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How effective are atropine eye drops at reducing myopia progression in children?

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Citation for published version (APA): Jinabhai, A., & Glover, M. (2019). How effective are atropine eye drops at reducing myopia progression in children? Optometry in Practice (OiP), 20(3), 1-18. [EV-59579 C-72220]. https://www.college-optometrists.org/oip- resource/atropine-eye-drops-to-control-myopia-progression.html Published in: Optometry in Practice (OiP)

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Download date:03. Oct. 2021 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, Atropine with a smaller proportion being either emmetropic or myopic. Atropine is a non-selective, competitive muscarinic Typically, around the age of 7 years, some children undergo acetylcholine receptor antagonist, with a high affinity for a marked shift in refractive error, resulting in manifest all five forms of muscarinic receptors (i.e. M1–M554) located myopia; this abrupt shift is often referred to as ‘myopia within the eye (particularly those in the sclera and retina55–57), progression’.13,15,18 A targeted reduction in the severity of which cause both cycloplegia and mydriasis.58 Atropine this ‘myopic shift’ has been the subject of a wide range of has been routinely used (off-label) in approximately 50% of research strategies (summarised in Figure 1), including: the paediatric myopic progression cases in Taiwan since 2007.59 use of rigid gas-permeable lenses19; orthokeratology contact Despite this popularity, atropine is not currently approved lenses20–26; bifocal or multifocal soft contact lenses27–31; for myopia control by the US Food and Drug Administration bifocal or multifocal spectacle lenses32–35; and ophthalmic (FDA),60 nor is it approved for myopia control in the UK. drugs such as atropine36–38 or pirenzepine.39–41 With a growing body of evidence indicating that

Date of acceptance: 4 July 2019. [email protected]

© 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 studies reviewed in this paper, whilst Table 2 presents a critical And Yearly Observation of Clinical measurements and study design list of key limitations for the same group of studies. Near-sightedness; LORIC, for assessing myopia progression 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 (%) Treatment group (D/year) Control receiving 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 63 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 children ), 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 of atropine on myopia control. A detailed description of –1.23 ± 0.32, to –0.91 ± 0.45 in 1 year) 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 been published elsewhere.69,70 Many scientists consider the N-R, NM 0.25% group mean: –1.45 ± 0.69; 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’ Previously in 0.10% group; mean: –4.31 ± N/A −0.41 N/A bias. However, compared to more conventional study with 0.01% 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, 63,71,72 –0.40) after 1 year of Tx) an appropriate control group. Although common, 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.

2 3 A Jinabhai and M Glover

Table 2. A list of some of the key limitations for Authors Key limitations research studies evaluating the use of atropine for the Did not measure axial length control of progressive myopia in child patients Did not measure distance visual acuity Authors Key limitations Did not measure amplitude of accommodation Did not measure axial length Lee et al.72 Did not measure pupil size Did not match study groups (e.g. for age, Did not measure visual performance at near gender, degree of myopia) Lacking investigator masking Did not measure amplitude of accommodation Shih et al.86 Lacking randomisation Did not measure pupil size Unclear what the ‘end point’ for amplitude of Did not measure visual performance at near accommodation measurements was Did not mask investigators Chia et al.37 No illuminance values for near acuity chart, Undercorrected some patients for distance or luminance values for distance chart Did not measure amplitude of accommodation Lacking a control group Did not measure pupil size Used non-validated questionnaires Shih et al.90 Did not measure visual performance at near No control group Unclear how investigators were masked High drop-out rate Did not measure amplitude of accommodation Used dynamic retinoscopy for accommodation Polling et al.63 measurements (partly hinders interstudy Chua et al.36 Did not measure pupil size comparability of accommodation data) Did not measure visual performance at near Lacking investigator masking Retrospective design Lacking randomisation Lacking investigator masking Lacking some pertinent statistical tests Lacking randomisation Concerns that some patients in the treatment Did not measure axial length group were over-minused at baseline? 100 Fang et al. Concerns about axial length measurements – 102 Did not measure amplitude of accommodation and Wu et al. how were these measured? Did not measure pupil size How was the cycloplegic refraction measured? Did not measure visual performance at near Wang et al.107 Unclear how investigators were masked Prepared their own concentrations but did not explain how they verified these Did not measure amplitude of accommodation Uneven patient numbers in the different Did not measure pupil size treatment groups Did not measure visual performance at near Some inappropriate statistical tests were Unclear how information about adverse events presented in the paper was collected Chia et al.93 Unclear what the ‘end point’ for amplitude of accommodation measurements was Lacking a control group Atropine eye drops to reduce myopia No illuminance values for near acuity chart, or luminance values for distance chart progression in children Retrospective design The early studies Lacking investigator masking Early studies evaluating 1% atropine for the treatment 73–77 Lacking randomisation of myopia were conducted in the 1970s. Arguably, Bedrossian’s78 results kick-started subsequent research in this Subject groups not matched for ethnicity field. Interestingly, Bedrossian78 treated 62 myopic children Did not measure axial length Clark and Clark103 with 1% atropine, unilaterally (once a night) for 1 year, whilst Did not measure amplitude of accommodation the fellow eye acted as the control. After 12 months, the Did not measure pupil size author switched the treatment programme to the contralateral Did not measure visual performance at near eye for a further year. Twenty-eight myopic children were treated for 4 years using this annual contralateral eye Did not carry out a full cycloplegic refraction 78 at follow-up switching methodology. Bedrossian reported that, over the Concerns that some patients in the treatment 4-year period, eyes receiving 1% atropine showed a mean group were over-minused at baseline? decrease in myopia progression, of +0.29 D/year, compared to the control eyes, which showed a mean increase of –0.81 Yi et al.104 Did not measure amplitude of accommodation D/year. At 54.8 months after treatment cessation, the mean Did not measure pupil size increase in myopia was found to be –0.06 D/year (data from Did not measure visual performance at near 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

