Update and guidance on management of myopia. European Society of Ophthalmology in cooperation with International Myopia Institute

Abstract

The prevalence of myopia is increasing extensively worldwide. The number of people with myopia in 2020 is predicted to be 2.6 billion globally, which is expected to rise up to 4.9 billion by 2050, unless preventive actions and interventions are taken. The number of individuals with high myopia is also increasing substantially and pathological myopia is predicted to become the most common cause of irreversible vision impairment and blindness worldwide and also in Europe. These prevalence estimates indicate the importance of reducing the burden of myopia by means of myopia control interventions to prevent myopia onset and to slow down myopia progression. Due to the urgency of the situation, the European Society of Ophthalmology decided to publish this update of the current information and guidance on management of myopia. The pathogenesis and genetics of myopia are also summarized and epidemiology, risk factors, preventive and treatment options are discussed in details.

Keywords

Myopia pathologic myopia preventive medicine blindness time spent outdoors myopia reduction interventions atropine orthokeratology

Introduction

Myopia is recognized as a significant global public health issue, expected to affect an increasing number of people in the next decades.¹ Pathology such as myopic maculopathy and optic neuropathy in highly myopic eyes can cause significant irreversible visual impairment and blindness.^1–3 Besides, myopia increases the risk of other pathological ocular changes such as cataract, glaucoma, and retinal detachment, all of which can cause irreversible vision loss.^4,5 Significant disease associations exist even at low and moderate levels of myopia. Current evidence suggests that there is no safe threshold level of myopia for any of the known ocular diseases linked to myopia.^6,7

The importance of the increase in the prevalence of myopia and its sequelae has been well documented particularly in East Asian countries that have experienced the most pronounced increase in myopia prevalence. Consequently, the experience in preventing the development and progression of myopia in children and adolescents is more advanced in East Asia. The prevalence of myopia also increased in Europe in recent decades and reached the level of 45–50% in the 25–29 years old age group.⁸ Thus, Europe is becoming aware of the importance of myopia both as a public health issue and as a significant socioeconomic burden.

The International Myopia Institute (IMI) with its group of 85 multidisciplinary experts in the field has recently published a series of white papers on the pathogenesis of myopia including the results of experimental studies,⁹ genetics,¹⁰ and the results of clinical studies including the outcome of randomized controlled trials.¹¹ Based on the IMI White Papers,¹¹ the main aim of this article is to increase awareness and to provide recommendations for European ophthalmologists to prevent the development and progression of myopia in children and adolescents.

Definition and classification

To be consistent with international standards, the definitions and classification of myopia as used in this article follow those described by the International Myopia Institute (IMI) in the IMI White Papers (Tables 1 and 2).¹²

Table 1.

Summary of proposed general and quantitative thresholds for myopia¹² (with permission from IMI).

Term	Definition
Qualitative definitions
Myopia	A refractive error in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina when ocular accommodation is relaxed. This usually results from the eyeball being too long from front to back, but can be caused by an overly curved cornea and/or a lens with increased optical power. It also is called nearsightedness.
Axial myopia	A myopic refractive state primarily resulting from a greater than normal axial length.
Refractive myopia	A myopic refractive state that can be attributed to changes in the structure or location of the image forming structures of the eye, that is, the cornea and lens.
Secondary myopia	A myopic refractive state for which a single, specific cause (e.g. drug, corneal disease, or systemic clinical syndrome) can be identified that is not a recognized population risk factor for myopia development.
Quantitative definitions
Myopia	A condition in which the spherical equivalent refractive error of an eye is ⩽−0.50 D when ocular accommodation is relaxed.
Low myopia	A condition in which the spherical equivalent refractive error of an eye is ⩽−0.50 and >−6.00 D when ocular accommodation is relaxed.
High myopia	A condition in which the spherical equivalent refractive error of an eye is ⩽−6.00 D when ocular accommodation is relaxed.
Pre-myopia	A refractive state of an eye of ⩽+0.75 D and >−0.50 D in children where a combination of baseline refraction, age, and other quantifiable risk factors provide a sufficient likelihood of the future development of myopia to merit preventative interventions.

Table 2.

Definitions for the structural complications of myopia¹² (with permission from IMI).

Term	Definition
Descriptive definitions
Pathologic myopia	Excessive axial elongation associated with myopia that leads to structural changes in the posterior segment of the eye (including posterior staphyloma, myopic maculopathy, and high myopia-associated optic neuropathy) and that can lead to loss of best-corrected visual acuity.
Myopic macular degeneration (MMD)	A vision-threatening condition occurring in people with myopia, usually high myopia that comprises diffuse or patchy macular atrophy with or without lacquer cracks, macular Bruch’s membrane defects, CNV, and Fuchs spot.
Diagnostic subdivisions of MMD
Myopic maculopathy	Category 0: no myopic retinal degenerative lesion. Category 1: tessellated fundus Category 2: diffuse chorioretinal atrophy. Category 3: patchy chorioretinal atrophy. Category 4: macular atrophy. ‘‘Plus’’ features (can be applied to any category): lacquer cracks, myopic choroidal neovascularization, and Fuchs spot.
Presumed myopic macular degeneration	A person who has vision impairment and vision acuity that is not improved by pinhole, which cannot be attributed to other causes, and: • The direct ophthalmoscopy records a supplementary lens <−5.00 D and shows changes such as “patchy atrophy” in the retina or, • The direct ophthalmoscopy records a supplementary lens <−10.00 D.
Specific clinical conditions characteristic of pathologic myopia
Myopic traction maculopathy (MTM)	A combination of macular retinoschisis, lamellar macula hole and/or foveal retinal detachment (FRD) in eyes with high myopic attributable to traction forces arising from adherent vitreous cortex, epiretinal membrane, internal limiting membrane, retinal vessels, and posterior staphyloma.
Myopia-associated glaucoma-like optic neuropathy	Optic neuropathy characterized by a loss of neuroretinal rim and enlargement of the optic cup, occurring in eyes with high myopia eyes with a secondary macrodisc or peripapillary delta zone at a normal IOP.

Pathogenesis

More than 50 years ago, myopia was believed to be mostly genetic in origin,¹³ although epidemiological studies have long ago shown the connection with education, near-work and higher occupational status.^14–16 Subsequently, experimental models have provided evidence that myopia may develop as an adaptation to environmental visual conditions through the same mechanisms used in emmetropization. Thus, myopia onset and progression is now understood to result from a complex interplay of visual/environmental conditions and genetic factors that modulate the visually guided eye growth so that the control mechanisms are no longer able to coordinate growth with the development of the optical components of the eye.^9,17

Most recent articles on the pathomechanism of accelerated eye growth refer to the influence of peripheral retinal defocus.^18–24 Animal and human studies have also examined additional ocular and environmental factors that may affect retinal image quality and influence eye growth. These factors include accommodation,^22,25–28 higher-order aberrations (HOA),^29–31 circadian rhythms,^32–34 light intensity and spectral composition,^35–37 and overstimulation of retinal OFF pathways³⁸ – for an overview see Figure 1.

Figure 1.

Model of the visually regulated control of eye growth and refractive state⁹ (with permission from IMI).

Work from animal models suggests that form deprivation and retinal defocus initiate a signaling cascade that leads to a number of cellular and biochemical changes in the retina and the retinal pigment epithelium (RPE). These chemical signals are transmitted through the choroid, causing changes in scleral extracellular matrix (ECM) synthesis which alters the biomechanical properties of the sclera, leading to increases in ocular growth and a more myopic refractive state.^39–41 The animal studies/models have show that the choroid plays an active role in emmetropization, both by modulation of its thickness to adjust the retina to the focal plane of the eye (choroidal accommodation), and well as through the release of growth factors that have the potential to regulate scleral extracellular matrix remodeling.⁴² Experimental studies have identified several biochemical compounds, such as retinal dopamine,⁴³ retinoic acid⁴⁴, and nitric oxide⁴⁵ that are involved in the modulation of axial length (AL) changes.

Epidemiology

According to Holden et al.¹ quoted in the World Report on Vision published by the World Health Organization (WHO) in October 2019, the estimated number of people globally with myopia in 2020 was predicted to be 2620 million, with a further expected increase to 3361 million by 2030. The number of individuals with high myopia was also expected to increase substantially from 399 million in 2020 to 516 million by 2030.^1,46 Both these estimates assume no impact of interventions intended to slow down myopia progression.

This means that pathological myopia is predicted to become the most common cause of irreversible vision impairment and blindness worldwide, and the prevalence estimates indicate the importance of reducing the global burden of myopia by means of myopia reduction interventions.

The predicted prevalence of myopia by 2050 is 65% of the population in Asia, 56% in Western Europe, 54% in Central Europe, and 50% in Eastern Europe¹ (Figure 2).

Figure 2.

Estimated increase in the prevalence (%) of myopia in three European regions. Adapted from article of Holden et al.¹

Many studies have reported substantial variations in the prevalence of myopia between different ethnic groups and different age groups.⁴⁷

Prevalence of myopia in different ethnic groups

The myopia burden is highest in East Asia and the high-income countries of the Asia-Pacific region (51.6% and 53.4% prevalence in 2020, respectively) but the prevalence is also high in Europe (Western Europe: 36.7%, Central Europe: 34.6%, and Eastern Europe: 32.2%).^1,48 An earlier meta-analysis from fifteen population-based adult cohorts and cross-sectional studies across Europe determined an age-standardised prevalence of 30.6% for myopia.⁴⁹ The peak prevalence of myopia was identified in the 25–29 years age group (47.2%) although the prevalence of high myopia was relatively low in Europe, with an age-standardised estimate of 2.7%.⁴⁹

A recent review by Grzybowski et al. showed that the prevalence of myopia in school-aged children was 73% in East Asia and 42% in North America. A low prevalence (under 10%) was described in African and South American children.⁸ In groups of White ethnicity there was no clear evidence of differences in myopia prevalence between studies of recent decades from Europe, the USA and Oceania.⁵⁰ (Tables 3 and 4).

Table 3.

Prevalence of myopia in children in Europe.

Authors	Publication time	Age (years)	Location	Number of participants	Definition (diopter) (D)	Myopia prevalence (%)
Matamoros⁵¹	2015	0–9	France	1781	⩽−0.5	19.6
Tideman⁵²	2017	6	Netherlands	5711	⩽−0.5	2.4
Enthoven et al.⁵³	2020	9	Netherlands	5074	⩽−0.5	11.5
Rudnicka et al.⁵⁴	2010	10–11	United Kingdom	233	⩽−0.5	3.4
O’Donoghue et al.⁵⁵	2015	12–13	Northern Ireland	661	⩽−0.5	17.7
Tideman et al.⁵⁶	2020	13	Netherlands	3600	⩽−0.5	22.2
Matamoros⁵¹	2015	10–19	France	8289	⩽−0.5	42.7
Lundberg⁵⁷	2017	Mean: 15.4	Denmark	307	⩽−0.5	33.6 cycloplegia: 17.9
Hagen et al.⁵⁸	2018	16–19	Norway	393	⩽−0.5	13

Table 4.

Prevalence of myopia in teenage Asian children.

Authors	Publication time	Age (years)	Location	Number of participants	Definition (diopter) (D)	Myopia prevalence (%)
Lam et al.⁵⁹	2004	13–15	Hong Kong	289	⩽−0.5	87.2
Matsumara et al.⁶⁰	1999	17	Japan	346	⩽−0.5	66.0
Wu et al.⁶¹	2013	17	China	6026	⩽−0.5	84.6
Lin et al.⁶²	2004	16–18	Taiwan	2474	<−0.25	84.0
Jung⁶³	2012	19	South Korea	23,616	<−0.5	96.5
Lee et al.⁶⁴	2013	19	South Korea	2805	⩽−0.5	83.3
Koh et al.⁶⁵	2014	Mean: 19.8	Singapore	28,908	<−0.5	81.6

Progression of myopia in different ethnic groups

Studies on the pattern of myopia progression in Asian and European children give contradicting results.^66–70

A meta-analysis determined 0.27 D/year faster progression in 1-year follow-up among 9-year-old Asian children than in age-matched European children.⁶⁹ However, an Australian study examining children of European White and East Asian ethnicity living in the same geographic location, found the progression of myopia to be similar between the two groups, primarily because the rate of progression was lower in the group of East Asian children living in Australia compared with children living in East Asia, suggesting that environmental differences can influence myopia progression.⁷⁰ Interestingly, in a recent study comparing Finnish and Singaporean children of the same age group, the 3-year myopia progression was faster among Finnish children.⁷¹

Prevalence of myopia across age groups

An early age of onset of myopia appears to be the strongest predictor of high myopia in both Asians and White children.^71–74

It was recently shown that parental myopia was associated with a greater risk of early-onset myopia in Asian, Hispanic, non-Hispanic white, and African American children.⁷⁵

In children younger than 6 years of age the prevalence of myopia is low. This is the case even in Asia where the prevalence of myopia is considered to be critically high in young adults (Table 5).

Table 5.

Prevalence of myopia in younger ages (<9 years).

Authors	Publication time	Age (years)	Location	Number of participants	Definition (diopter) (D)	Myopia prevalence (%)
Ma et al.⁷⁶	2016	3	Shanghai, China	8267	⩽−0.5	1.8
Guo et al.⁷⁷	2017	3	China	1127	⩽−0.5	0.0
Wu et al.⁶¹	2013	4	China	6026	⩽−0.5	1.2
Li et al.⁷⁸	2014	5-9	Northern China	1675	⩽−0.5	0.9

The prevalence of myopia increases markedly from approximately 6 years of age (Table 6, Figure 3). When comparing the indicators for the last 45 years (from 1971 to 2016), the frequency of myopia in Novosibirsk schoolchildren aged 7–10 years increased 5.1 times (from 4.5% to 23.0%), 11–14 years increased 3.8 times (from 10.5% to 40.0%), and 15–18 years increased 2.1 times (from 21.5% to 45.0%). It follows that the highest rate of onset of myopia is currently observed in children aged 7 to 10 years.^79,80

Table 6.

Increased prevalence of myopia with age.

Authors	Publication time	Location	Number of participants	Definition (diopter) (D)	Myopia prevalence changes (years of age: prevalence)
Ma et al.⁷⁶	2016	Shanghai, China	8267	⩽−0.5	3 years: 1.8% 10 years: 52.2%
Guo et al.⁷⁷	2017	China	1127	⩽−0.5	3 years: 0.0% 6 years: 3.7%
Wu et al.⁶¹	2013	China	6026	⩽−0.5	4 years: 1.2% 17 years: 84.6%
Giordano et al.⁸¹	2004	Hong Kong	2546	⩽−1.0	5 years: 4.6% 10 years: 43.5%
Matsumara et al.⁶⁰	1999	Japan	346	⩽−0.5	12 years: 43.5% 17 years: 66.0%
He et al.⁸²	2007	Southern China	2400	⩽−0.5	13 years: 36.8% 17 years: 53.9%

Figure 3.

Myopia prevalence in East Asia (dot) and in Europe (triangle) in different age groups of children (linear trend lines) (data published 1999–2020).^{51–65,76–78,81,82}

In the Correction of Myopia Evaluation Trial (COMET) study 426 ethnically diverse (African, Asian, Hispanic, Mixed, and White) myopic children were followed-up annually for at least 6 and up to 11 years to assess, amongst other things, when myopia seemed to stabilize. Nearly half (48%) of the children had stable myopia by age 15 years, 77% by 18 years and 90% by the age 21 years. There is evidence for myopia to have stabilized in most myopic individuals by the age 24 years, except in high myopes.^83–85 In a 23-year follow-up study of Finnish myopic children from mean age of 11 years at baseline, the adulthood myopic progression from the mean age of 24 years 8 years onwards was ⩾1.00 D in 17.9% of cases and mean annual change was -0.05 ± 0.09 D.⁸⁶ Other studies show a decline in progression rate with increasing age in young myopes of both European and Asian ethnicity.^69,87,88 In White European children, average yearly progression rates for myopia and axial length were −0.41 D and −0.30 mm respectively between 6 and 16 years of age and −0.16 D and 0.15 mm respectively between 12 and 22 years.⁸⁸

In 2000, Holden et al. showed that the greatest proportion of myopic people was between 10 and 39 years of age.¹ A European study also reported that myopia was most common in younger participants (47.2%), with those aged 25–29 years having a prevalence almost double (27.5%) that of those of middle and older age (55–59 years).⁸⁹

However, given the predicted increases in prevalence discussed above, the distribution of myopia in the population is expected to widen by 2050, with a significant proportion of the population exhibiting myopia from 10 years of age all the way through to 79 years of age; with the bulk of late onset (16 years or older) myopia, reflecting the significant lifestyle changes, mostly intensive near work over the past 10 to 25 years.^1,73,90 This may well be exacerbated by changes in working patterns following the Covid-19 pandemic (increased time indoors, increased time on electronic devices, etc.).

Based on a meta-analysis from 2015, there is a clear trend of higher myopia prevalence in the last 20 to 30 years across Western and Northern Europe.^89,91 In contrast, while the prevalence of myopia is reported to have been rising around the world, a similar trend in Southeast Norway appears to be absent.⁵⁸ Neither in Denmark, where nearly 140 years of myopia research did not find a convincing change in prevalence of myopia.⁹² Asian ancestry does not inevitably lead to myopia, since the prevalence of myopia in these areas was much lower two or three generations ago.^88,93 This suggests that environmental and social factors must be involved in the promotion of myopia in modern populations.

At the current time, the incidence of myopia is increasing in younger age groups, which means that prevalence rates in older adults are generally lower.^47,51,91,94 However, a bimodal pattern was observed in the prevalence of myopia among subjects of African-American ethnicity and in the population of Singapore. In both groups aged 40+ years, the prevalence was also highest among individuals in their forties and seventies.^95,96 A similar bimodal pattern was found in France, but the peak of myopia prevalence was in people in their twenties and above eighties (Figure 4).⁵¹ The bimodal distribution is probably due to the increase of the axial myopia among younger people, and secondary refractive myopization due to nuclear cataract in elderly people.⁴⁷

Figure 4.

