-
Special Issue
IMI – Interventions for Controlling Myopia Onset andProgression
Report
Christine F. Wildsoet,1 Audrey Chia,2 Pauline Cho,3 Jeremy A.
Guggenheim,4 Jan RoelofPolling,5,6 Scott Read,7 Padmaja
Sankaridurg,8 Seang-Mei Saw,9 Klaus Trier,10 Jeffrey J.
Walline,11
Pei-Chang Wu,12 and James S. Wolffsohn13
1Berkeley Myopia Research Group, School of Optometry and Vision
Science Program, University of California Berkeley,
Berkeley,California, United States2Singapore Eye Research Institute
and Singapore National Eye Center, Singapore3School of Optometry,
The Hong Kong Polytechnic University, Hong Kong4School of Optometry
and Vision Sciences, Cardiff University, Cardiff, United
Kingdom5Erasmus MC Department of Ophthalmology, Rotterdam, The
Netherlands6HU University of Applied Sciences, Optometry and
Orthoptics, Utrecht, The Netherlands7School of Optometry and Vision
Science and Institute of Health and Biomedical Innovation,
Queensland University of Technology,Brisbane, Australia8Brien
Holden Vision Institute and School of Optometry and Vision Science,
University of New South Wales, Sydney, Australia9Saw Swee Hock
School of Public Health, National University of Singapore,
Singapore10Trier Research Laboratories, Hellerup, Denmark11The Ohio
State University College of Optometry, Columbus, Ohio, United
States12Department of Ophthalmology, Kaohsiung Chang Gung Memorial
Hospital and Chang Gung University College of Medicine,Kaohsiung,
Taiwan13Ophthalmic Research Group, Aston University, Birmingham,
United Kingdom
Correspondence: Christine F. Wild-soet, School of Optometry,
Universi-ty of California Berkeley, 588 MinorHall, Berkeley, CA
94720-2020, USA;[email protected].
Submitted: October 11, 2018Accepted: December 24, 2018
Citation: Wildsoet CF, Chia A, Cho P, etal. IMI – Interventions
for ControllingMyopia Onset and Progression Report.Invest
Ophthalmol Vis Sci.2019;60:M106–M131.
https://doi.org/10.1167/iovs.18-25958
Myopia has been predicted to affect approximately 50% of the
world’s population basedon trending myopia prevalence figures.
Critical to minimizing the associated adversevisual consequences of
complicating ocular pathologies are interventions to prevent
ordelay the onset of myopia, slow its progression, and to address
the problem of mechanicalinstability of highly myopic eyes.
Although treatment approaches are growing in number,evidence of
treatment efficacy is variable. This article reviews research
behind suchinterventions under four categories: optical,
pharmacological, environmental (behavioral),and surgical. In
summarizing the evidence of efficacy, results from randomized
controlledtrials have been given most weight, although such data
are very limited for sometreatments. The overall conclusion of this
review is that there are multiple avenues forintervention worthy of
exploration in all categories, although in the case of
optical,pharmacological, and behavioral interventions for
preventing or slowing progression ofmyopia, treatment efficacy at
an individual level appears quite variable, with no onetreatment
being 100% effective in all patients. Further research is critical
tounderstanding the factors underlying such variability and
underlying mechanisms, toguide recommendations for combined
treatments. There is also room for research intonovel treatment
options.
Keywords: myopia control, optical, pharmacological, behavioral,
surgical
1. GENERAL INTRODUCTION
This article encompasses various interventions in current usefor
controlling myopia progression in children, organizedunder three
broad categories: optical, pharmacological andenvironmental
(behavioral). Surgical interventions aimed atstabilizing highly
myopic eyes are also covered as a fourthtopic. In each case,
current treatments, as well as those inlimited use and/or subjected
to clinical trial, are considered.The still climbing myopia
prevalence figures worldwide,including of high myopia, and the
association between highmyopia and sight-threatening ocular
pathologies, providesstrong motivation for research into underlying
mechanisms
and effective therapies that can limit ocular elongation,
withthe hope that the incidence of such pathologies also may
belimited. Other articles in this special issue of
InvestigativeOphthalmology and Visual Science offer
comprehensivecoverage of the experimental animal model literature
andapproaches for monitoring progression, with best
practicerecommendations in relation to assessing treatment
outcomes(see accompanying IMI – Clinical Management
GuidelinesReport).1 Thus in this article, coverage has been limited
to abrief background overview of the treatments themselves,evidence
for efficacy, with emphasis on high-quality random-ized clinical
trials, adverse effects, and future directions forresearch.
Copyright 2019 The Authors
iovs.arvojournals.org j ISSN: 1552-5783 M106
This work is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0 International
License.
Downloaded from iovs.arvojournals.org on 03/01/2019
https://creativecommons.org/licenses/by-nc-nd/4.0/
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2. OPTICAL INTERVENTIONS FOR MYOPIAMANAGEMENT
2.1 Introduction
Optical interventions for controlling myopia have an
extensivehistory, with early clinical studies largely based
aroundspectacles aimed at altering the near visual experience.
Clinicalstudies involving contact lens–based treatments are
largelylimited to the 21st century, with studies demonstrating
opticaldefocus-driven regulation of eye growth in animal
modelshelping to reawaken interest in, and drive new
opticalapproaches to myopia control. Specifically, as
demonstratedfirst in young chicks, imposed myopic defocus is known
toslow eye growth, whereas the converse is true for
hyperopicdefocus (i.e., eye growth accelerates).2 This report
summarizesthe results from clinical studies using spectacles,
contactlenses, and orthokeratology (OK). The evidence contained
inrelevant published studies has been evaluated and
recommen-dations for using optical strategies for myopia
controlprovided, based on the quality of reported results and
theevidence.
2.2 Spectacles
The utility of using spectacle lenses for slowing
myopiaprogression has many advantages over other forms of
myopiamanagement, as they are easy to fit, are mostly well
acceptedand tolerated, are affordable by most, and are
minimallyinvasive. The various spectacle lens–based approaches
aimedat slowing the progression of myopia include both standardand
customized single-vision (SV) lens designs, as well asbifocal and
progressive spectacle lenses.
There is equivocal evidence concerning whether fullcorrection
with SV spectacles causes faster myopic progressionthan full
correction with soft contact lenses.3–7 The evidencewould suggest
that if that is the case then the difference islikely clinically
irrelevant.
2.2.1 Undercorrection With Spectacles. Undercorrec-tion to slow
the progression of myopia has been in practice formany years and
was originally considered to slow theprogression of myopia by
reducing the accommodativedemand during near tasks. The
accumulating reports of slowedeye growth in response to
experimentally imposed myopicdefocus in animal models,2,8 also led
to parallels being drawnwith the myopic defocus experienced during
distance taskswith undercorrection, and thus speculation about this
poten-tial additional benefit.
An early nonrandomized trial of undercorrection, conduct-ed in
1960s,9 found this treatment to slow the progression ofmyopia. More
recently (since 2000), well-designed, random-ized controlled trials
(RCTs) examining undercorrection fordistance (byþ0.50 toþ0.75
diopters [D]) over 1.5 to 2.0 yearsfound this treatment to either
increase myopia progression orhave no benefit, when compared with
myopia progression infully corrected SV spectacle wearers (Table
1).10�12 Althoughall trials involved relatively young children at
an age whenprogression is common, the trials were only small to
moderatein size. However, the latter weakness does not explain
theconsistent trend of faster progression in undercorrected
eyesobserved in some studies. Nonetheless, although anotherlarger,
albeit nonrandomized trial also found no significantdifference
between comparable treatment groups, curiously,myopia progression
significantly decreased with increasingundercorrection.13 The
latter trend is also consistent withresults from a recent study
comparing myopia progression inuncorrected and fully corrected
12-year-old children; this studyfound slower progression in the
former group, the latter effect
increasing with the amount of undercorrection.14 The
possi-bility that the lack of sharp distance vision with
under-correction strategies may lead to behavioral changes, such
asreduced outdoor activities in some children, thereby
favoringmyopia progression, warrants investigation, although
thecontrasting study outcomes suggest additional factors are
atplay.
2.2.2 SV Peripheral Defocus-Correcting Lenses. Find-ings from
animal studies,2 including monkeys,29 offer strongevidence for
contributions by the peripheral retina to eyegrowth regulation and
refractive development (see accompa-nying IMI – Report on
Experimental Models of Emmetropiza-tion and Myopia).30 In addition,
a number of studies havereported relative peripheral hyperopia in
myopic eyes whenfully corrected with SV spectacles.31–33 Thus, it
has beenhypothesized that the hyperopic defocus experienced by
theretinal periphery may drive further axial elongation.
Three novel spectacle lens designs aimed at reducing therelative
peripheral defocus were tested in an RCT designed toevaluate this
notion.27 The results were generally disappoint-ing, with no
significant differences in myopia progressionbetween the groups
observed. In subgroup analysis, one of thelens designs (Type III)
that was specific to right and left eyesdemonstrated a small
benefit (of 0.25 D), compared with SVspectacles in younger children
with parental myopia. Likewise,a recent trial involving Japanese
children found no benefit ofthe MyoVision lens, a positively
aspherized design,34 and in afurther test of this treatment
approach, no benefit was foundby combining a peripheral defocus
correction with aprogressive addition zone for near work.28
2.2.3 Bifocal Spectacles. Traditional rationales for
pre-scribing bifocal spectacles for myopia control include
reducingor eliminating lags of accommodation during extended
nearwork, lags being a potential source of hyperopic
defocus.Reducing accommodative demand is another, with
theassociated reduction in ciliary muscle tension
potentiallyreducing stress on the overlying sclera. All multifocal
(MF)lens designs, including bifocal lens designs, also induce
relativemyopic shifts in peripheral refractive errors, at least in
superiorretinal field.31 Many of the bifocal spectacle trials, with
theexception of a single trial involving executive bifocal
lenses,26
were conducted before 2000, and mostly in 1980s.There have been
a number of RCTs involving bifocal
spectacle lenses. One such study,15 which involved childrenwith
near point esophoria followed over 2.5 years, reported amodest
(0.25 D), albeit statistically significant, reduction inprogression
with a 28-mm flat top bifocal lens compared withSV spectacles.
