Myopia control: Seeing beyond efficacy.

SIGNIFICANCE: The availability of a range of effective myopia control modalities enables the clinician to exercise judgment when discussing the treatment plan with the patient and their parents. This article outlines important considerations beyond efficacy.Clinically meaningful myopia control may be attained with some spectacle lenses, select soft contact lenses, some concentrations of atropine, and overnight orthokeratology. Given that satisfactory efficacy can be achieved with a range of modalities, other factors should be considered when deciding upon the best intervention for a given child. Four key factors-compliance, quality of vision, quality of life, and safety-are discussed in this review. Compliance directly impacts efficacy regardless of the modality and is the most important consideration, as it is influenced by quality of vision and comfort. Daily disposal myopia control contact lenses and overnight orthokeratology are generally associated with high compliance, provide better vision-related quality of life than spectacles, and carry a very low risk when used appropriately. A further benefit of overnight orthokeratology is the elimination of a need for optical correction during the day.

Juvenile-onset myopia-who to treat and how to evaluate success.

The risk of eye diseases such as myopic macular degeneration increases with the level of myopia, but there is no safe level of myopia and the burden of lower degrees of myopia remains considerable. Effective treatments are available that slow progression and thus limit the final degree of myopia. In this review, the rationale for slowing progression is summarized, and a case made for treating all myopic children. Measurement of refractive error and axial length is reviewed, stressing the precision of optical biometry, but also the need for cycloplegic autorefraction. The factors influencing progression are considered and the available tools for interpretation of progression rate are discussed. Finally, the need to set attainable treatment goals is emphasized.

The underestimated role of myopia in uncorrectable visual impairment in the United States.

We estimate the US prevalence of uncorrectable visual impairment in 2050 accounting for the changing distribution of both age and myopia. Age projections of the US population (from an estimated total of 379 million in 2050), were taken from the US census website. The distribution of myopia, by severity, was calculated from literature-derived prevalence estimates of 58.4% (≤ - 0.50 D, 2050 projection) and 33.1% (≤ - 1.00 D, 1999-2004 estimate) to provide predicted and conservative estimates, respectively. Uncorrectable visual impairment as a function of age and refractive error was modelled by multiple linear regression. Finally, the likely number of individuals in the US with visual impairment in 2050 was calculated. For a projected myopia prevalence of 58.4%, 222 million are projected to be myopic and 48 million will have high myopia (- 5 D or worse). The projected total number with uncorrectable visual impairment is 11.4 million of which 4.9 million cases (43%) of visual impairment will be directly attributed to increased risk of eye disease associated with myopia. For a projected myopia prevalence of 33.1%, 8.9 million are projected to have uncorrectable visual impairment of which 2.4 million cases (27%) will be directly attributed to myopia. It is predicted that between 27 and 43% of uncorrectable visual impairment in the US population in 2050 will be directly attributable to myopia. Failure to account for the increasing prevalence of myopia among the aging population leads to a substantial underestimate of the prevalence of visual impairment.

A Duration-Dependent Interaction Between High-Intensity Light and Unrestricted Vision in the Drive for Myopia Control.

Purpose: To evaluate the duration-dependent and synergetic impact of high-intensity light (HL) and unrestricted vision (UnV) on lens-induced myopia (LIM) development in chickens. Methods: Myopia was induced in one eye in chicks (10 groups, n = 126) from day 1 posthatching (D1) until day 8 (D8) using -10 diopter (D) lenses. Fellow eyes remained uncovered as controls. Nine groups were exposed daily to 2, 4, or 6 hours of HL (15,000 lux), UnV (removal of -10 D lens), or both (HL + UnV). One group served as the LIM group without any interventions. Ocular axial length (AL), refractive error, and choroidal thickness were measured on D1, D4, and D8. Outcome measures are expressed as interocular difference (IOD = experimental eye - control eye) ± SEM. Results: By D8, LIM increased AL (0.36 ± 0.04 mm), myopic refraction (-9.02 ± 0.37 D), and choroidal thinning (-90.27 ± 16.44 µm) in the LIM group (all, P < 0.001). Compared to the LIM group, exposure to 2, 4, or 6 hours of HL, UnV, or HL + UnV reduced myopic refraction in a duration-dependent manner, with UnV being more effective than HL (P < 0.05). Only 6 hours of HL + UnV (not 2 or 4 hours) prevented LIM and was more effective than UnV (P = 0.004) or HL (P < 0.001) in reducing myopic refraction and more effective than HL (P < 0.001) in reducing axial elongation. Conclusions: Daily exposure to 2, 4, or 6 hours of HL, UnV, or HL + UnV reduced lens-induced myopic refraction in a duration-dependent manner in chickens. Only 6 hours of HL + UnV completely stopped LIM development. The synergetic effect of HL and UnV is dependent on the duration of the interventions.