4 How effective are atropine eye drops at reducing myopia progression in children? example, at each of the patients’ follow-up appointments, with 0.50% atropine for a median period of 31.2 months. due to marked unilateral mydriasis, it would have been Compared to when using tropicamide, these children showed obvious which eye had been receiving the treatment, perhaps a significantly reduced progression rate of–0.01±0.09 unintentionally influencing how the practitioner performed D/month (p < 0.05). Although demonstrating a reduction the monocular refraction. Bedrossian78 did not evaluate in progression for children with high myopia (measured via axial length, or visual performance at near (such as near cycloplegic autorefraction), Chou et al.’s71 study is hindered visions/acuities), or AOA measurements, to confirm how by its non-randomised design, as the children’s parents many dioptres of accommodation were potentially lost, decided which cohort their child would be enrolled to. The prior to performing a cycloplegic refraction at each follow- authors did not evaluate changes in axial length in this report; up visit. The author also did not specify the exact method they also did not appear to control for potential observer bias, he used to measure each participant’s cycloplegic refractive neither did they evaluate visual performance at near, nor AOA. error. Furthermore, it was unclear whether or not using the contralateral eye as a control was suitable because of the Shih et al.86 trialled different concentrations of atropine potential systemic, residual effects of 1% atropine in the (0.50%, 0.25% or 0.10%), administered bilaterally, on a fellow eye.79 once-a-night basis, to inhibit myopia progression in a cohort of 137 Taiwanese, myopic children, aged between 6 and Further research using 1% atropine was undertaken in the 13 years, over a 2-year period. Recruited participants had 1980s80,81 and indicated a successful reduction in myopia an SE refraction between –0.50 D and –6.75 D, and were progression. Unfortunately, neither of these reports evaluated randomised to one of the three treatment groups, or to the axial length changes or near visual performance, and it is also control group. Children treated with 0.50% atropine (n = unclear if they each controlled for observer bias. However, 41) were also fitted with bifocals (+2.00 D add); children these studies confirmed significant side-effects and potential treated with 0.25% atropine (n = 47) were undercorrected for limitations of using this particular concentration. Yen et al.81 distance (by 0.75 D), whilst children treated with 0.10% reported that, due to discomfort glare and photophobia, some atropine (n = 49) were given their full distance correction only. children stopped playing outdoors and/or participating in The mean myopia progression was –0.04±0.63 D/year, gymnastics at school, whilst Kao et al.80 noted their subjects’ –0.45±0.55 D/year and –0.47±0.91 D/year for the 0.50%, dissatisfaction at wearing bifocals to overcome the induced 0.25% and 0.10% groups, respectively. The authors also cycloplegia. Nonetheless, these early reports indicated that evaluated a control group of 49 myopic children (recruited using atropine at a 1% concentration level might prove to be using the same enrolment criteria), who received 0.50% impractical on a long-term basis. tropicamide; comparatively, these control subjects showed a marked mean myopia progression of –1.06±0.61 D/year Combining atropine with bifocals (measured via cycloplegic autorefraction). Unfortunately, 86 To improve the suitability of using atropine, Chou et al.71 Shih et al. did not evaluate changes in axial length. They proposed the use of a lower concentration, of 0.50%, also did not investigate the potential impact that binocularly, on a once-a-night basis, in conjunction with undercorrection would have had on the results of the children receiving 0.25% atropine, as undercorrection is known to bifocal spectacles. It can be argued that this approach 87,88 was highly influential as, until that point in time, previous promote myopisation. Equally, the use of bifocals by studies had only used 1% atropine eye drops with bifocals.82–85 some of this study’s participants introduces a further Chou et al.71 evaluated 20 ‘highly’ myopic Taiwanese children confounding factor, as bifocals have been shown to have some degree of impact on myopia progression in young myopic (defined as a spherical equivalent (SE) refraction between 32,33 –6.25 and –12.00 D) aged between 7 and 14 years. Subjects children. Furthermore, it is also unclear if the different were also dispensed bifocals (+2.00 D add) for near tasks groups were matched with respect to age, gender or degree and were asked to wear sunglasses on sunny days. A cohort of myopia, or if the study investigators were masked. The of 8 children did not initially receive any eye drops for 6–12 authors also did not measure visual performance at near, months, and showed a mean pretreatment progression pupil size or AOA. rate of –0.14±0.07 D/month – this period was designed to offer control data for statistical comparisons. The same 8 Compliance children subsequently demonstrated a statistically significant One potential issue regarding the administration of atropine reduction in progression, to –0.04±0.06 D/month (p < 0.05), treatment is the degree of patient compliance, as good following 0.50% atropine treatment for a median period of compliance is required to ensure the drug’s efficacy. Chiang 38.4 months. et al.89 evaluated compliance amongst 706 myopic children (aged between 6 and 16 years, with baseline SE refraction Another cohort was also enrolled, where 12 children initially of <–0.50 D) receiving 1% atropine (bilaterally) and using received 0.50% tropicamide (also once a night) for a photochromic bifocal spectacles (+2.25 D add), over a period median period of 22.6 months, during which participants of 3.88±1.80 years. Study participants were instructed to demonstrated a mean myopia progression of –0.12±0.09 use one drop of 1% atropine, in each eye, ‘every other day’, D/month. This period was also designed to generate control for a period of 2 years. After this, participants were asked data for statistical comparisons; however, the authors did not to use the drops only once a week. The authors reported provide any myopia progression data relating to the period a statistically significant lower progression rate in children immediately before commencing tropicamide use. Upon who were ‘fully compliant’ (n = 496: –0.08 D/year), cessation of tropicamide, the same 12 children were treated compared to children who were deemed to be only ‘partially

