Special Issue

IMI 2023 Digest

Padmaja Sankaridurg,1,2 David A. Berntsen,3 Mark A. Bullimore,3 Pauline Cho,4–6
Ian Flitcroft,7,8 Timothy J. Gawne,11 Kate L. Gifford,10 Monica Jong,9 Pauline Kang,2
Lisa A. Ostrin,3 Jacinto Santodomingo-Rubido,12 Christine Wildsoet,13 and
James S. Wolffsohn14
1
Brien Holden Vision Institute, Sydney, Australia
2
School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
3
University of Houston, College of Optometry, Houston, Texas, United States
4
West China Hospital, Sichuan University, Sichuan, China
5
Eye & ENT Hospital of Fudan University, Shanghai, China
6
Affiliated Eye Hospital of Wenzhou Medical University, Wenzhou, China
7
Centre for Eye Research Ireland, School of Physics and Clinical and Optometric Sciences, Technological University Dublin,
Dublin, Ireland
8
Department of Ophthalmology, Children’s Health Ireland at Temple Street Hospital, Dublin, Ireland
9
Johnson & Johnson Vision, Jacksonville, Florida, United States
10
Queensland University of Technology, Brisbane, Australia
11
Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, Alabama, United States
12
Menicon Company Limited, Nagoya, Japan
13
UC Berkeley Wertheim School Optometry & Vision Science, Berkeley, California, United States
14
College of Health & Life Sciences, Aston University, Birmingham, United Kingdom

Correspondence: Padmaja Myopia is a dynamic and rapidly moving field, with ongoing research providing a better
Sankaridurg, School of Optometry understanding of the etiology leading to novel myopia control strategies. In 2019, the
and Vision Science Level 3, Rupert International Myopia Institute (IMI) assembled and published a series of white papers
Myers Building, University of New across relevant topics and updated the evidence with a digest in 2021. Here, we summa-
South Wales, NSW 2052, Australia; rize findings across key topics from the previous 2 years. Studies in animal models have
[email protected].
continued to explore how wavelength and intensity of light influence eye growth and
Received: January 29, 2023 have examined new pharmacologic agents and scleral cross-linking as potential strategies
Accepted: February 8, 2023 for slowing myopia. In children, the term premyopia is gaining interest with increased
Published: May 1, 2023 attention to early implementation of myopia control. Most studies use the IMI defini-
Citation: Sankaridurg P, Berntsen tions of ≤−0.5 diopters (D) for myopia and ≤−6.0 D for high myopia, although cate-
DA, Bullimore MA, et al. IMI 2023 gorization and definitions for structural consequences of high myopia remain an issue.
digest. Invest Ophthalmol Vis Sci. Clinical trials have demonstrated that newer spectacle lens designs incorporating multi-
2023;64(6):7. ple segments, lenslets, or diffusion optics exhibit good efficacy. Clinical considerations
https://doi.org/10.1167/iovs.64.6.7 and factors influencing efficacy for soft multifocal contact lenses and orthokeratology
are discussed. Topical atropine remains the only widely accessible pharmacologic treat-
ment. Rebound observed with higher concentration of atropine is not evident with lower
concentrations or optical interventions. Overall, myopia control treatments show little
adverse effect on visual function and appear generally safe, with longer wear times and
combination therapies maximizing outcomes. An emerging category of light-based ther-
apies for children requires comprehensive safety data to enable risk versus benefit anal-
ysis. Given the success of myopia control strategies, the ethics of including a control arm
in clinical trials is heavily debated. IMI recommendations for clinical trial protocols are
discussed.
Keywords: myopia, definitions, experimental models, interventions, ethical considera-
tions, clinical management

T echnological advances and innovations for managing

myopia are gathering pace. Compared to 2019 when
the first key International Myopia Institute (IMI) white
The principal purpose of the digests is to provide
a comprehensive and systematic review of the recently
published evidence across the various domains in the field of
papers were published, the needle with respect to “standard- myopia. The compilation and presentation of these digests
of-care” practice has shifted significantly toward manag- rely on the experts in the field of myopia to scour and
ing myopia with treatments to slow the progression of digest the vast trove of published data and provide a succinct
myopia. summary of the changes in the field. Aimed at academics

Copyright 2023 The Authors

iovs.arvojournals.org | ISSN: 1552-5783 1

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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 2

and practitioners as well as other interested professionals SER threshold for myopia with an uncorrected visual acuity
and the public, the digests aim to serve to disseminate the (VA) threshold in noncycloplegic studies.1 More sophisti-
latest advances in the field, to serve as a concise repository, cated corrective analyses may further improve the validity of
and to also provide a means of recording the progress in the noncycloplegic prevalence estimates. For example, He et al.5
field. The yearly digest 20211 reviewed the advances in the used a previously published correction formula that includes
field since the publication of the first set of IMI white papers uncorrected VA, age, and noncycloplegic refraction to esti-
in February 2019. mate the true cycloplegic refraction.6
In this digest, the panel has identified and summarized Myopia remains the refractive error of greatest research
the following key areas: interest at present, with other categories of refractive error
receiving less attention. The aim of recommending thresh-
• Definitions and classification of myopia olds for myopia and high myopia within the IMI white paper
• Experimental models of emmetropization on defining and classifying myopia was to promote consis-
• Myopia control trials and instrumentation tency in reporting and to aid study comparisons and meta-
• Interventions for controlling myopia onset and analyses. It is valid to ask if definitions for other forms of
progression refractive error show a high level of consistency. A recent
• Industry guidelines and ethical considerations meta-analysis of population refraction data that included 41
• Clinical management guidelines studies with over a million participants in China reveals an
interesting pattern, as shown in the Figure.7 Among the 41
All sections provide updates in the field since the yearly studies, there was good consensus on the threshold values
digest of 2021 except for the industry guidelines and ethi- of −0.5 D for myopia and −6.0 D for high myopia, but little
cal considerations section, which reviews the field since the agreement as to whether to use ≤ or < within the definition.
original IMI white paper on this topic.2 For hyperopia, there was clear preference for a threshold of
SE ≥2.0 D, but only just over half of the surveys (23/41)
actually reported a threshold or prevalence figure for hyper-
IMI DIGEST: DEFINITIONS AND CLASSIFICATION opia. Reports for astigmatism showed even more variability,
with a threshold of SE ≥0.75 D being commonest.
OF MYOPIA In this large collection of studies, emmetropia was
Thresholds for Myopia, High Myopia, Hyperopia, defined by exclusion, as is often the case (i.e., as eyes that
Astigmatism, and Emmetropia did not qualify as myopic or hyperopic), so the variability
in the definition of emmetropia reflects the combination of
Recognizing the challenges and limitations of fixed thresh- the variability of the definitions for myopia and hyperopia.
olds for defining myopia, the original IMI report recom- Although this leads to nine different numerical definitions
mended adapting the threshold to the nature of the research among the 23 studies that defined both myopia and hyper-
and providing sensitivity analyses at different thresholds.3 opia, there is a clear consensus leader where emmetropia
A recent large population survey covering over a million was defined as SE >−0.50 D and SE <2.0 D in 11 of these
participants described population-based prevalence figures studies. This definition can be considered a reasonable basis
for myopia in the city of Weifang, China.4 The study was for classifying functional emmetropia in children with good
conducted without cycloplegia, and myopia was defined accommodation but not in an older population. Further-
as a spherical equivalent (SE) refraction (SER) of ≤−0.75 more, it differs from the conventional optical definition of
diopters (D). Analyses were provided at two different thresh- emmetropia as a refractive state of the eye where a distant
olds for myopia and high myopia, which included the IMI object is in sharp focus on the retina when the ciliary muscle
recommended levels of ≤−0.5 D for myopia and ≤−6.0 is fully relaxed. Perhaps most critically, if emmetropia is to
D for high myopia. Setting a higher threshold for myopia be equated with clear distance vision, then defining it on the
in noncycloplegic surveys is becoming more common. He basis of SE ignores the detrimental visual impact of astigma-
et al.5 reported prevalence figures for myopia at a thresh- tism.
old of ≤−1.0 D on account of the lack of cycloplegia but The original white paper on defining and classifying
reported the prevalence for high myopia at a threshold of myopia proposed thresholds for myopia and high myopia
≤−5.0 D. It is well recognized that noncycloplegic studies based on the SER while acknowledging that consideration
will overestimate myopic prevalence and provide relatively of astigmatism and off-axis refraction may be more relevant
more myopic refractions, especially in hyperopic individu- for certain research questions. SER’s dominance in epidemi-
als. These differences support adoption of a more myopic ologic and myopia control trials is most likely based on
threshold for myopia but not a less myopic threshold for the statistical ease of analyzing refraction as a single scalar
high myopia. Note that He et al.5 did also report high myopia variable. But it is an imperfect characterization of refrac-
prevalence figures at a threshold of ≤−6.0 D to “enable tive status. As noted in a recent article, considering both
comparisons with previously published data.” astigmatism and interocular differences allows for a more
Changing the diagnostic thresholds of myopia to account complete description of refractive errors.8 The proposal for
for lack of cycloplegia is one valid approach. In the origi- emmetropia from the latter study provides for an abso-
nal IMI white paper, the proposed definition of myopia did lute SE error <0.50 D and ≤0.75 D of astigmatism, which
not stipulate cycloplegia as a requirement but included the would provide for age-independent, good unaided VA. In
condition “when ocular accommodation is relaxed.” This was the era of active refractive error management, emmetropia
intentional to avoid potentially invalidating many epidemi- can be considered the goal of myopia prevention. When the
ologic studies in adults, but a large number of studies are measure of success for myopia control is achieving a final
now reporting prevalence data for myopia in children with- refraction and/or axial length (AL) as close to emmetropic
out the use of cycloplegia. In the 2021 IMI digest, we noted values, the lack of consensus on defining emmetropia is all
the growing use of a combination of the recommended the more remarkable and merits addressing.

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FIGURE. Criteria used to define myopia, high myopia, hyperopia, and astigmatism in 41 studies as extracted from Tang et al.7 NA, not
available.

