SEARCH

SEARCH BY CITATION

Keywords:

  • aetiology;
  • accommodation;
  • causes;
  • myopia

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Early Myopia Research
  5. Contemporary Research
  6. Current Myopia Research—Trends and Predictors
  7. Concluding Remarks
  8. Acknowledgements
  9. References

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.

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

  1. Top of page
  2. Abstract
  3. Background
  4. Early Myopia Research
  5. Contemporary Research
  6. Current Myopia Research—Trends and Predictors
  7. Concluding Remarks
  8. Acknowledgements
  9. References

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.

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 1920.[21] 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

  1. Top of page
  2. Abstract
  3. Background
  4. Early Myopia Research
  5. Contemporary Research
  6. Current Myopia Research—Trends and Predictors
  7. Concluding Remarks
  8. Acknowledgements
  9. References

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 co-founded by AM Skeffington in 1928.[23] The possible value of visual training for myopia was tested in 1944, in relation to 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, 1945[25]), 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

  1. Top of page
  2. Abstract
  3. Background
  4. Early Myopia Research
  5. Contemporary Research
  6. Current Myopia Research—Trends and Predictors
  7. Concluding Remarks
  8. Acknowledgements
  9. References

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 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 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 full-time, 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 2012. 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 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 five-year 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 (non-orthokeratology 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, the effect is not related to the accommodative mechanism. Follow-up studies[104, 105] showed that daily injections of the M1 antagonist pirenzepine can also prevent form deprivation myopia in chicks and tree shrews by selectively blocking M1 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

  1. Top of page
  2. Abstract
  3. Background
  4. Early Myopia Research
  5. Contemporary Research
  6. Current Myopia Research—Trends and Predictors
  7. Concluding Remarks
  8. Acknowledgements
  9. References

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 (non-identical) 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.[123-126]

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 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.[139-141] 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

  1. Top of page
  2. Abstract
  3. Background
  4. Early Myopia Research
  5. Contemporary Research
  6. Current Myopia Research—Trends and Predictors
  7. Concluding Remarks
  8. Acknowledgements
  9. References

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 multi-focal 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 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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Background
  4. Early Myopia Research
  5. Contemporary Research
  6. Current Myopia Research—Trends and Predictors
  7. Concluding Remarks
  8. Acknowledgements
  9. References

The assistance of Alisa Sivak in the writing of this review is gratefully acknowledged.

