m
Recent Posts
Connect with:
Thursday / December 12.
HomemiophthalmologyHarnessing Axial Growth with Atropine

Harnessing Axial Growth with Atropine

Atropine can effectively slow the progression of myopia for many patients, however there is much to be learnt about how this therapy acts and when and how it should be used.

Myopia is not only the most common eye disorder but it has become evident that the prevalence is increasing worldwide. It has been predicted that 50% of the world’s population will be affected by 2025. The age of onset is also decreasing, leading to an increase in the incidence of pathological myopia (defined by the World Health Organization (WHO) as -5.0 D or greater).1 In East Asia the prevalence of myopia in young adults is approaching 80% and rates of high myopia are over 20%.2 Pathological myopia leads to an increased risk of sight threatening disease, including glaucoma, retinal detachment, choroidal neovascularisation and macular disease. Juvenile myopia develops when a child’s eye is in a phase of ocular growth and progresses with axial length growth. There are many factors affecting juvenile eye growth and possible interventions include genetic, environmental, refractive and pharmacological directions with the aim being to limit axial length growth.

it was the atropine for the treatment of myopia studies (ATOM)5,6 which consolidated interest in the use of atropine to retard the progression of myopia in children

Figure 1. Summary of findings from ATOM1 and ATOM2 studies: change in spherical equivalent13

Atropine, a nonselective muscarinic antagonist, has been at the forefront of the pharmacological interventions of myopia progression. Topical atropine has been clinically available since the 1900s with various ocular uses including use in children. There are no long-term adverse side effects associated with its use.3 Studies on topical atropine use were published in the 1960s and 1970s,4 however, it was the atropine for the treatment of myopia studies (ATOM)5,6 which consolidated interest in the use of atropine to retard the progression of myopia in children. Currently atropine 0.01% needs to be made at a compound pharmacy and its use for myopia progression is off label.

It is unclear how atropine retards axial length growth and therefore myopia progression in childhood. Atropine prevents myopia in the chick eye demonstrating that atropine is not working via accommodation as chicks do not have muscarinic receptors in their ciliary muscles.4 Current theories suggest it may act via a neurochemical cascade in the retina, possibly via amacrine cells or a direct effect on the scleral fibroblast by inhibiting glycosaminoglycan synthesis.7 The primary drive leading to elongation of the eye is still unclear and could be secondary to choroid thinning or thinning of the scleral.8–10

ATOM STUDIES

ATOM 15 was a Singapore based study involving 400 children aged six to 12 years with a refractive error of -1.00 to -6.00D with -1.5D astigmatism or less. The patients in the study were randomised to receive either atropine 1% or placebo drops in one eye over two years. Axial length was measured with an A scan ultrasound with an average of six measurements with a low standard deviation between values. The two-year results demonstrated that the treated eye had minimal axial length growth compared with the control eye or the placebo treated eye. This resulted in a 77% reduction in the progression of myopia in the treated eye, almost 1D. This dose of atropine was well tolerated; however, this was aided by the regiment of treating one eye only, which allowed the untreated eye to be free of near blur.

ATOM 26 followed to compare the efficacy and tolerance of lower doses of atropine. Again 400 children aged six to12 years, were randomised in a double masked study, with a refractive error of at least -2D and -1.5D astigmatism or less. Atropine doses of 0.5%, 0.1% or 0.01% were given bilaterally, nightly over a two year period. The Zeiss IOL master was used to measure axial length. The results were surprising and showed that the lowest dose had comparable efficacy to the highest dose in retarding the progression of myopia in their cohort. Myopia progression in the atropine 0.01% group was -0.49D compared with the untreated group in ATOM 1 of -1.2D. The higher doses (0.5% and 0.1%) had a greater effect in retarding myopia progression, which was statistically significant compared with 0.01%, however, it was not considered to be clinically significant and the lowest dose was better tolerated. It is unclear why, in this study, axial length increased 0.4mm in the 0.01% group, a similar amount to the placebo group in ATOM 1, but maintained the advantage of retarding the dioptre progression of myopia. Interestingly, the effect on axial length growth was more pronounced in the second year – the increase in axial length was a third less than in the first year on atropine 0.01%. Importantly, atropine 0.01% was well tolerated with local dermatitis of the skin and conjunctiva the most common side effect. This was still a rare side effect and was reported more often with the higher doses.