Myopia prevalence in France 2012–2013 across the different age groups. Adapted from article of Matamaros et al.⁵¹

Genetics

Myopia is caused by a complex interplay between genetic and environmental factors associated with exposure to the life of a school-child which may limit outdoor exposure. Myopia heritability estimates vary, but are mostly high. Oligogenic and polygenic risk scores indicate that persons at high genetic risk have an up to 40 times increased risk of myopia compared with persons at low genetic risk.¹⁰

To date, more than 600 genetic loci have been identified for refraction and myopia.⁹⁷ Risk variants mostly confer low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression.^10,97 Pathway analyses indicated a light-induced retina-to-sclera signaling pathway for myopia development. The involved genes appeared to play a role in synaptic transmission, cell-cell adhesions, calcium ion binding, cation channel activity, and plasma membrane function. Many are light dependent and related to the cell cycle and growth pathways.¹⁰

Secondary syndromic forms of high myopia, such as Marfan’s syndrome, congenital stationary night blindness, Stickler’s syndrome, and the Donnai-Barrow syndrome, are inherited predominantly in a Mendelian fashion.⁹⁸ These forms of myopia are rare. Furthermore, some retinal dystrophies have a myopia phenotype. Therefore, a clinician should be aware of their syndromic features and extensive ocular examinations should be performed in case of a young onset of myopia or clinical suspicion.

To date, there is no robust evidence to suggest that there are fundamental differences in the genetic background of myopia risk between European and Asian individuals.¹⁰

The recent global rise in myopia prevalence is unlikely to be due to genetic factors alone. Multiple searches of the 1966–2001 PubMed database clearly point to a strong environmental impact on the development and progression of myopia. Changes in environmental factors in Singapore have been so great that large numbers of children with non-myopic parents are now in the high myopia category, and hence at greater risk of developing pathological myopia. Environmental pressures increase the risk of myopia across the population to a similar extent, irrespective of parental refractive error,^99–101 although parental myopia is associated with a greater risk of early-onset of myopia.^71,75

Risk factors

Studies have identified a number of non-genetic risk factors which affect the prevalence, progression or prevention of myopia. Environmental factors (time spent outdoors), education, personal characteristics, and binocularity play important roles in the onset and progression of myopia.

Personal characteristics

Ethnicity

Epidemiological evidence regarding the prevalence of myopia shows major differences between ethnic groups, although the burden of available evidence for this may be explained primarily by environmental influences.^52,88,102

Gender

Females show faster progression than males,^69,103–107 however, this difference has not been observed in all studies.^108–110 In the ethnic groups studied (Whites and Asians), sex differences emerge in the myopia prevalence at approximately 9 years of age. In one study, by late adolescence, white females as compared to white males were twice as likely to be myopic.⁵⁰

Parental myopia

Parental history of myopia correlates with the rate of axial elongation and increase in myopic refractive error (myopia progression).^52,111–113 Studies from different ethnic groups have shown that having one or two myopic parents increased the risk of myopia^114–116 and with a significant association between a strong family history and the incidence of myopia.¹¹⁷ However, the number of myopic parents appears to have a lower predictive value for the development and progression of childhood myopia in some studies^118,119 with the amount of myopia in the family having stronger predictive value.^10,120 The effect of parental myopia on myopia in their offsprings may not be taken as proof for a genetic contribution to myopia, since the correlation might also be the result of a shared lifestyle¹²¹ and their higher education.⁷¹ However, parental myopia was associated with a greater risk of early-onset myopia in a recent study.⁷⁵

Cognitive functions and education

Education seems to be important in triggering the onset of myopia, but less important in determining the degree to which myopia progresses.^122,123 Study among 31–35 year-old Finnish men showed that myopic men scored better in all four cognitive tests done and their reaction and movement times were faster than non-myopic men.¹²⁴ It was recently shown that refractive error genetic risk was significantly correlated with intelligence, both in childhood and adulthood, and educational attainment (defined as the number of years spent in formal education).⁹⁷ In the Singapore Cohort Study of the Risk Factors for Myopia (SCORM) both academic grades and intelligence quotient (IQ) scores appear to be independently associated with myopia in Singaporean children. Interestingly nonverbal IQ could be a stronger risk factor for myopia than books read per week.¹²⁵ Both verbal and non-verbal components of the cognitive function were strongly and consistently associated with myopia among more than one million Israeli adolescents.¹⁰¹ Recent studies have gone beyond simply observing an association of myopia and education to providing evidence for a causal role.^126–128 However, it is challenging to disentangle the risk of myopia due to education and less time outdoors.

Physical attributes

The connection between physical attributes and myopia is not definite. Jung et al. found that body stature (height, weight) of 19 years old males from Seoul was not significantly associated with myopia.⁶³

In contrast, a recent study reported that in Caucasian children increase in body height and axial elongation were correlated in emmetropia. AL increased at a greater rate than body height in myopia. This indicates that at a time when body growth is stabilising, axial elongation is unregulated.¹¹³ In Japanese elementary school children aged 8 to 9 years, body weight and body mass index (BMI) were significantly and positively associated with myopia.¹²⁹ Another study from Europe determined that in Finnish men BMI was about 5% smaller, and fat content was lower among the myopic than non-myopic men.¹²⁴

Birth circumstances

Very low birth weight significantly impacts on the refractive state in the long term. By age 10–12 years, individuals with very low birthweight have an increased prevalence of all refractive errors with a shift toward myopia of 1 diopter.¹³⁰ Significant prematurity that is associated the development of retinopathy of prematurity is also a well recognised cause of myopia.

Studies assessing the association between myopia and birth month indicated that there was a higher prevalence of myopia in subjects born during summer or autumn months compared to the winter.^131,132 The exact mechanism is unclear but may be related to the level of exposure to natural light during the early perinatal period.¹³¹ The prevalence of myopia is higher in first-born versus non-first-born individuals.^133,134

Binocular vision/accommodation

Myopia onset and progression were found to be related to an elevated response accommodation-convergence/accommodation (AC/A) ratio which could be observed before the onset of myopia. The theory was proposed that poor or inaccurate accommodative response with increased (accommodative lag) and consequential hyperopic retinal blur during near viewing activities may be a stimulant to axial growth.^{107,135–137}

Myopia onset

Mutti and colleagues found that an increased AC/A ratio was a predictor of myopia onset and was associated with a greater accommodative lag.¹³⁶ In a 3-year follow-up study among myopic children, mean accommodation stimulus was significantly lower among the faster progressing myopes (0.3 D) than among the slower progressing myopes (1.5 D).¹³⁸ AC/A ratios of those individuals who became myopic began to increase approximately 4 years before the diagnosis of myopia was made, continued to increase until the diagnosis was made, but did not affect the rate of eventual myopia progression.¹³⁶

Myopia progression

Children and young adults with myopia also show reduced accommodative facility and greater accommodative convergence compared with age-matched emmetropic individuals. Accommodative deficits in myopia may be the functional consequences of the anatomy of any equatorial enlargement in the eye.^135,139,140 Still, some studies indicate that higher accommodative lag may be predictive of myopia progression in children and adults^141,66 whereas others do not.^142–144

Although abnormal binocularity might be a risk factor for myopia progression,^66,145,146 none of the studies has shown an additional effect on risk assessment compared to refractive error and axial length, genetics, or environmental effects.¹¹

Environment

The weight of scientific research over the last 5 to 6 decades suggests that environmental factors are driving the observed rise in the prevalence of myopia.^147,148

Time spent outdoors

To date, the most influential and consistent environmental factor associated to the onset of myopia is more time spent indoors versus outdoors. There are different theories about whether the beneficial effect of time spent outdoors is due to the brightness of light exposure,^149,150 to increased short-wavelength exposure (360–400 nm) and/or ultraviolet light exposure,^151,152 or to other mechanisms.

Increasing time outdoors is effective in preventing the onset of myopia as well as in slowing the myopic shift in refractive error in non-myopic eyes. But amount of time spent outdoors was not associated with a slowing of the myopic progression in eyes that were already myopic.¹⁵³ However, the latest review in this topic concluded that outdoor time helps not only to reduce the risk of development of myopia in non-myopic children, but also to slow down the speed of change in refractive error and axial length in myopic children.¹⁵⁴ A more recent prospective study suggested that a lower amount of time spent outdoors among Taiwan schoolchildren might be compensated by a higher bright light intensity (10,000 lux) indoors to achieve the same protective effects against development and progression of myopia.¹⁵⁵

Near work

Spending more time at school or other near work activities is associated with a higher amount of indoors time.^11,156 Several further studies have confirmed these connections. In a 3-year follow-up study more time spent reading and performing close work and less time spent outdoors were both connected with faster myopic progression.¹³⁸ There is strong evidence of rapid, environmentally induced change in the prevalence of myopia, associated with increased education and urbanisation.¹⁰² Based on the landmark studies by Mutti et al.¹¹⁵ and Rose et al.,¹⁵⁷ Huang and colleagues found more time spent on near-work activities was associated with a higher odds of becoming myopic, increasing by 2% for every additional 1 diopter-hour more of near work per week.²⁵ In a recent Chinese multivariate logistic analysis the time spent within a working distance of <20 cm was a risk factor for myopia.¹⁵⁸

In Europe as compared to East Asia, the prevalence of myopia has remained markedly lower possibly because of differences in the intensity of education from an early age.^148,159 Increasing educational achievement associated with a higher prevalence of myopia can be observed not only in Asia, but also in Europe.¹⁴⁸ A recent study from Israel showed an increase in the prevalence of myopia which could be associated with urbanization- and higher education-related factors among several subpopulations.¹⁶⁰

In a German study, higher levels of school and post-school professional education were associated with a more myopic refraction,¹⁶¹ and a study on discordant monozygotic twins from the United Kingdom (UK) has confirmed known environmental risk factors for myopia, namely higher occupational status, being resident in an urban area, and undertaking more close work.^162,104 Previous studies have linked the increase in myopia prevalence with an increasing intensity of the education system, without strong evidence for that it is near work that is the culprit, rather than the fact that an indoor environment lacks visual information necessary for healthy development.¹⁶³

The Consortium for Refractive Error and Myopia (CREAM) studies, using data from European and Asian participants from different age strata, observed that the overall risk of myopia was significantly affected by the educational level. Time spent performing near work and years of education carried a far greater risk for myopia than genetic factors alone.^127,164,165 Overall, it would seem clear that environmental and genetic factors interact which each other.

The mechanism linking education to myopia may be defocus signals in the central and peripheral retina^6,18,39–41 and persistent lags of accommodation,^22,25–28 which may stimulate axial elongation. A recent alternative hypothesis suggests that the problem may be associated with the use of black text on a white background, which heavily overstimulates retinal OFF pathways.³⁸ White text on black paper leads to an opposite situation, with an overstimulation of ON pathways in the retina. In young humans, the choroid became thinner in only 1 h when subjects read black text on white background but became thicker when they read white text on a black background.³⁸ Previous studies have shown in experimental condition that thinner choroids are associated with myopia development and thicker choroids with myopia inhibition.^39,40,42 Therefore, reading white text from a black screen or tablet may inhibit myopia, while conventional black text on white background may stimulate myopia.³⁸

Use of computers and smart phones

Digital devices nowadays constitute a significant form of near work, and correlate with myopia. Some recent studies have documented significant associations between myopia and digital screen time.^{49,53,121,166,167} However, a recent systematic review found mixed results.¹⁶⁸ It has to be taken into account that digital devices may favour indoor lifestyles, and it has remained elusive whether it was a primary or secondary effect. It is also clear that the sharp rise in myopia prevalence was reported before such devices became ubiquitous in childhood. Nonetheless, the increased availability and use of digital screens for both leisure and recreation by very young children may be further promoting myopia onset and progression. Quantitative data relating to screen use and other environmental factors in prospective studies of childhood eye growth and refractive error are needed to fully understand the influence of these ‘essentials’ of modern life on our children’s refractive outcomes.

Location of residency

Both country and location of residency (urban vs rural) of an individual are associated with the likelihood of myopia.

Children from urban environments have higher odds of developing myopia than those from rural environments.^50,163 In a Hong Kong study, ocular axial length was found to be significantly longer among those living in areas with a higher population density and in a smaller home as compared to those who were living in a low-population density and larger-size home.¹⁶⁹ Living in a flat or room on a lower floor was associated with a lower prevalence of myopia compared to living on a higher floor among school-aged children in China.¹⁷⁰

Socioeconomic status

The socioeconomic status (monthly house income, parental education) has been linked to the likelihood of myopia, with varying strengths of association.

A study examining Korean children demonstrated that being in the highest tertial of household monthly income, living in a home owned by parents, living in an urban area, and having a disability were significantly associated with myopia.¹⁷¹ Myopic children were also found to have a stronger parental history of myopia in families with higher parental level of education,⁴⁷ although parental income and occupation had weaker associations with childhood myopia in a study conducted by Xiang et al.¹¹⁶

Interestingly, in a sample from the Netherlands 6 year old children with myopia were more likely to live with unmarried parents and in a rental home. Families with low income and a low maternal education level showed an increased risk for myopia.⁵²

Interventions for controlling myopia

The main measures that can be taken for the prevention of the development of myopia and for the reduction of the progression of myopia include: (1) Public health (lifestyle) interventions – optimization of environmental influences, (2) Pharmacological approach with the topical application of atropine eye drops, (3) Optical devices including multifocal spectacles and multifocal contact lenses that can have aspheric or discrete dual-focus designs, and orthokeratology.

There is high quality evidence that all methods slow the development or progression of myopia although the efficacy is different for the various interventions.

Optimization of environmental influences

Outdoor activities

Many studies (including randomized clinical trials) highlight the protective role of increased outdoor/sport time on myopia prevention.^{115,155,157,172–177} In a meta-analysis, every additional hour of outdoor time per week lead to a reduction in the risk of myopia by 2%.¹⁷⁸ The chance of becoming myopic is reduced by around one third if time spent outdoors is increased from 0 to 5 h per week to 14 or more hours per week.^172,179

The mechanism of increased outdoor time as an intervention for myopia control is not completely clear. Spending time outdoors itself, instead of physical activities outdoors, has been suggested to be the protective factor.^150,180 Patterns of defocus on the retina by three-dimensional structures of the environment have also been proposed as a possible mechanism of protection during outdoor activities.⁶

The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the light-stimulated release of dopamine from the retina, since increased dopamine release appears to inhibit increased axial elongation.^179,181 The absence of ultraviolet (UV) light may provoke axial myopia.¹⁸² According to Flitcoft et al., compared to the spatial properties of the natural world, man-made (urban) environments and indoor environments have spatial features similar to those than created by diffusing filters that induce form deprivation myopia in animal models.¹⁶³ The spatial frequency composition of the constructed environment, both indoors and outdoors, is therefore different from the natural world. Enhancing spatial frequency content of the visual scene may help to limit myopia.

Evidence linking time outdoors to the prevention of myopia is stronger than that linking it to slowing the progression of existing myopia.¹⁷⁹

Wu et al. have shown that participation in outdoor activities during school recess (10–20 min in both the morning and afternoon) has a significant effect on myopic shift in non-myopic children but not on the myopic progression of children with myopia.¹⁷⁵ Confirming the above relationship, another study did not detect an effect of near work or time outdoors on the progression of myopia in those with established myopia.¹⁷⁴ However, other studies have shown faster myopia progression during the darker winter than the brighter summer months.^183,184

Vitamin D

A number of studies have reported lower levels of serum vitamin D in myopes compared with non-myopes.^185–189

Lower 25-hydroxyvitamin D concentration in serum was associated with longer AL and a higher risk of myopia in young children, and the effect was independent of outdoor exposure time. Associations were not different between European and non-European children.¹⁸⁵ In another study, total vitamin D and D3 were biomarkers for time spent outdoors, however there was no evidence they were independently associated with future myopia.¹⁹⁰

In a study by the CREAM consortium, a Mendelian randomization analysis did not support a direct involvement of vitamin D with myopic refractive error, as individuals genetically predisposed to lower 25(OH)D levels were not more myopic.¹⁵²

Indoor lighting

In a Chinese study, increasing the light levels from approximately 100 to 500 lux in school classrooms had a significant effect on myopia onset, refraction and axial elongation.¹⁴⁹ Another more recent multivariate logistic analysis reported that time spent with a light intensity of >3000 lux was a protective factor for myopia in China.¹⁵⁸

Studies are investigating if achieving light levels indoors similar to the outdoor environment can reduce the incidence and progression of myopia.^163,191 Torii et al. examined short wavelength violet (360–400 nm wavelength) light which is absent in indoor environments and may play a role in the inhibition of myopia progression.¹⁵¹ They showed that over a 1-year period, children who wore violet light transmitting contact lenses had significantly less axial length elongation compared to those wearing violet light blocking eyeglasses.¹⁵¹

During the last few years, light-emitting diode (LED) lights have been designed as a new generation of task lights instead of traditional light sources. A cross-sectional-study, based in China, determined the association of the types of lamp for homework (including incandescent lamp, fluorescent lamp, and LED lamp) with the prevalence of myopia in young teenagers. Using LED lamps was associated with more myopic refractive error and longer axial length.¹⁹²

Moreover, the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) recommended avoiding the use of LED light sources emitting cold-white light with a strong blue component in places frequently used by children, to prevent possible photochemical damages and photoreceptors loss. ANSES recommends limitation of the sale of LEDs for domestic use.¹⁹³

Conclusion environmental influences: Near work indoor and outdoor activity play important roles in the development of myopia and in the prevention of myopia, respectively. There is strong evidence that less near work and more outdoor activity provide protection against myopia development in the human eye.

Time outdoors itself, rather than physical activity outdoors, has been suggested to be the protective factor.^150,180 The link between time outdoors in the prevention of myopia is stronger than the link between time outdoors and slowing of the progression of existing myopia.¹⁷⁹

Optical

Spectacles

Wearing spectacles is non-invasive and generally well-tolerated.

Undercorrection

Undercorrection of myopia with spectacles has been common practice for many years. The theory is to reduce myopia progression by reducing the accommodative demand during near work. Current evidence suggests this is not beneficial and can be harmful.

An early non-randomized trial from 1965 found that undercorrection slowed the progression of myopia.¹⁹⁴ In another study from 2017, over a period of 2 years, 12-year-old Chinese children with no correction had slower myopia progression (diff: 0.29 D) and less axial elongation (0.08 mm) than children with full correction suggesting myopic defocus might act as an inhibitor of eye growth in humans.¹⁹⁵

However, other studies examining undercorrection found just the opposite, namely either an increase in myopia progression or significantly more baseline myopia and longer axial length in children with undercorrection than in children with full correction.^196–198

A 1-year study of myopic Chinese children, wearing spectacles which either under- or fully corrected their myopia did not show any differences in myopia progression or axial elongation.¹⁹⁸

Undercorrection strategies do not provide optimal distance visual acuity and may also lead to behavioural changes, such as a reduction in outdoor activities in some children which, as noted above, may promote myopia progression.¹⁹⁹

As also summarized in the recent Cochrane and other systematic reviews, an over-correction or under-correction of the myopic refractive error had no strong evidence of benefits and instead possible risks for myopia progression^200–202 and should be avoided.

