Optometry in Practice (Online) ISSN 2517-5696  Volume 20  Issue 3

How effective are atropine eye drops at reducing myopia

progression in children?
Amit Navin Jinabhai PhD BSc(Hons) MCOptom FBCLA FHEA FEAOO and Mark Glover BSc(Hons) MCOptom

The University of Manchester, Faculty of Biology Medicine and Health, School of Health Sciences, Division of Pharmacy and Optometry

EV-59579 C-72220
1 CET point for UK optometrists

Abstract
Myopia is a global problem which typically shows the highest prevalence in the Far East. As the number of myopes continues
to grow, worldwide, the incidence of myopia-related ocular pathology is also likely to increase. In a targeted attempt to reduce
these pathologies, a range of different types of clinical interventions have been designed and administered in order to try
and inhibit myopia progression in children, including the use of pharmaceutical agents such as atropine. To date, atropine has
predominantly been used in studies conducted in the Far East, where it has mainly been used in an ‘off-label’ capacity.

This review paper discusses the relative strengths and weaknesses of peer-reviewed, scientific research studies investigating
the efficacy of atropine, in varying concentrations, at regressing myopia progression in children. A critical appraisal of the
literature is needed in order to better understand key issues with regard to the clinical administration of atropine, such as the
optimum concentration to use; the optimal refractive error at which to start treatment; the longevity of the effect(s); what
possible side-effects could occur; the importance of compliance with the treatment regimen, and whether atropine could be
considered for use in combination with other established interventions (such as orthokeratology).

Although atropine is not yet readily available to use for the treatment of myopia progression in the UK, practising optometrists
would benefit from gaining a better understanding of the efficacy of this treatment and its limitations, in the anticipation that this
drug is adopted for wider clinical use, in a low concentration, in the near future.

Introduction Due to its multifactorial and complex nature, the process(es)

of and reason(s) for myopic progression are still, currently,
Myopia is a global problem,1–12
particularly in Far East
unclear.18,42 Animal models indicate causative effects
Asia,1,6,8,9,12,13 where the prevalence is approximately
such as form deprivation,43 relative peripheral hyperopic
80% amongst young adults in Taiwan8 and around 80%
defocus44 and biological feedback-loop interruption.18
amongst Chinese, young adult males in Singapore.14 Conversely,
Myopia progression may also be influenced by genetics,45 time
amongst European young adults, the prevalence varies
spent outdoors,46–49 performing intense periods of near-work
between 25% and 50%.10 Myopia is a key cause of preventable
tasks50,51 and accommodative lag.52,53 However, precisely
blindness and can lead to serious ocular complications,
how each of these factors might work together is still
such as glaucoma, choroidal neovascularisation and retinal
controversial and largely unclear.
detachment.15–17

Before the age of 6 years, most children are usually hyperopic,

with a smaller proportion being either emmetropic or myopic.
Typically, around the age of 7 years, some children undergo
a marked shift in refractive error, resulting in manifest
myopia; this abrupt shift is often referred to as ‘myopia
progression’.13,15,18 A targeted reduction in the severity of
this ‘myopic shift’ has been the subject of a wide range of
research strategies (summarised in Figure 1), including: the
use of rigid gas-permeable lenses19; orthokeratology contact
lenses20–26; bifocal or multifocal soft contact lenses27–31;
bifocal or multifocal spectacle lenses32–35; and ophthalmic
drugs such as atropine36–38 or pirenzepine.39–41
Atropine
Atropine is a non-selective, competitive muscarinic
acetylcholine receptor antagonist, with a high affinity for
all five forms of muscarinic receptors (i.e. M1–M554) located
within the eye (particularly those in the sclera and retina55–57),
which cause both cycloplegia and mydriasis.58 Atropine
has been routinely used (off-label) in approximately 50% of
paediatric myopic progression cases in Taiwan since 2007.59
Despite this popularity, atropine is not currently approved
for myopia control by the US Food and Drug Administration
(FDA),60 nor is it approved for myopia control in the UK.
With a growing body of evidence indicating that

Date of acceptance: 4 July 2019. Amit.Jinabhai@Manchester.ac.uk

© 2019 The College of Optometrists 1

 A Jinabhai and M Glover How effective are atropine eye drops at reducing myopia progression in children?

low-concentration atropine might be effective at reducing the recipients were myopic children. Studies which did not
Figure 1. Summary of different
myopia progression, the likelihood of its more global use, meet these criteria were not reviewed; for example, studies
myopia control strategies used
particularly in the west, also increases. This paper aims to that used atropine ointment were not included as part of
in child patients from peer-
critically review research studies conducted to reduce myopia this review. We were particularly interested in exploring
reviewed scientific research
progression in children, using atropine eye drops. differences in study designs between various research
studies. ATOM, Atropine for
investigations.
the Treatment Of Myopia;
For ease of comparison, Table 1 summarises some of the key
CRAYON, Corneal Reshaping
And Yearly Observation of
studies reviewed in this paper, whilst Table 2 presents a critical Clinical measurements and study design
list of key limitations for the same group of studies. for assessing myopia progression
Near-sightedness; LORIC,
Longitudinal Orthokeratology Compared to non-myopes, myopes tend to have longer
The search engine PubMed was used to search for studies
Research In Children; RGP, axial lengths, deeper vitreous chambers and flatter
using the keywords ‘atropine’ and ‘myopia’. Studies that were
rigid gas-permeable; ROMIO, corneas.61,62 In the majority of cases, the primary structural
not published in English were excluded. Abstracts of the
Retardation Of Myopia In cause of myopia is a long axial length, therefore axial length
remaining studies were reviewed to confirm that atropine eye
Orthokeratology. is recognised as a key determinant of refractive error.10
drops had been administered as part of the methods and that
Subsequently, myopia control studies typically focus on
slowing down axial elongation, thereby progressively reducing
the rate of myopisation. Measurements of changes in axial
length (either via amplitude scan ultrasonography or by
Table 1. Summary of research studies evaluating the use of atropine for the control of progressive myopia in child patients
partial coherence interferometry (PCI)) are fundamental
Authors Number of Study design Participant age Baseline refractive error range (SE in D) Study duration Atropine Control Myopia progression rate to evaluating the efficacy of myopia control treatments.
subjects range (years) (years) treatment (%)
receiving
Treatment group (D/year) Control However, it is worth noting that a number of atropine studies
group unfortunately did not measure this key parameter (discussed
atropine (D/year)
treatment later in this article).
Shih et al.86 137 RCT, NM 6 to 13 0.50% group mean: –4.89 ± 2.06; 2 0.50, n=41 0.50% –0.04 ± 0.63 –1.06 ± 0.61
0.25% group mean: –4.24 ± 1.74; 0.25, n=47 Tropicamide –0.45 ± 0.55 A cycloplegic refraction, usually through autorefraction
0.10% group mean: –4.41 ± 1.47;
control group mean: –4.50 ± 1.86 0.10, n=49 –0.47 ± 0.91 (however, retinoscopy could be considered to be more
Shih et al.90 66 RCT (+DB?) 6 to 13 Tx group mean: –3.20 ± 0.14; 1.5 0.50 PALs + placebo –0.28 –0.79 (PALs) suitable for less cooperative children63), is also essential to
PALs+placebo group mean: –3.34 ± 0.14; exclude cases of ‘pseudomyopia’. Additionally, Zadnik and
SVS+placebo group mean: –3.28 ± 0.13 SVS + placebo –0.93 (SVS) colleagues62,64 have demonstrated that cycloplegic refractive
Chua et al. 36 166 RCT + DB 6 to 12 Tx group mean: –3.36 ± 1.38; 2 1.00 (monoc) Contralateral eye –0.14 –0.60 error, measured by autorefraction, is a key predictor of the
control group mean: –3.58 ± 1.17 + Placebo onset of juvenile myopia in school children. Furthermore,
Fang et al.100 24 Retrospective 6 to 12 Tx group mean: –0.31 ± 0.45; 1 0.025 No treatment –0.14 ± 0.24 –0.58 ± 0.34 refractive error, measured using an open-field autorefractor
(cohort), control group mean: –0.17 ± 0.50 received (as has been used in a number of of atropine studies), has been
N-R, NM
shown to offer a high degree of repeatability.65–68
Wu et al.102 97 Retrospective 6 to 12 Tx group mean: –2.45 ± 1.63; Approximately 4.5 0.05 (increased to SVS –0.31 ± 0.26 –0.90 ± 0.30
(case–control), control group mean: –1.87 ± 0.94 0.10 in 44 (45%)
N-R, NM patients) As atropine causes both mydriasis and cycloplegia, it is also
Chia et al.93 355 RT + DB, 6 to 12 0.50%: –4.70 ± 1.80 First 2 (of the total 0.50, n=139 N/A −0.15 N/A important to evaluate changes in pupil size, amplitude
no control group 0.10%: –4.80 ± 1.50 5 of the ATOM 2) 0.10, n=141 N/A −0.19 N/A of accommodation (AOA) and near visual performance,
0.01%: –4.50 ± 1.50 0.01, n=75 N/A −0.25 N/A as atropine-induced changes in these parameters could
Clark and Clark103 28 Retrospective 6 to 15 Tx group mean: –2.00 ± 1.60; 1 0.01 SVS –0.10 ± 0.60 –0.60 ± 0.40 potentially lead to symptoms of photophobia and problems
(case–control), control group mean: –2.00 ± 1.50 with conducting near work.
N-R, NM
Yi et al.104 68 RCT + DB 7 to 12 Tx group mean: –1.23 ± 0.32; 1 1.00 Placebo +0.32 ± 0.22 (N.B.: the mean SE changed –0.85 ± 0.31 Study design is also a key factor when considering the impact
control group mean: –1.15 ± 0.30 from baseline of
–1.23 ± 0.32, to –0.91 ± 0.45 in 1 year)
of atropine on myopia control. A detailed description of
different study designs and the associated terminology has
Lee et al.72 44 Prospective, 6 to 12 0.125% group mean: –1.22 ± 0.55; 1 0.125 (n=32) SVS –0.05 –1.05
N-R, NM 0.25% group mean: –1.45 ± 0.69; been published elsewhere.69,70 Many scientists consider the
0.25 (n=12) Plano (no progression)
control group mean: –1.45 ± 1.00 double-blind, randomised, controlled trial (DBRCT) to be the
Chia et al. 37 192 deemed RT + DB no control 6 to 12 Previously in 0.50% group; mean: –4.41 ± Last 2 (of the total 5 0.01 N/A −0.42 N/A ‘gold standard’ of clinical research, particularly as ‘blinding’
to require group 1.89 (n=93) of the ATOM 2) both the patient and the researcher minimises assessment
‘retreatment’
with 0.01%
Previously in 0.10% group; mean: –4.31 ± N/A −0.41 N/A bias. However, compared to more conventional study
1.40 (n=82)
atropine designs, DBRCTs can be expensive to run, can require multiple
Previously in 0.01% group; mean: –4.07 ± N/A −0.35 N/A sites (due to the need for a large number of patients in order
1.26 (n=17)
to provide sufficient statistical power) and can often require
Polling et al.63 60 to Prospective 3 to 17 Mean at baseline: –6.70 ± 3.60 1 0.50 N/A from –1.00 ± 0.70 before Tx, to –0.10 ± 0.70 N/A
completion effectiveness study, (–5.60 ± 3.90 one year before Tx) after 1 year of Tx long study durations, which can unfortunately lead to a high
(17 dropped N-R, NM, no drop-out rate. Whilst it can be argued that retrospective
out) control group studies may better reflect the ‘real-life’ treatment situation
Wang et al.107 54 RCT (+DB?) 5 to 10 Tx group mean: –1.30 ± 0.40; 1 0.50 Placebo +0.50 (NB: mean SE changed from –1.30 –0.80 of a patient, they typically lack both randomisation and
control group mean: –1.20 ± 0.30 (baseline), to –0.80 (with 95% CI: –1.10,
–0.40) after 1 year of Tx)
an appropriate control group. Although common,63,71,72
non-randomised studies can suffer from selection bias, which
? information unclear in the original study; 95% CI, 95% confidence intervals; ATOM2, Atropine for the Treatment Of Myopia study 2; D, dioptres; DB, double-blinded; monoc, atropine was administered monocularly; n, number of participants; N/A, may impact on the validity of the final results.
not applicable; NM, no masking; N-R, non-randomised trial; PALs, progressive addition lenses; RCT, randomised, controlled trial; RT, randomised trial; SE, spherical equivalent refraction; SVS, single-vision spectacle lenses; Tx, treatment.

