ABSTRACT

The prevalence of myopia worldwide has been increasingsignificantly over the past decades, and it is currently a leading causeof visual impairment worldwide. This severe and significant publichealth problem has been addressed at the community level with the use ofatropine eye drops at a concentration of 0.01% (one drop daily). Thisregimen appears to offer an appropriate balance between costs andbenefits, indicated by a 50% reduction in the annual myopia progression rate in children without resulting in clinically significant adverseeffects. The therapeutic use of atropine eye drops to slow myopiaprogression in children is scientifically recognized and it has beenproven to be effective.

Keywords: Myopia; Child; Epidemiology; Atropine; Myopia/Complications

RESUMO

A prevalência da miopia vem aumentando significativamente em todo o mundo ao longo das últimas décadas e é hoje uma das principais causas de deficiência visual, globalmente. Para enfrentar esse grave e relevante problema de saúde pública, a comunidade oftalmológica conta hoje com o uso do colírio de atropina na concentração de 0,01% (1 gota diária). Esse regime terapêutico parece oferecer uma relação custo/benefício apropriada, representada pela significativa redução de 50% na taxa anual de progressão da miopia em crianças, sem desencadear efeitos adversos clinicamente significantes. O uso terapêutico do colírio de atropina para retardar a progressão de miopia em crianças é reconhecido cientificamente e possui eficácia comprovada.

Palavras-chave: Miopia; Criança; Epidemiologia; Atropina; Miopia/Complicações

1. MYOPIA IS A SERVER PUBLIC HEALTH PROBLEM

Overall, myopia is the leading cause of distance vision loss^1,2,3,4. In 2010, myopia affected 1.4 billion people, corresponding to 27% of global population³. Considering that the number of people with myopia should continue to increase in absolute and relative numbers, it is estimated that 2.5 billion people will be affected by myopia in 2020⁴.

Among adolescents and young adults in Korea, Taiwan, and China, myopia prevalence varies between 84% and 97%^5,6,7. In contrast to Western populations, in which myopia prevalence is low (<5%), the prevalence in Asian children aged ≤ 8 years is significantly higher. In Singapore, it is reported to be 9%–15% in school-aged children; 24.7% in children aged 7 years; 31.3% in children aged 8 years, and 49.7% in students aged 9 years^8,9. Among school children aged 12 years, myopia prevalence is 62% in Singapore and 49.7% in Guangzhou, China, compared with 20% in the United States, 11.9% in Australia, 9.7% in urban areas of India, and 16.5% in Nepal⁸.

The significant increase in myopia prevalence worldwide indicates that the pathogenesis of myopia is determined by a series of environmental factors and behavioral characteristics^10,11 and that the environment strongly influences the development of myopia. However, the strong association of myopia with family history¹² and heredity in the nonsyndromic forms of myopia, particularly in high myopia (−5.00 diopters (D) or more), indicates that >50% of the variability of refractive errors within populations is determined by genetic factors^13,14,15,16. In addition, Genome-Wide Association studies identified >20 loci associated with myopia, and preliminary results suggest that the genes associated with refractive errors can increase in number significantly by modifications in body weight, insulin metabolism, and fatty-acid metabolism, and that these genetic factors may influence growth regulationand neurotransmission¹⁷.

There is evidence that the overall increase in myopia prevalence is accompanied by the increase in myopia severity⁵. Vitale et al.¹⁸, found that the prevalence of moderate myopia in the United States (between −2.00 D and −7.90 D) increased almost 2-fold (from 11.4% in 1971–1972 to 22.4% in 1999–2000), and the prevalence of high myopia (greater than −8.00 D) increased 8-fold in the same period (from 0.2% to 1.6%). The overall prevalence of high myopia (greater than −5.00 D) was 2.9% (224 million people) in 2010⁵.