Peripheral defocus-correcting spectacle lenses

Studies have assessed different types of novel spectacle lens designs aimed at modulating the relative peripheral defocus in Asian children, with no differences in the rate of progression of myopia or axial elongation when compared with single vision (SV) control groups.²⁰³ Aspherization of the distance zone added to progressive additional lenses (PALs) did not enhance their therapeutic efficacy in slowing myopia progression.²⁰⁴

Moreover, novel spectacle lens design to reduce peripheral hyperopic defocus was reported to demonstrate a reduction in myopia progression in the younger subgroup of children aged 6 to 12 years with a parental history of myopia, in a 1-year trial.²⁰⁵ However, this beneficial effect was only observed in an exploratory subgroup analysis that had insufficient statistical power to produce definitive results.

More recently, a specially designed ‘competing defocus’ spectacle lens, called Defocus Incorporated Multiple Segments (DIMS) spectacle lens has been used for myopia control in a 2-year randomized trial by Lam et al.²⁰⁶ This lens design has a central optical zone for correcting refractive error and multiple segments of constant myopic defocus (+3.50 D) surrounding the central zone. This enables the lens to provide clear vision and myopic defocus simultaneously for distance, intermediate or near. The results from the clinical trial showed that children of East Asian ethnicity wearing DIMS lenses had 52% less myopia progression (average −0.41 ± 0.06 D in the DIMS group vs. average −0.85 ± 0.08 D in the single vision group) and 62% less axial elongation (mean difference 0.34 ± 0.04 mm) compared with single vision spectacle lenses and about 21.5% of the DIMS lens wearers had no myopia progression during the 2-year long study period while among the controls this was the case in only 6%.²⁰⁶

Bifocal spectacles and progressive additional lenses (PALs)

Bifocals and progressive addition lenses, which allow the wearer to see objects clearly in the distance and at near, have been used in an attempt to retard myopia progression by reducing accommodative effort and lag during extended near work.²⁰⁷ Studies with progressive addition lenses have typically shown a small but clinically insignificant effect on slowing myopia progression^{200,204,208,209} and two different European clinical treatment trials did not find bifocals to prevent myopia progression.^210,211 A meta-analysis noted small reductions in myopia progression (0.25 D) and axial elongation (−0.12 mm).²⁰⁴ This effect was greater for children with a higher level of myopia (<−3.0 D), accommodative lag, or near esophoria.^{144,207,212–215}

Cheng et al. found that, over 3 years, executive bifocal lenses slowed myopia progression by 39% and up to 51% with base-in prisms incorporated in a selected group of fast progressing myopic children when compared with single vision spectacles. For children with low lags of accommodation the prismatic bifocal lenses had a greater benefit.¹⁴⁵

Conclusion spectacle lenses: Undercorrection of myopia is not recommended as it increased myopia progression slightly (low-certainty evidence, Cochrane-2020)²⁰¹ and did not slow myopia progression as previously thought. Bifocal spectacles or progressive addition lenses versus single vision lenses (SVLs) yielded a small effect in slowing myopia progression (moderate-certainty evidence).²⁰¹ Studies evaluating different peripheral defocus-correcting lenses versus SVLs reported inconsistent results for refractive error and axial length outcomes (low-certainty evidence)²⁰¹ although results for DIMS spectacles are promising.²⁰¹

Contact lenses

Soft contact lens (SCL)

There is no substantial evidence in the literature that conventional soft contact lens wear leads to either slower or faster myopia progression than spectacle wear.^{199,216–218}

Rigid gas permeable (RGP)

In some studies, rigid gas permeable lenses were reported to slow myopia progression in children,^219–221 but more recent, well-designed studies showed that the use of these lenses did not impact axial elongation and that the apparent control of myopia progression observed with RGPs was most likely induced by temporary corneal flattening.^222,223

Bifocal/multifocal soft contact lens (BFSCL/MFSCL)

Bifocal contact lens designs often include a central distance focus, and peripheral rings with near add, creating a peripheral myopic defocus. In these designs, the peripheral region of the lens has relatively more positive power, incorporated a gradual increase toward the periphery (progressive design) or presented in distinct zones (concentric ring design). Concentric ring designs show better control over axial elongation than progressive designs (44.4% vs 31.6%), whereas their effects on refraction changes were similar (36.3% vs 36.4%).¹⁹⁹ Studies exploring the effect of these bifocal soft contact lenses^224–226 indicate slowing of myopia progression (refraction) by 30–38% and axial length by 31–51% over a period of 24 months.²²⁷

In a recent randomized controlled trial, MiSight, a multizone design contact lens produced lower myopia progression (59%) and lower axial growth of the eye (52%) at 3 years compared to spectacle use.^228,229

Different studies suggest that bifocal contact lens efficacy may improve with increase in wear time, in children with faster rates of progression,²³⁰ near esophoria,¹⁴⁶ and with designs possessing a higher hyperopic power in the mid-periphery.²⁰⁷

Soft radial refractive gradient (SRRG) experimental contact lenses increase the higher-order aberrations and relatively decrease the peripheral hyperopia to produce a peripheral myopic defocus. A myopia control study by Paune et al. showed a potential to decrease the accommodation lag, which is a factor in regulation of axial elongation.²³¹

The Cambridge Anti-Myopia Study (CAMS) randomised clinical trial (14–22 years of age participants) used aberration-controlled contact lenses to reduce the lag of accommodation and vision training to improve accommodative facility. The study was unable to demonstrate that the progression of myopia could be reduced over a 2-year period by improving accommodative function.²³²

The recent 3-year multicenter, randomized clinical BLINK (Bifocal Lenses in Nearsighted Kids) study use contact lenses with a central correction for myopia plus a high add (+2.50 diopters) or medium add (+1.50 diopters) power in peripheral concentric zones. These lenses were compared to conventional single-vision contact lenses. Contact lenses with a high add power slowed myopia progression by 0.45 D and eye growth by 0.23 mm compared with single-vision contact lenses, and slowed myopia progression by 0.29 D and eye growth by 0.16 mm compared with medium add power multifocal contact lenses.²³³

Orthokeratology (ortho-K)

Orthokeratology lenses are specially designed RGP contact lenses that are worn overnight. The redistribution of corneal epithelial cells temporarily corrects myopia the next day after the removal of the lens.²³⁴

Various clinical studies have demonstrated the effectiveness of inhibiting myopic progression with ortho-K (Table 7). The effect of slowing axial length elongation ranges from 30% to 63%. The overall treatment effect is around 50%. Ortho-K also has been shown to induce relative myopic shifts in peripheral refractive errors in all meridians,²³⁵ consistent with the most popular hypothesis for this myopia control effect²³⁶ although a role for altered higher-order aberrations cannot be excluded.^237,238 Another hypothesis of the mechanism behind the myopia control effect of ortho-K is that the changes in lag of accommodation may be due to increasing positive spherical aberration and changes in choroidal thickness.^239,240

Several meta-analyses^241–243 have confirmed the effectiveness of ortho-K for myopia control, although Si et al.^241,244 recommended further research, given that five of the seven studies included in their meta-analysis were from Asia.

Table 7.

Myopia control studies using ortho-K lenses.

Author (year)	Location	Number of participants (OK/control)	Study design	Study duration (years)	Control group	Reduction effect (%)
Cho et al.²⁴⁴	Hong Kong	35/35	Self-selected prospective, early study control	2	SV	46
Walline et al. (2009)²⁴⁵	USA	28/28	Prospective and historical control	2	SVCL	56
Kakita et al.²⁴⁶	Japan	42/50	Self-selected retrospective	2	SV	36
Cho and Cheung²⁴⁷	Hong Kong	37/41	Randomized single-masked	2	SV	43
Hiraoka et al.²⁴⁸	Japan	22/21	Self-selected retrospective	5	SV	30
Santodomingo- Rubido et al.²⁴⁹	Spain	31/30	Self-selected prospective	2	SV	32
Charm and Cho²⁵⁰	Hong Kong	20/16	Randomized single-masked	2	SV	63
Chen et al.²⁵¹	Hong Kong	35/23	Self-selected prospective toric ortho-K	2	SV	52
Zhu et al.²⁵²	China	65/63	Self-selected retrospective	2	SV	51
Na and Yoo²⁵³	Korea	9/9	Retrospective, monocular myopia	2	CLE	58

SV: single vision spectacle lens; SVCL: single vision contact lens; CLE: contralateral eye.

In orthokeratology studies, the parameters of older age, earlier onset of myopia, female sex, lower myopia at baseline, longer anterior chamber depth, greater corneal power, more prolate corneal shape, larger iris, and pupil diameters, and lower levels of parental myopia have been linked to slower axial elongation in children.^{200,247,254–260}

Myopia progression in orthokeratology was significantly associated with the peripheral myopization and asymmetric optical changes mostly induced by third-order aberrations.²⁶¹

In a few studies, early termination of ortho-K treatment has been suggested to lead to an increased rate of axial elongation in children (a rebound effect).^262,263 Some studies also suggest that relative treatment efficacy may decrease over time.^248,264,265

Overnight use of any contact lens is associated with a higher risk of microbial keratitis (MK) than daily use.²⁶⁶ Practitioners should be aware of this infectious risk because it is an important part of the risk-benefit ratio.²⁶⁷

A 12-month, population-based study estimated the risk of contact lens-related MK.²⁶⁶ The authors identified 285 eligible cases of contact lens-related MK and 1798 controls. For daily wear of rigid gas-permeable contact lenses, the annualized incidence was 1.2 per 10,000 wearers (95% CI = 1.1 to 1.5) and the incidence for overnight wear of soft contact lenses was higher: 19.5 per 10,000 wearers (95% CI = 14.6 to 29.5) for conventional hydrogels and 25.4 per 10,000 wearers (95% CI = 21.2 to 31.5) for silicone hydrogels.²⁶⁶

In comparison, the most in-depth attempts to quantify the risk of MK associated with overnight corneal reshaping (ortho-K) lenses with 2599 patient-years of wear reported the overall estimated incidence of MK, which was 7.7 per 10,000 years of wear. For children, the estimated incidence of MK was 13.9 per 10,000 patient-years and for adults the estimated incidence of MK is 0 per 10,000 patient-years.²⁶⁷

A systematic review, which analysed clinical studies from 1980 to 2015, incorporated a total of 170 publications, summarized the most common complication of ortho-K treatment, which was corneal staining. Other clinically significant side effects included epithelial iron deposit, prominent fibrillary lines and transient changes of corneal biomechanical properties, but no long-term effect on corneal endothelium. Evidences suggest that ortho-K is a safe option for myopia retardation and the risk of microbial keratitis was similar to other overnight modalities (194,183,308).^255,265,267 In another meta-analysis, the dropout rate in ortho-K studies was found to be between 6.7 and 30.0%, similar as in the controls at 2-year follow-up.²⁶⁸

Future research for contact lens design

A recent randomized clinical trial has reported 2-year results of novel contact lenses that either imposed myopic defocus at the retina or modulated retinal image quality.²⁶⁹ The first design principle aimed to reduce hyperopic defocus and induce myopic defocus across a large portion of the retina. The second design principle used extended depth of focus contact lenses that were designed to result in a global retinal image quality, which was improved for points on and anterior, and degraded for points posterior to the retina to prevent axial elongation.

At 2 years, the new lenses slowed myopia progression by 32% and 26% and reduced axial length elongation by 25% and 27%, respectively. Thus, these lens types resulted in slower eye growth compared to use of conventional, single vision contact lenses.²⁶⁹

Conclusion contact lenses

Ineffective: Rigid gas permeable contact lenses showed inconsistent results in myopia progression (very low-certainty evidence).²⁰¹ Comparing spherical aberration SCLs with single vision SCLs reported no difference in myopia (refractive) progression nor in axial length elongation (low-certainty evidence).²⁰¹

Effective: Axial elongation was slightly less for bifocal SCL wearers than for single vision SCL wearers (low-certainty evidence).²⁰¹ Orthokeratology contact lenses were more effective than SVLs in slowing axial elongation (moderate-certainty evidence).²⁰¹ There is evidence of myopia control with soft multifocal contact lenses (low-certainty evidence),²⁰¹ specific myopia control soft lens designs (moderate-certainty evidence)²⁰¹ and orthokeratology (moderate-certainty evidence).²⁰¹

Auditory biofeedback training

Current investigations demonstrated the efficacy of auditory biofeedback training to improve the accommodation response in myopic young adults. The training may cause a reduction of the accommodative lag, which can lead to a slowdown of myopia progression,²⁷⁰ and may enhance the therapeutic effect of multifocal contact lenses in myopia control.²⁷¹

Pharmacological

Atropine

Atropine is a nonselective muscarinic receptor antagonist. Atropine is reported to stimulate extracellular matrix (ECM) biosynthesis in scleral fibroblast cells, thus thickening the scleral tissue and reducing its elasticity and tendency to elongation. In addition, atropine may decrease ECM biosynthesis in other tissues such as choroidal fibroblasts thus improving scleral blood perfusion through the choroid, due to a higher permeability of its ECM and slowing down myopia progression.²⁷²

There is also evidence from studies on chickens for atropine to increase the release of the neurotransmitter dopamine into the extracellular space and the vitreous, which may cancel out a presumed retinal signal that controls eye growth and through this, myopia.²⁷³ Furthermore, it has been shown that dopamine could act directly on the cornea, as some dopaminergic receptor activity is located in rabbit and bovine corneas.^274,275 Thus, the primary site of action of atropine is controversial; some authors have even hypothesized that 0.01% atropine may primarily act on the cornea.²⁷⁶

Atropine has been reported to have a dose dependent inhibitory effect on myopia progression. The initial use of high doses of atropine (0.5%, 1.0%) slowed myopia progression by more than 75% over 2 years with essentially no change in mean axial length in the atropine-treated eyes compared to the placebo-treated eyes and the untreated fellow eyes in both atropine and placebo groups.²⁷⁷ Lower doses (0.1%, and 0.01%) can also slow myopia by up to 67% and have fewer side effects.^{243,277–279}

Data from the Atropine in the Treatment of Myopia (ATOM) two study showed that after a 1-year washout, there was a myopic rebound when atropine was stopped, especially for higher doses and in younger children.^280,281 After 36 months, treatment with 0.01% atropine showed the slowest progression of myopia,²⁷⁸ and over 5 years, 0.01% atropine eyedrops were more effective in slowing myopia progression with less visual side effects compared with higher doses of atropine.²⁸²

Nevertheless, in recent studies examining the rate of axial elongation, 0.01% atropine had minimal benefit.^283,284

These conflicting study results above are examples of conflicting evidence which seems to depend upon whether axial length or refractive change are used as outcome measures.

Brennan et al, examined the apparent discrepancy in refractive error change and axial elongation in studies and concluded that the relation between the two is confounded by use of atropine.²⁸⁵ To compare subjects from studies wearing spectacles alone and studies where atropine was used, utilizing best-fit slopes the two lines differ substantially with the slope for untreated spectacle wearers being −2.05 D/mm and that for studies using atropine being −0.83 D/mm. They felt their observation could result from the fact that atropine produces changes in the anterior optical structures of the eye or leads to an extreme cycloplegia in treated eyes thereby producing apparent reductions in refractive progression in the absence of corresponding reduction in axial elongation.²⁸⁵

In the Low-Concentration Atropine for Myopia Progression (LAMP) study involving children treated with concentrations of 0.01%, 0.025%, and 0.05% atropine for a 1 year, there was a reduction of spherical equivalent (SE) progression of 27%, 43%, and 67%, and a slowing of axial length growth of 12%, 29%, and 51%, respectively. Overall, the effect on spherical equivalent refraction was larger than that on axial length.²⁷⁹

In the LAMP study, compared with the first year of follow-up, the second-year efficacy of 0.05% atropine eye drops and 0.025% atropine eye drops remained similar (p > 0.1) and improved slightly in the 0.01% atropine group (p = 0.04). In the LAMP-II Study, the efficacy of 0.05% atropine eye drops was double that of the 0.01% eye drops with respect to the reduction of myopic progression, and therefore the 0.05% atropine concentration was considered by the authors to be the optimal concentration among the studied atropine concentrations for slowing the progression of myopia.²⁸⁶

Around 10% of children show a fast rate of myopia progression even on high-dose atropine. The studies performed to date cannot distinguish if this indicates that certain children respond less well to atropine than others, or if there is a limit to how much of a reduction in progression can be achieved. A poorer response was associated with younger age, a higher degree of myopia at baseline, starting spectacle wear at a younger age and a history of parental myopia.^282,287,288

A recent study in school children tested a novel 1% atropine treatment regimen in which one eye was treated at one time point and the other eye at another time point (one eye received treatment at day 1, the other eye received treatment at day 16) achieving a frequency of once a month in the first 2 years. Gradual withdrawal of the atropine to once every 2 months for 12 months, followed by no drops for 12 months, could effectively retard the progression of moderate myopia with a significant reduction in myopic rebound, while minimizing the side effects.²⁸⁹

Atropine has been shown to be effective in treating myopia in Europe suggesting that intervention with atropine could work irrespective of ethnicity.^290–295

Primary ocular side effects of topical atropine are due to the inhibitory actions of atropine on the iris sphincter and ciliary muscles, resulting in mydriasis, photophobia and reduced accommodation, with symptoms of glare and blur at near. Prescription of photochromatic and progressive spectacles may help. A report from the Erasmus Medical Center in Rotterdam, the Netherlands, has shown that in a real world setting, 72% of children stayed on 0.5% atropine therapy for 3 years, despite the side effects.²⁹⁵ More severe topical reactions such as allergic keratoconjunctivitis and lid erythema and rashes may occur^{277,278,296,297} and could lead to discontinuation of the eye drops. Other possible side effects include dry skin, mouth, and throat, drowsiness, restlessness, irritability, delirium, tachycardia, and flushing of the face or neck.^199,298 Nonetheless, in two of the largest clinical trials of topical atropine, the ATOM1 and ATOM2 studies, none of the reported serious adverse events were thought to be associated with atropine and there have been no significant adverse systemic side effects.^277,278 No differences in the incidence of adverse effects between Asian and White patients were identified.²⁹⁷

Pirenzepine

Pirenzepine is an M1 muscarinic receptor antagonist. In a 12-month study in an Asian population, 2% pirenzepine gel applied locally to the eye twice daily reduced myopia progression by 44% and axial elongation by 39% compared with the control group; adverse events were observed in 11%.²⁹⁹

Another 2-year, double masked, placebo controlled parallel trial with 2% pirenzepine from the USA yielded a 41% reduction in myopia progression with 2% pirenzepine compared to the placebo treatment, however, the difference in axial elongation between the groups did not reach statistical significance.³⁰⁰ As with atropine, the antimuscarinic properties of pirenzepine may lead to blurred near vision, sensitivity to light, some discomfort and itching, and medication residue on the eyelids or eyelashes. Some children may develop small nodules or bumps under the eyelid.^201,224,300

At this point in time, pirenzepine is not available as a treatment option for myopia control.¹⁹⁹

Seven-methylxantine (7-MX)

Oral 7-MX is an adenosine antagonist and a metabolite of caffeine and theobromine.

