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 Table of Contents  
MAJOR REVIEW
Year : 2019  |  Volume : 31  |  Issue : 1  |  Page : 4-10

Atropine in the treatment of childhood myopia


Department of Ophthalmology, Little Flower Hospital, Angamaly; Vettam Eye Clinic, Mulanthuruthy, Ernakulam, Kerala, India

Date of Web Publication15-Apr-2019

Correspondence Address:
Sanitha Sathyan
Vettam Eye Clinic, Perumpilly, Mulanthuruthy, Ernakulam - 682 314, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_6_19

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  Abstract 

The practice of using topical atropine to prevent the progression of myopia in children has been going on for decades in some Asian populations. The encouraging results obtained from Atropine for the treatment of childhood myopia (ATOM) studies and animal studies have created much interest among the practitioners regarding the use of atropine in preventing myopic progression. This review aims to summarize the major research works done on the subject and its implications in clinical practice.

Keywords: Atropine, childhood myopia, myopia, progression of myopia, treatment of myopia


How to cite this article:
Sathyan S. Atropine in the treatment of childhood myopia. Kerala J Ophthalmol 2019;31:4-10

How to cite this URL:
Sathyan S. Atropine in the treatment of childhood myopia. Kerala J Ophthalmol [serial online] 2019 [cited 2019 Jun 26];31:4-10. Available from: http://www.kjophthal.com/text.asp?2019/31/1/4/256271


  Introduction Top


Myopia is the most common cause of correctable visual impairment among adults as well as children in the developed countries.[1],[2],[3],[4],[5] It is an important cause of preventable blindness in developing countries.[6] It is estimated that one in six of the world's population has myopic refractive error.[7] The prevalence of myopia varies across different geographical regions and ethnicities. The prevalence of myopia in the United States rose from 25% to 42%, between 1971 and 1999.[8] In Asian countries, there is a rapid increase in the prevalence of childhood myopia, and about 80%–90% of school leavers are affected by this condition in East Asia.[9]

A study from Delhi conducted in 2015 reported prevalence of myopia as 13.1% among schoolgoing children,[10] which was much higher than the previous reports.[11],[12] This indicates that myopia is a growing public health problem among Indian children also, with huge social, educational, and economic implications.

Myopia has been known for more than 2000 years, and it was first described by the Greeks.[13] However, the optical correction for myopia could be instituted only in the 16th century, following the invention of concave lenses.[14] In addition to the optical correction, pharmacological agents such as pirenzepine, tropicamide, and atropine have been investigated regarding their potential to halt the progression of childhood myopia. The use of atropine in preventing the progression of childhood myopia has generated much interest in the recent years. This review discusses the use of atropine in childhood myopia, in the light of current evidence.


  Atropine for Myopia Top


Atropine is an alkaloid extracted from the plant “deadly nightshade” (Atropa belladonna) and is a nonselective muscarinic antagonist. The first report of the use of atropine for myopia was by Wells in the 19th century.[15] In 1979, Bedrossian[16] conducted a nonrandomized trial evaluating the effect of 1% atropine ointment instilled once at night in one eye for 1 year with the fellow eye as control. The control eyes showed a significant increase in the rates of myopia. After 1 year, treatment was switched to the fellow eye. Although the control eyes showed significant increases in myopia compared to the treated eyes, the possibility of residual effects of atropine in the fellow eye could not be eliminated from this study design.

There are many other studies which attempted to evaluate the effect of topical atropine on myopia progression.[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] Yen et al.[27] compared the effect of cyclopentolate 1% and atropine 1% against placebo drops in 96 myopic children, who were randomized to three groups. Group 1 received atropine 1% eye drops every other night; Group 2 received cyclopentolate 1% eye drops every night; and Group 3 received normal saline eye drops every night. The patients were rechecked every 3 months and the results were analyzed at the end of 1 year. Analysis showed that atropine and cyclopentolate were effective in slowing the progression of myopia and that the effect of atropine was better than that of cyclopentolate.