High myopia (greater than −6.00 D and an axial length ≥26 mm) is associated with an increased risk of blindness-inducing conditions such as myopic macular degeneration, retinoschisis, posterior staphyloma, glaucoma, retinal detachment, and cataract^19,20,21. The prevalence of visual loss by pathological myopia was 0.1%–0.5% in Europe and 0.2%–1.4% in Asia²¹. Yamada et al. (2010) found that 12.2% cases of visual impairment were caused by pathological myopiain a Japanese population²². Myopic macular degeneration is the leading cause of monocular blindness in Tajimi, Japan²³ and it is currently the primary cause of blindness in Shanghai, China²⁴. The absolute risk of visual impairment is 30% in individuals with an ocular axial length of 26 mm, and it increases to 95% among those with an axial eye length of ≥30 mm^25,26.

Brazil has a population of 201 million, and the estimated prevalence of myopia and degenerative myopia is 22–72 million and 2–7 million, respectively²⁷.

The total annual economic cost of myopia is estimated at USD 268 billion¹⁷. In addition to the cost of myopia correction, we should consider the risk of visual loss caused by eye diseases that are more prevalent in individuals with myopia, including glaucoma, cataracts, and retinal detachment^{19,20,21,22,23,24}. As part of the strategy to address this severe public health problem, the World Health Organization has chosen myopia as one of its five priorities, and has included myopia in the "Global Initiative to Eliminate Avoidable Blindness”²⁸.

Without the adoption of effective interventions to control myopia progression, the prevalence of pathological myopia is expected to continue to increase. At present, myopia prevalence worldwide is approximately 3%, and a high percentage of these individuals may develop myopic choroidal neovascularization, which is the leading cause of progressive visual loss²¹. The current options for controlling the rate of myopia progression include conservative and pharmacological interventions²⁹. The efficacy of conservative regimes, except orthokeratology, is relatively small³⁰. The effectiveness of pharmacological intervention is much higher, especially that of treatment regimens employing topical atropine³¹.

2. TOPICAL ATROPINE TO SLOW MYOPIA PROGRESSION IN CHILDREN

Brondstein et al. (1984)³², conducted follow-up observations up to age 9 years (mean age of 4 years and 3 months) in 253 individuals with myopia who were subjected to an instillation regimen of one drop of 1% atropine daily to slow myopia progression. In a comparison of myopia progression rate in this group to that of a control group of 146 individuals with myopia, the rate decreased during the treatment period. Upon treatment discontinuation, the rate was similar in both groups. However, starting with the ATOM study³³ —a randomized clinical trial involving 400 Asian children—use of atropine was effective in delaying myopia progression. In this study with a 2-year follow-up, the authors found that the myopia progression rate decreased 75% with topical1% atropine and found no severe side effects. A systematic Cochrane review²⁹ of studies involving atropine reported that the annual myopia progression rate could be decreased from −0.80 D to −1.00 D with the use of atropine 0.5% and 1.0%, respectively.

Topical atropine eye drops decreased the annual myopia progression in children by decreasing the rate of eye elongation (axial length)^{29,33,34,35,36}.

Chia et al.³⁴ evaluated children subjected to a 5-year treatment with atropine eye drops to control myopia progression;in this study, children used atropine at 0.5%, 0.1%, and 0.01% for 2 years and, 1 year after washout, atropine at 0.01% for 2 additional years. Children treated with atropine at 0.5% and 0.1% showed a higher rate of myopia progression in the washout year (rebound effect). Children who received atropine at 0.01% experienced a lower rebound effect during the washout year and myopia progression was significantly delayed in the 2-year treatment after the washout year, with a noticeable reduction of adverse effects, including the need to use photochromic lenses for higher-dose atropine (0.5% and 0.1%). Children treated with atropine 0.01% had minimal pupillary mydriasis (0.8 mm), minimum loss of accommodation (2–3 D), and did not require the use of progressive lenses.

Polling et al.³¹, (2016) evaluated 77 children with myopia who completed 1 year of follow-up under the treatment regimen of one drop of 0.5% atropine daily. This European study showed that 0.5% atropine might be an effective treatment for progressive myopia. The average myopia progression rate before the intervention year was −1.0 ± 0.7 D/year. The use of 0.5% atropine decreased the rate of progression to −0.1 ± 0.7 D/year during treatment. Despite the high frequency of adverse events (82.9%), most children maintained therapy for the entire study period. The main adverse effects were photophobia (72.4%), problems with reading (37.7%), and headache (22.4%).