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compliant’ (n = 210: –0.23 D/year; p < 0.001). Compliance in axial length, measured via ultrasound. However, as no was determined through questioning of both the child corresponding figure was presented in their paper, it is unclear and parent(s). The ‘partial’ compliance cohort included whether the authors plotted these data for each study group participants who ‘used the drops intermittently’, individually, or whether all 188 subjects (combined) were rather than every day, as well as participants who included in the correlation analysis. ‘used their bifocals for inconsistent time intervals’, whereas the ‘fully’ compliant cohort only included Although generally robust in its design, this study is limited participants who completely followed the treatment by a lack of assessment of pupil size, AOA and visual regimen. The primary reasons for poor compliance included performance at near. Furthermore, the authors did not appear photophobia, inconvenience and headache. Chiang et al.89 to match their study groups for age, axial length, gender or concluded that full compliance was critical in order to refractive error. Whilst the authors claim that their study maximise atropine’s potential for myopia control, and also was ‘double-blind’ in its design, it is highly likely that any advocated the use of photochromic bifocals in conjunction bilateral, atropine-induced mydriasis would have been with 1% atropine treatment. noticeable to the trained clinical examiners. Notably, these examiners were responsible for performing both ‘pre-’ and Unfortunately, this study has some limitations. For example, ‘post-cycloplegic’ autorefraction (using 0.50% tropicamide), Chiang et al.89 did not evaluate changes in axial length, nor ‘post-cycloplegic’ retinoscopy and for conducting an interview did they specify the exact method (of either autorefraction to evaluate the degree of regimen compliance – this could or retinoscopy) for how they measured each participant’s have potentially led to a degree of assessment bias of the cycloplegic refractive error. Furthermore, this retrospective study participants recruited to the PALs plus atropine group. study was designed as a non-comparative case series, meaning Whilst not perfect, Shih et al.’s90 study design of using that the groups’ sizes were unequal, not matched for age, placebo drops and randomising participants into treatment gender or degree of myopia, subjects were not randomised, groups set a precedent for future studies. and the degree of ‘partial compliance’ was not controlled amongst their study cohort of 210 children. Also, due to its The ATOM1 studies retrospective design, this study lacked a proper control group. The initial Atropine for the Treatment of Myopia (or ATOM1) study evaluated the safety and efficacy of 1% atropine Combining atropine with progressive addition treatment, administered once, on a nightly basis, in a lenses cohort of 166 myopic children.36 Study participants were Whilst a number of studies have issued bifocal lenses predominantly Chinese (with a smaller proportion of Indian alongside atropine treatment,71,82–86,89 the visible line ethnicity), aged 6–12 years, with a mean SE refraction associated with these lenses may prove to be unpopular between –1.00 and –6.00 D, which the authors defined as with children, potentially reducing compliance, or even low to moderate myopia. Chua et al.36 utilised a randomised, contributing to participant drop-out. To counter this, double-blind study design, where 1% atropine was progressive addition lenses (PALs) could be used instead. In administered monocularly (treated eyes were chosen their randomised study, Shih et al.90 divided a cohort of randomly) over a period of 2 years. One hundred and 188 Taiwanese myopic children, aged between 6 and 13 eighty control subjects, who received a placebo, were also years, into three groups: those treated with 0.50% atropine recruited; both study groups were matched in terms of age, (once a night, bilaterally) whilst wearing PALs (n = 66; mean gender, ethnicity and refractive error. All participants were baseline SE: –3.20±0.14 D), those wearing PALs and receiving a dispensed with photochromic SVS, irrespective of their placebo (n = 61; mean baseline SE: –3.34±0.14 D) and those treatment allocation. The control group’s mean refractive wearing single-vision distance spectacle lenses (SVS) and error (measured using cycloplegic autorefraction) increased receiving a placebo (n = 61; mean baseline SE: 3.28±0.13 D) – all by –1.20±0.63 D, compared to –0.28±0.92 D in the 1% refractive errors were measured via cycloplegic autorefraction. atropine-treated eyes. Furthermore, in the control group, the mean axial length (measured via ultrasound) increased After 18 months, the PALs plus atropine group exhibited a significantly, by 0.38±0.38 mm; however, there was significantly lower mean myopic progression, of –0.42±0.07 D, no significant change in the 1% atropine-treated eyes. compared to those in the PALs plus placebo (–1.19±0.07 D) or Unfortunately, the authors did not measure either AOA or SVS group (–1.40±0.09 D). Interestingly, unlike some previous pupil size for either cohort. Nonetheless, the study was reports,35,91,92 Shih et al.90 found no significant difference innovatively designed to preserve ‘masking’ at each follow- between the PALs plus placebo and SVS groups. Over the up visit, in that the study’s ‘co-ordinator’ administered 1% same time period, the mean axial elongation in the PALs plus cyclopentolate drops to both eyes of all participants, ahead atropine group was significantly lower (0.22±0.03 mm) than of them being seen by the clinical investigators. Additionally, in the PALs plus placebo group (0.49±0.03 mm), or in the both the atropine and placebo eye drops were packaged in SVS group (0.59±0.04 mm). Rather unusually, the authors ‘identical’ bottles. did not report any post hoc statistics to explain if there were any differences in axial elongation between the PALs plus The ATOM studies were conducted in different phases, which placebo and SVS groups. are briefly summarised in Figure 2. In phase 2 of the ATOM1 study, Tong et al.38 monitored the same cohort of myopic Shih et al.90 found that the measured increases in myopia children for a further 12 months, following cessation of a were significantly (negatively) correlated to the increases 24-month-long period of 1% atropine treatment, to explore

6 How effective are atropine eye drops at reducing myopia progression in children?

Figure 2. Flow diagram depicting the different phases of the Atropine for the Treatment Of Myopia (ATOM) 1 and 2 studies.