Recently, 7-MX has been shown to reduce the axial myopia produced by the hyperopic defocus in rhesus monkey and augmented hyperopic shifts in response to myopic defocus.³⁰¹

In a pilot study from Denmark, systemic treatment with 7-MX appeared to be efficient in retarding axial elongation and myopia progression among myopic children with relatively few adverse effects. At 24 months, axial elongation was reduced by 0.1 mm and refractive error by 0.22 D in the 7-MX group compared to the placebo group. The drug appears to be safe and without side effects.³⁰² Thus, it provides consolidated basis for further investigation to develop it into a drug for clinical use.³⁰³

Intraocular pressure (IOP) lowering eyedrops

Timolol

Timolol is a relatively nonselective beta-adrenergic antagonist. Jensen looked at the effect of 0.25% timolol maleate eyedrops used twice a day in a 2-year study.²¹⁰ This was compared with bifocal spectacles and SV spectacles. There was no evidence to suggest that timolol reduced the rate of myopia progression.²¹⁰

Latanoprost

In an analysis by El-Nimri et al., the efficacy of topical latanoprost was examined as a representative prostaglandin analog for controlling myopia progression in a form-deprived guinea pig model of myopia.³⁰⁴ The results showed that topically applied latanoprost was effective in both lowering IOP and slowing myopia progression in that model.³⁰⁴

Alpha 2-adrenergic agonists

A recent study reported evidence that form-deprivation myopia could be inhibited by high concentrations of brimonidine, clonidine, and guanfacine in the chick. The data suggested that α-adrenoceptors are valid target receptors for anti-myopia therapies.³⁰⁵

Future research for antimyopia drug development

The latest research focuses on the recent advances in genome-wide studies of the signaling pathways underlying myopia development and discusses the potential of systems genetics and pharmacogenomic approaches for the development of antimyopia drugs.³⁰⁶

Conclusion pharmaceutical agents: Antimuscarinic eye drugs such as atropine eye drop or pirenzepine eye gel may slow the progression of myopia (moderate-certainty evidence).²⁰¹ Axial elongation was lower for children treated with atropine than for those treated with placebo (moderate-certainty evidence)²⁰¹ in studies using higher doses. However, there is a weaker association between refractive error and axial length changes than optical studies. According to Cochrane summary, systematic seven-methylxanthine had a small effect on myopic progression and axial elongation compared with placebo in one study (moderate-certainty evidence).²⁰¹ One study did not find slowed myopia progression when comparing timolol eye drops with no drops (low-certainty evidence).²⁰¹

Surgical interventions

Posterior scleral reinforcement (PSR)/contraction (PSC)

PSR is a surgical approach modifying the sclera remodeling causing direct mechanical reinforcement of the eyeball wall, to slow down myopia progression and prevent the formation of a staphyloma.³⁰⁷ PSR involves surgical implantation under general anaesthesia. A variety of materials having been used, ranging from fascia lata, as well as lyophilized dura, strips of tendon, aorta, and donor sclera.¹⁹⁹

Several studies have shown that PSR can effectively limit the progression of axial elongation in highly myopic children with varying efficiency.^308–312

The non-crosslinked material has limited efficacy in preventing sclera from expanding into high myopia. A new surgical technique uses sclera treated by genipin (a natural crosslinker) to increase its strength in order to enhance AL shortening; this technique is referred to as posterior scleral contraction. Genipin has emerged as a safer choice as a crosslinking agent due to its stability, biocompatibility, and general safety.^313,314

Based on a recent study examining 26 clinical trials, postoperative complications of PSR are mainly ocular hypertension, conjunctival tissue oedema, vitreous haemorrhage, retinal, or choroidal haemorrhage, diplopia or eye movement disorder, retinal detachment, and optic atrophy. Reinforcement material expulsion, symblepharon, and choroidal effusions may also occur. Intraoperative complications may include injury of vortex vein and penetration of sclera. However, the common complications were transient.³⁰⁷

Currently, PSR for high myopia is mainly performed in Russia, Eastern Europe, and China, although there are also publications from the United States³¹⁰ and a case report on complications from Australia.³¹⁵

The use and safety of PSR is controversial, and more studies are needed to confirm its therapeutic benefits.³⁰⁷

Injection-based scleral strengthening (SSI)

SSI involves the injection under Tenon’s capsule of chemical reagents intended to biomechanically stabilize the extracellular (collagen) matrix of the sclera.

According to Golychev et al.³¹⁶ myopia was reported to stabilize with this method in 61% of cases after a follow up period of approximately 2 years.

In a study from Russia, a polymer gel containing a mixture of polyvinylpyrrolidone, acrilamidehydrazide, and ethylacrylate was delivered monocularly by a sub-Tenon’s capsule injection. Refractions are reported to have remained stable in 79.6% of eyes 1 year after the SSI intervention, and in 52.9% cases, after 4 to 9 years.³¹⁷

Another approach is the intravitreal injection of Aquaporin-1 (AQP-1), which is a membrane-locating protein that contributes to the water transmembrane transportation leading to a thicker choroid. A thicker choroid will impede the progression of axial length through modulating the expression of sclera-related growth factor and scleral fibril synthesis. On this topic there are only animal experiments.³¹⁸

In recent years, scientists have also proposed the concept of subscleral injection of mesenchymal stem cells and dopamine injection representing a promising new strategy against the progression of myopia.³¹⁹

Collagen cross-linking (CCL)

CCL is used worldwide for corneal tissue strengthening by using riboflavin as a photosensitizer and ultraviolet A (UVA) to increase the formation of intra- and interfibrillar covalent bonds by photosensitized oxidation, mainly in keratoconus patients. The use of this approach for stabilizing the sclera in pathological myopia has to-date been limited to experimental animals (rabbit models).^320,321

When using CCL treatment for myopia control in animal models, histologically serious side effects were found in the entire posterior globe with almost complete loss of the photoreceptors, the outer nuclear layer and the retinal pigment epithelium.^199,321,322

An alternative approach is non-enzymatic glycation using a sugar molecule, such as ribose or glucose, without the controlling action of an enzyme. Carbohydrate-based collagen crosslinking is advantageous because it requires a less invasive application procedure, does not use UVA, and reduces scleral toxicity since it does not require UV exposure.³²³

Conclusion surgical interventions: Because of the invasive nature and lack of large randomized trials, surgical interventions should not be recommended as first line treatment modalities for the prevention of the progression of myopia, neither for moderate myopia nor for high myopia.

Combination of interventions

To improve the efficacy of therapies against myopia progression, the combined effects of two or more interventions have been evaluated. Leshno et al. collected data from paediatric ophthalmologists related to the choice of treatment modalities (pharmacological, optical and behavioural) to slow down the progression of myopia according to geographical regions. Most respondents used a combination of either two (38%) or three modalities of treatment (56%); behavioural treatment was used by the highest number of respondents (92%). A combination of all three modalities was the most popular in most regions, apart from Central-Asia where the prevalence of optical and behavioural combinations was higher.³²⁴

Currently, numerous publications provide the evidence that combined treatment with atropine and ortho-K lenses provides an additive benefit in myopia control.^325–328 In a preliminary study, during a 1-year follow-up, the combination of ortho-K and atropine 0.01% ophthalmic solution was more effective in slowing axial elongation than ortho-K monotherapy in 8–12 years old children. The increase in axial length over 1 year was 0.09 ± 0.12 mm in the combination group and 0.19 ± 0.15 mm in the ortho-K monotherapy group.³²⁵

Atropine and ortho-K seem to slow the progression of myopia through different mechanisms.³²⁵ Atropine-induced pupil dilation increase retinal illumination and may expose more of the retinal periphery to relative myopic defocus, potentially enhancing the effect of the ortho-K lens to slow axial growth.³²⁸ A recent study showed an additive effect between 0.01% atropine and ortho-K over 1 year, with mean axial elongation in the atropin with orthokeratology group 0.09 mm/year slower than that in the ortho-K group.³²⁹ A review reported that all included studies improved myopia control by the synergistic effect of ortho-K with low-dose atropine, compared with orthokeratology treatment alone.³³⁰

Another pharmacological and optical combination therapy is the use of multifocal spectacles with 0.5% atropine. The combination treatment was found to slow the progression of myopia significantly more than each treatment alone.³³¹

The Bifocal & Atropine in Myopia (BAM) study, which started in 2017, is designed to investigate whether 0.01% atropine and +2.50-diopter add canter-distance soft bifocal contact lenses (SBCL) slows myopia progression more than SBCL alone. The study completion date was June 2020 and therefore the findings should be available soon.³³²

In a recent study, several daily disposable and multifocal contact lenses were investigated for their potential to release two anti-myopia drugs. All lenses showed some degree of drug release in an uncontrolled manner. A contact lens-based drug delivery system is an option worthy of further evaluation.³³³

Conclusion combination therapies: Myopia progression was slower in children treated with combinations of atropine eye drops and multifocal spectacles than in children treated with placebo eye drops and single vision lenses (moderate-certainty evidence).²⁰¹ Orthokeratology with low-dose atropine improved myopia control by the synergistic effect compared with orthokeratology treatment alone. Further studies are needed to fully assess the efficacy and safety of atropine and orthokeratology or bi- or multifocal soft contact lens combination therapy.

Guidelines for clinical management and control of myopia in children

Management of premyopes

Having one or two myopic parents or family members increases the risk and progression rates of myopia.^{10,115,116,118–120} There is a positive correlation between the number of myopic parents and the risk of developing myopia.¹¹⁷ Environmental factors such as excessive near work/indoor time and insufficient outdoor exposure are factors driving the recent epidemic rise in the prevalence of myopia.^147,148 It draws attention to the fact that these children need to be observed more closely.

To determine the first refraction in a child, cycloplegia must be used.³³⁴ Lack of cycloplegia in refractive error measurement increases the risk of misclassification for both myopia and hyperopia³³⁵ and makes application of an evidence-based approach to myopia management challenging; research studies from which evidence-based practices are derived have primarily used cycloplegic methods to define refractive error.

The presence of +0.75 D or less of hyperopia at the age of 6 years indicates that myopia is likely to develop in the near future.^334,336,338 In prospective data from White European children, McCullough et al. demonstrated that children presenting with a refractive error of <+0.63 D at 6–7 years and with at least one myopic parent were likely to develop myopia by age 13 years and those with no myopic parents were likely to develop myopia by 16 years.³³⁸

Other work suggests that premyopes may also show specific binocular vision disorders.¹³⁶ Since the visual profile of the myopic child is characterized by higher accommodative lag,^26,27 high AC/A ratio (esophoria at near)^135,139 and reduced accommodative flexibility,^26,27 it would be important to include tests that evaluate the binocular vision and not only refraction. More attention needs to be paid to children who have a strong family history of myopia and the management of binocular vision disorders is recommended.

The visual complications of myopia are strongly related to axial length growth, thereby monitoring the axial length changes should be primary target for myopia management. Where axial biometry measures are available, these can also be informative in identifying children at risk for myopia who should be provided behavioural advice and monitored closely for the onset of myopia in order that anti-myopia therapies can be applied.^93,337,338

Percentile growth curves for White European children are available for axial length in childhood and can be used to identify patients whose eye size puts them at increased risk for future myopia.^93,337,338 In addition to identifying risk for future myopia, these centiles can be used after the onset of myopia to monitor growth trajectories with/without anti-myopia intervention.

According to Tideman and Klaver, axial length does not have a stable growth rate with age, nor is it similar among the sexes and ethnicities. Their studies generated axial length growth curves as a function of age based on data from children with European ethnicity. These curves (boys/girls) give information to estimate the risk of developing high myopia in adulthood.^93,337

Data from McCullough et al. demonstrate that axial lengths greater than 23.07 mm at 6–7 years are associated with a strong risk of future myopia.³³⁸

Based on these findings, it is suggested to screen children before the age of 6 years or in the first school year for family history of myopia, time spent outdoors, time performing close activities (like, cell phone or tablet use, playing with toys, handwork, reading, drawing, etc.), and binocular vision.

Children with higher risk should be encouraged to spend more time outdoors as the key evidence-based strategy that appears effective in reducing the incidence of myopia.³³⁹

Selection of myopia control methods

Based on the child’s individual and parental factors, it should be possible to offer a strategy against myopia progression. Decision to treat should be based on age of onset and axial length or refraction at a given age.²⁸⁵ If there is a suspicion of any underlying ocular disease, additional examinations are recommended (corneal topography, electrophysiology, retinal imaging, or genetic testing).³³⁷

Lifestyle advices

Indoor and near work activity

Excessive near work may influence the development and progression of myopia.^11,100,340 Close reading distance (20–25 cm) and continuous reading (>45 min), head tilt, closer nib-to-fingertip distance (which means greater head tilt) have been associated with greater odds of myopia progression.^{158,340–342}

In a 23-year follow-up study of Pärssinen, myopic progression was highest among those whose reading posture in childhood was sitting and lowest among those who reported reading in suppine position.³⁴³ Short reading distance in childhood predicted higher adulthood myopia among females. Time spent on reading and close work in childhood was related to myopic progression during the first 3 years but did not predict adulthood myopia.⁸⁶

Children should not be prevented from participating in near work activity, but attention should be given to the following measures: regular breaks, appropriate reading distances without head tilt, and near-to-distance fixation changes while reading with sufficient outdoor activities.³³⁹ The Erasmus Myopia Research Group in the Netherlands recommends complete absence of close-up screen use for children up to 2 years old; maximum 1 h day, for children up to 5 years, and a maximum of 2 h day for children aged 5–12 years.^179,337,344

Time spent outdoors and lighting

Spending time outdoors without requiring physical activity or direct sunlight exposure appears to have a protective effect against myopia onset but not for myopic progression.^86,153,339

Every additional 1-h of outdoor time per week is associated with a reduction in the risk of myopia by 2%.¹⁷⁸ The chance of becoming myopic is reduced by around one third if time spent outdoors is increased from 0 to 5 h per week to 14 or more per week.^172,179

A minimum of 8 to 15 h of outdoor activity per week is recommended for school aged children to achieve clinically meaningful protection from myopiagenic stimuli.^{157,172,174,176,178,179,345} Individuals who are at risk of developing myopia should try to maximise natural lighting and to increase time spent outdoors.^{149,150,158,339} To maximise indoor lighting^149,150,339 use incandescent light bulbs rather than fluorescent or LED lighting.^192,334

Nutritional advice

Nowadays a lot of health issues may be connected to nutritional habits. Therefore, parents may enquire whether a change in dietary habits could decrease the probability of eye diseases.

In Chinese schoolchildren higher saturated fat and cholesterol intake were associated with longer axial length.³⁴⁶ As noted above, treatment with caffeine metabolite seven-methylxanthine has small effect on eye growth in children.³⁰²

Although caffeine-like stimulants may be part of nutritional advice for myopes in the future, there is no current high-level evidence to support nutritional treatments for myopia control.³³⁹

Refractive corrections

Spectacle lenses are non-invasive, simple, and affordable technique for optical correction of refractive errors, such as myopia.

Children should be encouraged to wear their myopic correction full time, as undercorrection of myopia has been shown in some studies to increase myopia progression.^196,197,198

Decreasing full distance myopic refractive error correction during near work will reduce accommodative demand and accommodative lag.³³⁹ However, in a 3-year randomized controlled clinical trial mildly myopic school children aged 9–11 years showed significantly less myopia progression when they wore full correction continuously than wearing spectacles only for distant vision. Neither the use of bifocals nor avoiding the use of spectacles in reading slows myopia progression.²¹¹ Spectacle with peripheral defocus designs such as the DIMS lenses²⁰⁶ should be considered over SV lenses in progressing myopes.

Contact lenses play an important role in myopia control. This includes ortho-K and regulatory approved soft contact lenses for myopia control, and studies are ongoing comparing the effect on myopia control of various recently developed contact lens types. Based on a meta-analysis, ortho-k and soft lenses for myopia control offer similar levels of axial length control.²⁴³

A recent report of American Academy of Ophthalmology concluded that ortho-K may be effective in slowing myopic progression for children and adolescents, however, safety remains a concern because of the risk of potentially blinding microbial keratitis from contact lens wear.³⁴⁷

Customizing ortho-K lens designs to limit the central treatment zone may help to bring more plus power inside the pupil and achieve a greater shift in relative peripheral myopia.^348–350 However, such approaches need to be evaluating in randomized controlled trials.

If customization of the ortho-K lenses is not possible, soft multifocal lenses are preferable for any patient who has less than 2.00 D of refractive error. Also, patients who have a photopic pupil size smaller than 4.5 mm will be better served by a soft multifocal lens with a design that is independent of pupil size. Using soft multifocal contact lenses, the highest plus power that does not generate blur at distance without over-minusing the original cycloplegic refractive power, was recommended by a recent myopia control summary.³³⁴

For orthokeratology lens wear should be encouraged every night for a minimum of 8 h per night to maximize correction for best-unaided vision during waking hours.³³⁹

The treatment effect of multifocal soft contact lens (MFSCL) is likely to be positively correlated with wearing time.²³⁰ Full time use of MFSCLs is recommended during school hours and for schoolwork at home, providing greater myopia control efficacy.³³⁹ Preferably, regulatory approved myopia controlling new designs, bifocal, progressive additional lenses (PAL), or single-vision spectacles may be prescribed for when children are not wearing their contact lenses.³³⁹

Another possibility is to add spectacles to supplement contact lens wear when accommodation is deficient.³³⁴

Children, who are intolerant of contact lenses or showing high exophoria at near, could be prescribed (prismatic) bifocal or anti-myopia spectacles. Fast progressors may not be treated sufficiently with low-add-power lenses, particularly in case of accommodative dysfunction. Spectacle lenses are also the first option of care in very young children (who are unable to wear contact lenses due to access or cost), any situations that associated with poor hygiene conditions, or if children grew up in locations with no or only limited access specialized eye care.³⁵¹

Atropine therapy

A report from American Academy of Ophthalmology concluded that the use of atropine to prevent myopic progression is supported by Level I evidence.³⁵² The World Society of Pediatric Ophthalmology and Strabismus in its Myopia Consesnus Statement argued that atropine 0.01% appears to offer an appropriate risk-benefit ratio, with no clinically significant visual side effects balanced against a reasonable and clinically significant 50% reduction in myopia progression (https://www.wspos.org/wspos-myopia-consensus-statement/ accessed 24 November 2020).

