# Updates on Myopia

A Clinical Perspective Marcus Ang Tien Y. Wong *Editors*

Updates on Myopia

Marcus Ang • Tien Y. Wong Editors

## Updates on Myopia

A Clinical Perspective

*Editors* Marcus Ang Singapore National Eye Center Duke-NUS Medical School National University of Singapore Singapore

Tien Y. Wong Singapore National Eye Center Duke-NUS Medical School National University of Singapore Singapore

This book is an open access publication. ISBN 978-981-13-8490-5 ISBN 978-981-13-8491-2 (eBook) https://doi.org/10.1007/978-981-13-8491-2

© The Editor(s) (if applicable) and The Author(s) 2020, corrected publication 2020

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### **Preface**

Myopia is now being recognized as a signifcant global public health problem that will affect billions of people in the next decades, especially in Asia. Currently, pathologic myopia is already a major cause of visual impairment in both Asian and Western populations. As the prevalence of myopia and pathological myopia increases around the world, there is increasing need for active prevention of myopia progression and management of its potential complications.

The purpose of this book is to provide updates on current understanding of myopia, new methods of evaluation of the myopic eye, and a focus on clinical management of myopia and its complications. This book will provide a unique perspective from the current world experts on the subject, with a focus on clinical aspects of understanding, evaluation, and management of myopia.

Chapter 1 provides a concise summary of all the key points from the book for busy readers who want a quick overview on clinical myopia. The rest of the book is comprehensive and provides updates on almost all aspects with regard to myopia. Chapters 2 and 3 describe epidemiology and economic burden; Chaps. 4 and 5 discuss genetic and pathogenetic mechanisms; Chaps. 6 to 8 describe risk factors and ways to prevent myopia development or progression. Next, Chaps. 9 and 10 discuss pathological myopia and advances (and challenges) in imaging myopic eyes. Finally, Chaps. 11 to 14 provide clinical pearls of managing myopia complications, i.e., glaucoma, retina, and choroidal neovascularization in adults.

As new data is constantly emerging, this book was generated with the inputs of all authors within 6 months to ensure that the evidence shared is as current as possible. Thus, it is important to keep updated with online material and literature review. Nonetheless, we hope you will fnd this book as a useful reference for optometry students, ophthalmology residents, and eye care professionals to have a comprehensive update on myopia with a clinical perspective.

Singapore, Singapore Marcus Ang Singapore, Singapore Tien Y. Wong

## **Acknowledgments**

Singapore National Eye Centre, Singapore

Singapore Eye Research Institute, Singapore

Duke National University of Singapore (DUKE NUS), Singapore

Singapore National Eye Centre Myopia Centre, Singapore

## **Contents**

## **About the Editors**

**Marcus Ang** is consultant ophthalmologist at the Corneal and External Eye Disease Department of the Singapore National Eye Center (SNEC) and Duke-NUS Medical School, National University of Singapore, as well as Clinical Director of the SNEC Myopia Centre. His clinical and research areas of expertise include the treatment, and prevention of visual impairment in adult myopia. He also has special research interests in corneal transplantation, such as Descemet membrane endothelial keratoplasty (DMEK) and anterior segment imaging including novel optical coherence tomography systems for the cornea. Dr. Ang has published over 120 peer-reviewed articles journals, coauthored several book chapters on corneal transplantation, and received numerous international awards.

**Tien Y. Wong** is Arthur Lim Professor in Ophthalmology and Medical Director at the Singapore National Eye Center (SNEC). He is concurrently Academic Chair of Ophthalmology and Vice-Dean of Duke-NUS Medical School, National University of Singapore. Prior to his current appointments, Prof. Wong was Executive Director of the Singapore Eye Research Institute; Chairman of the Department of Ophthalmology, National University of Singapore; Chairman of the Department of Ophthalmology at the University of Melbourne; and Managing Director of the Centre for Eye Research Australia, Australia. Professor Wong is a retinal specialist, whose clinical practice focuses on major retinal diseases. His research covers epidemiological, clinical, and translational studies of eye diseases, including epidemiology and risk factors of myopia, imaging in myopic macular degeneration, and clinical trials on treatment of myopic choroidal neovascularization. He has published more than 1000 papers in peer-reviewed journals, including the *New England Journal of Medicine* and the *Lancet*. Prof. Wong has received a number of national and international awards.

## **1 Introduction and Overview on Myopia: A Clinical Perspective**

Chee Wai Wong, Noel Brennan, and Marcus Ang

#### **Key Points**

C. W. Wong · M. Ang (\*) Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore

Duke-NUS Medical School, Singapore, Singapore e-mail<EMAIL_ADDRESS>
N. Brennan R&D, Johnson & Johnson Vision Care, Inc, Jacksonville, FL, USA

#### **1.1 Global Epidemiology**

Myopia has become a signifcant global public health and socioeconomic problem [1–4]. East Asia, and other parts of the world to a lesser extent, has been faced with an increasing prevalence of myopia [5, 6]. The prevalence of myopia and high myopia (HM) (the defnition of myopia and HM is spherical equivalence (SE) of −0.50 diopters (D) or less and SE −5.00 D or −6.00 D, respectively) in young adults in urban areas of East Asian countries has risen to 80–90% and around 20%, respectively [7, 8]. According to a summary of 145 studies regarding the global prevalence of myopia and HM, there are approximately 1950 million with myopia (28.3% of the global population) and 277 million with HM (4.0% of the global population), and these numbers are predicted to increase to 4758 million (49.8% of the global population) for myopia, and 938 million (9.8% of the global population) for HM by 2050 [9].

The prevalence of childhood myopia is substantially higher in urban East Asian countries (49.7–62.0% among 12-year-old children) [7, 10] compared with other countries (6.0–20.0% among 12-year-old children) [9]. Similarly, in teenagers and young adults, the prevalence of myopia is higher in East Asian countries (65.5– 96.5%) [8] compared with other countries (12.8–35.0%) [9]. However, the geographic difference of myopia prevalence in older populations is less than that in younger populations. The prevalence rates of myopia in adults in urban East Asian countries are only slightly higher than in Western countries.

The prevalence of myopia has remained consistently high among Chinese children in urban settings, but the evidence does not support the idea that it is caused by purely genetic difference [10]. The association of an urbanized setting with high myopia rates is likely to be infuenced by possible modifable risk factors such as near work and outdoor time.

Despite the relatively low prevalence in the general population, pathologic myopia (PM) is a major cause of blindness or visual impairment in both Asian and Western populations. One study has shown that the prevalence of PM was 28.7% among high myopes and 65% of those with HM and were over 70 years old had PM [11]. Based on the global prediction of HM on 2050, PM may increase to over 200 million in future [9]. Treatment strategies against PM have not been effective [12].

Generational differences in prevalence are seen with the highest rates in young adults (myopia 65.5–96.5% and HM 6.8–21.6%) and the lowest rates in older adults (myopia 25.0–40.0% and HM 2.4–8.2%). The disease progression pattern of HM and subsequent development of PM may be different between young adults and older adults due to generational differences, or changes in the lifestyle factors such as the education system, near work, and outdoor time exposure in rapidly developing urban Asian countries.

#### **1.2 Pathogenesis of Myopia**

**Ocular Biometric Changes in Human Myopia** The axial length of the eye or, more precisely, the vitreous chamber depth is the primary individual biometric contributor to refractive error in children, young adults, and the elderly [13–15], with the vitreous chamber depth accounting for over 50% of the observed variation in spherical equivalent refractive error (SER), followed by the cornea (~15%) and crystalline lens (~1%) [15]. However, the dimensions, curvature, and refractive index of each individual ocular structure contribute to the fnal refractive state. The choroid is typically thinner in myopic compared to non-myopic eyes (most pronounced at the fovea [16, 17]) and thins with increasing myopia and axial length in both adults [18–25] and children [26–28]. Signifcant choroidal thinning is also observed in eyes with posterior staphyloma [29], and has been associated with the presence of lacquer cracks [30], choroidal neovascularization [31], and reduced visual acuity [32]. The choroid also appears to be a biomarker of ocular processes regulating eye growth given that the central macular choroid thins during the initial development and progression of myopia [33–35] and thickens in response to imposed peripheral myopic retinal image defocus [36, 37], topical anti-muscarinic agents [38, 39], and increased light exposure [40]; clinical interventions associated with a slowing of eye growth in children.

**Visual Environment, Emmetropization, and Myopia** Much of the knowledge on vision-dependent changes in ocular growth has emanated from animal experiments in which either the quality of image formed on the retina is degraded (known as form deprivation [FD]), or the focal point of the image is altered with respect to the retinal plane (known as lens defocus). Both FD and lens defocus result in abnormal eye growth and development of refractive errors.

**Monochromatic Higher-Order Aberrations as a Myopigenic Stimulus** Myopia may develop due to the eye's emmetropization response to inherent ocular aberrations that degrade retinal image quality and trigger axial elongation [41]. Evidence concerning the relationship between higher order abberation (HOAs) during distance viewing and refractive error from cross-sectional studies is conficting [41, 42]. However, during or following near-work tasks, adult myopic eyes tend to display a transient increase in corneal and total ocular HOAs, suggesting a potential role for near-work-induced retinal image degradation in myopia development [43, 44]. Longitudinal studies of myopic children also indicate that eyes with greater positive spherical aberration demonstrate slower eye growth [45, 46].

**Accommodation** Given the association between near work and the development and progression of childhood myopia [47], numerous studies have compared various characteristics of accommodation between refractive error groups. Typically, this involves the accuracy of the accommodation response, since lag of accommodation (hyperopic retinal defocus) may stimulate axial elongation as observed in some animal models. The slowing of myopia progression during childhood with progressive addition or bifocal lenses, designed to improve accommodation accuracy and minimize lag of accommodation, adds some weight to the role of accommodation in myopia development and progression [48, 49]. However, the exact underlying mechanism of myopia control with such lenses may be related to imposed peripheral retinal defocus or a reduction in the near vergence demand [50]. Certainly, elevations in measured lag observed in myopes arise after rather than before onset [51].

#### **1.3 Key Environmental Factors on Myopia**

**Near work and education**: Many studies have established a strong link between myopia and education [52–57]. Moreover, Mountjoy et al. have shown that exposure to longer duration of education was a causal risk factor for myopia [53]. The exact mechanism linking increased education with myopia is unclear. Although it is possible that optical [43, 58] or biomechanical [59, 60] ocular changes associated with near work could potentially promote myopic eye growth in those with higher levels of education (and hence near-work demands), population studies examining the link between near-work activities and myopia have been conficting, with some studies suggesting an association between near work and myopia [47, 61], and others indicating no signifcant effects [62]. The relatively inconsistent fndings linking near work with myopia development suggests a potential role for other factors in the association between education and myopia.

**Outdoor Activity** A number of recent studies report that the time children spend engaged in outdoor activities is negatively associated with their risk of myopia [62–68]. Both cross-sectional and longitudinal studies indicate that greater time spent outdoors is associated with a signifcantly lower myopia prevalence and reduced risk of myopia onset in childhood. Although some studies report signifcant associations between myopia progression and outdoor activity [66, 68], this is not a consistent fnding across all longitudinal studies [69]. A recent meta-analysis of studies examining the relationship between outdoor time and myopia indicated that there was a 2% reduction in the odds of having myopia for each additional hour per week spent outdoors [70].

**Duration of Outdoor Activity and Myopia** In a large longitudinal study, Jones and colleagues [62] reported that children who engaged in outdoor activities for 14 h per week or more exhibited the lowest odds of developing myopia. A number of recent randomized controlled trials have reported that interventions that increase children's outdoor time (by 40–80 min a day) signifcantly reduce the onset of myopia in childhood [71–73]. In the "Role of outdoor activity in myopia study" [74], children who were habitually exposed to low ambient light levels (on average less than 60 min exposure to outdoor light per day) had signifcantly faster axial eye growth compared to children habitually exposed to moderate and high light. These fndings from human studies suggest that children who are exposed to less than 60 min a day of bright outdoor light are at an increased risk of more rapid eye growth and myopia development, and that approximately 2 h or more of outdoor exposure each day is required to provide protection against myopia development in the human eye.

#### **1.4 Genetics of Myopia**

Myopia is highly heritable; genes explain up to 80% of the variance in refractive error in twin studies. For the last decade, genome-wide association study (GWAS) approaches have revealed that myopia is a complex trait, with many genetic variants of small effect infuencing retinal signaling, eye growth, and the normal process of emmetropization. Particularly notable are genes encoding extracellular matrixrelated proteins (COL1A1, COL2A1 [75, 76], and MMP1, MMP2, MMP3, MMP9, MMP10 [77, 78]). For candidates such as PAX6 and TGFB1, the results were replicated in multiple independent extreme/high myopia studies and validated in a large GWAS meta-analysis in 2018, respectively [79, 80]. However, the genetic architecture and its molecular mechanisms are still to be clarifed, and while genetic risk score prediction models are improving, this knowledge must be expanded to have impact on clinical practice.