Huang et al.³⁷ (2016) conducted a meta-analysis to evaluate the efficacy and effectiveness of 16 interventions in slowing myopia progression in children. Its main findings were as follows:

1) High-dose atropine (1% and 0.5%), moderate-dose atropine (0.1%), and low-dose atropine (0.01%) showed clear effects in slowing myopia progression (all statistically significant); pirenzepine, orthokeratology, contact lenses that change the peripheral defocus, cyclopentolate, and ophthalmic bifocal prismatic lenses showed a moderate effect (all statistically significant except for cyclopentolate and ophthalmic bifocal prismatic lenses); progressive ocular lenses, bifocal ocular lenses, ocular lenses that change the peripheral defocus, and more outdoor activities showed a weak effect (only progressive ocular lenses showed a statistically significant effect); rigid gas-permeable contact lenses, soft contact lenses, ocular hypocorrected lenses, and timolol were ineffective (all without statistical significance).

2) High-dose atropine (1% and 0.5%) was significantly more effective than the other interventions except for moderate-dose atropine (0.1%) and low-dose atropine (0.01%). Pairwise comparisons between bifocal ocular lenses, cyclopentolate, more outdoor activities, orthokeratology, progressive ocular lenses, ophthalmic bifocal prismatic lenses, contact lenses that change the peripheral defocus, ocular lenses that change the peripheral defocus, and pirenzepine showed no significant differences, except the benefit of orthokeratology compared to progressive ocular lenses. Rigid gas-permeable contact lenses, soft contact lenses, timolol, and ocular hypocorrected lenses were worse than other interventions, with no statistically significant differences within this group.

3) Asian children appear to have greater benefits from treatment than Caucasian children, and most interventions stopped showing an effect after the second year.

The authors believe that topical atropine has the greatest efficacy in slowing myopia progression³⁷. However, atropine is rarely prescribed for the correction of progressive myopia in Western countries. The reasons may be the higher efficacy of treatmentin Asia than in Europe³¹. or the possibility of severe and irreversible complications after prolonged atropine use, but this possibility is not substantiated by literature³¹. The long-term effects of atropine were investigated in animal and human studies^38,39, and the potential photochemical damage to the retina because of pupillary mydriasis during prolonged daylight exposure has not been reported^40,41. Therefore, daily atropine use appears to be safe even with prolonged durations^36,42.

Atropine is a potent nonselective antagonist of muscarinic receptors present in human ciliary muscle, retina, and sclera, and it is the best-studied pharmacological agent for slowing myopia progression³³.

However, the mechanism underlying the delay in myopia progression and the site of action of atropine are not known⁴³. Initial studies suggest that the delay occurs via atropine effects on the accommodation of the crystalline lens, but recent studies indicate that it occurs via nonaccommodative mechanisms in the retina and sclera^44,45.

In the retina, amacrine cells express muscarinic receptors in the cell membrane⁴⁶. The binding of atropine to these receptors could increase dopamine release, which is a chemical mediator involved in the inhibition of ocular growth⁴⁴.Atropine decreased the retinal levels of the neurotransmitter γ-aminobutyric acid in mice with induced myopia⁴⁷.Another hypothesis is the effect of atropine on the sclera. Scleral fibroblasts express muscarinic receptors on their cell membranes, and the binding of atropine to these receptors could affect scleralremodeling⁴⁸. The effect of atropine on ocular growth probably does not occur via an accommodative mechanism because the inhibitory effect of atropine on ocular growth is also observed in chicks, in which the ciliary muscles are activated via nicotinic receptors instead of muscarinic receptors⁴⁴.

