Despite receiving its fair share of criticism in the literature, “evidence-based medicine” has emerged as the “gold standard” for medical practice over the past two decades.1–5 The foundation of evidence-based medicine is that medical decision-making should rely on solid scientific evidence from well-conducted clinical research combined with patient's values and preferences through shared decision-making. Consistent with this approach, recommendations and standards for quality of scientific evidence, methodology, systematic reviews, meta-analyses, and reporting have been developed resulting in multiple guidelines across multiple disciplines.6–9 Evidence is ranked according to quality with thorough meta-analyses or masked randomized controlled trials with minimal risk of bias being ranked highest (level 1) and case reports or nonanalytic studies being ranked lowest (level 3).
Myopia prevalence has increased around the world in the past few decades, but particularly in East Asian regions and Singapore.10 Because of this, and the link between increasing degrees of myopia and a range of eye diseases,11–15 there is intense interest in understanding the basic mechanisms and developing methods to control myopia onset and progression. Driven by the rapid expansion of knowledge and desire to find solutions, a range of hypotheses and conjectures has arisen. With repetition at conferences and, at times, unchecked enthusiasm leading to dilution of qualifiers over time, many of the hypotheses have blossomed from being interesting ideas to gaining a considerable acceptance base.
Here, we present some of these beliefs as understood to exist in sections of the vision science or vision care communities and then subject them to scrutiny. We do not necessarily contend that all of the viewpoints as stated are universally held but that there is at least some confusion, misunderstanding, misinterpretation, or controversy among scientists and practitioners on the topics. Furthermore, the statements are not necessarily incorrect per se, but should be held as speculative until their legitimacy is established. Notably, this is not a thorough list of unproven ideas circulating in the myopia research arena.
In certain sections of this document, a mention of investigational treatments for myopia progression is made and such reference is always intended in the context that these methods are experimental in nature, even when not explicitly stated. There are no devices or drugs cleared by the United States Food and Drug Administration for controlling myopia progression at the time of writing this article. The authors do not endorse off-label use of devices or drugs.
LOW-DOSE (0.01%) ATROPINE SLOWS MYOPIA PROGRESSION
The potential of atropine to influence myopia has been recognized for at least 150 years.16 Despite the longstanding recognition of its potential, atropine has not been used widely for myopia control except over the past few decades in Taiwan17 and, more recently, Singapore.18 There is little doubt that atropine can slow the progression of myopia, at least temporarily, when myopia is defined purely as refractive power. The principal data supporting the use of low-dose (0.01%) atropine for myopia control arise from the atropine for the treatment of myopia (ATOM) studies.18,19 In ATOM1, 1.0% atropine was compared to a placebo control over 24 months.18 In ATOM2, 0.5%, 0.1%, and 0.01% atropine were also compared over 24 months.19 Considered in toto, all treatments slowed refractive progression compared to the placebo control over the 24-month period in a dose-dependent fashion. However, a rebound effect that was also dose-dependent was observed in the 12-month period after withdrawal of the treatment. The extent of rebound was such that, after the withdrawal period, the greatest reduction in refractive progression was found with the 0.01% dose (−0.72D in the 0.01% treatment group vs. −1.56D in the placebo control group from ATOM1). The impact of 0.01% atropine on refractive progression has been replicated in a retrospective cohort study and two controlled, randomized studies.20–22
After considerable publicity around the ATOM2 findings, two recent reports in prominent ophthalmology journals highlight the possibility of slowing myopia progression with the use of atropine drops.23,24 Both reports arrived at similar conclusions, namely, that a low-dose (0.01%) regime provides an optimal balance between efficacy and potential side-effects and rebound on cessation of treatment. The sentiment has been enthusiastically embraced, and 0.01% atropine seems to have been adopted as the treatment of choice for myopia control by pediatric ophthalmologists internationally.25–39
Despite this excitement, the evidence base supporting the efficacy of 0.01% atropine in myopia control is deficient. It is widely held that axial elongation, rather than high absolute refractive error per se, is responsible for complications that accompany high myopia40 (although it is also fair to say that this, in itself, remains a belief without a comprehensive evidence base). Although axial length alone is not used as a criterion for defining myopia, it has been used as a criterion for defining high myopia in some studies.40 The principal study supporting the use of low-dose (0.01%) atropine, ATOM2, did not have a contemporaneous control group using vehicle only.19 Rather, the investigators used an historical control (from the ATOM1 study) to demonstrate the refractive benefit of low-dose atropine18—but axial elongation in the group treated with low-dose atropine was not appreciably less than that observed in the historical control, either after 2 years of treatment (0.41 mm vs. 0.38 mm in the 0.01% treatment and control groups, respectively) or the further 12 months after cessation of treatment (0.58 mm and 0.52 mm, respectively; see figure 4 of Chia et al.41). Despite this, a network meta-analysis reported that low-dose atropine (0.01%) can “markedly” slow myopia progression, including having a moderate effect on axial elongation.42 This analysis relied on the single prospective study (ATOM2) mentioned above and is indirect evidence.