Gene–environment (GxE) interaction analysis has focused primarily on education. An early study in North American samples examined GxE for myopia and the matrix metalloproteinases genes (MMP1–MMP10): a subset of single nucleotide polymorphism (SNPs) was only associated with refraction in the lower education level [78, 81]. A subsequent study in fve Singapore cohorts found variants in DNAH9, GJD2, and ZMAT4, which had a larger effect on myopia in a high education subset [82]. Subsequent efforts to examine GxE considered the aggregate effects of many SNPs together. A study in Europeans found that a genetic risk score comprising 26 genetic variants was most strongly associated with myopia in individuals with a university level education [83]. A study examining GxE in children considered near work and time outdoors in association with 39 SNPs and found weak evidence for an interaction with near work [83, 84]. Finally, a Consortium for Refractive Error and Myopia (CREAM) study was able to identify additional myopia risk loci by allowing for a GxE approach [85].

Mendelian randomization (MR) offers a better assessment of causality than that available from observational studies [86, 87]. Two MR studies found a causal effect of education on the development of myopia [53, 80]. Both found a larger effect through MR than that estimated from observational studies suggesting that confounding in observational studies may have been obscuring the true relationship [55, 79]. As expected, there was little evidence of myopia affecting education (−0.008 years/ diopter, *P* = 0.6). Another study focused on the causality of low vitamin D on myopia found only a small estimated effect on refractive error [88] suggesting that previous observational fndings were likely confounded by the effects of time spent outdoors.

Due to the high polygenicity of myopia and low explained phenotypic variance by genetic factors (7.8%), clinical applications derived from genetic analyses of myopia are currently limited. Risk predictions for myopia in children are based on family history, education level of the parents, the amount of outdoor exposure, and the easily measurable refractive error and axial length. Currently, we are able to make a distinction between high myopes and high hyperopes based on the polygenic risk scores derived from CREAM studies: persons in the highest decile for the polygenic risk score had a 40-fold greater risk of myopia relative to those in the lowest decile. A prediction model, including age, sex, and polygenic risk score, achieved an area under curve (AUC) of 0.77 (95% CI = 0.75–0.79) for myopia versus hyperopia in adults (Rotterdam Study I–III) [80]. To date, one study has assessed both environmental and genetic factors together and showed that modeling both genes and environment improved prediction accuracy [89].

#### **1.5 Prevention of the Onset of Myopia**

The vast majority of literature suggests that most cases of myopia develop during the school-going age in children. After the age of 6 years, the prevalence of myopia starts to rise [90–94]. The highest annual incidence of myopia is reported among school children from urban mainland China [92] and Taiwan [95], ranging from 20% to 30% through ages 7–14 years, with earlier onset of myopia also being identifed [94]. A study in Japan showed that while the prevalence of myopia has been increasing from 1984 to 1996, the prevalence among children aged 6 or younger has remained unchanged. This suggests that the majority of increased myopia onset is secondary to increased educational intensity [94].

Rates of progression increase dramatically with the year of onset and this has been suggested by spherical equivalent refraction and axial length [96]. Myopic refractions tend to stabilize in late adolescent but can remain progressive until adulthood. The mean age at myopia stabilization is 15.6 years but this can vary among children of different ethnicities [97].

Several factors have been found to be associated with the development of incident myopia in school. Asian ethnicity [93, 98], parental history of myopia [62, 99], reduced time outdoors [62], and level of near-work activity [47, 100] are risk factors for incident myopia, although the evidence can be seen as controversial in some instances.

Evidence of time spent outdoors as a risk factor for myopia progression was frst presented in a 3-year follow-up study of myopia in school children, showing that those who spent more time outdoors were less likely to progress [64]. Consistent results were reported in various studies, such as the Sydney Myopia Study, Orinda Study, as well as the Singapore Cohort Study of Risk Factors for Myopia [63, 65, 101]. This led to the commencement of several clinical trials which confrmed the protective effect and indicated a dose-dependent effect, among them, the randomized clinical trial in Guangzhou which reported that an additional 40 min of outdoor activity can reduce the incidence of myopia by 23% [63]. Additionally, the trial in Taiwan suggested that an extra 80 min may further reduce incidence by 50% [72, 73].

Near-work activity as a risk factor for myopia has not been entirely consistent. A meta-analysis reported a modest, but statistically signifcant, association between time spent performing near work and myopia (odds ratio, 1.14) [47]. Core techniques to implementing interventions of near-work activities include effective measures of near-work-related parameters, real-time data analyses, and alert systems. Wearable devices that possess these techniques have emerged in the last decade.

It has been estimated that without any effective controls or interventions the proportion of myopes in the population will reach up to 50% and 10% for high myopes by 2050 [9]. Approaches that have produced a reduction of at least 50% in incidence, such as time outdoors, lead to delayed onset and have the potential to make a signifcant difference on the impending myopia epidemic.

Another critical issue is the need to balance educational achievement and interventions to prevent myopia progression in East Asia. This balance can be seen in Australia [102], with not only some of the highest educational ranks in the world but also high levels of outdoor activity and light intensity. Preventing the onset of myopia is certainly challenging in the East Asian population and requires a collaborative effort among clinics, schools, parents, and the entire society.

#### **1.6 Understanding Pathologic Myopia**

Pathologic myopia (PM) is a major cause of blindness in the world, especially in East Asian countries [103–107]. The cause of blindness in patients with PM includes myopic maculopathy with or without posterior staphyloma, myopic macular retinoschisis, and glaucoma or glaucoma-like optic neuropathy. The term "pathologic myopia" describes the situation of pathologic consequences of a myopic axial elongation. According to a recent consensus article by Ohno-Matsui et al. [108], pathologic myopia was defned by a myopic chorioretinal atrophy equal to or more serious than diffuse atrophy (by Meta-analysis for pathologic myopia (META-PM) study group classifcation [109]) and/or the presence of posterior staphylomas.

A posterior staphyloma is an outpouching of a circumscribed area of the posterior fundus, where the radius of curvature is less than the curvature radius of the surrounding eye wall [110], and can be associated with, or lead to, vision-threatening complications such as myopic maculopathy [109, 111–114] and myopic optic neuropathy/glaucoma [115, 116]. Based upon and modifying Curtin's [117] classical categorization of posterior staphylomas, with types I–V as primary staphylomas and types VI–X as compound staphylomas, Ohno-Matsui [118] used 3D-magnetic resonance imaging (3D-MRI) and wide-feld fundus imaging to re-classify staphylomas into six types: wide macular, narrow macular, peripapillary, nasal, inferior, and others.

In the META-PM classifcation [109], myopic maculopathy lesions have been categorized into fve categories from "no myopic retinal lesions" (category 0), "tessellated fundus only" (category 1), "diffuse chorioretinal atrophy" (category 2), "patchy chorioretinal atrophy" (category 3), to "macular atrophy" (category 4). These categories were defned based on long-term clinical observations that showed the progression patterns and associated factors of the development of myopic choroidal neovascularization (CNV) for each stage. Three additional features were added to these categories and were included as "plus signs": (1) lacquer cracks, (2) fuch spot and (3) myopic CNV.

Myopic CNV is a major sight-threatening complication of pathologic myopia. It is the most common cause of CNV in individuals younger than 50 years, and it is the second most common cause of CNV overall [119, 120]. Anti-vascular endothelial growth factor (anti-VEGF) therapy is the frst-line treatment for myopic CNV, as shown by the RADIANCE study [121] and the MYRROR study [122].

Panozzo and Mercanti proposed the term "myopic traction maculopathy (MTM)" to encompass various fndings characterized by a traction as visualized by optical coherence tomography (OCT) in highly myopic eyes [123]. A dome-shaped macula (DSM) is an inward protrusion of the macula as visualized by OCT [124–126]. Imamura, Spaide, and coworkers reported that a DSM was associated with, and caused by, a local thickening of the subfoveal sclera [127]. It was postulated that the local thickening of the subfoveal sclera was an adaptive or compensatory response to the defocus of the image on the fovea in highly myopic eyes.

#### **1.7 Imaging in Myopia**

Imaging the myopic eye can be challenging due to various structural changes (abnormal eye elongation, scleral and corneal curvature irregularities, cataracts leading to poor clarity; or retinal thinning causing abnormal projections of the fnal image [128, 129]).

Optic disc imaging can also be used to predict the development of glaucoma, where visualization of myopic tilting of the optic disc with peripapillary atrophy (PPA) and pitting of the optic disc [130] is a possible predisposing factor [131, 132]. Serial imaging investigative measures can therefore be utilized for monitoring the development of open-angle, normal-tension glaucoma [133]. Features such as optic disc tilt, PPA, and abnormally large or small optic discs are the earliest known structural alterations that potentially predict the development of pathological myopia and can be observed even in young highly myopic adults. Unfortunately, these features (some also with associations to glaucoma) also interfere with the visualization of optic disc margins [134, 135] and are also not easy to discern in highly myopic eyes [136]. There is also added diffculty in eyes with myopic maculopathy, where visual feld defects result in further interference [137]. As such, the answer to these challenges may lie in imaging deep optic nerve head structures (such as parapapillary sclera, scleral wall, and lamina cribosa) [138] in highly myopic eyes for more precise diagnoses of glaucoma.

The ability to view distinct retinal layers with OCT has enhanced visualization of myopic traction maculopathy (MTM). Examples of features that can be seen include inner or outer retinal schisis, foveal detachment, lamellar or full-thickness macular hole, and/or macular detachment [139, 140]. Non-stereoscopic fundus photographs are inadequate for detailed studies of posterior staphylomas as the change in contour at the staphyloma edge is not always discernible. The OCT overcomes this limitation because of its excellent depth resolution [141, 142].

The OCT itself has its shortcomings; the sclera cannot be visualized using the OCT. These limitations also extend to the use of OCT angiography (OCTA). There is currently no standard protocol for segmentation; the outcome parameters for OCTA have not been clearly defned either. Although some authors have tried to use analysis of fow voids or signal voids in the choriocapillaris to quantify the area taken up by the microvasculature [143, 144], the data pertaining to myopic patients are but insuffcient [145]. Looking into the future, there is, however, incipient research suggesting that the comprehension of blood supply and changes in vasculature from the anterior to the posterior segment of the myopic eye is crucial to the understanding of the disease [146–149].

Photoacoustic imaging has shown promise recently to fll the gaps between OCT and ultrasound in terms of penetration depth [150]. This modality has been used before to image the posterior pole of the eye in vitro and in animal models *in vivo*. This can also be used in concurrence with angiography, measuring oxygen saturation and pigment imaging [151]. However, there are some limitations pertaining to this modality notwithstanding moderate depth resolution, pure optical absorption sensing, need for contact detection with ultrasound sensor, and a relatively long acquisition time. In view of these limitations, we are yet to receive tangible results from photoacoustic imaging for posterior pole imaging in humans.

#### **1.8 Glaucoma in Myopia**

Axial myopization leads to marked changes of the optic nerve head: (1) an enlargement of all three layers of the optic disc (i.e., optic disc Bruch's membrane opening, optic disc choroidal opening, optic disc scleral opening) with the development of a secondary macrodisc, (2) an enlargement and shallowing of the cup, (3) an elongation and thinning of the lamina cribrosa with a secondary reduction in the distance between the intraocular space with the intraocular pressure (IOP) and the retro-lamina compartment with the orbital cerebrospinal fuid pressure, (4) a direct exposure of the peripheral posterior lamina cribrosa surface to the orbital cerebrospinal fuid space, (5) an elongation and thinning of the peripapillary scleral fange with development and enlargement of the parapapillary gamma zone and delta zone, (6) an elongation and thinning of the peripapillary border tissue of the choroid, and (7) a rotation of the optic disc around the vertical axis, and less often and to a minor degree around the horizontal axis und the sagittal axis. These changes make it more diffcult to differentiate between myopic changes and (additional) glaucomaassociated changes such as a loss of neuroretinal rim and thinning of the retinal nerve fber layer, and these changes may make the optic nerve head more vulnerable, potentially explaining the increased prevalence of glaucomatous optic neuropathy in highly myopic eyes.

Population-based investigations and hospital-based studies have shown that the prevalence of glaucomatous optic neuropathy (GON) was higher in highly myopic eyes than in emmetropic eyes [152–166]. A previous study revealed that at a given IOP in patients with chronic open-angle glaucoma, the amount of optic nerve damage was more marked in highly myopic eyes with large optic discs than in nonhighly myopic eyes [165].

Highly myopic glaucomatous eyes as compared with non-highly myopic glaucomatous eyes may have a markedly lower IOP threshold to develop optic nerve damage. It could indicate that an IOP of perhaps lower than 10 mmHg might be necessary to prevent the development of GON in these highly myopic eyes, and that in highly myopic eyes with axial elongation-associated enlargement and stretching of the optic disc and parapapillary region as the main risk factors for GON in high myopia a normal IOP may be suffcient to lead to GON [136].