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 A Jinabhai and M Glover
Table 2. A list of some of the key limitations for
research studies evaluating the use of atropine for the
control of progressive myopia in child patients
Authors Key limitations
Did not measure axial length
Did not match study groups (e.g. for age,
gender, degree of myopia)
Did not measure amplitude of accommodation
Shih et al.86
Did not measure pupil size
Did not measure visual performance at near
Did not mask investigators
Undercorrected some patients for distance
Did not measure amplitude of accommodation
Did not measure pupil size
Shih et al.90
Did not measure visual performance at near
Unclear how investigators were masked
Did not measure amplitude of accommodation
Chua et al. 36 Did not measure pupil size
Did not measure visual performance at near
Retrospective design
Lacking investigator masking
Lacking randomisation
Did not measure axial length
Fang et al.100
and Wu et al.102 Did not measure amplitude of accommodation
Did not measure pupil size
Did not measure visual performance at near
Prepared their own concentrations but did not
explain how they verified these
Uneven patient numbers in the different
treatment groups
Some inappropriate statistical tests were
presented in the paper
Chia et al.93 Unclear what the ‘end point’ for amplitude of
accommodation measurements was
Lacking a control group
No illuminance values for near acuity chart, or
luminance values for distance chart
Retrospective design
Lacking investigator masking
Lacking randomisation
Subject groups not matched for ethnicity
Did not measure axial length
Clark and Clark103
Did not measure amplitude of accommodation
Did not measure pupil size
Did not measure visual performance at near
Did not carry out a full cycloplegic refraction
at follow-up
Concerns that some patients in the treatment
group were over-minused at baseline?
Did not measure amplitude of accommodation
Yi et al.104
Did not measure pupil size
Did not measure visual performance at near
4
Authors Key limitations
Did not measure axial length
Did not measure distance visual acuity
Did not measure amplitude of accommodation
Lee et al.72 Did not measure pupil size
Did not measure visual performance at near
Lacking investigator masking
Lacking randomisation
Unclear what the ‘end point’ for amplitude of
accommodation measurements was
Chia et al. 37 No illuminance values for near acuity chart,
or luminance values for distance chart
Lacking a control group
Used non-validated questionnaires
No control group
High drop-out rate
Used dynamic retinoscopy for accommodation
Polling et al.63 measurements (partly hinders interstudy
comparability of accommodation data)
Lacking investigator masking
Lacking randomisation
Lacking some pertinent statistical tests
Concerns that some patients in the treatment
group were over-minused at baseline?
Concerns about axial length measurements –
how were these measured?
How was the cycloplegic refraction measured?
Wang et al.107 Unclear how investigators were masked
Did not measure amplitude of accommodation
Did not measure pupil size
Did not measure visual performance at near
Unclear how information about adverse events
was collected
Atropine eye drops to reduce myopia
progression in children
The early studies
Early studies evaluating 1% atropine for the treatment
of myopia were conducted in the 1970s.73–77 Arguably,
Bedrossian’s78 results kick-started subsequent research in this
field. Interestingly, Bedrossian78 treated 62 myopic children
with 1% atropine, unilaterally (once a night) for 1 year, whilst
the fellow eye acted as the control. After 12 months, the
author switched the treatment programme to the contralateral
eye for a further year. Twenty-eight myopic children were
treated for 4 years using this annual contralateral eye
switching methodology. Bedrossian78 reported that, over the
4-year period, eyes receiving 1% atropine showed a mean
decrease in myopia progression, of +0.29 D/year, compared
to the control eyes, which showed a mean increase of –0.81
D/year. At 54.8 months after treatment cessation, the mean
increase in myopia was found to be –0.06 D/year (data from
24 patients), indicating that 1% atropine had the potential to
provide long-term myopia control. However, it was unclear
how the author controlled for potential observer bias; for
 How effective are atropine eye drops at reducing myopia progression in children?
example, at each of the patients’ follow-up appointments,
due to marked unilateral mydriasis, it would have been
obvious which eye had been receiving the treatment, perhaps
unintentionally influencing how the practitioner performed
the monocular refraction. Bedrossian78 did not evaluate
axial length, or visual performance at near (such as near
visions/acuities), or AOA measurements, to confirm how
many dioptres of accommodation were potentially lost,
prior to performing a cycloplegic refraction at each follow-
up visit. The author also did not specify the exact method
he used to measure each participant’s cycloplegic refractive
error. Furthermore, it was unclear whether or not using the
contralateral eye as a control was suitable because of the
potential systemic, residual effects of 1% atropine in the
fellow eye.79
Further research using 1% atropine was undertaken in the
1980s80,81 and indicated a successful reduction in myopia
progression. Unfortunately, neither of these reports evaluated
axial length changes or near visual performance, and it is also
unclear if they each controlled for observer bias. However,
these studies confirmed significant side-effects and potential
limitations of using this particular concentration. Yen et al.81
reported that, due to discomfort glare and photophobia, some
children stopped playing outdoors and/or participating in
gymnastics at school, whilst Kao et al.80 noted their subjects’
dissatisfaction at wearing bifocals to overcome the induced
cycloplegia. Nonetheless, these early reports indicated that
using atropine at a 1% concentration level might prove to be
impractical on a long-term basis.
Combining atropine with bifocals
To improve the suitability of using atropine, Chou et al.71
proposed the use of a lower concentration, of 0.50%,
binocularly, on a once-a-night basis, in conjunction with
bifocal spectacles. It can be argued that this approach
was highly influential as, until that point in time, previous
studies had only used 1% atropine eye drops with bifocals.82–85
Chou et al.71 evaluated 20 ‘highly’ myopic Taiwanese children
(defined as a spherical equivalent (SE) refraction between
–6.25 and –12.00 D) aged between 7 and 14 years. Subjects
were also dispensed bifocals (+2.00 D add) for near tasks
and were asked to wear sunglasses on sunny days. A cohort
of 8 children did not initially receive any eye drops for 6–12
months, and showed a mean pretreatment progression
rate of –0.14±0.07 D/month – this period was designed to
offer control data for statistical comparisons. The same 8
children subsequently demonstrated a statistically significant
reduction in progression, to –0.04±0.06 D/month (p < 0.05),
following 0.50% atropine treatment for a median period of
38.4 months.
Another cohort was also enrolled, where 12 children initially
received 0.50% tropicamide (also once a night) for a
median period of 22.6 months, during which participants
demonstrated a mean myopia progression of –0.12±0.09
D/month. This period was also designed to generate control
data for statistical comparisons; however, the authors did not
provide any myopia progression data relating to the period
immediately before commencing tropicamide use. Upon
cessation of tropicamide, the same 12 children were treated
with 0.50% atropine for a median period of 31.2 months.
Compared to when using tropicamide, these children showed
a significantly reduced progression rate of –0.01±0.09
D/month (p < 0.05). Although demonstrating a reduction
in progression for children with high myopia (measured via
cycloplegic autorefraction), Chou et al.’s71 study is hindered
by its non-randomised design, as the children’s parents
decided which cohort their child would be enrolled to. The
authors did not evaluate changes in axial length in this report;
they also did not appear to control for potential observer bias,
neither did they evaluate visual performance at near, nor AOA.
Shih et al.86 trialled different concentrations of atropine
(0.50%, 0.25% or 0.10%), administered bilaterally, on a
once-a-night basis, to inhibit myopia progression in a cohort
of 137 Taiwanese, myopic children, aged between 6 and
13 years, over a 2-year period. Recruited participants had
an SE refraction between –0.50 D and –6.75 D, and were
randomised to one of the three treatment groups, or to the
control group. Children treated with 0.50% atropine (n =
41) were also fitted with bifocals (+2.00 D add); children
treated with 0.25% atropine (n = 47) were undercorrected for
distance (by 0.75 D), whilst children treated with 0.10%
atropine (n = 49) were given their full distance correction only.
The mean myopia progression was –0.04±0.63 D/year,
–0.45±0.55 D/year and –0.47±0.91 D/year for the 0.50%,
0.25% and 0.10% groups, respectively. The authors also
evaluated a control group of 49 myopic children (recruited
using the same enrolment criteria), who received 0.50%
tropicamide; comparatively, these control subjects showed
a marked mean myopia progression of –1.06±0.61 D/year
(measured via cycloplegic autorefraction). Unfortunately,
Shih et al.86 did not evaluate changes in axial length. They
also did not investigate the potential impact that
undercorrection would have had on the results of the children
receiving 0.25% atropine, as undercorrection is known to
promote myopisation.87,88 Equally, the use of bifocals by
some of this study’s participants introduces a further
confounding factor, as bifocals have been shown to have some
degree of impact on myopia progression in young myopic
children.32,33 Furthermore, it is also unclear if the different
groups were matched with respect to age, gender or degree
of myopia, or if the study investigators were masked. The
authors also did not measure visual performance at near,
pupil size or AOA.
Compliance
One potential issue regarding the administration of atropine
treatment is the degree of patient compliance, as good
compliance is required to ensure the drug’s efficacy. Chiang
et al.89 evaluated compliance amongst 706 myopic children
(aged between 6 and 16 years, with baseline SE refraction