Recent studies have demonstrated that topical 0.01% atropine (one drop daily) in children is effective in slowing myopia progression and is safe, because this concentration induces clinical symptoms only in a few cases^34,37. Furthermore, low-dose atropine (0.01%) is not associated with the intensity of the rebound effect observed with high-dose atropine (1%, 0.5%, and 0.1%). This characteristic makes low-dose atropine (0.01%) one of the most effective strategies in the management of myopia progression, although the results needto be replicated in other populations. Chia et al.³⁴ showed that children using low-dose atropine (0.01%) for 5 years had less myopia than children treated with higher doses, that the use of one drop of 0.01% atropine per day slowed myopia progression by 50% compared tountreated children, and that the use of this concentration was safe to children aged 6–12 years for up to 5 years; however, additional studies are needed to confirm these findings. Atropine (0.01%) caused minimal pupillary mydriasis (<1 mm), decreased sensitivity to light—experienced with higher drug concentrations—and did not cause difficulties in near vision, eliminating the use of progressive lenses.

In Brazil, atropine use to slow myopia progression is off-label. Therefore, all children subjected to treatment should be involved in a clinical study with a protocol approved by the ethics committee, and parents or legal guardians need to sign informed consentforms.

REFERENCES

1. Resnikoff S, Pascolini D, Mariotti S, PokharelGP. Global magnitude of visual impairment caused by uncorrected refractive errors in 2004. Bull World Health Organ. 2008;86(1):63-70. http://dx.doi.org/10.2471/BLT.07.041210

2. Ventura LMVO, Carvalho KM, Alves MR, Resnikoff S. Estimativa global da baixa visão por erro refracional não corrigido. In: Alves MR, Nishi M, Carvalho KM, Ventura LMVO, Schellini SA, Kara-José N, editores. Refração ocular: uma necessidade social. Rio de Janeiro: Cultura Médica; 2014. p. 3-17.

3. Holden BA, Wilson DA, Jong M, Sankaridurg P, Fricke TR, Smith III EL, Resnikoff S. Myopia: a growing global problem with sight-threatening complications. CommEyeHealth [periódico na Internet]. 2015 [acesso em 2017 Feb 27];28(90):[aproximadamente 35 p.]. Disponivel em: http://europepmc.org/articles/pmc4675264

4. Morgan IG, Ohno-Matsui K, Saw SM. Myopia. The Lancet 2012;379(9827):1739-48. http://dx.doi.org/10.1016/S0140-6736(12)60272-4

5. Lin LLK, Shih YF, Hsiao CK, Chen CJ. Prevalence of myopia in Taiwanese schoolchildren: 1983 to 2000. Ann AcadMed Singapore [periódico na Internet]. 2004 [acesso em 2017 Feb 27];33(1):27-33. Disponível em: http://annals.edu.sg/pdf200401/V33N1p27.pdf

6. Wang TJ, Chiang TH, Wang TH, Lin LLK and Shih YF. Changes of the ocular refraction among freshmen in National Taiwan University between 1988 and 2005. Eye 2009;23:1168-9. http://dx.doi.org/10.1038/eye.2008.184

7. Jung SK, Lee JH, Kakizaki H and Jee D. Prevalence of myopia and its association with body stature and educational level in 19-year-old male conscripts in Seoul, South Korea. Invest OphthalmolVis Sci. 2012;53:5579-83. http://dx.doi.org/doi:10.1167/iovs.12-10106

8. World Society of Paediatric Ophthalmology & Strabismus. Myopia consensus statement [homepage na Internet, 3 p., acesso em 2017 Feb 27]. Disponível em: http://wspos.org/wp-content/uploads/2016/04/WSPOS_Consensus-Statement_Myopia.pdf

9. Saw SM, Tong L, Chua WH, Chia KS, Koh D, Tan DT et al. Incidence and progression of myopia in Singaporean school children. Invest Ophthalmol Vis Sci.2005;46(1):51-7. http://dx.doi.org/10.1167/iovs.04-0565

10. Wong TY, Foster PJ, Johnson GJ, Seah SKL. Education, socioeconomic status, and ocular dimensions in chinese adults: the TanjongPagar Survey. Br J Ophthalmol. 2002;86(9):963-8. http://dx.doi.org/10.1136/bjo.86.9.963