Although it has not yet been frmly proven that GON in high myopia is dependent on IOP, most researchers recommend lowering IOP in highly myopic patients with glaucoma. Based on the morphological fndings described above, the target pressure in highly myopic glaucoma may be lower than in non-highly myopic glaucoma. Due to the peculiar anatomy of the optic nerve head in highly myopic eyes, most diagnostic procedures fail in precisely assessing the status of the optic nerve in highly myopic eyes with glaucoma. It includes factors such as a decreased spatial and color contrast between the neuroretinal rim and the optic cup making a delineation of both structures more diffcult; a peripapillary retinoschisis leading to an incorrect segmentation of the retinal nerve fber layer upon optical coherence tomography; a large gamma zone (and delta zone) which makes using the end of Bruch's membrane as reference point for the measurement of the neuroretinal rim useless; and macular Bruch's membrane defects and other reasons for nonglaucomatous visual feld defects which reduces the diagnostic precision of perimetry for the detection of presence and progression of GON.

#### **1.9 Management of Myopic Choroidal Neovascularization**

Myopic choroidal neovascularization (myopic CNV) is the second most common cause of CNV after age-related macular degeneration (AMD) [167, 168]. It is one of the most sight-threatening complications of pathological myopia [119, 169] and is the most common cause of CNV in those 50 years or younger [167], with signifcant social and economic burden. The prevalence of myopic CNV is between 5.2% and 11.3% in individuals with pathological myopia [12], with female preponderance seen in most studies [167–170]. The long-term outcome of CNV is poor if left untreated. In a 10-year follow-up study of 25 patients with myopic CNV, visual acuity deteriorated to 20/200 or worse in 89% and 96% of eyes in 5 years and 10 years, respectively [168].

On slit-lamp biomicroscopy, myopic CNV manifests as a small, fat, grayish subretinal lesion adjacent to or beneath the fovea [109, 168, 169, 171]. On SD-OCT, myopic CNV presents as a hyper-refective material above the retinal pigment epithelium band (type 2 CNV), with variable amount of subretinal fuid. Clinical diagnosis is confrmed by fundus fuorescein angiography (FFA). Most myopic CNVs are type 2 neovascularization and present with a "classic" pattern on FA. OCT angiography (OCTA) was able to detect fow within myopic CNV vascular complexes and hence delineate vascular networks in these myopic neovascular membranes that lie above the retinal pigment epithelium (RPE) where fow signals are spared from attenuation [172].

Prior to the advent of anti-VEGF therapy, the main treatment options for myopic CNV were limited to thermal laser photocoagulation [173], photodynamic therapy with verteporfn (vPDT) [174, 175]. These treatments had limited effcacy in improving vision signifcantly and have now largely been relegated to the annals of history by anti-vascular endothelial growth factor (anti-VEGF) therapy [176]. Once active myopic CNV is diagnosed, prompt treatment with intravitreal anti-VEGF therapy should be administered as soon as possible [121, 177]. Current evidence suggests a pro-re-nata (PRN) regimen without a loading phase can be considered in most patients. Patients should be monitored monthly with OCT and treatment administered until cessation of disease activity on OCT or visual stabilization.

#### **1.10 Management of Myopia-Related Retinal Complications**

Myopic traction maculopathy (MTM) [123] is estimated to occur in approximately 8–34% in individuals with high myopia [178–180] and encompasses retinal thickening, macular retinoschisis, foveal detachment, lamellar macular hole with or without epiretinal membrane and/or vitreomacular traction [123], and/ or full-thickness macular hole (HM) with or without retinal detachment. Central to the pathogenesis of MTM is traction, which was postulated to arise from one or more of the following mechanisms [181]: vitreomacular traction associated with perifoveal posterior vitreous detachment (PVD) [182–184]; relative incompliance of the internal limiting membrane (ILM) [185–189], epiretinal membrane (ERM) [180, 182, 190–192], and cortical vitreous remnant after PVD [193] to the outer retina which conforms to the shape of the posterior staphyloma; and traction exerted by retinal arterioles [188, 194, 195]. Not all patients with MTM require interventions [184, 196, 197]. There are numerous reported interventions for MTM. The principles of the treatment are: (1) to relieve traction, mainly achieved through pars plana vitrectomy (PPV) with or without ILM peeling; (2) to minimize surgical damage to the weakened macula through technique modifcations in order to prevent the formation of postoperative MH; and (3) in the presence of full-thickness MH, to maximize the chance of hole closure through the use of various surgical adjuncts.

#### **1.10.1 Proposed Adjuncts to Improve Outcome of Macular Hole Surgery**

**Inverted Internal Limiting Membrane Flap** This technique involves leaving a hinge of ILM fap at the edge of MH during ILM peeling. This ILM fap is then inverted upside-down to cover or fll the MH [198].

**Autologous Internal Limiting Membrane Transplantation** In eyes where ILM around the macula hole has already been removed, an appropriately sized ILM can be peeled off from a distant site and placed as a free fap onto the persistent MH [199, 200].

**Autologous Blood** In order to prevent subretinal migration of dye and the resultant retinal toxicity associated with vital stains, it was proposed to use autologous blood to cover the MH before injection of brilliant blue dye. It has been demonstrated that compared to conventional method, the use of pre-staining autologous blood led to better visual acuity outcomes and continuity of ellipsoid zone at all post-operative time points [201].

**Lens Capsular Flap Transplantation** Chen et al. demonstrated a 100% MH closure rate with anterior capsular transplantation among patients with refractory MH,

**Fig. 1.1** Summary of the clinical management of pathologic myopia in adults

whereas the complete closure rate of MH after posterior capsular transplantation was only 50% and with another 30% enjoyed partial MH closure [202].

**Macular Buckle** Macular buckles have been used to shorten the axial length of myopic eyeballs in conditions such as macular hole retinal detachment (MHRD), myopic foveoschisis with or without foveal detachment, and MH with foveoschisis. There are many types of macular buckle, including scleral sponge, T-shaped or L-shaped buckle, Ando Plombe, wire-strengthened sponge exoplant, and even donor sclera and suprachoroidal injectable long-acting hyaluronic acid [203].

**Autologous Neurosensory Retinal Transplantation** The technique involves bimanually harvesting a free fap of neurosensory retina superior to the superotemporal arcade, with the harvest site frst secured by endolaser barricade and endodiathermy. The free fap was translocated in its correct orientation over the macular hole and perfuoro-*n*-octane heavy liquid (PFC) was instilled over it, followed by direct PFC–silicone oil exchange [204].

Figure 1.1 presents an overview of the management of myopia-related complications in adults.

#### **1.11 Management and Control of Myopia in Children**

Currently, there are many types of interventions to slow myopia progression in children, including spectacle lenses, contact lenses, pharmaceuticals, and environmental or behavioral modifcation. However, none of these myopia control methods have been proven to stop the development or progression of myopia completely and each method has their own limitations.

**Spectacle Lenses** Under-correction of myopia in clinical trials has shown conficting results and small, clinically insignifcant effect on slowing myopia progression [205–207]. In view of these conficting results, there is no convincing evidence to indicate that under-correction should be used to slow myopia progression.

**Bifocal or Multifocal Spectacles** Most studies showed that progressive addition lenses (PALs) have an insignifcant effect on slowing myopia progression rate (less than 0.2 D per year) overall [48, 208–214]. In contrast, a randomized, controlled trial showed that executive bifocal lenses slowed myopia progression in Chinese-Canadian children aged 8–13 years by 39% and up to 51% with basein prisms incorporated over 3 years [215]. More recently, the Defocus Incorporated Multiple Segments (DIMS) spectacle lens enabled clear vision and myopic defocus simultaneously for the wearer [216]. Hong Kong Chinese children aged 8–13 years wearing DIMS lenses had approximately 60% less myopia progression and axial elongation when compared with children wearing single vision spectacle lenses over 2 years. Moreover, about 20% of the DIMS lens wearers had no myopia progression during the study period.

**Peripheral Myopic Defocus Glasses** In 2010, Sankaridurg et al. published their results of three novel peripheral defocus spectacle lens. Unfortunately, there was no signifcant effect on myopic progression with all three designs [217]. In a recent randomized controlled trial (RCT) conducted in Japanese children with peripheral defocus lenses, no difference in myopia reduction was found [218].

**Rigid Gas Permeable Contact Lenses** Two randomized clinical trials [219, 220] showed that rigid gas permeable (RGP) contact lenses did not retard axial eye growth. However, Walline et al. [219] reported signifcant slower myopia progression in the group of RGP lenses compared with soft contact lenses, despite that no differences were found in axial elongation between the groups. The proposed reason for a treatment effect on refraction may be due to the changes in corneal curvature.

**Orthokeratology** Orthokeratology (Ortho-K) lenses are specially designed RGP contact lenses that are worn overnight to reshape the cornea and thereby temporarily correct low-to-moderate myopia. Various clinical studies have demonstrated the effectiveness of inhibiting myopic progression with Ortho-K. Individual studies and meta-analyses have shown a 32–63% reduction in the rate of axial elongation in East Asian children initially aged from 7 to 16 years and followed for up to 5 years [221–227]. Effcacy may decrease over time [224, 228], with a potential "rebound" after discontinuation, especially in children under 14 years [229]. There is also a potential non-response rate of 7–12% [223]. Interestingly, a recent study in Japan [230] showed that the combination of Ortho-K and low-concentration atropine (0.01%) eyedrops was more effective in slowing axial elongation over 12 months than Ortho-K treatment alone in myopic children. The risk of infective keratitis remains [231].

**Soft Bifocal and Multifocal Contact Lenses** These lenses are worn during the daytime. Compared to spectacles, contact lenses are more cosmetically acceptable, more easily handled, and are more convenient for daily activities of some children, especially during sports [232, 233]. For most of eye-care practitioners, the ftting procedures of soft bifocal contact lenses are relatively simpler than Ortho-K. Overall, soft bifocal and multifocal contact lenses slow the progression of myopia in children by an amount comparable to that of Ortho-K lenses. Studies exploring the effect of these bifocal soft contact lenses indicate slowing of myopia progression by 25–50% and axial length by 27–32% in children aged 8–16 of various ethnicities over a period of 24 months [234, 235].

**Atropine** The initial high doses of atropine (i.e., 0.5% or 1.0%) slowed myopia progression by more than 70% in Asian children aged 6–13 years over 1–2 years [229, 236–238]. However, lower doses (0.1% or less) can also slow refractive progression by 30–60% with less side effects (pupil dilation, glare, or blur) [238]. The Atropine Treatment of Myopia (ATOM) studies showed that there was a myopic rebound if atropine was stopped suddenly, especially at higher doses and in younger children [239, 240].

**Time Spent Outdoors** In the Sydney Myopia Study, exposure to more than 2 h of outdoor activity per day decreased the odds of myopia and countered the effects of near work [65]. Interventions involving increasing time outdoors appeared to reduce the onset of myopia and also its progression in myopic children [71]. A metaanalysis has suggested a 2% reduced odds of myopia per additional hour of time spent outdoors per week [70].

**Environmental Interventions** Based on new evidence, the advice has shifted from spending at least 2 h per day outdoors in addition to avoiding excessive near work. This has changed health and school messaging in many East Asian countries [71].

**Higher Light Intensities and Dopamine** Potential reasons why time outdoors may be protective include higher light intensities [241], differences in chromatic composition [242], the reduction in dioptric accommodative focus and psychometric infuences encountered outdoors [243]. The role of chromaticity (red and blue) and ultraviolet (UV) light is still uncertain [244], while that of higher vitamin D levels has been debunked [88].

Figure 1.2 presents an overview of the management and prevention of myopia in children.

**Fig. 1.2** Summary of the clinical management of myopia in children

#### **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

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## **2 Global Epidemiology of Myopia**

#### Saiko Matsumura, Cheng Ching-Yu, and Seang-Mei Saw

#### **Key Points**

S. Matsumura

C. Ching-Yu Singapore National Eye Centre, Singapore, Singapore

National University of Singapore, Singapore, Singapore

Duke-NUS Medical School, Singapore, Singapore e-mail<EMAIL_ADDRESS>
S.-M. Saw (\*) Singapore Eye Research Institute, Singapore, Singapore

National University of Singapore, Singapore, Singapore

Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore e-mail<EMAIL_ADDRESS><EMAIL_ADDRESS>
© The Author(s) 2020 27 M. Ang, T. Y. Wong (eds.), *Updates on Myopia*, https://doi.org/10.1007/978-981-13-8491-2\_2

Singapore Eye Research Institute, Singapore, Singapore e-mail<EMAIL_ADDRESS>
#### **2.1 Introduction**

Myopia has become a signifcant global public health and socioeconomic problem [1–4]. Developed countries, especially among East Asia, have been faced with high prevalence of myopia and high myopia (HM) and the same trend has been shown in other parts of the world with less extent [5, 6]. (The defnition of myopia and HM is spherical equivalence (SE) of −0.50 diopters (D) or less and SE −5.00 D or −6.00 D, respectively.) The prevalence of myopia and HM in young adults in urban area of East Asian countries has risen to 80–90% and around 20%, respectively [7, 8]. According to a summary of 145 studies regarding the global prevalence of myopia and HM, there are approximately 1950 million (28.3% of the global population) and 277 million (4.0% of the global population) cases, and they are predicted to increase to 4758 million (49.8% of the global population) for myopia, and 938 million (9.8% of the global population) for HM by 2050 [9].

