An epidemic of environmentally induced myopia, most prominent in countries in East and Southeast Asia with high achieving education systems, has emerged in the last two to three generations. This epidemic has stimulated development of methods for slowing the onset and progression of myopia, which may work with some of the numerous but rare forms of genetic myopia. Preventing myopia now needs to be part of routine clinical practice.
Brian Curtin1 entitled his classical book, The Myopias: Basic Science and Clinical Management, in recognition of the fact that, while the common feature of all the forms of myopia is a myopic refractive error, myopia is aetiologically heterogeneous. One of the most obvious distinctions is between axial, corneal and refractive or lenticular myopia. In all cases, the myopic refractive errors can, at least in principle, be corrected optically by changing the optics of the anterior eye to bring the images of distant objects into focus on, or behind rather than in front of, the retina. In the future, as prevention of the onset of myopia and control of progression becomes a more important part of public health and clinical practice, the detailed pathways involved in the development of myopia through differential changes in the biometric components will almost certainly require different approaches to prevention and control.
more intensive education for males characteristic of Ultra- Orthodox schools as compared to Orthodox and then to secular schools, (corresponds) to higher prevalences of myopia and high myopia
Myopia was once believed to be under tight genetic control, based largely on the results of twin studies that demonstrated high heritability values for myopia or spherical equivalent refraction. As the UK Medical Research Council stated in a foreword to the monograph by Sorsby and colleagues on their early studies on twins:2
“It may therefore be taken as established that the dimensions of the optical components, the efficiency of the mechanism co-ordinating the growth of the components and thus the refraction of the eye, are all genetically determined. The modes of inheritance and the possibility that environmental factors have a minor modifying influence are the principal problems now awaiting clarification.”
This view was challenged by the emergence, over one to two generations, of an epidemic of myopia in several countries in East and Southeast Asia since the Second World War. In these parts of the world, the prevalence of myopia in those completing 12 years of formal schooling has now reached around 80%, with 10–20% of that cohort having high myopia (more severe than -5D to -6D).3,4
With this severity of myopia, pathological changes can lead to uncorrectable reductions in visual acuity through myopic maculopathy and the development of staphyloma.5 The implications of these high levels of high myopia are yet to be thoroughly documented, let alone costed, but they certainly include a marked increase in retinal detachment in young and middle-aged adults,6 an increased incidence of choroidal neo-vascularisation in middle-aged adults,7 and a decreased age for cataract surgery in older adults.8
The simple argument, that a condition that is under tight genetic control cannot change that rapidly, has now been generally accepted.3,9,10 It is worth noting this East and Southeast Asian epidemic of myopia is not unique. Rapid increases in myopia were also seen in Inuit/Eskimo communities in North America, starting in the 1960s, as the communities were moved into settlements and started to receive some formal schooling.11 There is also good evidence that high levels of myopia and high myopia, similar to those seen in East and Southeast Asia, exist in Jewish males educated in Ultra-Orthodox and Orthodox schools in Israel.12,13 How long this has been the case is not clear, but the contrast with the much lower prevalences seen in their sisters, as well as in both males and females educated in more secular schools, is certainly striking. The parallel between the intensive religious education for boys in the more religious schools shows up in a dose-response relationship, with the more intensive education for males characteristic of Ultra-Orthodox schools as compared to Orthodox and then to secular schools, corresponding to higher prevalences of myopia and high myopia.
The evidence of an increasing prevalence of myopia in the higher latitudes of North America was initially rather bitterly contested, because it conflicted with the prevailing belief in the genetic determination of myopia. But, since then, the evidence for rapid increases in prevalence in some parts of the world has become overwhelming. What is less clear is how wide-spread these increases have been, with some projections suggesting that by the year 2050, almost half of the world’s population will be myopic, with about 10% affected by high, potentially pathological, myopia.14 However, the evidence for major increases in the prevalence of myopia outside East and Southeast Asia is far from conclusive.
The simple argument, that a condition that is under tight genetic control cannot change that rapidly, has now been generally accepted
While the hypothesis of genetic determination of most myopia did not stand up, the genetic hypothesis that the geographical localisation of the epidemic of myopia in East and Southeast Asia could be explained if people living in those areas were more susceptible to the impact of environmental factors, was not ruled out. This idea did not sit easily with the evidence for a similar epidemic of myopia and high myopia in Orthodox Jewish males but not in their sisters. And other epidemiological evidence did not support this idea. In particular, the prevalence of myopia and high myopia in Singapore is particularly high by international standards in the three major ethnic groups in Singapore,15 including the Indian population of Singapore, which is not of East Asian origin. The prevalence of myopia in this group is much higher than that seen in India, suggesting that the problem is the environment of Singapore and its schools, rather than anything to do with genetic background. Genomewide association study (GWAS) results on myopia are also consistent with this idea, since myopia-associated single-nucleotide polymorphisms (SNPs) are not more common in East Asian populations than in those of European origin, and they explain a lower percentage of the variation in spherical equivalent refraction,16 consistent with a greater role for environmental factors.
