A conceptual model can be designed that takes the form of dual intersecting feedback loops in which genetically programmed ocular growth of each eye is altered by visually driven ocular growth. Visually driven ocular growth results from time-average retinal blur derived (primarily) from peripheral retinal image defocus and (to a lesser extent) from the accuracy of central image focus developed from interactions between accommodation and vergence (
Fig. 23.3).
2 The blur magnitude output of the accommodative system is input into the visual growth mechanism because focus of the peripheral (and to a lesser extent the central) retinal images, rather than accommodation, is hypothesized to alter genetically programmed ocular growth. In the visual growth mechanism, continued relative hyperopic blur (e.g., from the relative peripheral retinal defocus and the lag of accommodation at near) increases scleral elasticity and promotes axial elongation; lens growth is retarded by concurrent reduction in zonular tension. Decreased lens growth ultimately results in a relatively thinner, shorter radius, and weaker powered lens. The resulting reduction in lens thickness (with a decrease in power) and the
increased axial length (AL) decrease the accommodative demand associated with near visual tasks. The visual growth then feeds into and combines with the genetically programmed ocular growth to result in the final RS.
2
Two crosslinks are present. First, the potential influence of suppression on visually directed ocular growth (the response of the RS to, primarily peripheral, retinal blur) is indicated by the crosslink between the blur mechanisms. Second, pharmacologic (e.g., atropine) effects are shown by the crosslink between visual and genetically programmed growth. Atropinization blocks development of axial growth in the presence of lid-suture myopia.
2,14 This result seems contradictory, because atropine clearly paralyzes accommodation. However, chronic use of atropine produces alterations in the retinal vasculature of developing kittens.
2,15 Atropine also causes an increase in the number of ciliary zonules, along with a concurrent increase in the number of elastic-fiber myofibrils.
2,14 Thus, it is likely that it is not blockage of accommodation per se, but rather other consequences of atropine use that result in decreases in the axial growth rate and less/slower myopia progression.
GROWTH OF OCULAR COMPONENTS
The shift from the large variation in RS seen in infancy to the nearly emmetropic state normally found in adults has been attributed to coordinated growth of the ocular components. For example, Sorsby et al
2,17 developed the concept that decrease in the magnitude and standard deviation of the RS in the population involves correlated growth of four ocular components: AL, corneal power, crystalline lens power, and anterior chamber depth. In their view, a high correlation produces emmetropia, whereas failure of correlated growth produces ametropia. During the first year of life, there is lesser variability in the AL as infant eyes undergo rapid growth from an average of about 17 mm to slightly more than 19 mm,
2,18 whereas the corneal power decreases from 50 to 43 D.
2,19 Hofstetter
2,20 suggested that development of a leptokurtic distribution of the RS, often described as emmetropization,
2,21 was a mathematical artifact because a given eye can be emmetropic regardless of its size,
provided that growth occurs in a manner that allows proportionate increases of the radii of the cornea and axial dimensions. Unfortunately, the human eye does not grow in such a manner (see later), calling this suggestion into question.
2
From ages 1 to 8 years, AL continues to increase to the adult value of about 24 mm with little change in the RS.
2,22 This increased AL, which could result in up to 15 D of myopia, must be largely negated by flattening of the lens (and deepening of the anterior chamber), because corneal power reaches approximately the adult values prior to the age of 2 years. Flattening of the lens is part of lens growth, which reduces its power (as well as causing a decrease in lens diameter, thickness, and radii). Thus, it is difficult to totally attribute maintained emmetropia to correlated growth because only the axial dimensions of the eye and the power of the crystalline lens seem to be correlated in their changes during early childhood. Indeed, a substantial amount of basic (animal) research suggests that visual feedback contributes to the RS developed from infancy (see, e.g., Ni and Smith
2,23).
Variations from “normal” ocular development can be inferred from the clinical differences seen in the RS. For example, 2% to 5% of infants begin life with, and maintain, significant myopia or hyperopia.