any atropine-related ‘rebound’ effect. Understanding the excessive light exposure. The option of PALs was offered for impact of ‘myopic rebound’ is of particular importance, children who were struggling with near work; however, this as there is a potential risk for a sudden and rapid change in again introduces a further confounding factor.34,35,91,92 the ocular structures (e.g. a marked increase in axial length) Over a 2-year period, the mean myopia progression values to occur upon cessation of atropine treatment, which could were −0.30±0.60 D, −0.38±0.60 D and −0.49±0.63 D for negatively impact on ocular health and/or visual function. the 0.50%, 0.10% and 0.01% atropine groups, respectively; Significant myopia progression was found in the previously the differences between all three groups did not reach atropine-treated group (mean SE increase of –1.14±0.80 statistical significance (p = 0.07). Whilst the authors reported D/year) compared to the placebo-treated group (–0.38±0.39 that their post hoc tests revealed a significant difference D/year). Nonetheless, the 1% atropine-treated group (mean between the 0.01% and 0.50% groups (p = 0.02), we would SE = –4.29±1.67 D) still exhibited significantly lower argue that this is an example of the inappropriate use of magnitudes of manifest myopia at the end of this statistical testing, as the difference between the three study than the placebo-treated eyes (–5.22±1.38 D). groups was not statistically significant. Interestingly, over the total 3-year period of both phases of the ATOM1 study, the mean increase in axial length Chia et al.93 found that the mean change in axial length was found to be significantly smaller in the atropine-treated (measured via PCI) over this period was statistically significant group (0.29±0.37 mm) versus the placebo-treated group between the three groups: 0.27±0.25 mm in the 0.50% (0.52±0.45 mm). 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 The ATOM2, phase 1 study SE refraction (0.19 D) and axial length (0.14 mm) between the Phase 1 of the ATOM2 study took a slightly different approach three groups were unlikely to be clinically significant. and investigated the efficacy of lower concentrations of atropine for myopia control, specifically, at 0.50%, 0.10% or The authors indicated that the most common adverse 0.01%, administered once nightly (bilaterally), for a period events (including allergic conjunctivitis and eyelid-related of 2 years.93 Chia et al.93 excluded myopic children who had dermatitis) from prolonged atropine use were greatly reduced previously received either pirenzepine or atropine treatment when using 0.01% atropine compared to 0.50% atropine. Also, (at any concentration). Participants were randomised into compared to at the higher concentrations, 0.01% atropine one of these three concentration groups, in a ratio of 2 induced negligible cycloplegia and mydriasis, and had virtually (0.50% group, n = 139) to 2 (0.10% group, n = 141) to 1 no effect on near vision, perhaps advocating its long-term use (0.01% group, n = 75). Unfortunately, the authors did not at this concentration. provide a bona fide rationale for why they chose to recruit unequal numbers to each group, nor did they did recruit a The ATOM2, phase 2 study control group; however, they did ensure a balance of gender During phase 2 of the ATOM2 study, all atropine treatments and age across all three treatment arms. were ceased and the 356 study subjects were monitored for a further year.94 Chia et al.94 reported a ‘myopic rebound’ The investigators offered the option of wearing photochromic effect for all subjects treated at each concentration level spectacles (either as SVS or PALs) to reduce glare and (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 Although some statistical analyses were presented in their the highest progression rate measured in the 0.50% group paper, the authors did not present any post hoc tests that (mean of –0.87±0.52 D/year). The mean progression rate specifically evaluated the differences between individual was –0.68±0.45 D/year in the 0.10% group and –0.28±0.33 treatment groups for changes in SE refraction, axial D/year in the 0.01% group. Compared to at baseline, the length, pupil size, AOA measures or near logMAR acuities. mean increase in SE refraction after 36 months, was found Nonetheless, the authors’ results demonstrated that using to be –1.15±0.81 D in the 0.50% group; 1.04±0.83 D in the 0.01% atropine provided a reasonable balance between 0.10% group and –0.72±0.72 D in the 0.01% group. safety (i.e. effects on pupil size and loss in AOA) and efficacy for controlling myopia progression. The authors measured a ‘rebound’ increase in mean axial length, which was significantly different across the three The ATOM2, phase 3 study groups, with the largest increase measured in the 0.50% In phase 3 of the ATOM2 study, Chia et al.37 retreated group (0.35±0.20 mm/year). The mean increase in axial children who had exhibited >0.50 D/year of myopia length was 0.33±0.18 mm/year in the 0.10% group and progression (in at least one eye) during phase 2,94 using 0.19±0.13 mm/year in the 0.01% group. Compared to atropine 0.01% for a further 2 years (administered once a at baseline, the mean increase in axial length after 36 night, bilaterally). Altogether, Chia et al.37 retreated a total months was found to be 0.61±0.35 mm in the 0.50% group, of 192 children, equating to 24% of the original 0.01% group, 0.60±0.38 mm in the 0.10% group and 0.58± 0.38 mm in the 59% of the 0.10% group and 68% of the 0.50% group. 0.01% group. Chia et al.37 reported that children who required retreatment had shown higher rates of myopic progression during both Immediately after stopping the atropine treatments, Chia phase 193 and 294 of the ATOM2 study. Over the course of et al.94 found that the mean mesopic and photopic pupil 5 years (i.e. including 24 months of retreatment with 0.01% sizes were significantly different across all three treatment atropine), mean myopia progression was significantly lower groups, with the largest values recorded for the 0.50% (p ≤ 0.003) in participants from the original 0.01% group group (mesopic: 7.76±1.10 mm and photopic: 7.55±1.20 (SE: –1.38±0.98 D) than for children in either the 0.10% mm). In the 0.10% group the mean values were mesopic: (–1.83±1.16 D) or 0.50% groups (–1.98±1.10 D). During the 6.89±0.99 mm and photopic: 6.66±1.07 mm, while in same 5-year period, the mean increase in axial length was the 0.01% group they were mesopic: 5.50±0.80 mm and 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% photopic: 5.07±0.92 mm. After a further 12 months, there group (0.87±0.49 mm); however, these increases in axial were no significant differences across the three groups for length, between the three treatment groups, were not either mesopic or photopic pupil sizes. Interestingly, the statistically significant. authors reported that at the end of phase 2, the mean photopic and scotopic pupil sizes were slightly smaller than Comparison of the results between all three phases of the at baseline (mesopic mean reduction: 0.22 mm, photopic 5-year ATOM2 study37,93,94 indicated that 0.01% atropine mean reduction: 0.37 mm). was just as efficacious in slowing myopia progression than at higher concentrations. Nonetheless, these studies have some Following the cessation of atropine treatments, the authors limitations which need addressing in future investigations. reported that mean AOA was were significantly different First, the number of children in the 0.01% group was across the three groups, with the lowest values measured in always lower (n = 70 at phase 3) than in the 0.10% (n = 139) the 0.50% group (4.10±2.60 D). In the 0.10% group the and 0.50% (n = 136) groups, respectively. Although not ideal, mean AOA was 6.81±3.38 D, while in the 0.01% group it in terms of statistical power and comparisons between was 11.78±3.20 D. Unlike for their pupil size data, 12 months different-sized groups, the authors justified this approach as later the AOA values were still found to be significantly it enabled them to stratify participants with respect to age different across the three groups, with the lowest values and gender, ensuring these parameters were balanced across again measured in the 0.50% group (13.24±2.72 D). The all groups. mean AOA values were 14.45±2.60 D in the 0.10% group Second, it is unclear whether the investigators repeated and 14.04±2.90 D in the 0.01% group. Compared to at their AOA measurements (and recorded an average) for their baseline, the AOA values were found to be much lower across participants, or even if these measurements were made all three groups (with a mean reduction of 2.56 D) 12 months binocularly, monocularly or both. Chia et al.93 explained that after treatment cessation. their AOA measurements were made by instructing each child to move the Royal Air Force (RAF) rule N5 print closer 94 Having ceased their atropine treatments, Chia et al. towards them until it just blurred (push-up method95), and discovered that the mean logMAR near acuities were then to move this N5 print further away again until it just significantly different across all three groups, with the became clear (push-down to recognition95); however, it is poorest acuities measured in the 0.50% group (0.29±0.18 unclear which of these two distances was deemed to be the logMAR). The mean near acuities in the 0.10% group were ‘near point of accommodation’,93 or if they used the average 0.11±0.17 logMAR and 0.02±0.07 logMAR in the 0.01% of the two. Burns et al.95 explain that it is widely accepted that group. However, after a further 12 months, the authors RAF rule AOA measurements have multiple sources of error, reported that there were no significant differences in near such as reaction time and practitioner bias. However, some of logMAR acuities between the three groups. these can be minimised by using automated techniques, such

8 How effective are atropine eye drops at reducing myopia progression in children? as using an open-field autorefractor, which has been widely D/year). The authors also reported that no side-effects were adopted in other studies of myopic children.52,53,96,97 experienced.