11. Rahi JS, Cumberland PM, Peckham CS. Myopia over the lifecourse: prevalence and early life influences in the 1958 British birth cohort. Ophthalmology 2011;118(5):797-804. http://dx.doi.org/10.1016/j.ophtha.2010.09.025

12. Jones LA, Sinnott LT, Mutti DO, Mitchell GL, Moeschberger ML, Zadnik K. Parental history of myopia, sports and outdoor activities, and future myopia. Invest Ophthalmol Vis Sci. 2007;48(8):3524-32. http://dx.doi.org/10.1167/iovs.06-1118

13. Lopes MC, Andrew T, CarbonaroF, Spector TD, Hammond CJ. Estimating heritability and shared environmental effects for refractive error in twin and family studies. Invest Ophthalmol Vis Sci. 2009;50(1):126-31. http://dx.doi.org/10.1167/iovs.08-2385

14. Li YJ, Goh L, Khor CC, et al. Genome-wide association studies reveal genetic variants in CTNND2 for high myopia in Singapore Chinese. Ophthalmology 2011;118(2):368-75. http://dx.doi.org/10.1016/j.ophtha.2010.06.016

15. Zhang Q, Guo X, Xiao X, Jia X, Li S, Hejtmancik JF. A new locus for autosomal dominant high myopia maps to 4q22-q27 between D4S1578 and D4S1612. Mol Vis. 2005;11:554-60. Disponível em: http://www.molvis.org/molvis/v11/a65/v11a65-zhang.pdf

16. Yi Shi, Jia Qu, Dingding Zhang, Peiquan Zhao, Qingjiong Zhang, Pancy Oi Sin Tam, Liangdan Sun, Xianbo Zuo, Xiangtian Zhou, Xueshan Xiao, Jianbin Hu, Yuanfeng Li, Li Cai, Xiaoqi Liu, Fang Lu, Shihuang Liao, Bin Chen, Fei He, Bo Gong, He Lin, Shi Ma, Jing Cheng, Jie Zhang, Yiye Chen, Fuxin Zhao, Xian Yang, Yuhong Chen, Charles Yang, Dennis Shun Chiu Lam, Xi Li, Fanjun Shi, Zhengzheng Wu, Ying Lin, Jiyun Yang, Shiqiang Li, Yunqing Ren, Anquan Xue, Yingchuan Fan, Dean Li, Chi Pui Pang, Xuejun Zhang, Zhenglin Yang. Genetic variants at 13q12.12 are associated with high myopia in the Han Chinese population. Am J Hum Genet. 2011;88(6):805-13. http://dx.doi.org/10.1016/j.ajhg.2011.04.022

17. Hysi PG, Wojciechowski R, Rahi JS, Hammond CJ. Genome-Wide Association Studies of Refractive Error and Myopia, lessons learned, and implications for the future. Invest Ophthalmol Vis Sci. 2014;55(5):3344-51. http://dx.doi.org/10.1167/iovs.14-14149

18. Vitale S, Sperduto RD and Ferris III FL. Increased prevalence of myopia in the United States between 1971–1972 and 1999–2004. Arch Ophthalmol. 2009;127(12):1632-9. http://dx.doi.org/10.1001/archophthalmol.2009.303

19. Pan CW, Ramamurthy D, Saw SM. Worldwide prevalence and risk factors for myopia. Ophthalmic Physiol Opt. 2012;32(1):3-16. http://dx.doi.org/10.1111/j.1475-1313.2011.00884.x

20. Pan CW, Saw SM, Wong TY. Epidemiology of myopia. In: Spaide RF, Ohno-Matsui K, Yannuzzi LA, editors. Pathologic myopia. New York: Springer Science and Business Media; 2014. p. 25-38.