The ATOM study group went further, by following the ATOM 1 and 2 results, to assess the possibility of rebound when drops were stopped. Observing the cohort from ATOM 1 during wash out for one year, they found that myopia progression increased in the atropine 1% group compared with the untreated group.11 This was recognised as rebound ‘catch up’ once the atropine 1% was ceased. Analysing the progression over three years (two years with treatment and then one year without) the treatment group still had less severe myopia, with a spherical equivalent of -4.29DS compared with -5.22DS. Similarly, axial length progression was less in the treated group over the three year period, although there was catch-up in growth in the one year washout period. This meant that although some of the effect of atropine was lost in the wash out year, progression over the three years was still less than if no treatment had been given.

In the wash out period following ATOM 2, participants on the lower doses showed similar rebound. However, the rebound was also dose related, with the children on higher doses having more rebound catch up in the year atropine was ceased.12 Axial length showed comparative results, with growth increasing after atropine was ceased and the rebound being greater in higher dose groups. In 2016, the five year follow up of the ATOM 2 groups were published.13 The children that exhibited progression of -0.5D or more in at least one eye during wash out phase were restarted on atropine 0.01% for two years. The five year results, expressed as the five year mean myopia progression, for the atropine 0.01% group was less than the five year follow up of the children who received higher doses initially in ATOM 2 ( -1.38 +/- 0.98D compared with -1.98 +/- 1.10D in the atropine 0.5% group). Percentages of high myopia (> 6.0D) and very high myopia (>8.0D) were lowest in the atropine 0.01% group. The overall effect of atropine 0.01% was to slow progression by 50% (Figure 1).

REVIEW STUDIES

Meta-analysis confirms atropine is effective at retarding myopia progression. Initial meta-analysis publications did not include studies with atropine 0.01%, however, there seemed to be a dose response effect with high doses having a greater effect.14 This was reviewed by the Cochrane data base in 2011 and showed atropine to be the most effective intervention in retarding the progression of myopia in children.15 A later meta-analysis in 2016 showed atropine was most effective at slowing myopia progression compared to all other interventions including refractive methods, however, a dose response effect was not shown.16 With more studies comparing different doses of atropine it seems clear that the amount of retardation of axial growth is dose related with higher doses having a greater effect, however, the side effect profile also increases with higher doses.17

it seems clear that the amount of retardation of axial growth is dose related with higher doses having a greater effect, however, the side effect profile also increases with higher doses

In 2017, the American Academy of Ophthalmology reviewed the literature on topical atropine for the prevention of myopia progression and found level one evidence to support its use. They commented that to minimise rebound, low dose, in particular atropine 0.01%, might be indicated.18 

SAFETY

Adverse effects with the use of atropine include dilation leading to glare and photophobia, near blur due to cycloplegia and local skin and ocular reactions. The ATOM studies offered photochromatic (tinted) glasses and/or progressive addition for near blur if symptomatic. Only 7% of participants on atropine 0.01% in phase one of the ATOM 2 study, requested special glasses with 0% requesting special glasses in phase three when children were restarted on atropine 0.01%.13 There was little effect on pupil size and accommodation with treatment. However, adverse effects with higher dose atropine demonstrate a dose response relationship.5,6,19-21 It would seem the lowest dose is as effective and less likely to result in adverse side effects.17 Some concern has been raised that Caucasian children may experience more adverse effects due to their often lighter iris colour.22 Although many more trials have been conducted in Asia, studies undertaken in Europe and America show similar effects regarding the retardation of myopia progression in this patient group,22-24 with greater side effects reported at higher doses of atropine. Atropine 0.01% studies in Europe and America25-27 showed retardation of myopia and high tolerance of side effects in this patient cohort.

PERSISTING QUESTIONS

When to Start? 