A recent article from Taiwan provides strong evidence against this interpretation.22 It reported results of a masked, randomized, controlled trial of 0.05%, 0.025%, and 0.01% atropine eyedrops for myopia control compared to a placebo, with over 100 subjects in each arm, over a 12-month period.22 Despite a dose-dependent slowing of myopia progression as measured by both refractive error and axial length, the reduction in axial elongation for the 0.01% atropine group compared to the placebo group was only 12%, which was not statistically significant. Justifiably, the value of 0.01% atropine for myopia control has been questioned in the literature.43,44
The considerable publicity surrounding 0.01% atropine has led to the planning and execution of multiple studies. To the best of our knowledge, there are over 30 clinical trials that are underway or planned using 0.01% atropine for myopia control under a variety of different scenarios, with most being identifiable on clinical trial registries.45 Publication of the early results from one trial suggests that 0.01% atropine can augment the treatment effect of orthokeratology;46 so, it may prove to be a useful adjunct therapy. Nevertheless, because there are two studies showing no significant impact and no studies demonstrating a positive effect on axial elongation, one drop per day of 0.01% atropine should be considered ineffective as a sole, frontline treatment for myopia control.
RELATIVE PERIPHERAL HYPEROPIA LEADS TO MYOPIA DEVELOPMENT AND PROGRESSION IN CHILDREN
It is commonplace to hear on the podium or read in educational articles that relative peripheral retinal hyperopia is a driver of myopia onset and progression.47 There is little doubt that the optical signal can influence eye growth and that the retina is the mediator between cause and effect; however, the contribution of retinal location to central refraction remains controversial. Atchison et al.48 reviewed the existing literature on the topic. They noted that data from animal studies support a role for the peripheral retina in driving central refractive status. Furthermore, the mechanism by which the so-called “peripheral plus power” treatments control myopia progression in investigational studies is often attributed to reduction of peripheral retinal hyperopia or induction of peripheral myopia. Although this circumstantial evidence sounds persuasive, there are only limited human data to support the general thesis.49,50
Five reports from four prospective longitudinal studies have attempted to examine the role of peripheral refraction in the development and/or progression of myopia in children.48,51–54 (Table 1) Atchison et al. reported consistency across these studies wherein differences in relative peripheral refraction were observed between hypermetropes, emmetropes, and myopes, but that such effects neither predicted myopia onset nor progression reliably.47 A possible conclusion from this observation is that changes in peripheral refraction may be more a result of, rather than a cause of, myopic shift. However, it is noteworthy that, in all these studies, peripheral refraction was measured with cycloplegia and without correction in place. Because near work is strongly associated with myopia development,55 peripheral refraction measurement for the purpose of understanding its mechanistic role should ideally be performed at close distances without cycloplegia. Because myopic children may perform near work with or without correction, peripheral refraction would also be measured under both conditions. A further factor for consideration is the difference between relative and absolute peripheral refraction. Relative peripheral refraction is presented in most articles on the assumption that the fovea will be corrected and fully focused for normal viewing. Because of potential imprecision of the focusing mechanism (termed accommodative “lag”) and changes in spherical aberration of the eye during accommodation, absolute peripheral retinal hypermetropia may be present in the absence of peripheral hypermetropia relative to foveal refraction for viewing at near distances. Therefore, absolute values should be used for analytical purposes.
As noted above, interventions imparting peripheral plus power, such as orthokeratology and soft multizone lenses, have been shown to be effective in slowing myopia progression in investigational trials.56,57 Orthokeratology and soft multizone lenses have also been shown to shift peripheral refraction in the myopic direction.50,58 In one study, the extent of midperipheral corneal steepening after orthokeratology, potentially an indirect assessment of change in peripheral refractive error, was associated with progression of myopia.59 But, attribution of the impact on ocular growth in such cases solely to a peripheral retinal mechanism cannot necessarily be made. For example, in myopia control soft contact lenses, the peripheral plus power is fixed at the corneal plane. The central distance correction zone of the contact lens is in most circumstances smaller than the eye's pupil diameter. Thus, the peripheral plus will impact both central and peripheral retina. The proportion of rays at any given point on the retina that passed through the central versus peripheral optical zone is simply a function of the geometry of the optics.
