OPTOMETRY INVITED REVIEW. The cause(s) of myopia and the efforts that have been made to prevent it

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1 C L I N I C A L A N D E X P E R I M E N T A L OPTOMETRY INVITED REVIEW The cause(s) of myopia and the efforts that have been made to prevent it Clin Exp Optom 2012; 95: Jacob Sivak LScO PhD OD School of Optometry, University of Waterloo, Waterloo, Ontario, Canada jsivak@uwaterloo.ca Submitted: 12 April 2012 Revised: 31 May 2012 Accepted for publication: 5 June 2012 DOI: /j x In spite of a long history of study, as well as a significant, recent increase in research attention, the cause(s) and the means of preventing or mitigating the progression of myopia in children are still elusive. The high and growing prevalence of myopia, especially in Asian populations, as well as its progressive nature in children and its effect on visual acuity, have contributed to the recent surge in interest. Animal research carried out in the 1970s also helped spark this interest by legitimising the study of environmental influences on the refractive development of the eye. Efforts that include the use of visual training or biofeedback, bifocal and progressive lenses, contact lenses and pharmaceuticals are reviewed. Current research trends that focus on the relationship between genetics and environment, as well as studies, both animal and human, that explore the effect of peripheral refractive error on the refractive development of the central retina are also reviewed. Key words: aetiology, accommodation, causes, myopia Efforts to determine the cause or causes of myopia, as well as the means to prevent it, have been an important topic of scientific interest for at least 150 years. In spite of this long span of attention and a significant increase during the last two or three decades in the number of research studies addressing myopia (one computer search engine currently lists about 15,000 separate articles but of these, only 2,000 or so were published by 1977), these efforts have been singularly unsuccessful. There has been a number of reviews on the topic of myopia, including several excellent discussions by Grosvenor, 1,2 Goss, 3 Woo and Wilson, 4 Gilmartin, 5 the literature review of a PhD thesis on the use of bifocals to control myopia by Cheng 6 (available online) and a review of methods of myopic control by Lee. 7 Naturally, a single comprehensive review of a topic with such a voluminous literature is difficult, if not impossible and some topics, such as the relationship between myopia and ocular or systemic disease, as well as congenital myopia, are not addressed here. This review highlights some of the more controversial aspects of the history of the study of myopia. It also represents an effort to emphasise the interrelationship between the study of animal models and human studies of myopia. BACKGROUND Prevalence and progression of myopia and its effect on visual acuity Three significant factors are responsible for much of the attention paid to myopia. These are the high prevalence of myopia, its progressive nature in children and the deleterious effect of even modest amounts of uncorrected myopia on visual acuity. While not addressed in this review, it should also be mentioned that high myopia can lead to significantly increased risk of ocular disease. 572 Clinical and Experimental Optometry 2012 Optometrists Association Australia

2 Several reports indicate that the incidence of myopia is increasing and there is widespread support for the view that both genetics and environment must play roles. 8 A study of Taiwanese children highlights the extreme incidence of myopia among Asian populations. 9 Carried out on over 11,000 Taiwanese students aged six to 18 years, the study indicated that by the time they are 18 years old, over 84 per cent of these children are myopic, with extreme myopia (over 6.00 D) amounting to 18 per cent in girls and 12 per cent in boys. A report on the prevalence and progression of myopia in Singaporean children also found high levels for both, particularly in Chinese children. 10 Another study, published in 2009 by Vitale, Sperduto and Ferris 11 is important because it compares recent data on the incidence of myopia in the US with data collected using the same methods in the early 1970s. This study used a variety of criteria and methods, such as lensometry, pinhole visual acuity and retinoscopy, depending on the subjects visual acuity, to survey the prevalence of myopia in people 12 to 54 years of age. The important point is the consistancy of the methods used in the earlier and later studies. The results indicate a significant increase in overall prevalence from 25.0 per cent in the earlier to 41.6 per cent in the more recent study. The change for African Americans is even more dramatic (an increase from 13.0 to 33.5 per cent). Grosvenor 1 described the progressive nature of myopic development, particularly in young children, while Hirsch 12 provided evidence as to the effects of myopia on visual acuity. The latter work is particularly instructive in that it includes averages and ranges of acuity measures. Thus, even a moderate amount such as 1.00 D of myopia will result in an average visual acuity of 6/19.5. Moreover, the range to 95% confidence limits is 6/9 to 6/45. A more recent report 13 shows that even when corrected, myopes exhibit lower contrast sensitivity. Accommodation and myopia The literature concerning the association between accommodation and myopia is old and goes back to the early years of visual science in the mid-nineteenth century. Indeed, both von Helmholz 14 and Donders, 15 two of the most important scientific figures of this period, believed that myopia resulted from excessive near work. Donders 15 wrote in 1864 that: The distribution of myopia, chiefly in the cultivated ranks, points directly to its principal cause; tension of the eyes for near objects. In 1909, Helmholtz 14 stated that typical myopia is an acquired anomaly...the effect of over-exertion with close work. Thus, both scientists considered myopia to be an acquired anomaly. Tscherning, 16 a Danish ophthalmologist who measured the