Knowing when to initiate treatment is as difficult as the next question, which is when to stop treatment. Various recent review publications raise the issue of when best to treat.7,18,28 One publication considered providing guidelines after cycloplegic refraction categorised children into hyperopes, pre-myopes (between +0.5 and -0.5D) and myopes. It was discussed that all myopic children should then be offered low dose atropine, preferably 0.01%.1 Other articles have suggested treating the ‘at risk progressors’ only. This may include those with fast axial length growth or refractive change, early age of onset and family history of high myopia. A trial in Asia tested the hypothesis that treatment of premyopes did reduce the incidence of myopia and subsequently reduce the incidence of high myopia.29 

The average growth of the eye in childhood is around 0.2 mm per year.5,30 The five year data from the ATOM studies recommended initiating treatment with atropine 0.01% if myopia progression exceeded 0.5D the preceding year,13 which corresponds to elongation greater than 0.2mm.

In a study I have conducted in a clinical setting, I identified fast progressors using axial length parameters. Treatment with atropine 0.01% was initiated if the axial length progression was greater than 0.1mm in a six month period. This approach led to a 50% relative reduction in axial length progression in the subsequent six months (unpublished data).

In my experience, initial assessment of a myopic child often presents the possibility that accelerated myopia progression has already occurred and very slow progression is currently occurring. I recommend a baseline assessment with cycloplegic refraction and that axial length measurement is documented with a review in six months. With these criteria, many patients have been found to be stable, which negates the use of medication. Additionally, for many patients, this approach negates treating myopia progression which is not due to axial growth and which occurs in rare conditions such as spherophakia, a condition in which atropine could precipitate angle closure glaucoma. It also enables the trend of growth to be monitored, which guides the length of treatment.

REVIEW AFTER INITIATING TREATMENT

Regular six monthly reviews are recommended,1 including refraction and axial length measurement. This allows assessment of treatment effect, and ensures up to date refraction and assessment of any side effects the patient may be experiencing. I routinely check for pupillary response to light, ask about glare, and check near vision. In my practice, treatment has been very well tolerated with very few patients self-ceasing the drops. This is probably assisted by evidence of fast progression prior to treatment initiation which helps motivate compliance. Regular education on how to instil drops, and lifestyle information regarding sunlight exposure and reduction of recreational near work, is also given at each review.

HOW LONG TO TREAT?

Most publications hypothesise that once initiated, treatment should continue for at least two years, based on the ATOM 2 studies.1,13 Alternately, some centres recommend continuous treatment until late adolescence (15 to 18 years old) when myopia progression is known to slow down.31,32 This is mainly due to concerns about rebound once atropine has been ceased. As the age of children in whom intervention with low dose atropine is initiated gets lower, the length of treatment will become longer. In my clinical practice I usually start treatment on fast progressors once they are identified and continue for a minimum of two years. As I routinely monitor six monthly, if the axial length progression changes consistently drop to negligible amounts after two years, I consider a six month wash out. If the rate increases again in the wash out period above 0.1mm/six months, treatment with atropine 0.01% is reconsidered. This individualised approach addresses the patient who has progressed early and then slows down early in teen years.

NON-RESPONDERS

In the ATOM studies, of the children in the first phase, 9.3 % treated with atropine 0.01%; 6.4% on atropine 0.1%; and 4.3% on atropine 0.5% did not respond, instead experiencing progression of greater than 1.5D over the first two years of treatment.

questions regarding combining interventions aimed at treating myopia progression also exist

It is unclear if non-responders to atropine 0.01% would in fact respond to higher doses. Similar non response rates were found in another atropine study with 4.0% not responding to atropine 0.5%.20 In this retrospective cohort study, poor responders were defined as those having more than a 0.5D change in six months and 45% of participants treated with atropine 0.05% were in this group. These children were switched to atropine 0.1% and with a 4.5 year follow up, 20% continued to progress as poor responders. Importantly, this rate was still better than no treatment. In ATOM 1, even with the effect of atropine 1% on retardation of myopia, 12% of children continued to progress faster than 0.5D per year. This group were found to be younger, more myopic or to have two parents with myopia. In my patient cohort there was a very high rate of good responder documented. This is possibly due to patient selection, where only the fast progressors in a growth phase were treated.

The definition of poor or non-responder needs clarification. If a child is progressing at a fast rate, atropine seems to reduce that rate by 50%, which is clearly a high response. With the definition of fast progression of myopia being greater than 0.5D per year, some children could be considered to have failed treatment using this definition. As the accumulation of axial length growth continues for many years, is a reduction of growth by 50% yearly really treatment failure? Given that some patients do not slow down further on any treatment, then a 50% reduction in progression yearly is a good response.