2,17 These children suffer from substantially different ocular development than the up to 80% of children who become emmetropic only to subsequently become myopic during grade or middle school years. The infant with a high myopia or hyperopia typically has a very long or very short vitreous chamber, respectively—what Sorsby et al
2,17 considered to be an uncorrelated eye. Children who become myopic in grade school seldom acquire more than 6 to 8 D of myopia; these children also seem to differ substantially in ocular development from young adults who develop myopia of −1 to −3 D after 16 to 20 years of emmetropia (so-called
late-onset myopia).
2
Van Alphen
2,24 suggested that grade-school children may develop myopia when the cortico-subcortical control of tonus to the ciliary muscle is disrupted, either by ocular (cornea, optic nerve, or brain) or by non-ocular factors (extreme autonomic endowment, psychological factors, and stress). Adult-onset myopia seems to develop in association with substantial amounts of near work
2,25 and changes in certain underlying physiologic factors.
2,26 In any event, all classes of myopia typically share a common structural correlate, namely, increased AL when compared with emmetropic eyes.
2,27
For adults (by age 20), variations in lens power are unrelated to the RS (
Fig. 23.6A).
2,28,29,30,31,32,33 Anterior chamber depth and corneal curvature are linearly related to the RS (
Fig. 23.6B and C),
2 and variations in AL have a complex relation to the RS.
2,34 Figure 23.7 relates AL
2 to RS for adults aged 20 to 35 years, and indicates that for subjects who are nearly emmetropic (RS between +0.75 and −0.25), there can be substantial variation in AL. The slopes of the relation between the RS and AL are statistically different for subjects with RS between +1.75 and −1.75 (slope
B to
C) and those having 2 to 6 D hyperopia (slope
A to
B) or 2 to 7 D of myopia (slope
C to
D) (F = 10.91;
p = 0.0052). For patients with very high hyperopia (>6 D) or myopia (>7 D), it again appears that substantial variation in AL coexists with a similarly large RS, although there are not enough data for accurate statistical analysis.
2
Accepting the implications of Proposition I (i.e., The RS that ultimately develops is a result of genetically programmed ocular growth modified by visually driven ocular growth.), the large variation in AL with a near emmetropic RS would be due to a physiologic balance between visually driven and genetically programmed ocular growth. In this view, patients with a very high RS are probably born with an RS so large that visually driven ocular growth is unable to sufficiently influence genetically programmed growth, and they remain with the abnormal RS throughout life. Further, the similarity in the slope of the relation between AL and the RS for moderate hyperopia (2 to 6 D) and myopia (2 to 7 D) (
Fig. 23.7, slope
A to
B and slope
C to
D)
2 suggests that these forms of RS result from comparable breakdowns in ocular growth mechanisms. For example, normal strength genetically programmed ocular growth might be overwhelmed by visually driven growth, leading to moderate myopia. Conversely, if weak genetically programmed ocular growth is present, a concurrently weak visually driven growth might be insufficient to allow achievement of emmetropia, resulting instead in hyperopia.
† The slopes of the relation between AL and RS in moderate hyperopia and myopia (
Fig. 23.7, slope
C to
D and slope
A to
B)
2 are not statistically different (F = 0.62;
p = 0.44), lending additional support to the idea of a mismatch in visually driven growth and genetically programmed ocular growth contributing to these RSs. Two other possibilities may contribute to development of moderate myopia
2,35:
GENETICALLY PROGRAMMED OCULAR GROWTH
Genetically programmed (nonvisual) ocular growth accounts for the clinical finding that 2% to 5% of infants begin life with, and maintain, significant refractive error; their eyes obviously grow in size during the first years of life but fail to emmetropize. In addition, substantial genetically programmed ocular growth occurs for human eyes at two different times of life—infancy, where there is rapid growth that brings the anterior segment of the eye up to almost adult size and functional power by age 3 years
2,36; and childhood, where there is slower definitive growth between ages 3 to 14 years during which time the RS for the most part remains stable and change in power derived through axial elongation is mainly negated by flattening of the crystalline lens and deepening of the anterior chamber.
2,37 This latter growth may also have hereditary influences, explaining why myopia tends to “run in families”
38 and often manifests at similar ages from generation to generation.