This work was supported by a grant from Natural Sciences and Engineering Research Council of Canada. Also, the assistance provided by the Witer Learning Resource Centre (School of Optometry, University of Waterloo) was very helpful.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Early Myopia Research
  5. Contemporary Research
  6. Current Myopia Research—Trends and Predictors
  7. Concluding Remarks
  8. Acknowledgements
  9. References
  • 1
    Grosvenor TP. Primary Care Optometry, 2nd Ed. New York: Professional Press, 1989. p 1598.
  • 2
    Grosvenor TP. Management of myopia: functional methods. In: Grosvenor T , Flom MC , eds. Refractive Anomalies. Research and Clinical Applications. Boston: Butterworth-Heinemann, 1991. p 345370.
  • 3
    Goss DA. Attempts to reduce the rate of increase of myopia in young people-a critical literature review. Am J Optom Physiol Optics 1982; 59: 828841.
  • 4
    Woo GC, Wilson MA. Current methods of treating and preventing myopia. Optometry and Vis Sci 1990; 67: 719727.
  • 5
    Gilmartin B. Myopia: precedents for research in the twenty-first century. Clin Experiment Ophthalmol 2004; 32: 305324.
  • 6
    Cheng D. Bifocal Lens Control of Myopia Progression in Children. PhD dissertation, Brisbane, Queensland University of Technology, 2008. p 1131.
  • 7
    Lee D. Current methods of myopia control. J Behav Optom 2009; 20: 8793.
  • 8
    Mutti DO, Zadnik K, Adams AJ. Myopia. The nature versus nurture debate goes on. Invest Ophthalmol Vis Sci 1996; 37: 952957.
  • 9
    Lin, LL-K, Shih Y-F, Tsai C-B, Chen C-J, Lee L-A, Hung P-T, Hou P-K. Epidemiologic study of ocular refraction among schoolchildren in Taiwan in 1995. Optom Vis Sci 1999; 76: 275281.
  • 10
    Saw S-M, Tong L, Chua W-H, Chia K-S, Koh D, Tan DTH, Katz J. Incidence and progression of myopia in Singaporean school children. Invest Ophthalmol Vis Sci 2005; 46: 5157
  • 11
    Vitale S, Sperduto RD, Ferris FL III. Increased prevalence of myopia in the United States between 1971–1972 and 1999–2004. Arch Ophthalmol 2009; 127: 16321639.
  • 12
    Hirsch MJ. Relation of visual acuity to myopia. Arch Ophthalmol 1945; 34: 418421.
  • 13
    Stoimenova BD. The effect of myopia on contrast thresholds. Invest Ophthalmol Vis Sci 2007; 48: 23712374.
  • 14
    von Helmholtz H. Treatise on Physiological Optics. 3rd ed. Volume I. Hamburg, Germany: Verlag vonLeopold Voss; 1909. Translated by Southhall JPC. New York: Dover Publications, 1962.
  • 15
    Donders FC. On the Anomalies of Accommodation and Refraction of the Eye. London: The New Sydenham Society, 1864. p 1635.
  • 16
    Tscherning M. Studier over Myopiens Aetiology, Copenhagen: C Myhres Boghandel, Wenstroms Bogtryk. 1982, 1–99. Cited by: Working group on myopia prevalence and progression. Committee on vision. Commission on behavioral and social sciences and education. National Research Council. Washington National Academy Press 1989: 1–113.
  • 17
    von Helmholtz H. Uber die Akkommodation des Auges. Graefes Arch Ophthalmol 1855; 1: 174.
  • 18
    Glasser A, Wendt M, Ostrin L. Accommodative changes in lens diameter in rhesus monkeys. Invest Ophthalmol Vis Sci 2006; 47: 278286.
  • 19
    Tscherning M. The theory of accommodation. Ophthalmic Rev 1898; 18: 9199.
  • 20
    Schachar RA, Cudmore DP, Black TD. Experimental support for Schachar's hypothesis of accommodation. Ann Ophthalmol 1993; 25: 409409.
  • 21
    Bates WH. The Cure of Imperfect Sight by Treatment Without Glasses. New York: Central Fixation Publishing Company, 1920. p 1314.
  • 22
