of 1%
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atropine treatment; he concluded that the absolute myopia progression after 3 years was nevertheless significantly lower. In our study, there was a reduction of myopia in the treatment group. Moreover, there was essentially no change in mean axial length compared with a mean increase of approximately 0.32 mm in the control group. These results support the observation that progression of myopia was significantly correlated with an increase in axial length. Although the prevalence of myopia is increasing1-3 and has become an important public health issue in China, myopia progression in children is difficult to control, and providers do not routinely prescribe atropine to control myopia. There are potential hazards associated with atropine treatment, including potential toxicity to the retina and lens due to long-term dilation of pupils and exposure to ultraviolet light and the potential influence on body systems. Atropine treatment has been reported to be generally well tolerated, with no serious adverse effects observed.15,28,29 According to our experience, photophobia due to mydriasis is the main adverse effect, especially in summer. We therefore prescribed anti-UV sunglasses for patients with outdoor activities. Complaints of near blurring were uncommon in clinical practice, and only 7 cases were provided with near add glasses in our study. Tong and colleagues16 reported that using atropine 1% resulted in the accommodation amplitude decreasing from 13.76 D to 2.81 D.16 Theoretically, the 3 D of accommodation with low myopia might be sufficient for ordinary near work. The strength of this study was its randomized and placebo-controlled design. But there are several limitations. First, we could not make our study double-masked. We had to inform subjects about dilation and cycloplegia from atropine at the beginning. Second, the duration of atropine treatment in this study was only 1 year, so the long-term efficacy of atropine 1% for myopia control could not be determined. Third, we did not estimate the role of other confounding factors, such as parent myopia, near work time, and outdoor time.
Literature Search PubMed was searched in August 2014 without date restriction for English-language results, using the following search terms: atropine, eyedrops, low myopia, therapeutic effect, children.
Acknowledgments The authors thank Greg J. Reilly for his kind help in editing our work and Professor Bin Peng for his contribution to the statistical analysis. References 1. Zhao J, Mao J, Luo R, Li F, Munoz SR, Ellwein LB. The progression of refractive error in school-age children: Shunyi district, China. Am J Ophthalmol 2002;134:735-43. 2. Xu L, Li J, Cui T, et al. Refractive error in urban and rural adult Chinese in Beijing. Ophthalmology 2005;112:1676-83.
3. He M, Huang W, Zheng Y, Huang L, Ellwein LB. Refractive error and visual impairment in school children in rural southern China. Ophthalmology 2007;114:374-82. 4. Gwiazda J, Hyman L, Dong LM, et al. Factors associated with high myopia after 7 years of follow-up in the Correction of Myopia Evaluation Trial (COMET) Cohort. Ophthalmic Epidemiol 2007;14:230-37. 5. Saw SM, Tong L, Chua WH, et al. Incidence and progression of myopia in Singaporean school children. Invest Ophthalmol Vis Sci 2005;46:51-7. 6. Fredrick DR. Myopia. BMJ 2002;324:1195-9. 7. Liang CL, Yen E, Su JY, et al. Impact of family history of high myopia on level and onset of myopia. Invest Ophthalmol Vis Sci 2004;45: 3446-52. 8. Hsu WM, Cheng CY, Liu JH, Tsai SY, Chou P. Prevalence and causes of visual impairment in an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology 2004;111:62-9. 9. Iwase A, Araie M, Tomidokoro A, et al. Prevalence and causes of low vision and blindness in a Japanese adult population: the Tajimi Study. Ophthalmology 2006;113:1354-62. 10. 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. e1-11. 11. Saw SM. How blinding is pathological myopia? Br J Ophthalmol 2006;90:525-6. 