Optometry & Vision Science:
Hereditary and Environmental Contributions to Emmetropization and Myopia
Mutti, Donald O.*
*OD, PhD, FAAO
The Ohio State University College of Optometry, Columbus, Ohio.
Received October 14, 2009; accepted October 20, 2009.
Twenty years of investigation into emmetropization and the development of myopia has led to several recent insights. Accommodation appears to be an important visual signal for emmetropization. Lens thinning during emmetropization and its cessation at the onset of myopia suggest that interruption of lens stretch during growth is an important part of the process of developing myopia. The ciliary muscle may play a greater role in emmetropization and myopia than previously thought. Time spent outdoors, not near work, may be the more important environmental variable in myopia. The effect of time outdoors shows an important interaction with a substantial genetic contribution to the risk of myopia.
My research is focused on understanding the basic processes behind emmetropization and the development of myopia. The tools used in these studies typically involve specialized clinical examination of human subjects combined with long-standing techniques of risk research rooted in the fields of statistics and public health. I had the great fortune to begin my career when patient-based approaches were needed to fill in gaps in knowledge with respect to refractive error. There were no longitudinal studies of emmetropization in human infants, let alone with complete biometric data. Myopia had been studied for a century or more, however, the literature had major gaps. Technological limitations prevented measurement of all the major optical ocular components in the living eye. Risk factors such as near work, outdoor activity, school achievement, and the number of myopic parents had not been assessed in the same sample to find the unique contribution of each factor. The longitudinal studies needed to assess risk factors for myopia onset all had large losses to follow-up. My colleagues and I attempted to fill in these gaps by measuring all the relevant ocular components on a large sample of children, measuring the relevant environmental variables, assessing parental history of refractive error, school achievement, and then following up these children over time, hopefully without large losses to follow-up.
The rules of clinical research are deceptively simple: make valid measurements, maximize generalizability, and minimize bias. Anticipate the 100 ways that your data might mislead you and then figure out how to avoid these pitfalls. Get it right the first time, because you won't get a second chance. “Whatever you do, avoid clinical research at all costs.” This was the advice given to Karla Zadnik and myself at one of our early Association for Research in Vision and Ophthalmology meetings by a recently minted PhD beginning a career in bench science. The “what have we gotten ourselves into” looks Karla and I exchanged at that moment were motivated by our 1989 commitment to begin a clinical research project with Tony Adams that has taken us on what is now a 20-year journey. Karla was fond of the quote from Donders regarding von Jaeger's “… intention of following the course of the refraction in the same persons through their whole life. We wish him for that purpose a long life and faithful patients.”1 Our aim was a little lower than a lifetime at a mere 8 years per child. The following is a perspective on what I believe we have learned about refractive error development from our patient-based research. Ironically, bench science will play a large role by the end of the story, but much of what we have learned could only come from long-term measurements on free-ranging human subjects.
* How do the ocular optical components develop during childhood?
* What are the risk factors for myopia?
* Why does an individual eye become myopic?
* Why is emmetropization so successful in infancy when the eye is growing longer at about 10 times the rate of a school-age child and myopia so common in childhood when axial growth is relatively slow?
These few, seemingly simple questions have been the basis of my research into refractive error development. When I received the Borish Award in 1996, Karla, Tony, and I had worked out our measurement protocol,2 determined repeatability,3 and reported cross-sectional findings for all the major optical ocular components using data from our Orinda Longitudinal Study of Myopia.4 We concentrated on ocular components because of a realization early in our careers that nobody had the technology to measure everything, something was always left out. Stenstrom5 had axial length data but no measured lens thickness or radii. Sorsby et al.6 measured the crystalline lens through phakometry but did not have lens thickness data or direct measure of axial length. Larsen7 had data on axial length and lens thickness but not on lens radii. Larsen's data on lens thickness had the greatest impact on my research. Larsen noted that the crystalline lens thinned in infancy at a time when the lens was growing, adding layers, and increasing in wet weight.7,8 Data from the Berkeley Infant Biometry Study have repeated this observation.9 Extending the observations into childhood, we have shown that the crystalline lens thins from infancy all through the early school years.10 “Eyes grow, lenses thin” summed up where we were in 1996.