Clearly, the role of peripheral optics in myopia onset and progression, which may arise due to different mechanisms, has not been elucidated. More research is required to determine the mechanisms by which the retina detects dioptric blur and directs eye growth as well as to define the roles of the central and peripheral retina in myopia onset and progression.
UNDERCORRECTION SLOWS MYOPIA PROGRESSION
The issue of whether to fully correct myopia for distance vision has been a matter of contention for many years.60,61 Undercorrection of myopia seems to be practiced by some eyecare practitioners globally; certainly, Japan has a reputation anecdotally for undercorrection as a standard of care.62 However, there is ongoing confusion among practitioners about how myopia progression is comparatively influenced by lack of correction, undercorrection, intermittent correction (i.e., say, wearing spectacles for distance viewing but not for reading), and full correction.
There is minimal support in the literature for undercorrection as a means of slowing progression. The principal source of the belief and likely the basis of the practice in Japan arises from a study by Tokoro and Kabe.63 They reported differences in myopia progression among a population of myopes aged 7 to 15 years based on wearing patterns from the following data: (1) full-correction full-time wear (progression of −0.75D±0.27, N=13), (2) partial (i.e., “under”) correction (−0.54D±0.39, N=10), or (3) full-correction part-time wear (−0.62D±0.32, N=10). Chung et al.64 criticize the study on the basis of the small sample size, failure to match subjects for age, inclusion of subjects under simultaneous pharmaceutical treatment, and flawed statistical treatment of the data. Another report that studied the effect of monovision spectacle wear on myopia progression noted slower progression in eyes of subjects that were undercorrected for distance vision.65 Notably, all subjects accommodated to read with the fully corrected eye. The results of this study suggest that, by periodically alternating which eye is undercorrected, it may be possible to achieve myopia control. Tarutta et al.66 provided supporting data in a clinical trial in which the eye exposed to moderate myopic defocus was switched on a daily basis.
Studies that found binocular undercorrection does not slow myopia progression seem to have received more attention. Chung et al.64 reported on a 2-year study of 94 myopic Malaysian and Chinese subjects aged 9 to 14 years, who were evenly and randomly allocated to a fully corrected control group or an experimental group who were undercorrected by an amount that yielded 20/40 vision in each eye. The authors reported that undercorrection produced statistically significantly more rapid myopia progression (−1.00D vs. −0.77D) and axial elongation than full correction. However, the degrees of freedom in the reported analysis of variance suggest that appropriate partitioning of variance by eye and time has not been performed and so the statistics reported may be in error.
Adler and Millodot67 repeated the Chung experiment over an 18-month period on a population consisting principally of orthodox Jews. Their results were numerically consistent with those of Chung et al. in that progression in subjects who were undercorrected averaged −0.99D (N=25) compared with −0.82D (N=23) in subjects who were fully corrected. However, their sample size was smaller than that in the Chung experiment and the difference they observed was not statistically significant.