refractive states of 38,670 Danish military recruits, noted a correlation between myopia and level of education, as indicated by their work. For example, while only 2.5 per cent of farmers and fishermen were myopic, for students with advanced education the number was 32 per cent. The role of accommodation in the development of myopia has been the dominant and most controversial issue in the more than 100 years since the writings of Donders and Helmholtz. In part, this is a result of scientific disputes over the exact nature of accommodation in humans. The theory proposed by Helmholz 17 involving the release of zonular tension on the lens from the accommodative contraction of the ciliary muscle is by far the widely accepted view, 18 although authors such as Tscherning 19 and more recently Schachar, Cudmore and Black 20 have proposed the opposite: that is, an increase in zonular tension on the lens with accommodative contraction of the ciliary muscle. In addition, the past 100 years or so have also led to widespread general interest in the study of myopia and this has resulted in a plethora of books, pamphlets, articles and more recently internet writings, which deal with ocular development and myopia in terms that are unsupported by scientific evidence. An excellent example would be the book by WH Bates entitled The Cure of Imperfect Sight by Treatment Without Glasses, published in Bates used crude physiological experiments to propose that accommodative change is the responsibility of the extra-ocular muscles of the eye. The book promotes the benefits of exercises, such as palming (pressing the eyes with the palms of the hands) and gazing at the sun. Views such as the role of the extra-ocular muscles in the development of myopia are still expressed today, as an internet search for the words myopia and extraocular muscles will demonstrate. Moreover, Bates approach is still seriously referred to in a 1998 publication on the control of myopia published by the Optometric Extension Program. 22 EARLY MYOPIA RESEARCH Efforts to prevent or reduce myopia Traditionally, most of the methods that have been used clinically and or tested in research studies to prevent or reduce the magnitude of myopia are based on the view that accommodation is at least a part of the cause. The methods that have been explored include: 1. visual training and biofeedback 2. use of lenses (under-correcting the myopia or prescribing bifocals or progressive lenses) and 3. the use of pharmaceuticals. The effort to control myopia through the use of contact lenses is the one approach that is not directly related to the assumption that myopia has an accommodative cause. VISUAL TRAINING The use of visual training to control myopia is largely based on the assumed connection between accommodation and myopia. Once this connection is made, the further assumption is that myopia is caused by environmental visual factors and therefore, training can prevent or reduce myopia. This view was particularly promoted in North America by the profession of optometry, in part due to the influence of the Optometric Extension Program, a behaviourally oriented program of continuing education cofounded by AM Skeffington in The possible value of visual training for myopia was tested in 1944, in relation to Clinical and Experimental Optometry 2012 Optometrists Association Australia 573

3 recruitment needs for the war effort (World War II). 24 Known as the Baltimore Myopia Control Project, the study was carried out on 111 subjects, nine to 32 years of age, who were provided training sessions (three per week and ranging from five to 37 sessions) by optometrists. The results were interpreted positively by optometrists (for example, Ewalt 24 ), who provided the training and negatively by ophthalmologists (for example, Woods, ), who evaluated the results. As noted by Grosvenor, 2 none of the reports published described the training offered, although the Ewalt report 24 includes a photograph of a group of subjects looking into stereoscopes, while another shows a subject in front of a rotating spiral and two other subjects holding strings that control variable distance targets. Woods 25 notes that the training had nothing to do with the Bates approach, that it was carried out under the direction of Skeffington and that it was based on the postulate that seeing is a learned act and therefore susceptible to training. A summary of the project by Shepard 26 suggests that both sides are correct but it is clear that the reports of success are based simply on measures of improved visual acuity. Before and after measurements of refractive state, carried out by ophthalmologists at the Wilmer Institute at Johns Hopkins, indicated no refractive change. 25 Shepard writes: The only reasonable conclusion is that myopia was actually not reduced. He further states: Let us admit that nature will probably keep on making some eyeballs relatively large and some relatively small, just as she makes some feet disproportionate in size to the rest of the organism. TREATMENT WITH BIFOCALS LENSES The origins of the practice of prescribing bifocals for children to prevent or slow down the progression of myopia by reducing the need for accommodation, certainly go back at least to the 1940s, as indicated by early references, such as Betz 27 and Tait. 28 In his book, Visual Analysis, a text used in a number of optometric teaching programs in North America in the 1960s and 1970s, Manas 29 writes that progressive myopia can be avoided and the condition stabilised by the prescription of proper bifocal lenses. In fact, the first scientifically structured study 30 dealing with this issue provided negative results in that the bifocals prescribed for myopic subjects did not retard the progression of myopia. It is also pertinent that in the first edition of his text Clinical Refraction, Borish 31 writes:... the placing of bifocals upon children, who are frequently of introvertive character due to their visual handicap anyway and thus marking them as curious from a social standpoint, is of dubious psychological merit, even if the efficacy of the treatment were proven and accepted instead of being still conjecturable. He states further that bifocals cannot be credited with halting the progression of myopia. Early animal studies of myopia The question of whether myopia is genetically determined or whether it is caused by the environment, that is, nature versus nurture, is a question that has interested researchers from the start. Clearly, authors such as Helmholtz, Tscherning and Donders believed in an environmental cause. Studies using primates (usually macaque monkeys) to induce the development of myopia were carried out during the early part of the twentieth century and involved restricting the animals to a posture in which the head is kept lower than the rest of the body for extended periods of time (six hours per day for five to six months). 