Shih et al.[28] evaluated the effects of different concentrations of atropine in controlling myopia in 186 myopic children, between 6 and 13 years of age. The individuals were treated each night with different topical concentrations (0.5%, 0.25%, and 0.1%) of atropine groups. According to their results, all three concentrations of atropine had significant effects in controlling myopia at two years; however, treatment with 0.5% atropine was the most effective.

Another study[29] analyzed 227 school children with myopia, between 6 and 13 years, who were stratified based on gender, age, and the initial amount of myopia and were randomly assigned to three treatment groups: 0.5% atropine with multifocal glasses, multifocal glasses, and single vision spectacles. At 18 months, they concluded that 0.5% atropine with multifocal lenses slowed down the progression rate of myopia while multifocal lenses alone showed no difference in effect compared to the control group.

Many retrospective studies, Dyer,[20] Sampson,[21] Kennedy et al.,[24] Gimbel,[26] Kelly et al.,[30] Bedrossian,[31] Gruber[32] etc., have demonstrated that 1% atropine tends to slow the progression of myopia by almost 80%.


  Atropine in Myopia Studies Top


Atropine in myopia: 1 study

ATOM: 1 was a parallel-group, placebo-controlled, randomized, double-masked study conducted at Singapore, which evaluated the efficacy and safety of topical atropine, in slowing the progression of myopia and ocular axial elongation in Asian children.[33] Recruitment of participants was from the general public, primary schools, and ophthalmology practices through the distribution of standardized brochures and letters describing the study as well as public talks.

The study, conducted between 1999 and 2004, enrolled 400 children between 6 and 12 years of age, with spherical equivalent of refractive error between 1.00 and 6.00 diopters and astigmatism ≤1.50 diopters. Participants were assigned with equal probability to receive either 1% atropine or vehicle eye drops once nightly for 2 years. Only one eye of each individual, chosen through randomization, underwent treatment. The main efficacy outcome assessed was change in spherical equivalent of refraction as measured by cycloplegic autorefraction and change in ocular axial length as measured by ultrasonography. The primary safety outcome measure was the occurrence of adverse events.

Three hundred and forty-six (86.5%) children completed the 2-year study duration. In atropine-treated eyes, the mean myopia progression was only −0.28 ± 0.92 D whereas it was −1.20 ± 0.69 D in the placebo-treated eyes. The axial length remained essentially unchanged from baseline in atropine-treated eyes (0.02 ± 0.35 mm), compared to the placebo (0.38 ± 0.38 mm). The differences in myopia progression and axial elongation between the 2 groups were 0.92 D (95% confidence interval, 1.10–0.77 D; P0.001) and 0.40 mm (95% confidence interval, 0.35–0.45 mm; P = 0.001), respectively. No serious adverse events related to atropine. The progression of spherical equivalent in patients on 1% atropine versus controls.[33] The change in axial length in patients on 1% atropine versus control.[33]

Based on the above observations, they concluded that topical atropine was well tolerated and effective in slowing the progression of low and moderate myopia and ocular axial elongation in the study population.

Atropine in myopia: 2 study

Atropine in myopia: 2 study (ATOM 2), phase: 1 study

The ATOM 2 study was a single-center, double-masked, randomized study, conducted in the Singapore Eye Research Institute, Singapore, between 2006 and 2012. The aim of this study was to compare the efficacy and visual side effects of 3 lower doses of atropine: 0.5%, 0.1%, and 0.01%. A total of 400 children between 6 and 12 years with myopia of at least −2.0 diopters and astigmatism of −1.50 D or less were randomly assigned in a 2:2:1 ratio to 0.5% (n = 161), 0.1% (n = 155), and 0.01% (n-84) atropine, to be administered once nightly to both eyes, for 2 years. Cycloplegic refraction, axial length, accommodation amplitude, pupil diameter, and visual acuity were noted at baseline, 2 weeks, and then every 4 months for 2 years. The main outcome measure was myopia progression at 2 years.

