Myopia Regulation: Myth or Megatrend?

Many methods purportedly slow the progression of myopia. But, do they really work?

By Jerome A. Legerton, O.D., M.S., M.B.A., and Brian Chou, O.D.

Goal Statement:

Efforts to better understand myopic genesis are escalating. By isolating the stimulus and response factors behind myopia, researchers are learning how to regulate myopic progression. A thorough discussion of the causal factors of myopia, as well as past, present and developing strategies for myopia regulation, will prepare practitioners to utilize successful strategies, clinical findings and new technologies and therapies when diagnosing and managing their myopic patients.

Faculty/Editorial Board:

Jerome A. Legerton, O.D., M.S., M.B.A., and Brian Chou, O.D.

Credit Statement:

COPE approval for 2 hours of CE credit is pending for this course. Check with your local state licensing board to see if this counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Dr. Legerton is a consultant to Paragon Vision Sciences and the founder of Synergeyes, Inc. Dr. Chou has no relationships to disclose.

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In 1990, the financial cost of myopia in the United States was estimated at $4.8 billion.¹ And, in addition to this societal burden, myopia carries an increased risk of associated pathology, including cataract, retinal degeneration, retinal holes and choroidal neovascularization.² Although it is just the seventh most frequent cause of legal blindness in the U.S., myopia has a significant public health impact because resultant vision loss tends to extend over a longer period of life.³ Patients with myopic retinopathy are legally blind for an average of 17 lifetime years, vs. five lifetime years of blindness due to diabetes or age-related maculopathy.⁴

Efforts to better understand myopic genesis are escalating. By isolating the stimulus and response factors behind myopia, researchers are beginning to understand how to regulate myopic progression. Given the significant worldwide prevalence of myopia, interest in regulating myopic development runs high.^5-7

What Causes Myopia to Develop?

The question of nature vs. nurture persists. Most researchers agree that environmental and genetic factors contribute to myopia, yet the specific factors involved, as well as their relative contributions, remain elusive.⁸ Environment and genetics may interact together to determine myopia.

One recent review of familial studies indicates a definite genetic basis for high myopia, and a strong genetic basis for low myopia.⁹ Also, twin studies provide compelling evidence that myopia is inherited.¹⁰

Meanwhile, the concept of environmental influence on myopia was bolstered by a 2008 study that found higher levels of outdoor activity are associated with a reduced prevalence of childhood myopia-even after adjusting for near work, parental myopia and ethnicity.¹¹ Perhaps outdoor light releases a retinal neurotransmitter that inhibits eye growth.

A leading model for myopic progression incorporates important roles by optical stimuli, neurotransmitters, and choroidal and scleral growth factors. Data show that hyperopic defocus in the retinal periphery, even in the absence of visual signals from the fovea, can stimulate myopic progression.¹²

Hyperopic peripheral defocus is also implicated as a stimulus for myopic progression, according to research in which central refraction was compared to peripheral refraction.¹³ This study found that hyperopic peripheral defocus is present in eyes of myopic children. In his discussion of aberrations and myopia, William N. Charman, Ph.D., concluded, “There is stronger evidence in favour of differences in patterns of peripheral refraction in both potential and existing myopes, with myopes tending to show relative hyperopia in the periphery. These differences appear to be related to a more prolate eyeball shape.”¹⁴

Peripheral hyperopic defocus appears to further increase with accommodation due to induced negative spherical aberration. One study found that spherical aberration decreased and became negative as the accommodative response increased in those patients under the age of 40.¹⁵

Peripheral hyperopic defocus may cause the release of neurotransmitters that in turn lead to the release of growth factors that elongate the eye. In examining the role of growth modulators in elongating the eye, study researchers concluded, “Changes in scleral glycosaminoglycan synthesis accompany lens-induced changes in the length of the eye. Furthermore, changes in the thickness of the choroid are also associated with changes in the synthesis of glycosaminoglycans. These results are consistent with the regulation of the growth of the eye being bidirectional, and with the retina being able to sense the sign of defocus.”¹⁶

Strategies to Regulate Myopia

Although regulating myopia is desirable, the development of viable treatment demands emphasis on both safety and efficacy because these treatments target children, before significant myopic progression takes place. For example, a study of 11,178 children in Taiwan demonstrated that a 12% myopic rate at age six jumped to 84% for the age range of 16 to 18 years.¹⁷ So, the regulation of myopia requires intervention in children as young as six years of age, and it may be effective in patients through the late teen years.

