An in-depth review of current myopia control therapies

Paper title: Interventions for myopia control in children: a living systematic review and network meta‐analysis

Authors: Lawrenson, JG (1); Shah, R (1); Huntjens, B (1); Downie, LE (2); Virgili, G (3,4); Dhakal, R (5); Verkicharla, PK (5); Li, D (4,6); Mavi, S (4); Kernohan, A (7); Li, T (8); Walline JJ (9)

1. Centre for Applied Vision Research, School of Health & Psychological Sciences, City, University of London, London, UK.

2. Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Australia.
3. Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
4. Centre for Public Health, Queen's University Belfast, Belfast, UK.
5. Myopia Research Lab, Prof. Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India.
6. Department of Ophthalmology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
7. Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.
8. Department of Ophthalmology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.
9. College of Optometry, The Ohio State University, Columbus, Ohio, USA.

Date: Feb 2023

References: Lawrenson JG, Shah R, Huntjens B, Downie LE, Virgili G, Dhakal R, Verkicharla PK, Li D, Mavi S, Kernohan A, Li T, Walline JJ. Interventions for myopia control in children: a living systematic review and network meta-analysis. Cochrane Database Syst Rev. 2023 Feb 16;2(2):CD014758

[Link to open access paper]

Increasing prevalence of myopia worldwide has become a growing public health concern, causing increased rates of uncorrected refractive error and visual impairment risks from myopia-related ocular conditions.

Myopia can also impact lives for individuals by restricting sports or educational activities. This is particularly true for children where progression can occur rapidly in childhood, making it an important period to commence effective interventions that can limit progression as children grow.

Primary goals of this network meta-analysis were to:

• Compare the efficacy and safety of optical, pharmacological and environmental interventions for slowing myopia progression in children
• Generate a ranking to reflect the efficacy of the featured studies
• Review the extent of unwanted side-effects or risks
• Summarise the economic impact of myopia control in children
• Continually review current evidence for inclusion in a living systematic review

The authors searched 3 databases for randomised controlled trials (RCTs) which evaluated myopia control treatment interventions for children aged up to 18yrs. The studies assessed the use of interventions alone compared to a placebo or single vision control group or as a combination therapy.

The primary outcome was the rate of myopia progression expressed as changes in spherical equivalent error (SER) and axial length (AL) at one and two years. Secondary outcomes included assessing rebound effects after ceasing wear and adverse effects from intervention use.

The interventions examined in the review included optical therapies (soft multifocal contact lenses incorporating different powered zones to correct and slow myopia, orthokeratology and spectacle lenses designed to provide myopia control); pharmacological and environmental interventions.

Sixty-four studies were included in the review and a network map was established to allow direct and indirect comparisons of treatments to each other.

The duration of the studies ranged between 1 and 3yrs, were conducted mostly in China and other Asia countries (60.9%) and North America (20.3%) and featured 11,617 children aged 4-18yrs (average age 10.4yrs) with myopia of -0.50D or worse. Each study was assessed using a risk of bias tool (RoB) for bias arising from aspects such as study design, missing data or selection of reported results. Most of the featured studies (89%) compared myopia control treatments to an inert control.

Compared to control groups, reduced spherical equivalent refraction (SER) and axial length (AL) was seen at 12 and 24mths for most of the therapies. Reduction of myopic progression was seen to mostly occur within the first year of treatment.

Treatment efficacy and certainty of evidence

• High dose (≥ 0.5%) atropine was most effective for reducing SER and AL progression (0.90D and -0.33mm at 1yr and 1.26D and -0.47mm at 2yrs, respectively) with a moderate certainty for SER and AL changes for treatment up to 2yrs.
• Moderate dose  (0.1% to 0.5%) atropine showed moderate certainty for AL changes for 1 and 2yrs and for SER changes over 1 yr but showed low certainty for SER changes over 2yrs. Low dose (<0.1%) atropine demonstrated either low (SER and AL changes over 2yrs) or very low certainty (changes over 1yr).
• Ortho-K also showed moderate efficacy for AL over 1 and 2yrs (-0.19mm and -0.33mm reduction in AL, respectively.
• The most effective combination therapy was OrthoK and high dose atropine (≥0.5%), which showed moderate certainty of evidence and gave 0.3-0.5mm reduction in AL over 2yrs.  
• Multifocal soft contact lenses showed moderate certainty for AL over 2yrs but otherwise the evidence was low for efficacy in reducing SER changes up to 2yrs.

Pirenzipine and peripheral plus spectacles showed very low certainty and there was little to no evidence to support the use of single vision rigid gas permeable contact lenses (RGP), 7-methylxanthine or under-corrected single vision spectacle lenses (SVLs) as myopia control therapies.

No treatment therapy demonstrated a high certainty of evidence.

Treatment safety, adverse responses and rebound effects

The reporting of unwanted effects was not consistent across studies. Most were usually self-reported and evaluated with questionnaires, with objective clinical signs examined at follow-up visits.