At 2 years, the progression of myopia was −0.30 ± 0. 60 D, −0.38 ± 0.60, and −0.49 ± 0.63 D in the atropine 0.5%, 0.1%, and 0.01% groups, respectively (P = 0.02 between the 0.01% and 0.5% groups; between other concentrations P > 0.05). The mean increase in axial length was 0.27 ± 0.25, 0.28 ± 0.28, and 0.41 ± 0.32 mm in the 0.5%, 0.1%, and 0.01% groups, respectively (P < 0.01 between the 0.01% and 0.1% groups and between the 0.01% and 0.5% groups). However, the differences in myopia progression (0.19 D) and axial length change (0.14 mm) between groups were small and clinically insignificant. Atropine 0.01% had a negligible effect on accommodation and pupil size and no effect on near visual acuity. Based on the above observations, the investigators concluded that atropine 0.01% has minimal side effects compared with atropine at 0.1% and 0.5% and retains comparable efficacy in controlling myopia. The mean change in spherical equivalent for groups from baseline, 2 weeks, and 4–24 months with atropine 0.01%, 0.1%, and 0.5% from the atropine for the treatment of childhood myopia study 2, and placebo and atropine 1.0% from the atropine for the treatment of childhood myopia study 1.[34]

Atropine in myopia 2 phase: 2 study

The participants from ATOM 2 treatment phase 1 study entered the treatment phase 2 study at the third year, and atropine was stopped for 1 year (year: 3). 21 patients in the 0.5% group, 14 in the 0.1% group, and 9 in the 0.01% group withdrew from the study on their own accord. Therefore, after 2 years, data were analyzed with 139 individuals in the 0.5% group, 141 individuals in the 0.1% group, and 75 individuals in the 0.01% group. At the end of the third year, 24% of the 0.01% group, 59% of the 0.1% group, and 68% of the 0.5% groups in the original ATOM 2 trial showed progression of more than 0.5 D of myopia.

At the end of 1 year, there was a significant difference in myopia progression between the 0.5% atropine group and the 0.01% (P < 0.001) and 0.1% (P = 0.01) groups, but there was no statistically significant difference between the 0.01% and 0.1% groups. The final myopia progression over 2 years was − 0.49 ± 0.60 D, −0.38 ± 0.60 D, and −0.30 ± 0.63 D in the atropine 0.01%, 0.1%, and 0.5% groups, respectively (P = 0.07), with a significant difference between the 0.01% and 0.5% groups. Fifty percent of the 0.01% group had progressed by <0.5 D. However, 58% and 63% in the 0.1% and 0.5% groups had documented progression. On the whole, approximately 18% showed progression by −1.0 D, in all 3 groups. Axial length change at 1 year was higher in the 0.01% group (0.24 ± 0.19 mm) than in the 0.1% (0.13 ± 0.18 mm) and 0.5% (0.11 ± 0.17 mm) groups (P < 0.001). There was statistically significant change in the axial length measurements between the 0.01% group and the other 2 groups (P < 0.001), which persisted even at the end of the 24-month period.

In terms of effect on other ocular parameters, accommodation amplitude (−10.9 vs. −2.4 D), mesopic pupil diameter (2.7 versus 3.5 mm), and photopic pupil diameter (2.2 vs. 3.1 D) were also significantly less in the 0.1% group compared with the 0.5% group, making the overall efficacy side effect profile of atropine 0.1% better than atropine 0.5%.

In conclusion, ATOM 2 study in the phase 2 showed a clear rebound phenomenon in terms of myopia progression. This rebound was dose dependent, with 0.01% atropine having The change in spherical equivalent in the atropine forthe treatment of childhood myopia study 1 eyes that received 1.0% atropine and placebo, and atropine for the treatment of childhood myopia study 2 eyes that received 0.5%, 0.1%, and 0.01% atropine.[35] The proportional change in myopia (spherical equivalent) in atropine for the treatment of childhood myopia study 1 eyes that received 1.0% atropine and placebo, and atropine for the treatment of childhood myopia study 2 eyes that received 0.5%, 0.1% and 0.01% atropine at 24 and 36 months.[35] The change in axial length in atropine for the treatment of childhood myopia study 1 eyes that received 1.0% atropine and placebo, and atropine for the treatment of childhood myopia study 2 eyes that received 0.5%, 0.1%, and 0.01% atropine.[35]

Atropine in myopia 2: phase 3

In phase 3 (re-treatment phase), children who exhibited myopia progression of 0.50 D or more in at least 1 eye during the washout phase were restarted on atropine 0.01% for a further 24 months.