    Optometric Extension Program, Behavioral Aspects of Vision Care, Vol 39, No. 3, Myopia Control. Barber A. ed. Activities Appendix, Santa Ana, California, 1998. p 1162.
  • 23
    Cox JL. A M Skeffington, OD-The Man. J Behav Optom 1997; 8: 36.
  • 24
    Ewalt HW. The Baltimore myopia control project. J Am Optom Assoc 1946; 17: 167185.
  • 25
    Woods AC. A report from the Wilmer Institute on the results obtained in treatment of myopia by visual training. Trans Am Acad Ophthalmol Otolaryngol 1945; 49: 3765.
  • 26
    Shepard CF. The Batimore project. Optom Weekly 1946; 37: 133135.
  • 27
    Betz JN. Success with bifocals for children-credit to OEP Opt J Rev Optom. 1949; 86: 42.
  • 28
    Tait EF. Textbook of Refraction. Philadelphia: Saunders, 1951. p 1418.
  • 29
    Manas L. Visual Analysis. Chicago: The Professional Press, 1958. p 1334.
  • 30
    Mandell RB. Myopia control with bifocal correction. Am J Optom Arch Am Acad Optom 1959; 36: 652658.
  • 31
    Borish IM. Clinical Refraction. Chicago: The Professional Press, 1949. 1431.
  • 32
    Levinsohn FG. Zur Frage der kunstlich erzeugten Kurzischtigkeit bei Affen. Klin Monatsbl f Augenh 1919; 80: 794803.
  • 33
    Essed WFR, Soewarno M. Ueber Experimentalmyopie bei Affen. Klin Monatsbl f Augenh 1928; 80: 56. Cited by Young FA.35
  • 34
    Young FA. The development and retention of myopia by monkeys. Am J Optom Arch Am Acad Optom 1961; 38: 545555.
  • 35
    Young FA. The effect of restricted visual space on the refractive error of the young monkey eye. Invest Ophthalmol 1963; 2: 571577.
  • 36
    Young FA. Primate myopia. Am J Optom Physiol Opt 1981; 58: 560566.
  • 37
    Iwanoff A. Beitrage zur Anatomie des Ciliarmuskels. Graefe Arch Ophthalmol 1869; 15: 284298.
  • 38
    Heine L. Die Anatomie des akkommodierten Auges. Graefe Arch Ophthalmol 1889; 49: 1. Cited by: van Alphen GWHM40.
  • 39
    van Alphen GWHM. The structural changes in miosis and mydriasis of the monkey eye. Arch of Ophthalmol 1963; 69: 802814.
  • 40
    van Alphen GWHM. Scanning electron microscopy of the monkey eye in miosis and mydriasis. Exp Eye Res 1979; 29: 511526.
  • 41
    Curtin BJ. The Myopias. Philadelphia: Harper and Row, 1985. p 1495.
  • 42
    Wiesel TN, Raviola E. Myopia and eye enlargement after neonatal lid fusion in monkeys. Nature 1977; 266: 6668.
  • 43
    Wallman J, Turkel J, Trachtman J. Extreme myopia produced by modest change in early visual experience. Science 1978; 201: 12491251.
  • 44
    Lauber JK, McGinnis J. Eye lesions in domestic fowl reared under continuous light. Vision Res 1966; 6: 619626.
  • 45
    Hubel DH, Wiesel TN, Levay S. Functional architecture of area 17 in normal and monocularly deprived macaque monkeys. Cold Spring Harb Symp Quant Biol 1975; 40: 581589.
  • 46
    Pickett-Seltner RL, Sivak JG, Pasternak JJ. Experimentally induced myopia in chicks. morphometric and biochemical change. Vision Res 1988; 28: 323328.
  • 47
    Schaeffel F, Glasser A, Howland HC. Accommodation, refractive error and eye growth in chickens. Vision Res 1988; 5: 639657.
  • 48
    Irving EL , Callender MG, Sivak JG. Inducing myopia, hyperopia and astigmatism in chicks. Optom Vis Sci 1991; 68: 364368.
  • 49
    Irving EL , Callender MG, Sivak JG Inducing ametropias in hatchling chicks by defocus—effect of aperture size, shape and cylindrical lenses. Vision Res 1995; 35: 11651174.
  • 50
    Sivak JG. The role of the lens in refractive development of the eye: animal models of ametropia. Exp Eye Res 2008; 87: 38.
  • 51
    Zhu X, Park TW, Winawer J, Wallman J. In a matter of minutes, the eye can know which way to grow. Invest Ophthalmol Vis Sci 2005; 46: 22382241.