Premyopia eye, including the crystalline lens, as demonstrated in a

recent paper.16
In school-age children, refraction typically changes over As noted in the 2021 digest, there are several large ongo-
several years, with slow myopic shifts in hyperopes and ing trials targeting the premyopic phase with interventions
more rapid myopic shifts in myopes. In this age group, such as atropine, and results from a recent small trial indi-
emmetropia can be a transient state. Indeed, as very few cate that this represents a valid therapeutic approach, but
children are born myopic, nearly all adult myopes have tran- larger and more definitive studies are required.11
sitioned through emmetropia at some point. The concept of
premyopia, which was formally defined in a previous IMI
white paper, addresses the dynamic nature of emmetropia The Structural Consequences of High Myopia
in young children. In the 2021 digest, there were relatively The original IMI white paper on defining and classify-
few new publications addressing the concept of premyopia, ing myopia noted that the terminology around the struc-
but it has been gaining traction since and is the focus of tural consequences of high myopia is by no means settled.
several recent papers.9–11 While pathologic myopia remains a commonly used term
The fact that premyopia, as determined by cycloplegic to capture this overall concept, a range of terms is used to
refraction, is the commonest refractive state in preschool describe aspects of this condition. For the retinal complica-
children in Taiwan suggests that many of the factors driving tions, both myopic maculopathy and myopic macular degen-
the high rates of myopia in Asia are having an effect even eration are common and almost interchangeably used. A
before children start school.9 A similar distribution of refrac- recent paper has demonstrated the challenges of creating
tive errors in primary school students has recently been robust definitions. Choroidal neovascularization in eyes with
demonstrated by a series of papers from China, referring high myopia that do not meet the pathologic myopia defini-
to the feature as the concept of low hyperopia reserve, but tion of the META-Analysis of Pathologic Myopia Study group
it appears to be closely aligned with the concept of premy- ended up not being classified as either age-related macular
opia.12–14 degeneration or myopic choroidal neovascularization.17
While many studies have attempted to predict myopia Recent research in the area covered by the terms myopic
onset, identifying future myopes in their premyopic phase maculopathy and myopic macular degeneration can be
offers the prospect of early intervention. Identification of largely grouped into longitudinal observational studies,
predictive factors of progression into myopia will allow a anatomic/functional studies, and studies of interventions
more precise definition of premyopia. That, in turn, will to manage myopia-related complications. While the link
help to separate young premyopes from stable emmetropic between these conditions and age has been well docu-
peers.10,15 Detailed longitudinal studies offer the best mented, valuable supportive evidence was published in
prospect of understanding the dynamics of myopia develop- 2022 regarding the interaction between age and the macular
ment from the premyopic phase to manifest myopia. Ideally, complications of myopia in both Asia and Europe.18–21
such studies should consider all optical components of the Modern technology such as ultra-widefield optical

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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 4

coherence tomography is providing new insights into myopes who could potentially benefit from myopia control
the scleral complications of pathologic myopia.22 The role treatments. This could be a useful step in getting such treat-
of capillary perfusion in the evolution of the macular ments included in governmental and insurance-based health
complications of myopia remains a topic of major interest plans. There are currently no approved treatments to reduce
with a range of recent papers providing new insights.23–25 the risk of premyopia developing into myopia, but if, as is
In relation to surgical treatments for pathologic myopia, likely, such therapies are introduced, a diagnostic code for
the term myopic traction maculopathy is increasingly being premyopia would also be worth considering.
used in studies and meta-analyses of surgical outcomes A suggestion was also made in 2018 to the WHO to
from vitrectomy and inner limiting membrane peeling.26–28 replace the rather outdated term degenerative myopia that
While refractive error, AL, and age remain the strongest had been carried across from the ICD-10 to ICD-11 with
predictors for the development of pathologic myopia, iden- the term pathologic myopia, which is much more widely
tification of other modifiable risk factors for sight loss would used in clinical practice. A range of synonyms was suggested
be very valuable. An intriguing pilot study from Singapore to be included, which would increase the chance of accu-
has demonstrated a possible autoimmune contribution, with rate encoding of such cases. The latest version of the
one or more serum antiretinal autoantibodies present in ICD-11 coding tool (https://icd.who.int/ct11/icd11_mms/
all patients in this small cohort of 16 patients.29 Over 50% en/release) now includes an extensive list of matching terms,
of patients were positive for anti–carbonic anhydrase II, including pathologic myopia, which should make coding
antibodies that are more typically present in patients with more consistent, even with the multiplicity of terms in
cancer-associated retinopathy. Such new lines of research current use. Nonetheless, at the time of preparing this digest,
are important since for adult high myopes, neither their the term degenerative high myopia (code 9B76) remains the
refraction nor age represent modifiable risk factors. For the principal diagnostic term for myopic complications in the
large cohort of adult myopes who grew up in an era before ICD-11 classification listed under “Disorders of the Retina”
any myopia control therapies, there is an urgent need for and is defined as follows:
intervention studies that can make sight-threatening conse-
quences of their myopia less inevitable. “Macular lesions occurring in people with myopia, usually
high myopia, causing a decrease of the best corrected visual
acuity and comprising myopic chorioretinal atrophy, myopic
Myopia Definitions and the International choroidal neovascularization and myopic retinoschisis.”
Classification of Diseases, 11th Revision Other pending definitions within the ICD-11 include new
codes that reflect some specific retinal complications of
At the time of writing of the original 2019 IMI white paper
myopia, including the following:
on myopia definitions, a submission was made to the World
Health Organization (WHO) with suggestions for improving 9B76.1 Myopic maculopathy
several of the definitions within the then draft version of the 9B76.2 Myopic traction maculopathy
International Classification of Diseases, 11th Revision (ICD- 9B76.3 Macular hole in high myopia
11). The proposed descriptive definition for myopia (code 9B76.4 Retinal detachment in high myopia
9D00.0) has largely been incorporated within the current
definition, which now correctly attributes most myopia to Within the ICD-11, degenerative high myopia is catego-
axial elongation while acknowledging possible contribu- rized as a retinal condition but fails to capture the sight-
tions from the cornea and/or crystalline lens (see new threatening complications of high myopia such as posterior
definition below). This development represents a signifi- staphyloma and myopia-associated optic neuropathy. These
cant improvement over the International Classification of other additional features represents a challenge within the
Diseases, 10th Revision (ICD-10) definition. The ICD-11 and hierarchical structure of the ICD-11, since retinal, optic
IMI definitions of myopia are now well aligned with minor nerve, and scleral disorders are distinct categories. There-
differences in phrasing. fore, degenerative high myopia may most appropriately be
replaced either by the WHO-approved term myopic macu-
ICD-11 Myopia 9D00.0: A refractive error in which rays of lar degeneration or myopic maculopathy within the exist-
light entering the eye parallel to the optic axis are brought to ing structure. The definition could also be further updated
a focus in front of the retina when ocular accommodation is to replace myopic retinoschisis with myopic traction macu-
relaxed. This usually results from the eyeball being too long lopathy to better align it with modern usage. This would
from front to back, but can be caused by an overly curved require the recognized optic nerve and scleral complications
cornea, a lens with increased optical power, or both. It is also of high myopia to be placed elsewhere within the classifica-
called near-sightedness. tion structure.
Optic nerve conditions such as glaucomatous optic
IMI Myopia Definition: A refractive error in which rays
neuropathy (9C40.9) are listed under the category of “Disor-
of light entering the eye parallel to the optic axis
ders of the Visual Pathways or Centres” within code 9C40
are brought to a focus in front of the retina when
(disorder of the optic nerve). High myopia-associated optic
ocular accommodation is relaxed. This usually results
neuropathy could then reasonably be placed in the same
from the eyeball being too long from front to back,
grouping as 9C40.10. While there is an existing code for
but can be caused by an overly curved cornea and/or
scleral staphyloma (9B52), degenerative myopia (9B76) is
a lens with increased optical power. It also is called
listed as an explicit exclusion. Therefore, myopia-associated
nearsightedness.
posterior staphyloma does not exist within the current clas-
With the advent of approved interventions to slow sification, and a strong case can be made for a code such
myopia progression, a strong case could also be made to as 9B53 for “posterior staphyloma in high myopia.” Such a
include a code and definition for “progressive myopia.” Such solution would provide a coherent placement of the compo-
a code would facilitate identification of young, progressive nents of pathologic myopia within the ICD-11 but leave the

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term itself as the overarching concept covering all the struc- uses integrated visual experience over time to evaluate the
tural complications of myopia. This would also be in keeping magnitude and sign of defocus, with relatively brief peri-
with the perspective of the original 2019 IMI white paper on ods of myopic blur being able to counteract relatively longer
definitions and classifying myopia. periods of hyperopic blur.2,7,8
With the complexity of these issues and the range of Zhu et al.34 recently reported that, similar to previous
terminology currently in use, it may be some time before studies in chicks, marmosets with imposed hyperopic defo-
a consensus is reached, but establishing a logical frame- cus experienced less myopic eye growth when exposed to
work for the structural complications within the ICD-11 brief periods of unrestricted vision or darkness for approxi-
would be good starting point. Clear ICD-11 classifications mately 10% of the day. These findings demonstrate that the
and definitions of the various structural complications of integration of the defocus signals for emmetropization is
myopia may also help to bring attention to the need for nonlinear in nature, with implications for myopia control
better interventions to alter the natural history of pathologic strategies applied to children.
myopia.
Peripheral Retina as a Myopia Control Target
IMI DIGEST—EXPERIMENTAL MODELS OF
One of the more important findings using rhesus monkeys
EMMETROPIZATION AND MYOPIA was that the fovea is not critical for emmetropization,35
The use of animal models in the area of eye growth has meaning that the peripheral retina can direct eye growth.
been instrumental in shaping our understanding of myopia This result has had a profound influence on our understand-
and developing treatment strategies. Animal models have ing of emmetropization and on the design of optical lenses
allowed researchers to establish that emmetropization is an for myopia control. A recent study in rhesus monkeys sought
active process based on visual feedback.30 Expanding on to characterize the effects of eccentricity on the ability of
this, form deprivation and defocus-induced experimental peripheral positive power to influence refractive develop-
myopia have provided the framework in which to examine ment.36 The results showed that myopic defocus in the far
the influence of visual cues and pharmacologic agents on periphery, beyond 20° from the fovea, was not consistent
eye growth, which have, in numerous instances, translated in guiding refractive development. These findings under-
to myopia control strategies in children. Here, the state of score the importance of controlled studies in animal models
the field since the IMI 2021 yearly digest1 is reviewed and for designing effective optical treatments for myopia in
new findings on emmetropization and myopia using animal children.
models presented.
Pharmacologic Treatments
Signaling Pathways Based on previous studies in rhesus monkeys, as well
With exposure to defocus, the retina generates a signal- as humans, oral 7-methylxanthine (7-mx), a metabolite of
ing cascade that passes through the retinal pigment epithe- caffeine, was found effective in slowing myopia.37 Both
lium and choroid to ultimately exert an effect on fibroblasts caffeine and 7-mx are nonselective adenosine receptor
in the locally adjacent sclera. The scleral fibroblasts cause antagonists. Caffeine can be compounded into a topi-
alterations of the extracellular matrix that either promote or cal ophthalmic solution and is already a common, well-
restrain scleral remodeling and resultant changes in vitreous tolerated dietary element. Findings showed that indeed, topi-
chamber depth. However, the chemical signals and candi- cal caffeine was as effective as oral 7-mx in preventing exper-
date gene networks that mediate visually guided eye growth imental myopia in rhesus monkeys.38 The slowed eye growth
are as yet not well understood. Regarding the choroid, in monkeys receiving topical caffeine was reflected by
Summers and Martinez31 demonstrated in chicks that inter- shorter vitreous chamber depth and an increased choroidal
leukin 6, a proinflammatory cytokine, may play an impor- thickness. These findings suggest that topical caffeine may
tant role in the choroidal response in ocular growth. In the have potential in treatment strategies for myopia in children.
sclera, Wu et al.32 demonstrated that lumican overexpres- However, a recent study showed that 2% topical caffeine
sion contributed to form deprivation in rats by modulating had no positive effect in slowing the progression of myopia
the expression of TIMP-2, MMP-2, and MMP-14 and lead- in Vietnamese children compared to untreated myopic chil-
ing to scleral fibroblast apoptosis. Another recent study in dren.39
chicks, which used five well-established but diverse methods
of inhibiting myopia, found a universal activation of tran-
Circadian Rhythm, Dopamine, and Illumination
scription factor EGR1 and downstream products, suggesting
the existence of a well-defined retinal network that cannot Intensity
be bypassed.33 Follow-up research to further characterize For over 50 years, it has been suggested that circadian
the signaling pathways from the retina to sclera that influ- rhythms and emmetropization are linked.40 Considerable
ence axial elongation could lead to improved understanding research has resulted in the view that light during the
and new therapeutic interventions for myopia. day, especially high-intensity light characteristic of outdoors,
activates intrinsically photosensitive retinal ganglion cells
Temporal Integration of Myopiagenic Stimuli (ipRGCs), which communicate with dopaminergic amacrine
cells.41 Dopamine is released during the day, which in turn
Imposed myopic blur using positive (plus) lenses consis- has been shown to reduce the tendency of an eye to become
tently slows eye growth in animal models, resulting in hyper- myopic.42,43 Recent studies in chicks,44 guinea pigs,45 and
opia, while imposed hyperopic blur using negative (minus) mice46 further support a role for dopamine in emmetropiza-
lenses increases eye growth, resulting in myopia. The retina tion and myopia, with findings pointing to a D2-like receptor