In a recent protocol developed by Chia and Tay,³⁵³ children are first started on a lower dose of atropine with a plan to increase the dose as necessary. Once medication is started, progression (in terms of refraction and axial length) should be monitored every 6 months, for at least 2 years. Based on the protocol from the Netherland,^93,337 axial length and gender-specific growth curve charts are used to evaluate the risk of myopipa/high myopia. Children with risk of myopia at the 75th percentile or above are then started on atropine 0.5% eye drops.³³⁷

The ATOM 2 study showed that 0.01% atropine resulted in a 60% risk of a refractive error rebound effect in children aged 8–10 years, compared to 30% at age 10–12 years and 8% after the age of 12 years.²⁸¹ The change in spherical equivalent was greater than the change in axial length and not directly associated with the change in axial length alone.²⁸¹ This suggests that in children younger than 12 years who showed no progression in the past year, atropine 0.01% may be slowly tapered by reducing drop frequency (by 1–2 days/week each year). However, if children are older than 12 years, then the frequency of eye drops could be tapered more quickly (by 1–2 days/week every 6 months). Using this regime, most children will be off medication by about 14–15 years of age.³⁵³

The Low-Concentration Atropine for Myopia Progression (LAMP) study recommends the use of 0.05% atropine rather than 0.01%, as the lower concentration allowed unacceptable levels of axial length progression.²⁷⁹

In children who progress on low-dose atropine, the frequency of application, or dose could be increased (using atropine 0.01% twice a day; or using a higher concentration, 0.05%, 0.1%, 0.5%, or 1%). Increasing the dose of atropine needs to be balanced against side effects of loss of accommodation and glare/aberrations from large pupil. Once an adequate control of myopia is achieved, medication can be continued till the child reaches teenage years and then tapered as required. There are some children (11%), however, who may progress rapidly even on 0.5% atropine.³³¹ If this occurs, then the possibility of stopping treatment or trying other treatment modalities should be discussed. Even after stopping treatment, it may be necessary to monitor children for a further 6–12 months to ensure that there is no further rebound.³⁵³

Patients undergoing atropine therapy will require distance refractive error correction. It is recommended that patients be prescribed their full distance refractive correction; however, patients may require near addition correction to alleviate near visual symptoms and photochromic lenses or additional sunglasses to relieve glare issues if necessary.³³⁹

Combination therapy in practice

For patients using mono-therapy in the form of atropine or ortho-K and who still experience progression of myopia and axial elongation at a faster rate than expected, combination therapy should be considered. Ortho-K with low-dose atropine improved myopia control by the synergistic effect compared with orthokeratology treatment alone, presumably because it increases the pupil area and, therefore, allows more plus power to reach the peripheral retina.^328,330,334 The effectiveness and side effects of combination therapy with atropine and soft myopia control contact lens is unknown, and should be first evaluated in prospective clinical trials before being used in clinical practice.

Treatment duration

Axial length is the most important metric to monitor in pre-myopic and myopic children.^{93,285,334,337,338}

Myopia generally progresses most rapidly during preteenager years (7–12 years), subsequently slowing through adolescence and adulthood.^67,91,354 The mean age of myopia stabilization is around 15.6 years of age, and 95% of myopes stabilize by age of 24 years.⁸³

There are some publications of myopia onset and progression at a later age among specific occupational groups, during university education courses such as medicine, law or engineering.^355–357

The efficacy of some treatments may wane after the first 6 months to 2 years of treatment.^{248,285,358–360} There is insufficient evidence that faster progressors, or younger myopes, derive greater benefit from treatment.²⁸⁵ The same treatments and protocols as applied in childhood may be applicable in later-onset myopia, although the available evidence is limited.³³⁹

In case of atropine treatment parents and patients should be made aware that myopia progression may accelerate after stopping higher-dose atropine usage, but despite this rebound effect, the level of myopia post-treatment will be less than it would have been without treatment.^280,282 The long-term use of atropine should only be undertaken with caution as long-term side effects have not been evaluated.³³⁹ It may be beneficial to tail off dosage or dose frequency at the end of treatment to minimize rebound effects.

Although the results of the ATOM studies point to some loss of treatment efficacy with time, at least with the higher concentrations of atropine, a study by Wu and colleagues which involved concentrations between 0.05% and 0.1%, suggested that treatment effects with low-dose atropine can be maintained for up to 4.5 years.²⁸⁷

Discontinuation of ortho-K lens wear before age 14 has been shown to lead to a more rapid increase in axial length over a 7-month period, faster than concurrent single vision spectacle wearing controls; however, this slows again with resumed lens wear after another 6 months. This suggests that ortho-K wear should not be discontinued before age 14.²⁶²

Long-term use of soft myopia control contact lens and ortho-K is not contraindicated if ocular health is maintained through regular aftercares and strong compliance.^264,339,361 Progressive additional lenses can also be used for vision correction, but the long-term, clinically meaningful myopia control effect of such lenses is small in comparison with contact lens corrections, except in specific populations.^145,214 Bifocal spectacle lenses might be a good solution for longevity treatment.^362,363 A study of children wearing progressive addition lenses for 1 year, then switched to single vision glasses for 1 year showed no rebound.¹⁴³ No rebound effect was reported with soft contact lens for myopia control.³⁶⁴

Compliance and safety issues may require a change in treatment modality or a halting of treatment. Poor tolerance of visual side effects may also prompt cessation or change of myopia control therapy.³³⁹

In conclusion, outdoor time is the most promising intervention method. There is consistent evidence of a benefit of slowing myopia development by the use of atropine eye drops, while the optimum concentration of atropine and the value of a combined use of atropine eye drops with optical devices are yet to be fully explored. There is also evidence of myopia control with soft multifocal contact lenses, orthokeratology, and new types of multifocal spectacle lenses. Information is constantly evolving, so it is important to stay abreast of studies published in the peer-reviewed literature.

Footnotes

Acknowledgements

The authors would like to thank Monica Jong, Executive Manager of the International Myopia Institute for the arrangement of the cooperation and the financial support for open access and Jaakko Kaprio for reviewing the genetic aspects of the manuscript.

Abbreviations

7-MX: Seven-methylxantine

AC/A: accommodation-convergence/accommodation ratio

ANSES: Agency for Food, Environmental and Occupational Health and Safety

AL: axial length

AQP-1: Aquaporin-1

ATOM: Atropine in the Treatment of Myopia

BAM: Bifocal & Atropine in Myopia

BFSCL: bifocal soft contact lens

BMI: Body Mass Index

BLINK: Bifocal Lenses In Nearsighted Kids

CAMS: Cambridge Anti-Myopia Study

CCL: collagen cross-linking

CI: confidence interval

CLE: contralateral eye

COMET: Correction of Myopia Evaluation Trial

CREAM: Consortium for Refractive Error and Myopia

D: diopter

DIMS: Defocus Incorporated Multiple Segments

ECM: extracellular matrix

HOA: higher-order aberration

IMI: International Myopia Institute

IOP: intraocular pressure

IQ: intelligence quotient

LAMP: Low-Concentration Atropine for Myopia Progression

LED: light-emitting diode

MFSCL: multifocal soft contact lens

MK: microbial keratitis

OH: hydroxy

OK: orthokeratology

Ortho-K: orthokeratology

PAL: progressive additional lens

PSC: posterior scleral contraction

PSR: posterior scleral reinforcement

RGP: rigid gas permeable lens

RPE: retinal pigment epithelium

SBCL: soft bifocal contact lenses

SCL: soft contact lens

SCORM: Cohort Study of the Risk Factors for Myopia

SE: spherical equivalent

SRRG: soft radial refractive gradient

SSI: Injection-based scleral strengthening

SV: single vision

SVCL: single vision contact lens

SVL: single vision lens

UK: United Kingdom

USA: United States of America

UV: ultraviolet

UVA: ultraviolet A

WHO: World Health Organization

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JBJ discloses patent application: “Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia” (European patent application 16 720 043.5 and US patent application US 2019 0085065 A1). AG reports grants from Alcon, Zeiss, Topcon, Bausch, personal fees, and non-financial support from Santen, Thea, Polpharma, and Pfizer, outside the submitted work. JAG is unpaid Consultant for CooperVision Inc. KJS is funded by Nevakar Inc as part of their EU/US low dose atropine trial. JRP is consultant for Nevakar. JSW is on the advisory board of Alcon, Nevakar, and Novars. SW is employee of Carl Zeiss Vision International GmbH. The other authors declared no potential conflicts of interest with respect to the authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: AG is funded by Institute for Research in Ophthalmology (Number: Unrestricted Grant 1/2020). JAG is funded by Welsh Government and Fight for Sight (Number: 24WG201). The author(s) disclosed receipt of the following financial support for the online publication of this article: The open access fee for this publication is paid by the International Myopia Institute (IMI).

ORCID iDs

János Németh

Ingrida Januleviciene

Kathryn J Saunders

Annechien EG Haarman

Siegfried Wahl

Serge Resnikoff

References

Holden

Fricke

Wilson

, et al. Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050. Ophthalmology 2016; 123: 1036–1042.

Morgan

Ohno-Matsui

Saw

S-M.

Myopia. Lancet 2012; 379: 1739–1748.

Resnikoff

Jonas

Friedman

, et al. Myopia- a 21st century public health issue. Invest Ophthalmol Vis Sci 2019; 60: Mi–Mii.

Fricke

Holden

Wilson

, et al. Global cost of correcting vision impairment from uncorrected refractive error. Bull World Health Org 2012; 90: 728–738.

Sun

Zhou

, et al. Causes and 3-year-incidence of blindness in Jing-An District, Shanghai, China 2001–2009. BMC Ophthalmol 2011; 11: 10.

Flitcroft

DI.

The complex interactions of retinal, optical and environmental factors in myopia aetiology. Prog Retin Eye Res 2012; 31: 622–660.

Haarman

AEG

Enthoven

Tideman

JWL

, et al. The complications of myopia: a review and meta-analysis. Invest Ophthalmol Vis Sci 2020; 61: 49.

Grzybowski

Kanclerz

Tsubota

, et al. A review on the epidemiology of myopia in school children worldwide. BMC Ophthalmol 2020; 20: 27.

Troilo

Smith

III Nickla

, et al. IMI-experimental models of emmetropization and myopia. Invest Ophthalmol Vis Sci 2019; 60: M31–M88.

10.

Tedja

Haarman

AEG

Meester-Smoor

, et al. IMI-myopia genetics report. Invest Ophthalmol Vis Sci 2019; 60: 89–105.

11.

Wolffsohn

Flitcroft

Gifford

, et al. IMI-myopia control reports overview and introduction. Invest Ophthalmol Vis Sci 2019; 60: M1–M17.

12.

Flitcroft

Jonas

, et al. IMI-defining and classifying myopia: a proposed set of standards for clinical and epidemiologic studies. Invest Ophthalmol Vis Sci 2019; 60: M20–M30.

13.

Sorsby

Refraction and its components in twins. Privy council, Medical research council, Special report series, no. 303. London: HM Stationery Office, 1962. pp. 136–137.

14.

Kepler

Dioptrice, Agsburg (1611): Cited by Duke-Elder

Abrams

. Ophthalmic optics and refraction. In: Duke-Elder

(ed.) System of ophthalmology. Vol V. London: Henry Kimpton, 1970, p.341.

15.

Cohn

(1867): Untersuchungen der Augen von 10060 Schoolkindern nebst Vorschlägen 3 fur Verbesserung der Augen nachtheiligen Schul-Einrichtungen, Leipzig 1867. Cited by Rehm

. The myopia myth. Ligonier, IN: IMPA, 1981, p.57.

16.

Tscherning

Studien uber die Aetiologie der Myopie. Albrcht. Von Graefe’s Arvch Ophthalmol 1883; 29: 201–202.

17.

Chakraborty

Read

Vincent

SJ.

Understanding myopia: pathogenesis and mechanisms. In: Ang

Wong

(eds.) Updates on myopia. A clinical perspective. 1st ed. Singapore: Springer, 2020, pp.65–95.

18.

Smith

III Hung

LF.

Form-deprivation myopia in monkeys is a graded phenomenon. Vis Res 2000; 40: 371–381.

19.

Smith

III Hung

Huang

, et al. Effect of optical defocus on refractive development in monkeys: evidence for local, regionally selective mechanisms. Invest Ophthtlmol Vis Sci 2010; 51: 3864–3873.

20.

Wildsoet

Pettigrew

JD.

Experimental myopia and anomalous eye growth patterns unaffected by optic nerve section in chickens: evidence for local control of eye growth. Clin Vis Sci 1988; 3: 99–107.

21.

Smith

III Ramamirtham

Qiao-Grider

, et al. Effects of foveal ablation on emmetropization and form-deprivation myopia. Invest Ophthalmol Vis Sci 2007; 48: 3914–3922.

22.

Schaeffel

Glasser

Howland

HC.

Accommodation, refractive error and eye growth in chickens. Vision Res 1988; 28: 639–657.

23.

Smith

III Kee

Ramamirtam

, et al. Peripheral vision can influence eye growth and refractive development in infant monkeys. Invest Ophthtlmol Vis Sci 2005; 46: 3965–3972.

24.

Charman

Radhakrishnan

Peripheral refraction and the development of refractive error: a review. Ophthalmic Physiol Opt 2010; 30: 321–338.

25.

Huang

Chang

PC.

The association between near work activities and myopia in children-a systematic review and meta-analysis. PLoS One 2015; 10: e0140419.

26.

Gwiazda

Thorn

Bauer

, et al. Myopic children show insufficient accommodative response to blur. Invest Ophthalmol Vis Sci 1993; 34: 690–694.

27.

Gwiazda

Bauer

Thorn

, et al. A dynamic relationship between myopia and blur-driven accommodation in school-aged children. Vis Res 1995; 35: 1299–1304.

28.

Abbott

Schmid

Strang

NC.

Differences in the accommodation stimulus response curves of adult myopes and emmetropes. Ophthalmic Physiol Opt 1998; 18: 13–20.

29.

Charman

WN.

Aberrations and myopia. Ophthalmic Physiol Opt 2005; 25: 285–301.

30.

Lau

Vincent

Collins

, et al. Ocular higher-order aberrations and axial eye growth in young Hong Kong children. Sci Rep 2018; 8: 6726.

31.

Hiraoka

Kotsuka

Kakita

, et al. Relationship between higher-order wavefront aberrations and natural progression of myopia in schoolchildren. Sci Rep 2017; 7: 7876.

32.

Nickla

DL.

The phase relationships between the diurnal rhythms in axial length and choroidal thickness and the association with ocular growth rate in chicks. J Comp Physiol A 2006; 192: 399–407.

33.

Kearney

O’Donoghue

Pourshahidi

, et al. Myopes have significantly higher serum melatonin concentrations than non-myopes. Ophthalmic Physiol Opt 2017; 37: 557–567.

34.

Jee

Morgan

Kim

EC.

Inverse relationship between sleep duration and myopia. Acta Ophthalmol 2016; 94: 204–210.

35.

Cohen

Belkin

Yehezkel

, et al. Dependency between light intensity and refractive development under lightdark cycles. Exp Eye Res 2011; 92: 40–46.

36.

Norton

TT.

What do animal studies tell us about the mechanism of myopia-protection by light?

Optom Vis Sci 2016; 93: 1049–1051.

37.

Wang

Schaeffel

Jiang

, et al. Effects of light of different spectral composition on refractive development and retinal dopamine in chicks. Invest Ophthalmol Vis Sci 2018; 59: 4413–4424.

38.

Aleman

Wang

Schaeffel

Reading and myopia: contrast polarity matters. Sci Rep 2018; 8: 10840.

39.

Wildsoet

Wallman

Choroidal and scleral mechanisms of compensation for spectacle lenses in chicks. Vis Res 1995; 35: 1175–1194.

40.

Wallman

Wildsoet

, et al. Moving the retina: choroidal modulation of refractive state. Vis Res 1995; 35: 37–50.

41.

Harper

Summers

JA.

The dynamic sclera: extracellular matrix remodeling in normal ocular growth and myopia development. Exp Eye Res 2015; 133: 100–111.

42.

Summers

JA.

The choroid as a sclera growth regulator. Exp Eye Res 2013; 114: 120–127.

43.

Stone

Lin

Laties

, et al. Retinal dopamine and form-deprivation myopia. Proc Natl Acad Sci USA 1989; 86: 704–706.

44.

Seko

Shimokawa

Tokoro

In vivo and in vitro association of retinoic acid with form-deprivation myopia in the chick. Exp Eye Res 1996; 63: 443–452.

45.

Fujikado

Kawasaki

Fujii

, et al. The effect of nitric oxide synthase inhibitor on form-deprivation myopia. Curr Eye Res 1997; 16: 992–996.

46.

World Health Organisation. World report of vision. Geneva, Switzerland: WHO, 2019, p. 42.

47.

Foster

Jiang

Epidemiology of myopia. Eye (Lond) 2014; 28: 202–208.

48.

World Health Organisation. World report of vision. Geneva, Switzerland: WHO, 2019, p. 154.

49.

McCrann

Loughman

Butler

, et al. Smartphone use as a possible risk factor for myopia. Clin Exp Optom 2020; 104(1): 13092.

50.

Rudnicka

Kapetanakis

Wathern

, et al. Global variations and time trends in the prevalence of childhood myopia, a systematic review and quantitative meta-analysis: implications for aetiology and early prevention. Br J Ophthalmol 2016; 100: 882–890.

51.

Matamoros

Ingrand

Pelen

, et al. Prevalence of myopia in France: a cross-sectional analysis. Medicine 2015; 94: e1976.

52.

Tideman

JWL

Polling

Hofman

, et al. Environmental factors explain socioeconomic prevalence differences in myopia in 6-year-old children. Br J Ophthalmol 2017; 102: 243–247.

53.

Enthoven

Tideman

JWL

Polling

, et al. The impact of computer use on myopia development in childhood: the Generation R study. Prev Med 2020; 132: 105988.

54.

Rudnicka

Owen

Nightingale

, et al. Ethnic differences in the prevalence of myopia and ocular biometry in 10-and 11-year-old children: The Child Heart and Health Study in England (CHASE). Invest Ophthalmol Vis Sci 2010; 51: 6270–6276.

55.