  • 52
    Sherman SM, Norton TT, Casagrande VA. Myopia in the lid-sutured tree shrew (Tupaia glis). Brain Res 1977; 124: 154157.
  • 53
    McBrien NA, Moghaddam HO, New R, Williams LR. Experimental myopia in a diurnal mammal (Sciurus carolinensis) with no accommodative ability. J Physiol 1993; 469: 427441.
  • 54
    Tejedor J, de la Villa P. Refractive changes induced by form deprivation in the mouse eye. Invest Ophthalmol Vis Sci 2003; 44: 3236.
  • 55
    Howlett MHC, McFadden SA. Form-deprivation in the guinea pig (Cavia porcellus). Vision Res 2006; 46: 267283.
  • 56
    Ouyang CH, Chu RY, Hu WZ. Effects of pirenzepine on lens-induced myopia in the guinea pig. Zhonghua Yan Ke Za Zhi 2003; 39: 348351.
  • 57
    Kirby AW, Sutton L, Weiss H. Elongation of cats eyes following neonatal lid suture. Invest Ophthalmol Vis Sci 1982; 22: 272277.
  • 58
    Andison ME, Sivak JG, Bird DM. The refractive development of the eye of the American kestrel (falco sparverius): a new avian model. J Comp Physiol 1992; 170: 565574.
  • 59
    Wallman J, Adams JI. Developmental aspects of experimental myopia in chicks: susceptibility, recovery and relation to emmetropization. Vision Res 1987; 27: 11391163.
  • 60
    Troilo D, Nickla DL. The response to visual form deprivation differs with age in marmosets. Invest Ophthalmol Vis Sci 2005; 46: 18731881.
  • 61
    von Noorden GK, Lewis RA. Ocular axial length in unilateral congenital cataracts blepharoptosis. Invest Ophthalmol Vis Sci 1987; 28: 750752.
  • 62
    Troilo D, Wallman J. The regulation of eye growth and refractive state: an experimental study of emmetropization. Vision Res 1991; 31: 12371250.
  • 63
    Wallman J, Wildsoet C, Xu A, Gottlieb MD, Nickla DL, Marran L, Krebs W et al. Moving the retina: choroidal modulation of refractive state. Vision Res 1995; 35: 3750.
  • 64
    Shen W, Sivak JG. Eyes of a lower vertebrate are susceptible to the visual environment. Invest Ophthalmol Vis Sci 2007; 48: 48294837.
  • 65
    Shen W, Vijayan M, Sivak JG. Inducing form-deprivation myopia in fish. Invest Ophthalmol Vis Sci 2005; 46: 17971803.
  • 66
    Gwiazda J. Treatment options for myopia. Optom Vis Sci 2009; 86: 624628.
  • 67
    Trachtman JN. Biofeedback of accommodation to reduce functional myopia:a case report. Am J Optom Physiol Opt 1978; 55: 400406.
  • 68
    Trachtman JN, Giambalvo V, Feldman J. Biofeedback of accommodation to reduce functional myopia. Biofeedback Self Regul 1981; 6: 547562.
  • 69
    Gallaway M, Pearl SM, Winkelstein AM, Scheiman M. Biofeedback training of visual acuity and myopia: a pilot study. Am J Optom Physiol Opt 1987; 64: 6271.
  • 70
    Landolt E. The Refraction and Accommodation of the Eye and Their Anomalies. Translated by Culver CM. Edinburgh: Young J Pentland, 1886. p 1600.
  • 71
    Medina A. A model for emmetropization. The effect of corrective lenses. Acta Ophthalmol 1987; 65: 565571.
  • 72
    Filcroft DI. A model of the contribution of oculomotor and optical factors to emmetropization and myopia. Vision Res 1998; 38: 28692879.
  • 73
    Ong E, Grice K, Held R,Thorn F, Gwiazda J. Effects of spectacle intervention on the progression of myopia in children. Optom Vis Sci 1999; 76: 363369.
  • 74
    Chung K, Mohidin N, O'Leary DJ. Undercorrection of myopia enhances rather than inhibits myopia progression. Vision Res 2002; 42: 25552559.
  • 75
    Goss DA. Overcorrection as a means of slowing myopic progression. Am J Optom Physiol Opt 1984; 61: 8593.
  • 76