Vitreous chamber growth was also significantlyreduced, although the
change in axial length (AL) was not.However, in a previous 3-year
trial, mean rates of progressionwere less for SV spectacles worn on
a continuous basiscompared with bifocal spectacles or SV spectacles
for distanceonly (�1.46 D, continuous SV versus�1.58 D, bifocal
(þ1.75 D,straight top), versus �1.88 D, SV spectacles for
distanceonly).17 Similarly, no significant differences in myopia
progres-sion were observed in the Houston Myopia study,18
betweengroups wearing either of two executive bifocal lens
designs(þ1.00 orþ2.00 D add) or SV lenses. Retrospective analysis
oflongitudinal data from three optometry practices also found
nosignificant differences in myopia progression between
thosewearing SV spectacles and bifocal spectacles.16
The above results stand in sharp contrast to those of
arelatively recent RCT involving two high-set executive bifocallens
designs (þ1.50 D add alone andþ1.50 D add with 3D base-in prism),
both of which significantly reduced myopiaprogression in children
older than 3 years compared with SVspectacles (�1.25 D [bifocals]
versus �1.01 D, [prismaticbifocals] versus �2.06 D [SV]), in
children with progressing
IMI – Interventions for Controlling Myopia IOVS j Special Issue
j Vol. 60 j No. 3 j M107
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TA
BLE
1.
ASu
mm
ary
of
Resu
lts
Fro
mP
revio
us
Specta
cle
Myo
pia
Co
ntr
ol
Stu
die
sR
ep
ort
ed
inth
eP
eer-
Revie
wed
Lit
era
ture
Stu
dy
(Co
un
try
)
Sam
ple
Siz
e
[Age
Ran
ge,
y]
Co
ntr
ol
Stu
dy
Desi
gn
[Du
rati
on
,y]
%Lo
ssto
Fo
llo
w-U
p
%Slo
win
g
My
op
ia
Pro
gre
ssio
n
%Slo
win
g
Ax
ial
Elo
ngati
on
Base
lin
e
Age,
y
My
op
ia
Ran
ge,
D
Avera
ge
My
op
ia,
D
Un
derc
orr
ecti
on
Li
et
al.,
20
15
13
(Ch
ina)
25
3[1
0�
16
]FC
specs
No
nra
nd
om
ized
,
ob
serv
atio
nal
[1]
NA
5.8
0FC
:1
2.7
60
.4
UC
:1
2.7
60
.5
NP
FC
:�
3.7
56
1.2
3
UC
:�
3.1
26
1.2
9
Ad
ler
and
Millo
do
t,2
00
61
2
(UK
)
48
[6�
15
]FC
specs
Ran
do
miz
ed
[1.5
]2
2.5
Wo
rse
wit
hU
C:
20
.7
NC
FC
:1
0.2
62
.2
UC
:9
.96
2.7
FC
:1
.06
to
�4
.50
UC
:�
1.3
7to
�5
.30
FC
:�
2.8
26
1.0
6
�2
.95
61
.25
Ch
un
get
al.,
20
02
10
(Mal
aysi
a)
94
[9�
14
]FC
specs
Ran
do
miz
ed
[2]
NP
Wo
rse
wit
hU
C:
29
.8
NP
FC
:1
1.5
61
.5
UC
:1
1.6
61
.5
Gre
ater
than
�0
.50
FC
:�
2.6
86
1.1
7
�2
.68
61
.41
Ko
om
son
et
al.,
20
16
11
(Gh
ana)
15
0[1
0�
15
]FC
specs
Ran
do
miz
ed
[2]
0.6
7.4
12
.5FC
:1
2.4
61
.2
UC
:1
2.4
61
.4
�1
.25
to�
4.0
0FC
:�
1.9
66
0.5
7
�2
.02
60
.54
Bif
ocal
s
Fu
lket
al.,
20
00
15
(USA
)
82
[6�
13
]SV
specs
Ran
do
miz
ed
[2.5
]8
.52
0.2
18
.4B
F:
10
.76
1.3
SV:
10
.86
1.4
Gre
ater
than
�0
.50
and
near
po
int
Eso
ph
ori
a
BF:�
2.1
26
1.1
6
�2
.52
61
.40
Go
sset
al.,
19
86
16
(USA
)
11
2N
PSV
specs
No
nra
nd
om
ized
[NP
]
NA
15
.9N
AN
PN
PN
P
Pär
ssin
en
et
al.,
19
89
17
(Fin
lan
d)
24
0[9�
11
]SV
specs-
dis
tan
t
SVsp
ecs-
co
nti
nu
ou
s
Ran
do
miz
ed
[var
iab
le]
NP
20
.2vs.
SV*
8.2
wo
rse
vs.
SV
co
nt*
NA
SVD
ista
nt:
10
.9
SVC
on
t:1
0.9
BF:
10
.9
NP
SVD
ista
nt:
LE
:�
1.3
SVC
on
t:LE
:�
1.5
BF:
LE
:�
1.5
Gro
sven
or
et
al.,1
98
71
8(U
SA)
20
7[6�
15
]SV
specs
Ran
do
miz
ed
[3]
40
.1þ
1.0
0A
dd
:w
ors
e
5.8
þ2
.00
Ad
d:
5.8
NA
NP
Gre
ater
than
�0
.25
NP
Pro
gre
ssiv
ead
dit
ion
specta
cle
s
Leu
ng
et
al.,
19
99
19
(Ho
ng
Ko
ng)
80
[9�
12
]SV
specs
No
nra
nd
om
ized
[2]
15
.0PA
Lþ
1.5
0:
38
.2
PALþ
2.0
0:
46
.3
PALþ
1.5
0:
33
.7
PALþ
2.0
0:
44
.5
PALþ
1.5
0:
10
.5
PALþ
2.0
0:
10
.2
SV:
10
.4
�1
.00
to�
5.0
0PA
Lþ
1.5
0:�
3.7
36
1.1
3
PALþ
2.0
0:�
3.6
76
0.9
7
SV:�
3.6
76
1.1
5
Ed
war
ds
et
al.,
20
02
20
(Ho
ng
Ko
ng)
29
8[7�
10
.5]
SVsp
ecs
Ran
do
miz
ed
[2]
14
.71
1.1
3.1
PAL:
9.2
SV:
8.9
�1
.25
to�
4.5
0PA
L:�
2.8
26
0.9
9
SV:�
2.9
26
0.9
9
Yan
get
al.,
20
09
21
(Ch
ina)
17
8[7�
13
]SV
specs
Ran
do
miz
ed
[2]
16
.31
7.3
15
.7A
ll:
11
.06
1.6
�0
.50
to�
3.0
0PA
L:�
1.6
06
0.6
3
SV:�
1.7
86
0.6
8
Gw
iazd
aet
al.,
20
03
22
(USA
)
46
9[6�
11
]SV
specs
Ran
do
miz
ed
[3]
1.5
13
.51
4.6
PAL:
9.3
61
.3
SV:
9.4
61
.3
�1
.25
to�
4.5
0PA
L:�
2.4
06
0.7
5
SV:�
2.3
76
0.8
4
Has
eb
eet
al.,
20
08
23
(Jap
an)
92
[6�
12
]SV
specs
Ran
do
miz
ed
cro
sso
ver
[1.5
]
7.0
25
.8(p
has
eI)
NA
PAL:
10
.0
SV:
9.7
�1
.25
to�
6.0
0PA
L:�
3.1
7
SV:�
3.3
1
CO
ME
T2
01
12
4
(USA
)
11
8[8�
12
]SV
specs
Ran
do
miz
ed
[3]
7.0
24
.3N
APA
L:
10
.26
1.1
SV:
10
.06
1.1
�0
.75
to�
2.5
0PA
L:�
1.5
06
0.4
5
SV:�
1.4
56
0.4
7
IMI – Interventions for Controlling Myopia IOVS j Special Issue
j Vol. 60 j No. 3 j M108
Downloaded from iovs.arvojournals.org on 03/01/2019
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TA
BLE
1.
