Development and Management of Refractive Error: Binocular Vision-Based Treatment



Development and Management of Refractive Error: Binocular Vision-Based Treatment





There is substantial variation in the refractive state (RS) at birth1,2,*; yet, most people become nearly emmetropic, essentially needing no correction, by age 5.2,3 In the ensuing years 30% (to as many as 80%) become myopic at some point,4 and the majority of those who do not become myopic develop hyperopia during their presbyopic years. In addition to increased knowledge of the genetic profiles underlying RS development, knowledge of anomalous RS development and its subsequent treatment will likely be improved through understanding of:



  • The relationships between the ocular components that make up the RS and how changes in these components influence the ability to maintain a stable RS


  • The effects of unilateral and bilateral peripheral and central blur on the RS


  • How the interactions between vergence (both eyes) and accommodation (in each eye) influence changes in the RS2

In this chapter, we discuss development and maintenance of a stable RS using a conceptual model of emmetropization. We also present a management protocol for RS treatments that incorporates a binocular visionbased approach.2


Binocular Vision-Based Refractive Development

Early visually driven models of emmetropization considered accommodation to be an important aspect of emmetropization. However, these models failed to account for the fact that most objects are closer than infinity and therefore provide an effective stimulus for accommodation. If accommodation is so influential in development of the final RS, why doesn’t everyone become or remain myopic? It has become increasingly evident that significant factors in emmetropization include the influence of genetically programmed ocular growth on the RS, the role of peripheral retinal defocus on ocular growth, and the fact that neither the fovea nor the ability to accommodate accurately are well developed at birth.2


ACCOMMODATION AND THE SOURCE OF BLURRED IMAGES

Schor2,5 described the dual interactive model of accommodation and vergence portrayed in Figure 23.1.2 There are mutual interactions and feed-forward crosslinks between the accommodative and vergence motor control systems. The feed-forward crosslinks are accommodative convergence to accommodation (AC/A) and convergence accommodation to convergence (CA/C). Tonic vergence (vergence adaptation) occurs after the CA/C crosslink and feeds forward into the convergence system, because vergence adaptation does not affect dark focus.2,6 Vergence adaptation relieves the fusional vergence controller effort and reduces convergence accommodation, decreasing the exaggerated effects of sustained vergence on the AC/A ratio.2,7 These effects cause excessive accommodation-convergence interaction to be transient because they are relieved by vergence adaptation within 15 seconds.2,8 The knowledge of stimulus location (proximal input) increases vergence and accommodative responses. These effects occur prior to the feed-forward crosslinks as proximal effects increase both the CA/C and the AC/A ratios.2,9







Figure 23.1 In the dual interactive model of accommodation and vergence, there are mutual interactions and feed-forward crosslinks between the accommodative (AC/A) and vergence (CA/C) motor control systems. Vergence adaptation occurs after the CA/C crosslink and feeds forward into the convergence system. Vergence adaptation relieves the fusional vergence controller effort and reduces convergence accommodation, decreasing the exaggerated effects of sustained vergence on the AC/A ratio within 15 seconds. Knowledge of stimulus location (proximal input) increases vergence and accommodative response as well as the CA/C and AC/A ratios. (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)

The relation between the accommodative stimulus and accommodative response is represented by the accommodation stimulus-response curve (Fig. 23.2).2 This relation may be modified by factors such as target color,2,10 luminance,2,11 spatial frequency content,2,12 and the age of the person.2,13 However, in general, there is a “lead” of accommodation (relative myopia) for distance targets and an increasing “lag” (relative hyperopia) for near targets; this is especially evident after maximum plus refraction. Thus, near objects make the eye effectively hyperopic, which stimulates an accommodative response that tends to refocus the image. However, proportional controller-based negative feedback systems do not completely nullify the error signal and, at near, the accommodation response is not at the plane of the accommodative stimulus (vergence demand). For example, because of the approximately 0.5 D lead of accommodation at distance, an object at 40 cm (a 2.5 D stimulus) typically results in only approximately 1.25 to 1.50 D of accommodation as a lag of accommodation of 0.5 D ensues (an error signal of 0.5 D, which is a steady-state effective hyperopia). This error is typically not perceived as blur because it is within the depth of focus of the eye.2


A Conceptual Model

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






Figure 23.2 The relation between the accommodative stimulus and accommodative response is represented by the accommodation stimulus-response curve, which exhibits a “lead” of accommodation (relative myopia) for distance targets and an increasing “lag” (relative hyperopia) for near targets. This relation may be modified by factors such as target color, luminance, spatial frequency content, and age of the viewer. (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)






Figure 23.3 A conceptual model takes the form of dual intersecting feedback loops in which genetically programmed ocular growth of each eye is altered by blur derived from interactions between accommodation and vergence. The potential influence of suppression on the response of the refractive state (RS) to blur is indicated by the crosslink between the blur mechanisms. In the visual growth mechanism, continued relative hyperopic blur (e.g., lag of accommodation at near) increases scleral tension and promotes axial elongation; lens growth is retarded by concurrent reduction in zonular tension. The resulting reduction in lens thickness (with an increase in power) and the increased axial length decrease the accommodative demand associated with near visual tasks. Visual growth feeds into and combines with genetically programmed ocular growth to result in the final RS. (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)

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.

The following sections present and describe the implications of three propositions regarding how the genetically programmed ocular growth of each eye might be altered by visually driven ocular growth (blur derived from peripheral retinal defocus along with that resulting from interactions between accommodation and vergence).2



  • Proposition I: The RS that ultimately develops is a result of genetically programmed ocular growth modified by visually driven ocular growth; implied in this proposition is that, rather than occurring separately, the two kinds of growth occur in tandem.


  • Proposition II: 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 (although there is individual variation in both the overall pace of growth and the age of termination).