DIFFERENT DOSES

Since the initial ATOM studies there have been many other studies confirming the effect of myopia retardation with the use of atropine. These studies have included the use of many different concentrations of atropine.21,33 The most recent trial series (LAMP study) published their first phase, one year results earlier this year. Participants, consisting of four to 12 year olds who were progressing at a rate of at least 0.5D in the year prior to enrolment, were randomised for dose concentrations of atropine 0.05%, 0.025% and 0.01% as well as a placebo group. The efficacy of atropine was evident in a clear concentration-dependent response, with progression of -0.27, -0.46, -0.59, and -0.81D in the 0.05%, 0.025%, 0.01% and placebo groups respectively.21 Axial length change mirrored the dose response. The effect on accommodation and pupil diameter was also concentration-dependent, with the greatest effect seen with the highest concentrations of atropine used. In the study, even the highest dose was well tolerated with no statistical difference between reported side effects or the need for photochromatic or progressive glasses needed between groups. Although interesting, it remains to be seen which is the optimal concentration with the best balance between efficacy and safety. Additionally, atropine 0.01% had a greater effect on myopia retardation and slowing of axial length growth in the second year in the ATOM studies. We await phase two studies where the placebo group will be recruited in to the optimal group (best treatment to side effect ratio) and the other groups analysed after another year. Phase three will be a wash out year for all concentrations, except the cross over placebo group, to determine rebound. Phase four will run for two years, treating the patients who progressed more than 0.5D in the wash out year, however the cross over group will continue with their existing atropine treatment. This will help clarify the optimal dose/concentration and determine the effects of long-term treatment.

Current data would suggest lowest dose results in efficacy and the lowest side effect profile. Most review articles recommend that if treatment is to be initiated, atropine 0.01% would be indicated.7,13,17,18,34 The clinical question remains as to whether our non-responders should be treated with an increasing concentration of atropine in the hope of a better response and titrating the dose according to the side effects incurred, much like we treat glaucoma with an escalating armament of drops with known greater efficacy and monitor for side effects. We are still to know how best to administer this for best outcomes.

COMBINATION TREATMENT

Finally, in addition to the question of the worth of using greater atropine concentrations, questions regarding combining interventions aimed at treating myopia progression also exist. The scope of refractive intervention is large and diverse and includes orthokeratology (OK), soft and hard contact lenses and dual focus/peripheral defocus glasses. However, there is only one study35 that combines atropine 0.01% with OK lenses. The timing and precise combinations are unclear and whether the side effect profile increases with the additional use of OK and other contact lenses remains to be determined. The real concern of sight threatening complications, including microbial keratitis with the use of OK, should not be ignored.36 Monitoring progression also becomes difficult with OK negating the use of refraction or axial length growth as progression parameters which can be reviewed.

Additional counselling regarding outdoor exposure and reduction of recreational near work remains reasonable advice. Outdoor studies are extensive, including randomised controlled community-based trials,37-42 which includes Australia. The evidence is strongest for reducing incident myopia rather than retarding progression once myopia has occurred. Analysis links every hour of outdoor time per week to a 2% reduction of the risk of myopia.43 Near work remains controversial and a meta-analysis in 201616 showed a small effect of increased near work and myopia progression.

FUTURE DIRECTIONS

It remains paramount to decipher where myopia control/eye elongation occurs and the underlying mechanisms involved. This will help enable development of therapies to target tissues, which may result in more directed pharmacological treatment.

Better understanding of combination therapies is needed along with a greater understanding of the best time at which to introduce these therapies. Is there a therapy that works best at a certain stage of myopia progression? Who should we target and when? Finally, what are the long-term treatment outcomes in terms of both efficacy and safety profile of the interventions provided. Much research is needed to answer these questions and maybe provide novel interventions.

To earn your CPD points from this article, answer the assessment available at mieducation.com/ harnessing-axial-growth-with-atropine

Dr Loren Rose BSc (Hons I), MBBS (Hons), FRANZCO completed her medical degree from the University of Sydney, graduating with MBBS (Honours). Prior to that, she completed a Bachelor of Science from the University of Sydney, graduating with Honours (Class I) in Visual Neuroscience. 