O’Donoghue

Kapetanankis

McClelland

, et al. Risk factors for childhood myopia: findings from the NICER Study. Invest Ophthalmol Vis Sci 2015; 56: 1524–1530.

56.

Tideman

JWL

Enthoven

Jaddoe

, et al. Axial length growth from 6 to 13 years of age and risk of myopia at age 13: the Generation R study. Invest Ophthalmol Vis Sci 2020; 61: 852.

57.

Lundberg

Suhr Thykjaer

Søgaard Hansen

, et al. Physical activity and myopia in Danish children-The CHAMPS Eye Study. Acta Ophthalmol 2017; 96: 134–141.

58.

Hagen

Gjelle

JVB

Arnegard

, et al. Prevalence and possible factors of myopia in Norwegian adolescents. Sci Rep 2018; 8: 13479.

59.

Lam

Goldschmidt

Edwards

MH.

Prevalence of myopia in local and international schools in Hong Kong. Optom Vis Sci 2004; 81: 317–322.

60.

Matsumura

Hirai

Prevalence of myopia and refractive changes in students from 3 to 17 years of age. Surv Ophthalmol 1999; 44(suppl 1): S109–S115.

61.

Wang

, et al. Refractive error, visual acuity and causes of vision loss in children in Shandong, China: The Shandong Children Eye Study. PLoS One 2013; 8: e82763.

62.

Lin

Shih

Hsiao

, et al. Prevalence of myopia in Taiwanese schoolchildren: 1983 to 2000. Ann Acad Med Singapore 2004; 33: 27–33.

63.

Jung

Lee

Kakizaki

, et al. Prevalence of myopia and its association with body stature and educational level in 19- year-old male conscripts in Seoul, South Korea. Invest Ophthalmol Vis Sci 2012; 53: 5579–5583.

64.

Lee

Jee

Kwon

, et al. Prevalence and risk factors for myopia in a rural Korean population. Invest Ophthalmol Vis Sci 2013; 54: 5466–5471.

65.

Koh

Yang

Saw

, et al. Differences in prevalence of refractive errors in young Asian males in Singapore between 1996-1997 and 2009-2010. Ophthalmic Epidemiol 2014; 21: 247–255.

66.

Gwiazda

Hyman

Hussein

, et al. A randomized clinical trial of progressive addition lenses versus single vision lenses on the progression of myopia in children. Invest Ophthalmol Vis Sci 2003; 44: 1492–1500.

67.

Saw

Tong

Chua

, et al. Incidence and progression of myopia in Singaporean school children. Invest Ophthalmol Vis Sci 2005; 46: 51–57.

68.

Lam

Edwards

Millodot

, et al. A 2-year longitudinal study of myopia progression and optical component changes among Hong Kong schoolchildren. Optom Vis Sci 1999; 76:370–380.

69.

Donovan

Sankaridurg

, et al. Myopia progression rates in urban children wearing single-vision spectacles. Optom Vis Sci 2012; 89: 27–32.

70.

French

Morgan

Burlutsky

, et al. Prevalence and 5- to 6-year incidence and progression of myopia and hyperopia in Australian schoolchildren. Ophthalmology 2013; 120: 1482–1491.

71.

Pärssinen

Soh

Tan

, et al. Comparison of myopic progression in Finnish and Singaporean children. Acta Ophthalmol 2021; 99: 171–180.

72.

Chua

Sabanayagam

Cheung

, et al. Age of onset of myopia predicts risk of high myopia in later childhood in myopic Singapore children. Ophthalmic Physiol Opt 2016; 36: 388–394.

73.

Bullimore

Reuter

Jones

, et al. The study of progression of adult nearsightedness (SPAN): design and baseline characteristics. Optom Vis Sci 2006; 83: 594–604.

74.

Thorn

Gwiazda

Held

Myopia progression is specified by a double exponential growth function. Optom Vis Sci 2005; 82: 286–297.

75.

Jiang

Tarczy-Hornoch

Cotter

, et al. Association of parental myopia with higher risk of myopia among multiethnic children before school age. JAMA Ophthalmol 2020; 138: 501–509.

76.

Zhu

, et al. Age-specific prevalence of visual impairment and refractive error in children aged 3-10 years in Shanghai, China. Invest Ophthalmol Vis Sci 2016; 57: 6188–6196.

77.

Guo

Ding

, et al. Significant axial elongation with minimal change in refraction in 3- to 6- year-old Chinese preschoolers: the Shenzhen Kindergarten Eye Study. Ophthalmology 2017; 124: 1826–1838.

78.

, et al. Population-based survey of refractive error among school-aged children in rural northern China: the Heilongjiang Eye Study. Clin Exp Ophthalmol 2014; 42: 379–384.

79.

Smirnova

Prediger

Potykova

JU.

Epidemiology of disorders of refraction, accommodation and convergence, at schoolchildren of Siberia. Mod Optom 2017; 102: 19–28.

80.

Logan

Modern trends in refractogenesis in Siberian schoolchildren. Poster abstract P 003. Ophthalmic Physiol Opt 2018; 38(3): 215–216.

81.

Giordano

Friedman

Repka

, et al. Prevalence of refractive error among preschool children in an urban population: the Baltimore Pediatric Eye Disease Study. Ophthalmology 2009; 116: 739–746.

82.

Zeng

Liu

, et al. Refractive error and visual impairment in urban children in Southern China. Invest Ophthalmol Vis Sci 2004; 45: 793–799.

83.

COMET Group. Myopia stabilization and associated factors among participants in the Correction of Myopia Evaluation Trial (COMET). Invest Ophthalmol Vis Sci 2013; 54: 7871–7884.

84.

Lee

Lim

, et al. Longitudinal changes in axial length in high myopia: a 4-year prospective study. Br J Ophthalmol 2019; 104: 600–603.

85.

Lee

JTL

Guo

, et al. Progression and longitudinal biometric changes in highly myopic eyes. Invest Ophthalmol Vis Sci 2020; 61: 34.

86.

Pärssinen

Kauppinen

Viljanen

The progression of myopia from its onset at age 8-12 to adulthood and the influence of heredity and external factors on myopic progression. A 23-year follow-up study. Acta Ophthalmol 2014; 92: 730–739.

87.

Bullimore

Jones

Moeschberger

, et al. A retrospective study of myopia progression in adult contact lens wearers. Invest Ophthalmol Vis Sci 2002; 43: 2110–2113.

88.

Morgan

Rose

KA.

Is the nature-nurture debate finally over?

Clin Exp Optom 2019; 102: 3–17.

89.

Williams

Verhoeven

VJM

Cumberland

, et al. Prevalence of refractive error in Europe: the European Eye Epidemiology (E3) Consortium. Eur J Epidemiol 2015; 30: 305–315.

90.

Kinge

Midelfart

Jacobsen

, et al. The influence of near-work on development of myopia among university students: a three-year longitudinal study among engineering students in Norway. Acta Ophthalmol Scand 2000; 78: 26–29.

91.

McCullough

O’Donoghue

Saunders

KJ.

Six year refractive change among white children and young adults: evidence for significant increase in myopia among white UK children. PLoS One 2016; 11: e0146332.

92.

Hansen

Hvid-Hansen

Jacobsen

, et al. Myopia prevalence in Denmark - a review of 140 years of myopia research. Acta Ophthalmol 2021; 99: 118–127.

93.

Tideman

JWL

Polling

Vingerling

, et al. Axial in length growth and the risk of developing myopia European children. Acta Ophthalmol 2018; 96: 301–303.

94.

Wang

Klein

, et al. Refractive status in the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 1994; 35: 4344–4347.

95.

Katz

Tielsch

Sommer

Prevalence and risk factors for refractive errors in an adult inner city population. Invest Ophthalmol Vis Sci 1997; 38: 334–340.

96.

Wong

Foster

Hee

, et al. Prevalence and risk factors for refractive errors in adult Chinese in Singapore. Invest Ophthalmol Vis Sci 2000; 41: 2486–2494.

97.

Hysi

Choquet

Khawaja

, et al. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia. Nat Genet 2020; 52: 401–407.

98.

Zhang

Insight into the molecular genetics of myopia. Mol Vis 2017; 23: 1048–1080.

99.

Rose

Morgan

Smith

, et al. High heritability of myopia does not preclude rapid changes in prevalence. Clin Exp Ophthalmol 2002; 30: 168–172.

100.

Zylbermann

Landau

Berson

The influence of study habits on myopia in Jewish children. J Pediatr Ophthalmol Strabismus 1993; 30: 319–322.

101.

Megreli

Barak

Bez

, et al. Association of myopia with cognitive function among one million adolescents. BMC Public Health 2020; 20: 647.

102.

Morgan

Rose

How genetic is ‘school myopia’?

Prog Retin Eye Res 2005; 24: 1–38.

103.

Zhou

Zhang

, et al. Five-year progression of refractive errors and incidence of myopia in school-aged children in Western China. J Epidemiol 2016; 26: 386–395.

104.

Pärssinen

Relation between refraction, education, occupation, and age among 26- and 46-year-old Finns. Am J Optom Physiol Opt 1987; 64: 136–143.

105.

Midelfart

Kinge

Midelfart

, et al. Prevalence of refractive errors in young and middle-aged adults in Norway. Acta Ophthalmol Scand 2002; 80: 501–505.

106.

Sun

Zhou

Zhao

, et al. High prevalence of myopia and high myopia in 5060 Chinese university students in Shanghai. Invest Ophthalmol Vis Sci 2012; 53: 7504–7509.

107.

Mutti

Mitchell

Hayes

, et al. Accommodation lag before and after the onset of myopia. Invest Ophthtlmol Vis Sci 2006; 47: 837–846.

108.

Gwiazda

Hyman

Dong

, et al. Factors associated with high myopia after 7 years of follow-up in the Correction of Myopia Evaluation Trial (COMET) cohort. Ophthalmic Epidemiol 2007; 14: 230–237.

109.

Shrestha

Bhat

Binu

, et al. Pattern of refractive errors among the Nepalese population: a retrospective study. Nepal J Ophthalmol 2010; 2: 87–96.

110.

Rezvan

Khabazkhoob

Fotouhi

, et al. Prevalence of refractive errors among school children in Northeastern Iran. Ophthalmic Physiol Opt 2012; 32: 25–30.

111.

Zadnik

Satariano

Mutti

, et al. The effect of parental history of myopia on children’s eye size. JAMA 1994; 271: 1323–1327.

112.

Lee

Sheu

, et al. Risk factors for and progression of myopia in young Taiwanese men. Ophthalmic Epidemiol 2015; 22: 66–73.

113.

Kearney

Strang

Cagnolati

, et al. Change in body height, axial length and refractive status over a four-year period in Caucasian children and young adults. J Optom 2020; 13: 128–136.

114.

Huynh

Robaei

, et al. Ethnic differences in the impact of parental myopia: findings from a population-based study of 12-year-old Australian children. Invest Ophthalmol Vis Sci 2007; 48: 2520–2528.

115.

Mutti

Mitchell

Moeschberger

, et al. Parental myopia, near work, school achievement, and children’s refractive error. Invest Ophthalmol Vis Sci 2002; 43: 3633–3640.

116.

Xiang

Morgan

IG.

The impact of parental myopia on myopia in Chinese children: population-based evidence. Optom Vis Sci. 2012; 89: 1487–1496.

117.

Zhang

Zhou

Association between parental myopia and the risk of myopia in a child. Exp Ther Med 2015; 9: 2420–2428.

118.

Wenbo

Congxia

Hui

Genetic and environmental-genetic interaction rules for the myopia based on a family exposed to risk from a myopic environment. Gene 2017; 626: 305–308.

119.

Jones-Jordan

Sinnott

Manny

, et al. Early childhood refractive error and parental history of myopia as predictors of myopia. Invest Ophthalmol Vis Sci 2010; 51: 115–121.

120.

McMonnies

CW.

Clinical prediction of the need for interventions for the control of myopia. Clin Exp Optom 2015; 98: 518–526.

121.

Morgan

French

Rose

. Risk factors for myopia: putting causal pathways into a social context. In: Ang

Wong

(eds.) Updates on myopia. A clinical perspective. 1st ed. Singapore: Springer, 2020, pp.133–170.

122.

Teasdale

Fuchs

Goldschmidt

Degree of myopia in relation to intelligence and educational level. Lancet 1988; 2: 1351–1354.

123.

Rosner

Belkin

Intelligence, education, and myopia in males. Arch Ophthalmol 1987; 105: 1508–1511.

124.

Pärssinen

Era

Leskinen

AL.

Some physiological and psychological characteristics of myopic and non-myopic men. Acta Ophthalmol 1985; 173: 85–87.

125.

Saw

Tan

Fung

, et al. IQ and the association with myopia in children. Invest Ophthalmol Vis Sci. 2004; 45: 2943–2948.

126.

Cuellar-Partida

Kho

, et al. Assessing the genetic predisposition of education on myopia: a mendelian randomization study. Genet Epidemiol 2016; 40: 66–72.

127.

Mountjoy

Davies

Plotnikov

, et al. Education and myopia: assessing the direction of causality by mendelian randomisation. BMJ 2018; 361: k2022.

128.

Plotnikov

Williams

Atan

, et al. Effect of education on myopia: evidence from the United Kingdom ROSLA 1972 reform. Invest Ophthalmol Vis Sci 2020; 61: 7.

129.

Terasaki

Yamashita

Yoshihara

, et al. Association of lifestyle and body structure to ocular axial length in Japanese elementary school children. BMC Ophthalmol 2017; 17: 123.

130.

O’Connor

Stephenson

Johnson

, et al. Change of refractive state and eye size in children of birth weight less than 1701 g. Br J Ophthalmol 2006; 90: 456–460.

131.

Mandel

Grotto

El-Yaniv

, et al. Season of birth, natural light, and myopia. Ophthalmology 2008; 115: 686–692.

132.

McMahon

Zayats

Chen

, et al. Season of birth, daylight hours at birth, and high myopia. Ophthalmology 2009; 116: 468–473.

133.

Guggenheim

McMahon

Northstone

, et al. Birth order and myopia. Ophthalmic Epidemiol 2013; 20: 375–384.

134.

Guggenheim

Williams

and UK Biobank Eye and Vision Consortium. Role of educational exposure in the association between myopia and birth order. JAMA Ophthalmol 2015; 133: 1408–1414.

135.

Gwiazda

Thorn

Held

Accommodation, accommodative convergence, and response AC/A ratios before and at the onset of myopia in children. Optom Vis Sci 2005; 82: 273–278.

136.

Mutti

Mitchell

Jones-Jordan

, et al. The response AC/A ratio before and after the onset of myopia. Invest Ophthalmol Vis Sci 2017; 58: 1594–1602.

137.

Nakatsuka

Hasebe

Nonak

, et al. Accommodative lag under habitual seeing conditions: comparison between myopic and emmetropic children. Jpn J Ophthalmol 2005; 49: 189–194.

138.

Pärssinen

Lyyra

AL.

Myopia and myopic progression among schoolchildren: a three-year follow-up study. Invest Ophthalmol Vis Sci 1993; 34: 2794–2802.

139.

Gwiazda

Grice

Thorn

Response AC/A ratios are elevated in myopic children. Ophthalmic Physiol Opt 1999; 19: 173–179.

140.

Mutti

Jones

Moeschberger

, et al. AC/A ratio, age, and refractive error in children. Invest Ophthalmol Vis Sci 2000; 41: 2469–2478.

141.

Allen

O’Leary

DJ.

Accommodation functions: co-dependency and relationship to refractive error. Vision Res 2006; 46: 491–505.

142.

Rosenfield

Desai

Portello

JK.

Do progressing myopes show reduced accommodative responses?

Optom Vis Sci 2002; 79: 268–273.

143.

Berntsen

Sinnott

Mutti

, et al. 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: 640–649.

144.

Berntsen

Sinnott

Mutti

, et al. Accommodative lag and juvenile-onset myopia progression in children wearing refractive correction. Vision Res 2011; 51: 1039–1046.

145.

Cheng

Woo

Drobe

, et al. Effect of bifocal and prismatic bifocal spectacles on myopia progression in children: three-year results of a randomized clinical trial. JAMA Ophthalmol 2014; 132: 258–264.

146.

Aller

Liu

Wildsoet

CF.

Myopia control with bifocal contact lenses: a randomized clinical trial. Optom Vis Sci 2016; 93: 344–352.

147.

Dolgin

The myopia boom. Nature 2015; 519: 276–278.

148.

Williams

Bertelsen

Cumberland

, et al. Increasing prevalence of myopia in Europe and the impact of education. Ophthalmology 2015; 122: 1489–1497.

149.

Hua

Jin

, et al. Elevated light levels in schools have a protective effect on myopia. Ophthalmic Physiol Opt 2015; 35: 252–262.

150.

Read

Collins

Vincent

SJ.

Light exposure and physical activity in myopic and emmetropic children. Optom Vis Sci 2014; 91: 330–341.

151.

Torii

Ohnuma

Kurihara

, et al. Violet light transmission is related to myopia progression in adult high myopia. Sci Rep 2017; 7: 14523.

152.

Williams

Bentham

Young

, et al. Association between myopia, ultraviolet B radiation exposure, serum vita min D concentrations, and genetic polymorphisms in vitamin D metabolic pathways in a multicountry European study. JAMA Ophthalmol 2017; 135: 47–53.

153.

Xiong

Sankaridurg

Naduvilath

, et al. Time spent in outdoor activities in relation to myopia prevention and control: a meta-analysis and systematic review. Acta Ophthalmol 2017; 95: 551–566.

154.

Cao

Wan

Yusufu

, et al. Significance of outdoor time for myopia prevention: a systematic review and meta-analysis based on randomized controlled trials. Ophthalmic Res 2020; 63: 97–105.

155.

Chen

Lin

, et al. Myopia prevention and outdoor light intensity in a school-based cluster randomized trial. Ophthalmology. 2018;125:1239–1250.

156.

Pärssinen

The wearing of spectacles and occurrence of myopia. In: Acta Universitatis Tamperensis ser A. Vol 207. Tampere, Finland: University of Tampere, 1986.

157.

Rose

Morgan

, et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology 2008; 115: 1279–1285.

158.

Wen

Cao

Cheng

, et al. Objectively measured near work, outdoor exposure and myopia in children. Br J Ophthalmol 2020; 104: 1542–1547.

159.

Morgan

Rose

KA.

Myopia and international educational performance. Ophthalmic Physiol Opt 2013; 33: 329–338.

160.

Shapira

Mimouni

Machluf

, et al. The increasing burden of myopia in Israel among young adults over a generation: analysis of predisposing factors. Ophthalmology 2019; 126: 1617–1626.

161.