Co
nti
nu
ed
Stu
dy
(Co
un
try
)
Sam
ple
Siz
e
[Age
Ran
ge,
y]
Co
ntr
ol
Stu
dy
Desi
gn
[Du
rati
on
,y
]
%Lo
ssto
Fo
llo
w-U
p
%Slo
win
g
My
op
ia
Pro
gre
ssio
n
%Slo
win
g
Ax
ial
Elo
ngati
on
Base
lin
e
Age,
y
My
op
ia
Ran
ge,
D
Avera
ge
My
op
ia,
D
Bern
tsen
et
al.,
20
12
25
(USA
)
85
[6�
11
]SV
specs
Ran
do
miz
ed
[1]
1.1
34
.62
8.5
PAL:
9.6
61
.2
SV:
10
.16
1.5
�0
.75
to�
4.5
0PA
L:�
1.9
56
0.6
4
SV:�
2.0
46
0.9
1
Ch
en
get
al.,
20
14
26
(Can
ada)
13
5[8�
13
]SV
specs
Ran
do
miz
ed
[3]
5.2
DB
F:
51
.0
BF:
39
.3
DB
F:
34
.1
BF:
30
.5
DB
F:
10
.46
0.3
BF:
10
.16
0.3
SV:
10
.36
0.3
�1
.00
or
mo
re
wit
h‡
0.5
D
pro
gre
ssio
nin
pre
ced
ing
year
DB
F:�
3.2
76
0.1
6
BF:�
3.0
36
0.1
6
SV:�
2.9
26
0.1
9
Peri
ph
era
ld
efo
cu
sm
anag
em
en
t
San
kar
idu
rget
al.,
20
10
27
(Ch
ina)
21
0[6�
16
]SV
specs
Ran
do
miz
ed
[1]
4.4
Typ
eI:
Wo
rse
3.8
Typ
eII
:W
ors
e3
.8
Typ
eII
I:1
5.4
Typ
eI:
0
Typ
eII
:2
.83
.8
Typ
eII
I:1
3.9
Typ
eI:�
10
.76
2.4
Typ
eII
:�
11
.16
2.2
Typ
eII
I:�
11
.46
2.3
SV:
10
.86
2.5
�0
.75
to�
3.5
0;
cyl�
1.5
0
Typ
eI:�
1.8
26
0.6
2
Typ
eII
:�
1.8
16
0.6
7
Typ
eII
I:�
1.8
26
0.6
6
SV:�
1.8
76
0.6
8
Has
eb
eet
al.,
20
14
28
(Ch
ina/
Jap
an)
19
7[6�
12
]SV
specs
Ran
do
miz
ed
[2]
14
.3PA
-PA
Lþ
1.0
:1
3.7
PA-P
ALþ
1.5
:2
0
PA-P
ALþ
1.0
:7
.3
PA-P
ALþ
1.5
:
11
.7
PA-P
ALþ
1.0
:1
0.6
61
.5
PA-P
ALþ
1.5
:1
0.0
61
.5
SV:
10
.46
1.2
�0
.50
to�
4.5
0PA
-PA
Lþ
1.0
:
�2
.52
61
.01
PA-P
ALþ
1.5
:
�2
.80
61
.02
SV:�
2.6
16
1.0
0
BF,
bif
ocal
;FC
,fu
llco
rrecti
on
;N
A,
no
tap
plicab
le;
NP,
no
tp
rovid
ed
;PA
-PA
L,
peri
ph
era
las
ph
eri
zed
PAL;
Specs,
specta
cle
s;U
C,
un
derc
orr
ecti
on
;N
C,
no
chan
ge;
co
nt,
co
nti
nu
ou
sw
ear
.*
Left
eye
rath
er
than
avera
geac
ross
bo
theye
sco
mp
ared
.
IMI – Interventions for Controlling Myopia IOVS j Special Issue
j Vol. 60 j No. 3 j M109
Downloaded from iovs.arvojournals.org on 03/01/2019
-
myopia). Overall, the magnitude of change was similarbetween the
two bifocal groups, except for children withlow lags of
accommodation, for whom the prismatic bifocallenses had a greater
benefit.26 The investigators speculated thatfor children with low
lags, both convergence and lens-inducedexophoria were reduced by
the base-in prism; the latter effectspresumably led to improved
compliance.
2.2.4 Progressive Addition Spectacles (PALs). Of all
thespectacle interventions assessed for their efficacy in
slowingthe progression of myopia, PALs have been the most
studied.As with bifocal spectacles, the rationale for their use has
beento reduce the accommodative demand and/or reduce accom-modative
lag during near tasks.
Leung and Brown19 proposed the use of PALs as analternative to
bifocal lenses, which were considered to notadequately control
defocus for all distances. Their clinical trial,which compared
myopia progression withþ1.50 andþ2.00 DPALs and SV lenses over 2
years, found significantly reducedmyopia progression relative to
that with SV lenses with bothþ1.50 D (0.47 D difference) and þ2.00
D PAL (0.57 Ddifference).19 However, this study was not fully
randomizedand later RCTs conducted in the United States, Hong
Kong,China, and Japan (using either þ1.50 or þ2.00 D add
powercompared with SV lenses), found that although PALs
signifi-cantly reduced myopia progression, often the difference
fromprogression with SV lenses was
-
contralateral control RCT.48 Only three of the trials47,55,56
usedcommercially available contact lenses. Three trials
usedconcentric ring designs, with the other six trials
usingprogressive power designs. Five of the studies
followedsubjects for 2 years,50–52,54,55 with one of them involving
acrossover design.50 SV contact lenses were used as
controltreatments for most of the studies (7 of 9), with the
remainingtwo studies using SV spectacles. All studies had
similarboundary conditions for recruited subjects; ages ranged
from7 to 18 years, with low to moderate myopia (average
SE:approximately�2 D; range: –0.50 to –6.00 D) (Table 2). Acrossall
studies combined, 76% of subjects completed the trials.
Based on sample size–weighted averages, the eight
trialspublished over the 2011 to 2016 period showed a 38.0%slowing
of myopia progression and a 37.9% slowing of axialelongation with
MF soft contact lens interventions (see Figure).Some studies showed
greater apparent slowing of myopiaprogression than of axial
elongation,52,54 and others, greaterapparent slowing of axial
elongation than of myopia progres-sion,48,49 and some,
approximately matched slowing of myopiaprogression and axial
elongation.47,50,51,53,55 Interestingly,concentric ring designs
showed better control over axialelongation than progressive designs
(44.4% versus 31.6%),whereas their effects on myopia progression
were similar(36.3% versus 36.4%). The most recently published
compre-hensive data for the MiSight lens are from a
randomizedcontrolled but not masked trial.55 Reductions in
myopiaprogression and axial elongation at the end of a 2-year
trialperiod, of 39% and 38% respectively, are similar to the
groupaverages reported above, although the efficacy of the
MiSightlens could have been slightly overestimated as the subjects
inthe treatment arm were slightly older (by approximately 1year).
Nonetheless, significant reductions in myopia progres-sion were
also observed at 1-, 2-, and 3-year visits in a larger, 3-year RCT
of the same lens.57 The dropout rates for the MiSightand SV
(control) lenses over 3 years in the latter study weresimilar, 26%
and 24%, respectively.58
Only two of the eight trials examined the potentialinfluence of
peripheral refractive errors on myopia progres-sion.52,53
Noteworthy, both trials used SV spectacle lenses asopposed to SV
contact lenses as controls. Sankaridurg et al.53
reported a significant correlation between the
relativeperipheral hyperopia at 30 and 40 degrees nasal and
40degrees temporal, measured with correcting lenses in place,and
myopia progression. Likewise, Paune et al.52 reported asignificant
correlation between the relative peripheralrefractive errors at 30
degrees nasal and temporal and axialelongation over the first year
of treatment. In the crossover‘‘contralateral control’’ trial of
Anstice and Phillips,48 theeyes wearing the MF soft contact lenses
showed slowermyopia progression and axial elongation relative to
theirfellows, in both phases of the trial. Furthermore, under
themonocular MF lens condition of this study,
accommodativeresponses to near tasks were consistent with
accommodationbeing driven by the center-distance zone of the MF
lenses,the implication being that accommodative lags would havebeen
minimally affected. However, two other studiesreported positive
benefits on accommodative errors in thepresence of MF soft contact
lenses (i.e., decreased accom-modative lags46 and accommodative
leads59). An increase inhigher-order aberrations and a relative
decrease in peripheralhyperopia through the MF contact lenses were
also reportedin the study of Paune and colleagues,46 who speculated
onthe potential positive benefits for myopia control of both
ofthese optical effects.
2.3.4 Orthokeratology. OK, also known as cornealreshaping
therapy, involves reshaping of the cornea to reducemyopic
refractive errors.60–63 The development of speciallyT
AB
LE
2.
ASu
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ary
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ies
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y
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dy
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)
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ple
Siz
e
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Ran
ge,
y]
Co
ntr
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Tre
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t
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Desi
gn
[Du
rati
on
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]
%Lo
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llo
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p
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My
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ia
Pro
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n
%Slo
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Age,
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ow
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rget
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(Ch
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82
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ecta
cle
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ve
[1]
18
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10
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Wal
lin
eet
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20
13
54
(USA
)5
4[8�
11
]C
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len
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rical
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ntr
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[2]
19
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F:
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F:�
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1.0
2
SV:
10
.86
0.7
SV:�
2.3
56
1.0
5
Fu
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20
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(Jap
an)
24
[10�
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tact
len
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ized
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ver
[2]
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�0
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3.5
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2.5
26
1.6
9
SV:
13
.16
1.9
SV:�
3.6
16
0.9
8
Lam
et
al.,
20
14
51
(Ho
ng
Ko
ng)
12
8[8�
13
]C
on
tact
len
sR
and
om
ized
[2]
42
.12
5.3
32
.4M
F:
11
.16
1.6
�1
.00
to�
5.0
0M
F:�
2.9
06
1.0
5
SV:
10
.96
1.7
SV:�
2.0
86
1.0
3
Pau
ne
et
al.,
20
15
52
(Sp
ain
)4
0[9�
16
]Sp
ecta
cle
sP
rosp
ecti
ve
[2]
43
.74
2.9
26
.9M
F:
13
.36
2.0
�0
.75
to�
7.0
0M
F:�
2.4
46
0.9
1
Spec:
13
.16
2.8
Spec:�
2.6
46
1.1
Aller
et
al.,
20
16
47
(USA
)7
9[8�
18
]C
on
tact
len
sR
and
om
ized
[1]
8.1
77
.27
9.2
MF:
13
.06
2.5
�0
.50
to�
6.0
0M
F:�
2.5
76
1.3
4
SV:
13
.56
2.2
SV:�
2.8
16
1.4
6
Ch
en
get
al.,
20
16
49
(USA
)1
09
[8�
11
]C
on
tact
len
sR
and
om
ized
[1]
14
.22
0.6
38
.9M
F:
9.7
61
.1�
0.7
5to�
4.0
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F:�
2.4
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0.9
1
SV:
9.7
61
.1SV
:�
2.5
26
1.4
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Ru
iz-P
om
ed
aet
al.,
20
18
55
(Sp
ain
)8
9[8�
13
]Sp
ecta
cle
sR
and
om
ized
[2]
16
.93
9.3
23
6.0
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F:
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.06
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�0
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4.0
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BLIN
K,
Bif
ocal
Len
ses
inN
ear
sigh
ted
Kid
s;M
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ult
ifo
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ion
specta
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;SV
,si
ngle
-vis
ion
co
nta
ct
len
s.