of <–0.50 D) receiving 1% atropine (bilaterally) and using
photochromic bifocal spectacles (+2.25 D add), over a period
of 3.88±1.80 years. Study participants were instructed to
use one drop of 1% atropine, in each eye, ‘every other day’,
for a period of 2 years. After this, participants were asked
to use the drops only once a week. The authors reported
a statistically significant lower progression rate in children
who were ‘fully compliant’ (n = 496: –0.08 D/year),
compared to children who were deemed to be only ‘partially
5
 A Jinabhai and M Glover
compliant’ (n = 210: –0.23 D/year; p < 0.001). Compliance
was determined through questioning of both the child
and parent(s). The ‘partial’ compliance cohort included
participants who ‘used the drops intermittently’,
rather than every day, as well as participants who
‘used their bifocals for inconsistent time intervals’,
whereas the ‘fully’ compliant cohort only included
participants who completely followed the treatment
regimen. The primary reasons for poor compliance included
photophobia, inconvenience and headache. Chiang et al.89
concluded that full compliance was critical in order to
maximise atropine’s potential for myopia control, and also
advocated the use of photochromic bifocals in conjunction
with 1% atropine treatment.
Unfortunately, this study has some limitations. For example,
Chiang et al.89 did not evaluate changes in axial length, nor
did they specify the exact method (of either autorefraction
or retinoscopy) for how they measured each participant’s
cycloplegic refractive error. Furthermore, this retrospective
study was designed as a non-comparative case series, meaning
that the groups’ sizes were unequal, not matched for age,
gender or degree of myopia, subjects were not randomised,
and the degree of ‘partial compliance’ was not controlled
amongst their study cohort of 210 children. Also, due to its
retrospective design, this study lacked a proper control group.
Combining atropine with progressive addition
lenses
Whilst a number of studies have issued bifocal lenses
alongside atropine treatment,71,82–86,89 the visible line
associated with these lenses may prove to be unpopular
with children, potentially reducing compliance, or even
contributing to participant drop-out. To counter this,
progressive addition lenses (PALs) could be used instead. In
their randomised study, Shih et al.90 divided a cohort of
188 Taiwanese myopic children, aged between 6 and 13
years, into three groups: those treated with 0.50% atropine
(once a night, bilaterally) whilst wearing PALs (n = 66; mean
baseline SE: –3.20±0.14 D), those wearing PALs and receiving a
placebo (n = 61; mean baseline SE: –3.34±0.14 D) and those
wearing single-vision distance spectacle lenses (SVS) and
receiving a placebo (n = 61; mean baseline SE: 3.28±0.13 D) – all
refractive errors were measured via cycloplegic autorefraction.
After 18 months, the PALs plus atropine group exhibited a
significantly lower mean myopic progression, of –0.42±0.07 D,
compared to those in the PALs plus placebo (–1.19±0.07 D) or
SVS group (–1.40±0.09 D). Interestingly, unlike some previous
reports, 35,91,92 Shih et al.90 found no significant difference
between the PALs plus placebo and SVS groups. Over the
same time period, the mean axial elongation in the PALs plus
atropine group was significantly lower (0.22±0.03 mm) than
in the PALs plus placebo group (0.49±0.03 mm), or in the
SVS group (0.59±0.04 mm). Rather unusually, the authors
did not report any post hoc statistics to explain if there were
any differences in axial elongation between the PALs plus
placebo and SVS groups.
Shih et al.90 found that the measured increases in myopia
were significantly (negatively) correlated to the increases
6
in axial length, measured via ultrasound. However, as no
corresponding figure was presented in their paper, it is unclear
whether the authors plotted these data for each study group
individually, or whether all 188 subjects (combined) were
included in the correlation analysis.
Although generally robust in its design, this study is limited
by a lack of assessment of pupil size, AOA and visual
performance at near. Furthermore, the authors did not appear
to match their study groups for age, axial length, gender or
refractive error. Whilst the authors claim that their study
was ‘double-blind’ in its design, it is highly likely that any
bilateral, atropine-induced mydriasis would have been
noticeable to the trained clinical examiners. Notably, these
examiners were responsible for performing both ‘pre-’ and
‘post-cycloplegic’ autorefraction (using 0.50% tropicamide),
‘post-cycloplegic’ retinoscopy and for conducting an interview
to evaluate the degree of regimen compliance – this could
have potentially led to a degree of assessment bias of the
study participants recruited to the PALs plus atropine group.
Whilst not perfect, Shih et al.’s90 study design of using
placebo drops and randomising participants into treatment
groups set a precedent for future studies.
The ATOM1 studies
The initial Atropine for the Treatment of Myopia (or ATOM1)
study evaluated the safety and efficacy of 1% atropine
treatment, administered once, on a nightly basis, in a
cohort of 166 myopic children.36 Study participants were
predominantly Chinese (with a smaller proportion of Indian
ethnicity), aged 6–12 years, with a mean SE refraction
between –1.00 and –6.00 D, which the authors defined as
low to moderate myopia. Chua et al.36 utilised a randomised,
double-blind study design, where 1% atropine was
administered monocularly (treated eyes were chosen
randomly) over a period of 2 years. One hundred and
eighty control subjects, who received a placebo, were also
recruited; both study groups were matched in terms of age,
gender, ethnicity and refractive error. All participants were
dispensed with photochromic SVS, irrespective of their
treatment allocation. The control group’s mean refractive
error (measured using cycloplegic autorefraction) increased
by –1.20±0.63 D, compared to –0.28±0.92 D in the 1%
atropine-treated eyes. Furthermore, in the control group,
the mean axial length (measured via ultrasound) increased
significantly, by 0.38±0.38 mm; however, there was
no significant change in the 1% atropine-treated eyes.
Unfortunately, the authors did not measure either AOA or
pupil size for either cohort. Nonetheless, the study was
innovatively designed to preserve ‘masking’ at each follow-
up visit, in that the study’s ‘co-ordinator’ administered 1%
cyclopentolate drops to both eyes of all participants, ahead
of them being seen by the clinical investigators. Additionally,
both the atropine and placebo eye drops were packaged in
‘identical’ bottles.
The ATOM studies were conducted in different phases, which
are briefly summarised in Figure 2. In phase 2 of the ATOM1
study, Tong et al.38 monitored the same cohort of myopic
children for a further 12 months, following cessation of a
24-month-long period of 1% atropine treatment, to explore
 How effective are atropine eye drops at reducing myopia progression in children?
any atropine-related ‘rebound’ effect. Understanding the
impact of ‘myopic rebound’ is of particular importance,
as there is a potential risk for a sudden and rapid change in
the ocular structures (e.g. a marked increase in axial length)
to occur upon cessation of atropine treatment, which could
negatively impact on ocular health and/or visual function.
Significant myopia progression was found in the previously
atropine-treated group (mean SE increase of –1.14±0.80
D/year) compared to the placebo-treated group (–0.38±0.39
D/year). Nonetheless, the 1% atropine-treated group (mean
SE = –4.29±1.67 D) still exhibited significantly lower
magnitudes of manifest myopia at the end of this
study than the placebo-treated eyes (–5.22±1.38 D).
Interestingly, over the total 3-year period of both phases
of the ATOM1 study, the mean increase in axial length
was found to be significantly smaller in the atropine-treated
group (0.29±0.37 mm) versus the placebo-treated group
(0.52±0.45 mm).
The ATOM2, phase 1 study
Phase 1 of the ATOM2 study took a slightly different approach
and investigated the efficacy of lower concentrations of
atropine for myopia control, specifically, at 0.50%, 0.10% or
0.01%, administered once nightly (bilaterally), for a period
of 2 years.93 Chia et al.93 excluded myopic children who had
previously received either pirenzepine or atropine treatment
(at any concentration). Participants were randomised into
one of these three concentration groups, in a ratio of 2
(0.50% group, n = 139) to 2 (0.10% group, n = 141) to 1
(0.01% group, n = 75). Unfortunately, the authors did not
provide a bona fide rationale for why they chose to recruit
unequal numbers to each group, nor did they did recruit a
control group; however, they did ensure a balance of gender
and age across all three treatment arms.
The investigators offered the option of wearing photochromic
spectacles (either as SVS or PALs) to reduce glare and
Figure 2. Flow diagram
depicting the different
phases of the Atropine for
the Treatment Of Myopia
(ATOM) 1 and 2 studies.
excessive light exposure. The option of PALs was offered for
children who were struggling with near work; however, this
again introduces a further confounding factor.34,35,91,92
Over a 2-year period, the mean myopia progression values
were −0.30±0.60 D, −0.38±0.60 D and −0.49±0.63 D for
the 0.50%, 0.10% and 0.01% atropine groups, respectively;
the differences between all three groups did not reach
statistical significance (p = 0.07). Whilst the authors reported
that their post hoc tests revealed a significant difference
between the 0.01% and 0.50% groups (p = 0.02), we would
argue that this is an example of the inappropriate use of
statistical testing, as the difference between the three
groups was not statistically significant.
Chia et al.93 found that the mean change in axial length
(measured via PCI) over this period was statistically significant
between the three groups: 0.27±0.25 mm in the 0.50%
group; 0.28±0.27 mm in the 0.10% group; and 0.41±0.32
mm in the 0.01% group. However, the mean differences in
SE refraction (0.19 D) and axial length (0.14 mm) between the
three groups were unlikely to be clinically significant.
The authors indicated that the most common adverse
events (including allergic conjunctivitis and eyelid-related
dermatitis) from prolonged atropine use were greatly reduced
when using 0.01% atropine compared to 0.50% atropine. Also,
compared to at the higher concentrations, 0.01% atropine