1. Spectacle lens interventions were well tolerated and caused minimal responses of dizziness or blurred vision compared to control lenses.
2. Corneal infiltrative events (17 in 664 wearers), conjunctival papillae and corneal staining were commonly reported responses to soft contact lens wear, although the number of events was similar for both control and treatment groups. Although ortho-k was seen to be an effective treatment, adverse effects were slightly higher (7 in 254 wearers experienced corneal infiltrative events).
3. Side effects with atropine were more likely with higher doses: light sensitivity and blurred near vision were common side effects. Lower dose atropine caused fewer unwanted effects but was less effective in limiting progression. Pirenzipine was associated with unwanted effects such as cough, respiratory infections and rhinitis.

Evidence of rebound effects was dependent on the intervention. Fewer rebound changes were seen for optical interventions rather than for pharmacological. However, rebound effects were inconclusive for atropine, although tapering the dose before ceasing use seemed to reduce the likelihood of rebound effects.

No relevant studies were found which reported on the effect of the environment on myopia progression, or on the economic impact of myopia control in children.

This review showed high dose atropine and ortho-k to be the most effective therapies for reducing myopia progression, particularly if used in combination to enhance myopia control.

However, ortho-k carries a higher risk of events such as corneal infiltrates and high-dose atropine is more likely to cause adverse responses and may need to be carefully tapered at the end of treatment to avoid rebound effects.

Multifocal soft contact lenses and medium-to-low dose atropine were associated with fewer side effects, although the evidence to support efficacy claims was lower. Although the ideal dose of atropine which provides efficacy with minimal ocular discomfort has not yet been established, medium-to-low dose atropine is a viable alternative to higher doses. Eye care practitioners need to balance efficacy, safety and the risk of rebound effects when discussing myopia control therapies with patients and parents.

This living systematic review will be updated when new evidence or data is available in order to reflect changes in knowledge, allowing eye care practitioners to feel confident their clinical practice is based on current, sound evidence and for patients to feel able to make informed choices. 

Further research can investigate:

• methods for identifying children most at risk of rapid childhood myopia progression, where they are more likely to benefit from early intervention
• the sustained safety and efficacy of myopia control interventions for long-term use in children, particularly examining long-term enhanced efficacy of combination therapies. This will provide valuable data on the likely performance of myopia control with prolonged wear, reflecting the real world use of each treatment.
• the impact of myopia control therapies on vision and health-related quality of life and the economic consequences of myopia control for individuals and policy-makers

 Limitations to this review include:

• Varying length, quality and design of studies featured in the review. These differences could have introduced errors within each study and consequently affect generalisability of the meta-analysis results.
• Due to some poor networks connections in the network meta-analysis, some estimates were made based on direct comparisons which may limit the scope of the analysis.
• Many of the studies analysed reported on myopia control effects within 2yrs or less. This means the results may overestimate efficacy over longer periods, particularly where there was evidence that reduction of progression mostly occurred in the first year of treatment.
• Demographic differences in participants across studies, such age and ethnicity, which can mean different rates of progression. This can make it harder to directly compare studies. Younger children and those from South East Asian countries typically demonstrate faster myopia progression and although most studies had similar cohorts, some studies featured children from different ethnicities and ages.
• Some of the studies featured did not meet International Myopia Institute (IMI) guidance for myopia control trial protocols. This may have affected how outcomes and adverse effects were reported.

Title: Interventions for myopia control in children: a living systematic review and network meta‐analysis

Authors: John G Lawrenson, Rakhee Shah, Byki Huntjens, Laura E Downie, Gianni Virgili, Rohit Dhakal, Pavan K Verkicharla, Dongfeng Li, Sonia Mavi, Ashleigh Kernohan, Tianjing Li, Jeffrey J Walline

Purpose: Myopia is a common refractive error, where elongation of the eyeball causes distant objects to appear blurred. The increasing prevalence of myopia is a growing global public health problem, in terms of rates of uncorrected refractive error and significantly, an increased risk of visual impairment due to myopia-related ocular morbidity. Since myopia is usually detected in children before 10 years of age and can progress rapidly, interventions to slow its progression need to be delivered in childhood. To assess the comparative efficacy of optical, pharmacological and environmental interventions for slowing myopia progression in children using network meta-analysis (NMA). To generate a relative ranking of myopia control interventions according to their efficacy. To produce a brief economic commentary, summarising the economic evaluations assessing myopia control interventions in children. To maintain the currency of the evidence using a living systematic review approach. 

Methods: SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), MEDLINE; Embase; and three trials registers. The search date was 26 February 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of optical, pharmacological and environmental interventions for slowing myopia progression in children aged 18 years or younger. Critical outcomes were progression of myopia (defined as the difference in the change in spherical equivalent refraction (SER, dioptres (D)) and axial length (mm) in the intervention and control groups at one year or longer) and difference in the change in SER and axial length following cessation of treatment ('rebound'). DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. We assessed bias using RoB 2 for parallel RCTs. We rated the certainty of evidence using the GRADE approach for the outcomes: change in SER and axial length at one and two years. Most comparisons were with inactive controls.

