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.
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