12. Gwiazda J, Hyman L, Hussein M, et al. A randomized clinical trial of progressive addition lenses versus single vision lenses on the progression of myopia in children. Invest Ophthalmol Vis Sci 2003;44:1492-500. 13. Edwards MH, Li RW, Lam CS, Lew JK, Yu BS. The Hong Kong progressive lens myopia control study: study design and main findings. Invest Ophthalmol Vis Sci 2002;43:2852-8. 14. Katz J, Schein OD, Levy B, et al. A randomized trial of rigid gas permeable contact lenses to reduce progression of children’s myopia. Am J Ophthalmol 2003;136:82-90. 15. Chua WH, Balakrishnan V, Chan YH, et al. Atropine for the treatment of childhood myopia. Ophthalmology 2006;113:2285-91. 16. Tong L, Huang XL, Koh AL, Zhang X, Tan DT, Chua WH. Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. Ophthalmology 2009;116:572-9. 17. Chia A, Chua WH, Cheung YB, et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). Ophthalmology 2012;119:347-54. 18. McBrien NA, Stell WK, Carr B. How does atropine exert its antimyopia effects? Ophthalmic Physiol Opt 2013;33:373-8. 19. Arumugam B, McBrien NA. Muscarinic antagonist control of myopia: evidence for M4 and M1 receptor-based pathways in the inhibition of experimentally-induced axial myopia in the tree shrew. Invest Ophthalmol Vis Sci 2012;53:5827-37. 20. Gallego P, Martinez-Garcıa C, Perez-Merino P, Ibares-Frıas L, Mayo-Iscar A, Merayo-Lloves J. Scleral changes induced by atropine in chicks as an experimental model of myopia. Ophthalmic Physiol Opt 2012;32:478-84. 21. Lee JJ, Fang PC, Yang IH, et al. Prevention of myopia progression with 0.05% atropine solution. J Ocul Pharmacol Ther 2006;22:41-6. 22. Fang PC, Chung MY, Yu HJ, Wu PC. Prevention of myopia onset with 0.025% atropine in premyopic children. J Ocul Pharmacol Ther 2010;26:341-5. 23. Wu PC, Yang YH, Fang PC. The long-term results of using lowconcentration atropine eye drops for controlling myopia progression in schoolchildren. J Ocul Pharmacol Ther 2011;27:461-6. 24. Song YY, Wang H, Wang BS, Qi H, Rong ZX, Chen HZ. Atropine in ameliorating the progression of myopia in children with mild to moderate myopia: a meta-analysis of controlled clinical trials. J Ocul Pharmacol Ther 2011;27:361-8. 25. Ip JM, Rose KA, Morgan IG, Burlutsky G, Mitchell P. Myopia and the urban environment: findings in a sample of 12-year-old Australian school children. Invest Ophthalmol Vis Sci 2008;49:3858-63.
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Volume - Number - / - 2015 26. Morgan I, Rose K. How genetic is school myopia? Prog Retin Eye Res 2005;24:1-38. 27. Rose KA, Morgan IG, Ip J, et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology 2008;115: 1279-85.
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28. Chia A, Li W, Tan D, Luu CD. Full-field electroretinogram findings in children in the atropine treatment for myopia (ATOM2) study. Doc Ophthalmol 2013;126:177-86. 29. Wu TE, Yang CC, Chen HS. Does atropine use increase intraocular pressure in myopic children? Optom Vis Sci 2012;89:E161-7.
To evaluate the efficacy of topical atropine 1% in promoting unaided visual acuity, reducing myopia, and slowing the progression of ocular axial elongation in Chinese children with low myopia.
METHODS
Children with low myopia were randomly assigned to one of two groups, receiving either atropine 1% (treatment group) or placebo eyedrops (control group) once nightly for 1 year. After instillation of 3 drops of cyclopentolate 1%, unaided visual acuity, cycloplegic refraction, and ocular axial length were tested and recorded at baseline (2 weeks after atropine or vehicle eyedrops), 3 months, 6 months, 9 months, and 1 year.
RESULTS
A total of 132 children 7-12 years of age with a refractive error of spherical equivalent 0.50 D to 2.00 were included. After 1 year, the mean unaided visual acuity in the treatment group was 0.31 0.16 logMAR; in the control group, 0.66 0.15 logMAR, (P \ 0.0001). After treatment for 1 year, there was a decrease of 0.32 0.22 D from baseline in the treatment group and an increase of 0.85 0.31 D in the control group (P \ 0.0001). The axial elongation in the treatment group was 0.03 0.07 mm; in the control group, 0.32 0.15 mm (P \ 0.0001).