21. Wong TY, Ferreira A, Hughes R, Carter G, Mitchell P. Epidemiology and disease burden of pathologic myopia and myopic choroidal neovascularization: an evidence-based systematic review. Am J Ophthalmol. 2014;157(1),9-25. http://dx.doi.org/10.1016/j.ajo.2013.08.010

22. Yamada M, Hiratsuka Y, Roberts CB, Pezzullo ML, Yates K, Takano S. Prevalence of visual impairment in the adult japanese population by cause and severity and future projections. OphthalEpidemiol. 2010;17(1):50-7. http://dx.doi.org/10.3109/09286580903450346

23. Iwase A, Araie M, Tomidokoro A, Yamamoto T, Shimizu H, Kitazawa Y. Prevalence and causes of low vision and blindness in a japanese adult population: the Tajimi Study. Ophthalmology 2006;113(8):1354-62. http://dx.doi.org/10.1016/j.ophtha.2006.04.022

24. Wu L, Sun X, Zhou X, Weng C. Causes and 3-year-incidence of blindness in Jing-An District, Shanghai, China 2001-2009. BMC Ophthalmol. 2011;11(10):1-6. http://dx.doi.org/10.1186/1471-2415-11-10

25. Vongphanit J, Mitchell P, Wang JJ. Prevalence and progression of myopic retinopathy in an older population. Ophthalmology 2002;109(4):704-11. http://dx.doi.org/10.1016/S0161-6420(01)01024-7

26. Verhoeven VJM, Wong KT, Buitendijk GHS, Hofman A, Vingerling JR, Klaver CCW. Visual consequences of refractive errors in the general population. Ophthalmology 2015;122(1):101-9. http://dx.doi.org/10.1016/j.ophtha.2014.07.030

27. Avila M, Alves MR, Nishi M. As condições de saúde ocular no Brasil [homepage na Internet]. São Paulo: Conselho Brasileiro de Oftalmologia; 2015 [acesso em 2017 Mar 6]. Disponível em: http://www.cbo.net.br/novo/publicacoes/Condicoes_saude_ocular_IV.pdf

28. Global action plan 2014-2019 [homepage na Internet]. London: International Agency for the Prevention of Blindness [acesso em 2017 Mar 6]. Disponível em: http://www.iapb.org/advocacy/who-action-plan

29. Walline JJ, Lindsley K, Vedula SS, Cotter SA, Mutti DO, Twelker JD. Interventions to slow progression of myopia in children. Cochrane Database Syst Rev 2011;12. http://dx.doi.org/10.1002/14651858.CD004916.pub3

30. Sun Y, Xu F, Zhang T, Liu M, Wang D, Chen Y, et al. Orthokeratology to control myopia progression: a meta-analysis. PLoS One 2015;10(4): e0124535. http://dx.doi.org/10.1371/journal.pone.0130646

31. Polling JR, Kok RGW, Tideman JWL, Meskat B, Klaver CCW. Effectiveness study of atropine for progressive myopia in Europeans.Eye 2016;30:998–1004. http://dx.doi.org/10.1038/eye.2016.78

32. Brodstein RS, Brodstein DE, Olson RJ, Hunt SC, Williams RR. The treatment of myopia with atropine and bifocals: a long-term prospective study. Ophthalmology 1984; 91(11):1373-79. http://dx.doi.org/10.1016/S0161-6420(84)34138-0

33. Chua WH, Balakrishnan V, Chan YH, Tong L, Ling Y, Quah BL et al. Atropine for the treatment of childhood myopia. Ophthalmology 2006;113(12):2285-91. http://dx.doi.org/10.1016/j.ophtha.2006.05.062

34. Chia A, Lu QS, Tan D. Five-year clinical trial on atropine for the treatment of myopia 2: myopia control with atropine 0.01% eyedrops. Ophthalmology 2016;123(2):391-9. http://dx.doi.org/10.1016/j.ophtha.2015.07.004

35. Fang YT, Chou YJ, Pu C, Lin PJ, Liu TL, Huang N et al. Prescription of atropine eye drops among children diagnosed with myopia in Taiwan from 2000 to 2007: a nationwide study. Eye 2013;27(3):418–24. http://dx.doi.org/doi:10.1038/eye.2012.279

36. Tong L, Huang XL, Koh AL, Zhang X, Tan DTH, Chua WH. Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. Ophthalmology 2009;116(3):572-9. http://dx.doi.org/10.1016/j.ophtha.2008.10.020