    • Corollary II-a: Genetically programmed (nonvisual) ocular growth can be modified using pharmacologic agents, diet, and, perhaps in the future, genetic therapy.


  • Proposition III: 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 and may not be bilaterally symmetrical.



    • Corollary III-a: Visually driven ocular growth is altered by changes in refractive correction because input from the blur-driven feedback system is modified by the intervention, essentially reinitiating the blur-driven visual growth process with each new correction.


    • Corollary III-b: The lead of focus from distance fixation results in an effective myopia at distance and a stimulus for the eye to slow or cease growth, whereas the lag of accommodation for near and relative hyperopic peripheral retinal defocus result in an effective hyperopia at near and a stimulus for the eye to increase growth. As a result of these two conflicting growth signals, genetically programmed ocular growth is altered by visual growth as the eye fine-tunes its RS for the visual environment.2


THE REFRACTIVE STATE: DISTRIBUTION OF REFRACTIVE ERROR AND ITS COMPONENTS

The RS at birth averages to about 2 D of hyperopia and has a roughly normal distribution (Fig. 23.4).1,2 As the eye rapidly grows over the next few months, there is a substantial and rapid change in the RS toward tropia (Fig. 23.5).2,16 The decrease in both myopic and hyperopic RS results in a more peaked (leptokurtic)
distribution, with a corresponding decrease in the mean spherical refraction and standard deviation of the RS in the population by age 6 (Fig. 23.4 and Table 23.1).2,3






Figure 23.4 Distribution of refractive error. The refractive state at birth averages to about 2 D of hyperopia and has a roughly normal distribution but, by age 5, most people have become nearly emmetropic. (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)






Figure 23.5 As the eye rapidly grows over the first 6 months of life, there is a substantial and rapid modification of the refractive state (RS). The decrease in both myopic and hyperopic RS results in a more peaked (leptokurtic) distribution, with a corresponding decrease in the standard deviation of the RS in the population. (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)


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 al2,17 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 Hofstetter2,20 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








Table 23.1 MEAN AND STANDARD DEVIATION OF SPHERICAL REFRACTIVE ERROR BY AGE
























































Age


Spherical Refractive Error


Mean (d)


Lower 95% Range


Upper 95% Range


Standard Deviation


Newborna


2.2


−1.1


5.5


3.1


6 mo


1.8


−0.8


4.4


2.4


1 y


1.6


0.0


3.1


1.5


2 y


1.2


−0.5


3.1


1.8


3 y


1.0


−0.6


2.6


1.5


4 y


1.1


−0.6


2.9


1.7


6b


12


1.3


0.4


95% confidence intervals are most useful for prescribing decisions when the patient communication is limited; typically age 4 and below.


0.6


1.1


Abstracted from:


a Mayer DL, Hansen RM, Moore BD, et al. Cycloplegic refractions in healthy children aged 1 through 48 months. Arch Ophthalmol. 2001;119:1625-1628 (ages newborn to 48 months).

b Pi L-H, Chen L, Liu Q, et al. Refractive status and prevalence of refractive errors in suburban school-age children. Int J Med Sci. 2010;7(6):352-353 (ages 6 and 12 years).


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 Smith2,23).

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 al2,17 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 Alphen2,24 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 work2,25 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 AL2 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 myopia2,35:



  • 1. Some eyes may inexorably continue to grow once started.


  • 2. Initial growth may sufficiently stretch the choroidal/scleral collagen to facilitate subsequent growth.2







Figure 23.6 By the time we reach age 20, variations in lens power (A) are unrelated to the refractive state. Anterior chamber depth (B) and corneal curvature (C) are linearly related to the refractive state. Data from Stenstrom (N = 1,000).28,29,30,31,32,33 (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)







Figure 23.7 Variations in axial length have a complex relation to the refractive state. Three of the four visible breaks in the data (labeled A through D) are statistically significant by one-way ANOVA polynomial regression testing (B, C, and D; df = 1, F = 12.61, p = 0.0004). The available data are insufficient to adequately test for the significance of visible break A. The slopes of the relation between the refractive state and axial length are statistically different for nearly emmetropic patients (slope B to C) and those having 2 to 7 D of hyperopia (slope A to B) or 1 to 6 D of myopia (slope C to D) (F = 10.91; p = 0.0052). The slopes of the relation between axial length and the RS in moderate hyperopia and myopia (slope C to D and slope A to B) are not statistically different (F = 0.62; p = 0.44). Data from Stenstrom (N = 1,000).28,29,30,31,32,33 (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)


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 years2,36; 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 Larsen2,36 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






Figure 23.8 Growth of ocular components. The cornea and anterior chamber reach 95% of their adult structure before age 2. Lens thickness and axial length continue their growth for a substantially longer time and do not reach 95% of adult growth until ages 6 and 11, respectively. (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)

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







Figure 23.9 A: The ratio of vitreous chamber depth to lens thickness is higher in patients with moderate myopia than in those with emmetropia or hyperopia. Further, the axial length to corneal radius (AL/CR) ratio is higher than 3.0 for these patients (arrow), suggesting that high values of AL/CR ratio signal development of myopia. B: The age at which the AL/CR ratio becomes higher than 3.0 and the age at which development of myopia occurs are about the same, again suggesting a strong relation between these two occurrences. (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)








Table 23.2 INCIDENCE OF CHILDHOOD MYOPIA BASED ON PARENTAL MYOPIA





















Number of Myopic Parents


Incidence (%)


Odds Increase


0


3



1


8


2.67x


2


12


4x


Adapted from Zadnik K, Satariano WA, Mutti DO, et al. The effect of parental history of myopia on children’s eye size. JAMA. 1994;271:1323-1327.