    Oakley KH, Young FA. Bifocal control of myopia. Am J Optom Physiol Opt 1975; 52: 758764.
  • 77
    Goss DA. Effect of bifocal lenses on the rate of childhood myopia progression. Am J Optom Physiol Opt 1986; 63: 135141.
  • 78
    Grosvenor T, Perrigin DM, Perrigin J, Maslovitz B. Houston myopia control study: a randomized clinical trial. Part II. Final report by the patient care team. Am J Optom Physiol Opt 1987; 64: 482498.
  • 79
    Goss DA, Grosvenor T. Rates of childhood myopia progression with bifocals as a function of nearpoint phoria: consistency of three studies. Optom Vis Sci. 1990; 67: 637640.
  • 80
    Fulk GW, Cyert LA, Parker DE. A randomized trial of the effect of single vision vs. bifocal lenses on myopia progression in children with esophoria. Optom Vis Sci 2000; 77: 395401.
  • 81
    Leung JTM, Brown B. Progression of myopia in Hong Kong Chinese schoolchildren is slowed by wearing progressive lenses. Optom Vis Sci 1999; 76: 346354.
  • 82
    Edwards MH, Li RW, Lam C S, Lew JK, Yu BS. The Hong Kong progressive lens myopia study: study design and main findings. Invest Ophthalmol Vis Sci 2002; 43: 28522858.
  • 83
    Gwiazda J, Hyman L, Hussein M, Everett D, Norton TT, Kurtz D, Leske MC et al. A randomized clinical trial of progression addition lenses versus single vision lenses on the progression of myopia. Invest Ophthalmol Vis Sci 2003; 44: 14921500.
  • 84
    Hasebe S, Obtsuki H, Nonaka T, Nakatsuka C, Miyata M, Hamasaki I, Kinura S. Effect of progressive addition lenses on myopia progression in Japanese children: a prospective, randomized, double-masked, crossover trial. Invest Ophthalmol Vis Sci 2008; 49: 27812789.
  • 85
    Gwiazda J, Grice K, Thorn F. Response AC/A ratios are elevated in myopic children. Ophthalmic Physiol Opt 1999; 19: 173179.
  • 86
    Correction of Myopia Evaluation Trial 2 Study Group for the Pediatric Eye Disease Investigator Group. Progressive-addition lenses versus single-vision lenses for slowing progression of myopia in children with high accommodative lag and near esophoria. Invest Ophthalmol Vis Sci 2011; 52: 27492757.
  • 87
    Berntsen DA, Sinnott LT, Mutti DO, Zadnik K. A randomized trial using progressive addition lenses to evaluate theories of myopia progression in children with a high lag of accommodation. Invest Ophthalmol Vis Sci 2012; 53: 640649.
  • 88
    Mutti DO, Mitchell GL, Hayes JR, Jones LA, Moeschberger ML, Cotter SA, Kleinstein RN et al. Accommodative lag before and after the onset of myopia. Invest Ophthalmol Vis Sci 2006; 47: 837846.
  • 89
    Morrison RJ. Contact lenses and the progression of myopia. Optom Weekly 1956; 47: 14871488.
  • 90
    Morrison RJ. The use of contact lenses in adolescent myopic patients. Am J Optom Arch Am Acad Optom 1960; 37: 165167.
  • 91
    Stone J. Contact lens wear in the young myope. Br J Physiol Opt 1973; 28: 90134.
  • 92
    Stone J. The possible influence of contact lenses on myopia. Br J Physiol Opt 1976; 31: 89114.
  • 93
    Kerns RL. Research in orthokeratology. Part VIII: results, conclusions and discussion of techniques. J Am Optom Assoc 1978; 49: 308314.
  • 94
    Polse KA, Brand RJ, Schwalbe JS, Vastine DW, Keener RJ. The Berkeley orthokeratology study, part II: efficacy and duration. Am J Optom Physiol Opt 1983; 60: 187198.
  • 95
    Grosvenor T, Perrigin J, Perrigin D, Quintero S. Use of silicon-acrylate contact lenses for the control of myopia: results after two years of lens wear. Optom Vis Sci 1989; 66: 4147.
  • 96
    Bullimore MA, Jones LA, Moeschberger ML, Zadnik K, Payor RE. A retrospective study of myopia progression in adult contact lens wearers. Invest Ophthalmol Vis Sci 2002; 43: 21102113.