Li et al.68 investigated the effects of undercorrection on myopia progression in 12-year-old Chinese children in a cohort study. From a total sample of 2,363 eligible students, 253 myopes were identified with spectacles and relevant associated data, of which 47% were undercorrected and 53% were fully corrected. Undercorrection was considered to be present where presenting visual acuity was able to be improved by at least 2 lines with subjective refraction. Mean progression at 1-year follow-up was not statistically significant at −0.64 and−0.68D for the undercorrected and fully corrected groups, respectively. In a randomly assigned group of 150 myopic Ghanaian children, there was no difference in progression between the fully corrected (−0.54D) or undercorrected (−0.50D) groups over 2 years.69
Regardless of whether undercorrection exacerbates myopia progression, these articles provide solid evidence that binocular undercorrection is not an effective therapeutic intervention to slow progression of myopia. However, a more recent article adds an intriguing twist to this discussion. Sun et al.70 compared progression over 2 years in a cohort of 56 myopes of mean age 12.7 years who were fully corrected with that in a population of 65 myopes of mean age 12.8 years who were uncorrected. Full correction was considered to occur when the spectacle lens power was within 0.5D spherical equivalent of the baseline cycloplegic refraction. The two cohorts in this study showed considerable difference in baseline characteristics. Nonetheless, after adjusting for confounding factors, the authors found that children with full correction (mean progression±SD: −1.03±0.08D) progressed more rapidly than those who were not corrected at all (−0.76±0.07D). Furthermore, myopia progression decreased significantly as the amount of undercorrection increased. The authors suggested that the difference between their results and those in other articles which found that undercorrection did not slow progression may relate to a difference in the amount of undercorrection between studies.70 However, the option of leaving myopia uncorrected in children presents ethical challenges because lack of correction has been linked to missed educational opportunities.71
Another option often used in an attempt to slow progression by practitioners is the recommendation to wear a spectacle correction on a part-time basis. Parssinen et al.72 followed myopic children aged 9 to 11 years for approximately 3 years. The study design included allocation of 80 children to a group wearing full-correction spectacles for continuous use and another 80 to a group wearing full correction spectacles for distance vision only. There was no evidence that restricting wearing of spectacles for distance vision only slowed myopia progression; in fact, progression was observed to be faster in the left eyes of those using the spectacles for distance use only. In a subgroup analysis from another study, Yi and Li73 reported that more time wearing glasses was correlated with less myopia progression. In summary, there are limited data to support either binocular undercorrection or part-time wear of spectacles for slowing myopia progression.
PERCENTAGE TREATMENT EFFECT REMAINS CONSTANT WITH CONTINUING TREATMENT
Most articles reporting on experimental treatments for myopia progression present results as both absolute and relative treatment effects. Absolute effect is expressed as the mean difference in either refractive error progression or axial elongation between those exposed to an experimental treatment and those in a control group provided with standard myopic vision correction. Relative effect, usually expressed as a percentage, is presented as the mean difference between the two groups divided by the mean progression of the control group.
Expressing relative treatment effect as a percentage is conceptually attractive as it allows for generalization of the extent of myopia control for different progression rates and over different periods. For example, a child with early-onset myopia might be expected to become, say, a −6D myope. If treatment is started when the refractive error is at −1D and the relative myopia control effect is 50%, we might expect the refractive error to stabilize at −3.50D. As an example, an online calculator designed to demonstrate potential benefits of myopia control treatment over time uses the assumption that the percentage results obtained over a year or the first few years of treatment will be maintained for longer periods (up to 11 years).74 However, there are no data to support the proposition that treatment effects measured during the period of an investigational trial can be relied on over longer periods of treatment. To the contrary, available data suggest that efficacy wanes over time. For example, in the COMET study, the treatment effect based on the adjusted rate of change between baseline and 1 year was 0.18D (approximately 30%), but was only 0.20D at the three-year timepoint, meaning that there was essentially no treatment effect between years 1 and 3.75
Generally, treatment efficacy at different timepoints is presented as cumulative effect over the period of study relative to baseline values; so, efficacy values for individual segments of time are not always obvious. In Figure 1, we plot examples of treatment efficacy broken down into individual time segments. Figure 1A plots relative treatment efficacy of investigational myopia-control soft lenses from four studies that provided data for multiple timepoints and showed over 50% reduction in axial elongation during the first period of wear.50,76–78Figure 1B plots annual relative myopia control for a 5-year orthokeratology trial.79Figure 1C plots annual absolute myopia control effect for axial elongation during first and second years of treatment with atropine using the data provided in the analysis of Huang et al.42 In all these examples, both relative and absolute treatment efficacy diminished over time.
The data presented in Figure 1 are not intended to represent a formal analysis but make the point that the evidence base to demonstrate long-term continuation of treatment effect is lacking. In a more formal network meta-analysis of myopia control interventions, Huang et al.42 considered subgroups stratified by different treatment durations and, consistent with our proposition of diminishing treatment effect over time, reported that “most interventions lose their early effect in the second year, especially in the protection of axial length change.” It is worth noting that this analysis was restricted to absolute and not relative treatment differences. Because progression rates in children decrease after the initial onset of myopia,51,80,81 absolute treatment efficacy could feasibly be reduced while relative efficacy is maintained.