Applications of Genomics and Transcriptomics in Precision Medicine for Myopia Control or Prevention.

Myopia is a globally emerging concern accompanied by multiple medical and socio-economic burdens with no well-established causal treatment to control thus far. The study of the genomics and transcriptomics of myopia treatment is crucial to delineate disease pathways and provide valuable insights for the design of precise and effective therapeutics. A strong understanding of altered biochemical pathways and underlying pathogenesis leading to myopia may facilitate early diagnosis and treatment of myopia, ultimately leading to the development of more effective preventive and therapeutic measures. In this review, we summarize current data about the genomics and transcriptomics of myopia in human and animal models. We also discuss the potential applicability of these findings to precision medicine for myopia treatment.

The future of clinical trials of myopia control.

In the field of myopia control, effective optical or pharmaceutical therapies are now available to patients in many markets. This creates challenges for the conduct of placebo-controlled, randomised clinical trials, including ethics, recruitment, retention, selective loss of faster progressors and non-protocol treatments: Ethics: It is valid to question whether withholding treatment in control subjects is ethical. Recruitment: Availability of treatments is making recruitment into clinical trials more difficult. Retention: If masking is not possible, parents may immediately withdraw their child if randomised to no treatment. Selective loss: Withdrawal of fast progressors in the control group leading to a control group biased towards low progression. Non-protocol treatment: Parents may access other myopia treatments in addition to those within the trial. We propose that future trials may adopt one of the following designs: Non-inferiority trials using an approved drug or device as the control. The choice will depend on whether a regulatory agency has approved the drug or device. Short conventional efficacy trials where data are subsequently entered into a model created from previous clinical trials, which allows robust prediction of long-term treatment efficacy from the initial efficacy. Virtual control group trials based on data relating to axial elongation, myopia progression or both, accounting for subject's age and race. Short-term control data from a cohort, for example, 1 year or less, and applying an appropriate, proportional annual reduction in axial elongation to that population and extrapolating to subsequent years. Time-to-treatment-failure trials using survival analysis; once a treated or control subject progresses or elongates by a given amount, they exit the study and can be offered treatment. In summary, the future development of new treatments in myopia control will be hampered if significant changes are not made to the design of clinical trials in this area.

Myopia: An ounce of prevention is worth a pound of cure.

PURPOSE: Myopia severity has a profound impact on visual impairment in later life. A patient's final level of myopia may be lowered by myopia control, but also by delaying onset. Here, we evaluate the influence of the age of onset on the final recorded level of myopia. METHODS: Data were extracted from: (1) Three prospective cohort studies of myopia progression in East Asia and the United States where the final recorded level of myopia is presented as a function of the established age of onset. (2) Four retrospective studies of myopia progression in Finland, India, the Netherlands and China and two cross-sectional studies in Argentina and the UK where the age of onset was based on self-report of age at first spectacle prescription. (3) A cohort study of Finnish subjects originally recruited for a clinical trial and followed into adulthood. Subjects were divided into five groups according to age at recruitment that was used as a surrogate for the age of onset. RESULTS: Final recorded level of myopia was plotted as a function of age of onset for all studies. Among the three East Asian studies, the slopes are between 0.68 and 0.97 D/year, meaning that each later year of onset is associated with between 0.68 and 0.97 less myopia at the final recorded refraction. For six of the seven non-East Asian studies, the slopes are substantially flatter, with slopes between 0.23 and 0.50 D/year. By contrast, the slope for the Finnish study was 0.87 D/year. Increasing age of final recorded refraction tended to be associated with higher levels of myopia. CONCLUSION: Among East Asians, delaying the onset of myopia by 1 year has the potential to lower the final myopia level by 0.75 D or more-equivalent to 2-3 years of myopia control with existing modalities. The benefit is lower, but meaningful, among non-East Asians.