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 hyperopia2,56 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, Zadnik2,59 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


THE RELATIVE STRENGTHS OF THE GENETICALLY PROGRAMMED AND VISUALLY DRIVEN OCULAR GROWTH MECHANISMS

The data portrayed in Figure 23.82 for the growth of ocular parameters (Larson’s data2,36,44,45) and Sorsby et al’s data for myopic patients2,17,60,61 are essentially exponential decay curves. Thus, genetically programmed growth and visually directed growth have a combined growth curve that takes the mathematical form of an exponential decay curve, consistent with Goss’2,62 observation that myopic refractive changes in children are essentially linear during times of rapid RS change.2


RATE OF REFRACTIVE CHANGE


Myopia

Data from Kent2,63 indicate that the average change in RS for adults who develop myopia is about 0.112 D per year. Based on Propositions I and II, change in the RS of adults must be due solely to influences of visually driven ocular growth, because genetically programmed ocular growth ceases at age 14 to 16 years.2,36 According to Proposition I, both genetically programmed and visually driven ocular growth contribute to changes in RS seen up to age 14 to 16. Typical RS changes average from 0.42,64 to 0.5 D2,65 per year for children developing myopia, with standard deviations of about 0.3 D. Larson’s data2,45 for changes in AL yield similar numbers of 0.53 D per year. Smith2,66 described infant monkey experiments that suggest that the growth rate of infant eyes stimulated by progressive changes in lens correction is around 3 D per year (based in terms of human years). These values are useful in that changes substantially outside of these amounts (e.g., −0.75 to −1.0 D or more per year increase in myopia for children between ages 6 and 14 to 16 years) signal a need for more aggressive treatment.2


Hyperopia

For hyperopic patients, a similar relation can be developed. The infant hyperopic RS decreases at a rate similar to that of the infant myopic RS (Fig. 23.5).2,3 However, hyperopia present after age 3 seldom decreases
substantially, which may be attributed to a reduced combined rate of visually driven and genetically programmed ocular growth (and perhaps the influence of refractive correction—see next). This suggests that treatment of hyperopia should be started by age 3, if possible.2


The Effect of Lens Correction

According to the corollary to Proposition III, wearing a lens correction changes RS development because the blur signal utilized by the visual feedback system is altered by the visual correction, resulting in a new stimulus to RS development. The effect of corrective lenses on the RS state was described by Medina,2,67,68 who demonstrated statistically (p > 0.001) that the ultimate RS can be better predicted if lens correction has a significant effect on the developing RS. This was confirmed by Ong et al,69 who reported that non-wearers of myopic correction exhibit an age-adjusted 3-year progression approximately one-half that of full-time wearers (although statistical analysis of their results shows no significant difference, presumably because of the small sample size).2

Generally, the model suggests that the overall effect of corrective lenses on persons developing myopia is to increase the RS in amounts depending on the relative strength of the growth rate caused by peripheral retinal image defocus and the magnitude of the RS that might develop for a patient who remains uncorrected. For hyperopic patients, corrective lenses tend to minimize visually driven emmetropization because for hyperopic patients traditional plus correcting lenses provide an in-focus foveal image but do not correct the relative myopia that usually occurs in the periphery (see Fig. 23.10, bottom, middle panel). As a result, once traditional
visual correction is prescribed, further reduction in hyperopia is not expected unless tasks are performed that maximize persistent near blur (lag of accommodation) or correction is prescribed to stimulate an increase in AL by providing relative myopia in the periphery.2






Figure 23.10 Schematic of how optical treatment using a peripheral treatment strategy could be used to slow the progression of myopia (top) and decrease the ultimate hyperopic refractive state (bottom). The top left panel illustrates the typical position of the image shell for a distance object in an uncorrected myopic eye. The middle panel shows that traditional minus correcting lenses provide an in-focus foveal image but do not correct the relative hyperopia that usually occurs in the periphery. The right panel emphasizes the goal of the peripheral treatment strategy: to provide optimal central vision while eliminating peripheral visual signals that may stimulate growth and increase myopia progression. The bottom left panel illustrates the position of the image shell for a distance object in a typical uncorrected hyperopic eye. The middle panel shows that traditional plus correcting lenses provide an in-focus foveal image but do not correct the relative myopia that often occurs in the periphery. The lower right panel demonstrates the goal of the peripheral treatment strategy for patients with hyperopia: to provide optimal central vision while increasing the peripheral visual signals that may stimulate growth and decrease hyperopia. (Adapted with permission from Smith EL III. Prentice award lecture 2010: a case for peripheral optical treatment strategies for myopia. Optom Vis Sci. 2011;88(9):1029-1044. Copyright © 2011 American Academy of Optometry.)

For myopic patients, traditional minus correcting lenses provide an in-focus foveal image but do not correct the relative hyperopia that usually occurs in the periphery (see Fig. 23.10, top, middle panel). With full correction (FC), the remaining relative peripheral hyperopia (which tends to be the stronger stimuli to visually directed ocular growth) provides an ocular growth signal, increasing the myopia. Non-wear of a myopic correction could result in a reduction in the ocular growth rate once the eye grew to a point where the relative peripheral hyperopia was neutralized, at which time the peripheral visual stimuli to increase ocular growth would cease, leaving only genetically programmed growth. Slight to moderate under-correction (UC) would not be advised for the same reason that traditional minus special lens correction increases the refractive correction—slight UC may not provide an in-focus foveal image but is simply insufficient to correct the relative hyperopia that usually occurs in the retinal periphery. Thus, UC is clinically unsuccessful in reducing myopia progression,70 presumably because a myopia-increasing peripheral ocular growth signal remains.2 More discussion on this topic is presented later in this chapter.