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mechanism.47 In chicks, both levodopa (L-DOPA, a precur- tree shrews59–61 and rhesus monkeys.62,63 More recently, it
sor to dopamine) and levodopa plus carbidopa inhibited was shown that amber light, spanning a relatively broad
form deprivation myopia and increased vitreal dopamine.44 band of frequencies but omitting those shorter than 500 nm,
The authors concluded that coadministration of levodopa also promotes hyperopia in tree shrews.64 However, long-
with carbidopa may be a potential treatment for controlling wavelength light has not been consistently found to slow
myopia in children. eye growth in the other common animal models of myopia,
IpRGCs, which contain the photopigment melanopsin, and in fact, red light rearing induces eye growth in chick-
project to the suprachiasmatic nucleus to relay infor- ens,54,65,66 guinea pigs,67–70 and fish.71,72 Red light has not
mation about environmental light and mediate circa- been widely studied in mice, although one study did suggest
dian rhythm. A recent study used two strains of knock- that red light promotes hyperopia in this species.73 There
out mice: one that lacked melanopsin (encoded by the is currently no sufficient explanation for the divergence of
gene OPN4) but still had ipRGCs and one that lacked the effects of long-wavelength ambient lighting between
ipRGCs altogether.48 Findings showed that retinal dopamine species, and it remains a major puzzle in the field. Never-
signaling was reduced and myopia increased in form- theless, findings from tree shrews and rhesus monkeys have
deprived mice lacking melanopsin. Additionally, systemic recently been translated to short-duration red light therapy
L-DOPA treatment could partially reverse the myopia. The as myopia control in children.74,75 Further testing in animal
authors concluded that melanopsin is vital for refrac- models is necessary to understand dose–response effects
tive development and slowing myopia progression in and the underlying mechanism of action of long-wavelength
mice. light on eye growth.
The effects of reduced ambient lighting (about 50 lux) on Narrowband Short Wavelength Light – “Blue”
lens-induced myopia in rhesus monkeys were also exam- and “Violet”. Blue and violet light consist of shorter wave-
ined.49 While this low illumination did not directly cause lengths with higher energy than red and amber light. Studies
myopia, it significantly reduced the ability of emmetropiza- have reported that blue light rearing in chicks slows form
tion to compensate for refractive errors, such as recovering deprivation myopia76 and, in guinea pigs, slows defocus-
from myopia. These findings are in accordance with previ- induced myopia, potentially through a retinoic acid–related
ous studies suggesting that at least some exposure to high- mechanism.77 On the other hand, blue light rearing in tree
intensity illumination is critical for optimal refractive devel- shrews tends to dysregulate eye growth, ultimately lead-
opment.50 ing to variable refractive errors ranging from hyperopia to
myopia.78
Longitudinal Chromatic Aberration More recently, attention has turned to violet light. Violet
light, with wavelengths between about 360 and 400 nm, is
Virtually all vertebrate camera-type eyes have significant largely absent from our indoor environments and blocked
longitudinal chromatic aberration (LCA): short wavelengths by most spectacle and contact lenses. Additionally, the ocular
focus in front of longer wavelengths.51 LCA would thus seem media filter out most light of this wavelength in humans.79 It
to be an ideal visual cue for emmetropization, because both has been proposed that lack of violet light could be myopi-
the magnitude and the sign of defocus could be inferred agenic and that adding violet light back could be useful
from the relative sharpness of retinal images between in preventing myopia.80 Currently, the majority of research
shorter and longer wavelengths. However, some early results on violet light has been in the mouse. The finding of a
suggested that experimental animals could emmetropize novel opsin neuropsin, or OPN5, with an absorbance peak
under spectrally narrowband light that would not provide of about 385 nm,81 alongside human clinical trials suggest-
LCA cues for defocus.52–54 Because the shorter-wavelength ing that violet light could indeed be antimyopiagenic,82 has
cones are typically spatially sparse and seemingly unable resulted in increased interest in investigating violet light
to judge defocus accurately enough to achieve emmetropia, in animal models. A recent paper on mice showed that
LCA was not thought to be critical for emmetropization. violet light suppresses lens-induced myopia via an OPN5-
However, more recent results indicate that chromatic cues mediated mechanism.83 Again based on data from mice,
for defocus are generally essential for accurate emmetropiza- it has been suggested that the intrinsic circadian rhythms
tion,55 and optical modeling has demonstrated that the of the retina are mediated specifically by violet light and
spatial distribution of short-wavelength cones is adequate OPN5,84 although this interpretation has been disputed.85
for using longitudinal chromatic aberration to accurately Activity in this area continues to increase, and it is only a
guide emmetropization.56,57 A recent study using tree shrews matter of time before more data from other animal models
demonstrated that a video display with a chromatic simula- become available, most critically from diurnal mammals
tion of myopic blur could overcome a myopiagenic environ- with ocular media absorption properties close to the
ment, further demonstrating the great potency of chromatic human.
cues for emmetropization.58

Narrowband Ambient Illumination ON Versus OFF Pathways

While emmetropization typically operates under spectrally All classical photoreceptors (rods and cones) hyperpo-
broadband illumination, given the apparent importance of larize upon exposure to light. At the first synapse, the
chromatic cues, it should come as no surprise that drastic retina generates ON and OFF pathways, which are impor-
alterations to the ambient spectrum—in particular, narrow- tant for detecting luminance increments and decrements.
band light—can have profound effects on emmetropization. Evidence suggests that emmetropization depends more
Narrowband Long Wavelength Light – “Red” and on the ON than the OFF pathway,86,87 and work explor-
“Amber”. Long-wavelength red light produces a power- ing this topic using animal models continues. In further
ful and consistent hyperopic/antimyopiagenic effect in both support of the idea that the ON pathway is more generally

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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 7

important for retinal processing than OFF, a recent paper Participant Selection Criteria
on mice suggested that ON pathway disruption results in
greater deficits in visual function and dopamine signaling The recent trials have mainly used cycloplegic refraction,
than OFF pathway disruption.88 Note that while both short- with participant selection criteria for maximum astigmatism
and long-wavelength sensitive cones have dedicated ON ranging from –0.75 D to –2.50 D (generally lower for opti-
bipolar cells, the short-wavelength cones are lacking an OFF cal intervention studies) and for maximum anisometropia
bipolar.89 Thus, it would be possible to calculate a short- ranging from 1.00 to 2.00 D (although not reported in
versus long-wavelength chromatic signal using only the ON several studies), minimum distance VA from 16/20 to 20/40
pathway but not using only the OFF pathway (or, at least, (although more use 20/25 than the previously recommended
not as easily). Conceivably, the relative importance of the 20/20, with one study stating that the number of logMAR
ON versus OFF pathway could be due to the reliance of letters read which will differ between charts with different
emmetropization on short- versus long-wavelength contrast. maximum size letters presented),107 a minimum age from
Further research into this area could yield insight into the 3 to 9 years, and a maximum age typically between 10 to
specific retinal circuits driving emmetropization. 16 years (Table 1). Recruiting patients with high astigma-
tism and anisometropia makes it more difficult to evaluate
the effects of any myopia intervention as they are likely
to have a very different optical environment (such as an
Scleral Cross-linking increased depth of focus).123 Thus, it is recommended to
With increasing age, emmetropization ultimately ceases, exclude those patients unless it is the focus of the research.
possibly because the accumulation of natural cross-links The progression of childhood myopia slows with age. There-
between collagen fibers renders the sclera relatively fixed.90 fore, recruiting older children up to 16 years of age in a
It has therefore been proposed that accelerating collagen trial that lasts several years may reduce the apparent effec-
cross-linking in the sclera could be an effective means of tiveness of the intervention when considering the actual
myopia control.91 A recent study in tree shrews using retrob- reduction in eye growth in millimeters or diopters. On the
ulbar injections of the crosslinking agent genipin did show other hand, if treatment effects are reported as a percent-
effectiveness against form deprivation myopia92 but was age reduction, then as highlighted previously,1,124 enrolling
associated with significant retinal pathology.93 Pathologic older children could yield a falsely higher increased appar-
changes were also seen with scleral cross-linking in the ent efficacy. Enrolling older children also adds complexities,
guinea pig.94 Previous studies in rabbits have suggested for example, the necessity of additional exclusion criteria
that using a blue light–riboflavin combination to induce such as “negative pregnancy test for females with childbear-
scleral cross-linking can increase scleral stiffness with no ing potential” in new investigational device/pharmaceutical
pathologic effects.95 While another recent study in rhesus trials. Based on the evidence, none of the criteria, other than
monkeys also suggested this method to be relatively benign, the minimum VA, appear to warrant revision from the previ-
to date, the effectiveness of this approach in slowing myopia ously recommended participant selection criteria. Thus, the
has not been demonstrated.96 Scleral cross-linking could, in updated participant selection criteria are as follows:
principle, be an effective means of myopia control, but safe Inclusion Criteria
techniques of inducing scleral cross-linking must be devel- Refractive error: Cyclopleged spherical or SE myopia of at
oped. least –0.75 D in each eye
Astigmatism: ≤1.00 D in each eye
Anisometropia: ≤1.50 D
IMI DIGEST—CLINICAL MYOPIA CONTROL TRIALS Age: 6 to 12 years
Visual acuity: 0.10 logMAR in each eye
AND INSTRUMENTATION
Exclusion Criteria
The 2019 IMI Clinical Myopia Control Trials and Instrumen-
tation report97 reviewed the evidence from existing myopia History: Previous rigid lens wear or myopia control
treatment
control trials of at least 1 year in duration, along with
Ocular disease: Any (other than myopia)
supporting academic literature. The IMI 2021 yearly digest
Binocular vision: Anomaly (strabismus)
updated this evidence.1 These reviews provided informed
Systemic disease: Those that may affect vision, vision
recommendations on the design of future clinical trials development, or the treatment modality
to demonstrate the effectiveness of treatments at slowing Medications: Those that may affect pupil size,
myopia progression and the impact of these treatments on accommodation, or have an impact on
patients. Relevant publications since then up until Septem- the ocular tissue
ber 2022 include 5 studies on spectacle interventions98–101 (1
on part-time single vision wear),102 4 soft contact lens (SCL) Departure from these criteria will generally lead to the
trials,103–106 1 orthokeratology (ortho-k) study,107 10 studies apparent efficacy of a treatment being under- or overesti-
examining the effect of prescribing atropine (although only mated, with differences in approaches making it more diffi-
half assessed efficacy in a prospective trial),108–117 and trials cult to compare across studies.124 It is noted that the inclu-
of atropine combined with either ortho-k118 or SCL119 or sion criteria for age, VA, astigmatism, and anisometropia
auricular acupoint stimulation.120 The number of prospective have widened more recently, as reflected in the recent publi-
clinical trials on myopia control has risen substantially. As of cations of myopia control studies.
2018, there were 25 trials,97 with an additional 12 trials from
2018 to 20201 and a further 26 trials from 2020 to 2022. In Study Design
addition, there were two retrospective trials involving rigid
corneal lenses121 and atropine,122 but they are not included While previously, most studies followed their cohort for
in this report. 2 years, with an additional year in some studies to