Randomized Trial of Soft Contact Lenses with Novel Ring Focus for Controlling Myopia Progression.

Purpose: To evaluate efficacy and vision with 2 prototype myopia control soft contact lenses with noncoaxial ring-focus designs (for enhancing efficacy [EE] and enhancing vision [EV]) compared with dual-focus (DF) and single-vision (SV) designs. Design: Multicenter, 6-month, randomized, controlled, double-masked clinical trial. Participants: One hundred ninety-nine myopic (-0.75 diopters [D] to -4.50 D) children aged 7 to 12 years. Methods: Participants were randomized with stratification into myopia control (EE, EV, or DF) or SV arms at 9 clinical sites in 3 countries. Postcycloplegia axial length (AL) and spherical equivalent autorefraction (SECAR) were measured at baseline and 26 weeks. Axial length was also measured without cycloplegia at baseline, 1, 4, 13, and 26 weeks. Progression was analyzed using linear mixed models by intention-to-treat population. Visual acuity (VA) and vision quality were monitored. Main Outcome Measures: Axial elongation, change in SECAR. Results: A total of 185 subjects completed the study (n = 44, 49, 45, and 47 for EE, EV, DF, and SV, respectively). There were no serious/significant ocular adverse events. After 26 weeks, EE, EV, and DF all had statistically significantly less axial elongation than SV (unadjusted mean [standard deviation]: EE, 0.079 [0.125]; EV, 0.119 [0.101]; DF, 0.135 [0.117]; SV; 0.189 [0.121] mm). The estimated least-square mean (LSM) differences (adjusted 95% confidence interval) compared with SV were -0.105 (-0.149, -0.062), -0.063 (-0.106, -0.020), and -0.056 (-0.100, -0.013) mm for EE, EV, and DF, respectively. Enhancing efficacy alone had statistically significantly less progression of SECAR than SV (EE: -0.12 [0.27] D vs. SV: -0.35 [0.33] D; LSM difference: 0.22 D [0.09, 0.35]). Enhancing efficacy also had statistically significantly less axial elongation than DF (-0.049 mm [-0.093, -0.004]). Changes in AL and SECAR of EV and DF were not statistically different. All 3 myopia control lenses had mean VA close to 0.00 logarithm of the minimum angle of resolution (logMAR) with estimated 95% upper confidence limits <0.10 logMAR. Enhancing efficacy and DF produced similar reports of halos but more than EV and SV. Conclusions: The prototype contact lenses met the design intent; EE was more efficacious in slowing axial elongation than DF with comparable vision performance, whereas EV produced comparable efficacy to DF with similar vision performance to SV.

Choroidal Thickness in Early Postnatal Guinea Pigs Predicts Subsequent Naturally Occurring and Form-Deprivation Myopia.

Purpose: To identify choroidal characteristics associated with susceptibility to development of naturally occurring and experimentally induced myopia. Methods: We compared choroidal properties between pigmented and albino guinea pig (GP) strains. Biometry, cycloplegic refractive error (RE), and eye wall sublayer thickness were measured from 171 GPs at postnatal day (P)6, 14, and 28. Forty-three P14 GPs underwent two-week monocular form-deprivation myopia (FDM). En face images of choroidal vasculature were obtained with a customized swept-source optical coherence tomography. Multivariate regression analyses were performed, with P28 RE as the outcome and P14 choroidal thickness (ChT) as the main predictor variable. Proteomic analysis was performed on choroidal tissue from P14 albino and pigmented GPs. Results: At P14, RE was correlated with thickness of the choroid (ß = 0.06), sclera (ß = 0.12), and retina (ß = 0.27; all P < 0.001). P14 ChT was correlated with P28 RE both with (ß = 0.06, P = 0.0007) and without FDM (ß = 0.05, P = 0.008). Multivariate regression analysis, taking into account FDM (versus physiological growth) and strain, revealed that for every 10-µm greater ChT at P14, P28 RE was 0.50D more positive (P = 0.005, n = 70). En face images of choroidal sublayers showed that albino choroids were relatively underdeveloped, with frequent avascular regions. Consistent with this finding, proteomic analysis suggested abnormalities of the nitric oxide system in the albino GP choroid. Conclusions: Current results are consistent with the notion that greater ChT could protect from or delay the onset of myopia, while lower ChT is associated with greater susceptibility to myopia development. The underlying mechanism could be related to dysfunction of the choroidal vascular system.