Correction to Prescribe

Taken as a whole, the abovementioned description suggests that the optimal spectacle correction to minimize myopia progression is the least minus to best visual acuity (VA), without UC. For the hyperopic child, the optimal spectacle correction is a slight UC, but not enough UC to compromise binocular vision. These corrections would allow patients to have their best chance of achieving a “normal” RS. The timing (e.g., when should treatment be started?) and form of the optimal correction (e.g., why, rather than traditional spectacle correction, should orthokeratology [OK] or soft multifocal contact lenses be used?) that would appropriately stimulate (for hyperopia) or inhibit (for myopia) visually driven ocular growth form the basis for further discussion in this chapter.


Rates of Ametropia Progression

The general cases of RS progression are shown in Figure 23.11 for youth-onset myopia,2 late-onset myopia, and hyperopia. In each case, the dashed line represents the predicted value with changes in correction determined in a “standard” clinical manner (yearly changes in correction or at least 0.50 D change in RS required if longer than 1 year was necessary to attain such a change), and the solid line represents the amount of change predicted to occur if lens corrections were not prescribed. Three clinical examples (Fig. 23.12)2 are overlaid on the clinical

changes in the RS reported by Goss and Winkler2,71 for three female children with typical rates of myopia progression. In each figure, the solid line connecting open black squares represents the clinical data,2,71 the dashed line represents the predicted value with changes in correction prescribed at the ages the patient received new lenses (yearly or at least 0.5 D change), and the single solid line represents the amount of change predicted if no lens correction were prescribed.2






Figure 23.11 The general cases of refractive state (RS) progression are shown for youth-onset myopia, late-onset myopia, and hyperopia. The dashed lines represent the predicted value with changes in correction prescribed at the ages a patient would probably receive new lenses, and the solid lines represent the predicted change if lens corrections were not prescribed. The curves are constructed using average growth (k) and RS (c) constants, which predict RS progression similar to that observed clinically. If the effects of corrective lenses are not included (solid lines), the result is a significantly smaller myopic RS. (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)






Figure 23.12 A-C: Three examples are overlaid on the clinical changes in the refractive state (RS) for female children with typical rates of myopia progression. The curves are constructed by varying the growth (k) and RS constant (c). For (A), 1 SD of growth rate was added to both the growth and the RS constant; for (B), 1 SD was added to the growth and 0.5 SD to the RS constant; and for (C), 1.5 SD was added to the growth and 0.5 SD was subtracted from the RS constant. Predicted changes (dashed lines) correspond well to clinical findings (solid lines connecting black squares), assuming that effects of corrective lenses are included and that exponential growth ceases at age 14 to 16. Increases in the myopic RS are essentially linear during the growth period as long as refractive correction is prescribed at regular intervals. The single solid line represents the change predicted if lens correction is not prescribed. (Reprinted from Wick B. On the etiology of refractive error—part I. A conceptual model. J Optom Vis Dev. 2000;31(1):5-21 with permission from the College of Optometrists in Vision Development.)

As can be seen in Figure 23.12,2 predicted changes in the RS (dashed lines) correspond well to those observed clinically (solid lines connecting black squares), assuming that effects of corrective lenses are included and exponential growth ceases at age 14 to 16. If the effects of corrective lenses are not included (solid lines), a significantly smaller myopic RS is predicted than actually develops. It should be noticed that, for each example, increases in the myopic RS are essentially linear during the growth period, as described by Goss,2,62 as long as refractive correction is prescribed at regular intervals. After growth ceases, the exponential decay function results in a smooth decrease in the change, and future myopic changes are no longer linear.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








Table 23.3 CHANGES IN REFRACTIVE STATE FROM VISUALLY DRIVEN OCULAR GROWTH















































Age


Description


Probable Maximum Amount of Change


Time of Change


Basis for Prediction (Selected Examples)


0-1


Infancy


11 D


Months


Basic research54,55


Clinical measurement43


1-5


Toddler and preschool


9 D


Months to years


Basic research54,55


Clinical measurement61


6-12


Grade school


7 D


Years


Clinical observation33,35


12-19


Puberty


5 D


Years


Clinical observation47,59


20-44


Adult


3 D


Years


Clinical observation63


44+


Mature adult


1.5 D


Years


Clinical observation153


From Wick B. On the etiology of refractive error—part II. Prediction and research implications of a conceptual model. J Optom Vis Dev. 2000;31(2):48-63.


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 progression74,75,76 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).


Atropine

Myopia control is not listed as a current Food and Drug Administration (FDA) indication for use of atropine. However, 1% atropine has been clinically shown, over a wide range of myopia, to be very effective in minimizing the myopia progression. In two fairly large-scale clinical studies, Bedrossian78,79 found that progression of myopia essentially ceased with regularly scheduled atropine use. Perhaps because of induced complaints secondary to cycloplegia and dilation (both large disadvantages of atropine use), 1% atropine is still not widely used for myopia treatment in spite of its success in decreasing genetically driven ocular growth.72


ATROPINE 1%

Other studies80,81,82,83,84,85 have duplicated the early findings with respect to atropine use. Representative of these is the Atropine in the Treatment of Myopia (ATOM 1) Study84 where the effect of topical 1% atropine was evaluated on myopia progression of 400 Asian children 6 to 12 years of age. One eye of each child was treated using either 1% atropine or a placebo eye drop each night. In the randomized, double-masked, placebo-controlled trial, 346 of the initial 400 children (86.5%) completed the comprehensive 2-year study. After 2 years, myopia did not progress in 1% atropine-treated eyes, whereas there was myopia progression in placebo-treated eyes (atropine: +0.28 ± 0.92 D vs. placebo: −1.20 ± 0.69 D). Additionally, treated eyes displayed basically no change in AL (−0.02 ± 0.35 mm) compared with a 0.38 ± 0.38 mm AL increase in placebo-treated eyes.