Most cases of myopia are considered as a benign condition because vision is corrected with spectacles, contact lenses, or refractive surgery. However, severe cases of myopia are associated with the risk of irreversible vision impairment and blindness due to pathological changes in retina, choroid, and sclera. One study has shown that 25% of HM will develop pathologic myopia (PM) and 50% of those with PM will have low vision as older adults. Thus, HM and PM are likely to increase drastically in the older generation. Based on the global prediction of HM on 2050, PM may increase to over 200 million in future [9]. Treatment strategies against PM have not been effective and costly [10]. Considering the burden of PM in the future, it is important to develop public policies and preventive and early interventional measures to retard the epidemic myopia. In this chapter, we summarize data on the prevalence of myopia and HM in different generations and the prevalence of PM from recent epidemiological studies.

#### **2.2 Prevalence of Myopia in Children**

In children, cycloplegic refraction is a common procedure to measure refractive error because children have a possibility to have an overestimation of myopic refraction, due to increased tone of the ciliary muscle and a constant accommodative effort during the examination, and makes the refraction overestimated approximately over −1 to −2 D [11, 12]. Many population-based studies on children have proved that the prevalence of myopia is higher in urbanized East Asian countries. In surveys of 12-year-old children, the prevalence of myopia is higher in Singapore (62.0%) [13], Hong Kong (53.1%) [14], and Guangzhou, China (49.7%) [15] than in the United States (20.0%) [16], Northern Ireland (17.7%) [17], Australia (11.9%) [18], urban India (9.7%) [19], Nepal (16.5%) [20], and Cambodia (6.0%) [21]. We summarized the prevalence of myopia among children in population studies using cycloplegic refraction between Asian countries (Table 2.1) and non-Asian countries (Table 2.2).

30

**Table 2.1**

*NA* not applicable, *M* myopia, *HM* high myopia

*NA* not applicable, *NHW* non-Hispanic White, *A-A* African-American, *Euro* European, *M* myopia, *HM* high myopia

#### **2.2.1 Asian Countries**

#### **<IP_ADDRESS> East Asian Countries and Singapore**

Taiwanese school children have the highest prevalence of myopia among all school children worldwide. The prevalence of myopia among 8-year-old children is 36.4% in Taiwan [22], followed by 34.7% in Singapore [13], 30.8% in Shanghai [25] and 14.0% in Malaysia [48]. Lai et al. reported that the prevalence of myopia among 618 preschool Taiwanese children were also as high as 3.0%, 4.2%, 4.7%, and 12.2% in the age groups of 3, 4, 5, and 6 years, respectively [23]. A nationwide myopia survey in Taiwan showed that the prevalence of myopia among 7-year-olds increased from 5.8% in 1983 to 21% in 2000. At the age of 12, the prevalence of myopia was 36.7% in 1983 increasing to 61% in 2000, corresponding fgures for 15-year-olds being 64.2% and 81%, respectively [7]. In China, Ma et al. reported that the prevalence of myopia in Shanghai was 20.1% among 3-year-old to 10-year-old children. They also showed that the prevalence increased dramatically from 5.2% in 6-yearold children and 14.3% in 7-year-old children to 52.2% in 10-year-old children [25]. In the urban city of Guangzhou, the prevalence of myopia was 7.7% in 7-year-old, 30.1% in 10-year-old, and 78.4% in 15-year-old children, with an overall prevalence of 38.1% among 4364 children aged 5–15 years [15]. In a rural area of Beijing, Zhao et al. reported that the prevalence of myopia among school children aged 5–7 and 14–15 years were 1.2% and 38.8%, respectively, with an overall prevalence of 14.9% among 5884 children aged 5–15 years [29]. In a suburban area, the prevalence of myopia among 3070 school children aged 6, 7, 10, and 14 years was 0.42%, 1.92%, 9.4%, and 28.8%, respectively [27]. In another rural area of northern China, the prevalence of myopia among 1675 school children aged 5–9, 10–14, and 15–18 years was 0.9%, 4.5%, and 8.2%, respectively, with an overall prevalence rate of 5.0% [49]. In Hong-Kong, 2 population-based surveys were conducted in children aged 3–6 years during 1996–1997 and 2006–2007, which revealed that prevalence of myopia increased 2.3–6.3% in a decade [30]. In Singapore, the school-based population study of the Singapore Cohort Study of Risk factors for Myopia (SCORM) showed that the prevalence of myopia was 29.0% in 7-year-olds, 34.7% in 8-yearolds, and 53.1% in 9-year-olds [50]. In younger ages from 6 months to 6 years, the Strabismus, Amblyopia, and Refractive Error in Singapore (STARS) Study reported that the prevalence of myopia was 11.0% in Chinese children [31].

#### **<IP_ADDRESS> Rest of Asian Countries**

On the other hand, the prevalence of myopia is generally lower in other countries in Asia. In India, 6447 school children aged 5–15 years had 7.4% of the myopia prevalence in an urban population in New Delhi [19]. A population-based cross-sectional study was conducted among children in 1 urban and 3 rural areas. It reported that the prevalence of myopia among children ≤15 years of age and >15 years of age was 3.2% and 20.0%, respectively [32]. In Iran, the prevalence of myopia among 1854 school children aged 7, 10, and 14 years were 1.7%, 2.4%, and 7.6%, respectively, with an overall prevalence rate of 4.4% among 7-year-old to 15-year-old children in Shiraz [33]. In 4282 Nepalese secondary school children aged 10–15 years, the myopia prevalence was ranged from 10.9% in 10-year-olds to 27.3% in 15-yearolds [20]. In Thailand, the prevalence of myopia was 11.1% in 2360 children aged 6–12 years [37].

#### **2.2.2 Non-Asian Countries**

Nowadays, a rise of the myopia prevalence has also been shown in non-East-Asian countries that previously were only mildly or moderately affected, such as the UK, Australia, and the United States, although the prevalence is still lower than that in Asian countries. In the United States, the prevalence of myopia among 6–month-old to 6-year-old children was 1.20% and 3.98% in 1501 non-Hispanic White and 1507 Asian ethnicity children, respectively, as per the Multi-Ethnic Pediatric Eye Disease Study [38]. In the Baltimore Eye Study, the prevalence of myopia (SE <−1.00 D) was 1.2% in Whites, 6.6% in African-Americans among children aged 6 years, and an overall prevalence among 6-month-old to 71-month-old children was 0.7% and 5.5% in 1030 Whites and 1268 African-Americans, respectively [39]. Although few reports have been published on the prevalence of myopia in children in Europe, regional differences from country to country were shown even within the same geographical area. In England, the Aston Eye Study (AES) reported that the prevalence was 9.4% among children aged 6–7 years, and 29.4% among children aged 12–13 years, whereas the prevalence was 2.8% and 17.7% among children in the same age groups in Northern Ireland [17, 41]. In the Netherlands, the myopia prevalence rate was as low as 2.4% in 5711 children aged 6 years [40]. In Poland, the myopia prevalence was lower: 2.0% in 6-year-old, 8.4% in 8-year-old, and 14.7% in 12-year-old children [43]. In Australia, the Sydney Myopia Study (SMS) reported that myopia was present in 1.43% in 1765 children aged 7 years, with 0.79% in European children and 2.73% in other ethnicity children [45]. The Sydney Adolescent Vascular and Eye Study (SAVES) reported the myopia prevalence to be 18.9% among 12-year-old children, with 52.5% in East Asian, 8.6% in European Caucasian, and 12.0% in other ethnicity groups [44]. However, these ethnic differences may not be based solely on genetic differences. Studies on migrant populations suggest that the prevalence of myopia among Asian children living in non-Asian countries such as Australia is not as high as those living in East Asian countries [51]. Finally, in population-based studies, the lowest prevalence appears to be in Africa. The prevalence of myopia was 3.4% in 12-year-old to 15-year-old children in Ghana and 4.0% in 5-year-old to 15-year-old children in South Africa [46].

#### **2.2.3 Urban and Rural Areas**

Collectively, there are signifcant differences in the prevalence of myopia between urban areas and rural areas. In China, the prevalence of myopia was 38.1% in children aged 5–15 years in urban area, Guangzhou, whereas the prevalence of myopia was 5.0% in children aged 5–18 years in rural area. In an urban area,

Tehran, the prevalence of myopia was 7.2% in 809 children aged 5–15 years in the Tehran Eye Study, while a rural area, Dezful, had a lower prevalence of myopia which was 3.4% in children aged 7–15 years [35, 36]. A recent meta-analysis found a 2.6 times higher risk of developing myopia in children of urban residence compared with those who lived in rural areas [52]. These differences in the myopia prevalence among children may be caused by a rigorous education system which children especially living in urbanized are exposed to. Especially in Eastern Asian countries, academic success is important, and most children are enrolled in competitive, academically oriented schooling at a very early age [51]. It is infuenced by enduring patterns of behavior and cultural attitudes that may result in the myopic environmental factors, such as higher levels of more intense near-work and lower levels of outdoor activity.

In summary, the prevalence of myopia in children is higher in East Asian countries (49.7–62.0% among 12-year-old children) compared with non-Asian countries and other Asian countries (6.0–20.0%). The prevalence of myopia has remained consistently high among Chinese children in urban settings, but the evidence does not support the idea that it is caused by purely genetic difference [53]. The association of an urbanized setting with high myopia rates is likely to be infuenced by possible modifable risk factors such as near-work and outdoor time.

#### **2.3 Prevalence of Myopia and HM in Teenagers and Young Adults**

#### **2.3.1 East Asian Countries**

The prevalence of myopia in young adults is more than 80% in urbanized East Asian countries (Table 2.3). A remarkable increase in the myopia and HM prevalence was seen in the past decades. In China, Chen et al. conducted a 15-year populationbased survey using noncycloplegic autorefraction to investigate trends in the prevalence of myopia among 43,858 high school students in Fenghua city, eastern China, from 2001 to 2015. The overall prevalence of myopia and HM increased from 79.5% to 87.7% and 7.9% to 16.6%, respectively, during the 15-year period [54]. In Shandong, another city in eastern China, the prevalence of myopia and HM using cycloplegic autorefraction in school children aged 17 years was 84.6% and 13.9%, respectively [55]. A cross-sectional study among 5083 university students in Shanghai showed that 95.5% were myopic and 19.5% were high myopic (SE <−6.0 D) [56]. In Korea, the prevalence of myopia and HM (SE <−6.0 D) using cycloplegic autorefraction was higher in an urban population (96.5% and 21.6%) [8], compared to a rural population (83.3% and 6.8%) [26], among 19-year-old males in military conscripts. In Taiwan, the prevalence of myopia and HM (SE <−6.0 D) was 86.1% and 21.2%, respectively, in males aged 18–24 years in military conscripts [57]. In Singapore, the overall myopia and HM prevalence in 28,906 young males aged 16–25 years increased from 79.2% and 13.1% in 1996–1997 to 81.6% and 14.7% in 2009–2010, respectively [58].

**Table 2.3**Summary of prevalence of myopia and high myopia in teenager and adolescent in East Asian countries

*NA* not applicable,

*M* myopia, *HM* high myopia

#### **2.3.2 Rest of East Asian Countries**

In contrast to the uniformly high prevalence in Eastern Asian countries, the prevalence of myopia and HM in young adult populations in other countries varies among different ethnicity and geography (Table 2.4). In Israel, a 13-year series of population-based prevalence survey was conducted on young adults aged 16–22 years during the years 1990–2002. The overall prevalence of myopia and HM (SE <−6.0 D) using noncycloplegic autorefraction increased from 20.3% and 1.7% in 1990 to 28.3% and 2.05% in 2002, respectively [59]. In the Tehran Eye Study, the prevalence of myopia using cycloplegic autorefraction was 29.3% among young adults aged 16–25 years [36]. In Australia, the prevalence of myopia was 20.4% in a population-based cohort using cycloplegic autorefraction in mostly White subjects aged 19–22 years [60]. In the Sydney Adolescent Vascular and Eye Study (SAVES), myopia was present in 30.8%, with 59.1% in East Asian, 17.7% in European Caucasian, and 34.9% in other ethnicity group; and HM (SE <−6.00 D) was present in 1.9% among 17-year-old young adults [44]. In Europe, the prevalence of myopia and HM (SE <−6.50 D) among 4681 Danish conscripts was 12.8% and 0.3%, respectively [61]. A population-based study in Norway reported that 35.0% were myopic among 1248 young adults aged 20–25 years [62]. In the United States, the myopic prevalence rate was 27.7% in young adults aged 18–24 years [63].

As shown above, the myopia prevalence among young adults in East Asia is much higher than in Western countries. This is most likely refecting the higher myopia prevalence among school children in Eastern Asia and can be further accelerated by their education system. This age population usually spend much time in study and are expected to achieve high scores for competitive college entrance examination, especially in Asia. In one study conducted in China, the prevalence of myopia in postgraduates was higher than in undergraduates [56], suggesting that associated factors, such as higher school achievement and prolonged near-work and less outdoor time, might contribute to the increasing prevalence of myopia [51]. We summarized the myopia prevalence in East Asian countries (Table 2.3) and rest of East Asian countries (Table 2.4). When comparing the results, we must be cautious because some conscript-based studies investigated only men, and conducted eye examination without cycloplegic refraction, which may make the refraction overestimated approximately over −0.50 D in younger adults [64].