IMI – Interventions for Controlling Myopia IOVS j Special Issue
j Vol. 60 j No. 3 j M111
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-
designed reverse geometry rigid GP lenses has revolutionizedOK,
by allowing sufficient reshaping of the cornea to beachieved with
overnight wear. The reshaping is believed to bedue to a
redistribution of corneal epithelial cells followinginitial
compression.64 Although the initial goal of suchtherapies was to
eliminate the need for daytime opticalcorrections, OK has proven to
be effective in slowing myopiaprogression. OK also has been shown
to induce relativemyopic shifts in peripheral refractive errors in
all meridians,65
consistent with the most popular hypothesis for this
myopiacontrol effect,66 although a role for altered
higher-orderaberrations cannot be excluded.67,68
Most studies on the effectiveness and reliability of OK
formyopia control have focused on children,60,69–75 with
onlylimited reports on effects in adults.63 They include two RCTs
inchildren,60,72 one randomized crossover trial,61 and
severallongitudinal nonrandomized clinical trials. Details of
thesestudies are summarized in Table 3.
In the earliest of these trials, the Longitudinal
Orthokera-tology Research in Children (LORIC) study,69 35 children
aged7 to 12 years and undergoing OK treatment, were monitoredover
24 months. Comparative data were obtained from 35historical
controls (age-, sex-, and initial-spherical equivalentrefractive
error–matched children wearing SV spectacles).20
Axial elongation in the OK group over the 2-year trial periodwas
approximately half that in the control group (0.29 vs. 0.54mm),
with the respective increases in vitreous chamber depthlargely
accounting for this difference (0.23 vs. 0.48 mm).Following the
LORIC study, other quasi-experimental studieson children with low
to moderate myopia were conductedwith similarly positive
outcomes70,71,74,75; reported levels ofcontrol ranged from 32% to
55%, when changes werecompared against those in children wearing
either SVspectacles or SV soft contact lenses.
Results from the two published RCTs provided furtherevidence for
the efficacy of OK as a myopia control treatment.In the first
trial, the Retardation of Myopia in Orthokeratology(ROMIO) study,72
axial elongation was reported to be slowedby an average of 43%,
with treatment effects being propor-tionately larger in younger,
more rapidly progressing myopicchildren (7–8 years: 20% versus 65%
[control]) than in olderchildren (9–10 years: 9% versus 13%
[control]). Higher myopes(�5.75 D or above) were recruited into a
second trial, the HighMyopia–Partial Reduction Orthokeratology
(HM-PRO) study60
and randomly assigned into partial reduction (PR) OK and SV
spectacles groups. As the PR OK treatment targeted a
4.00-Dreduction only, treated subjects needed to wear SV
spectaclesto correct residual refractive errors during the day.
Nonethe-less, here also, axial elongation in the PR OK group was
63%less than that of the control group.
In a more recent study, the effect on ‘‘myopia progression’’of
OK was compared against conventional GP lenses using anovel
experimental design,61 in which one eye of each subjectwore an OK
lens and the other eye, a GP lens, each for two 6-month periods,
with the lens type worn by each eye switchedat the end of the first
6 months after a washout period of 2weeks. The eye wearing GP
lenses thus acted as a ‘‘self’’control. The subjects were of East
Asian ethnicity, aged 8 to 16years. No increases in AL over either
the first or second 6-month period were recorded for eyes subjected
to OK,compared with increases of 0.04 and 0.09 mm respectivelyin
eyes wearing the GP lenses. Note, however, that even thelatter
changes are small relative to changes recorded withcontrol
treatments in other studies.
All of the above studies used spherical design OK lenses andthus
were confined to children with low astigmatism.However, a
subsequent 2-year trial, the Toric OrthokeratologySlowing Eye
Elongation (TO-SEE) study, involving children withmoderate to high
astigmatism and OK lenses with toricperipheries,73 reported axial
elongation to be 52% less thanin their control group who wore SV
spectacles.
Two relevant meta-analyses by Si et al.76 and Sun et al.77
have confirmed the effectiveness of OK for myopia
control,although Si et al.76 recommended further research, given
thatfive of the seven studies included in their meta-analysis
werefrom Asia.
A few studies suggest that early termination of OKtreatment
might lead to a greater increase in axial elongationand myopia in
children,61,78,79 although this has not beenfound to be the case in
university students with adult-onset,progressive myopia.80 Some
studies also suggest that relativetreatment efficacy may decrease
with time.75,81,82 Reducedtreatment efficacy has been linked to
lower baseline myo-pia,69,82–84 although there may be confounding
factors notaccounted for. The magnitude of the treatment-induced
powerchange has also been reported to impact myopia
control,independently of baseline myopia,85 although not in
allstudies.71,72,75,86,87 On the other hand, larger pupil
diameters,deeper anterior chambers, and steeper, more prolate
corneas
FIGURE. Percent slowing of change in refractive error and axial
elongation for soft MF contact lens myopia control studies
published in the peer-reviewed literature.
IMI – Interventions for Controlling Myopia IOVS j Special Issue
j Vol. 60 j No. 3 j M112
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-
TA
BLE
3.
Sum
mar
yo
fR
esu
lts
Fro
mP
ub
lish
ed
Stu
die
so
fO
rth
okera
tolo
gy
for
Myo
pia
Co
ntr
ol
Stu
dy
(Co
un
try
)
Sam
ple
Siz
e
[Age
Ran
ge,
y]
Co
ntr
ol
Tre
atm
en
t
Stu
dy
Desi
gn
[Du
rati
on
,y
]
Lo
ssto
Fo
llo
w-U
p,
%
Ax
ial
Elo
ngati
on
,
mm
Slo
win
gin
Ax
ial
Elo
ngati
on
,%
Base
lin
eA
ge,
y
Base
lin
eM
yo
pia
[SE
R,
D]
Ch
oet
al.,
20
05
69
(Ho
ng
Ko
ng)
43
[þ3
5h
isto
rical
co
ntr
ols
]
7�
12
SVsp
ecs
His
tori
cal
co
ntr
ol
[2]
19
.0O
K:
0.2
96
0.2
7
C:
0.5
46
0.2
7
46
OK
:9
.66
1.5
C:
9.6
60
.69
OK
:[�
2.2
76
1.0
9]
C:
[�2
.55
60
.98
]
Wal
lin
eet
al.,
20
09
70
(Un
ited
Stat
es)
40
[þ2
8h
isto
rical
co
ntr
ols
]
8�
11
SCL
His
tori
cal
co
ntr
ol
[2]
30
.0O
K:
0.2
56
0.2
7
C:
0.5
76
0.2
7
55
OK
:1
0.5
61
.1
C:
10
.56
1.0
Un
kn
ow
n
Kak
ita
et
al.,
20
11
74
(Jap
an)
10
5SV
specs
No
nra
nd
om
ized
[2]
12
.4O
K:
0.3
96
0.2
73
6O
K:
12
.16
2.6
OK
:[�
2.5
56
1.8
2]
8�
16
C:
0.6
16
0.2
4C
:1
1.9
62
.1C
:[�
2.5
96
1.6
6]
Hir
aoka
et
al.,
20
12
75
(Jap
an)
59
SVsp
ecs
No
nra
nd
om
ized
[5]
27
.1O
K:
0.9
96
0.4
73
0O
K:
10
.04
61
.43
OK
:[�
1.8
96
0.8
2]
�1
2C
:1
.41
60
.68
C:
9.9
56
1.5
9C
:[�
1.8
36
1.0
6]
San
tod
om
ingo
et
al.,
20
12
71
(Sp
ain
)
61
SVsp
ecs
No
nra
nd
om
ized
[2]
13
.1O
K:
0.4
73
2O
K:
9.9
61
.6O
K:�
2.1
56
1.1
2
6�
12
C:
0.6
9C
:9
.96
1.9
C:�
2.0
86
1.2
3
Ch
oan
dC
heu
ng,
20
12
72
(Ho
ng
Ko
ng)
10
2SV
specs
Ran
do
miz
ed
[2]
23
.5O
K:
0.3
66
0.2
44
3O
K:
9.4
61
.4O
K:�
2.0
56
0.7
2
6�
10
C:
0.6
36
0.2
6C
:8
.96
1.6
C:�
2.2
36
0.8
4
Ch
en
et
al.,
20
13
73
(Ho
ng
Ko
ng)
80
SVsp
ecs
NR
[2]
27
.5O
K:
0.3
16
0.2
75
2O
K:
9.4
61
.4O
K:�
2.4
66
1.3
2
6�
12
C:
0.6
46
0.3
1C
:8
.96
1.6
C:�
2.0
46
1.0
9
Ch
arm
and
Ch
o,
20
13
89
(Ho
ng
Ko
ng)
52
SVsp
ecs
Ran
do
miz
ed
[2]
46
.2O
K:
0.1
96
0.2
16
3O
K:
Med
ian
10
,
ran
ge9
.0�
11
.0
OK
:M
ed
ian
6.5
0,
ran
ge6
.0�
8.3
0
8�
11
C:
0.5
16
0.3
2C
:M
ed
ian
10
,ra
nge
8.0�
11
.0
C:
Med
ian
6.1
3,
ran
ge5
.0�
8.3
0
Swar
bri
ck
et
al.,
20
15
61
(Au
stra
lia)
32
GP
Co
ntr
alat
era
leye
Ran
do
miz
ed
cro
sso
ver
[1]
25
Ph
ase
1–
13
.46
1.9
Ph
ase
1
8�
16
OK
:�
0.0
26
0.0
5O
K:�
2.4
36
0.9
8
C:
0.0
46
0.0
6G
P:�
2.3
96
0.9
3
Ph
ase
2P
has
e2
OK
:�
0.0
46
0.0
8O
K:�
2.6
06
1.2
1
C:
0.0
96
0.0
9G
P:�
2.2
26
1.1
0
Pau
ne
et
al.,
20
15
52
(Sp
ain
)7
0SV
specs
No
nra
nd
om
ized
[2]
44
.3O
K:
0.3
26
0.2
03
8O
K:
12
.27
61
.76
OK
:[�
3.5
16
2.1
3]
9�
16
C:
0.5
26
0.2
2C
:1
3.0
96
2.7
9C
:[�
3.6
16
0.9
8]
SCL,
soft
co
nta
ct
len
ses;
SER
,sp
heri
cal
eq
uiv
alen
tre
frac
tio
n;
C,
co
ntr
ol
gro
up
;G
P,gas
-perm
eab
leri
gid
co
nta
ct
len
ses.