LOW-DOSE ATROPINE

Yam et al,85 in a 1-year study, randomly assigned 438 children (age 4 to 12 years; myopia ≥ −1.0 D, astigmatism ≤ −2.5 DC) to receive either 0.05%, 0.025%, 0.01% atropine, or a placebo eye drop once nightly to each eye. Primary outcome measures were changes in cycloplegic spherical equivalent (SE) and AL. After 1 year, all concentrations of atropine eye drops reduced myopia progression along a concentration-dependent response (mean SE change was −0.27 ± 0.61 D, −0.46 ± 0.45 D, −0.59 ± 0.61 D, and −0.81 ± 0.53 D in the 0.05%, 0.025%, and 0.01% atropine groups, and placebo groups, respectively [p < 0.001], with a respective mean increase in AL of 0.20 ± 0.25 mm, 0.29 ± 0.20 mm, 0.36 ± 0.29 mm, and 0.41 ± 0.22 mm [p < 0.001]). There were no adverse effects on VA or vision-related quality of life and all concentrations were used without adverse effects. Atropine 0.05% was the most effective concentration for controlling myopia progression.

In the ATOM II Study, myopia progression and visual side effects were evaluated using three low doses of atropine.86 Asian children 6 to 12 years of age were randomized to receive 0.5%, 0.1%, or 0.01% atropine nightly in both eyes in a double-masked 2-year study which 355 of the initial 400 subjects (88.8%) completed. After 2 years, all three concentrations were effective at slowing myopia progression. Although there was a dose-related response, clinical differences between the treatments were small (myopia progression of the 0.01% atropine group: −0.49 ± 0.63 D; 0.5% atropine group: −0.30 ± 0.60 D).

Shih et al81 randomly prescribed one drop of 0.5%, 0.25%, or 0.1% atropine, or control (0.5% tropicamide) to 200 children (age 6 to 13 years) in both eyes nightly. Mean myopia progression was 0.04 ± 0.63 D per year for the 0.5% atropine group, 0.45 ± 0.55 D per year for the 0.25% atropine group, and 0.47 ± 0.91 D per year for the 0.1% atropine group, as compared to 1.06 ± 0.61 D per year in the control group. After 2 years, there
was no myopia progression in 61% of children in the 0.5% atropine group, 49% in the 0.25% atropine group, and 42% in the 0.1% atropine group. Gong et al87 also suggest, via meta-analysis, that all low-dose atropine concentrations are approximately equally effective in slowing myopia progression.

In another study, the concentration of atropine was varied from winter (0.5%) to summer (0.1%) based on the assumption that myopia progresses less during the summer (probably related to more light exposure from being outdoors in the summer, although perhaps to decreased reading demand as well). This regimen, which slowed myopic progression by 77%, allowed children to have less pupillary dilation during the summer months when the sunlight and photophobia is the greatest.88 More discussion of this concept is presented later in this chapter.


SAFETY AND SIDE EFFECTS OF ATROPINE


Atropine 1%

Among the largest disadvantages of 1% atropine use are induced complaints secondary to cycloplegia and dilation. Typically, the most noteworthy clinical side effect of atropine treatment is light sensitivity caused by pupillary dilation. In the absence of dry eye and ocular surface disease, increased light sensitivity from 1% atropine use can generally be successfully compensated with spectacles or sunglasses with ultraviolet (UV) protection for outdoor wear.

In amblyopia clinical trials, 1% atropine was used without significant side effects.89,90,91 However, there can be both ocular and systemic reactions. Ocular reactions include allergic conjunctivitis, contact dermatitis, decreased lacrimation, and lid edema. In the ATOM 1 Study (N = 400), there were no reported serious adverse events with the generally well tolerated 1% atropine treatment.84 Reasons for withdrawal included discomfort (4.5%), logistical difficulties (3.5%), glare (1.5%), blurred near vision (1%), rare allergic reactions or hypersensitivity reactions, and various others (0.5%). There was no decrease in best-corrected VA.

Toxic systemic overdose is possible after ocular instillation of 1% atropine92; elevation of blood pressure from systemic absorption has been reported along with other systemic adverse reactions including delirium, flushed skin of the face and neck, irritability, mouth, throat, and skin dryness, restlessness, and tachycardia. Because of potential for hypertensive crisis, 1% atropine is not recommended for use with monoamine oxidase inhibitors. Because of potential systemic reactions, 1% atropine is not recommended for children less than 3 months old and, for children under 3 years old, no more than one drop per eye per day is recommended.

The sequelae listed earlier are uncommonly seen with standard clinical doses. Atropine treatment is typically safe and seldom causes significant systemic distress. Further, for treatment of myopia which typically is initiated after age 6, these issues are very unlikely to be a significant clinical consideration. However, there are potential issues for use of atropine by pregnant women. Atropine is listed in U.S. FDA pregnancy category C. There have not been controlled studies on the use of atropine in human pregnancy; however, atropine crosses the placenta and may cause fetal tachycardia. Atropine has been used by a large number of pregnant women without increase in the frequency of fetal malformations and other harmful fetal effects have not been reported (although the effects of long-term atropine use on fetal development are not known).


Retinal Function and Accommodative Function

As part of the ATOM 1 Study,84 multifocal electro-retinograms (mfERG) were conducted in children 2 to 3 months after stopping the 2-year treatment. The mfERG findings suggested that 1% atropine treatment had no significant effect on retinal function.93 Because the atropine concentration in the retina would decrease over time, future retinal abnormalities from 1% atropine were considered unlikely. Six months after cessation of 1% atropine, the measured accommodative amplitude was larger than the pretreatment level and there was no significant difference in near VA of the atropine-treated eyes.