#### **2.4 Prevalence of Myopia and HM in Adults**

In adults, the prevalence rates of myopia vary widely with age refecting the hyperopic shift by aging in older generations. According to the results from the Beaver Dam Eye Study, the prevalence of myopia was likely to decrease with age among individuals aged above 43 years [65]. Wong et al. showed that the highest prevalence of myopia was in the age group of 40 years and above 70 years among Chinese-Singaporean adults aged 40–81 years old [66]. It suggested that the prevalence in elderly adults older 70 years could be overestimated due to lens nuclear sclerosis

*NA* not applicable, *Euro* European,

*M* myopia, *HM* high myopia

**Fig. 2.1** Reported prevalence of myopia in adult population based on population studies

inducing refractive myopia. Population-based data indicate that Asian adult population is more susceptible to myopia compared with similarly aged western population. However, compared to the prevalence of myopia in children, the regional difference is not obvious in adults. We summarized the prevalence of myopia in adult population-based studies in the world (Fig. 2.1). It must be noted that there is lack of consensus in defnitions of myopia and HM, and the defnition varies among studies and that there is a difference of age population affecting by nuclear cataract, thus not directly comparable among different studies.

#### **2.4.1 Asian Countries**

#### **<IP_ADDRESS> East Asian Countries**

In China, the prevalence of myopia and HM (SE <−6.0 D) was 32.3% and 5.0%, respectively, in 1269 adults aged 50 or more years in the Liwan Eye Study [67] conducted in an urban city of Guangzhou. In rural areas, 26.7% were myopic and 1.8% were high myopic in 6491 adults aged 30 or more years in the Handan Eye Study [4]. The Beijing Eye Study reported that the myopia and HM (SE <−6.0 D) prevalence was 22.9% and 2.6%, respectively, in 4319 adults aged 40 or more years in urban and rural Chinese populations [68]. However, these data may lead to substantial underestimation of the myopia prevalence because refraction data were obtained only from those with visual impairment. In Taiwan, the Shinpai Eye Study in adults aged over 65 years reported that the prevalence of myopia and HM (SD <−6.0 D) was 19.4% and 2.4%, respectively [69]. In Singapore, the prevalence of myopia in Singaporean-Chinese, Malay, and Indians was 38.7% [66], 26.2% [70], and 28.0% [71], and corresponding fgures for HM being 9.1%, 3.9%, and 4.1%, respectively. In Japan, the prevalence of myopia and HM in urban areas is relatively high, 41.8% and 8.2%, respectively, in 3021 adults above 40 years in the Tajimi Study [72]. However, the myopia rates may be overestimated because of the use of noncycloplegic refraction for the younger population who may have excessive residual accommodation. A latest population-based study from a rural area showed that the prevalence of myopia and HM was 29.5% and 1.9%, respectively, among adults aged 40 years or older in the Kumejima Study [73]. In this study, the prevalence of myopia was nearly the same as those in urban areas of China, while the prevalence of HM was similar to that reported in rural areas of other Asian countries. In South Korea, the prevalence of myopia and HM was 20.5% and 1.0%, respectively, among adults above 40 years in the Namil Study [74]. Relatively low prevalence in the study was refected by rural lesions, it was similar to that of rural Chinese population.

#### **<IP_ADDRESS> Rest of East Asian Countries**

In other Asian developing countries, the prevalence of myopia is slightly lower: 17.2% among adults aged 40 or more years in Mongolia, and 22.1% among adults aged 30 or more years in Bangladesh [75, 76]. Further, the myopia rate in the Bangladesh study may be overestimated because of the use of noncycloplegic refraction for the younger group aged 30–39 years who may have excessive residual accommodation. In a rural area in India, the prevalence of myopia and HM was 27.0% and 3.7%, respectively, in 2508 Indian adults aged above 39 years [77]. Relatively high prevalence in rural Indian population may be caused by higher rates of nuclear cataract. The prevalence of myopia is slightly higher at 36.5% among adults aged 30 or more years in Pakistan, and at 30.2% among adults aged 40 or more years in Iran [78, 79]. The myopia rate in the Pakistan study may be overestimated because of the cohort effect of younger group aged 30–39 years.

#### **2.4.2 Non-Asian Countries**

In the USA, the latest report in the Chinese American study showed the relatively high prevalence of myopia and HM, 35.1% and 7.4%, respectively, in 4144 Chinese adults aged 50 years or older [80]. This result is similar to or slightly higher than same Chinese populations from other studies in urban Asian countries (38.7% in the Tanjong Pagar Study, Singapore and 32.3% in the Liwan Eye Study). The Barbados Eye Study reported the prevalence of myopia was 21.9% in 4709 African-Americans aged 40–84 years [81]. Another population-based study in Latino showed that the overall prevalence of myopia (SE <−1.00 D) and HM in the worse eye was 16.8% and 2.4%, respectively, among 5927 adults aged 40 years or older [82]. In Europe, although the myopia rate varies across the countries, two latest population-based studies proved that it was nearly the same as those in urban Asian countries. The Gutenburg Health Study in Germany reported that the prevalence of myopia and HM was 35.1% and 5.6%, respectively, in 13,959 adults aged 35–74 years. The high prevalence of myopia in the study can be explained by the fact that this cohort had

younger participants than most other studies [83]. In the Netherlands, the prevalence of myopia was 32.5% in a total of 3530 adults aged above 46 years in the Rotterdam study [84]. This study may have overestimated the prevalence of myopia because the refraction method was subjective refraction. In UK, a population-based study showed that 23.0% were myopic among a total of 7444 adults aged above 48 years [85]. In other European countries, the prevalence of myopia is slightly lower: 19.4% among adults aged 38 or more years in Norway, 19.1% among adults aged 76 or more years in France, and 14.2% among adults aged 60 or more years in Greece [84]. In Australia, the prevalence of myopia was relatively lower, 15.0% in 3654 adults aged over 49 years in the Blue Mountain Eye Study in 1999 [86]. In the two population-based studies, the lowest prevalence appears to be in Africa. In Nigeria, the prevalence of myopia and HM was 16.1% and 2.1%, respectively, among 13,599 adults aged over 40 years as per the Nigeria National Blindness and Visual Impairment Study [87]. In South Africa, the prevalence of myopia was 11.4% in 1939 adults aged over 35 years [88]. In the same vein, the prevalence of myopia was relatively low 14.4% among adults aged 35–55 years in MIROR Study in Colombia [89].

#### **2.4.3 Generational Gap**

There is a difference in myopia and HM prevalence among age groups. In general, the generational differences of prevalence of myopia and HM are seen with the highest rates in young adults and the lowest rates in older adults. We have shown the higher prevalence rates of myopia (65.5–96.5%) and HM (14.7–21.6%) in East Asian young adults in the previous section [8, 57, 58]. By contrast, the lower prevalence rates of myopia (approximately 25–40%) and HM (2.4–8.2%) were reported among East Asian middle-aged and elderly adults [69, 72, 90]. Particularly, the burden of HM is important because HM is more likely to develop PM changes that tend to be visually disabling. Some studies supported the idea of two types of HM, one is related to educational parameters such as near-work and frequent among young adults, and the other is more likely related to the earlier onset of myopia by genetic factors in contrast to environmental factors and occurs in older adults [91, 92]. Jonas et al. compared highly myopic young individuals and highly myopic adult individuals and assessed the association of the prevalence of HM with parameters of education. It revealed that education-related parameters did not show a clear association with HM in older generation, while in contrast, HM in school children showed a strong association with education [91]. Thus, it has been assumed that the development of pathologic myopia (PM) in later life may be different depending on two forms of HM with different etiologies. One form of HM is caused by mutations of genes responsible to scleral modeling and leading to abnormal deformity and thin sclera [93], while the other form caused by insuffcient outdoor time in younger adults may be driven by reduced release of retinal dopamine [1].

In summary, the higher prevalence rates of myopia were also seen in urban East Asian countries (approximately 25–40%) and in Western Europe or the United States (approximately 20–35%), compared to other developing Asian countries and some countries in Western populations such as Australia (approximately 15–20%). Similarly, urban Asian countries have higher prevalence rates of HM (5–9%), compared with other Asian countries (2–5%) or non-Asian countries (2–7%). However, the geographic difference of myopia prevalence in older populations is not pronounced compared to that in younger populations. From a viewpoint of ethnicity difference, Chinese have a substantially higher prevalence of myopia compared with other racial groups, and a similar pattern of even greater magnitude was seen in HM prevalence. The prevalence of myopia and HM in Chinese ethnicity in western countries is similar to other studies of Chinese in urban Asian countries [80].

#### **2.5 The Prevalence of PM**

Pathologic myopia (PM) has been reported as one of the most common causes of blindness worldwide. Studies reported that PM is the major cause of blindness or visual impairment (VI) in 7% in Western populations and in 12–27% in Asian populations [94–99]. According to a review to estimate blindness and VI with myopic macular degeneration (MMD), 10.0 million people had VI from MMD (0.13%), 3.3 million of whom were blind (0.04%) in 2015, and furthermore 55.7 million people will have VI from MMD (0.33%), 18.5 million of whom will be blind (0.19%) in 2050 [100].

Before we discuss the prevalence of PM in detail, it must be noted that the defnition of PM has been inconsistent in previous studies. Avila et al. proposed a defnition of myopic maculopathy that included posterior staphyloma, and it has been used most frequently in earlier studies [101]. However, this classifcation was not based on the actual progression pattern. In 2015, the META-analysis for Pathologic Myopia (META-PM) study group proposed a new classifcation system for PM for use in future studies [102]. In this classifcation, myopic macular degeneration (MMD) is categorized into 5 categories according to severity: no myopic retinal lesions (category 0); tessellated fundus only (category 1); diffuse chorioretinal atrophy (category 2); patchy chorioretinal atrophy (category 3); and macula atrophy (category 4). And three additional lesions of MMD that cause central vision loss were included as plus sign: lacquer cracks, myopic choroidal neovascularization (CNV), Fuchs spot. PM is defned if an eye has category 2 or above, or presence of plus sign, or the presence of posterior staphyloma. We summarized populationbased studies on PM prevalence in adult populations (Fig. 2.2).

In China, the Beijing Eye Study showed a high PM prevalence, 3.1%, among 4319 Chinese subjects aged 40 years or older [103]. PM was defned with myopic chorioretinal atrophy or staphyloma or lacquer cracks or Fuch's spot. In the same defnition, the Handan Eye Study showed that the prevalence of PM and HM was 0.9% and 2.1%, respectively, among 6603 Chinese subjects aged 30 years or older

**Fig. 2.2** Prevalence of pathologic myopia (PM) among adults in population-based studies

[104]. The much lower prevalence in this study than Beijing might be due to urban and rural differences. Among 1058 Taiwanese subjects aged 65 years or older in the Shinpai Eye study, the prevalence of PM and HM was 3% and 4.2%, respectively, with the defnition by Avila et al. [105]. The high prevalence was infuenced by its older population than other population-based studies. The Hisayama study reported the prevalence of PM and HM was 1.7% and 5.7%, respectively, among 1892 Japanese aged 40 years or older with the defnition of PM as myopic chorioretinal atrophy, lacquer cracks, or Fuch's spot [106]. However, this study cannot exclude the possibility of sampling bias because the response rate was only 44.4%. In Western countries, the Blue Mountain Eye Study was performed in 3583 adults aged 49 years or older, who were mainly White urban population of Australia, using the same PM defnition with two studies in China [107]. The prevalence of PM and HM was 1.2% and 2.7%, respectively. Using the new META-PM classifcation, the prevalence of PM and HM was 0.2% and 0.5%, respectively, among 4561 Indian subjects aged 30 years or older in rural central India [108]. However, the population in this study may not be adequately representative of the whole population of India because this study was conducted in rural tribal regions.

As shown above, the prevalence of PM among adult populations was relatively low in the world. Furthermore, the prevalence of PM among middle-aged and elderly adults is higher in urban East Asian populations (1.7–3.1%) than rural Asian populations (0.2–0.9%) and non-Asian populations (1.2%) [109]. It is consistent with the results of higher prevalence of HM in East Asian countries because the risk of PM increases with HM [109]. Both the prevalence and severity of PM become higher in adult population aged 40 years and with severe high myopia. Compared to the PM prevalence in adult populations, adolescents and children have signifcantly lower prevalence [27, 110]. It supports the idea that myopic macular changes are time-dependent changes as a result of mechanical stretching of the retina from axial elongation. However, a recent report revealed that myopia-related changes of the optic disc and macula were commonly found in highly myopic eyes in young adults [111].

Thus, the disease burden of PM due to high myopia is likely to increase in future, contributed by the aging effect where young adults who have high rates of high myopia will grow older.