  • 97
    Chan B, Cho P, Cheung SW. Orthokeratology practice in children in a university clinic in Hong Kong. Clin Exp Optom 2008; 91: 453460.
  • 98
    Lee TT, Cho P. Discontinuation of orthokeratology and myopic progression. Optom Vis Sci 2010; 87: 10531056.
  • 99
    Kakita T, Hiraoka T, Oshika T. Influence of overnight orthokeratology on axial elongation in childhood myopia. Invest Ophthalmol Vis Sci 2011; 52: 21702174.
  • 100
    Blacker A, Mitchell GL, Bullimore MA, Long B, Barr JT, Dillehay SM, Bergenske P et al. Myopia progression during three years of soft contact lens wear. Optom Vis Sci 2009; 86: 11501153.
  • 101
    Dumbleton KA, Chalmers RL, Richter DB, Fonn D. Changes in myopic refractive error with nine months’ extended wear of hydrogel lenses with high and low oxygen permeability. Optom Vis Sci 1999; 76: 845849.
  • 102
    Jensen H, Goldschmidt E. Management of myopia: pharmaceutical agents. In: Grosvenor T , Flom MC , eds. Refractive Anomalies. Research and Clinical Applications. Boston: Butterworth-Heinemann, 1991. p 371383.
  • 103
    McBrien NA, Moghaddam HO, Reeder AP. Atropine reduces experimental myopia and eye enlargement via a non-accommodative mechanism. Invest Ophthalmol Vis Sci 1993; 34: 205215.
  • 104
    Leech EM, Cottriall CL, McBrien NA. Pirenzepine prevents form deprivation myopia in a dose dependent manner. Ophthalmic Physiol Opt 1995; 15: 351356.
  • 105
    Cottriall CL, McBrien NA. The M1 muscarinic antagonist pirenzepine reduces myopia and eye enlargement in the tree shrew. Invest Ophthalmol Vis Sci 1996; 37: 13681379.
  • 106
    Le QH, Cheng NN, Wu W, Chu RY. Effect of pirenzepine ophthalmic solution on form-deprivation myopia in the guinea pigs. Chin Med 2005; 118: 561566.
  • 107
    Bartlett JD, Niemann K, Houde B, Allred T, Edmondson MJ, Crockett RS. A tolerability study of pirenzepine ophthalmic gel in myopic children. J Ocul Pharmacol Ther 2003; 19: 271279.
  • 108
    Siatkowsky RM, Cotter SA, Crockett RS, Miller JM, Novack GD, Zadnik K: US Pirenzepine Study Group. Two year multicenter, randomized, double-masked, placebo-controlled, parallel safety and efficacy study of 2 % pirenzepine ophthalmic gel in children with myopia. JAAPOS 2008; 12: 332339.
  • 109
    Chen Z, Li T, Yao P, Xu Y, Zhou X. Effects of 0.05 % racanisodamine on pupil size and accommodation. Optom Vis Sci 2010; 87: 966970.
  • 110
    Galton F. The history of twins, as a criterion of the relative powers of nature and nuture. Nature 1875; 13: 59.
  • 111
    Goldschmidt E. On the Etiology of Myopia. An Epidemiological Study. Copenhagen: Munksgaard, 1968. p 1172.
  • 112
    Leary GA. The reconciliation of genetically determined myopia with environmentally induced myopia. Am J Optom Arch Am Acad Optom 1970; 47: 702709
  • 113
    Hammond CJ, Sneider H, Gilbert CE, Spector TD. Genes and environment in refractive error: the twin eye study. Invest Ophthalmol Vis Sci 2001; 42: 12321236.
  • 114
    Dirani M, Shekar SN, Baird PN. The role of educational attainment in refraction: the genes in myopia (GEM) twin study. Invest Ophthalmol Vis Sci 2008; 49: 534538.
  • 115
    Dirani M, Shekar SN, Baird PN. Adult-onset myopia: the genes in myopia (GEM) twin study. Invest Ophthalmol Vis Sci 2008; 49: 33243327.
  • 116
    Kurtz D, Hyman L, Gwiazda JE, Manny R, Dong LM, Wang Y, Scheiman M et al. Role of parental myopia in the progression of myopia and its interaction with treatment in COMET children. Invest Ophthalmol Vis Sci 2007; 48: 562570.
  • 117