32,33 Up to seven dioptres of myopia were reported. A later series of reports by Young 34,35 involving macaques, in which vision was restricted to a distance of 20 inches or less through the use of hoods worn for extended periods of time up to a year. Here, the myopia recorded was less, usually in the range of one to two dioptres, with younger animals developing more myopia. Neither the Levinsohn 32 nor the Young 34,35 studies were convincing, in spite of the fact that Young was a prolific author who made an effort to disseminate his results and views widely. Experiments involving monkeys over extended periods of time are difficult to carry out and the multiple variables that can affect the results are difficult to control. Usually, the number of animals tested was small (seven or less in the Young studies) and the refractive changes small (0.50 to 2.00 D in the Young studies). The earlier work involving body posture lacked clarity, as to the physiological connection between posture, eye location and refractive state. The Young experiments implicate extended periods of accommodation as the cause of myopia. This point is spelled out by Young 36 in a later paper in which myopia is described as developing in two stages. First, extended periods of accommodation produce a permanent change in lens radii of curvature and then the increase in intraocular pressure of the eye with accommodation results in an increase in vitreous chamber depth. The idea that prolonged accommodation can permanently affect ocular structure has a long history going back at least to Iwanoff, 37 who described different shapes for the ciliary muscle of hyperopes and myopes, and Heine, 38 who showed that monkey eyes, in which accommodation was stimulated or relaxed pharmacologically, demonstrated similar differences in ciliary muscle shape and fibre orientation; however, later work by van Alphen 39,40 also examined the structural changes involved in accommodation of the rhesus monkey eye. He notes that the dependence of the direction of the bundles of the ciliary muscle on its tone and tension warrants caution with respect to statements which describe an absence, atrophy or hypertrophy of the muscle. 39 CONTEMPORARY RESEARCH Animal models There has been an increase in the number of published reports dealing with myopia. In fact, the questionable scientific value of some of the early writings, as well as the controversy as to whether 574 Clinical and Experimental Optometry 2012 Optometrists Association Australia

4 myopia is environmentally induced or genetically determined, may have inhibited myopic research during the middle decades of the twentieth century. As an example, Investigative Ophthalmology and Vision Science published only one article on myopic research during the period 1961 to 1977, while in more recent years, it is rare to note an issue of IOVS without at least one article on the topic of myopia and often there are several. The same may be said of conference presentations at international eye research meetings. Animal models of the development of refractive error in the late 1970s are, at least in part, responsible for the increase in attention directed to research on myopia. In his book, The Myopias, published in 1985, Curtin 41 notes that while it is recognised that heredity and environment are the two factors involved in the production of myopia, There is almost unanimous acceptance of the former but major reservations continue to surround the latter. In a 1996 review on the role of genetics versus the environment in relation to myopia, Mutti, Zadnik and Adams 8 note that: This debate was at something of a standstill until the revolutionary discovery in the late 1970s that depriving a young animal eye of clear vision could result in myopia. During the past 35 years, the avian eye, particularly the chicken eye, has become a common animal model of ocular refractive development. This is a result of the discovery by Wiesel and Raviola 42 in 1977 and by Wallman, Turkel and Trachtman 43 in 1978, that it is possible to induce myopia in macaque monkeys and chickens by depriving the eye of clear form vision during early development. In fact, earlier work, such as that by Lauber, Macginnis and Boyd 44 in 1966 showed that it is possible to alter eye size and eye development in chickens by manipulating their exposure to light and through the use of occluding goggles; however, the emphasis of this study was on a glaucoma model rather than on a model of refractive development and this meant that these earlier examples of environmental manipulation of ocular development did not attract the attention of those of the late 1970s. The 1977 Wiesel and Raviola report 42 in Nature is often the starting point of reviews and introductions to this line of research. Curtin 41 felt it necessary to validate his description of the late 1970s and early 1980s period of animal research on myopia by pointing out that the initial monkey work involved the Nobel laureates Hubel and Wiesel... In fact, while Hubel 45 was an author on the study of the effect of monocular deprivation on the development of the visual cortex, which led to the discovery of the effects of deprivation on the eye, he is not an author on the latter work dealing with myopia. As a precocial bird that undergoes a rapid phase of early ocular growth, the chicken has become the predominant species used in this research because the manipulation of the visual environment can commence at hatching and the effects on ocular development take place within days or hours. 