How can such contradictory findings be reconciled, that the lens can thicken by adding layers of tissue yet thin at the same time? The answer was suggested by van Alphen's11 stretch factor, relating lower lens power and deeper anterior chamber depths to larger eyes. Although unmeasured, lenses thinned in the cartoon depiction of van Alphen's stretch factor.11 The importance of lens thinning is that it signifies a process that maintains emmetropia, whereas the interruption of that process is what we strongly suspect leads to myopia. When the crystalline lens is mechanically stretched in the equatorial plane, it will flatten, thin, and lose power.12,13 This physical connection between eye and lens seems a simple yet elegant way to maintain the balance between focal length and physical length required for maintaining emmetropia in a growing eye. During growth, the eye expands in all dimensions, with the equatorial growth presumably supplying this stretching and thinning. Why should thinning of lens matter? Consider the consequences of the failure of the crystalline lens to stretch. First, there would be no dioptric compensation for the continued axial elongation of the eye. Second, there would actually be an acceleration of axial elongation as spherical expansion became more prolate expansion. The prediction was about a threefold increase in the rate of axial elongation if the eye grew as an ellipse rather than as a sphere.14 Finally, the eye should become more prolate or less oblate in shape.
Our view is that myopia is the optical consequence of no crystalline lens compensation and faster axial growth because of interruption of the equatorial stretch that has been in place since infancy. The analyses of axial length, peripheral refraction, and crystalline lens results comparing children who become myopic with children who remain emmetropic were in good agreement with the predictions above. The onset of myopia is characterized by a cessation of lens thinning and an absence of the power loss needed to keep up with the growing eye (Fig. 115). There is an increase in the rate of axial elongation to a level precisely three times faster than that of emmetropic children in the year preceding and following myopia onset, in agreement with the threefold prediction above.16 Peripheral refraction becomes relatively more hyperopic, suggesting a distorted, less oblate ocular shape.16 What might be the source of the interruption of equatorial expansion? Recent results indicate that the ciliary muscle is thickened in myopes, whether in adults or in children.17,18 It is possible that this thickened muscle has altered mechanical properties that restrict equatorial expansion needed to maintain emmetropia. Fig. 2 illustrates the hypothetical consequences of an enlarged ciliary muscle on crystalline lens changes, ocular shape, axial elongation, and ultimately myopia.
Equatorial stretch during ocular growth can maintain emmetropia by producing balance between the crystalline lens and ocular expansion. How then is the eye ever supposed to make tuned headway against early infant hyperopia during emmetropization? The answer to this question requires the determination of the correct visual signal for emmetropization. Numerous animal studies suggest that hyperopic defocus will stimulate an increase in the rate of growth that will reduce the underlying hyperopia. When the hyperopic defocus is gone, the extra stimulus to eye growth will dissipate. We tested this hypothesis on 262 babies participating in the Berkeley Infant Biometry Study.19 The exposure to defocus was assessed by dynamic and Mohindra retinoscopy. Cycloplegic retinoscopy indicated that emmetropization occurred for the majority of infants with a strong linear relationship between their initial hyperopia and their reduction in hyperopia over a 6-month period, aged between 3 and 9 months. The surprising finding was that infants who emmetropized showed a good accommodative response, suggesting that they were not exposed to a graded level of defocus. More importantly, infants who showed the least robust emmetropization showed the poorest accommodative response and were exposed to the highest levels of hyperopic defocus. Our current thinking is that the visual signal for emmetropization is the degree of the accommodative response rather than hyperopic defocus. This hypothesis is, of course, at odds with the numerous animal studies suggesting that hyperopic defocus is the visual signal for infant emmetropization.20–26 Future work will hopefully be aimed at reconciling these two ideas. Is accommodation a credible visual signal; how might accommodation influence the growth of the eye? One possibility is that accommodation may influence the ciliary muscle of the growing eye such that eye shape may become less oblate, longer, and less axially hyperopic. The ciliary muscle and its influence on the eye may, therefore, be very relevant to both myopia development and emmetropization. Little is known about ciliary muscle development to date. This hypothesis is highly speculative at this stage but should be a testable one in animal and human emmetropization studies.