induced negligible cycloplegia and mydriasis, and had virtually
no effect on near vision, perhaps advocating its long-term use
at this concentration.
The ATOM2, phase 2 study
During phase 2 of the ATOM2 study, all atropine treatments
were ceased and the 356 study subjects were monitored for
a further year.94 Chia et al.94 reported a ‘myopic rebound’
effect for all subjects treated at each concentration level
(0.50%, 0.10% and 0.01%). Myopic progression was found
7
 A Jinabhai and M Glover
to be significantly different across all three groups, with
the highest progression rate measured in the 0.50% group
(mean of –0.87±0.52 D/year). The mean progression rate
was –0.68±0.45 D/year in the 0.10% group and –0.28±0.33
D/year in the 0.01% group. Compared to at baseline, the
mean increase in SE refraction after 36 months, was found
to be –1.15±0.81 D in the 0.50% group; 1.04±0.83 D in the
0.10% group and –0.72±0.72 D in the 0.01% group.
The authors measured a ‘rebound’ increase in mean axial
length, which was significantly different across the three
groups, with the largest increase measured in the 0.50%
group (0.35±0.20 mm/year). The mean increase in axial
length was 0.33±0.18 mm/year in the 0.10% group and
0.19±0.13 mm/year in the 0.01% group. Compared to
at baseline, the mean increase in axial length after 36
months was found to be 0.61±0.35 mm in the 0.50% group,
0.60±0.38 mm in the 0.10% group and 0.58± 0.38 mm in the
0.01% group.
Immediately after stopping the atropine treatments, Chia
et al.94 found that the mean mesopic and photopic pupil
sizes were significantly different across all three treatment
groups, with the largest values recorded for the 0.50%
group (mesopic: 7.76±1.10 mm and photopic: 7.55±1.20
mm). In the 0.10% group the mean values were mesopic:
6.89±0.99 mm and photopic: 6.66±1.07 mm, while in
the 0.01% group they were mesopic: 5.50±0.80 mm and
photopic: 5.07±0.92 mm. After a further 12 months, there
were no significant differences across the three groups for
either mesopic or photopic pupil sizes. Interestingly, the
authors reported that at the end of phase 2, the mean
photopic and scotopic pupil sizes were slightly smaller than
at baseline (mesopic mean reduction: 0.22 mm, photopic
mean reduction: 0.37 mm).
Following the cessation of atropine treatments, the authors
reported that mean AOA was were significantly different
across the three groups, with the lowest values measured in
the 0.50% group (4.10±2.60 D). In the 0.10% group the
mean AOA was 6.81±3.38 D, while in the 0.01% group it
was 11.78±3.20 D. Unlike for their pupil size data, 12 months
later the AOA values were still found to be significantly
different across the three groups, with the lowest values
again measured in the 0.50% group (13.24±2.72 D). The
mean AOA values were 14.45±2.60 D in the 0.10% group
and 14.04±2.90 D in the 0.01% group. Compared to at
baseline, the AOA values were found to be much lower across
all three groups (with a mean reduction of 2.56 D) 12 months
after treatment cessation.
Having ceased their atropine treatments, Chia et al.94
discovered that the mean logMAR near acuities were
significantly different across all three groups, with the
poorest acuities measured in the 0.50% group (0.29±0.18
logMAR). The mean near acuities in the 0.10% group were
0.11±0.17 logMAR and 0.02±0.07 logMAR in the 0.01%
group. However, after a further 12 months, the authors
reported that there were no significant differences in near
logMAR acuities between the three groups.
8
Although some statistical analyses were presented in their
paper, the authors did not present any post hoc tests that
specifically evaluated the differences between individual
treatment groups for changes in SE refraction, axial
length, pupil size, AOA measures or near logMAR acuities.
Nonetheless, the authors’ results demonstrated that using
0.01% atropine provided a reasonable balance between
safety (i.e. effects on pupil size and loss in AOA) and efficacy
for controlling myopia progression.
The ATOM2, phase 3 study
In phase 3 of the ATOM2 study, Chia et al.37 retreated
children who had exhibited >0.50 D/year of myopia
progression (in at least one eye) during phase 2,94 using
atropine 0.01% for a further 2 years (administered once a
night, bilaterally). Altogether, Chia et al.37 retreated a total
of 192 children, equating to 24% of the original 0.01% group,
59% of the 0.10% group and 68% of the 0.50% group.
Chia et al.37 reported that children who required retreatment
had shown higher rates of myopic progression during both
phase 193 and 294 of the ATOM2 study. Over the course of
5 years (i.e. including 24 months of retreatment with 0.01%
atropine), mean myopia progression was significantly lower
(p ≤ 0.003) in participants from the original 0.01% group
(SE: –1.38±0.98 D) than for children in either the 0.10%
(–1.83±1.16 D) or 0.50% groups (–1.98±1.10 D). During the
same 5-year period, the mean increase in axial length was
found to be lowest in the 0.01% group (at 0.75±0.48 mm)
compared to either the 0.10% (0.85±0.53 mm) or 0.50%
group (0.87±0.49 mm); however, these increases in axial
length, between the three treatment groups, were not
statistically significant.
Comparison of the results between all three phases of the
5-year ATOM2 study37,93,94 indicated that 0.01% atropine
was just as efficacious in slowing myopia progression than at
higher concentrations. Nonetheless, these studies have some
limitations which need addressing in future investigations.
First, the number of children in the 0.01% group was
always lower (n = 70 at phase 3) than in the 0.10% (n = 139)
and 0.50% (n = 136) groups, respectively. Although not ideal,
in terms of statistical power and comparisons between
different-sized groups, the authors justified this approach as
it enabled them to stratify participants with respect to age
and gender, ensuring these parameters were balanced across
all groups.
Second, it is unclear whether the investigators repeated
their AOA measurements (and recorded an average) for their
participants, or even if these measurements were made
binocularly, monocularly or both. Chia et al.93 explained that
their AOA measurements were made by instructing each
child to move the Royal Air Force (RAF) rule N5 print closer
towards them until it just blurred (push-up method95), and
then to move this N5 print further away again until it just
became clear (push-down to recognition95); however, it is
unclear which of these two distances was deemed to be the
‘near point of accommodation’,93 or if they used the average
of the two. Burns et al.95 explain that it is widely accepted that
RAF rule AOA measurements have multiple sources of error,
such as reaction time and practitioner bias. However, some of
these can be minimised by using automated techniques, such
 How effective are atropine eye drops at reducing myopia progression in children?
as using an open-field autorefractor, which has been widely
adopted in other studies of myopic children.52,53,96,97
Third, neither the illumination of the near logMAR charts nor
the luminance of the distance logMAR charts was specified
for the acuity measurements made during the different
phases, so it is unclear if these were kept consistent for all
subjects over the duration of the entire ATOM2 study.
Lastly, the authors did not fully investigate the visual
performance of their subjects; for example, neither contrast
sensitivity nor higher-order aberrations were evaluated.
These measurements would have provided useful
information, as a proportion of the children enrolled in
the ATOM2 study experienced some degree of mydriasis
throughout the duration of the study, particularly at the
higher atropine concentrations (0.10% or 0.50%).93 Whilst
such measurements may not be part of a routine eye
examination for children, other researchers have successfully
measured these parameters in young myopic participants
within the age range of the ATOM2 study’s enrolment
criteria; e.g. Pelli–Robson contrast sensitivity28; high-
(100%) and low-contrast (10%) logMAR acuity26; and higher-
order aberration measurements.98,99 As this is the case, we
believe that measurements of higher-order aberrations and
contrast sensitivity should be incorporated as routine for all
children who are treated with atropine.
Examples of retrospective studies
Fang et al.100 evaluated a cohort of 24 ‘pre-myopic’ children,
aged between 6 and 12 years, treated with 0.025% atropine
bilaterally on a once-a-night basis for 12 months. Here,
‘pre-myopia’ was defined as SE refraction of <+1.00 D,
whereas ‘myopia’ was defined as SE refraction of <–1.00D.
Data were compared to an age- and gender-matched control
group of 26 pre-myopic children. The mean baseline SE was
–0.31±0.45 D in the treatment group and –0.17±0.5D in
the control group. At the end of the study, participants in
the control group had a significantly higher mean final SE
refraction of –0.96±0.51 D than participants receiving
0.025% atropine (–0.49±0.47 D). All refractive errors were
measured via cycloplegic autorefraction. Although four
children (17%) from the treatment group complained of
photophobia, none of the cohort experienced blurring at
near and no other side-effects were reported.
Following on from their preliminary study,101 Wu et al.102
treated 97 myopic children, aged between 6 and 12 years,
with 0.05% atropine eye drops once every night in both
eyes; the concentration was then increased to 0.10%
(rather than the 0.50% concentration suggested by previous
studies71,86,90) if their myopia increased by more than –0.50D
over a 6-month period. Treatments were administered
over a mean period of 4½ years, with 44 of the 97 subjects
being switched to 0.10% atropine. The treatment group’s
findings were compared to a control group consisting of
20 age- and gender-matched myopic children. Baseline SE
was –2.45±1.63 D in the treatment group, and –1.87±0.94
D in the control group – all refractive errors were measured
via cycloplegic autorefraction. Overall, myopia progression
for the treatment group was significantly lower (–0.31±0.26
D/year) compared to the control group (–0.90±0.30
D/year). The authors also reported that no side-effects were
experienced.
Clark and Clark103 evaluated the efficacy of 0.01% atropine
eye drops, administered bilaterally on a once-a-night basis,
in controlling myopia in 28 US-based myopic children, aged
between 6 and 15 years, over a 12-month period. Unlike
previous studies, which predominantly included East Asian
children, 36,72,93,100–102,104 Clark and Clark103 recruited