#### **2.6 Conclusion**

In children, the prevalence of myopia is substantially higher in urban East Asian countries (49.7–62.0% among 12-year-old children) compared with other countries (6.0–20.0% among 12-year-old children). Similarly, in teenagers and young adults, the prevalence of myopia is higher in East Asian countries (65.5–96.5%) compared with other countries (12.8–35.0%). However, the geographic difference of myopia prevalence in older populations is less than that of younger populations. The prevalence rates of myopia in adults in urban East Asian countries are only slightly higher than in Western countries.

A relationship between myopia prevalence and community development is apparent, and most data have shown urban areas have a higher prevalence of myopia than rural areas. The association of an urbanized environment with myopia development in Asia could be mediated by factors such as intensive education and greater levels of near-work and less outdoor time. Overall, the prevalence of myopia in child population seems to be strongly related to the region where they grow up and the environmental factors such as urbanization, economy, and education.

Generational differences are seen with the highest rates in young adults (myopia 65.5–96.5% and HM 6.8–21.6%) and the lowest rates in older adults (myopia 25.0–40.0% and HM 2.4–8.2%). The disease progression pattern of HM and subsequent development of PM may be different between young adults and older adults due to generational differences, or changes in the lifestyle factors such as the education system and near-work and outdoor time exposure in rapidly developing urban Asian countries.

Current data show a relatively low prevalence of PM among middle-aged and elderly adults so far, and PM increases with age over 40 years and severity of myopia. Despite the relatively low prevalence in general population, PM is the major cause of blindness or visual impairment in both Asian populations and Western populations. According to a previous study, early grades of PM lesions are observed in young highly myopic adults in urban Asian population, and these structure changes are likely to worsen with age [111]. Considering the increasing prevalence of HM among young generations, we must be prepared for the expected increase of disease burden of PM in the near future.

#### **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

## **3 The Economic and Societal Impact of Myopia and High Myopia**

### Sharon Yu Lin Chua and Paul J. Foster

#### **Key Points**

S. Y. L. Chua · P. J. Foster (\*)

Integrative Epidemiology Cluster, NIHR Biomedical Research Centre, UCL Institute of Ophthalmology and Moorfelds Eye Hospital NHS Foundation Trust, London, UK e-mail<EMAIL_ADDRESS>

#### **3.1 Introduction**

The prevalence of myopia is most pronounced in the industrialized nations of East Asia, where rates of 95% among young adults have been recorded [1]. In this context, the impact of myopia is profound and far reaching, and recent study by Naidoo et al. [2] suggests that myopia has a global economic impact, with the greatest burden throughout Asia. Its economic impact is very signifcant. This chapter seeks to examine the impact of myopia on individuals and the wider society, both from the monetary perspective and also in terms of emotional well-being and quality of life. Peer-reviewed data on this subject are comparatively sparse, and in some areas, it is necessary to make inferences on the basis of indirect evidence.

The impact of myopia illustrates an interesting dichotomy. The condition appears to be an exaggerated adaptive response which has a predilection for the most affuent and educated in society. Low myopia [up to around −3 D (diopters)] is arguably an ideal state for the older urban professional, in that the frustration of presbyopia is avoided, and hence maximum effciency in an offce-based career is maintained, and the ability to pursue leisure activities, such as reading, creative arts, and many household tasks, is enhanced. Myopes are among the best educated and thus highest earning members of any society. Furthermore, they confer on their children a range of advantages—they are typically well educated, and in turn beneft from higher career prospects and incomes. The offspring are also more likely to be myopes [3].

#### **3.2 Economic Impact of Myopia**

Myopia is the most common distance refractive error. The global prevalence of myopia is expected to increase from 27% of the world's population in 2010 to 52% by 2050 [4]—a 2.6-fold increase. A recent meta-analysis estimated a signifcant

increase in the global prevalence of myopia and high myopia, affecting nearly fve billion people and one billion people, respectively, by 2050 [4]. The projected increases in myopia and high myopia may be due to environmental factors, such as a combination of decreased time outdoors and increased near work activities, among other factors [5]. Uncorrected distance refractive error was estimated in 2013 to affect 108 million people globally, and myopia is the most common refractive error [6]. It is the leading cause of moderate and severe vision impairment (VI; 42%) and a major cause of blindness (3%) [2]. Uncorrected myopia as low as −1.50 D will result in moderate VI, and uncorrected myopia of −4.00 D is suffcient refractive error to be classifed as blindness [7]. Depending on national legislation, people with moderate VI may not be allowed to drive. Moderate VI may also require the use of aids and/or accommodations/adaptions for some tasks in the learning environment.

If the increasing prevalence of myopia is not addressed, a similar increase in uncorrected refractive error can be expected. These projections are based on conservative assumptions and, given the published relationship between level of education and myopia, increased provision of education could markedly increase these trends. Furthermore, uncorrected distance refractive error has been estimated to result in a global loss of productivity of international dollar (I\$) 269 billion [8] (US \$202 billion) annually [9], which will also increase if there is a signifcant increase in uncorrected myopia. International dollar allows comparison of prices and currency values between countries after adjustment of currency exchange rate. An international dollar has the same purchasing power as the U.S. dollar has in the United States [10]. A recent meta-analysis estimated the global potential loss associated with VI in 2015 was US \$244 billion/annum [95% confdence interval (CI) US \$49 billion—US \$697 billion] from uncorrected myopia and US \$6 billion/annum (95% CI US \$2 billion–US \$17 billion) from myopic macular degeneration [2]. The cost of care is also likely to increase signifcantly, and will be exacerbated by an even greater increase in the prevalence of high myopia, from 2.8% (190 million people) to 9.7% (924 million people) by 2050 [4], representing a 4.9-fold increase in high myopia. In some populations of young adults in Asia, the prevalence of high myopia has already reached 38% [11]. The annual direct cost of optical correction of myopia for Singaporean adults has been estimated at US \$755 million. Refractive correction comprising of optometry visits, spectacles, and/or contact lenses is the most signifcant cost domain and it accounts for 65.2% of the total costs [12]. In Singapore, the estimates in an adult (SG \$587 or US \$455 per patient per year) is signifcantly higher than a child aged 7–9 years (SG \$222 or US \$175 per patient per year) [13]. The higher cost could be because of the greater likelihood that adults may undergo laser-assisted in situ keratomileusis (LASIK), wear contact lens, or develop ocular complications due to high myopia. Furthermore, adults tend to have higher spending power compared to a child. It has been estimated that if such prevalence rates were extrapolated to all cities in Asia in which the prevalence of myopia is approximately equal to the rates in Singapore, the estimated direct cost would be US \$328 billion/annum. It is estimated that US \$8.1 billion/annum was spent on vision products including eyeglass frames, lenses, and contact lenses in the USA in 1990 [14]. In United States, a cross-sectional study demonstrated that 110 million Americans could achieve normal vision with refractive correction and the estimated cost was US \$3.8 billion/annum [15]. Of this amount, the annual cost of providing distance vision correction for adults older than 65 years old was US \$780 million. The types of refractive error included correction for myopia, hyperopia, and presbyopia. This represents approximately US \$35 per person or US \$13 per capita annually, based on the cost of a pair of spectacles and refractive examination. Possible reasons for the difference in direct costs of refractive correction are the treatment costs may be borne by the individual, who may be willing to pay for other factors such as aesthetics. Whereas in some countries (e.g., the United Kingdom), some segments of the population are entitled to free eye glasses subsidized by the government. As the prevalence of myopia increase in East Asia, the total cost of treating myopia will be high. There is likely to be an increase in the demand for optical services as the number of older people increases and if, as suggested, the number of younger people with myopia increases. It is estimated that partial sight and blindness in adults costs the UK economy around £22 billion per year [16].

The cost of spectacles varies, but there may some individuals who may not be able to afford a basic pair of spectacles, and hence refractive error may not be fully corrected. Health economic analyses in the United States and Australia have reported the economic burden of refractive correction associated with medical care expenditure, informal care days, and healthy utility is greater than age-related macular degeneration, primary open-angle glaucoma, and diabetic retinopathy, while it was secondary to the medical cost of age-related cataract [17, 18]. As the economic costs of myopia are high, more efforts and resources could be directed toward having new strategies to prevent and slow down myopia progression to high myopia and its associated visually disabling ocular complications.

#### **3.3 Secondary Impact of Myopia from Other Eye Diseases and Sight Loss**

High myopia increases the risk of other eye diseases such as cataract, glaucoma, retinal detachment, and myopic macular degeneration (MMD), which may lead to irreversible vision loss. MMD has been reported to cause 12.1% of VI (approximately 200,000 people) in Japan [19]. Visual impairment and blindness impact the individuals, their families, caregivers, and the community, which lead to a signifcant cost burden. In Australia, visual disorders were ranked seventh among diseases in terms of economic burden on the health system, which is ahead of coronary heart disease, diabetes, depression, and stroke [20]. Naidoo et al. estimated the potential global economic productivity loss resulting from VI and blindness as a result of uncorrected myopia and MMD in 2015 [2]. Their study suggests that the greatest burden of VI resulting from uncorrected refractive error is older people in rural areas of the least developed countries. The regional productivity loss owing to VI resulting from myopia may be refected in Southeast Asia, South Asia, and East Asia as having a percentage gross domestic product (GDP) of 1.35%, 1.3%,

57

and 1.27%, respectively. Differences in productivity loss arises from the interplay between country-specifc variables, such as myopia and high myopia prevalence, demographics, Health Development Index (HDI), health expenditure, urbanization, labor force participation, employment, GDP, and population. There are other components that contribute to the overall burden of myopia, such as cost of eye examinations, refractive corrections, managing pathologic consequences of myopia such as MMD, and related opportunity costs. The value of any investment to prevent myopia, slow progression of myopia, improve spectacle correction rates, and improve outcomes in MMD depends on a comparison of lost productivity owing to VI resulting from myopia with the cost of prevention and management interventions. Fricke et al. estimated the global cost of facilities and personnel for establishing refractive care services US \$20 billion over 5 years [9]. Direct medical costs occur mostly due to hospitalization, the use of direct medical services, and medical products. Hospitalization and use of medical services around diagnosis and treatment at the onset of VI and blindness were the two largest components related to direct medical costs. The mean annual expenses per patient to be US\$ purchasing power parities (PPPs) 12,175–14,029 for moderate VI, US\$ PPPs 13,154–16,321 for severe VI, and US\$ PPPs 14,882–24,180 for blindness [21]. PPPs account for differences in price levels between countries, and convert local currencies into international dollars by taking into account the purchasing power of different national currencies and eliminates the difference in price levels between countries [22]. Direct nonmedical costs include assistive devices and aids, home modifcations, and costs for healthcare services such as home-based nursing or nursing home placements. The cost for support services and assistive devices increased from US\$ PPP 54 for a person with visual acuity (VA) 20/20 or better up to US\$ PPP 609 for a person with VA 20/80 or worse. Indirect costs include productivity losses, changes in employment (employer and/or area of work), loss of income, premature mortality, and dead-weight losses [21]. Dead-weight losses, also known as excess burden, describe the costs to society created by market ineffciency. In the study by Köberlein et al., it is referred to as an excess fnancial burden on society caused by VI and blindness [21]. The annual estimates of productivity losses and absenteeism range from US\$ PPP 4974 to 5724 million and a decrease in workforce participation range was estimated to be US\$ PPP 7.4 billion [21].

#### **Value of the Commercial Optical Good Sector**

In the UK in 2017, the optical goods and services industry had total consumer spending estimated at £3.1 billion (2.0 billion US\$ = @ 0.66 £:\$). Growth was estimated at 2% for 2017, and forecasts projected further 3.2% growth in 2018. Market research suggests this was primarily driven by an aging population. In the UK, 70% of consumers are reported to wear some form of prescription eyewear. Just 11% of those with vision correction need wear contact lenses, with this sector characterized by a high rate of premium and daily wear lenses. Contact lenses account for 20% of the total spending on optical products, with the sale of contact lens solutions made up an additional 3% of the market, compared to 60% market share for spectacle frames and lenses. Only one in six (18%) people have

purchased optical products online. Reports suggest that consumers perceive buying prescriptions eyewear online as harder—49% of people buying prescription eyewear saying it is more diffcult than buying in-store, although 45% of consumers who said they have not bought optical products online before, would consider doing so in the future [23].

#### **3.4 Quality of Life**

Quality of life is a multidimensional construct with different domains. The identifed domains related to ophthalmic quality of life include activity limitation, mobility, convenience, health concerns, visual symptoms, ocular-comfort symptoms, general symptoms, emotional well-being, and social and economic issues [24]. Impaired vision will lead to signifcant reduction in activities associated with participation in society and religion, mobility, daily living, and visually intensive tasks. This may impact education, employment, child development, mental health, and functional capacity in older people, increasing the risk of hip fractures and the need for community or family support or nursing home placement [25–27]. A cross-sectional study in Germany reported that mild VI affected emotional well-being [28]. Depression was considered to cause further functional decline in visually impaired patients by reducing motivation, initiative, and resiliency [29–31]. Visual impairment and blindness associated with myopic macular degeneration will increase signifcantly, hence affecting the quality of life and causing socioeconomic impact [32]. A cross-sectional study reported the functional status in daily life and quality of life of pathologic myopia patients were reduced compared with control subjects [33]. The infuence of pathologic myopia on a patient's daily life was primarily the result of three major factors: handicap, disability, and support. Wong et al. reported that those with VI, measured in terms of presenting vision (i.e., wearing their habitual correction), had statistically signifcantly lower scores for total quality of life (−3.8; 95% CI −7.1 to −0.5; *P* = 0.03), psychosocial functioning (−4.2; 95% CI −8.1 to −0.3; *P* = 0.03), and school functioning (−5.5; 95% CI −10.2 to −0.9; *P* = 0.02) [34]. Another study indicates that correction of refractive errors by the provision of spectacles in low socioeconomic areas in China would markedly improve educational outcomes since the major medium of instruction is the blackboard [35].