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 IMI Digest

TABLE 1. Selection Criteria in Prospective Recent Myopia Control Clinical Trials

Author, Year Intervention SER (Min to Max), D Cycloplegia Ast Limit, D Aniso Limit, D VA Min Age, Min to Max, y
Bao et al. 2022101 Spectacles (highly aspherical −4.75 to −0.75 Y 1.50 1.00 20/22 (0.05 logMAR) 8 to 13
lenslets or slightly aspherical
lenslets)
Chamberlain et al. 2022103 SCL (concentric dual zone) −4.00 to −0.75 Y 0.75 1.00 20/25 8 to 12
Chan et al. 2022108 0.01% atropine −5.00 to −0.50 Y 1.00 NR 20/20 7 to 10

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Chuang et al. 2021109 0.05% atropine (concentration −0.50 to −5.00 Y 2.00 NR NR NR (figures show ∼5 to 8)
increased if >0.50 D 6-month
progression)
Cui et al. 2021110 0.02% or 0.01% atropine −6.00 to −1.25 Y 2.00 1.00 16/20 (20/25) 6 to 14
Fu et al. 2021111 0.01% or 0.02% atropine −6.00 to −1.25 Y 2.00 1.00 20/25 6 to 14
Han et al. 2021125 Auricular acupressure −0.50 to +0.50 Y NR NR 20/25 (from decimal) 8 to 9
Hieda et al. 2021104 SCL (multifocal) −6.00 to −1.00 Y 1.50 1.50 20/20 Grades 1 to 6 in school
( Japan)
Hieda et al. 2021112 0.01% atropine −6.00 to −1.00 Y 1.50 1.50 20/20 6 to 12
Jakobsen and Moller 2022107 ortho-k −4.75 to −0.50 (sphere) Y 2.50 1.50 78 ETDRS letters 6 to 12
Jiang et al. 202274 Low-level red light therapy −5.00 to −1.00 Y 2.50 1.50 20/20 8 to 13
Jones et al. 2022119 0.01% atropine with multifocal SCL −5.00 to −0.50 Y 1.00 2.00 20/25 7 to 11
(spherical component)
Kong et al. 2021120 0.01% atropine plus auricular −6.00 to +0.50 Y 1.50 1.50 NR 7 to 12
acupoint stimulation
Lam et al. 202198 Spectacle (novel plus powered −5.00 to −1.00 Y 1.50 1.50 20/20 8 to 13
multiple segments)
82
Mori et al. 2021 Violet light transmitting spectacles −4.40 to −1.50 Y 1.50 1.50 NR 6 to 12
Moriche-Carretero et al. 2021113 0.01% atropine −4.50 to −0.50 Y 1.50 1.00 20/30 5 to 11
Prousali et al. 2022102 Part-time single-vision spectacles −6.00 to −0.50 Y 1.50 1.50 20/25 4 to 16
Rappon et al. 202299 Spectacles (two novel diffusion −4.50 to −0.75 Y 1.25 1.50 20/25 6 to10
optics patterns)
Ruiz-Pomeda et al. 2021105 SCL (concentric dual zone) −4.00 to −0.75 Y 1.00 1.00 20/25 8 to 12
Saxena et al. 2021114 0.01% atropine −6.00 to −0.50 Y 1.50 1.00 20/40 6 to 14
Shen et al. 2022106 SCL (extended depth of focus) −8.00 to −1.00 Y 1.75 2.00 20/25 9 to 14
Wang et al. 2022115 0.02% or 0.01% atropine −6.00 to −1.25 Y 2.00 1.00 20/25 6 to 14
Weng et al. 2022117 SCL (extended depth of focus and −3.50 to −0.75 Y 0.75 0.75 20/32 7 to 13
concentric dual zone)
Yam et al. 2022116 Atropine (0.01%, 0.025%, 0.05%) −1.00 or more myopic Y 2.50 NR NR 4 to 12
refraction
Yuan et al. 2021118 ortho-k with 0.01% atropine −4.00 to −1.00 N 1.50 NR 25/25 stated 8 to 12
Zhu et al. 2022100 Customized PALs −4.00 to −0.50 Y 1.50 1.00 20/20 7 to 14

Ast, astigmatism; Aniso, anisometropia; ETDRS, early treatment diabetic retinopathy study; N, no/none; NR, not reported; PAL, progessive addition lens; Y, yes.
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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 9

examine for any rebound, study results are being published modative changes, ocular alignment, pupil size, outdoor
earlier74,102,106,111,114,120,125 and/or becoming more complex, activity/lighting levels, anterior and posterior segment imag-
sometimes involving longer durations with a “crossover” for ing, and tissue biomechanics).97 Visual disturbances (subjec-
the control group103 or longer tracking for faster-progressing tively reported symptoms such as halos and glare or
myopia109 (Table 2). However, all studies still show a reduced measured objectively such as with halometry) and patient-
effectiveness of treatments in the second year, demonstrat- reported outcomes were added to the minimum data
ing the need for more than 1 year of follow-up to adequately requirements for different modalities of treatment in the
assess the long-term efficacy of the treatment. The extrap- 2021 digest.129 In addition, choroidal thickness has been
olation of a 1-year treatment effect to multiple years (an added as a recommended key exploratory and possibly
approach taken by many myopia calculators, for example) predictive130,131 measurement for all forms of myopia control
can lead to incorrect conclusions,124 and hence the prior (Table 3; also see IMI 2023 white paper on choroid).132
IMI recommendation for a clinical trial assessing the effi- The 2021 digest advocated reporting of both a percent-
cacy of a treatment for myopia control of a 3-year mini- age and an absolute amount of reduced myopia progres-
mum study duration (at least 2 years of treatment plus an sion/axial elongation in future clinical trial reports,129 and
additional year of no treatment to examine any rebound this was supported by a position paper published shortly
effect) is still upheld. More recent studies have not applied after.124 Percentages can be misleading and so should never
randomization,109,119 while others that randomize partici- be reported alone. Ninety-five percent confidence intervals
pants have not appropriately applied masking,102,105,107,113 should also be reported along with the magnitude of change.
and stratification of participants has also become more Subgroup analysis must be planned a priori along with
common.99,104,105,112,116,118,120 Several recent studies did not appropriate statistical power/sample size calculations. Any
have a control group109,111 while others used histori- post hoc subgroup analyses should be clearly identified as
cal controls.98,119 Nonetheless, appropriate controls were exploratory and, as such, should be used for forming new
selected for the comparison group in most studies, and in hypotheses rather than proof of efficacy.
the case of ortho-k and rigid corneal lens use, which cannot
be easily masked, single-vision spectacles (SVSs) were used
as controls.107 However, some atropine studies110,115 and one Instrumentation
SCL study105 used a SVS control (no drops), and thus partic-
ipants would not have been masked and compliance poten- There has been a focus on imaging and segmenting (partic-
tially altered. In addition, many studies made no attempt at a ularly using machine learning) choroidal thickness using A-
true sham for their control group,74,82,113,120,125 thus increas- scan (traditionally termed biometers)133 and B-scan (termed
ing the potential for bias. optical coherence tomography)131,134,135 based techniques to
The ethical dilemma of including a control group in better understand the mechanism(s) of myopia control and
studies1 remains unresolved despite the increasing evidence also as a potential predictor of long-term efficacy of treat-
for the effectiveness of various myopia control treatments. ments (see IMI 2023 white paper on choroid).132 A model
Terminating a treatment to investigate the possibility of using principally baseline pupil area, 1-month change of the
rebound presents a similar ethical issue. As also highlighted zone 3-mm (flat) and zone 5-mm (flat/steep) keratometry
in the section on industry guidelines and ethical considera- was able to predict between 54% and 63% of the variation
tions, several studies have suffered from a high control group in 1-year AL elongation with ortho-k.136 In addition, models
dropout (particularly if participants are not well masked) have been developed to predict cycloplegic refractive error
and more difficult recruitment due to parents not wanting from demographics, noncycloplegic SER, AL/corneal curva-
their child to risk receiving the placebo. An alternative is use ture radius ratio, uncorrected VA, and intraocular pressure,
of historical controls as applied by two recent studies,98,119 with the results explaining 92% to 93% of the variability in
but careful matching for important covariates such as age, Chinese school children (aged 5–18 years)137,138 and 96% in
sex, season (for shorter studies), refractive error, AL, envi- children in Japan (aged 2–9 years).139
ronmental exposure, parental myopia, and race/ethnicity is
required. Other alternatives include comparison with a gold
standard, although equivalence analysis has statistical chal- IMI DIGEST: INTERVENTIONS FOR CONTROLLING
lenges that need to be carefully considered,126 or survival ONSET AND PROGRESSION OF MYOPIA
analysis,127 such as the time taken for participants’ myopia
to progress more than –0.50 D, allowing participants on Interventions to slow myopia progression are increas-
placebo to exit early while other treatments should still be ingly becoming the “standard of care,” with the use of
beneficial, although this approach precludes the assessment specialty optical products also steadily climbing.140 Further-
of efficacy over longer time periods. Multisite studies gener- more, combination or multimodal interventions (for exam-
ally include a larger number of participants, a population ple, ortho-k with low-concentration atropine) are being
cohort recruited from wider geographic locations, and the explored, with the goal of improving efficacy. The evidence
ability to compare results across study sites, all of which since the original IMI white paper141 and the IMI yearly
increase the generalizability of the study results, but so far, digest 20211 was reviewed, and this update is largely limited
they are rare.99,128 to results from recent prospective, randomized clinical or
group-matched trials, with a focus on SE refractive error
Outcome Measures and/or AL data as key outcome measures of efficacy and
rebound effects on treatment discontinuation. Not compre-
The outcomes of myopia progression clinical trials can hensively reviewed are data covering aspects such as visual
still be classified as primary (refractive error and/or performance and safety; data from studies that do not
AL), secondary (patient-reported outcomes and treatment conform with standard clinical trial designs (e.g., see various
compliance), and exploratory (peripheral refraction, accom- studies102,142–146 ) were also not comprehensively reviewed.

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 IMI Digest

TABLE 2. Control Group, Randomization, and Masking of Recent Myopia Control Trials
Rebound
Author, Year Intervention Control Randomization Stratification Masking Study Length, y Assessment

Bao et al. 2022101 Spectacles (highly Spectacle (SV) Y N Y 2 N

aspherical lenslets or

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slightly aspherical
lenslets)
Chamberlain et al. SCL (concentric dual zone) SCL (SV) Y† N Y 6† Y (planned)
2022103
Chan et al. 2022108 0.01% atropine Vehicle drop Y N Y 1.5 N
Chuang et al. 2021109 0.05% atropine N N N N 10 N
(concentration
increased if >0.50
six-month progression)
Cui et al. 2021110 0.02% or 0.01% atropine No treatmentSelf- Y/N (if self-selected N Y (if in an atropine 2 N
selected atropine, arm)
randomized to
0.01% or 0.02%)
Fu et al. 2021111 0.01% or 0.02% atropine N Y (to 0.01% or N Y 1 N
0.02% atropine)
Han et al. 2021125 Auricular acupressure No treatment Y N Y (examiner only, 1 N
not participant)
Hieda et al. 2021104 SCL (multifocal) SCL (SV) Y Y (adaptive Y 2 N
randomization)
Hieda et al. 2021112 0.01% atropine Vehicle drop Y Y Y 2 N
Jakobsen and Moller OK Spectacle (SV) Y N N 1.5 N
2022107
Jiang et al. 202274 Low-level red light therapy No treatment Y N Y (examiner only, 1 N
not participant)
Jones et al. 2022119 0.01% atropine with Historical controls N N N 3 N
multifocal SCL (multifocal SCL
group and SV
SCL group)
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 IMI Digest

TABLE 2. Continued

Rebound
Author, Year Intervention Control Randomization Stratification Masking Study Length, y Assessment