2,38,39,40
Relative Strength of Genetically Programmed Ocular Growth: Axial Length to Corneal Radius Ratio
The concept of genetically programmed ocular growth might allow prediction of who will become myopic, at what age myopia might occur, and how much myopia might result, if an estimation of the relative strength of genetically programmed ocular growth could be developed. The AL (mm) to corneal radius (mm) (AL/CR) ratio is usually very close to 3.0:1 (e.g., AL = 22.5 mm, CR = 7.5 mm [or 45.00 K] gives AL/CR ratio of 22.5/7.5 = 3.0/1). There have been clinical suggestions that when the ratio is higher than 3.0:1, emmetropic subjects are at risk for development of myopia.
2,41,42,43 The usefulness of the AL/CR ratio owes to the fact that relative timing of the growth of the components of the eye varies substantially. For example, based on data from York and Mandell,
2,19 the cornea reaches 95% of its adult curvature before age 2, and Larsen
2,36 found a similar result for the depth of the anterior chamber (
Fig. 23.8).
2 However, the lens (lens growth results in increased lens diameter, thickness, and radii and a decrease in power) and AL continue growth for a substantially longer time and are not within 95% of adult growth until ages 6 and 11 years, respectively (
Fig. 23.8).
2,36,44,45
Proposition I portrays the ultimate RS as a balance between genetically programmed and visually driven ocular growth. In the case of a person who might develop myopia, for example, corneal growth and changes in
anterior chamber depth typically cease at about age 2. If emmetropia is to be maintained, a continued increase in AL must be compensated for by a corresponding decrease in lens power (
Fig. 23.9A).
2 If axial growth continues, it will eventually reach a point at which the other ocular components can no longer compensate for the continued growth. Thus, the AL/CR ratio is of clinical predictive value because it provides an estimation of when the point has been reached beyond which further axial growth cannot be compensated by other ocular components (e.g., relative lenticular thinning, which is a result of lens growth, which increases lens diameter, thickness, and radii with a decrease in lens power;
Fig. 23.9A, arrow).
2
Considering the AL/CR ratio, Proposition II (i.e.,
Genetically programmed [nonvisual] ocular growth, which is typically the same in both eyes, decreases in rate with age and ceases at about age 14 to 16.) suggests that the strength of genetically programmed growth is indicated by values significantly higher or lower than 3.0.
2,46 Measurement of the AL and corneal radius could allow clinical RS predictions. For emmetropic children, a high AL/CR value (≥3.0) indicates that visually driven growth may be about to overwhelm genetically programmed growth and that myopia development is impending (
Fig. 23.9B, arrow).
2 For emmetropic adults, a high value indicates that the maximum AL that can sustain emmetropia has been achieved and that further visually directed axial growth will lead to (late-onset) myopia. Thus, clinical measurement of the AL and corneal radius might allow determination of whether and when to consider intervention to maintain a desired RS.
2
Heredity
An additional clue to a strong genetically programmed growth is the relation seen between parental myopia and the development of myopia in children.
2,47,48,49 Table 23.2 presents the odds of the incidence of childhood myopia based on the presence of myopia in the parents.
2,50 This apparent hereditary influence would suggest that the parents pass along a strong genetically programmed ocular growth tendency (although it could also be that they foster a “reading environment”), which in some cases may be circumvented by visually driven ocular growth, explaining why not all children of myopic parents develop myopia.
2
In infants, growth toward an emmetropic RS occurs rapidly, whereas (myopic) changes away from this normal (emmetropic) condition occur much more slowly during childhood or adulthood. Evidence from basic research suggests that a genetically programmed growth mechanism exists which assists in maintaining the RS.
2,51 According to Proposition I, visually directed ocular growth adds to genetically programmed ocular growth, resulting in rapid attainment of normal eye proportions in infants who emmetropize. If this is correct, for adults only the blur-driven (i.e., visual) mechanism would remain (because genetically programmed growth would be complete by about age 14 to 16), resulting in a more stable and less malleable RS. In this manner, visually driven ocular growth modifies genetically programmed ocular growth (as described next).
2
VISUALLY DRIVEN OCULAR GROWTH
Accepting Proposition III (i.e.,
Visually driven ocular growth, which results from the time-average retinal blur derived [primarily] through peripheral retinal image defocus along with [secondarily] central accommodative accuracy resulting from interactions between accommodation and convergence, decreases to its minimum magnitude by about age 21.), growth of each eye is stimulated by blur that is derived from visual stimuli (especially relative peripheral hyperopic retinal defocus). Small amounts of sustained peripheral retinal blur promote axial elongation (presumably by increasing scleral tension) and retard lens growth by reducing zonular tension.