46 Form deprivation usually results in the induction of myopia. In 1988, Schaeffel, Glasser and Howland 47 demonstrated that it is possible to induce either myopia or hyperopia by using concave or convex lenses to alter the retinal image, and Irving, Callender and Sivak 48,49 and others have demonstrated the wide range of refractive states that can be induced using lightweight goggles and lenses. Essentially, a concave lens simulates hyperopia, causing a compensatory increase in ocular growth with the result that the eye is myopic when the lens is removed. The opposite, a slowing of ocular growth, occurs with the application of convex lenses. Although attention has focused on change in axial length in studies of visually induced refractive error, the roles of the cornea and lens are less clear. 50 Zhu and colleagues 51 have shown that the imposition of positive or negative lenses causes ocular changes in chick eyes within one or two hours. While experiments dealing with the development of refractive error are frequently based on animal models such as the chick, 44 various mammals such as monkeys 43 and tree shrews 52 have also been studied. Other vertebrates that have been used to induce form deprivation myopia include: grey squirrel, 53 mouse, 54 guinea pig, 55,56 cat 57 and another bird, the American kestrel. 58 It is assumed that mammal models are more comparable to the human eye in terms of ocular structure and function, as well as genetic profile; however, when it comes to diurnal vision and the existence of significant accommodative ability, the avian eye is a reasonable model as well. All of these are higher vertebrates. Typically, experimental myopia is induced in young animals, not adults, and the younger the animal the higher the induced refractive error. 46,47,60 Moreover, it has been shown that unilateral congenital cataracts can result in axial eye elongation in humans. 61 Experiments, such as those in which the chick optic nerve is cut, show that refractive error development is determined by a local retinal mechanism. 62 Somehow the eye distinguishes whether the input visual signal is over- or under-focused and in chicks at least, rapidly adjusts retinal position and focal length of the eye, by thinning or thickening of the choroid. 63 Ocular growth then accelerates or slows down for a more permanent change in refractive state, resulting in an eye that is either too long or too short. Form deprivation and positive or negative lenses can be applied to the fish eye, with results that are very similar to those obtained with higher vertebrates, such as chicks. This suggests that a universal mechanism controls the refractive development of the eye, regardless of differences in morphology, physiology and habitats and the fact that fish continue to grow through life. 64,65 Contemporary efforts to prevent or reduce myopia In a review of treatment options for myopia, Gwiazda 66 specifies that to be considered seriously, myopic treatment studies should include a concurrent control group, random assignment to the treatment and control groups, masking of investigators who collect the data, standardised measurements, a large enough sample and a small loss to follow-up. In general, results published on myopia Clinical and Experimental Optometry 2012 Optometrists Association Australia 575

5 during the last quarter of the twentieth and into the twenty-first century are based on experiments carried out on larger numbers of subjects, with better controls, standardised measurements and appropriate masking. VISUAL TRAINING AND BIOFEEDBACK Efforts to improve training through the use of auditory biofeedback were made in the 1970s and 1980s. 67,68 This involved the development of an instrument, the Accommotrac, which is essentially an optometer that measures the vergence of light reflected by the retina and also provides a tone that varies in pitch with accommodation. Subjects are trained to use the sound to accommodate and unaccommodate, a form of accommodative facility training; however, a careful study that included the use of blind examiners to measure refractive state after training concluded that positive findings are based on a learned effect on visual acuity, not a reduction of myopia. 69 UNDERCORRECTION A long-standing method used by clinicians to slow down the progression of myopia is to undercorrect the myopic eye by as much as a dioptre, as an effort to avoid excessive accommodation. 3,28 In fact, virtually all texts dealing with refractive procedures, going back at least to the time of Landolt in the 1880s, 71 instruct the clinician to record as a subjective endpoint the least minus correction that provides maximum visual acuity to minimise accommodation. It is tempting to suggest that the original reasons for withholding some of the minus correction were superstitious in nature, although no evidence has been found in the literature to support this notion. Mutti, Zadnik and Adams 8 note in their nature versus nurture review that the study of myopia is characterised more by deeply held belief than by research. The rationale behind undercorrection is not clear, although recent models of emmetropisation suggest that explanations based on a closed feedback loop model of ocular refractive development can provide an explanation. 