CONCLUSIONS
In this study cohort, topical atropine1% reduced the degree of low myopia and slowed the progression of ocular axial elongation in children. ( J AAPOS 2015;-:1-5)
T
he prevalence of myopia in China is increasing and has become an important public health problem.1-3 In China, the prevalence of all myopia is 27% in primary school students and as high as 73% in high-school students. Studies have shown that myopia progresses faster in children when myopia occurs at a younger age.4-6 Early-onset myopia in childhood is associated with high myopia (. 6 D) in adult life.7 High myopia is associated with increased risk of several ocular diseases, including retinal break, retinal detachment, macular degeneration, choroidal neovascularization, and glaucoma, which adversely affect vision and are often irreversible.8-11 Recent clinical trials using progressive addition lenses or rigid gas-permeable contact lenses to halt or slow progression of myopia have had disappointing results or positive results of marginal clinical significance.12-14 To date, only topical atropine, a nonselective muscarinic antagonist, has been demonstrated through randomized
Author affiliations: aThe Third People’s Hospital of Chongqing City, China; bThe Affiliated Hospital of Luzhou Medical College, China Submitted August 23, 2014. Revision accepted April 26, 2015. Correspondence: Xiao-Li Zeng, MB, 104# Piba Shan Zheng Jie, Yuzhong Qu, Chongqing China, 400014 (email: [email protected]). Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.04.006
Journal of AAPOS
trials to have some clinical effect on the progression of myopia.15-17 However, the participants of these atropine studies were children with refractive error of spherical equivalent between 1.00 D and 6.00 D. There are few reports of medical interventions to prevent or reduce the progression of low myopia. The purpose of this study was to evaluate whether topical atropine administered over a period of 1 year can reduce the degree of low myopia in children.
Subjects and Methods Patients seen at the Third People’s Hospital of Chongqing City, Chongqing, China, between January 2012 and October 2012 were recruited. Inclusion criteria were as follows: (1) spherical equivalent of refractive status range of 0.50 to 2.00 D in both eyes as measured by cycloplegic autorefraction; (2) normal binocular function and stereopsis; (3) normal intraocular pressure (IOP) of\21 mm Hg; (4) willingness and ability to tolerate cycloplegia and mydriasis. Patients meeting any of the following criteria were excluded: (1) astigmatism . 1.00 D; (2) children with other combined ocular diseases, such as amblyopia, strabismus, congenital cataract, glaucoma, corneal scar, optic neuropathy, traumatic ocular injury, uveitis, or ocular tumor; (3) history of any ocular surgery; (4) any systemic diseases or conditions that could affect visual function and development, including diabetes mellitus and/or chromosome anomaly; (5) previous or current use of contact lenses, bifocals, progressive addition lenses,
1
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or other forms of treatment (including atropine) for myopia. Power analysis was performed to justify the number of patients enrolled in the study. Every child gave assent, and written informed consent was obtained from their parents or legal guardians after thorough explanation of the nature and risks of the study before enrollment. Overall study performance and child safety were reviewed and approved by the independent institutional data and safety monitoring committee. This randomized and placebo-controlled trial study was performed according to the guidelines from Ethics Committee of Chongqing Medical University, which abides by the Helsinki Declaration on ethical principles for medical research involving human subjects. Participants were randomized to one of two groups, receiving either atropine 1% (treatment group) or vehicle eyedrops (control group) once nightly for 1 year in both eyes. The vehicle eyedrops (Tears Naturale Free; Alcon, Fort Worth, TX) consisted of hypromellose 2910, dextran 70, and glycerol. Trial medications were prepacked so that bottles were prelabeled with subject number and of similar appearance. After assessment at the time of recruitment, children were reassessed 2 weeks after starting atropine or vehicle eyedrops (baseline) and then at 3, 6, 9, and 12 months. At each visit, subjects were given 3 drops of cyclopentolate 1% at 5 minute intervals 30 minutes before examinations. Unaided distance visual acuity was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart and converted to logarithm of the minimum angle of resolution (logMAR). The spherical equivalent of refractive status was obtained by autorefractor (KR-7000/8100; Topcon, Tokyo, Japan). Five readings, all of which had to be \0.25 D apart, were obtained and averaged. After cycloplegic refraction, axial length was measured by contact A-scan ultrasonography using the Nidek US-800 EchoScan (Nidek Co. Ltd, Tokyo, Japan). Six readings, with a maximum– minimum deviation of #0.10 mm were taken and averaged. Adverse events of atropine use were recorded based on interrogation and examination. Best-corrected visual acuities were obtained using the ETDRS chart, and IOPs were obtained via noncontact tonometry. Ophthalmoscopy, slit-lamp biomicroscopy, and fundus examination with optical coherence tomography were also performed. To minimize observational bias, both pupils of every child were dilated fully and checked by nurses before being examined by the study investigators, who were kept masked to the assigned trial medications. To aid compliance with the trial medications, each child was given a small calendar to tick off the days when the eyedrops were used. Children were also offered photochromatic glasses (which darken on exposure to ultraviolet or sunlight) if they experienced glare or their parents were worried about excessive light exposure, or progressive glasses (reading add) if children experienced difficulty with near vision. Because a hyperopic shift may occur after atropine administration, myopic progression was calculated from the baseline, after children had been on the trial medication for 2 weeks.