SIDE EFFECTS OF LOWER DOSES OF ATROPINE


Ocular Reactions

Several studies involving atropine concentrations varying from 1.0% to 0.01% reported no serious adverse events.84,94,95 Chua et al84 only observed allergic conjunctivitis and allergic dermatitis with 0.5% and 0.1% atropine. Shih et al96 reported 22% incidence of adverse effects with 0.5% atropine, mostly related to complaints of light sensitivity. With 0.25% or 0.1% atropine, there were no reported ocular or systemic complications. Only 7% of children using 0.25% atropine, and none using 0.1% atropine, complained of photophobia or blurred near vision. In a study of children using 0.05% atropine, seven complained of photophobia in the morning (which only continued into the afternoon for one patient) and two reported blurred near vision.84 There were no reports of irritation or allergic reaction. In another study, using 0.025% atropine,97 6 of 700 children (four in the treatment group) reported photophobia. None reported blurred near vision or systemic side effects.



Visual Side Effects

Visual side effects and adverse events are least with 0.01% atropine and increase successively with 0.1% atropine and 0.5% atropine. In the ATOM 2 Study, accommodation measured 11.8 D for the 0.01% atropine group versus 6.8 and 4.0 D for the 0.1% and 0.5% groups, respectively.86 The (logMAR) near VA was 0.01 for the 0.01% versus 0.10 and 0.29 for the 0.1% and 0.5% groups, respectively. Cooper et al98 investigated visual side effects of diminished accommodation and pupillary dilation caused by systematically varying the dosage of atropine. The strongest dosage for which their study participants did not report significant associated symptoms was 0.02% atropine. Loughman and Flitcroft reported no side effects or symptoms when 0.01% atropine was used in Caucasians.99 With meta-analysis, Gong et al87 also found stronger atropine dosages to be associated with more symptoms.


DOSAGE

Even though 1% atropine profoundly reduces genetically programmed ocular growth, lower concentrations of atropine also have a significant effect. Indeed, clinical research suggests that even as little as 0.01% atropine is efficacious in controlling myopia progression, while exhibiting minimal side effects compared to stronger doses.84 Cooper et al suggest that 0.01% atropine may not always be clinically effective and suggest that 0.02% atropine is the maximal dose that can be used without causing symptoms related to dilation or decreased accommodation.98


REBOUND EFFECT

Chia et al examined the children from the ATOM 2 study 12 months after discontinuation of (0.5%, 0.1%, or 0.01%) atropine treatment.100 Some patients resumed progression of myopia with the least increase for the 0.01% group (−0.28 ± 0.33 D), followed by the 0.1% group (−0.68 ± 0.45 D), and the largest increase in the 0.5% group (−0.87 ± 0.52 D). Of the initial 0.01% atropine group 76% did not require retreatment (compared to the 41% and 32% from the 0.1% and 0.5% groups, respectively). Those who progressed were prescribed 0.01% atropine and reassessed 3 years later (total of 5 years). At completion of the study, AL increase was smallest for the 0.01% group. Recovery of pupil size and accommodation was also more rapid for patients in the 0.01% atropine group.

In summary, atropine seems to pharmacologically inhibit ocular growth. According to the model, this pharmacologic treatment provides a “stop signal” for genetically programmed ocular growth and a concomitant decrease in myopia progression. Although the exact mechanism for the ability of atropine to pharmacologically inhibit ocular growth is currently not known, the decrease in myopia progression seen with atropine probably results from two factors:



  • The unspecified effect of atropine on the retina, choroid, and zonules.


  • The use of bifocals to restore clear near focus when prolonged cycloplegia is utilized (1% atropine) or accommodative symptoms result (from lower doses of atropine).

Bifocal correction (when used in conjunction with atropine) would inhibit visually driven ocular growth and add to the genetically programmed ocular growth reduction seen with atropine treatment. Bifocal wearing patients would have a decreased stimulus to become myopic because the bifocals effectively eliminate the usual lag of accommodation at near and provide no stimulus to increase myopia after prolonged periods of near work, assuming an appropriate working distance to achieve a lead (rather than a lag) of accommodation is actually used. The normal lead of focus at distance then gets added to by the lead at near, reversing the typically myopia-developing visually driven stimulus for refractive change and minimizing further myopic shift in the RS.


Methylxanthines

Methylxanthines are available in appreciable amounts in a limited number of botanical species, including cacao (Theobroma cacao L.), coffee (Coffea sp.), and tea (Camellia sinensis L.). The most relevant naturally occurring methylxanthines are caffeine (1,3,7-trimethylxanthine), theophylline (1,3-dimethylxanthine), and theobromine (3,7-dimethylxanthine).101 Theobromine shows significantly less central nervous system (CNS) activity than caffeine and theophylline, possibly as a result of physiochemical properties that obstruct its distribution into the CNS.102 Because theobromine is a lesser homologue of methylxanthine isomers, it is not prescribed therapeutically for respiratory diseases such as chronic obstructive pulmonary disease and asthma.

Because it is commonly accepted that theobromine is generally harmless to humans, studies focusing on its chronic effects are limited. However, because minimal amounts of theobromine reach the brain, it has little stimulatory effect on behavior. As a result, arousal effects of other adenosine antagonists, such as caffeine, are
seen less frequently when using theobromine. In aggregate, moderate methylxanthine consumption from common dietary sources is considered safe103 for humans (although methylxanthine is poisonous to dogs because they metabolize it at a much slower rate).104


THEOBROMINE

Cornish and Christman105 examined methylxanthines excreted in urine after ingestion of theobromine. Two subjects were placed on a diet without cocoa, coffee, and tea. Two 500 mg doses of theobromine were then taken 4 hours apart and 24-hour urine samples were collected over a 3-day period. The major metabolites of theobromine excreted in the urine (expressed as percent of dose) were 7-methylxanthine (28/30%), 3-methylxanthine (14/21%), and unchanged theobromine (11/12%). Studying healthy adults, Rodopoulos et al found similar urine analysis; 7-methylxanthine was 36 ± 5% of metabolites in total excretion.106

Trier et al107 used pigmented rabbits to investigate effects of theobromine (3,7-dimethylxanthine) and 7-methylxanthine on the sclera. Treatment with theobromine produced significant increase in hydroxyproline and proline in both anterior and posterior sclera, whereas 7-methylxanthine increased hydroxyproline and proline more selectively in posterior sclera. These results indicate that theobromine and 7-methylxanthine each increase the concentration of collagen and thickness of collagen fibrils in sclera of rabbits. Axial myopia results from excessive elongation (stretching) of the sclera.27 If development of axial myopia among humans results from insufficient or inferior scleral fibrils, preventive treatment of myopia with theobromine or 7-methylxanthine may be beneficial.