Dr Rose completed her ophthalmic training at the Royal Eye and Ear Hospital in Victoria. Following this, she underwent a fellowship in paediatric ophthalmology at the Royal Children’s Hospital, Melbourne. Now based in Sydney, she is a clinical senior lecturer at Macquarie University and is currently enrolled in a PhD at Macquarie University, titled Myopia in Children. 

References 

  1. Wu, P.C., et al., Update in myopia and treatment strategy of atropine use in myopia control. Eye (Lond), 2019. 33(1): p. 3-13. 
  2. Wong, T.Y., et al., Epidemiology and disease burden of pathologic myopia and myopic choroidal neovascularization: an evidence-based systematic review. Am J Ophthalmol, 2014. 157(1): p. 9-25 e12. 
  3. Curtin, B.J., The Myopias: Basic science and clinical management. 1985, Philadelphia: Harper and Row. 222. 
  4. Wildsoet, C.F., et al., IMI – Interventions Myopia Institute: Interventions for Controlling Myopia Onset and Progression Report. Invest Ophthalmol Vis Sci, 2019. 60(3): p. M106-M131. 
  5. Chua, W.H., et al., Atropine for the treatment of childhood myopia. Ophthalmology, 2006. 113(12): p. 2285-91. 
  6. Chia, A., 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(2): p. 347-54. 
  7. Tan, D., et al., Topical Atropine in the Control of Myopia. Asia Pac J Ophthalmol (Phila), 2016. 5(6): p. 424-428. 
  8. Nickla, D.L. and J. Wallman, The multifunctional choroid. Prog Retin Eye Res, 2010. 29(2): p. 144-68. 
  9. McBrien, N.A. and A. Gentle, Role of the sclera in the development and pathological complications of myopia. Prog Retin Eye Res, 2003. 22(3): p. 307-38. 
  10. Jiang, W.J., et al., Amphiregulin Antibody and Reduction of Axial Elongation in Experimental Myopia. EBioMedicine, 2017. 17: p. 134-144. 
  11. Tong, L., et al., Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. Ophthalmology, 2009. 116(3): p. 572-9. 
  12. Chia, A., et al., Atropine for the treatment of childhood myopia: changes after stopping atropine 0.01%, 0.1% and 0.5%. Am J Ophthalmol, 2014. 157(2): p. 451-457 e1. 
  13. Chia, A., Q.S. Lu, and D. Tan, Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops. Ophthalmology, 2016. 123(2): p. 391-9. 
  14. Song, Y.Y., et al., Atropine in ameliorating the progression of myopia in children with mild to moderate myopia: a metaanalysis of controlled clinical trials. J Ocul Pharmacol Ther, 2011. 27(4): p. 361-8. 
  15. Walline, J.J., et al., Interventions to slow progression of myopia in children. Cochrane Database Syst Rev, 2011(12): p. CD004916. 
  16. Huang, J., et al., Efficacy Comparison of 16 Interventions for Myopia Control in Children: A Network Meta-analysis. Ophthalmology, 2016. 123(4): p. 697-708. 
  17. Gong, Q., et al., Efficacy and Adverse Effects of Atropine in Childhood Myopia: A Meta-analysis. JAMA Ophthalmol, 2017. 135(6): p. 624-630. 
  18. Pineles, S.L., et al., Atropine for the Prevention of Myopia Progression in Children: A Report by the American Academy of Ophthalmology. Ophthalmology, 2017. 124(12): p. 1857-1866. 
  19. Yen, M.Y., et al., Comparison of the effect of atropine and cyclopentolate on myopia. Ann Ophthalmol, 1989. 21(5): p. 180-2, 187. 
  20. Shih, Y.F., et al., Effects of different concentrations of atropine on controlling myopia in myopic children. J Ocul Pharmacol Ther, 1999. 15(1): p. 85-90. 
  21. Yam, J.C., et al., Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control. Ophthalmology, 2019. 126(1): p. 113-124. 
  22. Polling, J.R., et al., Effectiveness study of atropine for progressive myopia in Europeans. Eye (Lond), 2016. 30(7): p. 998-1004. 