Caucasian (n = 15), Asian (n = 8), Hispanic (n = 3) and African-
American children (n = 2). The treatment group’s findings
were compared to 28 age- and gender-matched spectacle-
wearing control subjects; however, these control subjects
were not matched for ethnicity, and included Caucasian
(n = 12), Asian (n = 3) and Hispanic children (n = 13). Baseline
SE refraction was –2.00±1.60D in the treatment group,
and –2.00±1.50 D in the control group. Overall, the control
group showed a statistically significant increase in mean
myopia progression (of –0.60±0.40 D/year) compared to the
0.01% atropine-treated group (of –0.10±0.60 D/year).
Whilst showing some degree of promise, all three
studies100,102,103 were retrospective in design, and therefore
lacked investigator masking and randomisation of their study
participants. Other disadvantages of these three studies
include a lack of near visual performance assessments,
a lack of axial length measurements, a lack of pupil size
measurements and a lack of AOA measurements. Although
only Wu et al.102 reported that their subjects did not
experience any side-effects, all three papers100,102,103 did
not clearly explain how the authors collected information
about any experienced side-effects. So, it is unclear if this
information was collected through a questionnaire, via
spontaneous reporting or through verbal questioning. Another
concern is that both Wu et al.102 and Fang et al.100 prepared
their drug concentrations themselves; however, their papers
do not explain how they each verified the accuracy of their
final preparations. Further limitations include the fact that
Wu et al.102 used an unbalanced number of participants in
each of their study groups, and that Clark and Clark103 did
not carry out a cycloplegic refraction at each of their study
follow-up visits. Finally, we would argue that the participants
recruited by Fang et al.100 were actually ‘low’ myopes,
rather than true ‘pre-myopes’, due to their negative mean
SE refraction at the start of the study (in both groups).
Examples of prospective studies
In a prospective, randomised study, Yi et al.104 evaluated the
impact of using 1% atropine (bilaterally, once a night) to treat
68 Chinese children with ‘low’ myopia (defined as myopia
between –0.50 D and –2.00 D in both eyes), aged between
7 and 12 years, over a 1-year period. Unlike previous studies,
the authors evaluated the impact of atropine on unaided
distance vision. Results were compared to a control group of
64 Chinese children who received a placebo (artificial tears).
The groups were matched for age, unaided vision, axial length
(measured via ultrasound), gender and initial SE refraction.
At baseline, the control group had a mean SE refraction of
–1.15±0.30 D, compared to the treatment group, whose
SE refraction was –1.23±0.32 D. After 12 months, the control
group’s myopia progressed significantly to –2.00±0.54 D,
9
 A Jinabhai and M Glover
whereas the atropine-treated group showed a relative
positive shift to –0.91±0.45 D. Although in agreement
with Bedrossian,78 this latter finding was rather
surprising, as atropine is believed to reduce myopia
progression, rather than to ‘reverse’ it, perhaps suggesting
that the children in the treatment groups were
over-minused at baseline. Mean axial length showed a
statistically insignificant change in the treatment group,
compared to a significant increase from 23.72±0.12
mm (baseline) to 24.05±0.33 mm in the control group
(p < 0.0001). As expected, after 12 months, mean unaided
logMAR vision improved significantly (p < 0.0001) in
the treatment group, to +0.31±0.16 logMAR (baseline =
+0.43±0.11 logMAR) compared to +0.66±0.15 logMAR
(baseline = +0.40±0.10 logMAR) in the control group. Similar
to the ATOM1 study, 36 Yi et al.104 employed nurses to
administer 1% cyclopentolate to both eyes of all participants
before they were examined by study investigators at
follow-up visits, where all refractive errors were measured
via autorefraction. Yi et al.104 also ensured that both the
‘treatment’ and ‘placebo’ medication bottles were identical
in appearance. However, the authors issued some children
(n = 7) with PALs to help with near blur, which induces an
additional confounding factor.35,91,92
Lee et al.’s72 prospective study investigated different low
concentrations of atropine for myopia control in Taiwanese
children aged between 6 and 12 years, over a 12-month
period. Participants were assigned to one of three
groups: receiving 0.25% atropine drops (n = 12), 0.125%
atropine drops (n = 32) or no drops, thereby acting as a
control group (n = 12). Drops were instilled bilaterally in
both treatment groups. All three groups were matched
for age, gender and baseline SE refraction. The mean
myopic progression was significantly higher in the control
group (–1.05 D/year) than in both the 0.125% atropine-
(0.00 D/year) and 0.25% atropine-treated groups (–0.05
D/year). Although prospective in its design, this study did not
utilise investigator masking. Furthermore, participants were
not randomised, as children who preferred wearing spectacles
were automatically enrolled in the control group. It is accepted
that negative SVS may induce relative peripheral hyperopic
defocus,44,105,106 which perhaps explains the significant
myopic progression measured in the control group.
Unfortunately, Lee et al.72 did not confirm at what time
of day their treatment drops were administered by
their participants. Although the authors claimed that a
cycloplegic autorefraction was performed at each visit, they
did not explain which drug or concentration they used to
achieve cycloplegia.
Polling et al.63 conducted a prospective study to investigate
the effectiveness of 0.50% atropine as a potential treatment
for Europe-based children with high myopia (i.e. mean SE
refraction of <–6 D). The authors initially enrolled 77 myopic
children, aged between 3 and 17 years, whose ethnicities
were European (69%), Asian (23%) or African (8%), with a
mean SE refraction of –6.63±3.31 D at baseline. Subjects were
evaluated for 1 year before commencing treatment, to establish
the degree of myopia progression ahead of starting treatment
with 0.50% atropine. The treatment was administered
10
bilaterally before bedtime for 12 months. Seventeen of the
77 subjects ceased treatment before the end of the study
due to adverse events (11 within the first month). Of the
remaining 60 subjects, their mean myopic progression
was –1.00±0.70 D/year before starting treatment,
which substantially decreased to –0.10±0.70 D/year.
Unfortunately, the authors did not report any statistical
analyses comparing the differences in results between
baseline and the end of the study for either mean SE refraction
or mean axial length data (measured using PCI). Compared
to those completing the study, the 17 subjects who ceased
treatment early showed significantly greater rates of myopic
progression over the 12 months, with a mean increase of
–0.50±0.60 D/year (p = 0.03).
As this was an ‘effectiveness’ study, a control group was
not used and the investigators were not masked. Unlike the
ATOM136 and ATOM293 studies, Polling et al.63 did not instil
a cycloplegic agent at each follow-up visit. Instead the
authors presumed that the instillation of atropine the
previous evening would have induced sufficient cycloplegia
to enable cycloplegic refractive error to be measured using
an autorefractor. However, as the authors did not clarify the
time(s) at which their follow-up appointments occurred, this
might not be entirely accurate, particularly as some children
may have attended after a whole day at school, rather than in
the morning.
Wang et al.107 conducted a randomised, controlled study to
investigate the efficacy of 0.50% atropine eye drops versus
a placebo (artificial tears). All eye drops were applied once
a night bilaterally for a period of 12 months. The authors
recruited 109 Chinese children with ‘low’ myopia (defined
as SE refraction between –0.50 and –2.00 D), aged between
5 and 10 years. The 0.50% atropine group included 54
subjects and the control group 55 subjects. Both groups were
matched at baseline for SE, ethnicity, age, gender and axial
length. The baseline mean SE refraction was –1.30±0.40 D
in the intervention group versus –1.20±0.30 D in the control
group. After 12 months, the mean SE refraction had increased
to –2.00 D (95% confidence intervals (CIs) of –2.50 D and
–1.60 D) in the control group. However, similarly to Yi et
al.,104 the mean SE refraction appeared to decrease in the
intervention group, with Wang et al.107 reporting a mean
value of –0.80 D (95% CIs of –1.10 D and –0.40 D). This again
perhaps indicates the possibility of some participants in the
intervention group being over-minused at baseline.
At baseline, the mean axial length was 24.1±1.0 mm in
the intervention group versus 23.8±0.9 mm in the control
group. After 12 months, the mean axial length had increased
to 24.3 mm (95% CIs of 21.2 and 26.8 mm) in the control
group. However, rather unusually, the mean axial length
was found to have reduced to 23.00 mm (95% CIs of 20.7 and
25.5 mm) in the intervention group. Wang et al.107 did not
provide an explanation for how this measured ‘reversal’ might
have occurred, nor did the authors state which technique
they used to measure axial length. The authors also claim to
have conducted cycloplegic autorefraction at each follow-up
visit; however, the methods used to achieve cycloplegia were
not described, nor did they specify which autorefractor they
used. It was also unclear if the same instruments/methods,
 How effective are atropine eye drops at reducing myopia progression in children?
for measuring axial length and cycloplegic autorefraction
were used for all participants at each follow-up.
Wang et al.107 also claimed that they ‘blinded the outcome
assessors and data analysts’; however, unlike the methods
described by Chua et al.36 and Yi et al.,104 Wang et al.107
did not provide clear explanations of how this was achieved.
Nevertheless, the authors explained that they carefully
designed both sets of eye drop bottles such that they had
similar appearances.
Although presenting some encouraging results, there are
some key limitations to these four prospective
studies63,72,104,107; for example, three studies72,104,107 did not
assess near visual performance, pupil size or AOA. However,
instead of measuring AOA using an RAF rule, Polling et al.63
chose to use dynamic retinoscopy, which partly hinders
comparability with other published studies.37,38,93,94 Rather