EFFECT OF TIME OUTDOORS
In parallel with this more detailed genetic understanding, the environmental factors implicated in the development of myopia have also been clarified. The long-standing hypothesis that myopia is associated with intensive education has been consistently supported,3 and in addition, a protective factor, the amount of time that children spend outside has been extensively documented.17-19 The ability of increased time outdoors to slow the onset of myopia has been demonstrated in randomised controlled trials,20-22 and the hypothetical mechanism involved in this protective effect,18 increased release of retinal dopamine in the brighter environments typically encountered outdoors during the day, has been confirmed in experimental studies.23,24 In contrast, one of the plausible alternative hypotheses, that the lower levels of Vitamin D caused by less time outdoors could lead to the development of more myopia, has not received consistent support. Distinguishing between these competing hypotheses has not been easy, because less time outdoors during daylight hours is naturally associated with lower Vitamin D levels. However, two definitive observations are that myopia development in experimental models can be inhibited by increasing exposure to UV-free light,23 and that in mendelian randomisation experiments, genetically determined changes in Vitamin D levels are not reflected in changes in myopia.25 Resolution of this issue is of great importance for clinical practice, because it suggests that controlling myopia through increased time outdoors will be fully compatible with the sun-smart policies now practised in Australia.
myopia development in experimental models can be inhibited by increasing exposure to UV-free light
Initial results suggested that increased time outdoors did not slow the progression of myopia, but seasonal differences in progression rates26 are consistent with the idea that progression is regulated by the same sort of factors involved in the regulation of onset. More recent results are starting to provide more direct epidemiological evidence of regulation of progression as well.21 Since both depend primarily on axial elongation, this overcomes what would otherwise constitute a significant paradox. Overall, clinical recommendations aimed at controlling myopia onset and progression with more time outdoors now have a substantial evidence base, and can be safely managed, even in the bright light environments encountered in Australia.
OTHER METHODS OF CONTROL
In parallel with these developments in our understanding of the aetiology of myopia, there has also been considerable independent progress with other methods for controlling myopia progression. The use of atropine to slow axial elongation, which had been used sporadically for many years, is now backed up by strong evidence from randomised clinical trials that low dose atropine (0.01% to 0.05%) can be used to significantly slow the development of high myopia.27,28 There is still uncertainty about the mechanism of this effect, in particular whether muscarinic receptors are involved,29,30 and the most effective concentration to be used, but much more widespread use of this drug can be anticipated in the future, particularly by paediatric ophthalmologists.
In addition, the technique of orthokeratology has been developed considerably, and there is now good evidence of its effectiveness in myopia control,31 along with continued debate about its safety. Additionally, there are several optical products which have been designed to impose myopic defocus simultaneously with corrected vision, such as the MiSight32 soft contact lenses, and DIMS spectacles.33 With rapid progress in this area, clinicians need to look closely at the detailed evidence on safety and efficacy for each approach and product, before recommending them to patients.
There now seem to be products suitable for use with school myopia, the form of myopia that has increased markedly. For the future, we need to start thinking about two further issues. With many of the available products, there appears to be a significant percentage of non-responders. It is possible, but by no means proven, that this could be related to aetiological heterogeneity, and taking this into account might help in the design of alternative treatments.
The other important question is whether the emerging techniques that work with school myopia can also be used with the very much rarer, but generally more severe, genetic forms of myopia.34 Here, aetiological heterogeneity is more obvious, with some forms involving mutations that directly affect scleral constituents.35 These might not be affected by time outdoors, or atropine, or optical devices. Other genetic forms, such as congenital stationary night blindness,36 involve mutations that affect signal processing in the outer retina, with the potential to change the rate of dopamine release and affect the same pathways that are involved in the development of school myopia. These forms of genetic myopia may be amenable to control of myopia progression with light and atropine. Obviously, interventions of this kind will not reverse the underlying condition, but it may be possible to reduce the severity of the myopia, and the associated pathology.
WORKING TOWARDS THE FUTURE
We are only at the very beginning of an era of precision medicine in relation to myopia. While parts of the pathways involved in the effects of time outdoors and light are now reasonably clear, our understanding is far from complete. We know much less about the pathways involved in the effects of optical devices. But evidence-based hypotheses about what might work are now possible, and need to be followed up with careful clinical exploration of the possibilities. There is still a long way to go, but compared to the situation of only a few years ago, when the only realistic clinical option in a case of developing severe myopia was to update the optical prescription as often as required, there are now many exciting clinical options to be explored. These can only increase as our understanding of the cellular and molecular basis of the myopias expands with further research.
Professor Ian G Morgan is a biological scientist with the Division of Biochemistry and Molecular Biology, Research School of Biology, Australian National University, Canberra, ACT, Australia. He also holds a visiting research appointment at the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yatsen University, Guangzhou, China.
Dr Amanda N French is a lecturer in the Discipline of Orthoptics, Graduate School of Health, University of Technology Sydney. Her research interests include the development and progression of refractive errors, particularly myopia and associated environmental risk factors such as time spent outdoors.