Third, neither the illumination of the near logMAR charts nor Clark and Clark103 evaluated the efficacy of 0.01% atropine the luminance of the distance logMAR charts was specified eye drops, administered bilaterally on a once-a-night basis, for the acuity measurements made during the different in controlling myopia in 28 US-based myopic children, aged phases, so it is unclear if these were kept consistent for all between 6 and 15 years, over a 12-month period. Unlike subjects over the duration of the entire ATOM2 study. previous studies, which predominantly included East Asian 36,72,93,100–102,104 103 Lastly, the authors did not fully investigate the visual children, Clark and Clark recruited performance of their subjects; for example, neither contrast Caucasian (n = 15), Asian (n = 8), Hispanic (n = 3) and African- sensitivity nor higher-order aberrations were evaluated. American children (n = 2). The treatment group’s findings These measurements would have provided useful were compared to 28 age- and gender-matched spectacle- information, as a proportion of the children enrolled in wearing control subjects; however, these control subjects the ATOM2 study experienced some degree of mydriasis were not matched for ethnicity, and included Caucasian throughout the duration of the study, particularly at the (n = 12), Asian (n = 3) and Hispanic children (n = 13). Baseline higher atropine concentrations (0.10% or 0.50%).93 Whilst SE refraction was –2.00±1.60D in the treatment group, such measurements may not be part of a routine eye and –2.00±1.50 D in the control group. Overall, the control examination for children, other researchers have successfully group showed a statistically significant increase in mean measured these parameters in young myopic participants myopia progression (of –0.60±0.40 D/year) compared to the within the age range of the ATOM2 study’s enrolment 0.01% atropine-treated group (of –0.10±0.60 D/year). criteria; e.g. Pelli–Robson contrast sensitivity28; high- (100%) and low-contrast (10%) logMAR acuity26; and higher- Whilst showing some degree of promise, all three 100,102,103 order aberration measurements.98,99 As this is the case, we studies were retrospective in design, and therefore believe that measurements of higher-order aberrations and lacked investigator masking and randomisation of their study contrast sensitivity should be incorporated as routine for all participants. Other disadvantages of these three studies children who are treated with atropine. include a lack of near visual performance assessments, a lack of axial length measurements, a lack of pupil size Examples of retrospective studies measurements and a lack of AOA measurements. Although only Wu et al.102 reported that their subjects did not Fang et al.100 evaluated a cohort of 24 ‘pre-myopic’ children, experience any side-effects, all three papers100,102,103 did aged between 6 and 12 years, treated with 0.025% atropine not clearly explain how the authors collected information bilaterally on a once-a-night basis for 12 months. Here, about any experienced side-effects. So, it is unclear if this ‘pre-myopia’ was defined as SE refraction of <+1.00 D, information was collected through a questionnaire, via whereas ‘myopia’ was defined as SE refraction of <–1.00D. spontaneous reporting or through verbal questioning. Another Data were compared to an age- and gender-matched control concern is that both Wu et al.102 and Fang et al.100 prepared group of 26 pre-myopic children. The mean baseline SE was their drug concentrations themselves; however, their papers –0.31±0.45 D in the treatment group and –0.17±0.5D in do not explain how they each verified the accuracy of their the control group. At the end of the study, participants in final preparations. Further limitations include the fact that the control group had a significantly higher mean final SE Wu et al.102 used an unbalanced number of participants in refraction of –0.96±0.51 D than participants receiving each of their study groups, and that Clark and Clark103 did 0.025% atropine (–0.49±0.47 D). All refractive errors were not carry out a cycloplegic refraction at each of their study measured via cycloplegic autorefraction. Although four follow-up visits. Finally, we would argue that the participants children (17%) from the treatment group complained of recruited by Fang et al.100 were actually ‘low’ myopes, photophobia, none of the cohort experienced blurring at rather than true ‘pre-myopes’, due to their negative mean near and no other side-effects were reported. SE refraction at the start of the study (in both groups).

Following on from their preliminary study,101 Wu et al.102 treated 97 myopic children, aged between 6 and 12 years, Examples of prospective studies with 0.05% atropine eye drops once every night in both In a prospective, randomised study, Yi et al.104 evaluated the eyes; the concentration was then increased to 0.10% impact of using 1% atropine (bilaterally, once a night) to treat (rather than the 0.50% concentration suggested by previous 68 Chinese children with ‘low’ myopia (defined as myopia studies71,86,90) if their myopia increased by more than –0.50D between –0.50 D and –2.00 D in both eyes), aged between over a 6-month period. Treatments were administered 7 and 12 years, over a 1-year period. Unlike previous studies, over a mean period of 4½ years, with 44 of the 97 subjects the authors evaluated the impact of atropine on unaided being switched to 0.10% atropine. The treatment group’s distance vision. Results were compared to a control group of findings were compared to a control group consisting of 64 Chinese children who received a placebo (artificial tears). 20 age- and gender-matched myopic children. Baseline SE The groups were matched for age, unaided vision, axial length was –2.45±1.63 D in the treatment group, and –1.87±0.94 (measured via ultrasound), gender and initial SE refraction. D in the control group – all refractive errors were measured At baseline, the control group had a mean SE refraction of via cycloplegic autorefraction. Overall, myopia progression –1.15±0.30 D, compared to the treatment group, whose for the treatment group was significantly lower (–0.31±0.26 SE refraction was –1.23±0.32 D. After 12 months, the control D/year) compared to the control group (–0.90±0.30 group’s myopia progressed significantly to –2.00±0.54 D,