The established metric for determining effective myopia regulation is the axial length of the eye—or, more specifically, the change in vitreous chamber depth as measured by ultrasonography. Refractive stability alone is a poor indicator of successful myopia regulation, because temporary changes in cor-neal curvature or crystalline lens thickness can overshadow increased vitreous chamber depth. Unfortunately, early myopia research often did not measure vitreous chamber depth.

Researchers have evaluated several purported treatments for regulating myopia in children. These include spherical rigid and soft contact lenses, undercorrection of myopia, drug therapy, vision training and corneal reshaping. Thus far, the cumulative evidence has not supported any single intervention. Rather, it leans heavily toward the potential for optical intervention.

Spherical Contact Lenses

As early as 1956, anecdotal reports suggested that spherical, rigid contact lenses could slow myopic progression. Several study results investigating this theory were confounded by flaws, such as inadequate control of important variables, incomplete follow-up and poor selection of study participants.¹⁸

More recently, the National Eye Institute funded the Contact Lens and Myopia Progression (CLAMP) study, the results of which were published in 2004.¹⁹ CLAMP evaluated myopia progression over a three-year period in more than 100 eight- to 11-year-old patients. Rigid contact lens wearers experienced less myopic progression than soft lens wearers. However, the reduced progression appeared temporary and was not due to stabilization in vitreous chamber depth.¹⁹ The growth in axial length between rigid and soft lens wearers was similar.

Because CLAMP found that rigid lenses do not slow myopic eye growth, the study authors concluded that their findings “do not indicate that [rigid gas-permeable lenses] should be prescribed primarily for myopia control.” CLAMP results were corroborated by findings from a randomized clinical trial in Singapore, which also demonstrated that rigid lenses do not slow axial growth in myopia children.²⁰ A related study, the Adolescent and Child Health Initiative to Encourage Vision Empowerment study (ACHIEVE), investigated if wearing spherical soft contact lenses affected myopic progression in children.²¹ Children between the ages of eight and 11 with -1.00D to -6.00D myopia and less than 1.00D of astigmatism were randomly assigned to wear soft contact lenses (n = 247) or spectacles (n = 237) for three years. Researchers found an average rate of myopic change of 0.06D per year more for contact lens wearers than spectacle wearers. After three years, the adjusted difference between contact lens wearers and spectacle wearers was not statistically significant, and there was no difference between the two groups regarding change in axial length or steepest corneal curvature.

Study authors concluded, “These data provide reassurance to eye care practitioners concerned with the phenomenon of ‘myopic creep.’ Soft contact lens wear by children does not cause a clinically relevant increase in axial length, corneal curvature or myopia relative to spectacle lens wear.” But, while spherical soft lenses prescribed for distance correction do not cause nor inhibit myopic progression, they are frequently an excellent form of vision correction.

Undercorrection

For years, a handful of practitioners have advocated undercorrecting myopia in order to slow its progression. But, one study found no significant difference between groups that received full correction vs. undercorrection.²² Two recent studies even found that undercorrecting myopia actually increases myopic progression.^23,24

Despite the questionable value of undercorrection, a pilot study to evaluate Neural Vision Correction (NVC, NeuroVision) is underway.²⁵ NeuroVision has developed patient-specific computerized visual stimulation for the purpose of facilitating the neural connections responsible for vision. This NVC technology has received FDA 510(k) market clearance for the treatment of amblyopia in patients over the age of nine. The pilot study now seeks to evaluate the improvement of visual acuity in undercorrected children and to evaluate any reduction of myopia progression.

An alternate method of undercorrection involves prescribing bifocal or progressive addition spectacle lenses, reducing the accommodation required for near work and reducing the accommodative lag associated with a high accomodative convergen/ROExams/accomodation (AC/A) ratio or near point over-convergence.

The National Eye Institute funded a randomized clinical trial called the Correction of Myopia Evaluation Trial (COMET). This ongoing study has found that progressive addition lenses, compared to single vision lenses, slowed the progression of myopia in children by a small but statistically significant amount during the first year. But, the treatment effect did not significantly change over the next two years. The authors concluded that the “small magnitude of the effect does not warrant a change in clinical practice.”²⁶ In response to these COMET findings, the NEI released a statement that doctors should not routinely prescribe progressive eyeglasses for myopia control.²⁷

Despite undercorrection’s seeming inefficacy, another study reported the value of multifocal contact lenses for controlling myopia in patients with accommodative lag, high AC/A and near point esophoria. This study of identical twins documented the reduction in myopic progression in the twin wearing multifocal contact lenses vs. the twin wearing single-vision soft lenses.²⁸ Researchers suggest that this is caused by the control of accommodative lag, but it could also be due to peripheral myopic defocus similar to that provided by corneal reshaping for myopia.