surprisingly, some studies did not evaluate distance visual
acuities as part of their follow-ups.72,107 Lee et al.72 did not
measure axial length for their subjects, nor did they report on
any side-effects or adverse events. On the other hand, Wang
et al.107 claimed that they ‘recorded’ any adverse events during
their follow-up visits; however, the authors did not explain
if this was by verbal questioning, spontaneous reporting or
via a questionnaire. Nonetheless, Wang et al.107 reported
no adverse events for their study. In contrast, Yi et al.104
claimed to record any adverse events based on ‘interrogation
and [ocular] examination’. Although the authors stated
that they performed a slit-lamp examination at each
follow-up, they did not explain if they ‘interrogated’
both the child participants and their parents, or just the
participants. Polling et al.63 used questionnaires to monitor
side-effects; these were given to both the child patients
and their parents. For the 17 patients who ended the study
early, the most common reasons for discontinuation were
photophobia, reading problems and headache. However, these
questionnaires seemed to be designed by the researchers
themselves, therefore it is not possible to confirm their validity
or reliability, which may limit their usefulness.
Is atropine a viable option to inhibit
myopic progression?
Long-term atropine use can have several potential side-effects
and safety concerns, including rare symptoms such as a dry
throat, dry mouth, flushed skin, difficulties with micturition
and constipation.10 At present, the long-term safety of using
atropine in child patients, in relation to potential systemic
side-effects, is largely unknown. However, the most
common side-effects reported in the reviewed literature
(typically when administering the higher concentrations
of atropine) include photophobia,63,71,81,89 headaches,63,89
blurred near vision93,104 and an increased risk of ultraviolet
radiation exposure through pupillary mydriasis.108 Reports
of infrequent cases of non-serious adverse events, including
allergic conjunctivitis and dermatitis, also exist, 36,93 perhaps
contributing to the high drop-out rate reported in some
studies.63,86
Some of these effects also have the potential to introduce
further confounding factors. For example, increased
light sensitivity would likely lead to a reduction in time
spent outdoors, which is known to impact on myopia
progression.46–49,109 Furthermore, blurry near vision might
not be acceptable for school work, indicating the need for a
near vision correction in the form of bifocals/PALs,
particularly for those on higher concentrations84,89,93,104;
however, bifocals/PALs are known to impact on myopia
development.32,33,35,91,92 It is also probable that these side-
effects can negatively affect patient compliance, which is
directly related to treatment efficacy.63,89
Unfortunately, following treatment cessation, atropine
causes ‘myopic rebound’ (at the 1%38 and 0.50%
concentrations,94 but to a lesser extent at 0.10%94),
potentially limiting its viability. With 1% atropine, Tong et
al.38 reported a greater mean ‘myopic rebound’, of –0.76±0.70
D/year, in their treatment group than in their placebo-control
group (–0.38±0.58 D/year). Fortunately, even after 1 year of
treatment cessation, the positive effect of atropine was not
cancelled out by the ‘rebound’. It is unknown if, over time,
the degree of ‘myopic rebound’ would progress enough to
match that of the placebo-control group; however, such an
experiment might be deemed unethical, as it would involve
withholding a potentially effective treatment from patients
who clinically require it.
Although the ATOM1, phase 1 study suggested that 1%
atropine was both safe and effective at reducing myopia
progression, 36 the later ATOM2 studies found that lower
concentrations (specifically at 0.01%) were able to control
myopia whilst minimising side-effects and ‘myopic
rebound’.37,94 The findings of Shih et al.86 supported these
conclusions and reported no complaints of photophobia or
near vision problems when using 0.25% atropine. Equally,
Cooper et al.110 have suggested that a concentration of less
than 0.02% would not produce significant side-effects.
In phase 3 of the ATOM2 study, Chia et al.37 demonstrated
that a tapering of the ‘rebound’ effect was possible by
retreating cases with still advancing myopia (≥0.50 D/year)
using low-concentration atropine. The authors concluded
that retreatment with a concentration of 0.01% atropine
was just as effective as a primary treatment of 0.01% atropine.
The majority of randomised, controlled atropine research
studies for myopia control have been conducted on
‘moderate’ myopes (whose mean baseline SE refractions have
ranged between –2.45 D and –4.89 D).36,86,90,102 However,
both Yi et al.104 and Wang et al.107 have recently widened
the scope by showing its efficacy in subjects with ‘low’ myopia
(SE refraction between –0.50 D and –2.00 D). Although
Wang et al’s.107 study may not have been truly ‘double-
blinded’, their results support the conclusions of Yi et al.,104
suggesting that atropine treatment could be appropriate for
a wider range of myopic children.
Due to the side-effects of atropine, a significant factor
for consideration is accurate monitoring of participant
compliance, particularly as this impacts on the treatment’s
efficacy.89 Compliance with the usage of drops has been
evaluated using a variety of techniques: Yi et al.104 provided
a calendar to mark on when drops were instilled, whereas
11
 A Jinabhai and M Glover
Chua et al.36 weighed their medication bottles prior to
dispensing, and after collection from each child’s parent/
guardian at each follow-up visit. Although not yet implemented
for monitoring the compliance of atropine treatment, Tan
et al.41 and Siatkowski et al.39,40 have proposed the use of a
SmartCap to monitor the usage of pirenzepine. Whilst each
of these different methods has some merit, none is foolproof,
nor did they prevent participant drop-outs. Nonetheless,
several authors have proposed the use of photochromic
lenses to help improve compliance, particularly to alleviate
photophobia.36,84,89
Possible limitations to the adoption of
atropine-based myopia control in the
western world
How does atropine actually work?
Research suggests that low-concentration atropine treatment
is a safe and effective method to reduce myopia progression;
however, it has not yet been adopted in the western world
for this purpose, and is still to receive approval from the
US FDA for myopia control. One possible reason is the
lack of understanding about the mode of action. Animal
emmetropisation studies have indicated that accommodation
does not cause myopic progression, as chicks with ablated
Edinger–Westphal nuclei, sectioned optic nerves111 and ciliary
ganglion destruction112 (effectively eyes without an ability to
accommodate) still underwent axial elongation. Therefore,
atropine’s cycloplegic effect is not the cause of myopic
inhibition. A study of chick eyes concluded that atropine is
capable of stimulating the release of dopamine within the
vitreous and/or retina, as well as potentially 'depressing’
retinal nerve impulses which could signal axial elongation.113
However, this was previously disputed by Fischer et al.,114 who
suggested that lesions of cholinergic retinal neurones do not
alter form deprivation myopia, nor do they affect atropine’s
inhibition of myopic progression.115
To date, there is no substantial evidence or widespread
consensus to explain precisely how atropine controls myopia
progression. Nonetheless, it is known that all five muscarinic
receptor types (M1–M5) can be found in the sclera and
retina, as well as some receptors in the conjunctiva, lens and
iris.55–57,116 Therefore, Chia et al.37,94 propose that atropine
can act, either indirectly or directly, on the sclera and/or
retina to adjust the degree of scleral remodelling (i.e. stretching
and thinning) typically associated with axial elongation.
Axial elongation is likely to depend on a series of biochemical
reactions, and atropine is presumed to inhibit one or more
of these reactions (or their chemical pathways), thereby
creating changes in the feedback mechanisms linked to
scleral remodelling.55,117,118
What evidence is there for using atropine for
Caucasian myopic children?
The current evidence base for atropine’s efficacy in
controlling myopia progression lacks sufficient investigation
into the effects on non-Asian, myopic children. In their
meta-analysis, Li et al.119 compared the effect of atropine on
Asian and Caucasian myopic children; the authors reported
that atropine had a reduced effect on myopia control with
12
Caucasian cohorts. However, nine studies of Asian children
were included in their analysis, compared to only two studies
of Caucasian children.
During a trial of 0.50% atropine in subjects predominantly
of European heritage, Polling et al.63 found that, although
myopic progression was reduced, 63 of their 77 subjects
reported symptomatic side-effects. Photophobia was
reported by 70% of children who continued, and by 81.2%
who discontinued therapy. Reading problems were reported
by 25.9% of children who maintained therapy and by 80%
who discontinued treatment. These findings indicate that
a concentration of 0.50% may prove to be too high for a
non-Asian population. In contrast, Clark and Clark103
reported that a much lower concentration, of 0.01%
atropine, was effective and well tolerated in a cohort of
28 myopic children, 15 of whom were Caucasian. Minor
symptoms, including light sensitivity or intermittent blur,
were only reported by three subjects. Nonetheless, Clark and
Clark’s103 study is limited by a relatively small sample size
and a retrospective design.
Loughman and Flitcroft120 claimed that a once-daily bilateral
treatment of 0.01% atropine, in a Caucasian population of 14
university students, was generally well tolerated over a 5-day
period and caused no serious side-effects. However, by the
end of the study, only four out of the 14 subjects remained
completely asymptomatic, with glare being the most
common reported symptom. Unfortunately, the mean age
of these students (22±3 years) was significantly higher than
most typical myopia control patients reported in studies
of Asian children,72,94,107 which partly hinders interstudy
comparability.
Cooper et al.’s110 USA-based study evaluated 12 child patients
who were treated using different concentrations of atropine