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whereas the atropine-treated group showed a relative bilaterally before bedtime for 12 months. Seventeen of the positive shift to –0.91±0.45 D. Although in agreement 77 subjects ceased treatment before the end of the study with Bedrossian,78 this latter finding was rather due to adverse events (11 within the first month). Of the surprising, as atropine is believed to reduce myopia remaining 60 subjects, their mean myopic progression progression, rather than to ‘reverse’ it, perhaps suggesting was –1.00±0.70 D/year before starting treatment, that the children in the treatment groups were which substantially decreased to –0.10±0.70 D/year. over-minused at baseline. Mean axial length showed a Unfortunately, the authors did not report any statistical statistically insignificant change in the treatment group, analyses comparing the differences in results between compared to a significant increase from 23.72±0.12 baseline and the end of the study for either mean SE refraction mm (baseline) to 24.05±0.33 mm in the control group or mean axial length data (measured using PCI). Compared (p < 0.0001). As expected, after 12 months, mean unaided to those completing the study, the 17 subjects who ceased logMAR vision improved significantly (p < 0.0001) in treatment early showed significantly greater rates of myopic the treatment group, to +0.31±0.16 logMAR (baseline = progression over the 12 months, with a mean increase of +0.43±0.11 logMAR) compared to +0.66±0.15 logMAR –0.50±0.60 D/year (p = 0.03). (baseline = +0.40±0.10 logMAR) in the control group. Similar to the ATOM1 study,36 Yi et al.104 employed nurses to As this was an ‘effectiveness’ study, a control group was administer 1% cyclopentolate to both eyes of all participants not used and the investigators were not masked. Unlike the before they were examined by study investigators at ATOM136 and ATOM293 studies, Polling et al.63 did not instil follow-up visits, where all refractive errors were measured a cycloplegic agent at each follow-up visit. Instead the via autorefraction. Yi et al.104 also ensured that both the authors presumed that the instillation of atropine the ‘treatment’ and ‘placebo’ medication bottles were identical previous evening would have induced sufficient cycloplegia in appearance. However, the authors issued some children to enable cycloplegic refractive error to be measured using (n = 7) with PALs to help with near blur, which induces an an autorefractor. However, as the authors did not clarify the additional confounding factor.35,91,92 time(s) at which their follow-up appointments occurred, this might not be entirely accurate, particularly as some children Lee et al.’s72 prospective study investigated different low may have attended after a whole day at school, rather than in concentrations of atropine for myopia control in Taiwanese the morning. children aged between 6 and 12 years, over a 12-month period. Participants were assigned to one of three Wang et al.107 conducted a randomised, controlled study to groups: receiving 0.25% atropine drops (n = 12), 0.125% investigate the efficacy of 0.50% atropine eye drops versus atropine drops (n = 32) or no drops, thereby acting as a a placebo (artificial tears). All eye drops were applied once control group (n = 12). Drops were instilled bilaterally in a night bilaterally for a period of 12 months. The authors both treatment groups. All three groups were matched recruited 109 Chinese children with ‘low’ myopia (defined for age, gender and baseline SE refraction. The mean as SE refraction between –0.50 and –2.00 D), aged between myopic progression was significantly higher in the control 5 and 10 years. The 0.50% atropine group included 54 group (–1.05 D/year) than in both the 0.125% atropine- subjects and the control group 55 subjects. Both groups were (0.00 D/year) and 0.25% atropine-treated groups (–0.05 matched at baseline for SE, ethnicity, age, gender and axial D/year). Although prospective in its design, this study did not length. The baseline mean SE refraction was –1.30±0.40 D utilise investigator masking. Furthermore, participants were in the intervention group versus –1.20±0.30 D in the control not randomised, as children who preferred wearing spectacles group. After 12 months, the mean SE refraction had increased were automatically enrolled in the control group. It is accepted to –2.00 D (95% confidence intervals (CIs) of –2.50 D and that negative SVS may induce relative peripheral hyperopic –1.60 D) in the control group. However, similarly to Yi et defocus,44,105,106 which perhaps explains the significant al.,104 the mean SE refraction appeared to decrease in the myopic progression measured in the control group. 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 Unfortunately, Lee et al.72 did not confirm at what time perhaps indicates the possibility of some participants in the of day their treatment drops were administered by intervention group being over-minused at baseline. their participants. Although the authors claimed that a cycloplegic autorefraction was performed at each visit, they At baseline, the mean axial length was 24.1±1.0 mm in did not explain which drug or concentration they used to the intervention group versus 23.8±0.9 mm in the control achieve cycloplegia. 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 Polling et al.63 conducted a prospective study to investigate group. However, rather unusually, the mean axial length the effectiveness of 0.50% atropine as a potential treatment was found to have reduced to 23.00 mm (95% CIs of 20.7 and for Europe-based children with high myopia (i.e. mean SE 25.5 mm) in the intervention group. Wang et al.107 did not refraction of <–6 D). The authors initially enrolled 77 myopic provide an explanation for how this measured ‘reversal’ might children, aged between 3 and 17 years, whose ethnicities have occurred, nor did the authors state which technique were European (69%), Asian (23%) or African (8%), with a they used to measure axial length. The authors also claim to mean SE refraction of –6.63±3.31 D at baseline. Subjects were have conducted cycloplegic autorefraction at each follow-up evaluated for 1 year before commencing treatment, to establish visit; however, the methods used to achieve cycloplegia were the degree of myopia progression ahead of starting treatment not described, nor did they specify which autorefractor they with 0.50% atropine. The treatment was administered used. It was also unclear if the same instruments/methods,

10 How effective are atropine eye drops at reducing myopia progression in children? for measuring axial length and cycloplegic autorefraction light sensitivity would likely lead to a reduction in time were used for all participants at each follow-up. spent outdoors, which is known to impact on myopia progression.46–49,109 Furthermore, blurry near vision might Wang et al.107 also claimed that they ‘blinded the outcome not be acceptable for school work, indicating the need for a assessors and data analysts’; however, unlike the methods near vision correction in the form of bifocals/PALs, described by Chua et al.36 and Yi et al.,104 Wang et al.107 particularly for those on higher concentrations84,89,93,104; did not provide clear explanations of how this was achieved. however, bifocals/PALs are known to impact on myopia Nevertheless, the authors explained that they carefully development.32,33,35,91,92 It is also probable that these side- designed both sets of eye drop bottles such that they had effects can negatively affect patient compliance, which is similar appearances. directly related to treatment efficacy.63,89

Although presenting some encouraging results, there are Unfortunately, following treatment cessation, atropine some key limitations to these four prospective causes ‘myopic rebound’ (at the 1%38 and 0.50% studies63,72,104,107; for example, three studies72,104,107 did not concentrations,94 but to a lesser extent at 0.10%94), assess near visual performance, pupil size or AOA. However, potentially limiting its viability. With 1% atropine, Tong et instead of measuring AOA using an RAF rule, Polling et al.63 al.38 reported a greater mean ‘myopic rebound’, of –0.76±0.70 chose to use dynamic retinoscopy, which partly hinders D/year, in their treatment group than in their placebo-control comparability with other published studies.37,38,93,94 Rather group (–0.38±0.58 D/year). Fortunately, even after 1 year of surprisingly, some studies did not evaluate distance visual treatment cessation, the positive effect of atropine was not acuities as part of their follow-ups.72,107 Lee et al.72 did not cancelled out by the ‘rebound’. It is unknown if, over time, measure axial length for their subjects, nor did they report on the degree of ‘myopic rebound’ would progress enough to any side-effects or adverse events. On the other hand, Wang match that of the placebo-control group; however, such an et al.107 claimed that they ‘recorded’ any adverse events during experiment might be deemed unethical, as it would involve their follow-up visits; however, the authors did not explain withholding a potentially effective treatment from patients if this was by verbal questioning, spontaneous reporting or who clinically require it. via a questionnaire. Nonetheless, Wang et al.107 reported no adverse events for their study. In contrast, Yi et al.104 Although the ATOM1, phase 1 study suggested that 1% claimed to record any adverse events based on ‘interrogation atropine was both safe and effective at reducing myopia 36 and [ocular] examination’. Although the authors stated progression, the later ATOM2 studies found that lower that they performed a slit-lamp examination at each concentrations (specifically at 0.01%) were able to control follow-up, they did not explain if they ‘interrogated’ myopia whilst minimising side-effects and ‘myopic 37,94 86 both the child participants and their parents, or just the rebound’. The findings of Shih et al. supported these participants. Polling et al.63 used questionnaires to monitor conclusions and reported no complaints of photophobia or side-effects; these were given to both the child patients near vision problems when using 0.25% atropine. Equally, 110 and their parents. For the 17 patients who ended the study Cooper et al. have suggested that a concentration of less early, the most common reasons for discontinuation were than 0.02% would not produce significant side-effects. photophobia, reading problems and headache. However, these 37 questionnaires seemed to be designed by the researchers In phase 3 of the ATOM2 study, Chia et al. demonstrated themselves, therefore it is not possible to confirm their validity that a tapering of the ‘rebound’ effect was possible by or reliability, which may limit their usefulness. retreating cases with still advancing myopia (≥0.50 D/year) using low-concentration atropine. The authors concluded Is atropine a viable option to inhibit that retreatment with a concentration of 0.01% atropine myopic progression? was just as effective as a primary treatment of 0.01% atropine. Long-term atropine use can have several potential side-effects The majority of randomised, controlled atropine research and safety concerns, including rare symptoms such as a dry studies for myopia control have been conducted on throat, dry mouth, flushed skin, difficulties with micturition ‘moderate’ myopes (whose mean baseline SE refractions have and constipation.10 At present, the long-term safety of using ranged between –2.45 D and –4.89 D).36,86,90,102 However, atropine in child patients, in relation to potential systemic both Yi et al.104 and Wang et al.107 have recently widened side-effects, is largely unknown. However, the most the scope by showing its efficacy in subjects with ‘low’ myopia common side-effects reported in the reviewed literature (SE refraction between –0.50 D and –2.00 D). Although (typically when administering the higher concentrations Wang et al’s.107 study may not have been truly ‘double- of atropine) include photophobia,63,71,81,89 headaches,63,89 blinded’, their results support the conclusions of Yi et al.,104 blurred near vision93,104 and an increased risk of ultraviolet suggesting that atropine treatment could be appropriate for radiation exposure through pupillary mydriasis.108 Reports a wider range of myopic children. of infrequent cases of non-serious adverse events, including allergic conjunctivitis and dermatitis, also exist,36,93 perhaps Due to the side-effects of atropine, a significant factor contributing to the high drop-out rate reported in some for consideration is accurate monitoring of participant studies.63,86 compliance, particularly as this impacts on the treatment’s efficacy.89 Compliance with the usage of drops has been Some of these effects also have the potential to introduce evaluated using a variety of techniques: Yi et al.104 provided further confounding factors. For example, increased a calendar to mark on when drops were instilled, whereas