7-METHYLXANTHINE

A naturally occurring (e.g., a component of chocolate) metabolite of caffeine, 7-methylxanthine increases collagen in the sclera of rabbits108,109 and also prevents development of myopia in guinea pigs.109,110 Fourteen 3-week-old guinea pigs were subjected to monocular form deprivation and fed either 7-methylxanthine (300 mg/kg body weight; n = 7) or control saline (equal volume to 7-methylxanthine; n = 7). In guinea pigs fed 7-methylxanthine, form deprivation produced significantly less myopia and axial elongation than in control animals. Treatment with 7-methylxanthine appeared to decrease the amount of myopia by around 50%, eliminate eye elongation induced by form deprivation, and prevent form deprivation myopia-related scleral changes (e.g., less scleral thinning and reduced thinning of collagen fibril diameter in the posterior sclera).

Hung et al111 reared infant monkeys wearing −3 or +3 D lenses over the treated eye and plano-powered lenses (PL) over the other eye. Throughout the lens-rearing period, monkeys took 100 mg per kg of 7-methylxanthine orally twice daily. Comparison data were obtained from lens-reared controls and normal monkeys maintained on a standard diet. Refractive status, corneal power, and axial dimensions were assessed biweekly. The −3 and +3 D/PL lens-reared controls developed compensating myopic and hyperopic anisometropias, respectively. Monkeys taking 7-methylxanthine did not exhibit compensating myopia in treated eyes and were on average isometropic, suggesting that 7-methylxanthine decreased myopia progression. Further, 7-methylxanthine appeared to exaggerate reduction in axial elongation produced by imposed myopic defocus. These results demonstrate that treatment to inhibit genetically programmed ocular growth (7-methylxanthine) and visually directed growth (lenses) both successfully reduce axial elongation and decrease myopia progression. Further, the results support the concept that combining genetically programmed and visually directed ocular growth treatments is more effective than using either alone to influence RS development.111

To test whether the scleral collagen-enhancing effects of 7-methylxanthine could affect eye elongation in childhood myopia, Trier et al76 studied 68 myopic children (mean age 11.3 years) with a minimum baseline axial growth rate of 0.075 mm per 6 months. Children received tablets of either 400 mg per day 7-methylxanthine or a placebo. After 12 months, all participants received 7-methylxanthine for another 12 months. At 24 months, a significantly slower axial growth was found among children treated with 7-methylxanthine compared with those who had only been treated for 12 months. With 7-methylxanthine treatment, axial growth continuously decreased; the effect disappeared when treatment was stopped, confirming that 7-methylxanthine reduces eye elongation in myopia.77


SAFETY AND SIDE EFFECTS OF METHYLXANTHINE

Because 7-methylxanthine does not reach the brain, it has no stimulatory effect on behavior. Thus, arousal effects of other adenosine antagonists, such as caffeine, do not occur using 7-methylxanthine; it has low toxicity,112,113 no carcinogenic effects,114 and there have been no reported adverse side effects in children.76 Overall, 7-methylxanthine treatment seems to be effective, safe, and without side effects. Theobromine from common dietary sources is also considered safe for humans.103


There may, however, be issues for use of theobromine and 7-methylxanthine by pregnant women. Although theobromine and 7-methylxanthine have fewer stimulant effects than caffeine, they are still related to caffeine. Caffeine crosses the placenta and the fetus cannot fully metabolize caffeine. As a result, any amount of caffeine may cause changes in fetal sleep patterns during pregnancy. Also, women who consume more than 200 mg of caffeine daily have been found to be twice as likely to have a miscarriage as those who consume no caffeine. Until conclusive studies demonstrate no detrimental effects on fetal health from long-term theobromine or 7-methylxanthine use, pregnant women should probably limit intake to less than 200 mg per day.


Diet and Supplements

Considering the implication of Proposition I (i.e., The RS that ultimately develops is a result of genetically programmed ocular growth modified by visually driven ocular growth.), there must be (at least) a functional as well as a hereditary facet of myopia. The tenet of this chapter is that the functional facet can be modified by visual experience to influence ocular growth; however, the hereditary factor (genetically programmed ocular growth, which can be affected by atropine drops and 7-methylxanthine) is also likely to be modified by diet. For those who do not think that environment can influence health, here is an analogy: consider that many people smoke all their lives but most long-term smokers do not develop lung cancer; should we therefore conclude that lung cancer must be hereditary and not caused by smoking? It is probably also reasonable to apply such reasoning to development of myopia; factors relating to development of myopia may be inherited but are also influenced by environment (diet).