Drug Therapy

Drug studies, including use of atropine, have concentrated on the role of accommodation in myopia progression. Perhaps the most convincing information was documented in the recent Atropine in the Treatment of Myopia (ATOM) study, which was the largest randomized controlled trial of its kind to date.²⁹ The ATOM study followed 400 eligible children between the ages of six and 12 for two years. After two years, in the placebo-treated eyes, the mean progression of myopia was -1.20±0.69D with axial elongation of 0.38±0.38mm. In the atropine-treated eyes, myopia progression was only -0.28±0.92D with an axial length essentially unchanged (-0.02±0.35mm).

Despite the efficacy of atropine in reducing childhood myopia progression, atropine therapy is not accepted as a standard treatment. Although no serious adverse events related to atropine were reported in the ATOM study, side effects include increased light sensitivity due to mydriasis and cycloplegia, which together can impair a child’s ability to perform well in school and athletics. The cosmetic issues of pupil dilation caused by atropine can be awkward for children during a critical period of social development, when they seek the acceptance of their peers. It is unknown whether the myopia control derived from atropine therapy is due to cycloplegia, increase in pupil-dependent aberrations, or other effects.

While atropine therapy is not appropriate for most children, ATOM results suggest that pharmaceutical management has potential. Indeed, other atropine-like drugs, including pirenzepine and cyclopentolate, are under investigation. One study found that 2% pirenzepine gel slowed childhood myopia progression by almost half after a year of treatment; however, 11% of subjects withdrew from the study due to adverse effects.^30,31 Further safety and efficacy data is expected. Currently, pirenzepine is not FDA approved or available in the U.S.

Other pharmacologic research has evaluated neurotransmission, as well as scleral and choroidal growth factors. One such study examined the effect of a nitric oxide synthase inhibitor, NG-nitro-Larginine methyl ester (L-NAME), on modulating choroidal thickness in conjunction with myopic defocus. Results showed that L-NAME inhibited choroidal thickening.³² Thus, nitric oxide may play a role in modulating choroidal thickness.

Another study examined the effect of 7-methylxanthine, a metabolite of caffeine, on the collagen fibrils in the sclera in rabbits.³³ Researchers found that 7-methylxanthine increased collagen density and the diameter of collagen fibrils in the posterior sclera, which may prevent axial myopia. This study’s sponsor, Trier Research Laboratories, has registered a Phase II trial for the oral administration of 400mg of 7-methylxanthine per day vs. placebo to a study population of children between the ages of eight and 13.

New technology that measures corneal hysteresis, a viscoeleastic property of the cornea thought to reflect its biomechanical integrity, may offer a method to evaluate efficacy of pharmacologic intervention in myopic progression and diagnosing eyes at risk for myopic progression.^34,35 In a study of corneal hysteresis measured with the Ocular Response Analyzer (Reichert Ophthalmic Instruments) high corneal viscoelasticity correlated with high scleral viscoelasticity.³⁶ Patients with high scleral viscoelasticity may have greater risk for myopic progression.

Vision Training

Vision training has also been investigated as a regulator of myopic progression. But to date, efforts to control accommodation have failed to alter progression.³⁷ Even so, there is evidence of the role of accommodative lag and its relationship to measured AC/A ratios in children who are developing myopia.

Donald O. Mutti, O.D., Ph.D., and colleagues concluded that, “An elevated AC/A ratio was associated with myopia and was an important risk factor for its rapid onset.”³⁸ In another recent study, Jane Gwiazda, Ph.D., and colleagues found that myopic children with esophoria under-accommodate at near and noted that, “This [finding] suggests that a child who is esophoric must relax accommodation to reduce accommodative convergence and maintain single binocular vision. The reduction in accommodation could produce blur during near work, which could induce myopia as in animal models.”³⁹

A related study examined the AC/A ratios before and at the onset of myopia in children and found that myopes, when compared to emmetropes, had elevated AC/A ratios at one to two years before the onset and at all times later.⁴⁰ “These findings suggest that the abnormal oculomotor factors found before the onset of myopia may contribute to myopigenesis by producing hyper-opic retinal defocus when a child is engaged in near-viewing tasks,” the researchers concluded.

Another study modeled AC/A and convergence accommodation/ convergence (CA/C) interactions and their influence on accommodative lag. “Adaptable tonic accommodation and tonic vergence could potentially reduce the progression of myopia by reducing the lag of accommodation, ” found researchers.⁴¹

Currently, the Cambridge Anti-Myopia Trial: Accommodation Training and Aberration Control in Myopia Development is investigating the role of contact lenses along with vision training in the regulation of myopic progression. Multifocal contact lenses worn in conjunction with vision training for modulating the AC/A ratio may hold promise.