PERCENTAGE TREATMENT EFFECT APPLIES ACROSS THE PROGRESSION RANGE
The second problem with the acceptance of percentage reduction as a reasonable metric for myopia control is a presumption that the reported percentage treatment effect generally applies to individuals across the progression range. For example, a treatment might be found to limit myopia progression on average to −0.50D, whereas a control group may progress by −1.00D during the same time, resulting in a mean myopia control effect of 50%. By such reasoning, an individual who might normally progress by, say, −2.00D over a given time is projected to progress by only −1.00D with such treatment. Preliminary analyses suggest that this is not the case and, to the contrary, treatment tends more to an absolute effect rather than a relative effect across the progression range.82 As a result, the individual in this example may be more likely to progress by −1.50D during the period and thus only achieve 25% reduction in progression. If this is the case, faster progressors, who are in greatest need of myopia control, would not benefit to the extent expected from quoted relative efficacy values.
This, along with the previous point regarding consistency of the relative treatment effect over time, is a matter of major concern when projecting the likely future impact of myopia control treatments. Predicted reductions in the future prevalence of high myopia due to myopia control treatments rely on the mean relative treatment effect being maintained across the progression range as well as across time. Therefore, anticipated reductions in high myopia and associated pathology resulting from myopia control treatments may be substantially overestimated.83,84
Consistent with this point, the largest effects observed in experimental trials reported in the literature have been a reduction of myopia progression by about 1.00D with high-dose atropine over 18 to 24 months or the axial length equivalent over 5 years of orthokeratology.18,79,85 There are no examples in the literature to the best of our knowledge demonstrating that an effect greater than about 1.00D reduction in progression can be achieved in any individuals. Although any reduction in the refractive error is beneficial in terms of risk of myopia-related disease,11 reducing the stabilized refractive error from, say, −6D to −5D is a vastly different proposition to restricting it to −3D in terms of the implications for myopia-related pathology.
A further consideration is the transferability of treatment efficacy across ethnic groups. Because populations of Asian descent are on average more likely to progress at a faster rate than whites,80 neither relative nor absolute treatment effects measured in one group are necessarily applicable to the other.
To summarize, percentage treatment as a metric is based on a group average. It does not tell what percentage of a population can expect a certain treatment effect nor that a given individual can expect a certain percentage treatment effect. From an evidence-based perspective, efficacy can only be expressed as the cumulative absolute reduction in myopia progression over the period for which a treatment is tested.
HAND-HELD DIGITAL DEVICES CONTRIBUTE TO THE MYOPIA EPIDEMIC
A common headline in print, television, and online news is that hand-held digital devices are associated with myopia. Along these lines, the Taiwanese government took the extraordinary step of making it illegal for children younger than 2 years to use digital devices and restricting usage among children up to the age of 18 years.86 There are relatively limited data linking digital device use to myopia progression considering the attention it receives in the lay press. In a study of students aged 6 to 14 years in Northeast China, there was significantly less refractive shift in the direction of myopia among nonmyopic children, but not myopic children, who spent less time in screen-viewing activities.87 Greater than 4 hr per week use of computers and video games was associated with increased progression of myopia among Indian schoolchildren.88 In a cross-sectional study of Polish school students, computer use and spherical equivalent refractive error were correlated, although no causality was demonstrated.89 There were no specific separate analyses of hand-held devices, such as smartphones or tablets, in these studies and there seem to be little additional data to the best of our knowledge linking mobile technology use with myopia.
Although the link between spending time on hand-held devices and myopia seems intuitive at first glance, a deeper look gives a reason as to why this may not be the case. The first commercially successful smartphone was launched in 2007. But, escalating myopia prevalence in East Asia and Singapore became apparent in the 1980s and early 90s with reports from Hong Kong, Singapore, and Taiwan.90–92 Similarly, the myopia rate in the United States rose from 25% to 41.6% between the early 1970s and the turn of the century before the introduction of the smartphone.93 Desktop computers are a more likely candidate contributor to this epidemic than hand-held devices because their introduction more closely matches the timeline.
Another reason to question the role of hand-held devices relates to the level of optical defocus across the retinal field. Despite the tenuous nature of the association between relative peripheral retinal hyperopia and onset and progression of myopia in humans described above, foveal visual experience is evidently not the sole source of retinal input to refractive development.94,95 In his seminal work, Flitcroft11 provided a detailed discussion of the dioptric structure of various environmental settings. His examples included outdoors scenes, as well as use of a desktop computer and reading at a desk. Color-coded images of the 3-dimensional structure of the environment showed the outside world to be much flatter dioptrically than interior scenes. Interestingly, the investigation did not analyze the dioptric field with hand-held devices. This will be clearly influenced by the size of the device, the distance at which it is held, accommodation, and the surrounding environment. While viewing a hand-held smartphone, the bulk of the peripheral visual field will show myopic defocus notwithstanding that some degree of accommodative lag may be present. This might actually be protective against myopia progression according to the principle that defocus across the retinal field influences refractive development. Obviously, contradictory forces would be at play as the device is held closer. Increased accommodation to view the device clearly would lead to even more peripheral field myopia. But, the near object would also subtend a larger proportion of the retinal field. And admittedly, for a large tablet device held at a very close distance, the screen may well occupy a substantial amount of the visual field. Even so, when compared to, say, working on a computer at a desk set against a wall, the degree of peripheral hyperopia over a large area of the visual field can be expected overall to be less for hand-held devices.