Patients with cataract may experience vision-related problems, such as decreased visual acuity, loss of contrast sensitivity, problems under glare conditions, and altered color recognition [36]. Studies in Japan and Canada reported a loss of wellbeing as disability adjusted life years (DALYs) and an associated cost of US\$ PPP 51.8 billion/annum and US\$ PPP 15.11 billion/annum, respectively [37, 38]. The global burden of diseases study 2010 estimated the burden of disease related to vision disorders has increased by 47% from 12,858,000 disability adjusted life years (DALYs) in 1990 to 18,837,000 DALYs in 2010 [39]. The Melbourne Visual Impairment Project (VIP) cohort showed the association between VI and mortality to increase linearly from 4.5% in people with a VA of 20/20 or better to 22.2% in blind people with VA of 20/200 or worse [40].

#### **3.5 Impact of Myopia Treatments on Quality of Life**

Current treatment options for control of myopia progression include optical correction such as bifocal spectacle lenses, progressive addition spectacle lenses, under-correction, orthokeratology, multifocal contact lenses, increased exposure to outdoor activities, and the use of atropine eye drops. Surgical techniques, such as LASIK, have become increasingly popular and over a million surgical procedures are performed annually in the United States [41]. Choice of refractive correction leads to various quality-of-life implications. Often, the type of refractive correction depends on prescription, lifestyle including occupational and recreational needs, economic issues, and personality. If refractive error may be corrected through the provision of corrective spectacles, visual acuity, and therefore functional vision could be improved. Patient reported outcomes (PROs) have been used to assess the outcomes of interventions on people's lives. A PRO is described as a report that comes directly from a patient regarding the impact of the condition and outcome of an intervention [42]. The Quality of Life Impact of Refractive Correction (QIRC) is useful to detect differences in quality of life impact from various refractive corrections (spectacles, contact lenses, and refractive surgery). Pesudovs et al. reported that QIRC score was highest in refractive surgery patients (mean QIRC score of 50.2 ± 6.3), followed by contact lens wearers (mean QIRC score 46.7 ± 5.5), and spectacle wears (mean QIRC score 44.1 ± 5.9) [43]. Orthokeratology (OrthoK) contact lenses (CL) are worn while sleeping to reshape the cornea and are used to correct refractive error and slow the progression of myopia [44]. Quality of life using the National Eye Institute Refractive Error Quality of Life (NEI RQL)-42 questionnaire was evaluated in a group of subjects with low to moderate myopia who had undergone four types of refractive correction, namely, LASIK, OrthoK, soft contact lens (SCL), and spectacles [45]. Results showed decrease in quality of life for most of the subscales in the treatment groups compared to emmetropic subjects. The average decrease in quality of life compared with emmetropes were −7.1% (*P* = 0.021) for LASIK, −13.0% (*P* = 0.001) for OrthoK, −15.8% (*P* = 0.001) for spectacles, and −17.3% (*P* = 0.001) for SCL. The subscales which were affected in LASIK and OrthoK patients compared to emmetropes were as follows: clarity of vision, expectations, glare, and worry. This suggests that both types of treatment affected the quality of life due to high-order aberrations [46]. LASIK and OrthoK are commonly associated with experiencing haloes and glare because of the dramatic changes in the corneal shape [47]. Spectacle wearers had the worse scores in expectations, dependence on correction, worry, and appearance as compared to the other three treatment modalities [45]. The primary motivation for undergoing LASIK was a desire to improve uncorrected visual acuity, without a need to wear glasses and improved ease to pursue sports or recreational activities [48]. Although LASIK patients may have excellent vision during day time, they may experience disturbances in night vision such as halo and glare disability [49]. An estimated 12–57% of patients experience night vision symptoms and 30% have diffculty with night driving after undergoing photorefractive keratectomy (PRK) and LASIK [50, 51]. In addition, these patients may experience poor vision in low light setting due to contrast sensitivity decreasing initially after LASIK [52].

OrthoK allows patients to enjoy good vision without needing to wear vision correction during their waking hours. This benefts patients who have an active lifestyle as they are more mobile without the need for refractive correction. OrthoK provides excellent vision and improves vision related quality of life [45, 53]. Side effects of OrthoK include halos secondary to spherical aberration, which may reduce visual acuity and contrast sensitivity or discomfort from the lenses [54]. Although the most serious complication with CL wear is infection, these occurrences are relatively rare [55, 56]. Most common complaints are related to intolerance or limited wearing time due to fuctuations of vision, dryness and discomfort [57]. Atropine has been used to control myopia progression [58]. As atropine causes pupil dilation and temporary paralysis of accommodation, patients may experience glare, discomfort, blurred vision, or allergic/hypersensitivity reactions. Complications of LASIK include corneal ectasia [59], dry eyes [60], and night vision disturbances [49].

Cataract surgery is a highly effective, cost-effective health-care intervention [61], and results in almost immediate visual rehabilitation. In addition to visual rehabilitation from media opacities, it offers once in a lifetime opportunity for refractive manipulation that benefts the majority of people with a refractive error. Previous studies have utilized Visual Functioning Index-14 (VF-14) or similar vision-functioning tools and reported the impact of cataract surgery can be translated beyond visual acuity. Evidence has shown several fold improvements in other critical daily tasks such as read critical daily living tasks such as reading newspapers or books; driving; watching TV; cooking; negotiating steps; sewing, knitting, crocheting, or doing handicrafts; noticing traffc, information or shop signs; and recognizing people [62]. In addition, there are improvements in several psychosocial aspects such as social interaction; mental and emotional well-being; psychological distress; adaptation; and coping.

#### **3.6 Summary**

Myopia is a major global public health concern due to its high and increasing prevalence in Asian countries, where it is a common cause of vision dysfunction. Uncorrected myopia is a leading cause of visual impairment. People with high myopia have increased risk of developing myopic pathologies which may lead to blindness. The economic burden of uncorrected distance refractive error, largely caused by myopia, is estimated to be US \$202 billion annually. Direct cost of refractive correction comprises of cost from spectacles, contact lenses, and refractive surgeries. Other medical costs include those associated with treatment of ocular complications from high myopia, such as retinal detachment, myopic macular degeneration, glaucoma and cataract, and its associated visual impairment and blindness. This global cost will continue to increase as the number of people with myopia rises. Patients with higher myopic refractive error tend to have adverse effect on the quality of life and lead to lower health, economic, and social outcomes. Effective methods to control or correct myopia include the use of optical devices, pharmacological drops, surgical, or outdoor exposure. Each treatment method will have various quality of life implications; thus, it is important to ensure prescription, lifestyle including occupational and recreational needs, and economic issues are discussed. Although a broader societal perspective is useful for informing policy, the patient's perspective is essential for designing service models to improve the social interaction and mental and emotional well-being of these individuals. In conclusion, the impact that myopia and its associated visual impairment have on individuals is substantial. Myopia preferentially affects the more highly educated and potentially most productive sectors of the population, the individual and societal costs involved. Developing appropriate public health policies to prevent and reduce myopia progression will beneft the individual and the wider society.

#### **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

## **4 Understanding Myopia: Pathogenesis and Mechanisms**

### Ranjay Chakraborty, Scott A. Read, and Stephen J. Vincent

#### **Key Points**

#### **4.1 Emmetropization and Normal Ocular Growth in Human Eyes**

When incident parallel rays of light from distant objects are brought to a focus upon the retina without accommodation, it is known as emmetropia. During postnatal eye growth, the precise matching of the axial length (the distance from the anterior corneal surface to the retina along the visual axis) and the optical power of the eye brings the eye to emmetropia [1, 2]. This active regulatory process that harmonizes the expansion of the eye with the optical power of the cornea and the crystalline lens

R. Chakraborty (\*)

Flinders University, Adelaide, SA, Australia e-mail<EMAIL_ADDRESS>
S. A. Read · S. J. Vincent Queensland University of Technology, Brisbane, QLD, Australia

is known as emmetropization [1]. Any disruption to these highly coordinated ocular changes results in the development of refractive errors, wherein distant images are focused either behind (hyperopia) or in front (myopia) of the retina [1].

Human eyes exhibit a distinctive pattern of eye growth during the early period of visual development. The distribution of refractive errors at birth appears to be normally distributed [3, 4]. Apart from some exceptions [5], the majority of newborn infants are moderately hyperopic (~+2.00 to +4.00 D) and this refractive error reduces signifcantly during the frst 18 months of life [3, 6–8] (Fig. 4.1). By about 2–5 years of age, the distribution becomes leptokurtic with a peak around emmetropia to low hyperopia of about +0.50 to +1.00 D [5, 6, 8, 11, 12]. Although studies have reported small reductions in hyperopic refraction until the middle to late teen years [13, 14], emmetropization is believed to be largely completed by 5–6 years of age [5, 6, 8, 14].

Based on the visually guided ocular growth observed in a variety of animal models [15–17] (see Sect. 4.3), the growth of the human eye is also believed to be modulated by an active visual feedback from the hyperopic refractive error in neonatal eyes [18]. Studies have found a strong correlation between the rapid reduction in hyperopia and the changes in axial length during early ocular development [18, 19]. Human eyes are ~17 mm long after birth and grow to about 20 mm after the frst year [11, 18–20]. This rapid expansion of the eye is largely attributed to the

**Fig. 4.1** Comparison of refractive error distribution among newborns [3] and 6–8-year-old children [9]. The distribution of refractive errors narrows between infancy to early childhood during the process of emmetropization. Adapted from FitzGerald and Duckman [10]

expansion of the vitreous chamber [18, 21]. From 2–3 years of age, axial elongation slows to approximately 0.4 mm/year until preschool age [11]. Consistent with changes in ocular refraction, the growth of the eye stabilizes further at 5–6 years, and only increases by 1–1.5 mm through the teenage years [11, 20, 21]. Together, these studies suggest that axial length is the most infuential factor for emmetropization in human eyes.

In addition to changes in axial length, there is also a signifcant reduction in the refractive power of the cornea and the crystalline lens that contributes to the overall reduction in hyperopia in the frst year of life [11, 18, 22]. Mutti et al. [18] reported a reduction of 1.07 and 3.62 D in corneal and crystalline lens powers, respectively, associated with fattening of the corneal and lens radii in newborn infants, between the ages of 3 and 9 months. Studies have also found higher degrees of corneal astigmatism in newborn infants [23–28], which reduces during the frst 4 years of life and is associated with corneal fattening [24, 27, 29, 30]. Overall, these studies suggest that emmetropization in human eyes is largely attributed to the changes in axial length with minor contributions from corneal and crystalline lens powers.

Refractive errors occur as a result of either variations in (a) axial length with respect to the total refractive power of the eye (termed axial myopia or hyperopia) or (b) refractive power of the cornea and the crystalline lens with respect to the axial length of the eye (termed refractive myopia or hyperopia). This chapter focuses on the pathogenesis and potential underlying mechanisms of myopia, and the following section discusses the changes in different ocular parameters during myopic eye growth.

#### **4.2 Ocular Biometric Changes in Human Myopia**

As discussed earlier, the axial length of the eye is the primary biometric determinant of refractive error; however, the dimensions, curvature, and refractive index of each individual ocular structure contribute to the fnal refractive state. Ocular biometrics vary considerably throughout childhood, during the development and progression of myopia, and in response to clinical myopia control interventions.

#### **4.2.1 Cornea**

Several cross-sectional analyses have revealed a weak association between increasing corneal power (a steeper radius of curvature) and increasing levels of myopia [31–33], while others report no association [34], or the opposite relationship [35]. Longitudinal studies indicate that changes in corneal curvature during childhood [36–38] and early adulthood [39] are minimal and not associated with the magnitude of myopia progression. However, since the correlation between spherical equivalent refraction (SER) and the axial length to corneal radius ratio is typically stronger than that of axial length alone (by 15–20%) [40–43], corneal curvature does appear to make a modest contribution to the magnitude of myopia. Although corneal thickness does not vary systematically with refractive error [44–47], a reduction in corneal hysteresis (an estimate of corneal biomechanical strength or viscoelasticity) has been observed with increasing levels of myopia in children [48, 49] and adults [50–52]. However, the causal nature of this relationship remains unclear, or if such corneal metrics correlate with posterior scleral biomechanics.