The primary outcome was progression of myopia, defined as change in spherical equivalent over phase 3 and the entire 5-year study period of the ATOM trials. The secondary outcome was change in AL. Other study variables include changes in photopic pupil size, accommodation, and distance/near visual acuity.

Of the 345 children, 192 (56%) were restarted on atropine 0.01% because they had progressed 0.5 D or more during phase 2 washout year. This included 17 of 70 children (24%) in the 0.01% group, 82 of 139 children (59%) in the 0.1% group, and 93 of 136 children (68%) in the 0.5% group. A baseline characteristic to be noted is that compared with children who did not progress after phase 2, those were restarted on atropine 0.01% in phase 3 were younger, had less myopia, and had shorter axial lengths. Also to be noted that these children had greater myopia progression and change in axial length during the first year of the study.

At 1 year, those children retreated during phase 3 with atropine 0.01% had mean myopia progression of −0.38 to −0.52 D. This was lower than the progression they demonstrated during the phase 2 washout period (−0.62 to −1.09 D) and was true in all the three atropine groups. However, the mean myopia progression (−0.38 to −0.52 D) seen in the participants of the phase 3 trial were higher than those children who did not require retreatment (−0.30 to −0.38 D).

The overall mean myopia progression in phase 3 was − 0.69 ± 0.46 D, −0.81 ± 0.57 D, and −0.84 ± 0.61 D in the atropine 0.01%, 0.1%, and 0.5% groups, respectively (P = 0.09). In contrast, the mean myopia progression over the entire 5 years was less in the 0.01% group (−1.30 ± 0.98 D) than in the 0.1% (−1.83 ± 1.16 D, P = 0.003) and 0.5% (-1.98 ± 1.10 D, P < 0.001) groups.

Among the children restarted on atropine 0.001% during phase 3, there was a reduction in the rate of myopic progression. The mean increase in myopia over the 4th and 5th years was − 0.86 ± 0.56 D in 0.01% group, −0.87 ± 0.59 D in 0.1% group, and −0.90 ± 0.66 D in 0.5% group, respectively. This was similar to the progression in children originally assigned to the 0.01% group (−0.77 ± 0.49 D, P > 0.286). This suggests that retreatment with atropine 0.01% was as effective as primary treatment with atropine 0.01%.

By the end of phase 3, the mean axial length progression was smaller in the 0.01% group (0.19 ± 0.18 mm) compared with the 0.1% (0.24 ± 0.21 mm, P = 0.042) and 0.5% (0.26 ± 0.23 mm, P = 0.013) groups. The mean overall change in axial length over 5 years was 0.75 ± 0.48 mm, 0.85 ± 0.53 mm, and 0.87 ± 0.49 mm in the 0.01%, 0.1%, and 0.5% groups, respectively (P = 0.185).

In the children who were not restarted on atropine, axial length elongation gradually slowed during phase 3 and there was no difference in axial lengths among the groups at 5 years (P = 0.56). In children in whom atropine was restarted, axial length elongation slowed in all groups (0.32 ± 0.22 mm in the 0.01% group, 0.27 ± 0.25 mm in the 0.1% group, 0.29 ± 0.25 mm in the 0.5% group) over phase 3 to a rate lower than that noted during phase 1 (0.58 ± 0.27 mm, P < 0.001). The mean change in spherical equivalent overtime me within different treatment groups (atropine 0.01%, 0.1%, and 0.5%).[36] The mean change in axial length over time within different treatment groups (atropine 0.01%, 0.1%, and 0.5%).[36]