Mirshahi

Ponto

Hoehn

, et al. Myopia and level of education: results from the Gutenberg Health Study. Ophthalmology 2014; 121: 2047–2052.

162.

Ramessur

Williams

Hammond

CJ.

Risk factors for myopia in a discordant monozygotic twin study. Ophthalmic Physiol Opt 2015; 35: 643–651.

163.

Flitcroft

Harb

Wildsoet

. The spatial frequency content of urban and indoor environments as a potential risk factor for myopia development. Invest Ophthalmol Vis Sci 2020; 61: 42.

164.

Verhoeven

VJM

Buitendijk

GHS

Rivadeneira

, et al. Consortium for refractive error and myopia (CREAM). Education influences the role of genetics in myopia. Eur J Epidemiol 2013; 28: 973–980.

165.

Fan

Guo

Tideman

JWL

, et al. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: the CREAM Consortium. Sci Rep 2016; 6: 25853.

166.

Williams

Kraphol

Yonova-Doing

, et al. Early life factors for myopia in the British twins early development study. Br J Ophthalmol 2019; 103: 1078–1084.

167.

Saxena

Vashist

Tandon

, et al. Incidence and progression of myopia and associated factors in urban school children in Delhi: The North India Myopia Study (NIM Study). PLoS One 2017; 12: e0189774.

168.

Lanca

Saw

SM.

The association between digital screen time and myopia: a systematic review. Ophthalmic Physiol Opt 2020; 40: 216–229.

169.

Choi

Lam

CHI

, et al. Childhood exposure to constricted living space: a possible environmental threat for myopia development. Ophthalmic Physiol Opt 2017;37: 568–575.

170.

Gao

Jin

, et al. Housing type and myopia: the mediating role of parental myopia. BMC Ophthalmol 2016; 16: 151.

171.

Lim

Yoon

Hwang

, et al. Prevalence and associated sociodemographic factors of myopia in Korean children: the 2005 Third Korea National Health and Nutrition Examination Survey (KNHANES III). Jpn J Ophthalmol 2012; 56: 76–81.

172.

Jones

Sinnott

Mutti

, et al. Parental history of myopia, sports and outdoor activities, and future myopia. Invest Ophthalmol Vis Sci 2007; 48: 3524–3532.

173.

Jones-Jordan

Mitchell

Cotter

, et al. Visual activity prior to and following the onset of juvenile myopia. Invest Ophthalmol Vis Sci 2011; 52: 1841–1850.

174.

Jones-Jordan

Sinnott

Cotter

, et al. Time outdoors, visual activity, and myopia progression in juvenile-onset myopes. Invest Ophthalmol Vis Sci 2012; 53: 7169–7175.

175.

Tsai

, et al. Outdoor activity during class recess reduces myopia onset and progression in school children. Ophthalmology 2013; 120: 1080–1085.

176.

Xiang

Zeng

, et al. Effect of time spent outdoors at school on the development of myopia among children in China: a randomized clinical trial. JAMA Ophthalmol 2015; 314: 1142–1148.

177.

Jin

Hua

Jiang

, et al. Effect of outdoor activity on myopia onset and progression in school-aged children in northeast china: The Sujiatun Eye Care Study. BMC Ophthalmol 2015; 15: 73.

178.

Sherwin

Reacher

Keogh

, et al. The association between time spent outdoors and myopia in children and adolescents: a systematic review and meta-analysis. Ophthalmology 2012; 119: 2141–2151.

179.

French

Ashby

Morgan

, et al. Time outdoors and the prevention of myopia. Exp Eye Res 2013; 114: 58–68.

180.

Jacobsen

Jensen

Goldschmidt

Does the level of physical activity in university students influence development and progression of myopia? A 2-year prospective cohort study. Invest Ophthalmol Vis Sci 2008; 49: 1322–1327.

181.

Feldkaemper

Schaeffel

An updated view on the role of dopamine in myopia. Exp Eye Res 2013; 114: 106–119.

182.

Prepas

SB.

Light, literacy and the absence of ultraviolet radiation in the development of myopia. Med Hypotheses 2008; 70: 635–637.

183.

Donovan

Sankaridurg

, et al. Myopia progression in Chinese children is slower in summer than in winter. Optom Vis Sci 2012; 89: 1196–1202.

184.

Gwiazda

Deng

Manny

, et al. Seasonal variations in the progression of myopia in children enrolled in the correction of myopia evaluation trial. Invest Ophthalmol Vis Sci 2014; 55: 752–758.

185.

Tideman

JWL

Polling

Voortman

, et al. Low serum vitamin D is associated with axial length and risk of myopia in young children. Eur J Epidemiol 2016; 31: 491–499.

186.

Mutti

Marks

AR.

Blood levels of vitamin D in teens and young adults with myopia. Optom Vis Sci 2011; 88: 377–382.

187.

Choi

Han

Park

, et al. Low serum 25-hydroxyvitamin D is associated with myopia in Korean adolescents. Invest Ophthalmol Vis Sci 2014; 55: 2041–2047.

188.

Yazar

Hewitt

Black

, et al. Myopia is associated with lower vitamin D status in young adults. Invest Ophthalmol Vis Sci 2014; 55: 4552–4559.

189.

Kwon

Choi

TY.

Serum 25-hydroxyvitamin D level is associated with myopia in the Korea national health and nutrition examination survey. Medicine 2016; 95: e5012.

190.

Guggenheim

Williams

Northstone

, et al. Does vitamin D mediate the protective effects of time outdoors on myopia? Findings from a prospective birth cohort. Invest Ophthalmol Vis Sci 2015; 55: 8550–8558.

191.

Zhou

Chen

Wang

, et al. Pilot study of a novel classroom designed to prevent myopia by increasing children’s exposure to outdoor light. PLoS One 2017; 12: e0181772

192.

Pan

Liu

, et al. Types of lamp for homework and myopia among Chinese school-aged children. Ophthal Epidemiol 2018; 25: 250–256.

193.

Behar-Cohen

Martinsons

Viénot

, et al. Light-emitting diodes (LED) for domestic lighting: any risks for the eye? Prog Retin Eye Res 2011; 30: 239–257.

194.

Tokoro

Kabe

. Treatment of the myopia and the changes in optical components. Report II. Full- or under-correction of myopia by glasses [in Japanese]. Nippon Ganka Gakkai Zasshi 1965; 69: 140–144.

195.

Sun

, et al. Effect of uncorrection versus full correction on myopia progression in 12-year-old children. Graefes Arch Clin Exp Ophthalmol 2017; 255: 189–195.

196.

Chung

Mohidin

O’Leary

DJ.

Undercorrection of myopia enhances rather than inhibits myopia progression. Vision Res 2002; 42: 2555–2559.

197.

Adler

Millodot

The possible effect of undercorrection on myopic progression in children. Clin Exp Optom 2006; 89: 315–321.

198.

Zhou

, et al. Effect of undercorrection on myopia progression in 12-year-old children. Graefes Arch Clin Exp Ophthalmol 2015; 253: 1363–1368.

199.

Wildsoet

Chia

Cho

, et al. IMI-interventions for controlling myopia onset and progression report. Invest Ophthtlmol Vis Sci 2019; 60: M106–M131.

200.

Walline

Lindsley

Vedula

, et al. Interventions to slow progression of myopia in children. Cochrane Database Syst Rev 2011; 12: CD004916.

201.

Walline

Lindsley

Vedula

, et al. Interventions to slow progression of myopia in children. Cochrane Database of Syst Rev 2020; 1: CD004916.

202.

Logan

Wolffsohn

JS.

Role of un-correction, under-correction and over-correction of myopia as a strategy for slowing myopic progression. Clin Exp Optom 2020; 103: 133–137.

203.

Kanda

Oshika

Hiraoka

, et al. Effect of spectacle lenses designed to reduce relative peripheral hyperopia on myopia progression in Japanese children: a 2-year multicenter randomized controlled trial. Jpn J Ophthalmol 2018; 62: 537–543.

204.

Hasebe

Jun

Varnas

SR.

Myopia control with positively aspherized progressive addition lenses: a 2-year, multicenter, randomized, controlled trial. Invest Ophthalmol Vis Sci 2014; 55: 7177–7188.

205.

Sankaridurg

Donovan

Varnas

, et al. Spectacle lenses designed to reduce progression of myopia: 12-month results. Optom Vis Sci 2010; 87: 631–641.

206.

Lam

CSY

Tang

Tse

, et al. Defocus incorporated multiple segments (DIMS) spectacle lenses slow myopia progression: a 2-year randomised clinical trial. Br J Ophthalmol 2020; 104: 363–368.

207.

Tang

Leung

Wong

ACK

, et al. Optical interventions for myopia control. In: Ang

Wong

(eds.) Updates on myopia. A clinical perspective. 1st ed. Singapore: Springer, 2020, pp.289–305.

208.

Gwiazda

Hyman

Everett

, et al. Five–year results from the correction of myopia evaluation trial (COMET). Invest Ophthalmol Vis Sci 2006; 47: 1166.

209.

Hasebe

Ohtsuki

Nonaka

, et al. Effect of progressive addition lenses on myopia progression in Japanese children: a prospective, randomized, double-masked, crossover trial. Invest Ophthalmol Vis Sci 2008; 49: 2781–2789.

210.

Jensen

Myopia progression in young school children. A prospective study of myopia progression and the effect of a trial with bifocal lenses and beta blocker eye drops. Acta Ophthalmol Suppl 1991; 200: 1–79.

211.

Pärssinen

Hemminki

Klemetti

Effect of spectacle use and accommodation on myopic progression: final results of three-year randomised clinical trial among schoolchildren. Br Med J 1989; 73: 547–551.

212.

, et al. Multifocal versus single vision lenses intervention to slow progression of myopia in school-age children: a meta-analysis. Surv Ophthalmol 2011; 56: 451–460.

213.

Gwiazda

Hyman

Norton

, et al. Accommodation and related risk factors associated with myopia progression and their interaction with treatment in COMET children. Invest Ophthalmol Vis Sci 2004; 45: 2143–2151.

214.

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: 2749–2757.

215.

Yang

Lan

, et al. The effectiveness of progressive addition lenses on the progression of myopia in Chinese children. Ophthalmic Physiol Opt 2009; 29: 41–48.

216.

Horner

Soni

Salmon

, et al. Myopia progression in adolescent wearers of soft contact lenses and spectacles. Optom Vis Sci 1999; 76: 474–479.

217.

Walline

Jones

Sinnott

, et al. A randomized trial of the effect of soft contact lenses on myopia progression in children. Invest Ophthalmol Vis Sci 2008; 49: 4702–4706.

218.

Marsh-Tootle

Dong

Hyman

, et al. Myopia progression in children wearing spectacles vs. switching to contact lenses. Optom Vis Sci 2009; 86: 741–747.

219.

Kelly

Chatfield

Tustin

Clinical assessment of the arrest of myopia. Br J Ophthalmol 1975; 59: 529–538.

220.

Perrigin

Quintero

, et al. Silicone-acrylate contact lenses for myopia control: 3-year results. Optom Vis Sci 1990; 67: 764–769.

221.

Stone

The possible influence of contact lenses on myopia. Br J Physiol Opt 1976; 31: 89–114.

222.

Katz

Schein

Levy

, et al. A randomized trial of rigid gas permeable contact lenses to reduce progression of children’s myopia. Am J Ophthalmol 2003; 136: 82–90.

223.

Walline

Jones

Mutti

, et al. A randomized trial of the effects of rigid contact lenses on myopia progression. Arch Ophthalmol 2004; 122: 1760–1766.

224.

Walline

JJ.

Myopia control: a review. Eye Contact Lens 2016; 42: 3–8.

225.

Anstice

Phillips

JR.

Effect of dual-focus soft contact lens wear on axial myopia progression in children. Ophthalmology 2011; 118: 1152–1161.

226.

Paune

Morales

Armengol

, et al. Myopia control with a novel peripheral gradient soft lens and orthokeratology: a 2-year clinical trial. Biomed Res Int 2015; 2015: 507572.

227.

Kang

, et al. Studies using concentric ring bifocal and peripheral add multifocal contact lenses to slow myopia progression in school-aged children: a meta-analysis. Ophthalmic Physiol Opt 2017; 37: 51–59.

228.

Ruiz-Pomeda

Perez-Sanchez

Valls

, et al. MiSight Assessment Study Spain (MASS). A 2-year randomized clinical trial. Graefes Arch Clin Exp Ophthalmol 2018; 256: 1011–1021.

229.

Chamberlain

Peixoto-de-Matos

Logan

, et al. A 3-year randomized clinical trial of MiSight lenses for myopia control. Optom Vis Sci 2019; 96: 556–567.

230.

Lam

CSY

Tang

Tse

DY-Y

, et al. Defocus incorporated soft contact (DISC) lens slows myopia progression in Hong Kong Chinese schoolchildren: a 2-year randomised clinical trial. Br J Ophthalmol 2014; 98: 40–45.

231.

Paune

Thivent

Armengol

, et al. Changes in peripheral refraction, higher-order aberrations, and accommodative lag with a radial refractive gradient contact lens in young myopes. Eye Contact Lens 2016; 42: 380–387.

232.

Allen

Radhakrishnan

Price

, et al. A randomised clinical trial to assess the effect of a dual treatment on myopia progression: The Cambridge Anti-Myopia Study. Ophthalmic Physiol Opt 2013; 33: 267–276.

233.

Walline

Walker

Mutti

, et al. Effect of high add power, medium add power, or single-vision contact lenses on myopia progression in children: The BLINK Randomized Clinical Trial. JAMA 2020; 324: 571–580.

234.

Choo

Caroline

Harlin

, et al. Morphologic changes in cat epithelium following continuous wear of orthokeratology lenses: a pilot study. Cont Lens Anterior Eye 2008; 31: 29–37.

235.

Queiros

Amorim-de-Sousa

Lope-Ferreira

, et al. Relative peripheral refraction across 4 meridians after orthokeratology and LASIK surgery. Eye Vis (Lond) 2018; 5: 12.

236.

Smith

III . Prentice award lecture 2010: a case for peripheral optical treatment strategies for myopia. Optom Vis Sci 2011; 88: 1029–1044.

237.

Hiraoka

Kakita

Okamoto

, et al. Influence of ocular wavefront aberrations on axial length elongation in myopic children treated with overnight orthokeratology. Ophthalmology 2015; 122: 93–100.

238.

Tarrant

Spherical aberration, accommodation and myopia. PhD Thesis, University of California, Berkeley, CA, 2010.

239.

Han

, et al. A comparison of the effects of orthokeratology lens, medcall lens, and ordinary frame glasses on the accommodative response in myopic children. Eye Contact Lens 2018; 44: 268–271.

240.

Chen

Xue

Zhou

, et al. Effects of orthokeratology on choroidal thickness and axial length. Optom Vis Sci 2016; 93: 1064–1071.

241.

Tang

, et al. Orthokeratology for myopia control: a meta-analysis. Optom Vis Sci 2015; 92: 252–257.

242.

Sun

Zhang

, et al. Orthokeratology to control myopia progression: a meta-analysis. PLoS One 2015; 10: e0124535.

243.

Huang

Wen

Wang

, et al. Efficacy comparison of 16 interventions for myopia control in children: a network meta-analysis. Ophthalmology 2016; 123: 697–708.

244.

Cho

Cheung

Edwards

The longitudinal orthokeratology research in children (LORIC) in Hong Kong: a pilot study on refractive changes and myopic control. Curr Eye Res 2005; 30: 71–80.

245.

Walline

Jones

Sinnott

LT.

Corneal reshaping and myopia progression. Br J Ophthalmol 2009; 93: 1181–1185.

246.

Kakita

Hiraoka

Oshika

Influence of overnight orthokeratology on axial elongation in childhood myopia. Invest Ophthalmol Vis Sci 2011; 52: 2170–2174.

247.

Cho

Cheung

S-W.

Retardation of myopia in orthokeratology (ROMIO) study: a 2-year randomized clinical trial. Invest Ophthalmol Vis Sci 2012; 53: 7077–7085.

248.

Hiraoka

Kakita

Okamoto

, et al. Long- term effect of overnight orthokeratology on axial length elongation in childhood myopia: a 5-year follow-up study. Invest Ophthalmol Vis Sci 2012; 53: 3913–3919.

249.

Santodomingo-Rubido

Villa-Collar

Gilmartin

, et al. Myopia control with orthokeratology contact lenses in Spain: refractive and biometric changes. Invest Ophthalmol Vis Sci 2012; 53: 5060–5065.

250.

Charm

Cho

High myopia-partial reduction ortho-k: a 2-year randomized study. Optom Vis Sci 2013; 90: 530–539.

251.

Chen

Cheung

Cho

Myopia control using toric orthokeratology (TO-SEE study). Invest Ophthalmol Vis Sci 2013; 54: 6510–6517.

252.

Zhu

Feng

, et al. The control effect of orthokeratology on axial length elongation in Chinese children with myopia. BMC Ophthalmol 2014; 14: 141.

253.

Yoo

The effect of orthokeratology on axial length elongation in children with myopia: contralateral comparison study. Jpn J Ophthalmol 2018; 62: 327–334.

254.

Santodomingo-Rubido

Villa-Collar

Gilmartin

, et al. Factors preventing myopia progression with orthokeratology correction. Optom Vis Sci 2013; 90: 1225–1236.

255.

Lipson

Brooks

Koffler

BH.

The role of orthokeratology in myopia control: a review. Eye Contact Lens 2018; 44: 224–230.

256.

Wang

Naidu

Factors related to axial length elongation and myopia progression in orthokeratology practice. PLoS One 2017; 12: e0175913.

257.

Zhong

Chen

Xue

, et al. Corneal power change is predictive of myopia progression in orthokeratology. Optom Vis Sci 2014; 91: 404–411.

258.

Chen

Niu

Xue

, et al. Impact of pupil diameter on axial growth in orthokeratology. Optom Vis Sci 2012; 89: 1636–1640.

259.

Lee

Wang

Chiu

CJ.

Effect of orthokeratology on myopia progression: twelve-year results of a retrospective cohort study. BMC Ophthalmol 2017; 17: 243.

260.

Chen

, et al. Higher spherical equivalent refractive errors is associated with slower axial elongation wearing orthokeratology. Cont Lens Anterior Eye 2016; 39: 62–66.

261.

Kim

Lim

Han

, et al. Predictive factors associated with axial length growth and myopia progression in orthokeratology. PLoS One 2019; 14: e0218140.

262.

Cho

Cheung

SW.

Discontinuation of orthokeratology on eyeball elongation (DOEE). Cont Lens Anterior Eye 2017; 40: 82–87.