#### **4.2.2 Crystalline Lens and Anterior Chamber Depth**

While the cornea fattens substantially during infancy and then remains relatively stable throughout childhood, the crystalline lens continues to thin, fatten, and reduce in optical power until approximately 10 years (a 0.25–0.50 D reduction per year), concurrent with lens fber compaction [53–55]. These changes may be part of an emmetropization mechanism to compensate for continued axial elongation or a mechanical consequence of equatorial eye growth. Across a range of ethnicities, Mutti et al. [56] observed that within 1 year of myopia onset, compensatory crystalline lens thinning and fattening abruptly halted compared to children who remained emmetropic (Fig. 4.2), suggesting that childhood myopia is not purely axial in nature, but involves a decoupling of highly correlated anterior and posterior segment eye growth. In Singaporean children, Iribarren et al. [57] reported a transient acceleration in the reduction of lens power during myopia onset when the rate

**Fig. 4.2** The change in crystalline lens thickness as a function of age in myopes and emmetropes during childhood (after Mutti et al. [56]). Shortly after myopia onset (10–12 years), compensatory crystalline lens thinning abruptly halted compared to children who remained emmetropic suggesting that myopia development involves a decoupling of anterior and posterior segment eye growth

**Fig. 4.3** The change in crystalline lens power during childhood (calculated from refraction and biometric measurements) in young Singaporean children for a range of refractive error groups (after Iribarren et al. [57]) The reduction in lens power increases during myopia onset (to a greater extent than other refractive error groups), but is not sustained throughout myopia progression

of axial growth was high, which was not sustained as myopia progressed (Fig. 4.3). Paradoxically, after 10 years of age, the lens continues to thicken and increase in curvature with the bedding down of additional fbers, but reduces in optical power, most likely due to a steepening of the gradient refractive index [58]. Changes in anterior chamber depth throughout childhood are inversely related to changes in lens thickness (as the lens thins, the anterior chamber deepens), and the anterior chamber is typically deeper in myopes compared to emmetropes and vice versa for the crystalline lens [53].

#### **4.2.3 Vitreous Chamber and Axial Length**

In contrast to the anterior segment, changes in the posterior segment (particularly, the vitreous chamber, choroid, and sclera) are more pronounced in myopic compared to non-myopic eyes (Fig. 4.4). Axial length, or more precisely, the vitreous chamber depth is the primary individual biometric contributor to refractive error in children, young adults, and the elderly [34, 59, 60], with the vitreous chamber depth accounting for over 50% of the observed variation in SER, followed by the cornea (~15%) and crystalline lens (~1%) [60]. Modeling of cross-sectional and

**Fig. 4.4** Optical low coherence refectometry A-Scan output from two 11-year-old males (one myope and one emmetrope). The predominant biometric differences are the deeper vitreous chamber (19.05 mm compared to 15.47 mm) and the longer axial length (25.87 mm compared to 22.69 mm) in the myopic eye. The anterior chamber depth is slightly shallower in the emmetropic eye (by 0.13 mm) while the crystalline lens is thicker (by 0.49 mm) in comparison to the myopic eye. The corneal thickness varies by only 0.04 mm

longitudinal data from emmetropic children indicates that axial length and vitreous chamber depth increase by approximately 0.16 mm per year from age 6–10 years, slowing to 0.05 mm per year from 11 to 14 years [61]. In myopic children aged between 6 and 11 years (corrected with single vision spectacles or contact lenses) average growth rates of approximately 0.30 mm per year have been reported [37, 62, 63], with greater vitreous chamber and axial elongation observed in younger females with myopic parents [37]. A range of myopia control interventions signifcantly slow the rate of eye growth and myopia progression during childhood, in some cases by up to 50% [64], and this reduction in axial elongation appears to be initially modulated by changes in the choroid underlying the retina.

#### **4.2.4 Choroid**

The choroid supplies the outer retina with oxygen and nutrients and regulates intraocular pressure and ocular temperature. The choroid is typically thinner in myopic compared to non-myopic eyes (most pronounced at the fovea [65, 66]) and thins with increasing myopia and axial length in both adults [67–74] and children [75– 77]. Signifcant choroidal thinning is also observed in high myopia (<−6.00 D) or eyes with posterior staphyloma [78], and has been associated with the presence of lacquer cracks [79], choroidal neovascularization [80], and reduced visual acuity [81]. The choroid also appears to be a biomarker of ocular processes regulating eye growth given that the central macular choroid thins during the initial development and progression of myopia [82–84] and thickens in response to imposed peripheral myopic retinal image defocus [85, 86], topical anti-muscarinic agents [87, 88], and increased light exposure [89] (clinical interventions associated with a slowing of eye growth in children).

#### **4.2.5 Sclera**

Scleral thinning associated with axial myopia is primarily restricted to the posterior pole [90–92], due to scleral tissue redistribution [93]. Scleral thinning may alter the tissue strength surrounding the optic nerve head, rendering myopic eyes more susceptible to glaucomatous damage [94, 95]. Consequently, posterior reinforcement surgery using donor scleral tissue has been refned over the years to arrest further axial elongation and scleral thinning in highly myopic eyes [96, 97]. Although anterior scleral thickness is similar between myopic and non-myopic eyes [98–100], there is growing evidence that the anterior sclera thins slightly during accommodation, particularly in myopic eyes [101, 102], most likely due to biomechanical forces of the ciliary muscle. A greater thinning observed in myopic eyes may be a result of a thicker posterior ciliary muscle [103–105] or changes in biomechanical properties of the sclera reported in animal models of form-deprivation myopia [106, 107].

#### **4.3 Visual Environment, Emmetropization, and Myopia: Evidence from Animal Models**

Over the last four decades, numerous animal models have provided valuable insight into the mechanisms underlying emmetropization and refractive error development. Much of the knowledge on vision-dependent changes in ocular growth has emanated from animal experiments in which either the quality of image formed on the retina is degraded (known as form-deprivation [FD]), or the focal point of the image is altered with respect to the retinal plane (known as lens induced defocus). Both FD and lens induced defocus result in abnormal eye growth and development of refractive errors. This section summarizes the attributes of experimental ametropias derived from these two visual manipulations, their differences, and signifcance for understanding refractive error development in humans.

#### **4.3.1 Form-Deprivation Myopia**

FD is the most commonly used experimental paradigm to model axial myopia in animals. Depriving the retina of form or patterned vision through eyelid suture

**Fig. 4.5** Ocular compensation for form-deprivation (FD). (**a**) A diffuser causes nondirectional blur and a reduction in contrast of the retinal image. (**b**) The absence of visual feedback related to the effective refractive state of the eye causes a thinning of the posterior choroid and an increase in ocular growth, resulting in myopia

[108–110], or translucent diffusers [2, 15, 111–114] consistently produces axial myopia (Fig. 4.5). The use of noncontact translucent diffusers offers a more reliable representation of ocular changes with FD since they do not induce corneal changes (unlike eyelid fusion techniques). The ocular changes observed in response to FD clearly illustrate that degrading retinal image quality can produce robust myopic changes. Schaeffel et al. [115] proposed that FD is an open-loop condition, in which myopia develops as a result of uncoordinated ocular growth due to reduced retinal image contrast (or mid-range spatial frequency vision) [116] and the absence of visual feedback related to the effective refractive state of the eye [117].

The myopic response to FD varies among different animals. It is generally greatest in chickens (−9 D after 5 days of FD) [118], followed by tree shrews (−8 D after 12 days in young animals) [119] and guinea pigs (−6.6 D after 11 days) [113], and is less pronounced and much more variable in marmosets (−8 D after 4.5 weeks) [120] and rhesus monkeys (~−5 to −6 D after 17 weeks) [121, 122]. Variations observed between individual studies and animal models may be due to differences in experimental paradigms, the duration and extent of FD, inherent ocular anatomical variations, and/or differences in susceptibility to environmental myopia. Nevertheless, the myopic response to FD is conserved across a wide range of animal species (including fsh, rabbit, mouse, and kestrel) [123]. In all species, axial myopia is predominantly caused by a signifcant elongation of the vitreous chamber, along with thinning of the choroid and the sclera [16, 17, 113, 124–132]. Few studies have also reported changes in corneal curvature and lens thickness with FD [131, 133–135]. Interestingly, ocular conditions that cause varying degrees of visual deprivation in humans such as ptosis [136], congenital cataract [137], corneal opacity [138], and vitreous hemorrhage [139] are associated with myopia, which may result from mechanisms similar to FD myopia observed in animals.

FD myopia is a graded phenomenon, where increasing degrees of image degradation are positively correlated with the magnitude of induced axial myopia [129, 140]. In addition, the effects of FD declines with age. Younger chicks [141, 142], macaques [143], tree shrews [119], and marmosets [144] show greater ocular changes in response to image degradation compared to older animals, potentially due to age-related reductions in sensory processing of blur stimuli or changes in scleral growth [144].

#### **4.3.2 Lens Defocus Ametropias**

Perhaps the strongest evidence of visual regulation of ocular growth comes from animal studies that show eyes can actively compensate for artifcially induced myopic and hyperopic defocus by adjusting the axial length to the altered focal plane (i.e., emmetropization through the treatment lenses) (Fig. 4.6) [145]. Myopic defocus with plus lenses simulates artifcial myopia that leads to a thickening of the choroid (moving the retina forward) and a reduction in the overall growth of the eye, thus, causing a hyperopic refractive error. Conversely, hyperopic defocus with minus lenses induces artifcial hyperopia that leads to a thinning of the choroid

**Fig. 4.6** (**a**) Schematic of imposed lens defocus. With no lens (black arrow), incident parallel rays of light from distant objects are focused on the retina. A plus lens (green, convex) causes the retinal image to focus in front of the retina known as myopic defocus, whereas a minus lens (blue, concave) focuses the image behind the retina known as hyperopic defocus. (**b**) A normal eye with no imposed lens defocus (black) exhibits normal ocular growth and choroidal thickness. Myopic defocus with plus lenses (green) causes a thickening of the choroid (moving the retina forward) and a reduction in the overall growth of the eye, causing a hyperopic refractive error. Hyperopic defocus with minus lenses (blue) leads to a thinning of the choroid (moving the retina backward) and an increase in ocular growth, resulting in myopia. Adapted from Wallman J and Winawer J, 2004 [1]

(moving the retina backward) and an increase in ocular growth, resulting in myopia to re-establish the optimal refractive state. This phenomenon was frst documented in chicks [145], and has been extensively studied in chicks [16, 17, 146–148], tree shrews [149], rhesus monkeys [15, 150], marmosets [151], guinea pigs [152, 153], and mice [154] thereafter, indicating that the mechanisms regulating ocular growth can distinguish the sign of the imposed defocus in a wide range of animal species.

Chick eyes can compensate for a remarkable range of +15 to −10 D of imposed defocus [16, 147]. However, the operating range of defocus is much smaller for other animal species (monkey: −2 to +8 D [15], marmosets: −8 to <+4 D [151], tree shrew: −10 to +4 D [155], guinea pig: −7 to +4 D) [152, 156]. Compared to birds, the inability of primates to compensate for greater magnitudes of defocus may be due to bigger eye size [15, 150], the process of emmetropization [150], differences in the accommodative response to defocus stimuli, and/or the degree of independent accommodation between fellow eyes [15, 150, 157]. In all animals, the axial response to lens induced defocus is dependent upon the power of the treatment lens [147, 149–152, 158], and is predominantly attributed to the changes in vitreous chamber depth [16, 147, 159]. Similar to FD, the ocular response to lens induced defocus decreases with age [16]. Recent evidence suggests that the human visual system may also be able to detect the sign and magnitude of imposed defocus and make compensatory changes in axial length, similar to other animals. A number of studies have reported small bidirectional changes in axial length and choroidal thickness in response to 1–2 h of myopic and hyperopic defocus in children and young adults [160–165].

Studies have shown that the biological mechanisms underlying alterations in ocular growth to myopic and hyperopic defocus may be completely different (and not merely opposite to each other), and that the visual system is perhaps more sensitive to myopic defocus [166, 167]. In fact, the ocular response to lens induced defocus depends on the frequency and duration of lens wear, and not simply the "total duration" per day [166–169]. These fndings argue for a nonlinear processing of myopic and hyperopic defocus signals across the retina [166, 167].

#### **4.3.3 Comparing Form-Deprivation and Lens Defocus**

Although FD and lens induced defocus use different visual stimuli to induce compensatory changes in ocular growth, there are features that are common to both visual manipulations. Removal of the visual manipulation triggers "recovery" from both FD and lens induced defocus [16, 17, 170]. During this recovery phase, the eyes quickly return to emmetropia by reversing the changes in choroidal thickness and axial eye growth (mainly by changing the vitreous chamber depth) [16, 17, 119, 150, 151, 170–173].

Further evidence from animal work suggests that the elimination of accommodation by cycloplegia, ciliary nerve section or damage to the Edinger-Westphal nucleus does not prevent the response to imposed FD [145, 174] or lens induced defocus [148, 175]. These results suggest that intact accommodation is not essential for visually guided growth [176] or there might be another accommodative pathway (not through ciliary and iris sphincter muscles) underlying optical defocus induced alterations in ocular growth [175].