2,52 Both the resulting axial elongation and the reduction in lens thickness, with corresponding decreased lens power through increased refractive index,
2,53 decrease the blur associated with a given visual task (reduced lag of accommodation). Based on the growth rate observed for ocular components (
Fig. 23.8),
2 most of the changes induced by visual growth affect the AL and lens power. To a lesser extent, anterior chamber depth and corneal shape may also be influenced, especially in infants and very young children.
2
Blur versus Accommodation
Proposition III suggests that sustained peripheral (and, to a lesser extent, central) retinal blur, and not accommodation, is the stimulus to ocular axial growth. This conclusion is supported by results of research on infant monkeys in which blurred peripheral images cause the infant eye to become either hyperopic or myopic, depending on the type of blur induced.
2,54,55 Accommodation might be hypothesized to be the stimulus for development of myopia when a minus lens is placed before an infant eye and there is a resulting increase in AL (a relative decrease in hyperopia or increase in myopia) concurrent with the stimulus to accommodation caused by the lens. However, accommodative change is less likely to be helpful in clearing a blurred image caused by a plus lens that artificially induces myopia and a hyperopic growth shift. In addition, eyes that have been rendered surgically aphakic ultimately develop shorter ALs and relative hyperopia
2,56 compared with fellow untreated (non-cataractous) eyes, hardly an accommodation-related change given the induced aphakic state. Further, stimulation of accommodation by parasympathomimetic agents (e.g., pilocarpine) during development does not facilitate development of lid-suture myopia.
2,57 Also, overcorrection of myopia in childhood does not appear to increase the rate of progression.
2,58 Finally, Zadnik
2,59 demonstrated that diopter-hours of near work do not significantly influence developing myopic RS. Taken together, these studies lend strong support to the hypothesis that sustained peripheral blur of the retinal images is the primary stimulus to visually driven emmetropization, rather than accommodation (or diopter-hours of near work, per se).
2
CLINICAL ASPECTS OF THE MODEL
Recall that Proposition I characterizes the RS that ultimately develops as resulting from genetically programmed ocular growth modified by visually driven ocular growth. It is likely that, rather than occurring separately, the two kinds of growth occur in tandem. Thus, a prescribed treatment will probably be more successful if the management provided addresses both genetically programmed and visually driven ocular growth.
Treatment Strategies Based on Altering Genetically Programmed Ocular Growth
The basic components of the visual connections between the eye and the brain are present at birth. However, the substance of these components can be dramatically modified based on environmental influences. For example, it is well known that decreased visual experience in one eye of an infant animal (e.g., monocular lid suture) results in diminished input to the cells in the visual cortex driven by that eye.
73 It is probable that a similar
mechanism exists for the RS; that is, the basic components of the refractive system are largely in place at birth, and genetically programmed ocular growth continues after birth but at a rate that is altered by visually driven ocular growth. During the first 12 months of life, the eye elongates and the cornea flattens—largely a mechanistic change. By about age 18 to 24 months, further changes in corneal curvature are virtually nonexistent,
19 and changes in lenticular structure must primarily compensate for subsequent increases in AL.
72
Although development of the final RS is likely to be polygressive in genetic nature, gene modification techniques may ultimately exist that can positively influence the rate of genetically programmed ocular growth. Such gene modification is currently unavailable; however, there are pharmacologic therapies and diet modifications that influence ocular growth. For example, many clinical studies suggest that daily use of 1% atropine drops substantially decreases the rate of myopia progression
74,75,76 and methylxanthines (e.g., Theobromine [3,7-dimethylxanthine] and 7-methylxanthine) have also been shown to lessen myopia progression.
77 Additionally, there are many studies which show that diet and supplement modifications might also decrease myopia progression. Pharmacologic treatments, which effectively decrease the ocular growth rate of myopic patients, are not appropriate for hyperopic patients where the treatment goal is to decrease the amount of hyperopia (by
increasing the ocular growth rate).