71,72 Grosvenor 2 noted that there were no studies of the effects of undercorrection on myopia; however, Goss 3 refers to two poorly controlled and unconvincing studies involving small numbers of subjects in his review. Later, Ong and colleagues 73 showed that spectacle intervention, in terms of whether young myopes wore their corrections fulltime, part-time or not at all, had no effect on the progression of myopia, while Chung, Mohidin and O Leary 74 found that an undercorrection of 0.75 D resulted in a more rapid progression of myopia. Finally, Goss 75 demonstrated that an overcorrection of the same amount (0.75 D) had no effect on myopic progression. BIFOCALS The idea behind the use of bifocals is based on the supposition that excessive accommodation can affect the eye mechanically and structurally or to the possibility that a change in the relationship between accommodation and convergence can affect refractive development. Early investigations concerning the value of prescribing bifocals to children were described above in the section on early efforts to prevent or reduce myopia. Subsequent research into the utility of bifocals in controlling myopic development were carried out by Oakley and Young, 76 Goss 77 and Grosvenor and colleagues 78 (also known as the Houston Study). Neither the Goss report nor the Houston Study, the largest and best-controlled study, showed any retardation in progression of myopia with bifocal wear. While the Oakley and Young 76 study did show a positive effect, it has been criticised on the basis of lack of adequate controls for experimenter bias, as the authors themselves note. Moreover, the Houston Study 78 was a three-year prospective approach, whereas the other two efforts were retrospective ones. A re-examination of the data of this study and two others by Goss and Grosvenor 79 showed a small reduction in the rate of myopic progression (about a fifth of a dioptre less per year) in subjects with esophoria. This has also been shown more recently by Fulk, Cyert and Parker, 80 who followed 82 children with near-point esophoria for 30 months and found a slight reduction (0.25 D) for those wearing bifocals. PROGRESSIVE LENSES In 1999 Leung and Brown 81 published the results of a two-year longitudinal study in which the rate of myopic progression was compared in Hong Kong Chinese children wearing single vision correction versus those wearing progressive addition lenses. The progressive lenses were used to improve subject compliance in wearing the correction and to provide clear vision at all working distances. The results indicated that the progression of myopia is significantly reduced in those subjects wearing progressive lenses; however, a later study, 82 in which the examiners were masked (unlike the Leung and Brown work) and which involved a larger number of children from the same population produced results indicating no significant difference between the single vision and progressive lens groups. Finally, a large multi-centre study, the COMET study, involving 469 ethnically diverse children, who were followed for three years, concluded that there was a small and significant difference in myopic progression between the single vision group and the group wearing progressive lenses; however, the difference (0.20 D) does not indicate that there should be a change in clinical practice. 83 A similar result was reported from a Japanese clinical trial involving 92 children. 84 Earlier, Gwiazda, Grice and Thorn 85 found that myopic children with esophoria also demonstrate large lags of accommodation at the near point. The question of whether progressive lenses can be effective at retarding the progression of myopia in children with near point esophoria and large lags of accommodation has been addressed in a couple of recent reports published in 2011 and One large 120 collaborator multi-centre double masked study 86 involving 118 children found a statistically small but clinically unimportant effect on slowing myopia. A similar result was found for 85 children with high accommodative lags, 87 that is, a small statistically significant effect but one with little or no clinical relevance. A few 576 Clinical and Experimental Optometry 2012 Optometrists Association Australia

6 years earlier, a report from the CLEERE (Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error) Study Group 88 involving over 1,100 children showed that the amount of accommodative lag is not a valid predictor of which children will become myopic, although increased accommodative lag was noted in children after they became myopic. CONTACT LENSES AND ORTHOKERATOLOGY The potential for using contact lenses to more than just correct refractive errors was noted during the period of corneal contact lens development in the early 1950s and 1960s, particularly since the early fitting strategies involved using base curvatures that were flatter than the curvature of the cornea to maximise tear flow under the lens. 89,90 The resultant flattening of the cornea meant that myopia was reduced, at least for a time. This led practitioners to deliberately flatten the cornea through a regimen referred to as orthokeratology; however, in 1960, Morrison 90 noted anecdotally that myopic progression in children seems to diminish, even when the contact lenses are prescribed with base curvatures that parallel the corneal surface. The basic conundrum that has bedevilled the approach involving the use of contact lenses to treat myopic progression was, and still is, whether the sole effect of the lenses is to flatten the cornea, at least temporarily, or whether the lenses also have a slowing effect on the growth of the eye. Stone 91,92 carried out a substantial fiveyear study of myopic progression involving 124 children, both with and without contact lenses. The initial study concluded that two years of contact lens wear stabilised the progression of myopia but the effect was due to corneal flattening and not to a change in axial length of the eye. In the later study, over a longer period, myopia was significantly reduced in contact lens wearers. While some of the effect was due to corneal flattening, not all of it was, suggesting that the lenses do affect the axial elongation of the eye. There has been a resurgence of interest in orthokeratology to prevent myopia as a result, due to the high prevalence of myopia, especially among Asian populations. An early scientific study of the efficacy of orthokeratology by Kerns 93 found that the approach reduced myopia in some cases but the permanence of the changes once the lenses are removed, was not clear. A large study by Polse and colleagues 94 published in 1983 also showed that while it is possible to reduce myopia in this way, the effect is temporary and continued wearing of lenses, at least intermittently, is required to maintain an effect. Moreover, during periods when lenses are not worn, visual acuity can be unstable. Another relatively large study involving 100 children followed for three years involved the use of regular (nonorthokeratology designed) gas permeable contact lenses. 