(i.e. 0.012% (n = 3), 0.025% (n = 6) and 0.05% (n = 3))
over a period of 1 week. Subjects were aged between 8 and
16 years, with an SE refraction between +0.75 D and
–1.75 D. The most common complaints of light sensitivity and
glare (attributed to mydriasis) and blur at near (attributed
to cycloplegia) were mainly reported by subjects receiving
either the 0.05% or 0.025% treatments. However, these
complaints were reported to have reduced between the
concentrations of 0.025% and 0.0125% atropine, as well
as providing acceptable findings of AOA and pupil size.
The authors concluded that 0.02% atropine would be the
highest concentration that did not produce significant
clinical symptoms due to either cycloplegia or mydriasis.
Unfortunately the studies of Loughman and Flitcroft120 and
Cooper et al.110 are both limited by small sample sizes and
very short study durations. Furthermore, Loughman and
Flitcroft120 did not recruit any control subjects, therefore
their study lacked both randomisation and investigator
masking. In comparison, Cooper et al.110 used each subject’s
placebo-receiving contralateral eye as control, and carefully
randomised which eye would receive the treatment. However,
their study lacked both participant and investigator masking,
and they also did not present their participants’ ethnicities in
their paper.
 How effective are atropine eye drops at reducing myopia progression in children?
Overall, there is certainly a requirement for a DBRCT with
several years of follow-up, using low concentrations of
atropine to treat a sufficiently sized Caucasian cohort of
young myopic children, including subjects with light-coloured
irides. Such a study would help to determine whether
lower concentrations are as effective and produce minimal
side-effects as has been reported in Far East Asian cohorts.
The need for further research
To date, atropine studies have yet to determine the optimum
refractive error at which to initiate treatment. Although
both Yi et al.104 and Wang et al.107 have reported a relative
‘positive’ shift in mean SE refraction following their
atropine treatments in children with ‘low’ myopia (SE
refraction between –0.50 D and –2.00 D), it is highly unlikely
that atropine treatment will halt myopia progression
entirely.36,93,108 Fang et al.100 proposed that the treatment
of ‘pre-myopic’ children (SE refraction <+1.00 D, and aged
between 6 and 12 years) would reduce the risk of advancing
myopia before its onset; their results indicated that myopia
was controlled in their subjects using 0.025% atropine.
However, Shih et al.108 argued that, because Fang et al.’s100
patients had a low, myopic mean baseline SE refraction
of –0.31±0.45 D, their cohort was at a low risk of rapid
myopic progression.
Evidence regarding the optimal age at which to start
treatment is also currently inconclusive. Polling et al.63 reported
a lower efficacy of atropine for children aged <9 years, whereas
Brodstein et al.83 proposed a benefit for a similar age group,
of 8–12 years. Wu et al.102 found no statistically significant
difference in treatment when comparing age between their
two study groups, whilst Huang et al.’s121 meta-analysis
suggested that most forms of myopia-controlling interventions
tend to lose their effectivity in the second year of treatment,
and hypothesised that this was due to ‘increased age’.
All atropine treatments must be stopped at some stage;
however, the current literature does not provide any consensus
on how long this should be after commencing treatment
– for example, Chiang et al.89 recommended that myopic
children were treated up until the age of 16 years, whereas
Brodstein et al.83 indicated that myopes aged up to 18 years
would still benefit from using atropine. It is anticipated that
atropine cessation will depend on both the patient’s age and
the stability of their refractive error.108 In relation to concerns
of 'rebound myopia' following treatment cessation, Chia et
al.94 confirmed that 0.01% atropine showed the least degree
of 'rebound' compared to higher concentrations. Wu et al.102
suggested that long-term treatment could aim to suppress
progression until the patient reaches early adulthood, when
advancing myopia typically plateaus, and the effects of any
‘rebound’ might be less. In broad agreement with Wu et al.,102
both Chia et al.37 and Tong et al.38 also concluded that the ideal
treatment could be restricted to short periods (for a minimum
of 2 years), where clinicians could readily titrate their patient’s
treatment by stopping and starting treatment as and when
required in accordance with any change in progression rate.
However, further evidence is needed to explore the possibility
of individualising treatments to curtail faster-progressing
myopia whilst minimising ‘rebound’.
Another key consideration is: what is the optimum
concentration to use? Although the ATOM2 studies found
0.01% atropine to be the most effective concentration
over a 3-year period,93,94 both Shih et al.108 and Wu et al.102
propose that 0.10% atropine, or higher, could be required
for fast-progressing myopic eyes; however, this would most
likely increase the risk of ‘myopic rebound’. Conversely, Chia
et al.37 hypothesised that, if 0.01% atropine proved to be
ineffective, then higher concentrations were also unlikely to
work. This theory is partially supported by Li et al.’s119 meta-
analysis results, which found that differences in atropine
concentration did not significantly affect the level of
myopia control.
Recommendations for future studies
In addition to age, gender and ethnicity, all future DBRCTs
should aim to match treatment and control groups for
key factors such as parental myopia, time spent outdoors,
time spent doing near work, baseline refractive error and
baseline axial length. However, it may be argued that such an
‘ideal’ study is unlikely to be practical. Before commencing
treatment, all subjects should be carefully interviewed to
ensure that they have not previously undertaken any form
of myopia treatment. Investigators should carefully assess
all aspects of visual function that might be affected by
cycloplegia and mydriasis, such as pupil size, AOA, both
distance and near visions/visual acuities, higher-order
aberrations and contrast sensitivity. Key ocular biometric
parameters, such as axial length, should be measured using
the same methodology for all subjects, preferably with
PCI, low-coherence reflectometry or optical coherence
tomography.122,123 Investigators also need to ensure that
they assess patient compliance with the drug, such as
weighing drug bottles, 36 or even the use of SmartCap
technology.39–41 Subjects should also be asked to complete
validated questionnaires, to capture information about
side-effects/adverse events or any associated visual
problems.120 When arranging the frequency of follow-ups, it
would be helpful to start with the first return visit at 1 week
after starting treatment (then at 1 month and then every
3 months thereafter) to investigate any potential side-effects
as this may help to reduce drop-outs. To permit interstudy
comparisons, cycloplegic autorefraction measurements
should be performed at each return visit, by a masked
clinician, using the same device at each visit for all participants.
A primary disadvantage of the use of atropine for the
treatment of myopia progression is that there is still a need
for a distance vision correction to be worn. Therefore, research
that combines orthokeratology with low-concentration
atropine could prove to be invaluable, and may provide more
efficacious myopia control. Undoubtedly, this has started to
become a new area of clinical optometric research.124–126
Conclusion
Epidemiology studies report that myopia progression is a
rapidly expanding global health concern, especially in
Far East Asian countries. The first two phases of the
ATOM2 study93,94 indicate that a bilateral, once-nightly
treatment of 0.01% atropine can effectively reduce
myopic progression with minimal side-effects for children
13
 A Jinabhai and M Glover
aged between 6 and 12 years, whose progression was
≥0.50 D in the previous 12 months. In particular, phase 3 of
the ATOM2 study37 recommends that treatments are
maintained for at least 24 months, and that retreatments
are possible if there is further myopic progression. However,
atropine treatment is still not widely accepted in the west.
Further research into the mechanism of action, duration
of treatment, tailoring of concentration and impact on
non-Asian children is likely to encourage further global
acceptance. To support this need, a recent UK-based research
study at the University of Ulster – the Childhood Atropine for
Myopia Progression (CHAMP) study – has been initiated to
help explore the impact of atropine on myopia progression.
Additional DBRCTs are also needed, that evaluate large
cohorts (containing a wide range of refractive errors) which
can be monitored over a period of up to 10 years, to
fully investigate treatment efficacy, optimum atropine
concentration, ‘rebound’ effects and long-term side-effects
(both ocular and systemic).
Summary
This paper critically reviews scientific studies
investigating the efficacy of atropine at regressing
myopia progression in children. Eye care practitioners
will benefit from gaining a better understanding of
the efficacy of this treatment and its limitations in the
anticipation that this drug is adopted for clinical use in
the UK in the near future.
Practitioners will gain a better understanding of the
key issues surrounding the clinical administration of
atropine, such as the optimum concentration; the
range of refractive errors that are treatable, the age
at which to commence treatment; the longevity of
the effect(s); potential side-effects; and the importance
of compliance.
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CET multiple choice questions
This article has been approved for one non-interactive
point under the GOC’s Enhanced CET Scheme. The reference
and relevant competencies are stated at the head of the
article. To gain your point visit the College’s website
www.college-optometrists.org/oip and complete the multiple
choice questions online. The deadline for completion is
31 October 2020. Please note that the answers that you will
find online are not presented in the same order as in the
questions below, to comply with GOC requirements.
1. Which of the following atropine concentration levels has
not been investigated for controlling myopia progression?
• 0.025%
• 0.015%
• 0.01%
• 0.25%
17
 A Jinabhai and M Glover