The real problem with hand-held digital devices may be related to their entertainment value. Children may find that remaining indoors with a device is more appealing than playing outside and, as discussed below, the ratio of time spent indoors to outdoors is a known influence in myopia onset. However, given our current knowledge, myopia onset and progression might be related to either hand-held digital devices or peripheral retinal hyperopia but probably not both.
MORE TIME OUTDOORS SLOWS MYOPIA PROGRESSION
The influence of time spent outdoors on myopia has been the subject of many studies over the past decade, since the original reports of Jones et al. and Rose et al.96,97 In their systematic review and meta-analysis on the subject, which included interventional clinical trials, Xiong et al.98 found that an increase by some 9 hr per week of time spent outdoors would reduce incident myopia by 50%. Implementation of such a “treatment regime” would require a considerable cultural shift in at-risk populations but comes with minimal associated risk; more time spent outdoors is considered a healthy lifestyle option in the face of increasing obesity and type 2 diabetes globally. However, the longer-term impact of spending more time outdoors on myopia prevalence is not clear. The analyses conducted to date suggest that increasing outdoor time merely delays onset of myopia in prone individuals. This could be a very useful benefit because age of onset of myopia is linked to risk of developing high myopia.99 However, the impact in some studies is modest and studies of potential rebound, a problem observed with use of higher-dose atropine, have not been undertaken. And clearly, it is not a solution for all children; assuming simple cumulative probability, after 2 years of intervention that raised the time spent outdoors in a population of primary schoolchildren by 9 hr per week as per the recommendation of Xiong et al., 75% of treated children would still become myopic. Ideally, future research will isolate the attribute of the outdoor environment that delays onset, whether it be light levels, wavelength, the dioptric stimuli, or some other factor (see below for further discussion), for development of a targeted treatment regime.
Perhaps, a more important question for those involved clinically in myopia control is whether greater time spent outdoors can slow myopia progression. Despite its importance, there is relatively little literature on this topic compared to the large body reporting an effect on myopia onset. In their article, Xiong et al.98 reported that “… paradoxically, outdoor time was not effective in slowing progression in eyes that were already myopic.” Certainly, the authors of one of the early studies that identified the effect of outdoor activity on myopia onset later published a paper using the same cohort that showed absence of impact of outdoor activity on myopia progression.100 The true test of whether intervention by increasing outdoor activity can impact progression is through randomized clinical trials. Four prospective randomized trials were identified by Xiong et al.98 He et al.101 studied a young age group (grade 1, mean age of 6.6 years) with correspondingly low initial prevalence of myopia, excluding the possibility of analysis of the effect of increasing outdoor time on progression of existing myopes. The study of Wu et al.102 was confounded by a proportion of the myopic population receiving atropine treatment. Among those myopes who were not being treated with atropine, mean progression was not statistically significantly different between the increased outdoor activity group and the control group. However, the mean values did show a sizeable numerical ratio (−0.20D vs. −0.37D, respectively), and the study was presumably not powered to test for this effect. Furthermore, the overall progression rates for the population 7 to 11 years old in this study were surprisingly moderate, making statistical separation challenging. In the study by Jin et al.,103 the available data for the main study population were limited to visual acuity measurements. There was a breakdown into “suspected” and “nonsuspected” myopia, and there was some suggestion of differences in progression rates between the intervention and control groups among suspected myopes. Analysis of a subgroup in which refractive parameters were measured did not provide a breakdown into myopic and nonmyopic groups. The impact of outdoor activity on myopia progression in the study of Yi and Li73 is confounded by assignation of behavioral changes including modification to the amount of near and intermediate work being done as well as increased outdoor activity. The annual mean myopia progression in the group with this combined intervention was less than that in the control group (−0.38 vs. −0.52, respectively). However, it is not clear how much outdoor time was responsible for this result.