95 The results also indicate that there is a reduction in myopia and not all of this change is a result of changes in the cornea, suggesting a possible effect on the growth of the eye. A retrospective study 96 in young adults more than 20 years of age indicates that while myopic progression does take place in young adults, there is no association with type of refractive correction (spectacles or contact lenses). In 2008, a retrospective study by Chan, Cho and Cheung 97 on Hong Kong children seen in a university clinic reported that orthokeratology lenses for overnight wear were effective in reducing low to moderate levels of myopia. That orthokeratology retards the axial elongation of the eye is supported by a case report, 98 which indicates that suspension of orthokeratology results in faster axial growth of the eye. Finally, a Japanese study 99 shows that while orthokeratology cannot stop axial elongation in progressive myopia, it can slow it down. The increase in the wearing of soft contact lenses made of varying materials and varying oxygen permeability has also led to retrospective 96,100 and prospective studies 101 of the effects of various contact lenses on myopic progression. The results indicate that lens material can affect myopic progression, although whether the differences are due purely to varying mechanical effects on the cornea is not clear. PHARMACEUTICALS There is a substantial history of efforts to manage the development of myopia through the use of pharmaceuticals. The drugs used have been primarily cycloplegics meant to paralyse the ciliary muscle to cause a loss of accommodation, but mydriatics and anti-glaucoma drugs have been used as well. Thorough reviews of the earlier efforts are provided by Curtin 41 and by Jensen and Goldschmidt, 102 who refer to studies that were carried out without appropriate controls, with high dropout rates and also poor subject compliance. Both reviews express reservations about the use of drugs in dealing with myopia, in terms of potential dangers from side effects and both refer to the possible danger to the retina from larger than normal amounts of solar radiation entering the eye through a dilated pupil. In addition, Jensen and Goldschmidt 102 note that: In our opinion, it is of very limited value to reduce the final amount of myopia from 4.00 D to 3.00 D, especially if the reading capability or binocularity of the child is negatively influenced by the drug. One can add the additional concern about the use of cycloplegic drugs to control myopia when the original rationale was based on an unproven link between accommodation and myopia. There have been animal studies that have addressed the issue of accommodation, drugs and myopia, either directly or indirectly. As mentioned earlier, myopia can be induced by depriving the eye of form vision in the grey squirrel (Sciurus carolinensis), one of the few non-primate diurnal mammals, even though the eye has no accommodative ability. 53 Experiments showing that form deprivation myopia can still be produced in chicks, in which the optic nerve is cut, also suggest that accommodation is not involved. 62 This point is also emphasised by the fact that myopia and hyperopia can be induced in fish, 64,65 where accommodation takes place by movement of the lens, not through a change in lens shape. McBrien, Moghaddam and Reeder 103 also found that while atropine prevents the experimental induction of myopia and the axial elongation of the eye in chicks, Clinical and Experimental Optometry 2012 Optometrists Association Australia 577

7 the effect is not related to the accommodative mechanism. Follow-up studies 104,105 showed that daily injections of the M 1 antagonist pirenzepine can also prevent form deprivation myopia in chicks and tree shrews by selectively blocking M 1 receptors in the retina or choroid. A similar result was found in form deprivation experiments with guinea pigs, in which the topical application of pirenzepine prevents the development of myopia. 106 In 2003, Bartlett and colleagues 107 reported positive results on the tolerability of the application of 0.5 to 2.0 per cent pirenzepine to the eyes of children to evaluate its potential use in the prevention of myopia without producing the side effects on pupil size and accommodation associated with atropine. In 2008, the results of a large multi-centre study involving 174 children (eight to 12 years of age), in which the treated group (n = 117) received daily applications of pirenzepine (2 per cent) were published. 108 The results show that after two years there was a mean 0.58 D increase in myopia for the pirenzepine group, compared to a mean increase in myopia of 0.99 D for the placebo group; however, 14 of the treated group dropped out of the study because of adverse effects such as medication residue and accommodative dysfunction. Also, the difference in axial length of the eyes of the two groups was not significant. Chen and colleagues 109 reported the effects of racanisodamine (0.5 per cent), a racemic isomer of anisodamine on the pupil and accommodation of the eyes of 20 children, nine to 12 years of age. There was a moderate effect on pupil size and no effect on accommodation, suggesting that this drug, a non-selective muscarinic antagonist, may be a good candidate for study as a means of retarding the progression of myopia. In summing the situation vis à vis the use of pharmaceuticals as a treatment of myopia, it is instructive to repeat the point made by Jensen and Goldschmid, 102 which questions the value of modest reductions of myopia if there are associated risks, particularly in children. Of course, the same point can be made with regard to other treatments, such as bifocals or progressive lenses. Why promote treatments that may have, at best, moderate results, if it means that there is the possibility of negative side effects? CURRENT MYOPIA RESEARCH TRENDS AND PREDICTORS Genetics and environment The study of the genetics of myopia has a long and prolific history that usually involves the study of twins, both monozygotic (identical) and dizygotic (nonidentical) twins, the genealogical study of familial incidence of myopia, or the study of the distribution of refractive errors in isolated communities and a variety of ethnic populations. Research on twins as a method of evaluating the relative importance of genetics versus environment goes back to an 1875 report by Galton, 110 in which the terms nature and nurture were first coined. Reviews of much of the earlier research with genetic (as well as environmental) impact are provided by Goldschmidt 111 and Curtin. 