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Chua et al.36 weighed their medication bottles prior to Caucasian cohorts. However, nine studies of Asian children dispensing, and after collection from each child’s parent/ were included in their analysis, compared to only two studies guardian at each follow-up visit. Although not yet implemented of Caucasian children. for monitoring the compliance of atropine treatment, Tan et al.41 and Siatkowski et al.39,40 have proposed the use of a During a trial of 0.50% atropine in subjects predominantly SmartCap to monitor the usage of pirenzepine. Whilst each of European heritage, Polling et al.63 found that, although of these different methods has some merit, none is foolproof, myopic progression was reduced, 63 of their 77 subjects nor did they prevent participant drop-outs. Nonetheless, reported symptomatic side-effects. Photophobia was several authors have proposed the use of photochromic reported by 70% of children who continued, and by 81.2% lenses to help improve compliance, particularly to alleviate who discontinued therapy. Reading problems were reported photophobia.36,84,89 by 25.9% of children who maintained therapy and by 80% who discontinued treatment. These findings indicate that Possible limitations to the adoption of a concentration of 0.50% may prove to be too high for a atropine-based myopia control in the non-Asian population. In contrast, Clark and Clark103 western world reported that a much lower concentration, of 0.01% atropine, was effective and well tolerated in a cohort of How does atropine actually work? 28 myopic children, 15 of whom were Caucasian. Minor Research suggests that low-concentration atropine treatment symptoms, including light sensitivity or intermittent blur, is a safe and effective method to reduce myopia progression; were only reported by three subjects. Nonetheless, Clark and however, it has not yet been adopted in the western world Clark’s103 study is limited by a relatively small sample size for this purpose, and is still to receive approval from the and a retrospective design. US FDA for myopia control. One possible reason is the lack of understanding about the mode of action. Animal Loughman and Flitcroft120 claimed that a once-daily bilateral emmetropisation studies have indicated that accommodation treatment of 0.01% atropine, in a Caucasian population of 14 does not cause myopic progression, as chicks with ablated university students, was generally well tolerated over a 5-day Edinger–Westphal nuclei, sectioned optic nerves111 and ciliary period and caused no serious side-effects. However, by the ganglion destruction112 (effectively eyes without an ability to end of the study, only four out of the 14 subjects remained accommodate) still underwent axial elongation. Therefore, completely asymptomatic, with glare being the most atropine’s cycloplegic effect is not the cause of myopic common reported symptom. Unfortunately, the mean age inhibition. A study of chick eyes concluded that atropine is of these students (22±3 years) was significantly higher than capable of stimulating the release of dopamine within the most typical myopia control patients reported in studies vitreous and/or retina, as well as potentially 'depressing’ of Asian children,72,94,107 which partly hinders interstudy retinal nerve impulses which could signal axial elongation.113 comparability. However, this was previously disputed by Fischer et al.,114 who suggested that lesions of cholinergic retinal neurones do not Cooper et al.’s110 USA-based study evaluated 12 child patients alter form deprivation myopia, nor do they affect atropine’s who were treated using different concentrations of atropine inhibition of myopic progression.115 (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 To date, there is no substantial evidence or widespread 16 years, with an SE refraction between +0.75 D and consensus to explain precisely how atropine controls myopia –1.75 D. The most common complaints of light sensitivity and progression. Nonetheless, it is known that all five muscarinic glare (attributed to mydriasis) and blur at near (attributed receptor types (M1–M5) can be found in the sclera and to cycloplegia) were mainly reported by subjects receiving retina, as well as some receptors in the conjunctiva, lens and either the 0.05% or 0.025% treatments. However, these iris.55–57,116 Therefore, Chia et al.37,94 propose that atropine complaints were reported to have reduced between the can act, either indirectly or directly, on the sclera and/or concentrations of 0.025% and 0.0125% atropine, as well retina to adjust the degree of scleral remodelling (i.e. stretching as providing acceptable findings of AOA and pupil size. and thinning) typically associated with axial elongation. The authors concluded that 0.02% atropine would be the Axial elongation is likely to depend on a series of biochemical highest concentration that did not produce significant reactions, and atropine is presumed to inhibit one or more clinical symptoms due to either cycloplegia or mydriasis. of these reactions (or their chemical pathways), thereby Unfortunately the studies of Loughman and Flitcroft120 and creating changes in the feedback mechanisms linked to Cooper et al.110 are both limited by small sample sizes and scleral remodelling.55,117,118 very short study durations. Furthermore, Loughman and Flitcroft120 did not recruit any control subjects, therefore What evidence is there for using atropine for their study lacked both randomisation and investigator 110 Caucasian myopic children? masking. In comparison, Cooper et al. used each subject’s placebo-receiving contralateral eye as control, and carefully The current evidence base for atropine’s efficacy in randomised which eye would receive the treatment. However, controlling myopia progression lacks sufficient investigation their study lacked both participant and investigator masking, into the effects on non-Asian, myopic children. In their and they also did not present their participants’ ethnicities in 119 meta-analysis, Li et al. compared the effect of atropine on their paper. Asian and Caucasian myopic children; the authors reported that atropine had a reduced effect on myopia control with