Kong et al. 2021120 0.01% atropine plus 0.01% atropine Y Y Y (examiner only, 0.5 N
auricular acupoint not participant)
stimulation
Lam et al. 202198 Spectacle (novel plus Historical controls Y N Y 2ǂ (original control N

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powered multiple group followed 1
segments) year on
treatment)
Mori et al. 202182 Violet light transmitting Spectacle (SV) Y Y Y 2 N
spectacles
Moriche-Carretero et al. 0.01% atropine No treatment Y N N 2 N
2021113
Prousali et al. 2022102 Part-time spectacle SV Full-time spectacle Y N N 1 N
SV
Rappon et al. 202299 Spectacles (two novel Spectacle (SV with Y Y Y 3 (reported 1-year N
diffusion optics tint) results)
patterns)
Ruiz-Pomeda et al. SCL (concentric dual zone) Spectacle (SV) Y Y N 3 Y (last year of
2021105 study)
Saxena et al. 2021114 0.01% atropine Vehicle drop Y N Y 1 N
Shen et al. 2022106 SCL (extended depth of SCL (SV; Y N Y 1 N
focus) contralateral eye)
Wang et al. 2022115 0.02% or 0.01% atropine No treatment Y (to 0.01% or N Y (only in atropine 2 N
0.02% only if arms)
chose atropine
instead of
spectacles)
Weng et al. 2022 117 SCL (extended depth of SCL (SV; Y N Y 1 N
focus and concentric contralateral eye)
dual zone)
Yam et al. 2022116 Atropine (0.01%, 0.025%, Vehicle drop (year Y Y Y 3 Y (study year 3, half
0.05%) 1 only) of each group)
Yuan et al. 2021118 ortho-k with 0.01% ortho-k with Y Y Y 2 N
Atropine vehicle drop
Zhu et al. 2022100 Customized PALs Spectacle (SV) Y N Y 2 N
† Followed for an additional period after ending randomization.
ǂ Randomized first 2 years, then all wore intervention lenses for an additional year with original control group compared to historical control group matched on age and refractive error.
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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 12

Spectacle Lens Designs

Compliance Outcomes
Wearing Instillation Reported
Patient-
Novel spectacle lens designs represent a significant growth

X
X
X
X
area with respect to myopia control. New performance data
for the defocus incorporated multiple segments (DIMS) lens,
which was covered in the 2021 digest, are now available.
Specifically, at the end of year 2 of the trial, some of the

X
control group were switched from SVS lenses to DIMS lenses
and tracked for another year along with the DIMS group,
with children in both groups being approximately 10 years
Time
old. Switching from the control to DIMS group led to signifi-
X
X
X
cantly reduced progression compared to that over the previ-
ous year (i.e., change in SE/AL of –0.52 ± 0.69 D/0.31 ± 0.26
Centration*

mm as compared to –0.92 ± 0.81 D/0.57 ± 0.33 mm, respec-

Lens

tively) and comparable to the progression of the DIMS group

X
X

in year 1.98 Note, however, that age represents a potential

confounder in the latter comparison.
Two-year clinical trial data are now also available for two
Disturbances

other closely related spectacle lens designs incorporating

Visual

either slightly or highly aspherical lenslets in their periph-

X
X
X
X

eries (SAL and HAL, respectively) (Table 4).101,147 Children

aged 8 to 14 years were randomly assigned to wear SAL,
HAL, or SVS lenses. Myopia progression was significantly
Length Accommodation*

reduced with both lenses, with the HAL lens outperform-

Amplitude of

ing the SAL lens.147 The myopia control effects evident at

the end of year 1, indexed by unadjusted mean changes in
X
X
X
X

SER and AL, were enduring; at the end of 2 years, progres-

sion remained significantly reduced with HAL and SAL
lenses as compared to SVS lenses: –0.66 (0.09), –1.04 (0.06),
Axial

and –1.46 (0.09) D for SER and 0.34 (0.03), 0.51 (0.04), and
X
X
X
X

0.69 (0.04) mm for AL in the HAL, SAL, and SVS lens groups,
respectively.101
Sensitivity* Pupil Size Refraction Thickness*
Cycloplegic Choroidal

Year 1 data are also now available for a 3-year trial

of another novel spectacle lens design incorporating diffu-
X
X
X
X

sion optics technology, which are intended to reduce spatial

contrast (only a small, ∼ 5-mm, central area of the lens is
free of diffusing elements). In this trial, children aged 6 to
10 years were randomly assigned to wear either a lightly
X
X
X
X

tinted SVS lens (control) or one of the two test lenses, which
varied in the density of dots, with test 1 lens having a lower
dot density compared to test 2 lens. Year 1 results suggest
robust myopia control effects, with the apparently greater
X
X
X
X

response with the test 1 lens. Mean changes in SER/AL were

TABLE 3. Expected Minimum Data for Each Treatment Modality

–0.14 D/0.15 mm and –0.22 D/0.20 mm with test 1 and test

2 lenses compared to –0.54 D/0.30 mm with the SVS lens.99
Contrast

X
X
X
X

SCL Designs
Near Visual

Indicates at least in a powered subgroup.

Recent clinical trials confirmed that myopia control strate-

Acuity

gies are effective in older children. In an extension of a 3-

X
X
X
X

year trial of dual-focus compared to single vision SCL (SV

SCLs), a subset of participants who were approximately 13
Distance

years of age were continued in dual-focus SCLs for a further

Acuity
Visual

X
X
X
X

3 years, over which period myopia progression was found

to slow significantly in those switched from SV SCLs to
Soft multifocal contact lenses

dual-focus SCLs and the treatment effect sustained in those

continuing with dual-focus SCLs.103
In a 12-month randomized, contralateral, crossover clin-
Treatment Modality

ical trial involving bilateral SV SCLs, contralateral SV versus

Orthokeratology
Pharmaceuticals

extended depth of focus (EDOF) SCLs, and contralateral SV

versus MiSight SCLs (lens assignments randomized by eye
Spectacles

in contralateral groups), both EDOF and MiSight SCLs were

found to slow myopia progression as compared to SV SCLs,
*

with similar efficacy.148 Participants were aged 7 to 13 years.

In another, similarly designed trial, a center-near EDOF SCL

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 TABLE 4. Summary of Key Study Design Features and Outcomes for Myopia Intervention Trials Involving Novel Spectacle or Soft Contact Lenses
Mean
% Loss to Change in % Slowing % Slowing
IMI Digest

Sample Follow-up/ SE (D)/AL Myopia Axial Age Myopia Range Average Myopia
Author, Year Country Size Lenses Length, y Discontinued (mm) Progression Elongation Range, y Baseline Age, y (D) (D)
Spectacle lens designs
Bao et al. year 1147 China 167 HAL and SAL vs. 1 3.4 HAL: HAL: 63 HAL: 61 8–13 HAL: 10.7 ± 0.2 −0.75 to −4.75 HAL:
SV spectacles −0.30/0.14 SAL: 40 SAL: 31 SAL: 10.1 ± 0.2 −2.70 ± 0.14
SAL: SV: 10.4 ± 0.2 SAL:
−0.48/0.24 −2.31 ± 0.13
SV: SV:
−0.79/0.35 −2.46 ± 0.12
Bao et al. year 2101 China 167 HAL and SAL vs. 2 7.8 HAL: HAL: 55 HAL: 51 8–13 HAL: 10.7 ± 0.2 −0.75 to −4.75 HAL:
SV spectacles −0.68/0.35 SAL: 28.8 SAL: 26 SAL: 10.1 ± 0.2 −2.70 ± 0.14

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SAL: SV: 10.4 ± 0.2 SAL:
−1.04/0.50 −2.31 ± 0.13
SV: SV:
−1.45/0.68 −2.46 ± 0.12
Rappon et al. 202299 USA 258 Test 1 and test 2 1 9.3 Test 1: Test 1: 74 Test 1: 50 6–10 Test 1: 8.0 ± 1.2 −0.75 to −4.50D Test 1:
vs. SV −0.68/0.35 Test 2: 59 Test 2: 33 Test 2: 8.2 ± 1.2 −2.00 ± 0.93
spectacles Test 2L: SV: 8.2 ± 1.2 SAL:
−1.04/0.50 −1.85 ± 0.91
SV: SV:
−1.45/0.68 −1.95 ± 1.02
Contact lens designs
Shen et al. 2022106 Taiwan 72 Contralateral 1 6.9 EDOF: 20.5 10.5 9–14 12.4 ± 1.5 −1.00 to −8.00 EDOF:
center near −0.70/0.34 −3.31 ± 1.26
EDOF vs. SV SV: SV:
−0.88/0.38 −3.32 ± 1.17
Weng et al. 2022117 China 95 Group I: Bilateral Stages 1 and 33.3 Refer to — — 7–13 10.9 ± 1.5 −0.75 to −3.5 Group I:
SV 2: 0.5/0.5 48.4 article as 39 and 64 63 and 66 10.8 ± 1.5 −2.08 ± 0.64
Group II: Stages 1 and 50.0 multiple 41 and 30 48 and 42 10.8 ± 1.6 Group II:
Contralateral SV 2: 0.5/0.5 stages/lens −2.01 ± 0.64
vs. EDOF Stages 1 and combina- Group III:
Group III: 2: 0.5/0.5 tions −1.91 ± 0.72
Contralateral SV
vs. MiSight
Fang et al. 2022160 China 81 Group I: SVCL 1 3.8 SVCL: — — 7–15 13.0 ± 0.2 −1.00 to −8.00 Group I:
Group II: ortho-k 17.2 −1.00/0.45 ortho-K: NA ortho-K: 31.1 12.5 ± 0.2 −3.00 ± 0.28
Group III: MFSCL 7.7 ortho-k: MFSCL: 37.2 MFSCL: 24.4 12.8 ± 0.1 Group II:
NA/0.34 −2.66 ± 0.21
MFSCL: Group III:
−0.63/0.31 −3.14 ± 0.30
Jones et al. 2022119 USA 138 MFSCL (+2.50 D) 3 Age matched 52.2 42.6 7–11 10.4 −0.75 to −5.00 −2.21 ± 0.80
+ 0.01% atropine 49.5 54.4 10.1* −2.31 ± 1.00
MFSCL (+2.50 D) — — 10.2* −2.31 ± 0.89
SVCL
Garcia-del Valle et al. Spain 70 Reverse geometry 1 17.1 Test CL: 51 41 7–15 12.2 ± 2.2 −0.50 to −8.75 −2.80 ± 1.79
2021149 SCL vs. SVCL −0.28/0.13 11.9 ± 2.1 −3.31 ± 1.76
SVCL:
−0.57/0.22

CL, contact lens.