Because of keen interest in the area, results from multiple studies investigating the role of outdoor activity on refraction have been published since the meta-analysis by Xiong et al. We identified a single article that provided evidence from a prospective, randomized, controlled interventional trial that myopia progression could be slowed by spending more time outdoors.104 Over 1 year in 693 grade-one children from 16 schools in Taiwan, Wu et al. found a reduction of 25.6% in refractive progression and 10% in axial elongation among nonmyopes and 29.1% in refractive progression and 25% in axial elongation among myopes for the intervention group compared with the controls. These results may reflect the difficulty of achieving behavioral change and the modest impact that increased time outdoors has on refractive progression.
THE IMPACT OF OUTDOOR ACTIVITY ON MYOPIA INCIDENCE IS DUE TO DAYLIGHT
As mentioned above, there is little doubt that increased time spent outdoors is protective against myopia onset.98,105 Numerous authors tend to the opinion that this effect is due to daylight, whether it be the higher light levels outdoors or to the difference in spectral intensity of the light compared with those indoors.106–111 Certainly, animal experiments have shown that (1) different light levels can result in different refractions, (2) bright light can reduce or block form-deprivation myopia, (3) bright light slows defocus-induced myopia (although there seems to be full compensation), and (4) there is wavelength dependence.112–116 An early study that failed to find defocus-induced myopia in macaque monkeys may be explained in part by the animals spending time in an outdoor environment.117 In humans, individuals involved in outdoor occupations, such as farmers and fishermen, show a lower prevalence of myopia.118
The idea that light level may be the protective feature of outdoor activity arose because a key alternative, time engaged in near activities, had been interpreted in initial studies as providing modest and inconsistent effect.119–121 Accumulated knowledge since then, however, consistently demonstrates that measures of near activity (e.g., time spent studying, in screen-viewing activities and reading, continuous reading, close distances of reading, television viewing, and reading more books for pleasure) correlate with the presence, onset, or progression of myopia, often independently in multivariate analyses to the significant influence of time spent outdoors.87,104,122–128 The difficulty in proving that light level is the key factor protecting against myopia onset with time spent outdoors is the inability to isolate the effect of either retinal focus or light.
As noted above, Flitcroft has studied panretinal focus in different environments and found that, outdoors, the visual field is relatively uniform with limited opportunity for hyperopic retinal defocus in a near emmetropic eye. Indoors, the visual environment is dioptrically heterogeneous and, notwithstanding variation in activities and a viewer's accommodation level, there is considerable scope for sustained hyperopic retinal defocus.11 Flitcroft has also pointed out that defocus modulates eye growth through a closed-loop system.129 That is, the active, coordinated change in defocus of the eye over time varies with the level of defocus.130 There is no corresponding feedback system in relation to light levels and thus it is an open-loop stimulus. For light to be the principal driver maintaining a near-emmetropic state, there would need to be a preprogrammed ideal eye shape that it guides growth toward. Although evidence to date strongly favors a sophisticated feedback system in which visual focal input steers eye axial growth in a coordinated fashion to a low-defocus state,130 there is also the suggestion of a “set-point” to which the eye grows.131,132 Even then, the ultimate refraction of an individual animal in these studies seems to be a function of defocus plus the consistent deviation of that animal about a group mean value. More evidence of a set-point independent of defocus is necessary to establish light as the primary driver in regulating refraction with time spent outdoors.
Further argument in favor of defocus as the main driving feature of refractive control with time spent outdoors arises in animal studies. Defocus is a potent and predictable regulator of ocular growth in these models where light is less so. Wildsoet and Wallman noticed near-perfect compensation (median of +16.3D) in chick eyes exposed to +15D of defocus and, although incomplete, substantial compensation for hyperopia induced by negative lenses (median refractive errors: −4.8 and −8.6D for lenses of −6 and −15D, respectively).133 By contrast, high and low light levels in the absence of imposed defocus were found to produce refractive errors in chick eyes across a much reduced range (+1.1D to −2.4D, respectively).114 Although the brightest light levels from the latter study are lower than those found outdoors, we would not expect much deviation from these results in full daylight. Furthermore, light may not be the only independent factor in this study, because pupil size is variable, raising the possibility that depth of focus and aberrations might also influence the refractive state.
There is much more to be learnt about the interplay between defocus and light levels on refraction. However, we contend that attributing the influence of time spent outdoors on myopia suppression specifically to daylight is not justified with our current knowledge.