Statistical Analysis The data of the right eye were used for further statistical analysis. All statistical analyses were based on the intention-to-treat prin-
Table 1. Baseline demographic characteristics Characteristic
Treatment group (n 5 68)
Control group (n 5 64)
P value
Male/female Age Unaided VA Initial SER, D Axial length
30/38 9.91 1.36 0.43 0.11 1.23 0.32 23.75 0.12
35/29 9.72 1.40 0.40 0.10 1.15 0.30 23.72 0.12
0.23 0.42 0.34 0.27 0.43
D, diopter; SER, spherical equivalent refraction; VA, visual acuity.
FIG 1. Mean distance unaided visual acuity change from baseline. ciple and performed using SAS software version 9.13 (Cary, NC). For continuous variables, such as unaided visual acuity, spherical equivalent refraction and axial length, analysis of variance of repeated measure data was used to determine the statistical significance of the between-group differences. The c2 test was used to compare the categorical variables.
Results Between January 2012 and October 2012, 140 children were enrolled in the study, with equal randomization for the treatment and the control groups. A total of 132 subjects completed this 1-year study; 8 subjects withdrew on their own accord: 6 (8%) from the treatment group and 2 (3%) from the control group (P 5 0.31). At baseline, there were no significant differences between the groups in mean age, sex, unaided visual acuity, refractive status, and axial length (Table 1). After 1 year, mean distance unaided visual acuity (logMAR) in the treatment group was 0.31 0.16 and in the control group, 0.66 0.15 (P \ 0.0001; Figure 1). Mean myopia in the treatment group was 0.91 0.45 D, but in the control group it was 2.00 0.54 D (P \ 0.0001; Figure 2). The mean progression of myopia in the control group was 0.85 0.31 D. In the atropine group there was a reduction of myopia by 0.32 0.22 D. After 1 year, the mean axial length in the treatment group was 23.71 0.15 mm; in the control group, 24.05 0.33 mm (P \ 0.0001; Figure 3). The mean axial elongation in the control group was 0.32 0.15 mm, but in the treatment group the axial length remained unchanged compared to baseline
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FIG 3. Mean axial length change from baseline. FIG 2. Mean spherical equivalent change from baseline.
( 0.03 0.07 mm, P 5 0.11). The difference between groups in myopia progression was 1.17 D (P \ 0.0001); in axial elongation, 0.35 mm (P \ 0.0001). No patients complained of itching and distention of eyes, ocular redness, or foreign body sensation, and so forth. During this trial, there was no deterioration in best-corrected visual acuity in either group. There were no changes observed in IOPs, crystalline lenses, optics disk, or macula following atropine administration.