* Median.
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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 14

TABLE 5. Axial Elongation in Millimeters Reported in the Various Studies Involving Orthokeratology
Author, Year Lenses Eye 12 Months 18 Months 24 Months

Guo et al. 2021151 OK (BOZD 6 mm) (n = 32) 0.17 ± 0.13

OK (BOZD 5 mm) (n = 26) 0.04 ± 0.15
Lau et al. 2022153 OK (n = 29)* 0.53 ± 0.29
OK (IC) (n = 35) 0.35 ± 0.29
Loertscher et al. 2021 (n = 28)150 OK (1 eye) 0.129
OK (MF) (the other eye) −0.044
Long et al. 2020154
Unilateral anisometropes SV spectacles (n = 38) NME 0.31 ± 0.32
ME 0.33 ± 0.29
OK (n = 79) NME† 0.34 ± 0.21
ME 0.05 ± 0.19
Bilateral anisometropes SV spectacles (n = 37) LME 0.35 ± 0.28
MME 0.38 ± 0.21
OK (n = 98) LME 0.15 ± 0.19
MME 0.05 ± 0.17
Tan et al. 2022166 OK (n = 35) 0.35 ± 0.20
OK (A) (n = 34) 0.17 ± 0.19
A, 0.01% atropine; IC, increased compression by 1 D; LME, less myopic eye; ME, myopic eye; MME, more myopic eye; NME, nonmyopic
eye.
* Lens parameters were not modified to correct significant residual myopia (if any), to maintain 1 D difference in compression factor
between the two groups of subjects.
† No lens wear.

was found to significantly slow myopia progression relative The efficacy of ortho-k as an intervention for control-
to that with an SV SCL over 12 months,106 although the treat- ling anisometropia has also been recently explored,154–158
ment effects (i.e., 0.18 D/0.04 mm) are small compared to with the unanimous conclusion that it is an effective treat-
findings with other lens designs. ment. Specifically, AL elongation slowed more in the more
The list of myopia control contact lens (CL) designs myopic eyes, effectively reducing the anisometropia. Inter-
continues to grow. A custom-made, lathe-cut SCL with a peri- estingly and potentially indirectly related, in another study,
pheral progressive +2.00 D add on the front surface is one 20 subjects who were initially categorized as slow progres-
such design. While details on this design are scant, its reverse sors based on their rates of axial elongation showed no clin-
geometry design is intended to aid in lens stability, while ically significant change 7 months after being switched from
providing continuous peripheral defocus.149 In a random- SVS to ortho-k, whereas 21 of 24 subjects identified as fast
ized trial of this SCL involving children aged 7 to 15 years, progressors did.159
myopia progression was reduced by approximately 50% over In another comparative efficacy trial, aspheric multifo-
12 months (i.e., mean change in SE/AL of –0.28 D/0.13 mm cal soft contact lenses (MFSCLs, +6.00 D max. peripheral
compared to –0.57 D/0.22 mm for the control group). power), ortho-k, and SVS lenses were included in a 1-
year single-blind, randomized clinical trial.160 The MFSCLs
and ortho-k showed similar efficacy; AL changes, used as
Orthokeratology indices of progression, were 0.30 and 0.31 mm, respectively,
Novel (ortho-k) lens designs have been the subject of some compared to 0.41 mm with SVS lenses.160
recent, mostly small-scale, trials. In one such trial involv-
ing a contralateral design, significantly different increases in Pharmaceutical Interventions
AL were reported after 18 months for a multifocal ortho-
k lens (center-distance, +2.50 D) compared to a conven- Oral 7-Methylxanthine. This adenosine antagonist, a
tional ortho-k lens, consistent with superior efficacy of the close relative of caffeine, is already approved for use in
former.150 That myopia control can be enhanced by reducing Denmark, the location of a recent observational study,161
the back optic zone diameter (BOZD) of ortho-k lenses is the in which data from a patient cohort of 7 to 15 years (<–
shared conclusion of two additional studies. In one study,151 0.50 D or worse myopia; n = 711) were used to examine
AL increases over 12 months were significantly less with a the effects of age and dose (range, 400–1200 mg). The main
5 mm compared with a 6 mm BOZD lens (by 0.13 mm) conclusion was that dose counts—the highest dose offered
(Table 5), with the difference in the treatment zone also the best control.
positively correlated with the AL change. The second study, Topical Atropine. Topical atropine remains the only
which involved young adolescents (13.34 ± 1.38 years of widely accessible ophthalmic formulation with an estab-
age), reported a 0.13-mm absolute reduction in AL elonga- lished efficacy profile, but differences in formulating the
tion over 12 months.152 The compression factor represents a composition may likely affect the outcome.162 Recent data
third ortho-k design feature examined in this context, with indicate that age matters, at least in Chinese children, with
a compression factor of 1.75 D versus 0.75 D with new younger children requiring higher concentrations to achieve
versus conventional ortho-k lenses (i.e., an additional 1.00 similar reductions in myopia progression110,163 (e.g., 0.05%
D compression factor) linked to slower axial elongation, by vs. 0.025% for 6- vs. 8-year-olds).110 That concentration and
34% (0.35 ± 0.29 mm vs. 0.53 ± 0.29 mm) after 2 years of age influence rebound responses were well demonstrated in
lens wear.153 year 3 data of the LAMP study, which compared washout

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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 15

(no therapy) versus continued therapy (0.05%, 0.025%, the mechanism underlying this AL shrinkage remains uncer-
and 0.01%). Those previously receiving higher concentra- tain and cannot be explained by changes in choroidal thick-
tions exhibited faster (rebound) progression, with differ- ness. Likewise, why are there only modest rebound effects
ences between washout and continued therapy groups being on termination of the LLRL therapy?168,169 The safety of such
smaller for older age groups.116 In one of two other stud- LLRL therapies remains to be established, as none of the
ies of interest, monocular 0.125% atropine therapy, adminis- trials to date have included suitably sensitive objective func-
tered to the longer eye of anisometropes, was found effective tional testing and plans for long-term follow-up. Addition-
in reducing interocular differences by slowing axial elonga- ally, adverse event monitoring has been largely question-
tion.164 The second study, a small trial involving premyopic naire based, with passing reference to optical coherence
children (4–12 years old) and 0.01% atropine, indicated that tomography (OCT) imaging in certain studies.74,168,169
topical atropine may delay the onset of myopia.165 Violet Light and Myopia Control. In the only clin-
Trials combining topical atropine and myopia control ical trial to date,82 myopia progression was tracked in 6- to
optical interventions have yielded mixed results. In a 3-year 12-year-old children assigned to either violet light (360–400
trial involving MFSCL with a +2.50 D add,119 the addition nm) transmitting spectacles or conventional spectacle lenses.
of daily 0.01% atropine did not lead to improved efficacy. The treatment effect of the violet light lenses proved to be
However, in another randomized clinical trial involving chil- small and not significant (0.03-mm and 0.11-D slowing over
dren assigned to either an ortho-k alone (OK) group or a 2 years with relative reduction in axial elongation by 21.4%).
combined 0.01% atropine-ortho-k (AOK) group,166 signifi-
cantly slower axial elongation was found in the AOK group
compared to the OK group at the end of the 2-year trial. IMI DIGEST: INDUSTRY GUIDELINES AND ETHICAL
Slower axial elongation was also associated with a larger CONSIDERATIONS
increase in the photopic pupil size, potentially implicating
increased higher-order aberrations as a source of directional Since the original IMI report on industry guidelines and
defocus cues.166 ethical considerations,2 there have been significant advance-
ments and developments in the field of myopia control
with an increasing adoption of myopia control strategies
Rebound Effects—Relative Risks for Optical by eye care practitioners worldwide. This digest updates on
Versus Pharmaceutical Interventions the findings since the last report and expands on areas of
recently acquired knowledge.
Rebound phenomena, as observed after the termination of
long-term use of pharmacologic agents, are of debatable
relevance to optical interventions. It is thus not surprising Safety
that progression after discontinuation of MiSight SCLs was The original 2019 IMI report on industry guidelines and ethi-
similar to progression with SVSs, albeit in a small sample.105 cal considerations2 asserted that “children do not have a
Likewise in a contralateral trial comparing progression with higher risk than adults of suffering from contact lens-related
EDOF and MiSight SCLs and contralateral SV SCLs, no complications with either OK or soft contact lens wear”.
“rebound” was observed after discontinuation of the two Recent studies have largely supported this assertion.170–174
“myopia control” SCLs.117 While spectacle lenses present no risk with regard to
infection, they may affect vision. Thus, it is important to
note that new novel spectacle lenses specifically designed
Light Therapies for myopia control have some influence on visual perfor-
Since 2021, there have been four publications reporting mance (measured using high- and low-contrast visual acuity,
results from clinical trials involving low-level red light (LLRL) reading speed, and peripheral contrast sensitivity),175–177
therapy and a single retrospective study.74,75,167–169 In all although the use of contact lenses has been shown to
cases, two 3-minute direct exposures to LLRL per day, spaced improve how children and teenagers feel about their appear-
at least 4 hours apart, were provided via desktop, long- ance and participation in activities, leading to greater satis-
wavelength (635–650 nm) laser diode devices, with energy faction with their refractive error correction.178–181 Atropine
outputs in a range of 0.29 to 0.4 mW. In some but not can cause cycloplegia and photophobia at higher concen-
all cases, therapy was limited to weekdays, with participa- trations,182 requiring the supply of photochromic progres-
tion largely limited to children, down to 3 years of age in sive addition lenses, although they are not necessary at
one retrospective study.75 Only one short (6-month) trial lower concentrations.183 As discussed in the “Light Thera-
included a sham treatment, in the form of a dimmer red pies” section, at the present time, there is a lack of compre-
light treatment (0.03 compared to 0.29 mW).167 Across trials, hensive data and review of safety with the newly emerging
the longest follow-up period was 2 years,168 with change light therapies.
in AL/SE with LLRL being 0.16 ± 0.37 mm/–0.31 ± 0.79 D as
compared to 0.64 ± 0.29 mm/–1.24 ± 0.63 D with SVS alone. Efficacy
While the large treatment effects, which are generally greater
in magnitude than those reported with other pharmaco- The 2019 IMI report on industry guidelines and ethical
logic and optical interventions, are attracting much attention, considerations2 noted that both refractive error and AL can
there remain important issues related to these trial data that be used to assess the efficacy of myopia control—the former
need to be addressed. Consistent across all studies was an ideally using cycloplegic autorefraction to minimize patient
early (detectable within first month) AL shrinkage in a large and examiner biases and the latter using optical biome-
number of eyes, a parallel reduction in myopia (i.e., hyper- ters because of their exquisite precision. A compelling case
opic shift),74,168 and choroidal thickening, contrasting with for axial elongation being the preferred primary outcome124
the choroidal thinning in control groups.74,75,168,169 However, is based on its stronger relation to visual impairment,184

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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 16