ATOM 1 established the clinical safety and efficacy of atropine 1% at least in the short term.[33] Phase 1 of ATOM 2 established that atropine 0.01% was almost as effective in reducing myopia progression as higher concentrations but with minimal pupil dilation accommodation and near vision loss.[34] In phase 2, ATOM 2 further established that children receiving lower doses had less myopic progression after atropine was stopped, resulting in 0.01% being more effective in reducing myopia progression at 3 years.[35] ATOM 2 phase 3 proved that retreatment with atropine 0.01% could be as effective as primary treatment with atropine 0.01%. This indicates that the clinicians may be able to titrate the treatment by stopping and restarting treatment according to individual progression rates.[36]


  Low-Concentration Atropine for Myopia Progression Study Top


Low concentration atropine for myopia progression study was a randomized, placebo-controlled, double-masked trial, conducted at Hong Kong,[37] which evaluated the efficacy and safety of low-concentration atropine eye drops at 0.05%, 0.025%, and 0.01% compared with placebo over 1-year period. A total of 438 children aged 4–12 years with myopia of at least −1.0 diopter and astigmatism of −2.5 D or less were randomly assigned in a 1:1:1:1 ratio to receive 0.05%, 0.025%, and 0.01% atropine eye drops, or placebo eye drop, respectively, once nightly to both eyes for 1 year. Cycloplegic refraction, axial length, accommodation amplitude, pupil diameter, and best-corrected visual acuity were measured at baseline, 2 weeks, 4 months, 8 months, and 12 months. Visual Function Questionnaire was administered at the 1-year visit.

After 1 year, the mean change in spherical equivalent of refraction was −0.27 ± 0.61 D, −0.46 ± 0.45 D, −0.59 ± 0.61 D, and −0.81 ± 0.53 D in the 0.05%, 0.025%, and 0.01% atropine groups, and placebo groups, respectively (P < 0.001). The mean increase in axial length was 0.20 ± 0.25 mm, 0.29 ± 0.20 mm, 0.36 ± 0.29 mm, and 0.41 ± 0.22 mm (P < 0.001), respectively. The accommodation amplitude was reduced by 1.98 ± 2.82 D, 1.61 ± 2.61 D, 0.26 ± 3.04 D, and 0.32 ± 2.91 D, respectively (P < 0.001). The pupil sizes under photopic and mesopic conditions were increased, respectively, by 1.03 ± 1.02 mm and 0.58 ± 0.63 mm in the 0.05% atropine group, 0.76 ± 0.90 mm and 0.43 ± 0.61 mm in the 0.025% atropine group, 0.49 ± 0.80 mm and 0.23 ± 0.46 mm in the 0.01% atropine group, and 0.13 ± 1.07 mm and 0.02 ± 0.55 mm in the placebo group (P < 0.001). Visual acuity and vision-related quality of life were not affected in each group.

Based on the above observations, the study concluded that 0.05%, 0.025%, and 0.01% atropine eye drops reduced myopia progression along a concentration-dependent response. All concentrations were well tolerated without any adverse effect on vision-related quality of life. Of the 3 concentrations used, 0.05% atropine was most effective in controlling spherical equivalent progression and axial length elongation over a period of 1 year.


  How Does Atropine Prevent Progression of Myopia? Top


Initially, it was thought that atropine prevents progression of myopia through its cycloplegic action exerted on ciliary muscles and thereby causing changes in accommodation. Wallman documented that atropine blocks accommodation and reduces the putative effects of excessive accommodation on the progression of myopia.[38]

Atropine is a muscarinic antagonist and acts through M1 to M5 receptors. However, experiments in chicks, which possesses striated ciliary muscles, innervated by nicotinic receptors rather than muscarinic receptors, also documented reduction in the progression of myopia following the use of topical atropine.[39] This animal model demonstrates that atropine prevents myopia through a nonaccommodative mechanism and is the reason why optical approaches to reduce accommodation (e.g., bifocals and progressive addition lenses) failed to have any effect on retarding the progression of myopia.[40] These evidences have prompted research on the posterior structures of the eye rather than the accommodative mechanism as the likely sites of action of antimyopia effect of atropine.