The Limited Value of Prior Change in Predicting Future Progression of Juvenile-onset Myopia.

SIGNIFICANCE: Identifying children at highest risk for rapid myopia progression and/or rapid axial elongation could help prioritize who should receive clinical treatment or be enrolled in randomized clinical trials. Our models suggest that these goals are difficult to accomplish. PURPOSE: This study aimed to develop models predicting future refractive error and axial length using children's baseline data and history of myopia progression and axial elongation. METHODS: Models predicting refractive error and axial length were created using randomly assigned training and test data sets from 916 myopic participants in the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error Study. Subjects were 7 to 14 years of age at study entry with three consecutive annual visits that included cycloplegic A-scan ultrasound and autorefraction. The effect of adding prior change in axial length and refractive error was evaluated for each model. RESULTS: Age, ethnicity, and greater myopia were significant predictors of future refractive error and axial length, whereas prior progression or elongation, near work, time outdoors, and parental myopia were not. The 95% limits for the difference between actual and predicted change were ±0.22 D and ±0.14 mm without prior change data compared with ±0.26 D and ±0.16 mm with prior change data. Sensitivity and specificity for identifying fast progressors were between 60.8 and 63.2%, respectively, when the cut points were close to the sample average. Positive predictive value and sample yield were even lower when the cut points were more extreme. CONCLUSIONS: Young, more myopic Asian American children in the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error Study were the most likely to progress rapidly. Clinical trials should expect average progression rates that reflect sample demographics and may have difficulty recruiting generalizable samples that progress faster than that average. Knowing progression or elongation history does not seem to help the clinical decision regarding initiating myopia control.

Efficacy in myopia control.

There is rapidly expanding interest in interventions to slow myopia progression in children and teenagers, with the intent of reducing risk of myopia-associated complications later in life. Despite many publications dedicated to the topic, little attention has been devoted to understanding 'efficacy' in myopia control and its application. Treatment effect has been expressed in multiple ways, making comparison between therapies and prognosis for an individual patient difficult. Available efficacy data are generally limited to two to three years making long-term treatment effect uncertain. From an evidence-based perspective, efficacy projection should be conservative and not extend beyond that which has been empirically established. Using this principle, review of the literature, data from our own clinical studies, assessment of demonstrated myopia control treatments and allowance for the limitations and context of available data, we arrive at the following important interpretations: (i) axial elongation is the preferred endpoint for assessing myopic progression; (ii) there is insufficient evidence to suggest that faster progressors, or younger myopes, derive greater benefit from treatment; (iii) the initial rate of reduction of axial elongation by myopia control treatments is not sustained; (iv) consequently, using percentage reduction in progression as an index to describe treatment effect can be very misleading and (v) cumulative absolute reduction in axial elongation (CARE) emerges as a preferred efficacy metric; (vi) maximum CARE that has been measured for existing myopia control treatments is 0.44 mm (which equates to about 1 D); (vii) there is no apparent superior method of treatment, although commonly prescribed therapies such as 0.01% atropine and progressive addition spectacles lenses have not consistently provided clinically important effects; (viii) while different treatments have shown divergent efficacy in the first year, they have shown only small differences after this; (ix) rebound should be assumed until proven otherwise; (x) an illusion of inflated efficacy is created by measurement error in refraction, sample bias in only treating 'measured' fast progressors and regression to the mean; (xi) decision to treat should be based on age of onset (or refraction at a given age), not past progression; (xii) the decreased risk of complications later in life provided by even modest reductions in progression suggest treatment is advised for all young myopes and, because of limitations of available interventions, should be aggressive.

Thirty years of 'quiet eye' with etafilcon A contact lenses.