IMI – Interventions for Controlling Myopia IOVS j Special Issue
j Vol. 60 j No. 3 j M113
Downloaded from iovs.arvojournals.org on 03/01/2019
-
are among ocular parameters that have been linked to sloweraxial
elongation in children.88
2.3.5 Visual and Ocular Side Effects. Vision-relatedcomplaints
tend to be defocus-related in origin across alloptical
interventions, and correctible with appropriate adjust-ment to
prescriptions, although substantial changes to resolvethe such
complaints also may lessen the likelihood of adequatemyopia
control. Significant ocular side effects are largelylimited to
contact lenses used for myopia control. In OKwearers, pigmented
ring formation60,90 and altered cornealnerve pattern (fibrillary
lines)91,92 have been reported,although none of these changes
appear to have adverse clinicalramifications. A number of cases of
microbial keratitisassociated with OK have been reported in the
literature, morefrequently encountered in the early years of
OK,93,94 withcontact lens storage cases being one potential source
ofcontamination.95 Nonetheless, Bullimore and colleagues96
compared the incidence of microbial keratitis associated withOK
in children and adults and concluded that, within the limitsof
their study, there is no difference in the risk of
microbialkeratitis with OK and other overnight contact lens
modalities,although the risk is higher for overnight compared with
dailywear.
3. PHARMACOLOGICAL CONTROL OF MYOPIA
3.1 Introduction
In relation to pharmacological control of myopia
progression,to-date topical atropine has dominated both clinical
trials andclinical practice, where it is now used widely as either
anapproved product or off-label. Atropine is a
nonselectiveirreversible antimuscarinic antagonist, with a long
history ofuse in ophthalmology as a potent and long-acting
mydriatic andcycloplegic agent. Clinically, it is used as a
diagnostic aid in theassessment of refractive errors in very young
children,97 topenalize the preferred eye in therapy for
amblyopia,98 and toimmobilize the iris and ciliary muscles as a
component oftherapy for uveal inflammatory conditions such as
iritis.99 Itsuse to treat myopia dates back to the
1960s.100�103
The earliest cohort studies involving topical atropine
werepublished in the 1970s.100�103 Since that time,
numerousretrospective and cohort studies have been
published.104�112
The first randomized controlled trials (RCTs) to be publishedare
those by Yen et al. (1989)113 and Shih et al. (1999).114
Morerecently, two large, back-to-back trials were undertaken
inSingapore: the Atropine for Treatment Of Myopia studies(ATOM1 and
2),115�119 followed by two smaller studies inChina by Yi et al.
(2015)120 and Wang et al. (2017),121 and avery recent larger trial
in Hong Kong.122 Table 4 summarizesdetails of these seven trials,
including the tested atropineconcentrations, which vary widely,
from as low as 0.01% to1.0%. Two other antimuscarinic drugs appear
in these studies:tropicamide, which is a short-acting drug and was
used as acontrol treatment, and cyclopentolate, which has an
interme-diate duration of action and was tested for its efficacy as
amyopia control agent.
Other pharmacological approaches trialed for myopiacontrol
include topical timolol, a nonselective beta-adrenergicantagonist,
and oral 7-methylxanthine (7-MX), an adenosineantagonist. The
latter was approved for use in Denmark, aspharmacy-compounded
tablets, with reimbursement from theDanish National Health
Insurance for patients up to 18 years ofage, after a small clinical
trial of 7-MX in that country123; 7-MXis also generated by
metabolism in the body from caffeine andtheobromine, which are both
ingredients of dark chocolate. To-date there have been no follow-up
trials in other countries,
although it remains a drug of interest, with related
on-goingstudies in the monkey myopia model.124
Although recommendations for the use of ocular hypoten-sive
drugs for myopia control appear in a number of earlypublications,
including that by Curtin (1985),125 well-de-scribed clinical trials
of these agents are limited, althoughthere are reports of positive
treatment outcomes for epineph-rine,126,127 labetolol,128 a
combination of pilocarpine andtimolol,129 and timolol alone.128
Denmark was the site of thelargest RCT of twice-daily topical 0.25%
timolol for myopiacontrol, by Jensen (1991).130 The driving
principle for thisapproach is biomechanical (i.e., to lower IOP as
a method ofslowing ocular elongation). Topical timolol is widely
availablein many countries as a topical ophthalmic drug, approved
forthe treatment of open angle glaucoma.
Reviews covering pharmacological interventions for myopiacontrol
include one focused on primary research,131 aCochrane review,56 and
a more recent one focused onatropine.132 In this article, results
of relevant meta-analysesare also presented.
3.2 Atropine
3.2.1 Changes in Spherical Equivalent RefractiveError as an
Outcome Measure. Based on changes inspherical equivalent refractive
error as the outcome measureall studies have shown that atropine
slows myopia progression.Bedrossian (1971)100 in an early study of
150 children aged 7 to13 years reported no myopia progression in
75% of eyes treateddaily with 1% atropine over a 1-year period
compared withonly 3% of controls. Similarly another early study by
Gimbel(1973)103 in which 279 children received 1% atropine over
3years reported a 66% reduction in myopia progressioncompared with
that of 572 controls (�0.41 vs. �1.22 D).
The first two randomized controlled trials of atropine,
bothpublished in the 1990s, also reported very good control
overmyopia progression in children, with reductions exceeding60%
reported for the highest, 1% concentration. In the firstrandomized
controlled trial by Yen and colleagues (1989),113
247 children aged 6 to 14 years received either topical
1%atropine, 1% cyclopentolate, or saline drops over a 1-yearperiod.
They reported 76% and 36% reductions in myopiaprogression in the
groups treated with atropine and cyclopen-tolate, respectively,
compared with the group treated withsaline, although unfortunately,
there was a large loss to follow-up (61%). In the second randomized
controlled trial by Shihand colleagues (1999),114 200 children aged
6 to 13 years weretreated with 0.5%, 0.25%, or 0.1% atropine over a
2-year period;reported reductions in myopia progression were 61%,
49%,and 42%, respectively, compared with children treated with0.5%
tropicamide as the control treatment.
The ATOM1 and 2 studies, which were performed between1996 and
2013, involved 400 children, aged 6 to 12 years,randomized in each
case, to atropine 1% and placebo in a 1:1ratio in ATOM1, and to
0.5%, 0.1%, and 0.01% atropine in a2:2:1 ratio in ATOM2.115�119
Both trials involved a 2-yeartreatment period. On entering the
studies, children had low tomoderate myopia; baseline spherical
equivalent refractiveerrors ranged between �1.0 and �6.0 D in
ATOM1, andbetween�2.0 and�6.0 D in ATOM2. Overall, the profiles of
theparticipants in these two trials were very similar,
althoughslightly younger, with lower myopia in the first compared
withthe second trial (9.2 vs. 9.6 years; �3.4 vs.�4.7 D).116,118
Thereported mean progression rates for these trials were
�0.2,�0.3,�0.4, and�0.5 D for the four atropine groups (1%,
0.5%,0.1%, and 0.01%) compared with �1.2 D in the
placebogroup,115�119 amounting to reductions in myopia
progressioncompared with the latter group of approximately 80%,
75%,
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67%, and 58%, respectively. Loss to follow-up over the
2-yeartreatment periods was 13% and 11% for ATOM1 and
ATOM2,respectively.
Analysis of the changes in the ATOM1 study, year by
year,revealed a hyperopic shift in the 1% atropine group of
þ0.03versus �0.79 D in the control arm.118 The comparable valuesfor
the 0.5%, 0.1%, and 0.01% atropine treatment groupsincluded in
ATOM2 are �0.17, �0.31, and �0.43 D respective-ly.116 Thus, myopia
progression rates appear to directly reflectthe atropine
concentration used, decreasing with increasingconcentration.
However, dose-dependent differences were notapparent over the
second year of the trial, with all threeconcentrations achieving
similar slowing of myopia progres-sion. The net increases in myopia
over the 2-year trial periodwere�0.49,�0.38, and�0.30 D for the
0.01%, 0.1%, and 0.5%concentrations, respectively.116
Two of three more recent RCTs involved relatively
highconcentrations of atropine, being 1% (n¼ 126) and 0.5 % (n¼132)
in the studies by Yi et al. (2015)120 and Wang et al.(2017),121
respectively. Both reported hyperopic shifts in theatropine-treated
groups, presumably reflecting, at least in part,the enduring strong
cycloplegic action of this treatment, whilecontinued progression in
control groups over the same periodof time was observed (i.e.,þ0.3
vs.�0.9 D andþ0.5 vs.�0.8 D).Three lower concentrations of
atropine, 0.01%, 0.025%, and0.05%, were tested in the most recent
of these studies, by Yamet al. (2018) (n ¼ 438),122 who reported a
concentration-dependent reduction in myopia progression, with the
highestconcentration approximately halving the rate of axial
elonga-tion, as compared with the placebo control. All
concentrationswere well tolerated.