superior precision,185,186 and its immunity to accommo- the two terms are used interchangeably by eye care practi-
dation artifacts.187 Most important, some myopia control tioners and optometric associations both within and outside
modalities, primarily overnight ortho-k,188 modify corneal the United States.
shape, thus affecting the refractive status of the eye and Low-concentration atropine eye drops appear to be
making refraction measures untenable for assessing myopia commercially available for slowing myopia progression in
progression.124 children in parts of Asia, notably Singapore. Also, a propri-
Myopia control efficacy is usually assessed by compar- etary solution of 0.01% atropine eye drops has recently
ing annual refractive error progression, axial elongation, or obtained regulatory approval in Australia to slow the
both between treated and untreated myopic children. An progression of myopia in children (https://www.nps.org.au/
important observation is that the efficacy in the first year of medicine-finder/eikance-0-01). In other countries, including
treatment is generally greater than in subsequent years,124 a the United States, low concentrations of atropine are increas-
feature that appears to be true for both optical and pharma- ingly used off-label but must be compounded with variations
ceutical modalities. This comparison of mean progression is in procedures and thus formulations.162
also the primary outcome in US Food and Drug Administra- The regulatory approval process varies around the world
tion (FDA) clinical trials of devices, be they contact lenses in its scope and rigor. The FDA typically requires 3-year
or spectacles.128,189 Investigational drugs are evaluated by data from a controlled randomized clinical trial, with 1-year
a different unit of the FDA, where the favored primary follow-up after termination of treatment to assess the poten-
outcome appears to be the overall between-group difference tial for rebound effects,189 while other jurisdictions may
in proportion of subjects who show a given difference in accept shorter-term studies or other forms of evidence. For
myopia progression after 3 years, either –0.50 or –0.75 D. example, regulatory agencies in parts of Asia may base their
The rigorous requirements for FDA approval include positions on those of the FDA, and discussion of its stances
assessment of safety and patient-reported outcomes, as well here is germane to other regions. The range of products that
as evaluation for potential rebound effect, as has been have been approved for slowing myopia progression and
demonstrated in some,190–192 though not all,116,193,194 stud- are now marketed in different countries has grown dramati-
ies involving myopia control interventions. cally since the 2019 IMI reports, and their number and diver-
sity are expected to continue to expand. Thus, any attempt
Worldwide Regulatory Status of Modalities to document approved products by region would likely be
incomplete and, very soon, obsolete.
The term myopia management is used by eye care
practitioners and optometric associations worldwide Dissemination of Information
to broadly refer to clinical strategies used by eye care
practitioners to address a patient’s immediate refractive The 2019 IMI report on industry guidelines and ethical
error condition, namely, correcting their myopia, as well considerations2 states, “One major issue relates to the fact
as assessing the progression of their condition over time that myopia control treatments do not impart an immediate
(i.e., reducing myopia progression) and axial elongation. effect but rather an expected outcome that is several years in
This terminology does not distinguish, however, between the future.” Recent work has quantified the long-term reduc-
products specifically approved for myopia control (on-label) tion in years of visual impairment that might be expected
from those only approved for the correction or temporary from a program of myopia control and placed it in the
reduction of myopia—although the latter may slow myopia context of the short-term risks.195 Nonetheless, some bodies
progression in children (off-label). Typically, regulatory feel that long-term visual benefits in adult life accrued as a
approval is required to ensure that medical products meet result of myopia control in childhood should be confirmed
certain standards of safety and efficacy before being autho- by prospective studies (College of Optometrists Myopia
rized for use. When prescribing a treatment for myopia Management, https://www.college-optometrists.org/the-co-
control, where possible, the eye care professional should llege/policy/myopia-management.html, accessed January
ideally start by considering on-label products and contem- 2023), despite the 50 to 60 years that such an enterprise
plate off-label prescribing when on-label products are not would take. Furthermore, the potential benefits of myopia
effective or appropriate.2 control should be placed in the context of its cost.196
At the time of the original 2019 IMI reports, there
appeared to be only two products that had regulatory Consideration of Location of Studies
clearance anywhere in the world—both were multizone
SCL lenses that were Conformité Européenne (CE) marked, The 2019 IMI report on industry guidelines and ethical
which is the manufacturer’s self-certification that the prod- considerations2 opined that “previous studies have shown
ucts conform to the standards within Europe. Since then, that a given treatment (e.g., ortho-k) might not present the
several soft and ortho-k contact lenses have obtained CE- same efficacy in clinical trials conducted in different coun-
marked approval specifically for reducing myopia progres- tries and ethnic groups.” Most clinical trials are single-center
sion in children, which not only permits commercializa- studies with limited ethnic and racial diversity. Multicenter
tion of these products for this indication within the Euro- trials are rare and multicountry studies even rarer.99,128
pean Union but also facilitates pursuing marketing autho- Nonetheless, a growing body of evidence shows that
rization for myopia control in other parts of the world, such overnight ortho-k slows axial elongation to a similar degree
as Australia and Singapore. Of special interest is that the in East Asian197–201 and non–East Asian107,202–204 popula-
FDA has approved the first SCL (MiSight; Coopervision Inc., tions, with studies conducted in diverse locations across the
Pleasanton, California, USA) specifically for myopia control. world also reporting remarkably similar treatment effects.205
Although the FDA makes a distinction between myopia Likewise, progressive addition spectacles lenses are equally
control—an indication reserved for devices slowing myopia ineffective in East Asian206–208 and non–East Asian193,209,210
progression—and the broader term of myopia management, populations. Finally, low-concentration atropine has limited

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efficacy across East Asian, South Asian, and Australian study duration and participant characteristics, which may
populations,110,112,114,183,211,212 although underpowered vary significantly between clinical trials, percentage effica-
analyses of small subgroups suggest differences may cies cannot be validly compared across studies. Instead,
exist.212 it was recommended that myopia control treatment effi-
cacy be reported as an absolute value—the total reduction
in axial growth of the treatment group compared to the
Ethical Issues of the Future of Clinical Trials in control group. This paper was the first to compare abso-
Myopia Control lute efficacy outcomes for a variety of spectacle, MFSCL,
The IMI 2021 Digest129 questions, “If the treatment is well and ortho-k studies, all of which included at least 10
enough established to slow or prevent myopia progres- data points. While pharmacologic interventions were not
sion, is it ethical to randomly assign subjects to an ineffec- included due to concentration-dependent efficacies, there
tive sham/control group given their likelihood to develop was no apparent superior treatment, with “the best of
myopia or have myopic progression?” The conclusion was ortho-k, MFSCLs, spectacles and atropine showing similar
that “at present, an appropriately selected concurrent control effect.” Further support for this statement was provided in
group is still ethical for myopia control trials.” There are recent clinical trials, which found similar myopia control
concerns about the ethics of removing a successful myopia efficacy between MFSCLs and ortho-k compared to the
control treatment from a participant. As the evidence for control group,160 as well as between MFSCLs and EDOF
the relation between myopia level and visual impairment lenses.117
grows,184,195 along with that for effective therapies for slow- While some myopia control treatments may be less effec-
ing progression, the above question should be visited peri- tive, and both side effects and the potential for rebound
odically. There are additional, practical challenges to the can impact outcomes, eye care practitioners should factor
conduct of clinical trials where an effective treatment is in their own skill set, treatment availability of treatments,
withheld in control subjects in order to evaluate a new patient and parent preferences and capacity, and, finally,
therapy. As summarized in the “Study Design” section and regulatory considerations when choosing a treatment for the
a recent study,213 these include parents immediately with- individual patient.124
drawing a child assigned to a no-treatment group192,214 Although the concept of CARE has the potential to
and a higher proportion of longer-term withdrawals among further expand our understanding of myopia control treat-
control subjects.212,215 Ultimately, ethical questions are best ment efficacy, eye care practitioners need to compare patient
answered region by region, with the availability of on- outcomes with a control reference group, which can vary
label myopia control modalities and the prevailing stan- based on age, ethnicity, gender, and parental myopia, to
dard of care being key considerations. Alternative clin- determine if a patient is experiencing lower than expected
ical trial designs have been summarized in the “Study cumulative absolute progression, indexed by axial elonga-
Design” section,213 including using a virtual control group tion. Furthermore, CARE does not consider variations in
based on previous studies,216 comparison with established treatment effect or a proportional treatment outcome (i.e.,
treatments, or a time-to-treatment-failure (survival analysis) where children showing faster progression prior to treat-
approach.217 ment experience a larger myopia control effect), as was
shown in one 6-year study.103 Despite the ongoing debate
over reporting absolute versus proportional treatment effect,
IMI DIGEST: CLINICAL MANAGEMENT GUIDELINES proactive treatment of all young myopes, especially those
under age 12 years, is recommended.124
This digest supplements the 2019 IMI white paper on clinical Maximizing Outcomes: Wearing Time. Research
management guidelines218 and the IMI 2021 yearly digest1 supports wearing time and/or treatment compliance as
by providing a broad update on the previous IMI publica- a potential avenue to explore to maximize treatment
tions. For specific updates on new treatments for myopia, outcomes, with data indicating that full-time wear of myopia
the reader is referred to the previous section on interven- control treatment achieves the best outcome. For HAL spec-
tions for controlling myopia onset and progression. In this tacles, myopia control efficacy was highest in children who
section, new information on the comparative efficacy, safety, wore their HAL spectacles for at least 12 hours per day, 7
and visual outcomes of myopia control interventions was days per week.101 This observation also aligns with results
extracted from relevant publications and collated to inform from previous MFSCL trials that found increased efficacy
and guide clinical practice. Clinical considerations, including with improved wearing time, measured in hours per day219
balancing short-term risks and long-term benefits, are also or days per week.217 Other studies of dual-focus SCLs128 and
explored. DIMS spectacle lenses220 have reported similar benefits with
longer wearing times.
New Understanding of Treatments and Efficacy Maximizing Outcomes: Combination and
Enhanced Treatments. Combination strategies offer
Comparative Treatment Efficacy. A recent review another method to further improve the efficacy of existing
of myopia control treatments highlighted gaps in current myopia control treatments. However, as indicated in the
myopia research.124 One key posit was the concept of previous section on interventions for controlling onset and
Cumulative Absolute Reduction in Axial Elongation (CARE), progression of myopia, outcomes have been mixed with
proposed as an alternative to “percentage efficacy” in eval- some demonstrating a benefit,166 while others report no
uating treatments and when comparing treatments outside added benefit over monotherapy.119 It would be of interest
of a single study. Within a study, percentage efficacy repre- to determine if efficacy can be enhanced by combining
sents the percentage reduction in myopia progression in the atropine with myopia control spectacle lenses or by using
treatment compared to the control group. However, as the higher concentrations of atropine in combination treat-
treatment outcome is influenced by many factors, such as ments. However, a retrospective study found that combining