The queries regarding the mechanism of action of atropine in preventing progression of myopia can be consolidated as the following:

  1. Where is the exact locus of action of atropine in preventing myopic progression? Is it retina, sclera, or choroid?
  2. Whether the effect of atropine involves muscarinic receptors at all, if so, which are the receptors involved (m1, m2, m3, m4, m5), and where are they located?


Let us attempt to answer these questions in the light of current evidence.

Animal studies have strongly suggested that neurochemical signaling cascade causing myopia begins at the level of retina level. An example in support of this is the sign of defocus changes found in the amacrine cells of the retina.[41] Interestingly, there are other studies also which suggest that muscarinic antagonist control of myopia is initiated at the sclera.[42]

As relatively higher dose of atropine was needed to prevent myopia in experimental studies, previously, it was thought that the site of action is more likely the sclera than the retina. However, the ATOM studies have categorically established that even low dose of atropine can exert substantial influence on the progression of myopia.[35],[36],[37] These developments in research point toward retinal site of action of atropine.

Experimental evidence from the mammal tree shrew has demonstrated that the highly selective muscarinic antagonists MT3 (M4 receptor antagonist) and MT7 (M1 receptor antagonist) are effective in preventing experimentally induced myopia at nanomolar concentrations.[43] Further evidence comes from the finding that MT3 (M4 receptor antagonist) inhibition of myopia in chicks prevents the choroidal thinning normally associated with induced myopia.[44] As choroid, which is located earlier in the drug pathway than sclera is affected, this finding argues against a scleral site of action. These animal studies emphasize the possibility of a retinal site of action, rather than scleral/choroidal.

Further molecular receptor level studies have demonstrated that an M1-specific antagonist and a highly selective M4 antagonist inhibit myopia.[43],[44],[45] This strongly indicates that both the M1 and M4 muscarinic receptor signaling pathways are involved in the mechanism by which atropine prevents myopia. Atropine also found to affect dopamine neurotransmitter release from cellular stores and thus may influence retinal signals that control the growth of the eye.[46]


  Conclusion Top


The use of atropine for preventing progression of myopia has received a firm clinical base with the randomized control studies, the most significant being the ATOM studies. ATOM 1 has demonstrated the clinical safety and efficacy of atropine 1%.[33] Phase 1 of ATOM 2 established that atropine 0.01% was almost as effective in reducing myopia progression as higher concentrations, but with minimal pupil dilation accommodation and near vision loss.[34] The phase 2 of ATOM 2 further underlined that children receiving lower doses of atropine had less myopic progression after atropine was stopped. The 3-year results showed that 0.01% atropine is more effective in reducing myopia progression after the washout period.[35] Phase 3 of ATOM 2 proved that retreatment with atropine 0.01% could be as effective as primary treatment with atropine 0.01%. This opens up the possibility of titrating the treatment by stopping and restarting treatment according to individual progression rates.[36]

Animal experiments and molecular studies have strongly suggested that mechanism of action of atropine in myopia occurs at the level of retina and that both the M1 and M4 muscarinic receptor signaling pathways are involved.


  Future Scope Top


Even after all this meticulous clinical and molecular level researches, the critical data are too meager, and there are too many unanswered questions for these interpretations to be conclusive. Future research related to the use of atropine with respect to the progression of myopia is necessary to form a better understanding of the exact mechanism of myopic progression and the underlying effect of atropine on this pathogenesis. Importantly, studies on non-Asian ethnic groups are required to determine if the effect on non-Asians is as significant as it has been reported to be for Asian children. The myopic rebound associated with all doses of atropine needs to be studied further to formulate guidelines regarding tapering of treatment or discontinuation of therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Introduction
Atropine for Myopia
Atropine in Myop...
Low-Concentratio...
How Does Atropin...
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Future Scope
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