Although retrospective studies typically lack the same levelof
control of key study design variables as RCTs, overall theirresults
are consistent with those of the RCTs just described.Several
retrospective, cohort studies have tested higher, 0.5%to 1.0%
concentrations of atropine, reporting treatment effectsranging from
70% to 100%.104�106,108,109 In one of four studies
involving lower concentrations of atropine, children treatedwith
0.025% atropine over 22 months were reported toprogress by an
average of �0.28 D per year, compared with�0.75 D in untreated
children (a reduction of 63%).107Similarly, Fang and colleagues
(2010),111 using the same0.025% atropine concentration with
‘‘premyopic’’ children(spherical equivalent refractive error: þ1 to
�1 D), reported areduction in incident myopia and reduced
progressioncompared with controls (21% versus 54%, �0.14 vs.
�0.58D). Wu and colleagues110 also noted reduced progression
withatropine treatments, although interpretation of their
studyfindings is complicated by the variation in atropine
concentra-tions used to treat individual patients over the
4.5-yearmonitoring period, between 0.05% and 0.1%; the overall
meanprogression was�0.23 D per year, compared with�0.86 D peryear
in historical ‘‘controls.’’ A surprisingly low average
myopiaprogression of�0.1 D per year was reported for 0.01%
atropinein the only retrospective study involving this
concentration,referenced against a control rate of �0.6 D per
year,112although interestingly, this study included children of
bothAsian and Caucasian ethnicity.
3.2.2 Changes in AL as an Outcome Measure. Fewerstudies have
included AL as an outcome measure althougharguably it more
accurately reflects the treatment effect, beingfree from the
confounding effect of cycloplegia, which affectsrefractive error
data (see accompanying IMI – Clinical MyopiaControl Trials and
Instrumentation Report).133 Notably, cyclo-plegic agents, by
reducing ciliary muscle tone, reduce manifestmyopia. Indeed, the
latter effect likely accounts for, at least inpart, the more
promising results of lower concentrations ofatropine, when
expressed in refractive error terms, ascompared with AL changes,
given that the ciliary muscle isreadily accessible to topically
applied drugs. It can be furtherargued that AL changes are more
clinically relevant, given thatmany of the pathological
complications of myopia are by-products of excessive eye elongation
(see accompanying IMI –Defining and Classifying Myopia
Report).134
TABLE 4. Summary of Design and Key Results From Randomized
Trials Involving Topical Atropine for Myopia Control
Study (Country)
Size;
Duration,
y Treatments
Age
Range,
y
Baseline
Age, y*
Myopia
Range,
D
Average
Myopia,
D*
Change
in SER*#
Change
in AL, mm*#
Loss to
Follow-Up,
%
Yen et al. (1989)113
(Taiwan)
247; 1 A 1% and 6, 14 10.5 �0.5, �4 �1.5 (0.9) �0.2 D (76%) –
61Cyclo 1% 10.0 �1.4 (0.8) �0.6 D (37%)vs. Saline 10.4 �1.6 (0.9)
�0.9 D
Shih et al. (1999)114
(Taiwan)
200; 2 A 0.5% 6, 13 9.8 �0.5, �7 �4.9 (2.1) �0.04 D/y (61%) – 7A
0.25% 9.7 �4.2 (1.7) �0.45 D/y (49%)A 0.1% 8.9 �4.1 (1.5) �0.47 D/y
(42%)vs. Trop 0.5% 8.3 �4.5 (1.8) �0.61 D/y
Chua et al. (2006)118
(Singapore)
400; 2 A 1% 6, 12 9.2 �1, �6 �3.6 (1.2) �0.3 (0.9) (77%) �0.02
(0.35) (105%) 13vs. Placebo 9.2 �3.4 (1.4) �1.2 (0.7) 0.38
(0.38)
Chia et al. (2016)119
(Singapore)
400; 2 A 0.5% 6, 12 9.5 (1.5) �2, �6 �4.5 (1.5) �0.3 (0.6) (75%)
0.27 (0.25) 11A 0.1% 9.7 (1.6) �4.8 (1.5) �0.4 (0.6) (67%) 0.28
(0.28)A 0.01% 9.7 (1.5) �4.7 (1.8) �0.5 (0.6) (58%) 0.41 (0.32)
Wang et al.
(2017)121 (China)
126; 1 A 0.5% 5, 10 9.1 (1.4) �0.5, �2 �1.3 (0.4) �0.8 (160%)
�1.1 (300%) 13vs. Placebo 8.7 (1.5) �1.2 (0.3) �2.0 þ0.50
Yi et al. (2015)120
(China)
140; 1 A 1% 7, 12 9.9 (1.4) �0.5, �2 �1.2 (0.3) þ0.3 (0.2)
(138%) �0.03 (0.07) (109%) 6vs. Placebo 9.7 (1.4) �1.2 (0.3) �0.9
(0.5) 0.32 (0.15)
Yam et al. (2018)122
(Hong Kong)
438; 1 A 0.05% 4, 12 8.45 (1.81) �1 (min) �3.98 (1.69) �0.27
(0.61) 0.20 (0.25) 12A 0.025% 8.54 (1.71) �3.71 (1.85) �0.46 (0.45)
0.29 (0.20)A 0.01% 8.23 (1.83) �3.77 (1.85) �0.59 (0.61) 0.36
(0.29)vs. Placebo 8.42 (1.72) �3.85 (1.95) �0.81 (0.53) 0.41
(0.22)
Cyclo, cyclopentolate; min, minimum; Trop, tropicamide.*
Standard deviations in brackets.# Percent change from placebo.
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In the ATOM1 study, in which AL was measured using A-scan
ultrasonography, changes in AL at the end of years 1 and 2of �0.14
and �0.02 mm, respectively, were reported forchildren treated with
1% atropine compared with 0.20 and0.38 mm in the placebo
group.118
In the ATOM2 study, in which ALs were measured using anoncontact
method (IOL Master; Zeiss, Oberkochen, Ger-many), changes in AL
over the first year were 0.11, 0.13, and0.24 mm in the 0.5%, 0.1%,
and 0.01% atropine concentrationsrespectively.116 Equivalent values
for the total 2-year studyperiod were 0.27, 0.28, and 0.41 mm.
Without a control group,the true effect of lower doses of atropine
on axial elongation isdifficult to evaluate, given that there was
also no differencebetween changes in the group treated with 0.01%
atropine andhistorical controls in the ATOM1 study.118 However,
althoughAL increases with the lowest, 0.01% concentration was
greatestover the first year in the ATOM2 study, the changes with
the0.5%, 0.1%, and 0.01% concentrations were more similar overthe
second year of the study (0.16, 0.15, and 0.17
mm,respectively).116
Of the two more recent RCTs, one also used
A-scanultrasonography, as in ATOM1; over the 1-year of this study,
themean change in AL was�0.03 mm in the 1% atropine treatmentgroup,
compared with 0.32 mm in the control group.120 In thesecond RCT,
which involved 0.5% atropine, AL data are notprovided in an easily
accessible form, although there appearsto be a surprising reduction
over the 1-year study period in ALof approximately 0.4 mm in the
treated children comparedwith an increase of 0.5 mm in the control
group.121
3.2.3 Poor and Nonresponders to Atropine and Time-Dependent
Reductions in Efficacy. Although the studiesjust described confirm
the efficacy of topical atropine as amyopia control treatment, the
range of responses withintreatment groups also implies that some
individuals respondless well and there is also evidence that
treatment efficacy maychange over time.
In the early studies by Bedrossian,100,101 5% to 25% ofchildren
treated with 1% atropine for 1 year were reported toexhibit
continued myopia progression. Likewise, for the sametreatment
regimen, progression of more than �0.5 D wasreported in 22% of
children in the Yen et al. study113 and 12%of children in the ATOM1
study.135 Nonetheless, results fromthe Shih et al. study114 imply a
related dose-dependence, with4%, 17%, and 33% of children showing
myopic progression>1.0 D, with 0.5%, 0.25%, and 0.1% atropine,
respectively,after 1 year of treatment (compared with 44% of those
treatedwith 0.5% tropicamide). Likewise, for the ATOM1 and
ATOM2studies, 4%, 7%, 11%, and 18% of children recorded
progres-sion rates of >1 D after 1 year of treatment with 1.0%,
0.5%,0.1%, and 0.01%, respectively. Poor responders, as
identifiedthrough multivariate analysis, tend to be younger, to be
moremyopic at baseline, to start wearing spectacles at a
youngerage, and to have myopic parents.135 Note, however, that
thetrends evident after year 1 in the ATOM1 and ATOM2 studieswere
not sustained over the total 2-year treatment period dueto loss of
efficacy with the higher doses over the second year oftreatment;
thus, after 2 years, progression of >1 D wasreported in 14%,
15%, 17%, and 17% of children treated with1.0%, 0.5%, 0.1%, and
0.01% atropine, respectively.116,118
Nonetheless, although the results of the ATOM studies pointto
some loss of treatment efficacy with time, at least with thehigher
concentrations of atropine, those from the study by Wuand
colleagues,110 which involved concentrations between0.05% and 0.1%,
suggest that treatment effects can bemaintained for up to 4.5
years.