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ortho-k with a higher concentration of atropine (0.125%) Vision and Visual Function Outcomes in Myopia
was not as effective as a lower concentration (0.025%) of Control Treatments
atropine.221 This result is seemingly paradoxical, given the
concentration-dependent results of several atropine-only Overall, myopia control treatments appear to have a minimal
studies,110,183,222 although only one trial to date has directly negative impact on VA and binocular vision function, but it
compared concentrations above and below 0.1%.222 should be noted that studies investigating impacts of other
Modifying ortho-k lens designs may also influence treat- visual functions and subjective quality of vision and quality
ment effect. As outlined in the section on interventions, wear of life are limited.
of ortho-k lenses with 6-mm compared to a 5-mm BOZD Clinical trials of dual-focus and center-distance MFSCLs
resulted in slower axial elongation in the latter case, after with either a +1.50 or +2.50 D add have reported high-
1 year of wear, despite the lenses having a slightly lower contrast distance and near VAs to be comparable to the
first-fit success rate. However, the difference in axial elonga- control SV groups.128,226 Similarly, distance and near VAs
tion of 0.12 mm was significantly different between groups with DIMS220 and HAL101 spectacle lenses were no different
only in the first 6 months, with axial elongation continuing than VAs achieved with SVS. When subjects viewed through
at a similar rate in both groups during the second 6-month the “treatment” zone of the lens, DIMS and HAL spectacles,
period.151 both were found to reduce distance VA by less than one
Rebound of Myopia. A review of myopia control effi- line (0.09 and 0.07 logMAR units, respectively). However,
cacy stated that “rebound should be assumed until proven the lenslet configurations in both the DIMS and aspheri-
otherwise.”223 In this respect, although the aggregate of cal lenslet designs had a relatively more negative impact
data as summarized here and in the previous section on on spatial contrast vision, especially in lower illumination
interventions indicates minimal rebound upon cessation of and with low contrast, although there was minimal impact
current myopia control SCL and low-concentration atropine of glare on acuity outcomes.175
treatments, discontinuation of treatment before 13 to 14 Distance and near VAs in children undergoing 0.05%,
years of age should be undertaken with caution. Specifi- 0.025%, and 0.01% atropine treatment have been shown
cally, no rebound was observed when children aged 13.2 ± as similar to each other and to a placebo control group,
1.2 years discontinued dual-focus SCL wear after 2 years of achieving VAs around 0.00 logMAR units in all cases.183
lens wear.105 Similarly, discontinuation of low-concentration Ortho-k combined with atropine 0.01% reportedly had no
atropine (0.025% and 0.01%) after 2 years of treatment did impact on distance acuity, but the specific outcomes were
not result in any significant rebound effects, while a faster not reported.166 Reducing ortho-k BOZD from 6 mm to
eye growth was observed after discontinuation from 0.05% 5 mm did not impact distance acuity, with 0.00 LogMAR units
atropine (0.04 mm over 1 year), although deemed to be clin- or better in both groups, but near acuity was not reported.151
ically insignificant. Also, in 6- to 8-year-old children, discon- Recent studies have explored the impact of myopia
tinuation of all three concentrations (0.05%, 0.025%, and control treatments on accommodation and vergence func-
0.01%) resulted in comparable rates of eye growth.116 tions in comparison to SV correction. In children, DIMS220
A previous study found that ceasing ortho-k lens wear and HAL227 spectacle lenses were found to have no impact
before 14 years of age resulted in eye growth comparable on phoria or accommodation at near. Dual-focus SCL
to that of younger children wearing SVSs and greater than also had a minimal impact on phoria and accommoda-
a concurrent control group, suggestive of a likely rebound tive response.228–230 New data on ortho-k propensity to
effect. Axial elongation was slowed again when ortho-k wear increase the accommodation response231,232 and create an
was recommenced after 6 months.192 So far, there have been exophoric shift in children at near232 are in agreement with
no data on rebound with myopia control spectacles. results from previous studies233,234 and appear linked to
Commencing Myopia Control Treatment in a greater myopia control.231 In contrast, aspheric MFSCLs
Older Children. More recent data suggest that even older were found to reduce the accommodation response and yet
children may benefit from myopia control treatments. In clin- induce a small exophoric shift in children235,236 and young
ical trials, efficacy was demonstrated with wear of dual-focus adults,228,237,230,237 with different peripheral add powers
SCLs in older children at ages 11 to 15 years,103 DIMS spec- having no differential impact on these responses.228,230 For
tacle lenses in children aged 10 to 15 years,98 and atropine ortho-k, a more accurate accommodation response has been
0.05% for children with a commencement age of 8 to correlated with a larger myopia control effect.235
12 years.116 Each of these trials involved children who were
originally assigned to the control group but were switched Safety of Myopia Control Treatments
to the treatment group after 3, 2, and 1 years, respectively.
However, with the elimination of a control group with this Although the various myopia control treatments have vary-
switch in each of these studies, efficacy in these older chil- ing safety profiles, the current data indicate that myopia
dren could only be assessed through comparisons to a control treatments are generally safe. Myopia control spec-
historical control group. There appears to be an “accumu- tacles have minimal associated physical risk, comparable
lating treatment effect” indicating early and more extended to that of conventional SVS. For contact lenses, the most
treatment having the largest overall benefit, but with significant risk is microbial keratitis, an event that is poten-
demonstrated benefit even when treatment was initiated tially sight-threatening. However, the incidence of micro-
later.103 bial keratitis is extremely low, with quantification of this
With new data indicating that 38% of adult myopes rare occurrence challenging and requiring large samples to
progress by at least 0.50 D in their third decade, accompa- provide definitive estimates of incidence. The 6-year clin-
nied by small but significant longitudinal changes in AL and ical trial of dual-focus SCLs reported three discontinua-
lens thickness,224 further research on young adult myopia tions, of which only one was related to contact lens wear
progression is warranted as outlined in the IMI: Young Adult (infiltrative keratitis).174 Other nonsignificant adverse events
myopia white paper.225 included papillary conjunctivitis, blepharitis, meibomianitis,

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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 19

conjunctivitis (bacterial, viral, or allergic), superficial punc- sents an essential starting point for that line of research.
tate keratitis, and mild pannus. No adverse events were Animal studies are continuing to build and improve our
observed in children under 10 years of age.174 The incidence understanding of the role of visual feedback and the vari-
of corneal infiltrative events or microbial keratitis in children ous pathways controlling visual experience and growth in
12 years and younger is also not greater than that observed myopia. Studies are addressing key issues, such as charac-
in adults, further supporting the use of contact lenses in terizing light processing and signaling pathways from the
children.170 retina to sclera that influence axial elongation, the nature of
A recent analysis of microbial keratitis in Russian chil- temporal integration of stimuli influencing refractive error
dren wearing ortho-k reported an annual incidence rate of development, and the influence of circadian rhythms and
4.9 to 5.3 per 10,000 patient years.170 This value is lower illumination. Recent research offers further support for the
than a previous estimate from the United States of 13.9 per role of dopamine and melanopsin in emmetropization and
10,000 patient years,238 which is comparable to or lower than myopia and, additionally, also indicates that low light plays
that observed with other overnight contact lens modalities a role in myopia. In attempts to elucidate the role of light,
in adults.195 narrowband long- and short-wavelength light have been
The ocular side effects of atropine are well established linked to dysregulation of eye growth. Newer treatment
and include photophobia and near-vision difficulties due to strategies such as topical caffeine and scleral cross-linking
loss of accommodation.116,239 Allergic conjunctivitis has also are currently also being explored.
been reported with atropine treatment and is assumed to be In human clinical trials, newer spectacle lens designs
related to the preservative in the formulation.195 However, incorporating multiple segments, lenslets, or diffusive dots
with the rising availability of preservative-free formulations, have shown promise in slowing myopia. A new category
it is anticipated that there will be fewer reports of allergic of myopia control treatment involves light-based therapy,
conjunctivitis. with low-level red light delivered through a desk-based
Although observational data suggest that myopia control device among options being trialed with promising efficacy
treatments are generally safe, their long-term safety has not but insufficient safety data. Currently, topical atropine is
been rigorously studied, with clinical trials typically limited the only widely available pharmacologic treatment, with a
to 2- to 3-year treatment periods. Thus, for example, longer- recent clinical study finding topical caffeine to have no posi-
term effects of atropine use and associated increased retinal tive effect on myopia progression. The role for combination
light exposure linked to atropine-induced mydriasis are yet treatments to improve efficacy is still under consideration,
to be determined.195 with some studies showing improved efficacy and others
not. Rebound effects as observed with higher concentra-
tion of atropine appear to be avoided with lower concen-
Balancing Risks and Benefits trations and optical strategies. In translating the research
findings to clinical practice, treatments are shown to have
The main purpose of myopia control treatment is to slow
minimal negative impact on VA and binocular vision func-
progression of myopia and reduce the risk of develop-
tions and are seen to be effective even in older children,
ing associated sight-threatening ocular pathology, especially
and longer wearing time maximizes outcomes for some
myopic maculopathy later in life.184,240 The potential bene-
optical treatments. Although additional long-term efficacy,
fits are particularly significant for myopes with longer AL as
safety, tolerance, and visual function data are needed for
these eyes are at greater risk of irreversible vision loss.184
such treatments, in both children and young adult progress-
The benefits of reducing myopia progression relative to the
ing myopes, their benefits appear to outweigh the risks,
risks associated with control treatments124,195 are the subject
and current evidence weighs in favor of proactive myopia
of ongoing discussion, and although the long-term benefit
control prescribing in clinical practice. Future trials evalu-
of myopia control in reducing the risk of irreversible vision
ating the efficacy of myopia control treatments should be
loss remains to be confirmed, the potential benefits are
designed in a manner that informs both clinical practice and
considered to outweigh the risks.195 It appears that gener-
underlying mechanism of action. Some of the recent trials
ally, myopia control treatments can be used safely with no
were found lacking in elements that minimize bias, such as
increased risk. Other benefits of achieving a lower level of
masking, randomization, a simultaneous control group, and
myopia include better VA (both corrected and uncorrected),
clearly defined enrolment criteria, with inaccurate conclu-
improved vision-related quality of life, and reduced depen-
sions a potential consequence. Researchers, industry, clin-
dence on correction and further support the use of myopia
icians, and regulatory bodies are encouraged to use the
control treatments.241
information presented in this update along with the origi-
nal IMI report97 and the IMI 2021 yearly digest1 to interpret
SUMMARY the strength of published evidence as it appears, compare
risks and benefits between treatments, and design clinical
The field of myopia research is continuing to rapidly expand. trials and plans for implementing myopia control in clinical
The IMI definitions of ≤–0.5 D for myopia and ≤–6.0 D practice.
for high myopia are now widely adopted, and there is an
increasing interest in the term premyopia. There is still
a need to categorize, define, and understand the struc-
tural consequences of high myopia and to understand and Acknowledgments
explore treatments specific for high myopia. In addition to Supported by the International Myopia Institute. The publi-
slowing myopia progression in children, we need effective cation and dissemination costs of the International Myopia
treatments for slowing the age-dependent progression of Institute reports were supported by donations from the
pathologic myopia. Establishing clear definitions and classi- Brien Holden Vision Institute, Carl Zeiss Vision, CooperVi-
fications of the various aspects of pathologic myopia repre- sion, EssilorLuxottica, Hoya, Thea, Alcon, and Oculus. A special

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 IMI Digest IOVS | Special Issue | Vol. 64 | No. 6 | Article 7 | 20

acknowledgement to Christine Wildsoet for harmonization of 10. Liu L, Li R, Huang D, et al. Prediction of premyopia
this white paper. and myopia in Chinese preschool children: A longitudinal
cohort. BMC Ophthalmol. 2021;21:283.
Disclosure: P. Sankaridurg, EssilorLuxottica (F, R), Shamir (F), 11. Fang PC, Chung MY, Yu HJ, Wu PC. Prevention of myopia
CooperVision (F, R), SEED (R), Oculus (F), SightGlass Vision onset with 0.025% atropine in premyopic children. J Ocul
(R), Mark Ennovy (R), Myopia Control- optical and pharma- Pharmacol Ther. 2010;26:341–345.
ceutical (P), ZEISS (C); D.A. Berntsen, Bausch & Lomb (F); 12. Yue Y, Liu X, Yi S, Liu B, Yi H, Li H. High prevalence
M.A. Bullimore, Alcon Research (C), CooperVision (C), of myopia and low hyperopia reserve in 4411 Chinese
Corneagen (C), EssilorLuxottica (C), Euclid Systems (C), Eyen- primary school students and associated risk factors. BMC
ovia (C), Genentech (C), Johnson & Johnson Surgical (C), Ophthalmol. 2022;22:212.
Johnson & Johnson Vision (C), Lentechs (C), Novartis (C), 13. Li SM, Wei S, Atchison DA, et al. Annual incidences
Oculus(C), Pentavision (C), Presbia (C), Vyluma (C), Ridge- and progressions of myopia and high myopia in Chinese
vue Publishing (O), Ridgevue Vision (O); P. Cho, Johnson schoolchildren based on a 5-year cohort study. Invest
and Johnson Vision (C), Menicon (C); I. Flitcroft, CooperVi- Ophthalmol Vis Sci. 2022;63:8.
sion (C), EssilorLuxottica (C), Johnson & Johnson Vision (C),
Vyluma (C), Thea (C), Ocumetra (O), Myopia control moni- 14. Li SM, Kang MT, Li L, et al. Cohort study on the associ-
toring tools and devices (P); T.J. Gawne, P (patents pending ation between hyperopia reserve and myopia incidence
for several optical methods for myopia control); K.L. Gifford, in primary school students: The Anyang Childhood Eye
Alcon (C), CooperVision (C), EssilorLuxottica (C), Hoya Vision Study. Zhonghua Yan Ke Za Zhi. 2022;58:754–759.
(C), Johnson & Johnson Vision (C), Menicon (C), SightGlass 15. Guo C, Ye Y, Yuan Y, et al. Development and validation
Vision (C), Topcon Healthcare (C), OCULUS (C), Visioneer- of a novel nomogram for predicting the occurrence of
ing Technologies (C), Vyluma (C); M. Jong, Johnson&Johnson myopia in schoolchildren: A prospective cohort study. Am
Vision (E); P. Kang, Coopervision (F), Johnson and Johnson (F); J Ophthalmol. 2022;242:96–106.
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