Corneal Reshaping

The aforementioned treat-ments—spherical contact lenses, undercorrection, drug therapy and vision training—are not accepted as standard treatments for regulating myopia progression. However, significant interest exists in controlling progression with non-surgical cor-neal reshaping, or corneal refractive therapy (CRT), in which the patient wears special therapeutic lenses overnight.

In 2002, strong anecdotal evidence of myopia control came from investigators in the first FDA pre-market approval overnight corneal shaping study conducted by Paragon Vision Sciences, Inc. In the study, adolescent myopes were followed for 12 months. Investigators found that many subjects did not require changes in their lens parameters at the two and three year anniversaries from the initial fitting. This change would have been expected if the axial lengths of the eyes were increasing due to anticipated myopia progression.⁴²

Corneal reshaping is hypothesized to inhibit myopia progression by inducing peripheral retinal myopic defocus. Spherical aberration increases following CRT as a result of the oblate corneal shape induced by the central flattening in CRT.^43,44 Spherical aberration allows the central image to focus on the fovea, while the peripheral image field is focused in a significantly shorter focal distance.

Peripheral refractions out to 34º of eccentricity in four subjects undergoing corneal reshaping resulted in a central decrease in myopia with little change in their myopic peripheral refraction.⁴⁵ Researchers concluded that if converting peripheral hyperopia to peripheral myopia limits axial elongation, then corneal reshaping is an excellent option for the achievement of peripheral myopia.

The first controlled trial of cor-neal reshaping for myopia control was published in 2005: Longitudinal Orthokeratology Research in Children (LORIC).⁴⁶ The authors of the two-year pilot study concluded that corneal reshaping could both correct and control childhood myopia. They also noted that substantial variations exist in changes in axial length among children and that there is no way to predict the effect for individual subjects.

An additional two-year study, Corneal Reshaping and Yearly Observation of Myopia (CRAYON), was recently completed.⁴⁷ The results of CRAYON confirmed that cor-neal reshaping slowed eye growth in children at one and two years of treatment. The authors concluded, “Corneal reshaping contact lenses hold promise for myopia control. It has now been shown by two separate controlled trials to slow axial growth of the eye.”

Interim data from the Stabilization of Myopia via Accelerated Reshaping Technologies (SMART) study were reported at the Global Specialty Contact Lens Symposium in January 2009. This five-year study, funded by Bausch & Lomb, seeks to compare changes in vitreous chamber depth in a test group wearing lenses for myopic corneal reshaping against a control group wearing soft contact lenses. At one year, data demonstrated less progression in myopia in the test group; however, there was no significant difference in vitreous chamber depth growth between the test and control groups.⁴⁸

Other studies are underway to determine the optimum peripheral myopic defocus to make such treatment more predictable and consistent. Prototype instruments now exist that conduct a peripheral refraction in order to ameliorate the problem of the variance in equatorial diameter in eyes that have the same refractive error. In order to properly focus a peripheral field on or in front of the peripheral retina, one must know the peripheral refraction circumferentially. With these data, it is possible to design a contact lens that optimally defocuses the peripheral image field.

A ‘Farsighted’ Perspective on Nearsightedness

The prevalence of myopia, its impact on quality of life, and the related economic cost collectively underscore the value of preventing myopia. Corneal reshaping, multifocal contact lenses with a peripheral near add, and modulating accommodative convergence may each play a role in reducing myopic progression.

As more research comes forth, eye care professionals may find diagnostic instruments, such as peripheral refractors, A-scan ultrasonographers, wavefront aberrometers and scleral rigidity analyzers, valuable for assessing myopic progression and treatment efficacy. Further, pharmacologic treatment to control neurotransmission and choroidal and scleral growth may complement the armament for regulating myopia.

Accumulating evidence tells us that the regulation of myopia is plausible. The next few years may bring a critical mass in understanding myopic progression. Viable treatment will require a robust dioptric effect and intervention at the first sign of childhood myopia.

Dr. Legerton was in private practice in San Diego for 26 years, followed by 14 years in product development with Pilkington Barnes Hind, VISX, Paragon Vision Sciences and SynergEyes. He holds 20 patents for aberration-blocking contact lenses, presbyopic laser refractive surgery, corneal refractive therapy, hybrid contact lenses and myopia progression control.

Dr. Chou is an industry consultant and private practitioner in San Diego. He is a frequent contributor to eye care publications and is the co-developer of the online contact lens reference, www.EyeDock.com.

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