41 Both authors weigh the strengths of the genetic versus environment divide but both authors indicate a preference for a genetic cause of myopia, at least as far as low to moderate amounts are concerned. At least as far back as 1970, Leary 112 made an argument for accepting that both heredity and environment are involved in the development of myopia and this has been the thrust of more recent work. This point was also made by Mutti, Zadnik and Adams 8 in noting the need to determine the relative contributions of each of these two influences. The importance of genetics is emphasised by the results of a study carried out on 506 monozygotic and dizygotic twins. 113 In 2008, two additional twin studies by Dirani, Shekar and Baird 114,115 involving 1,224 twins, demonstrate that genetics plays a role even in myopia that develops late in life (adult-onset myopia) and that level of education is also related, in part, to genetics and should not be considered to be solely an environmental factor. Recent research 116,117 has explored the relationship with parental myopia and shows clearly that the risk of developing myopia is greater when both parents are myopic but less when one parent is myopic. Finally in 2011, an elegant approach by Chen and colleagues 118 used selective breeding and the chick form deprivation model to show that the susceptibility to environmental influences such as form deprivation is strongly genetic. The association between near work and myopia has a long history, going back to the time of Donders and Helmholtz and this association continues to be a common topic of investigation. On the basis of refractive data for 971 individuals from three isolated communities in Newfoundland, Canada, Richler and Bear 119 concluded that exposure to formal education is associated with increased myopia. A similar result was found by Alsbirk 120 among West Greenland Eskimos and among 1,005 young Singaporean children, whose parents completed questionnaires concerning each child s activity in such areas as reading and computer and video games. 121 In contrast, a 2011 study 122 involving 1,318 children, some of whom were myopes and others emmetropes, did not show a difference in near work activity before the onset of myopia, suggesting that near work does not play an important causative role in the onset of myopia; however, those who became myopic were less involved in sports and outdoor activity, both before and after the onset of myopia. The associations between lifestyle, educational activity and parental refractive history in relation to the development of myopia in children have been demonstrated in recent studies involving 366 to 1,249 children of Asian and non-asian ethnicity It is pertinent to highlight that in 1998, Rosenfield and Gilmartin 127 noted that while myopia and near work are associated, efforts to show a causal connection are made difficult because of other environmental factors and it is difficult to separate genetic and environmental factors that influence the refractive development of the eye. The blurring of the separation between inherited risks and environmental risks is especially emphasised in papers by Dirani, Shekar and Baird, 114,115 which make the point that educational attainment is 578 Clinical and Experimental Optometry 2012 Optometrists Association Australia

8 not necessarily just an environmental factor and the same reasoning may apply to other risks that are being explored. Peripheral refraction and myopia Studies 62 show that the myopia induced in chicks is governed locally by the retina. In fact, an earlier report (1987) showed that partial deprivation of the retina of chicks with an occluder that covers part of the anterior globe results in a corresponding asymmetry in eye shape. 128 Hemi-retinal form deprivation in monkeys produced results similar to those with chicks. 129 It is well established that form deprivation myopia, as well as myopia and hyperopia from the wearing of convex and concave lenses, can be induced in monkeys (Macaques). 42,130,131 Furthermore in 2005, Smith and colleagues 132 found that form deprivation of the peripheral retina, while central vision is maintained, can result in myopia. Moreover, when the fovea is ablated after the deprivation, the recovery process is not affected 133 and foveal ablation did not affect peripheral or central refractive states when form deprivation was induced in young Macaque monkeys. 133 Smith and colleagues 132 also suggested that peripheral image quality may be used as a treatment strategy to control eye growth and the refractive development of the eye. In fact, from a study of young pilots, Hoogerheide, Rempt and Hoogenboom 134 suggested in 1971 that the peripheral refractive state of the eye can be an indicator for the onset of myopia. In 2007, Mutti and colleagues 135 concluded from a long-term study of 979 children, 605 of whom became myopic, that relative peripheral hyperopia can be a predictor of future development of myopia in children. Tse and colleagues 136 and Tse and To, 137 used lenses with concentric rings of opposing defocus cues or a lens-cone system to produce patches of positive and negative defocus, to show that chick eyes can integrate concave- and convex-induced blur. Using lenses with two concentric zones, Liu and Wildsoet 138 found that peripheral defocus can influence both central and peripheral refractive development in chicks. They also showed that hyperopic peripheral defocus