12 How effective are atropine eye drops at reducing myopia progression in children?

Overall, there is certainly a requirement for a DBRCT with Another key consideration is: what is the optimum several years of follow-up, using low concentrations of concentration to use? Although the ATOM2 studies found atropine to treat a sufficiently sized Caucasian cohort of 0.01% atropine to be the most effective concentration young myopic children, including subjects with light-coloured over a 3-year period,93,94 both Shih et al.108 and Wu et al.102 irides. Such a study would help to determine whether propose that 0.10% atropine, or higher, could be required lower concentrations are as effective and produce minimal for fast-progressing myopic eyes; however, this would most side-effects as has been reported in Far East Asian cohorts. likely increase the risk of ‘myopic rebound’. Conversely, Chia et al.37 hypothesised that, if 0.01% atropine proved to be The need for further research ineffective, then higher concentrations were also unlikely to 119 To date, atropine studies have yet to determine the optimum work. This theory is partially supported by Li et al.’s meta- refractive error at which to initiate treatment. Although analysis results, which found that differences in atropine both Yi et al.104 and Wang et al.107 have reported a relative concentration did not significantly affect the level of ‘positive’ shift in mean SE refraction following their myopia control. atropine treatments in children with ‘low’ myopia (SE refraction between –0.50 D and –2.00 D), it is highly unlikely Recommendations for future studies that atropine treatment will halt myopia progression In addition to age, gender and ethnicity, all future DBRCTs entirely.36,93,108 Fang et al.100 proposed that the treatment should aim to match treatment and control groups for of ‘pre-myopic’ children (SE refraction <+1.00 D, and aged key factors such as parental myopia, time spent outdoors, between 6 and 12 years) would reduce the risk of advancing time spent doing near work, baseline refractive error and myopia before its onset; their results indicated that myopia baseline axial length. However, it may be argued that such an was controlled in their subjects using 0.025% atropine. ‘ideal’ study is unlikely to be practical. Before commencing However, Shih et al.108 argued that, because Fang et al.’s100 treatment, all subjects should be carefully interviewed to patients had a low, myopic mean baseline SE refraction ensure that they have not previously undertaken any form of –0.31±0.45 D, their cohort was at a low risk of rapid of myopia treatment. Investigators should carefully assess myopic progression. all aspects of visual function that might be affected by cycloplegia and mydriasis, such as pupil size, AOA, both Evidence regarding the optimal age at which to start distance and near visions/visual acuities, higher-order treatment is also currently inconclusive. Polling et al.63 reported aberrations and contrast sensitivity. Key ocular biometric a lower efficacy of atropine for children aged <9 years, whereas parameters, such as axial length, should be measured using Brodstein et al.83 proposed a benefit for a similar age group, the same methodology for all subjects, preferably with of 8–12 years. Wu et al.102 found no statistically significant PCI, low-coherence reflectometry or optical coherence difference in treatment when comparing age between their tomography.122,123 Investigators also need to ensure that two study groups, whilst Huang et al.’s121 meta-analysis they assess patient compliance with the drug, such as suggested that most forms of myopia-controlling interventions weighing drug bottles,36 or even the use of SmartCap tend to lose their effectivity in the second year of treatment, technology.39–41 Subjects should also be asked to complete and hypothesised that this was due to ‘increased age’. validated questionnaires, to capture information about side-effects/adverse events or any associated visual 120 All atropine treatments must be stopped at some stage; problems. When arranging the frequency of follow-ups, it however, the current literature does not provide any consensus would be helpful to start with the first return visit at 1 week on how long this should be after commencing treatment after starting treatment (then at 1 month and then every – for example, Chiang et al.89 recommended that myopic 3 months thereafter) to investigate any potential side-effects children were treated up until the age of 16 years, whereas as this may help to reduce drop-outs. To permit interstudy Brodstein et al.83 indicated that myopes aged up to 18 years comparisons, cycloplegic autorefraction measurements would still benefit from using atropine. It is anticipated that should be performed at each return visit, by a masked atropine cessation will depend on both the patient’s age and clinician, using the same device at each visit for all participants. the stability of their refractive error.108 In relation to concerns of 'rebound myopia' following treatment cessation, Chia et A primary disadvantage of the use of atropine for the al.94 confirmed that 0.01% atropine showed the least degree treatment of myopia progression is that there is still a need of 'rebound' compared to higher concentrations. Wu et al.102 for a distance vision correction to be worn. Therefore, research suggested that long-term treatment could aim to suppress that combines orthokeratology with low-concentration progression until the patient reaches early adulthood, when atropine could prove to be invaluable, and may provide more advancing myopia typically plateaus, and the effects of any efficacious myopia control. Undoubtedly, this has started to 124–126 ‘rebound’ might be less. In broad agreement with Wu et al.,102 become a new area of clinical optometric research. 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 Conclusion of 2 years), where clinicians could readily titrate their patient’s Epidemiology studies report that myopia progression is a treatment by stopping and starting treatment as and when rapidly expanding global health concern, especially in required in accordance with any change in progression rate. Far East Asian countries. The first two phases of the However, further evidence is needed to explore the possibility ATOM2 study93,94 indicate that a bilateral, once-nightly of individualising treatments to curtail faster-progressing treatment of 0.01% atropine can effectively reduce myopia whilst minimising ‘rebound’. myopic progression with minimal side-effects for children

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Cooper J, Eisenberg N, Schulman E et al. Maximum atropine CET multiple choice questions dose without clinical signs or symptoms. Optom Vis Sci 2013; 90: This article has been approved for one non-interactive 1467–1472. point under the GOC’s Enhanced CET Scheme. The reference 111. McBrien NA, Moghaddam HO, Reeder AP. Atropine and relevant competencies are stated at the head of the reduces experimental myopia and eye enlargement via a article. To gain your point visit the College’s website nonaccommodative mechanism. Invest Ophthalmol Vis Sci 1993; www.college-optometrists.org/oip and complete the multiple 34: 205–215. choice questions online. The deadline for completion is 31 October 2020. Please note that the answers that you will 112. Troilo D. Experimental studies of emmetropization in the chick. find online are not presented in the same order as in the Ciba Found Symp 1990; 155: 89–102; discussion 102–114. questions below, to comply with GOC requirements. 113. Schwahn HN, Kaymak H, Schaeffel F. Effects of atropine on refractive development, dopamine release, and slow retinal potentials 1. Which of the following atropine concentration levels has in the chick. Vis Neurosci 2000; 17: 165–176. not been investigated for controlling myopia progression? 114. Fischer AJ, Miethke P, Morgan IG et al. Cholinergic amacrine • 0.025% cells are not required for the progression and atropine-mediated suppression of form-deprivation myopia. Brain Res 1998; 794: • 0.015% 48–60. • 0.01% 115. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin • 0.25% Eye Res 2010; 29: 144–168.

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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

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