3.2.4 Rebound Effects After Termination of AtropineTreatment.
The first evidence of apparent rebound effects onmyopia progression
after the termination of atropine treatment
comes from the study of Bedrossian (1979),101 which
involvedmonocular 1% atropine, with treatment being
alternatedbetween right and left eyes on a yearly basis for 4
years;progression rates for eyes under treatment ranged from 0.17
to0.29 D, substantially lower than those in fellow, untreated
eyesof 0.81 to 0.91 D. However, it is not possible to judge
whetherthese values represent exaggerated progression, due to the
lackof an untreated control group. For 33 children reviewed 1 and3
years after stopping atropine, myopia progression eventuallyslowed
to an annualized rate of 0.06 D per year, presumablyreflecting at
least in part, the normal age-related decline inmyopia
progression.
In the ATOM studies, concentration- and age-relatedrebound in
myopia progression was observed in childrenfollowed for a year
after termination of atropine treat-ment.115,117,119 Measured in
refractive error terms, thisrebound effect is likely to reflect, at
least in part, the recoveryof ciliary muscle tone, which will have
been most stronglyinhibited by the highest concentration. However,
pharmaco-dynamic mechanisms are also likely to be at play;
specifically,continuous long-term exposure to pharmacological
antagonistsis well known to cause upregulation of receptors,
resulting in aloss of efficacy (tolerance) to the applied drug over
time, andexaggerated symptoms when treatment is terminated.131
Younger children and those previously treated with
higherconcentrations of atropine proved most at risk in these
ATOMstudies. Specifically, over a 1-year washout period following
2years of treatment, progression of >0.5 D was observed in
68%and 59% of children treated with 0.5% and 0.1% atropinecompared
with 24% for 0.01% atropine. For 0.01% atropine,progression of
>0.5 D was observed in 62%, 27%, and 8% ofchildren who were 8 to
10, 10 to 12, and 12 to 14 years old,respectively, when the
treatment was terminated.119 Interest-ingly, children who recorded
almost no myopia progression(
-
results of a meta-analysis by Gong et al.,136 who
reportedphotophobia rates of 6.5%, 17.5%, and 43.1% for low
(0.01%),moderate (0.01%–0.5%), and high (1%) concentrations.
Theyalso noted less near vision symptoms with the low, comparedwith
moderate and high concentrations of atropine (2.3%,11.9%, and
11.6%, respectively; Table 5).
Allergic reactions represent the other, most common ocularside
effect of atropine, with symptoms ranging from mild itchto
follicular reactions and lid erythema, and reportedincidences
ranging from 0% to 4%.108,114,118�120,136 Moresevere forms of
allergic keratoconjunctivitis and lid erythemaand rashes also can
occur, and on occasion, may be sufficientlysevere as to preclude
continued use of atropine.
Concerns over the possibility of adverse effects on IOP,lens,
and retina secondary to pupil dilation appear not to
bejustified.102 In one study involving 1% atropine, IOPsremained
within 5.5 mm Hg of baseline values.118 Likewise,Wu and
colleagues137 and Lee and colleagues138 reported nosignificant
changes in IOP over a range of atropine concen-trations. To-date
there also has not been any report oflenticular changes linked to
chronic topical atropine therapyapplied for 2 to 3 years.117,137
Studies of retinal effects ofchronic topical atropine are limited
to MF electroretinogram(mfERG) and full-field electroretinogram
(ffERG) recordingsas part of the ATOM studies. In ATOM1, no
significantdifferences in mfERG amplitude and implicit times
betweentreatment and placebo groups for posterior pole
responseswere found after 2 years of treatment.139 In the ATOM2
study,ffERG recordings revealed a reduction in cone function
overtime (i.e., after 24 and 32 months), but the changes
appearedtied to AL changes, with no significant atropine
concentra-tion–related differences.140
Systemic adverse effects of topical atropine eye drops arealso
possible, with the risk of systemic toxicity being higher inyounger
patients, due to their smaller body size. Possible sideeffects
include dry skin, mouth, and throat, drowsiness,restlessness,
irritability, delirium, tachycardia, and flushing ofthe face or
neck.141 Nonetheless, in two of the largest clinicaltrials of
topical atropine, the ATOM1 and ATOM2 stud-ies,115�119 none of the
reported adverse events were thoughtto be associated with atropine,
and there have been no reportsof significant adverse systemic side
effects in other studiesusing topical atropine for myopia
progression (i.e., in childrenolder than 6 years).140 However,
practitioners using atropineneed to be aware of these side effects,
as some children may behypersensitive to atropine.142
3.3 Pirenzepine
3.3.1 Effects on Myopia Progression. Pirenzepine, anM1
muscarinic receptor antagonist, has shown promisingeffects in
reducing myopia progression in children.145�147 Adouble-masked,
placebo-controlled, randomized study in anAsian population used 2%
pirenzepine gel administered twicedaily and found myopic
progression was reduced by 44% andaxial elongation by 39% compared
with the control group over12 months.146 A US-based, two year
multisite clinical trialyielded a similar reduction in myopia
progression with 2%pirenzepine compared to the placebo treatment,
at 41% (0.58vs. 0.99 D respectively).147 However, the difference in
axialelongation between the groups (0.28 vs. 0.40 mm) did notreach
statistical significance. At this point in time, pirenzepineis not
currently available as a treatment option and appears notto be
targeted by industry for development.
3.3.2 Side Effects of Pirenzepine. Numerous side effectswere
noted with 2% pirenzepine gel administered twice dailyover 12
months in one RCT involving an Asian cohort,146
whereas in contrast, 2-year results from the multisite
US-based
clinical trial found the drug to have a clinically acceptable
safetyprofile.
3.4 7-Methylxanthine
The study of oral 7-MX, an adenosine antagonist, in
humansubjects has been limited to Denmark. In relation to
myopiacontrol, it has been the subject of a number of animal
studies(see accompanying IMI – Report on Experimental Models
ofEmmetropization and Myopia).30 An initial small (n ¼ 68) 12-month
RCT tested 400 mg of 7-MX once per day in myopicchildren aged 8 to
13 years and included a placebo control.123
The study was extended for a further 12 months over which
allsubjects were treated with 7-MX, either as a once or twice
perday treatment, before treatment was terminated in all
subjects.Although slowing of axial elongation and slowing of
myopiaprogression were both recorded in this trial, treatment
effectswere relatively small. Efficacy was apparently tied to
pretreat-ment (baseline) rates of eye growth and myopia
progression.Thus, for those classified as having moderate and high
axialgrowth rates, the differences between 7-MX and placebogroups
were �0.055 mm/y (95% confidence interval [CI]�0.114 toþ0.005 mm/y,
P¼ 0.073), and�0.031 mm/y (95% CI�0.150 toþ0.087 mm/y, P¼0.593),
respectively. The matchingrefractive error differences were �0.108
andþ0.070 D/y, withneither difference reaching statistical
significance. Interpreta-tion of the 2-year data collected from
this study is challenging,as all subjects at this time had been
treated for at least 12months with 7-MX, with the only placebo data
being thatcontained in the initial 12-month data set. Overall, a
reductionin eye elongation appears to be achievable in children
withmoderate baseline axial growth rates, although it may not
beachievable in children with high baseline axial growth rates. Asa
currently nonregistered compounded drug in Denmark,dosage decisions
for 7-MX remain the responsibility of theprescribing doctor.
3.4.1 Side Effects of 7-MX. The treatment appears to besafe. In
the above clinical trial, both participants and theirparents were
subject to structured interviews about gastro-intestinal,
cardiopulmonary, and central nervous system–related side effects.
No ocular or systemic side effects werereported.123
TABLE 5. Summary of Design of Meta-Analyses Covering
TrialsInvolving Topical Atropine for Myopia Control
Studies and Design Features Key Findings
Huang et al. (2016)143
4 RCT studies
0.5�1.0% atropine: 0.68 D/y and�0.21 mm/y
0.1% atropine: 0.53 D/y and �0.21mm/y
0.01% atropine: 0.53D/y and �0.15mm/y
Li et al. (2014)144
4 RCT and 7 cohort studies
Asian children: 0.54 D/y
White children: 0.35 D/y
Odds ratio: 4.47 (95% CI 0.91�21.94)Gong et al. (2017)136
7 RCT and 9 cohort studies
0.57�0.62 D/y and 0.27 mm/y(higher doses)
Pooled effect sizes
RCTs: 2.67 (95% CI 1.46�3.88)Cohort studies: 1.30 (95% CI
0.61�
1.98)
Higher doses: 3.67 (95% CI 1.85
�5.50)Lower doses: 0.68 (95% CI 0.08
�1.27)
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3.5 Timolol
3.5.1. Effects on Myopia Progression. The RCT byJensen130 had
three treatment arms: SV spectacles (n ¼ 51),bifocal spectacles (n
¼ 57), and SV spectacles þ timolol (n ¼51). The timolol arm used
0.25% timolol maleate, twice a day.Children were followed for 2
years, with additional examina-tions 1 year after completion of the
trial. The results weregenerally disappointing, with mean myopia
progression overthe 2-year study period in the control and timolol
groups beingalmost identical (1.14 vs. 1.18 D, respectively), and
notsignificantly different from each other. This was
despiteconfirmation that timolol lowered IOP significantly,
byapproximately 3 mm Hg, with those with high IOP showingthe
largest treatment effect. Also, although there appeared tobe a
trend toward increasing noncompliance over time,progression rates
did not appear to reflect compliance.Curiously, higher progression
rates appeared associated withhigher IOP in the control group, with
this relationshipreaching statistical significance for the girls,
with a similarbut not significant trend for boys.
3.5.2. Side Effects of Timolol. In the above trial, sideeffects
resulted in timolol treatment being discontinued in sixchildren.