  23. Brodstein, R.S., et al., The treatment of myopia with atropine and bifocals. A long-term prospective study. Ophthalmology, 1984. 91(11): p. 1373-9. 
  24. Kennedy, R.H., et al., Reducing the progression of myopia with atropine: a long term cohort study of Olmsted County students. Binocul Vis Strabismus Q, 2000. 15(3 Suppl): p. 281-304. 
  25. Clark, T.Y. and R.A. Clark, Atropine 0.01% Eyedrops Significantly Reduce the Progression of Childhood Myopia. J Ocul Pharmacol Ther, 2015. 31(9): p. 541-5. 
  26. Diaz-Llopis, M. and M.D. Pinazo-Duran, Superdiluted atropine at 0.01% reduces progression in children and adolescents. A 5 year study of safety and effectiveness. Arch Soc Esp Oftalmol, 2018. 93(4): p. 182-185. 
  27. Loughman, J. and D.I. Flitcroft, The acceptability and visual impact of 0.01% atropine in a Caucasian population. Br J Ophthalmol, 2016. 100(11): p. 1525-1529. 
  28. Sankaridurg, P., et al., Controlling Progression of Myopia: Optical and Pharmaceutical Strategies. Asia Pac J Ophthalmol (Phila), 2018. 7(6): p. 405-414. 
  29. Fang, P.C., et al., Prevention of myopia onset with 0.025% atropine in premyopic children. J Ocul Pharmacol Ther, 2010. 26(4): p. 341-5. 
  30. Jonas, J.B., et al., Association between axial length and horizontal and vertical globe diameters. Graefes Arch Clin Exp Ophthalmol, 2017. 255(2): p. 237-242. 
  31. Xiang, F., M. He, and I.G. Morgan, Annual changes in refractive errors and ocular components before and after the onset of myopia in Chinese children. Ophthalmology, 2012. 119(7): p. 1478-84. 
  32. Donovan, L., et al., Myopia progression rates in urban children wearing single-vision spectacles. Optom Vis Sci, 2012. 89(1): p. 27-32. 
  33. Wang, Y.R., H.L. Bian, and Q. Wang, Atropine 0.5% eyedrops for the treatment of children with low myopia: A randomized controlled trial. Medicine (Baltimore), 2017. 96(27): p. e7371. 
  34. Wu, P.C., et al., Update in myopia and treatment strategy of atropine use in myopia control. Eye (Lond), 2018. 
  35. Kinoshita, N., et al., Additive effects of orthokeratology and atropine 0.01% ophthalmic solution in slowing axial elongation in children with myopia: first year results. Jpn J Ophthalmol, 2018. 62(5): p. 544-553.
  36. VanderVeen, D.K., et al., Use of Orthokeratology for the Prevention of Myopic Progression in Children: A Report by the American Academy of Ophthalmology. Ophthalmology, 2019. 126(4): p. 623-636. 
  37. Jones, L.A., et al., Parental history of myopia, sports and outdoor activities, and future myopia. Invest Ophthalmol Vis Sci, 2007. 48(8): p. 3524-32. 
  38. Saw, S.M., et al., A cohort study of incident myopia in Singaporean children. Invest Ophthalmol Vis Sci, 2006. 47(5): p. 1839-44. 
  39. Guggenheim, J.A., et al., Time outdoors and physical activity as predictors of incident myopia in childhood: a prospective cohort study. Invest Ophthalmol Vis Sci, 2012. 53(6): p. 2856-65. 
  40. French, A.N., et al., Risk factors for incident myopia in Australian schoolchildren: the Sydney adolescent vascular and eye study. Ophthalmology, 2013. 120(10): p. 2100-8. 
  41. Li, S.M., et al., Time Outdoors and Myopia Progression Over 2 Years in Chinese Children: The Anyang Childhood Eye Study. Invest Ophthalmol Vis Sci, 2015. 56(8): p. 4734-40. 
  42. Shah, R.L., et al., Time Outdoors at Specific Ages During Early Childhood and the Risk of Incident Myopia. Invest Ophthalmol Vis Sci, 2017. 58(2): p. 1158-1166. 
  43. Sherwin, J.C., et al., The association between time spent outdoors and myopia using a novel biomarker of outdoor light exposure. Invest Ophthalmol Vis Sci, 2012. 53(8): p. 4363-70.