A great deal of progress has been made in the last several years in identifying risk factors associated with the onset of myopia. The precise utility of these factors has not yet been established, i.e., we cannot yet say how accurate a clinician might be at placing a probability for myopia onset on every nonmyopic grade-school child. However, being able to make such predictions would be tremendously valuable if an effective myopia preventive treatment were to become available. The most significant recent development, and perhaps biggest surprise, is the growing consensus that time spent outdoors appears to be protective against the onset of myopia.27 Most cross-sectional studies agree that existing, prevalent myopes spend less time outdoors than nonmyopes.28–30 This cross-sectional finding could be an effect of myopia rather than a cause. More importantly, our Orinda longitudinal data indicate that this difference precedes the onset of myopia and may represent a true protective effect of time outdoors. The effect can be quite powerful, reducing the probability of myopia by the eighth grade, if a child has two myopic parents, from 0.60 if outdoor time in the third grade is low (0 to 5 h per week) to 0.20 if outdoor time is high (>14 h per week).27 Before parents start sending their nonmyopic children outdoors to avoid wearing glasses but increasing their risk of skin cancer, studies need to be performed to understand the mechanism behind this effect. Recent theories include more time spent in distance fixation, suggested by animal studies, and light-induced changes in retinal dopamine levels.31 Surprisingly, this effect of time outdoors is not backhanded evidence for near work. Several studies have looked, but none has ever seen evidence that children spend less time outdoors because they are spending more time reading.27,29,30 Higher intelligence quotient (IQ) test scores also appear to be related to myopia.32 The reason for this association is unknown, but does not appear to be the influence of near work on IQ testing. With respect to environmental influences on myopia risk, near work has taken a back seat to outdoor activity as the most relevant variable.
Heredity appears to be another important risk factor. Myopic parents tend to have myopic children more often than nonmyopic parents. Our estimate of the odds ratio for myopia developing in a child given myopia in one parent was 2.05, increasing to 4.92 for two myopic parents.27 This finding joins a vast body of literature that shows a strong genetic component to refractive error. Heritabilities are often very high, on the order of 0.8 to nearly 1.0.33–36 In recent years, there has been an explosion of research using molecular genetics techniques. In 1998, there were three named loci for myopia, and each was associated with higher, pathological levels of myopia. Today there are at least 18 named loci, with many more sure to follow. Some have been associated with refractive error as a continuous trait across a spectrum rather than just pathological amounts. Several loci related to myopia have intriguing candidate genes attached to them related to collagen type-II,37 growth factors,38,39 mitochondrial function,40 and early ocular organization.40 However, the precise functional significance of any of these loci or candidate genes as they relate to myopia is unknown. Our research identified an association between variation in SNP rs1635529 at 12q13.11 (within the collagen, type II, alpha 1 gene) and myopia greater than −0.75 diopter.41 This finding was recently confirmed, but there is some disagreement about whether it pertains to more ordinary levels of myopia or is specific to pathological myopia.37 Regardless, most researchers would agree that myopia displays heterogeneity, i.e., a different set of genes may relate to lower levels compared with higher levels of myopia.
Twenty years seems a long time to address four simple questions. On the positive side, it seems fair to say that some progress has been made in answering them. Of course, controversies remain, and any decent answer will always raise more questions. One gratifying aspect of the journey is that some of these insights could only be gleaned from a long-term study of human subjects in patient-based research. Just as satisfying is the prospect that both basic science and patient-based approaches are needed to make further progress. Learning what the functional basis is for the protective effect of outdoor activity requires both. The correct mechanism may suggest behavior modifications or a pharmaceutical that captures the outdoor effect in a pill or drop. Discovery requires the bench, whereas proof requires the clinical trialist. Molecular genetics studies need the clinician for ascertainment, the bench for genotyping, and the statistician for analysis. Bench science can suggest the functional significance of a genetic variation, but clinical data are needed to establish a valid context. Variations in the complement factor H gene related to age-related macular degeneration (AMD) are a case in point.42 Patient-based research supplied cases and controls from the age-related eye disease study. The genotyping could not be accomplished without the tremendous strides made in molecular genetics. Bench science suggested that the complement cascade could be implicated in AMD pathology. The connection gained plausibility because of the presence of activated complement in patient drusen and the effects on complement levels from patient-based risk factors of age and smoking for AMD. That kind of synergy will be required for the equally large problem of myopia.
Dr. Irvin Borish has been an inspiration to me from the start of my education. Treasured desk pictures include one with him shaking my hand when I received my Borish Award plaque and another of me singing Happy Birthday to You for his 90th. I have a vivid memory of taking the shrink wrap off of Clinical Refraction and noting the dedication to his wife, “as small reparation for many thousands of hours forever irrestorable.” We will all dedicate many thousands of hours trying to accomplish something in our personal and professional lives. I feel the same today as at the time of the award. If at the end of our day the thousands of hours add up to a fraction of Dr. Borish's contributions, we can count ourselves as successful indeed.
The Ohio State University College of Optometry
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myopia; emmetropization; crystalline lens; ciliary muscle; genetics
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