2. What was the duration of the third phase of the second

Atropine for the Treatment Of Myopia (ATOM2) study? CPD exercise
• 12 months After reading this article, can you identify areas in
which your knowledge of the effectiveness of atropine
• 6 months
eye drops at reducing myopia progression in children
• 24 months has been enhanced?
• 36 months How do you feel you can use this knowledge to offer
3. Which of the following is not a rare symptom of better patient advice?
long-term atropine use? Are there any areas you still feel you need to study and
• Flushed skin how might you do this?

• Dry throat Which areas outlined in this article would you benefit
from reading in more depth, and why?
• Difficulties with micturition
• Forgetfulness
4. In relation to myopia development theories, which of the
following has not been proven through animal studies?
• Overactive accommodation
• Interruption of the biological feedback loop
• Inducement of relative peripheral hyperopic defocus
• Form deprivation
5. Although SmartCap technology is not yet used with
atropine, which antimyopia drug has the SmartCap
technology been designed and implemented for?
• Scopolamine
• Cyclopentolate
• Tropicamide
• Pirenzepine
6. If myopia progression control, through atropine use,
is successful, how might this impact on the key ocular
biometric parameter axial length?
• Axial length increases whilst myopic progression rate
increases
• Axial length decreases whilst myopic progression rate
reduces
• Axial length decreases whilst myopic progression rate
increases
• Axial length increases whilst myopic progression rate
reduces

18