37. Huang J, Wen D, Wang Q, McAlinden C, Flitcroft I, Chen Haisi, Saw SM, Chen Hao, Bao F, Zhao Y, Hu L, Li X, Gao R, Lu W, Du Y,Jinag Z, Yu A, Lian H, Jiang Q, Yu Y, Qu J, . Efficacy comparison of 16 interventions for myopia control in children: a network meta-analysis. Ophthalmology 2016;123(4):697-708. http://dx.doi.org/10.1016/j.ophtha.2015.11.010

38. Lawwill T, Crockett S, Currier G. Retinal damage secondary to chronic light exposure, thresholds and mechanisms. Doc Ophthalmol. 1977;44(2):379–402. http://dx.doi.org/10.1007/BF00230089

39. Noell WK, Walker VS, Kang BS, Berman S. Retinal damage by light in rats. Invest Ophthalmol Vis. 1966;5(5):450–473. Disponível em: http://iovs.arvojournals.org/article.aspx?articleid=2128202

40. Wu J, Seregard S, Algvere PV. Photochemical damage of the retina. Surv Ophthalmol 2006; 51(5): 461–81. http://dx.doi.org/10.1016/j.survophthal.2006.06.009

41. Luu CD, Lau AMI, Koh AHC, Tan D. Multifocal electroretinogram in children on atropine treatment for myopia. Br J Ophthalmol 2005;89(2):151–153. http://dx.doi.org/10.1136/bjo.2004.045526

42. Kennedy RH, Dyer JA, Kennedy MA, Parulkar S, Kurland LT, Herman DC, McIntire D, Jacobs D, Luepker RV. Reducing the progression of myopia with atropine: a long term cohort study of Olmsted County students. Binocul Vis Strabismus Quart. 2000;15(3Suppl):281–304. Abstract disponível em: https://www.ncbi.nlm.nih.gov/pubmed/?term=Reducing+the+progression+of+myopia+with+atropine%3A+a+long+term+cohort+study+of+Olmsted+County+students

43. McBrien NA, StellWK, Carr B. How does atropine exert its antimyopia effects? Ophthalmic Physiol Opt 2013;33(3):373–8. http://dx.doi.org/10.1111/opo.1205

44. McBrien NA, Moghaddam HO, Reeder AP. Atropine reduces experimental myopia and eye enlargement via a non accommodative mechanism. Invest Ophthalmol Vis 1993;34(1):205–15. Disponível em: http://iovs.arvojournals.org/article.aspx?articleid=2179117

45. Stone RA, Lin T, Laties AM. Muscarinic antagonist effects on experimental chick myopia. Exp Eye Res 1991;52(6):755–8. http://dx.doi.org/10.1016/0014-4835(91)90027-C

46. 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(9):5827–37. http://dx.doi.org/10.1167/iovs.12-9943

47. Barathi VA, Chaurasia SS, Poidinger M, Koh SK, Tian D, Ho C et al. Involvement of GABA transporters in atropine-treated myopic retina as revealed by iTRAQ quantitative proteomics. J Proteome Res. 2014; 13(11):4647–58. http://dx.doi.org/10.1021/pr500558y

48. Gallego P, Martinez-Garcia C, Perez-Merino P, Ibares-Frias L, Mayo-Iscar A, Merayo-Lloves J. Scleralchangesinducedbyatropine in chicks as an experimental modelofmyopia. Ophthalmic Physiol Opt 2012;32(6):478–484. http://dx.doi.org/10.1111/j.1475-1313.2012.00940.x

Milton Ruiz Alves
http://orcid.org/0000-0001-6759-5289
http://lattes.cnpq.br/6210321951145266

Nicolas Chiu Ogassavara
http://lattes.cnpq.br/3520149452017072

Gustavo Victor de Paula Baptista
http://orcid.org/0000-0002-2916-205X
http://lattes.cnpq.br/4851190387659602

Received on: December 16, 2016.
Reviewed in: March 31, 2017.
Accepted on: December 16, 2016.