can inhibit eye growth and myopia development. Recent efforts have addressed the question of whether peripheral refractive error can be used to reduce the progression of myopia in children. Studies have demonstrated that myopic children and young adults show relative hyperopia in the periphery of the eye Mutti and colleagues 135 concluded that relative peripheral hyperopia may be a useful predictor for the onset of myopia; however, two very recent studies 142,143 that evaluated peripheral refraction over time in children did not indicate that peripheral refractive error is an influence. Clinical trials involving children do indicate that myopic progression, in terms of change in both refractive state and axial length, can be slowed by wearing lenses that provide more peripheral positive power. One study 144 using three different specialised spectacle lens designs intended to reduce peripheral defocus worn by 210 Chinese children for 12 months, indicated that there was some reduction in myopic progression in children with parents who were myopic. Two recent studies used multi-focal contact lenses with the expectation that they would remain properly aligned on the eye with ocular movement. One involved 40 children of multi-ethnic backgrounds wearing special contact lenses with central correction and peripheral treatment zones for two 10-month periods, 145 while the other involved use of multifocal contact lenses worn by 45 Chinese children for 12 months. 146 The results of both indicate that this approach can affect central refractive error and significantly reduce the rate of myopic progression. CONCLUDING REMARKS This review makes it clear that most of the various treatment options that have been explored to prevent or halt the progression of myopia in children have either not been successful or, at best, modestly so. For example, in some esophoric children treated with progressive lenses, it has been claimed that small but statistically significant reductions in myopic progression have been achieved; however, these reductions are relatively small and it is appropriate to again ask the question posed by Jensen and Goldschmid 102 with respect to the value of using drugs or possibly another treatment, if the effect is at best limited. This negative view is not meant to imply that the effort to study myopia has not produced interesting and useful information about the eye and how it develops. One discovery that springs to mind is the role of the choroid, in at least some species, as a means of controlling ocular focal length. 63,147,148 In attempting to provide a comprehensive review, including some of the historical highlights associated with the study of myopia prevention, not all research topics, particularly in relation to animal models, could be described in detail. For example, this review refers three times to the point that refractive errors can still be induced in chicks with severed optic nerves to emphasise that retinal factors can regulate refractive development in the absence of accommodation. 62 In fact, once the inducing lens or goggle is removed, the recovery process is hampered in chicks with severed optic nerves, suggesting that higher centres in the nervous system are still needed to refine the refractive state. 62,149 The research related to the possible connection between relative peripheral hyperopia and the onset of myopia in children, and efforts to reduce the progression of myopia by adjusting peripheral refractive corrections are still at an early stage and one can say that the jury is still out as far as this approach is concerned, although the results reported for multifocal contact lenses designed to reduce peripheral hyperopia show significant reductions in myopic progression. 145,146 The study of the influence of relative peripheral refractive error on the refractive development of the eye has occurred through an interaction of research involving animal models and research on human refractive development. Charman and Radhakrishnan 150 point out that the relative peripheral hyperopia that is associated with the onset of myopia may be a consequence rather than a cause of the development of myopia. They 151 also draw Clinical and Experimental Optometry 2012 Optometrists Association Australia 579

9 attention to a report, which suggests that eye shape in people of Chinese origin is more axially symmetric than in Caucasians. Thus, peripheral refractive characteristics may not be associated with the development of myopia in all ethnic populations. In spite of a significant worldwide effort by numerous scientists and clinicians over many years, the answers to the questions of what causes myopia and how can it be prevented or mitigated are still not clear. The intense research carried out over the past two or three decades has made it clear that the prevalence of myopia is increasing, and not just in Asian populations, and the development of myopia is related both to genetics and environment/lifestyle, but we are far from understanding how this interaction takes place. According to Sagan and Druyan 152 in their book Shadows of Forgotten Ancestors : Science is never finished. It proceeds by successive approximations, edging closer and closer to a complete and accurate understanding of Nature, but it is never fully there. One hour per day of vision through positive lenses (+4.00 D) can prevent the myopia induced by the wearing of negative (-9.50 D) lenses in tree shrews. 153 Similarly, the intermittent wearing of inducing lenses, either negative and or positive, can reduce the resulting hyperopia or myopia; 154,155 however, the recent article by McBrien, Arumugam and Metlapally 153 suggests that by determining the optimum positive lens power, the best period and the appropriate stage of development to apply it may lead to an effective strategy for the prevention of myopia in children. This recent article also serves as a reminder that research into myopia is continuing at a rapid pace and publications with new and potentially important findings need to be weighed and possibly acted upon on an ongoing basis. 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