    Lam DSC, Fan DSP, Lam RF, Rao SK, Chong KS, Lau JTF, Cheung EYY. The effect of parental history of myopia on children's eye size and growth: results of a longitudinal study. Invest Ophthalmol Vis Sci 2008; 49: 873876.
  • 118
    Chen YP, Hocking PM, Wang L, Povazay B, Prashkar A, To CH, Erichsen JT et al. Selective breeding for susceptibility to myopia reveals a gene-environment interaction. Invest Ophthalmol Vis Sci 2011; 52: 40034011.
  • 119
    Richler A, Bear JC. The distribution of refraction in three isolated communities in Western Newfoundland. Am J Optom Physiol Opt 1980; 57: 861871.
  • 120
    Alsbirk PH. Refraction in adult West Greenland Eskimos. Acta Ophthalmol 1979; 57: 8495.
  • 121
    Saw SM, Chua WH, Hong CY, Wu HM, Chan WY, Chia KS, Stone RA et al. Nearwork in early-onset myopia. Invest Ophthalmol Vis Sci 2002; 43: 332339.
  • 122
    Jones-Jordan LA, Mitchell GL, Cotter SA, Kleinstein RN, Manny RE, Mutti DO, Twelker JD et al. Visual activity before and after the onset of juvenile myopia. Invest Ophthalmol Vis Sci 2011; 52: 18411850.
  • 123
    Mutti DO, Mitchell GL, Moeschberger, Jones LA, Zadnik K. Parental myopia, near work, school achievement and children's refractive error. Invest Ophthalmol Vis Sci 2002; 43: 36333640.
  • 124
    Jones LA, Sinnott LT, Mutti DO, Mitchell GL, Moeschberger MI, Zadnik K. Parental history of myopia, sports and outdoor activities, and future myopia. Invest Ophthalmol Vis Sci 2007; 48: 35243532.
  • 125
    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: 527530.
  • 126
    Dirani M, Tong L, Gazzard G, Zhang X, Chia A, Young TL, Rose KA et al. Outdoor activity and myopia in Singapore teenage children. Br J Ophthalmol 2009; 93: 9971000.
  • 127
    Rosenfeld M, Gilmartin B. Myopia and nearwork: causation or merely association? In: Rosenfeld M , Gilmartin B , eds. Myopia and Nearwork. Oxford: Butterworth Heinemann, 1998. p 193206.
  • 128
    Gottlieb MD, Fugate-Wentzek LA, Wallman J. Different visual deprivations produce different ametropias and different eye shapes. Invest Ophthalmol Vis Sci 1987; 28: 12251234.
  • 129
    Smth EL 3rd, Huang J, Hung LF, Blasdel TL, Hummbird TL, Bockhorst KH. Hemiretinal form deprivation: evidence for local control of eye growth and refractive development in infant monkeys. Invest Ophthalmol Vis Sci 2009; 50: 50575069.
  • 130
    Smith EL 3rd, Harwerth RS, Crawford MLJ, von Noorden GK. Observations on the effects of form deprivation on the refractive status of the monkey. Invest Ophthalmol Vis Sci 1987; 28: 12361245.
  • 131
    Hung LF, Crawford MLJ, Smith EL 3rd . Spectacle lenses alter growth and the refractive status of young monkeys. Nat Med 1995; 1: 761765.
  • 132
    Smith EL 3rd , Kee CS, Ramamirtham R, Qiao-Grider Y, Hung LF. Peripheral vision can influence eye growth and refractive development in infant monkeys. Invest Ophthalmol Vis Sci 2005; 46: 39653972.
  • 133
    Huang J, Hung LF, Smith EL 3rd . Effects of foveal ablation on the pattern of peripheral refractive errors in normal and form-deprived infant rhesus monkeys (Macaca mulatta). Invest Ophthalmol Vis Sci 2011; 52: 64286434.
  • 134
    Hoogerheide J, Rempt F, Hoogenboom WPH. Acquired myopia in young pilots. Ophthalmologica 1971; 163: 209215.
  • 135
    Mutti DO, Hayes JR, Mitchell GL, Jones LA, Moeschberger ML, Cotter SA, Klienstein RN et al. Refractive error, axial length, and relative peripheral refractive error before and after the onset of myopia. Invest Ophthalmol Vis Sci 2007; 48: 25102519.
  • 136