Professor Kathryn A Rose is Head of Discipline (Orthoptics) at the Graduate School of Health, University of Technology, Sydney. She is also a leading international researcher on the development of vision and refractive errors in children and adolescents. She has combined her clinical and research skills to focus on ophthalmic epidemiology and childhood vision.
- Curtin BJ. The Myopias. Basic Science and Clinical Management, Harper and Row, Phiadelphia, 1985.
- Sorsby A, Sheridan, M, Leary GA. Refraction and its components in twins. Special Reports Series of the Medical Research Council 1962; 303-362.
- Morgan IG, French AN, Ashby RS, et al. The epidemics of myopia: Aetiology and prevention. Prog Retin Eye Res 2018; 62: 134-49.
- Morgan IG, Ohno-Matsui K, Saw SM. Myopia. Lancet 2012; 379: 1739-48.
- Ohno-Matsui K, Lai TY, Lai CC, Cheung CM. Updates of pathologic myopia. Prog Retin Eye Res 2016; 52: 156-87.
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- Morgan IG, Rose KA. Myopia: is the nature-nurture debate finally over? Clin Exp Optom 2019; 102: 3-17.
- Young FA, Leary GA, Baldwin WR, et al. The transmission of refractive errors within eskimo families. Am J Optom Arch Am Acad Optom 1969; 46: 676-85.
- Bez D, Megreli J, Bez M, Avramovich E, Barak A, Levine H. Association Between Type of Educational System and Prevalence and Severity of Myopia Among Male Adolescents in Israel. JAMA Ophthalmol EPub May 30, 2019.
- Zylbermann R, Landau D, Berson D. The influence of study habits on myopia in Jewish teenagers. J Pediatr Ophthalmol Strabismus 1993; 30: 319-22.
- Holden BA, Fricke TR, Wilson DA, et al. Global Prevalence of Myopia and High Myopia and Temporal Trends from 2000 through 2050. Ophthalmology 2016; 123: 1036-42.
- Koh V, Cheung CY, Wong WL, et al. Prevalence and risk factors of epiretinal membrane in Asian Indians. Invest Ophthalmol Vis Sci 2012; 53: 1018-22.
- Tedja MS, Wojciechowski R, Hysi PG, et al. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. Nat Genet 2018; 50: 834-48.
- French AN, Ashby RS, Morgan IG, Rose KA. Time outdoors and the prevention of myopia. Exp Eye Res 2013; 114: 58-68.
- Rose KA, Morgan IG, Ip J, et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology 2008; 115: 1279-85.
- Rose KA, Morgan IG, Smith W, Burlutsky G, Mitchell P, Saw SM. Myopia, lifestyle, and schooling in students of Chinese ethnicity in Singapore and Sydney. Arch Ophthalmol 2008; 126: 527-30.
- He M, Xiang F, Zeng Y, et al. Effect of Time Spent Outdoors at School on the Development of Myopia Among Children in China: A Randomized Clinical Trial. JAMA 2015; 314: 1142-8.
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- Wu PC, Tsai CL, Wu HL, Yang YH, Kuo HK. Outdoor activity during class recess reduces myopia onset and progression in school children. Ophthalmology 2013; 120: 1080-5.
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- Cuellar-Partida G, Williams KM, Yazar S, et al. Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study. Int J Epidemiol 2017; 46: 1882-90.
- Gwiazda J, Deng L, Manny R, Norton TT, Group CS. Seasonal variations in the progression of myopia in children enrolled in the correction of myopia evaluation trial. Invest Ophthalmol Vis Sci 2014; 55: 752-8.
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- Yam JC, Jiang Y, Tang SM, 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: 113-24.
- Carr BJ, Mihara K, Ramachandran R, et al. Myopia- Inhibiting Concentrations of Muscarinic Receptor Antagonists Block Activation of Alpha2A-Adrenoceptors In Vitro. Invest Ophthalmol Vis Sci 2018; 59: 2778-91.
- Carr BJ, Nguyen CT, Stell WK. Alpha2 -adrenoceptor agonists inhibit form-deprivation myopia in the chick. Clin Exp Optom 2019; 102: 418-25.
- Cho P, Tan Q. Myopia and orthokeratology for myopia control. Clin Exp Optom 2019; 102: 364-77.
- Chamberlain P, Peixoto-de-Matos SC, Logan NS, Ngo C, Jones D, Young G. A 3-year Randomized Clinical Trial of MiSight Lenses for Myopia Control. Optom Vis Sci 2019; 96: 556-67.
- Lam CSY, Tang WC, Tse DY, et al. Defocus Incorporated Multiple Segments (DIMS) spectacle lenses slow myopia progression: a 2-year randomised clinical trial. Br J Ophthalmol May 29, 2019.
- Flitcroft DI, Loughman J, Wildsoet CF, Williams C, Guggenheim JA, Consortium C. Novel Myopia Genes and Pathways Identified From Syndromic Forms of Myopia. Invest Ophthalmol Vis Sci 2018; 59: 338-48.
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- Zeitz C, Robson AG, Audo I. Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms. Prog Retin Eye Res 2015; 45: 58-110.