Frequent replacement contact lenses made from the etafilcon A hydrogel lens material were introduced onto the market over 30 years ago, and etafilcon A remains the most widely used hydrogel lens material today. Although the prescribing of silicone hydrogel lenses is increasing, millions of lens wearers globally have been wearing hydrogel lenses for many years and exhibit a physiologically-stable 'quiet eye', with a low profile of adverse events. Hydrogel lenses are demonstrated to maintain a low inflammatory response and infection risk profile during daily wear, which in the case of etafilcon A, may be related to its low modulus, and the naturally-protective, anti-microbial, non-denatured lysozyme absorbed into the lens from the tear fluid. Although improved corneal physiology from decreased hypoxia with silicone hydrogel lenses is well accepted, equivalent levels of corneal oxygenation are maintained during daily wear of low to medium powered hydrogel lenses, which do not impede the daily corneal de-swelling process, and do not induce clinically significant changes in ocular health. Therefore, hydrogel lenses remain an important alternative for daily wear in modern contact lens practice.

Safety of soft contact lenses in children: retrospective review of six randomized controlled trials of myopia control.

PURPOSE: To examine the rate and types of ocular adverse events among children wearing soft contact lenses. METHODS: This study is a retrospective review of ocular adverse event data from six randomized controlled trials among a total of 581 myopic children (aged 7-15 years at baseline) administered daily disposable hydrogel contact lenses (etafilcon A). RESULTS: During 816 patient years of contact lens wear, no significant or serious ocular adverse events were reported. A total of 86 non-significant ocular adverse events occurred in 53 children. The crude rate of ocular adverse events was 10.6 per 100 patient years with the estimated pooled incidence being 8.9 per 100 patient years (95% CI: 4.5-17.4). Two asymptomatic corneal infiltrative events were reported (both non-significant), which is an incidence of 0.3 (95% CI: 0.1-0.9) per 100 patient years. The most common ocular adverse events (n) were slit-lamp findings of Grade 2 or less requiring treatment (26), unspecified conjunctivitis (14), and allergic conjunctivitis (13). No cases of microbial keratitis were observed. Of the 86 adverse events, 37 were classified as highly likely or possibly lens-related, giving a crude incidence of 4.5 per 100 patient years for contact lens-related events. The crude incidence of ocular adverse events among spectacle wearers was 1.8 per 100 patient years. CONCLUSION: These data suggest that daily disposable soft contact lenses can be safely worn by children. Additional studies will be needed to precisely quantify the adverse event rate of soft contact lenses in normal clinical practice.

Commonly Held Beliefs About Myopia That Lack a Robust Evidence Base.

PURPOSE: To subject a number of commonly held beliefs or areas of confusion in the myopia field to scientific scrutiny. METHOD: A collection of statements about myopia are provided with references to demonstrate that a section of the research or clinical community supports the statement. The topics under discussion are reviewed critically with reference to the literature. RESULTS: The following statements are considered to lack sufficient supporting data to be considered as evidence-based: low-dose (0.01%) atropine slows myopia progression; relative peripheral hyperopia leads to myopia development and progression in children; undercorrection slows myopia progression; percentage treatment effect remains constant with continuing treatment; percentage treatment effect applies across the progression range; hand-held digital devices contribute to the myopia epidemic; more time outdoors slows myopia progression; the impact of outdoor activity on myopia incidence is due to daylight; subclassifications for myopia are effective; and myopia is a condition with a negative dioptric number. CONCLUSION: There are many hypotheses proposed to explain phenomena in the myopia field. Caution should be exercised in adopting conjecture until a robust evidence base is provided in support.

Myopia Control: Why Each Diopter Matters.

SIGNIFICANCE: Reducing the incidence or prevalence of any disease by 40% is of huge public health significance. Slowing myopia by 1 diopter may do just that for myopic maculopathy-the most common and serious sight-threatening complication of myopia. There is a growing interest in slowing the progression of myopia due to its increasing prevalence around the world, the sight-threatening consequences of higher levels of myopia, and the growing evidence-based literature supporting a variety of therapies for its control. We apply data from five large population-based studies of the prevalence of myopic maculopathy on 21,000 patients. We show that a 1-diopter increase in myopia is associated with a 67% increase in the prevalence of myopic maculopathy. Restated, slowing myopia by 1 diopter should reduce the likelihood of a patient developing myopic maculopathy by 40%. Furthermore, this treatment benefit accrues regardless of the level of myopia. Thus, while the overall risk of myopic maculopathy is higher in a -6-diopter myope than in a -3-diopter myope, slowing their myopic progression by 1 diopter during childhood should lower the risk by 40% in both.