    Tse DY, Lam CS, Guggenheim JA, Lam C, Li KK, Liu Q, To CH. Simultaneous defocus integration during refractive development. Invest Ophthalmol Vis Sci 2007; 48: 53525359.
  • 137
    Tse DY, To CH. Graded competing regional myopic and hyperopic defocus produce summated emmetropization set points in chick. Invest Ophthalmol Vis Sci 2011: 52: 80568062.
  • 138
    Liu Y, Wildsoet C. The effect of two-zone concentric bifocal spectacle lenses on refractive error development and eye growth in young chicks. Invest Ophthalmol Vis Sci 2011: 52: 10781086.
  • 139
    Mutti DO, Sholtz RI, Friedman NE, Zadnik K. Peripheral refraction and ocular shape in children. Invest Ophthalmol Vis Sci 2000; 41: 10221030.
  • 140
    Atchison DA, Prichard N, Schmid KL. Peripheral refraction along the horizontal and vertical visual fields in myopia. Vision Res 2006; 46: 14501458.
  • 141
    Chen X, Sankaridurg P, Donovan L, Lin Z, Li L, Martinez A, Holden B et al. Characteristics of peripheral refractive errors of myopic and non-myopic Chinese eyes. Vision Res 2010; 50: 3135.
  • 142
    Mutti DO, Sinnott LT, Mitchell GL, Jones-Jordan LA, Moeschberger ML, Cotter SA, Kleinstein RN et al. Relative peripheral refractive error and the risk of onset and progression of myopia in children. Invest Ophthalmol Vis Sci 2011; 52: 199205.
  • 143
    Sng CCA, Lin XY, Gazzard G, Chang B, Dirani M, Lim L, Selvaraj P et al. Change in peripheral refraction over time in Singapore Chinese children. Invest Ophthalmol Vis Sci 2011; 52: 78807887.
  • 144
    Sankaridurg P, Donovan L, Varnas S, Ho A, Chen X, Martinez A, Fisher S et al. Spectacle lenses designed to reduce progression of myopia: 12-month results. Optom Vis Sci 2010; 87: 631641.
  • 145
    Anstice NS, Phillips JR. Effect of dual-focus soft contact lens wear on axial myopia progression in children. Ophthalmology 2011; 118: 11521161.
  • 146
    Sankaridurg P, Holden B, Smith EL 3rd , Naduvilath T, Chen X, de la Jara PL, Martinez A et al. Decrease in rate of myopia progression with a contact lens designed to reduce relative peripheral hyperopia: one-year results. Invest Ophthalmol Vis Sci 2011; 52: 93629367.
  • 147
    Wildsoet C, Wallman J. Choroidal and scleral mechanisms of compensation for spectacle lenses in chicks. Vision Res 1995; 9: 11751194.
  • 148
    Hung LF, Wallman J, Smith EL 3rd . Vision-dependent changes in the choroidal thickness of macaque monkeys. Invest Ophthalmol Vis Sci 2000; 41: 12591269.
  • 149
    Wildsoet CF, Schmid KL. Optical correction of form deprivation myopia inhibits refractive recovery in chick eyes with intact or sectioned optic nerves. Vision Res 2000; 40: 32733282.
  • 150
    Charman WN, Radhakrishnan H. Peripheral refraction and the development of refractive error: a review. Ophthalmic Physiol Opt 2010; 30: 321338.
  • 151
    Logan NS, Gilmartin B, Wildsoet CF, Dunne MCM. Posterior retinal contour in adult anisometropia. Invest Ophthalmol Vis Sci 2004; 45: 21522162.
  • 152
    Sagan C, Druyan A. Shadows of Forgotten Ancestors. A Search for Who We Are. New York: Ballentine Books, 1993. p xiv.
  • 153
    McBrien NA, Arumugam B, Metlapally S. The effect of daily transient +4 D positive lens wear on the inhibition of myopia in the tree shrew. Invest Ophthalmol Vis Sci 2012; 53: 15931601.
  • 154
    Schmid KA, Wildsoet CF. Effects on the compensatory responses to positive and negative lenses of intermittent lens wear and ciliary nerve section in chicks. Vision Res 1996; 36: 10231036.
  • 155
    Shaikh AW, Siegwart JTJr, Norton TT. Effect of interrupted lens wear on compensation for a minus lens in tree shrews. Optom Vis Sci 1999; 76: 308315.