SUBCLASSIFICATIONS FOR MYOPIA ARE EFFECTIVE
Myopia has been classified in numerous ways. It is clear that there are relatively rare syndromic conditions of which myopia, often high myopia, is a feature. Another common and ongoing classification is to divide myopia as either physiological or pathological. However, until recently, there was no clear definition as to what constitutes pathologic myopia. Tokoro had defined pathologic myopia as “myopia caused by pathological axial elongation,” a concept that would place those at risk of future pathology due to excessive axial length in the “pathological” category.134 The Meta-Analysis for Pathologic Myopia (META-PM) group has recently proposed a much-needed, reproducible, classification system for myopic maculopathy.135 Ohno-Matsui stipulates that myopia classified as “pathologic” myopia requires the presence of myopic maculopathy equal to or more severe than diffuse chorioretinal atrophy.136,137 Pathological myopia is therefore merely myopia where pathological findings above a certain threshold are manifested. Under this definition, a young adult with, say, −12D of myopia and no apparent fundus changes other than some peripapillary atrophy and fundus tessellation is said to not have pathological myopia despite the likelihood of its future development. But, we are also unlikely to classify such myopia as the classic alternative—that is, physiological. A definition of physiological, or simple, myopia is variation within normal limits of the optical system of the eye.138 However, in Flitcroft's11 seminal review article, he provided convincing evidence that there is no safe level of myopia. Although risk of disease complications is very low at low amounts of myopia and exponentially correlated with the degree of refractive error,139 it is apparently present for all myopes. All nonpathological myopia might therefore be considered “prepathological,” where the risk of future pathology is a function of refractive error and age. We currently have little indication aside from these factors as to which individuals will develop complications.
Myopia is also commonly classified as low, medium, or high, although the boundaries vary somewhat arbitrarily between investigators.138 This grouping may also serve to mislead. High myopia and pathological myopia have been informally grouped together and perhaps used interchangeably in the past. With the new definition for pathological myopia,136,137 perhaps a new category of “high prepathological” myopia is needed. But, defining a threshold for high myopia remains complicated. Common definitions of high myopia used in previous studies include −5.0D, −6.0D, −8.0D, −10.0D, and −12.0D.140 However, there is no apparent inflection point in the relation between refractive error and log of the odds of having myopic retinopathy.139 Imposing a threshold is largely an artificial and arbitrary exercise. The major problem arising from segregating groups of myopes by refractive error is that risk of pathology is routinely equated to high myopia alone, which may serve to dismiss legitimate concerns for those with less myopia. In a separate analysis (not shown here) of population-based studies that have reported myopic retinopathy in different refractive error groupings,141–144 we estimate that some 30% of cases occur in myopes not classified as highly myopic (i.e., more than 6.00D of myopia).
MYOPIA IS A CONDITION WITH A NEGATIVE DIOPTRIC NUMBER
The criteria for the presence of myopia vary widely across studies. In some cases, any degree of myopia (−0.25D or more myopia) is used, whereas in other cases, a more stringent threshold is used (more than, say, −1.00D of myopia); however, inevitably, the criterion involves a negative dioptric value. The findings from studies that have considered annual change in refraction show that the greatest myopic shift occurs before diagnosis.51,81 Indeed, the changes to ocular biometry start up to 4 years before diagnosis.51,145 Furthermore, prediction of myopia onset can be achieved with confidence from knowledge of refraction at a specific age among young children, as described by Zadnik et al.146 The refractive errors given in this guide are low amounts of hypermetropia. This suggests that children are already “programmed” to become myopic before their refraction becomes a negative number. Certainly, the term “myopia” is one of the definition and is unlikely to be changed any time soon, but the biological processes underlying myopia onset and progression are clearly underway while the refraction of a child still measures as slightly hypermetropic.
There have been exciting advances in understanding myopia onset and progression in recent times, particularly in this millennium. Many hypotheses have been proposed to explain different observations in this field but the evidence base for many commonly held beliefs is lacking. We have highlighted some of them in this review but there are many more to consider. This should not dissuade practitioners from attempting to slow onset and progression of myopia but hopefully will provide them with information so that they are able to educate parents and children appropriately based on credible science. Among our recommendations are that greater rigor in clinical trials is required and conclusions about efficacy of treatments should not be based on favorable results over a single year of study. We also advise against accepting data where a disconnect occurs between axial elongation and myopia progression or where axial elongation is not measured. For now, we recommend caution in readily adopting assertions about myopia as fact, no matter how intuitively plausible they may seem, until supporting, robust evidence is established.
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