Discussion Atropine is a nonspecific muscarinic receptor antagonist. To date, it is uncertain how atropine acts to retard progression of myopia and axial elongation, likely the cause of myopia.18 Initially, atropine was used based on the putative role of excessive accommodation in causing myopia. Subsequent studies have shown that atropine also inhibits myopia in animals (eg, chickens) that have no accommodative facility. Arumugam and McBrien19 hypothesized that atropine’s anti-myopia effect was based on a retinal site of action: muscarinic antagonist control of myopia is mediated via M1 and M4 muscarinic receptors. Muscarinic antagonist control of myopia has also been linked with the sclera.20 Unanswered questions remain as to the full signaling pathway by which atropine prevents axial myopia in humans and animal models. The prevention of myopia progression may reduce the threat of visual complications associated with high myopia in later life. Therefore, delaying the onset of myopia and initiating intervention to stop or retard myopia progression from childhood to adolescence are important goals. In the present study a once nightly instillation of atropine 1% achieved a reduction in the progression of low-level childhood myopia that was both statistically and clinically significant. A number of studies have evaluated the efficacy of atropine in preventing the progression of childhood myopia. To date, atropine eyedrops are still the only treatment demonstrated to have a consistent effect on the retardation of myopia progression.21-24 Although there have been multiple reports about the effect of atropine in the
Journal of AAPOS
treatment of myopia progression, most studies include moderate or high myopic or premyopic patients. To our knowledge, the present report is the first to show atropine 1% effectively retarding early myopia: 93% of patients in the treatment group had reduction in myopia and experienced an improvement in uncorrected distance visual acuity. In the present study, we chose to test myopia of 0.50 D to 2.00 D. After 1 year of atropine treatment, there was a reduction of myopia by 0.32 0.22 D. In the study by Fang and colleagues,22 although the participants’ spherical refraction was 0.31 0.45 D, there was a slight increase in the spherical refraction of atropine-treated subjects. We believe that the this result could be explained by the low concentration of atropine (0.025%)—perhaps too low to develop the full effect. To avoid the phenomenon of pseudomyopia, the baseline assessment took place 2 weeks after treatment began. The mild hyperopic shift after atropine treatment might be due to a stronger cycloplegic response and persistent inhibition of myopic shift by long-term atropine use. In our study, myopia declined in most cases, while there was no response to atropine in a few cases. Many factors might explain heterogeneous drug response, including genetics, environmental exposures, disease severity, amplitude of accommodation, and participation in outdoor activities.25-27 More studies are needed to elucidate this issue. After 1 year, uncorrected distance visual acuity in 35 patients among 68 in the atropine group was #0.3 (20/ 40). These patients should be able to see clearly without glasses for most tasks. In the control group, by contrast, all the patients would likely need spectacle correction for distance vision. In China, many parents do not want their children to wear glasses at the onset of myopia, and atropine could prove a good treatment for early myopia. No study of the effect of atropine on myopia has followed subjects for more than 5 years. Yet as children grow older, compliance with treatment declined, perhaps as a result of increased pressure to study. Spectacle correction may be required in such cases, but atropine treatment could reduce the degree of final myopia. Recently, Tong and colleagues16 reported that rebound myopia progression was noticed after 2 years of 1%
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atropine treatment; he concluded that the absolute myopia progression after 3 years was nevertheless significantly lower. In our study, there was a reduction of myopia in the treatment group. Moreover, there was essentially no change in mean axial length compared with a mean increase of approximately 0.32 mm in the control group. These results support the observation that progression of myopia was significantly correlated with an increase in axial length. Although the prevalence of myopia is increasing1-3 and has become an important public health issue in China, myopia progression in children is difficult to control, and providers do not routinely prescribe atropine to control myopia. There are potential hazards associated with atropine treatment, including potential toxicity to the retina and lens due to long-term dilation of pupils and exposure to ultraviolet light and the potential influence on body systems. Atropine treatment has been reported to be generally well tolerated, with no serious adverse effects observed.15,28,29 According to our experience, photophobia due to mydriasis is the main adverse effect, especially in summer. We therefore prescribed anti-UV sunglasses for patients with outdoor activities. Complaints of near blurring were uncommon in clinical practice, and only 7 cases were provided with near add glasses in our study. Tong and colleagues16 reported that using atropine 1% resulted in the accommodation amplitude decreasing from 13.76 D to 2.81 D.16 Theoretically, the 3 D of accommodation with low myopia might be sufficient for ordinary near work. The strength of this study was its randomized and placebo-controlled design. But there are several limitations. First, we could not make our study double-masked. We had to inform subjects about dilation and cycloplegia from atropine at the beginning. Second, the duration of atropine treatment in this study was only 1 year, so the long-term efficacy of atropine 1% for myopia control could not be determined. Third, we did not estimate the role of other confounding factors, such as parent myopia, near work time, and outdoor time.
Literature Search PubMed was searched in August 2014 without date restriction for English-language results, using the following search terms: atropine, eyedrops, low myopia, therapeutic effect, children.
Acknowledgments The authors thank Greg J. Reilly for his kind help in editing our work and Professor Bin Peng for his contribution to the statistical analysis. References 1. Zhao J, Mao J, Luo R, Li F, Munoz SR, Ellwein LB. The progression of refractive error in school-age children: Shunyi district, China. Am J Ophthalmol 2002;134:735-43. 2. Xu L, Li J, Cui T, et al. Refractive error in urban and rural adult Chinese in Beijing. Ophthalmology 2005;112:1676-83.
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