Results: We included 64 studies that randomised 11,617 children, aged 4 to 18 years. Studies were mostly conducted in China or other Asian countries (39 studies, 60.9%) and North America (13 studies, 20.3%). Fifty-seven studies (89%) compared myopia control interventions (multifocal spectacles, peripheral plus spectacles (PPSL), undercorrected single vision spectacles (SVLs), multifocal soft contact lenses (MFSCL), orthokeratology, rigid gas-permeable contact lenses (RGP); or pharmacological interventions (including high- (HDA), moderate- (MDA) and low-dose (LDA) atropine, pirenzipine or 7-methylxanthine) against an inactive control. Study duration was 12 to 36 months. The overall certainty of the evidence ranged from very low to moderate. Since the networks in the NMA were poorly connected, most estimates versus control were as, or more, imprecise than the corresponding direct estimates. Consequently, we mostly report estimates based on direct (pairwise) comparisons below. At one year, in 38 studies (6525 participants analysed), the median change in SER for controls was -0.65 D. The following interventions may reduce SER progression compared to controls: HDA (mean difference (MD) 0.90 D, 95% confidence interval (CI) 0.62 to 1.18), MDA (MD 0.65 D, 95% CI 0.27 to 1.03), LDA (MD 0.38 D, 95% CI 0.10 to 0.66), pirenzipine (MD 0.32 D, 95% CI 0.15 to 0.49), MFSCL (MD 0.26 D, 95% CI 0.17 to 0.35), PPSLs (MD 0.51 D, 95% CI 0.19 to 0.82), and multifocal spectacles (MD 0.14 D, 95% CI 0.08 to 0.21). By contrast, there was little or no evidence that RGP (MD 0.02 D, 95% CI -0.05 to 0.10), 7-methylxanthine (MD 0.07 D, 95% CI -0.09 to 0.24) or undercorrected SVLs (MD -0.15 D, 95% CI -0.29 to 0.00) reduce progression. At two years, in 26 studies (4949 participants), the median change in SER for controls was -1.02 D. The following interventions may reduce SER progression compared to controls: HDA (MD 1.26 D, 95% CI 1.17 to 1.36), MDA (MD 0.45 D, 95% CI 0.08 to 0.83), LDA (MD 0.24 D, 95% CI 0.17 to 0.31), pirenzipine (MD 0.41 D, 95% CI 0.13 to 0.69), MFSCL (MD 0.30 D, 95% CI 0.19 to 0.41), and multifocal spectacles (MD 0.19 D, 95% CI 0.08 to 0.30). PPSLs (MD 0.34 D, 95% CI -0.08 to 0.76) may also reduce progression, but the results were inconsistent. For RGP, one study found a benefit and another found no difference with control. We found no difference in SER change for undercorrected SVLs (MD 0.02 D, 95% CI -0.05 to 0.09). At one year, in 36 studies (6263 participants), the median change in axial length for controls was 0.31 mm. The following interventions may reduce axial elongation compared to controls: HDA (MD -0.33 mm, 95% CI -0.35 to 0.30), MDA (MD -0.28 mm, 95% CI -0.38 to -0.17), LDA (MD -0.13 mm, 95% CI -0.21 to -0.05), orthokeratology (MD -0.19 mm, 95% CI -0.23 to -0.15), MFSCL (MD -0.11 mm, 95% CI -0.13 to -0.09), pirenzipine (MD -0.10 mm, 95% CI -0.18 to -0.02), PPSLs (MD -0.13 mm, 95% CI -0.24 to -0.03), and multifocal spectacles (MD -0.06 mm, 95% CI -0.09 to -0.04). We found little or no evidence that RGP (MD 0.02 mm, 95% CI -0.05 to 0.10), 7-methylxanthine (MD 0.03 mm, 95% CI -0.10 to 0.03) or undercorrected SVLs (MD 0.05 mm, 95% CI -0.01 to 0.11) reduce axial length. At two years, in 21 studies (4169 participants), the median change in axial length for controls was 0.56 mm. The following interventions may reduce axial elongation compared to controls: HDA (MD -0.47mm, 95% CI -0.61 to -0.34), MDA (MD -0.33 mm, 95% CI -0.46 to -0.20), orthokeratology (MD -0.28 mm, (95% CI -0.38 to -0.19), LDA (MD -0.16 mm, 95% CI -0.20 to -0.12), MFSCL (MD -0.15 mm, 95% CI -0.19 to -0.12), and multifocal spectacles (MD -0.07 mm, 95% CI -0.12 to -0.03). PPSL may reduce progression (MD -0.20 mm, 95% CI -0.45 to 0.05) but results were inconsistent. We found little or no evidence that undercorrected SVLs (MD -0.01 mm, 95% CI -0.06 to 0.03) or RGP (MD 0.03 mm, 95% CI -0.05 to 0.12) reduce axial length. There was inconclusive evidence on whether treatment cessation increases myopia progression. Adverse events and treatment adherence were not consistently reported, and only one study reported quality of life. No studies reported environmental interventions reporting progression in children with myopia, and no economic evaluations assessed interventions for myopia control in children.

[Link to open acces paper]