For five of the children, symptoms were ocular innature, involving
stinging, itching, and foreign body sensations,these symptoms being
possibly related to the formulationrather than to timolol per
se.130 Although reports of changes inciliary muscle tone with
timolol have been reported,148 thiseffect tends to be small in
magnitude and unlikely to explainthe disturbance to vision reported
for two subjects. Moreserious systemic side effects of headaches
and difficulty inbreathing were reported in only one subject,
although theseare well-known side effects of beta-blockers.148
4. ENVIRONMENTAL INFLUENCES AND THE ROLE OFTIME OUTDOORS FOR
MYOPIA PREVENTION ANDCONTROL OVER PROGRESSION
4.1 Introduction
‘‘A robust child, well fed, enjoying a maximum of outdoorlife,
is less likely to get tired eyes and subsequent stretchingof the
coats of the eyeball and myopia than is a child thatis cooped up
indoors all day, sitting over lessons, andnever joining in vigorous
outdoor games.’’
This advice from Harman (1916),149 a century ago, was basedon
his observations that myopic children tended to engage inmore
indoor, near-viewing tasks than their emmetropic peers,coupled with
the obvious point that, at any moment in time, achild could be only
either indoors or outdoors.
The above example reflects much early interest in environ-mental
influences on ocular development. The first rigorousscientific
evaluation of the relationship between time spentoutdoors and
myopia was reported in 1989 by Pärssinen et al.150
In a clinical trial testing whether bifocal spectacles
slowedmyopia progression, 237 myopic children were asked tocomplete
a questionnaire detailing, among other things, thetime they spent
engaged in outdoor activities. Self-reported timeoutdoors was found
to correlate with the child’s myopiaprogression over 3 years (r ¼
0.17, P ¼ 0.004). On furtheranalysis, the association was found to
be largely restricted toboys.151 The authors surmised that the
correlation with timeoutdoors might be attributable ‘‘simply to
being away fromreading and close work.’’ Perhaps because other
myopiaresearchers also made the very plausible assumption that
nearwork and outdoor play were inversely correlated,
investigation
of the link between time outdoors and myopia stalled foranother
decade, until the publication of a series of influentialstudies
that stressed the potential importance of time outdoorsor time
engaged in sports/outdoor activities as being protectiveagainst
myopia.152�157 It has been hypothesized that theincreased intensity
of visible light outdoors may be one factorplaying a critical role
in these protective effects.155 Data fromanimal studies indicating
that bright light exposure during theday protects against the
development of experimental form-deprivation myopia (findings are
less consistent for lens-inducedmyopia)158,159 support this notion,
although other factors suchas differences in the patterns of
retinal image blur exposureassociated with the outdoor environment
also may playroles.160,161 Achieving light levels indoors
comparable withthose typical of the outdoor environment would be
challenging,even with high-efficiency light emitting diode (LED)
sources.
4.2 Outdoor Studies
In the past decade, the relationship between time outdoorsand
myopia has been extensively studied.162�166 Althoughseveral
cross-sectional152,155,167�170 and cohort stud-ies154,171�175 have
addressed the issue of the protective roleof increased outdoor time
on myopia prevention, randomizedcontrolled community-based trials
are limited to four stud-ies.176�179 Because the evidence linking
time outdoors to theprevention of incident myopia is stronger than
that linking it toslowing the progression of existing myopia,164
with potentialimplications for the ocular health management
strategies forchildren, these two lines of enquiry are reviewed
separately.The key features of the randomized controlled trials
aresummarized in Table 6 and of other relevant studies in Table
7.
4.2.1 Outdoors Studies and Myopia Onset. A recentrandomized
controlled trial among Chinese elementary schoolchildren in
Guangzhou (GOAL),177 reported a 9.1% reductionin the myopia
incidence rate among children participating inan outdoor program
that included a 40-minute-long, compul-sory outdoor sports class at
the end of each school daycompared with the control group (i.e.,
30.4% compared with39.5% [P < 0.01]). Similar protection was
reported in anearlier, albeit much smaller, intervention study
involvingTaiwanese primary school children; the myopia
incidencerates were 8.4% and 17.7% for the intervention and
controlgroups, respectively (9.2% reduction, P ¼ 0.001).176 A
thirdlarge-scale trial of primary school children, also based in
China,reported a reduction in the myopia incidence rate by 4.8%
inthe intervention group compared with the control group
(3.7%versus 8.5%).178 Most recently, an intervention trial in
Taiwaninvolving grade 1 school children exposed to increasedoutdoor
time during school hours (approximately 40 minutesper day), coupled
with encouragement of greater outdoor timeoutside of school hours,
reported a modest intervention-relatedreduction in the myopia
incidence rate (14.5% versus 17.4%, P¼ 0.054).179 The smaller
reduction in myopia incidence in thisstudy compared with the
previous Taiwan-based interventionstudy176 may reflect the greater
daily outdoor time of theintervention (80 minutes) in the earlier
study, coupled with therecent introduction of the ‘‘Tien-Tien 120’’
policy designed topromote 120 minutes of outdoor time per day in
Taiwaneseschools, which would have increased the outdoor time of
allparticipants in the trial.
The association between increased time spent outdoors
andprotection against myopia in children and adolescents hasbeen
summarized in a recent meta-analysis,162 which linkedevery
additional 1 hour of outdoor time per week with areduction in the
risk of myopia by 2% (odds ratio 0.98; P <0.001). This pooled
estimate equates to an odds ratio of 0.87for every additional 1
hour of outdoor time per day.162 One
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surprising outcome from epidemiology studies in children hasbeen
the consistent finding that the time children spendengaged in near
work outside of school is not, in fact, related tothe time spent
outdoors; instead of the expected inverserelationship, most
investigations have found no correlationbetween time engaged in
near work and time out-doors,154,155,167,172,174,180 although there
have been exceptionsin which an inverse correlation has been
reported.181 Thus,certain children seem to spend relatively long
times, bothoutdoors and indoors, engaged in reading or studying,
whereasother children spend little time doing either. However, it
mustalso be recognized that most such studies have relied
onsubjective reporting of time spent in such activities.
4.2.2 Outdoor Studies and Myopia Progression. Theevidence for
outdoor time being protective against myopiaprogression is
mixed.174 In two of the four randomized studiesreferred to above,
the effect of increased outdoor exposure onmyopia progression was
weaker than that on incident myopia.In the first Taiwanese study,
mean progression rates in
intervention versus control groups differed by 0.12 D (P ¼0.18)
in myopic children and by 0.18 D (P ¼ 0.02) innonmyopic children,
with an overall difference of 0.13 D (P¼ 0.029; Table 6).
Similarly, in the more recent interventionstudy in Taiwan, an
overall 0.12 D difference in progressionwas observed (�0.35 vs.
�0.47 D, P ¼ 0.002), with significanteffects on progression rates
observed in both myopic andnonmyopic children. In this study,
children spending greatertime exposed to bright outdoor light
conditions (>1000 lux)each day at school, as measured by
wearable sensors, alsoexhibited significantly slower myopia
progression (0.14 D, P¼0.02). Substantial differences in myopia
progression ratesbetween the two China-based studies (e.g., �1.59
vs. �0.27D; control groups), are also reflected in differences in
thestatistical significance of the difference between
interventionand control groups, which was 0.17 D for both groups
(�1.42vs. �1.59 D, P ¼ 0.04; �0.10 vs. �0.27 D, P ¼ 0.005).
Seasonal trends in myopia progression have been interpret-ed as
indirect evidence of outdoor effects on myopia
TABLE 6. Outdoor Intervention Studies for Myopia Prevention and
Progression
Author (Year),
Study Location,
Study Design Type of Intervention Age at Baseline, Refraction
Main Findings
He et al. (2015)177
China
School-based, randomized clinical
trial (GOAL study); N ¼ 1848
Intervention group: One
additional 40-minute class of
outdoor activities on each
school day.
Control group: No additional
class.
3-year RCT
6�7 y, Cycloplegic auto-refraction
Myopia incidence rate: Intervention
group: 30.4%; Control group: 39.5%;
Diff: �9.1 (95% CI �14.1 to �4.1); P< 0.001) after 3 y
Myopia progression rates: Intervention
group: �1.42 D (95% CI �1.58 to�1.27 D); Control group: �1.59
D(95% CI �1.76 to �1.43 D)
Diff: 0.17 D (95% CI 0.01 to 0.33 D); P
¼ 0.04 after 3 yLost to follow-up: 4.7%
Jin et al. (2015)178
China
School-based, prospective,
interventional study; N ¼ 3051
Intervention group: Two
additional 20-minute ROC
programs, in the morning and
afternoon.
Control group: No program.
1-year RCT
6�14 y, Cycloplegic auto-refraction
Myopia incidence rate: Intervention
group: 3.7%; Control group: 8.5%; Diff:
4.8% (P ¼ 0.048) after 1 yearMyopia progression rate:
Intervention
group: �0.10 6 0.65 D; Controlgroup: �0.27 6 0.52 D; Diff: 0.17
D(P ¼ 0.005) after 1 year
Lost to follow-up rate: 10.7%
Wu et al. (2013)176
Taiwan
School-based, interventional trial;
N ¼ 571
Intervention group: Two
additional 40-minute ROC
programs, in the morning and
afternoon.
Control group: No program
1-year RCT
7�11 y, Cycloplegic auto-refraction
Myopia incidence rate: Intervention
group: 8.41%; Control group: 17.65%;
Diff: 9.24% (P ¼ 0.001) after 1 yearMyopia progression rate:
Intervention
group: �0.25 6 0.68 D; Controlgroup: �0.38 6 0.69 D; Diff: 0.13
D(P ¼ 0.029) after 1 y
Wu et al. (2018)179
Taiwan
School-based interventional trial;
N ¼ 693
Intervention group: 40-minute
ROC in morning and
encouragement to undertake 4
additional outdoor leisure
activity programs; in addition to
120 min/d outdoors during
school hours (‘‘Tien-Tien 120’’),
150 min/wk outdoor sports
(‘‘Sport and Health 150’’).
Control group: 120 min/d
outdoors during school hours
(‘‘Tien-Tien 120’’), 150 min/wk
o