263.

Lee

Cho

Discontinuation of orthokeratology and myopic progression. Optom Vis Sci 2010; 87: 1053–1056.

264.

Santodomingo-Rubido

Villa-Collar

Gilmartin

, et al. Long-term efficacy of orthokeratology contact lens wear in controlling the progression of childhood myopia. Curr Eye Res 2017; 42: 713–720.

265.

Liu

Xie

The safety of orthokeratology-a systematic review. Eye Contact Lens 2016; 42: 35–42.

266.

Stapleton

Keay

Edwards

, et al. The incidence of contact lens-related microbial keratitis in Australia. Ophthalmology 2008; 115: 1655–1662.

267.

Bullimore

Sinnott

Lones-Jordan

LA.

The risk of microbial keratitis with overnight corneal reshaping lenses. Optom Vis Sci 2013; 90: 937–944.

268.

Wen

Huang

Chen

, et al. Efficacy and acceptability of orthokeratology for slowing myopic progression in children: a systematic review and meta-analysis. J Ophthalmol 2015; 2015: 360806.

269.

Sankaridurg

Bakaraju

Naduvilath

, et al. Myopia control with novel central and peripheral plus contact lenses and extended depth of focus contact lenses: 2 year results from a randomised clinical trial. Ophthalmic Physiol Opt 2019; 39: 294–307.

270.

Wagner

Ohlendorf

Schaeffel

, et al. Reducing the lag of accommodation by auditory biofeedback: a pilot study. Vision Res 2016; 129: 50–60.

271.

Wagner

Schaeffel

Troilo

Changing accommodation behaviour during multifocal soft contact lens wear using auditory biofeedback training. Sci Rep 2020; 10: 1–10.

272.

Cristaldi

Olivieri

Pezzino

, et al. Atropine differentially modulates ECM production by ocular fibroblasts, and its ocular surface toxicity is blunted by colostrum. Biomedicines 2020; 8: 78.

273.

Schwahn

Kaymak

Schaeffel

Effects of atropine on refractive development, dopamine release, and slow retinal potentials in the chick. Vis Neurosci 2000; 17: 165–176.

274.

Cavallotti

Pescosolido

Artico

, et al. Localization of dopamine receptors in the rabbit cornea. Cornea 1999; 18: 721–728.

275.

Grüb

Mielke

Rohrbach

, et al. Dopamine receptors of the corneal epithelium and endothelium in German. Klin Monbl Augenheilkd 2012; 229: 822–825.

276.

Gong

Janowski

Liu

. Low-dose atropine for myopia control: considering all the data. comment and response. In reply. JAMA Ophthalmol 2018; 136: 303–304.

277.

Chua

Balakrishnan

Chan

, et al. Atropine for the treatment of childhood myopia. Ophthalmology 2006; 113: 2285–2291.

278.

Chia

Chua

Cheung

, et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (atropine for the treatment of myopia 2). Ophthalmology 2012; 119: 347–354.

279.

Yam

Jiang

Tang

, et al. Low-concentration atropine for myopia progression (LAMP) study: a randomized, double-blinded, placebo-controlled trial of 0.05%, 0.025%, and 0.01% atropine eye drops in myopia control. Ophthalmology 2019; 126: 113–124.

280.

Tong

Huang

Koh

, et al. Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. Ophthalmology 2009; 116: 572–579.

281.

Chia

Chua

Wen

, et al. Atropine for the treatment of childhood myopia: changes after stopping atropine 0.01%, 0.1% and 0.5%. Am J Ophthalmol 2014; 157: 451–457.

282.

Chia

Tan

Five-year clinical trial on atropine for the treatment of myopia 2: myopia control with atropine 0.01% eyedrops. Ophthalmology 2016; 123: 391–399.

283.

Bullimore

Berntsen

DA.

Low-dose atropine for myopia control: considering all the data. JAMA Ophthalmol 2018; 136: 303.

284.

Bullimore

Richdale

Myopia control 2020: where are we and where are we heading?

Ophthalmic Physiop Opt 2020; 40: 254–270.

285.

Brennan

Toubouti

Cheng

, et al. Efficacy in myopia control. Prog Retin Eye Res. Epub ahead of print 27 November 2020. DOI: 10.1016/j.preteyeres.2020.100923.

286.

Yam

Zhang

, et al. Two-year clinical trial of the low-concentration atropine for myopia progression (LAMP) study: phase 2 report. Ophthalmology 2020; 127: 910–919.

287.

Yang

Fang

PC.

The long-term results of using low-concentration atropine eye drops for controlling myopia progression in schoolchildren. J Ocul Pharmacol Ther 2011; 27: 461–466.

288.

Loh

Tan

, et al. Risk factors for progressive myopia in the atropine therapy for myopia study. Am J Ophthalmol 2015; 159: 945–949.

289.

Zhu

, et al. Efficacy and safety of 1% atropine on retardation of moderate myopia progression in Chinese school children. Int J Med Sci 2020; 17: 176–181.

290.

Brodstein

Olson

, et al. The treatment of myopia with atropine and bifocals. A long-term prospective study. Ophthalmology 1984; 91: 1373–1379.

291.

Kennedy

Dyer

Kennedy

, et al. Reducing the progression of myopia with atropine: a long term cohort study of Olmsted County students. Binocul Vis Strabismus Q 2000; 15(3 Suppl): 281–304.

292.

Syniuta

Isenberg

SJ.

Atropine and bifocals can slow the progression of myopia in children. Binocul Vis Strabismus Q 2001; 16: 203–208.

293.

Polling

Kok

Tideman

JWL

, et al. Effectiveness study of atropine for progressive myopia in Europeans. Eye 2016; 30: 998–1004.

294.

Diaz-Llopis

Pinazo-Durán

MD.

Superdiluted atropine at 0.01% reduces progression in children and adolescents. A 5 year study of safety and effectiveness. Arch De la Soc Esp De Oftalmol (Engl Ed) 2018; 93: 182–185.

295.

Polling

Tan

Driessen

, et al. A 3-year follow-up study of atropine treatment for progressive myopia in Europeans. Eye (Lond) 2020; 34: 2020–2028.

296.

Shih

Chen

Chou

, et al. Effects of different concentrations of atropine on controlling myopia in myopic children. J Ocul Pharmacol Ther 1999; 15: 85–90.

297.

Gong

Janowski

Luo

, et al. Efficacy and adverse effects of atropine in childhood myopia: a meta-analysis. JAMA Ophthalmol 2017; 135: 624–630.

298.

North

Kelly

ME.

A review of the uses and adverse effects of topical administration of atropine. Ophthalmic Physiol Opt 1987; 7: 109–114.

299.

Tan

Lam

Chua

, et al. One-year multicenter, double- masked, placebo-controlled, parallel safety and efficacy study of 2% pirenzepine ophthalmic gel in children with myopia. Ophthalmology 2005; 112: 84–91.

300.

Siatkowski

Cotter

Crockett

, et al. Two-year multicenter, randomized, double-masked, placebo-con- trolled, parallel safety and efficacy study of 2% pirenzepine ophthalmic gel in children with myopia. J AAPOS 2008; 12: 332–339.

301.

Hung

Arumugab

Ostrin

, et al. The adenosine receptor antagonist, 7-methylxanthine, alters emmetropizing responses in infant macaques. Invest Opthalmol Vis Sci 2018; 59: 472–486.

302.

Trier

Munk Ribel-Madsen

Cui

, et al. Systemic 7-methylxanthine in retarding axial eye growth and myopia progression: a 36-month pilot study. J Ocul Biol Dis Infor 2008; 1: 85–93.

303.

Singh

Sahajpal

Singh

, et al. Pre-clinical and cellular toxicity evaluation of 7-methylxanthine: an investigational drug for the treatment of myopia. 2019; 12: 1–10.

304.

El-Nimri

Wildsoet

CF.

Effects of topical latanoprost on intraocular pressure and myopia progression in young guinea pigs. Invest Ophthalmol Vis Sci 2018; 59: 2644–2651.

305.

Carr

Nguyen

Stell

WK.

Alpha 2-adrenoceptor agonists inhibit form-deprivation myopia in the chick. Clin Exp Optom 2019; 102: 418–425.

306.

Tkatchenko

AV.

Pharmacogenomic approach to antimyopia drug development: pathways lead the way. Trends Pharmacol Sci 2019; 40: 833–852.

307.

Huang

Duan

Posterior scleral reinforcement to prevent progression of high myopia. Asia Pac J Ophthalmol 2019; 8: 366–370.

308.

Xue

Bao

Zheng

, et al. Posterior scleral reinforcement on progressive high myopic young patients. Optom Vis Sci 2014; 91: 412–418.

309.

Yang

, et al. Posterior scleral reinforcement for the treatment of pathological myopia. Int J Ophthalmol 2016; 9: 580–584.

310.

Ward

Tarutta

Mayer

MJ.

The efficacy and safety of posterior pole buckles in the control of progressive high myopia. Eye 2009; 23: 2169–2174.

311.

Coroneo

Beaumont

Hollows

FC.

Scleral reinforcement in the treatment of pathologic myopia. Aust N Z J Ophthalmol 1988; 16: 317–320.

312.

Dong

Liu

The efficacy of modified posterior scleral reinforcement with round scleral patches in Chinese children with high myopia. Graefes Arch Clin Exp Ophthalmol 2020; 258: 1543–1547.

313.

Pan

, et al. The efficacy of posterior scleral contraction in controlling high myopia in young people. Am J Trans Les 2018; 10: 3628–3634.

314.

Xue

Zheng

Tan

, et al. Genipin-crosslinked donor sclera for posterior scleral contraction/reinforcement to fight progressive myopia. Invest Ophthalmol Vis Sci 2018; 59: 3564–3573.

315.

Park

Gole

GA.

Corticosteroid-induced glaucoma in a child after a scleral reinforcement procedure. Clin Exp Ophthalmol 2002; 30: 372–374.

316.

Golychev

Medvetskaia

Golubeva

, et al. Our experience with the use of sclera-strengthening injections in the prevention of progressive myopia [in German]. Vestnik Oftalmologii 1989; 105: 26–27.

317.

Avetisov

Tarutta

Iomdina

, et al. Nonsurgical and surgical methods of sclera reinforcement in progressive myopia. Acta Ophthalmol Scand 1997; 75: 618–623.

318.

Chen

Zhang

, et al. The aquaporin-1 depletion downregulates the sclera biomechanical strength. Curr Eye Res 2020; 20: 1–5.

319.

Janowski

Bulte

Handa

, et al. Concise review: using stem cells to prevent the progression of myopia-a concept. Stem Cells 2015; 33: 2104–2113.

320.

Dotan

Kremer

Livnat

, et al. Scleral cross-linking using riboflavin and ultraviolet-a radiation for prevention of progressive myopia in a rabbit model. Exp Eye Res 2014; 127: 190–195.

321.

Wollensak

Iomdina

Dittert

, et al. Cross-linking of scleral collagen in the rabbit using riboflavin and UVA. Acta Ophthalmol Scand 2005; 83: 477–482.

322.

Saw

Matsumura

Hoang

QV.

Prevention and Management of Myopia and Myopic Pathology. Invest Ophthalmol Vis Sci 2019; 60: 488–499.

323.

Kim

Choi

, et al. Effects of scleral collagen crosslinking with different carbohydrate on chemical bond and ultrastructure of rabbit sclera: future treatment for myopia progression. PLoS One 2019; 14: e0216425.

324.

Leshno

Farzavandi

Gomez-de-Liano

, et al. Practice patterns to decrease myopia progression differ among paediatric ophthalmologists around the word. Br J Ophthalmol 2020; 104: 535–540.

325.

Kinoshita

Konno

Hamada

, et al. Additive effects of orthokeratology and atropine 0.01% ophthalmic solution in slowing axial elongation in children with myopia: first year results. Jpn J Ophthalmol 2018; 62: 544–553.

326.

Tan

Ng A

Cheng

GPM

. Combined atropin with orthokeratology for myopia control: study design and preliminary results. Curr Eye Res 2019; 44: 671–678.

327.

Chen

Huang

Zhou

, et al. Adjunctive effect of orthokeratology and low dose atropine on axial elongation in fast-progressing myopic children-a preliminary retrospective study. Cont Lens Anterior Eye 2019; 42: 439–442.

328.

Wan

Wei

C-C

Chen

, et al. The synergistic effects of orthokeratology and atropine in slowing the progression of myopia. J Clin Med 2018; 7: 259.

329.

Tan

Choy

, et al. One-year results of 0.01% atropine with orthokeratology (AOK) study: a randomised clinical trial. Ophthalmic Physiol Opt 2020; 40: 557–566.

330.

Sánchez-González

De-Hita-Cantalejo

Baustita-Llamas

, et al. The combined effect of low-dose atropine with orthokeratology in pediatric myopia control: review of the current treatment status for myopia. J Clin Med 2020; 9: 2371.

331.

Shih

Hsiao

Chen

, et al. An intervention trial on efficacy of atropine and multi-focal glasses in controlling myopic progression. Acta Ophthalmol Scand 2001; 79: 233–236.

332.

Huang

Mutti

Jones-Jordan

, et al. Bifocal & atropine in myopia study: baseline data and methods. Optom Vis Sci 2019; 96: 335–344.

333.

Hui

Bajgrowitz-Cieslak

Phan

, et al. In vitro release of two anti-muscarinic drugs from soft contact lenses. Clin Ophthalmol 2017; 11: 1657–1665.

334.

Michaud

Myopia management: how to get started. Contact Lens Spectrum 2020; 1: 25–30.

335.

Zhu

Wang

Yang

, et al. Pre- and postcycloplegic refractions in children and adolescents. PLoS One 2016; 11: e0167628.

336.

Zadnik

Sinnott

Cotter

, et al. Prediction of juvenile-onset myopia. JAMA Ophthalmol 2015; 133: 683–689.

337.

Klaver

Polling

and Erasmus Myopia Research Group. Myopia management in the Netherlands. Ophthalmic Physiol Opt 2020; 40: 230–240.

338.

McCullough

Adamson

Breslin

KMM

, et al. Axial growth and refractive change in white European children and young adults: predictive factors for myopia. Sci Rep 2020; 10: 15189.

339.

Gifford

Richdale

Kang

, et al. IMI-clinical management guidelines report. Invest Ophthtlmol Vis Sci 2019; 60: M184–M203.

340.

Kang

, et al. Near work related parameters and myopia in Chinese children: the Anyang Childhood Eye Study. PLoS One 2015; 10: e0134514.

341.

Charman

WN.

Myopia, posture and the visual environment. Ophthalmic Physiol Opt 2011; 31: 494–501.

342.

Guo

Yang

Mai

, et al. Prevalence and associated factors of myopia among primary and middle school-aged students: a school-based study in Guangzhou. Eye 2016; 30: 796–804.

343.

Pärssinen

Kauppinen

Associations of reading posture, gaze angle and reading distance with myopia and myopic progression. Acta Ophthalmol 2016; 94: 775–779.

344.

French

Morgan

Mitchell

, et al. Risk factors for incident myopia in Australian schoolchildren: the Sydney adolescent vascular and eye study. Ophthalmology 2013; 120: 2100–2108.

345.

Guggenheim

Northstone

McMahon

, et al. Time outdoors and physical activity as predictors of incident myopia in childhood: a prospective cohort study. Invest Ophthalmol Vis Sci 2012; 53: 2856–2865.

346.

Lim

Gazzard

Low

, et al. Dietary factors, myopia, and axial dimensions in children. Ophthalmology 2010; 117: 993–997.

347.

VanderVeen

Kraker

Pineles

, et al. Use of orthokeratology for the prevention of myopic progression in children: a report by the American Academy of Ophthalmology. Ophthalmology 2019; 126: 623–636.

348.

Marcotte-Collard

Simard

Michaud

Analysis of two orthokeratology lens designs and comparison of their optical effects on the cornea. Eye Contact Lens 2018; 44: 322–329.

349.

Gifford

Tran

Priestley

, et al. Reducing treatment zone diameter in orthokeratology and its effect on peripheral ocular refraction. Cont Lens Anterior Eye 2020; 43: 54–59.

350.

Smith

III . Optical treatment strategies to slow myopia progression: effects of the visual extent of the optical treatment zone. Exp Eye Res 2013; 114: 77–88.

351.

Jones

Drobe

González-Méijome

, et al. IMI-industry guidelines and ethical considerations for myopia control report. Invest Ophthtlmol Vis Sci 2019; 28; 60: 161–183.

352.

Pineles

Kraker

VanderVeen

, et al. Atropine for the prevention of myopia progression in children: a report by the American Academy of Ophthalmology. Ophthalmology 2017; 124: 1857–1866.

353.

Chia

Tay

SA.

Clinical management and control of myopia in children. In: Ang

Wong

(eds) Updates on myopia. A clinical perspective. 1st ed. Singapore: Springer, 2020, pp.187–200.

354.

Wong

Machin

Tan

, et al. Ocular component growth curves among Singaporean children with different refractive error status. Invest Ophthalmol Vis Sci 2010; 51: 1341–1347.

355.

Zadnik

Mutti

DO.

Refractive error changes in law students. Am J Optom Physiol Opt 1987; 64: 558–561.

356.

Kinge

Midelfart

Refractive errors among engineering students in Norway. Ophthalmic Epidemiol 1994; 1: 5–13.

357.

Zhang

Pattern of myopia progression in Chinese medical students: a two-year follow-up study. Graefes Arch Clin Exp Ophthalmol 2013; 251: 163–168.

358.

Ganesan

Wildsoet

CF.

Pharmaceutical intervention for myopia control. Expert Rev Ophthalmol 2010; 5: 759–787.

359.

Cheng

Chehab

, et al. Soft contact lenses with positive spherical aberration for myopia control. Optom Vis Sci 2016; 93: 353–366.

360.

Aller

TA.

Clinical management of progressive myopia. Eye 2014; 28: 147–153.

361.

Walline

Greiner

McVey

, et al. Multifocal contact lens myopia control. Optom Vis Sci 2013; 90: 1207–1214.

362.

Fulk

Cyert

Parker

. A randomized trial of the effect of single-vision vs. bifocal lenses on myopia progression in children with esophoria. Optom Vis Sci 2000; 77: 395–401.

363.

Cheng

Schmid

Woo

, et al. Randomized trial of effect of bifocal and prismatic bifocal spectacles on myopic progression: two-year results. Arch Ophthalmol 2010; 128: 12–19.

364.

Zhu

Liu

Tighe

, et al. Retardation of myopia progression by multifocal soft contact lenses. Int J Med Sci 2019; 16: 198–202.