HIGH PROTEIN/LOW CARBOHYDRATE

The structural defect that occurs in myopia development is typically an increase in AL,27 and better nutrition may increase the stability of scleral connective tissue with corresponding reduction in myopia progression. Gardiner115 found that, compared with emmetropic children, myopic children tend to refuse protein from fish, milk, cheese and eggs more often. Furthermore, myopia was found to be more common and more severe in children who refused animal protein from those sources. Milk consumption was the preeminent difference between the two groups; over three times as many advancing myopes (16%) refused milk as compared to emmetropes (5%).115 Decrease in myopia progress with high-protein diets is a significant reason to consider diet modification; however, it is not clear what effect high-protein diets have on general health as there are studies that suggest a negative effect,116 whereas other reports find high-protein diets have positive effects on cardiac health.117


CARBOHYDRATES VERSUS PROTEIN


Refined Carbohydrates

Consistent with the hypothesis that high intake of dietary fiber may be protective, there is evidence from both animal and human studies that a high intake of refined carbohydrates may promote myopia progression. Rats that received a high-sucrose diet upon weaning had the normal hyperopia significantly reduced compared with controls (relative myopia developed). When the sucrose and control group were reversed, myopia developed in the rats that then received the high-sucrose diet. This myopia failed to reverse when they were switched to a sucrose-free diet.118 When diets of optometric patients between the ages of 7 and 38 years were studied, myopes had a significantly higher consumption ratio of refined carbohydrates to total carbohydrates than hyperopes. Hyperopes also had a lower ratio of consumption of refined to total carbohydrates than emmetropes.119


High Protein

Gardiner115,120 and Lane119 suggest that high-protein (low-carbohydrate) diets decrease myopia progression. This may be due to the increase in chronic hyperinsulinemia119 caused by diets rich in carbohydrates, although other components of the diet, including zinc and vitamin intake, also seem to contribute to myopia development.121


Supplements


Calcium Caseinate

In a clinical trial,119 myopic schoolchildren (n = 91) were placed on a diet where animal protein made up 10% of caloric intake, without a change in total calories. Calcium caseinate was used as a supplement for 72 children who refused animal protein as ordinary food. After 1 to 2 years, treated children had substantially less myopia
increase than untreated controls. For younger children, myopia progression was greater in the controls by an average of 0.5 diopter per year; in the older treated group, myopia progression in the treatment group was essentially halted. After 6 months, for 16 children who consumed the advised amount of calcium caseinate, refraction was essentially unchanged (annualized improvement of 0.02 diopters); in 42 taking “some” calcium caseinate, there was a mean annual myopia increase of 0.32 diopters; and in 14 who refused both calcium caseinate and animal protein, there was an annual myopia increase of 0.44 diopters.119

An 8 oz glass of milk contains about 8 g of protein, constituting approximately 2 g of quickly metabolized whey protein and 6 g of slowly metabolized casein (calcium caseinate) protein. A pregnant woman’s requirement for calcium increases during the third trimester when the fetus’ skeleton is rapidly developing. Taken as milk, consumption of calcium caseinate during pregnancy is not only safe, but recommended. Calcium caseinate is widely accepted as a safe food additive in many countries, including the United States where the FDA affirms that calcium caseinate is “generally recognized as safe”; Campbell, in contrast, suggests that calcium caseinate is a strong carcinogen.122


Dietary Fiber/Folate

In a retrospective study123 of binocular non-strabismic optometric patients (N = 120; age 7 to 38 years), dietary fiber intake was significantly related to refractive strata with hyperopes consuming 2.56 times as much fiber as myopes (13.55 vs. 5.3 g). This may be because hyperopes with higher fiber intake eat more unrefined foods with better trace mineral availability, which might result in more thorough mixing with saliva and improved nutrient absorption. Additionally, dietary fiber often correlates with dietary folate and dietary folate intake is highly correlated with myopia prevention/reversal.123 Pregnant women are routinely given a prenatal vitamin with at least 400 mcg of folic acid to prevent birth defects of the brain and spinal cord. Foods naturally high in folate include asparagus, beans, fruits (e.g., bananas, melons, and lemons), juices (orange and tomato), leafy vegetables (e.g., baby kale, broccoli, lettuce, and spinach), meat (e.g., beef liver and kidney), mushrooms, okra, and yeast.


Vitamin D

Using data from the Korea National Health and Nutrition Examination Survey, Choi et al4 examined the vitamin D levels of people aged 13 to 18 years old and noted the incidence and severity of myopia. Of 2,038 participants, 80.1% had myopia and 8.9% had very severe (>6 D) myopia. Lower vitamin D levels were related to more severe myopia among the participants, suggesting that raising vitamin D levels through supplementation and outdoor activity could reduce myopia development. Deficiency in vitamin D has also been demonstrated in Caucasian adults with myopia progression.124 Fetal needs for vitamin D increase during the last 20 weeks of pregnancy, when bone growth and ossification are prominent. Vitamin D travels to the fetus by passive transfer, and the fetus is entirely dependent on maternal stores. Pregnant women are routinely given a prenatal vitamin with at least 400 international units (IU) of vitamin D per tablet (although up to 4,000 IU are often recommended).


Omega-3

Omega-3, an essential dietary component, refers to the polyunsaturated fatty acid group that includes alpha-linolenic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Alpha-linolenic acid is a precursor of DHA and EPA. Omega-3s are essential in maintaining overall health including that of the cardiovascular, immune, nervous, and reproductive systems. Omega-3s also play an important role in eye health. DHA naturally concentrated in the retina promotes healthy retinal function. Results of several studies indicate that eating larger amounts of fish or Omega-3s may help promote macular health125 and studies also show that Omega-3s can help reduce dry eye syndrome. Although studies show a positive effect of Omega 3 on ocular health, there is no current evidence that Omega 3 intake affects myopia progression. Omega-3 can be found in foods like bread, fish oil, nuts, oil-rich fish, and fortified foods such as eggs and fruit juices.


TREATMENT STRATEGIES BASED ON ALTERING VISUALLY DIRECTED GROWTH

The basic goals of strategies aimed at altering the influence of visually directed growth are:



  • 1. To minimize or provide peripheral retinal defocus that inhibits (in the case of myopic patients) or stimulates (in the case of hyperopic patients) visually directed ocular growth.


  • 2. To minimize the near lag or even create a lead of accommodation (in the case of myopic patients) or maximize accommodative accuracy/leave a lag of accommodation (for hyperopic patients) by controlling interactions between vergence and accommodation.


Figure 23.10 depicts the ocular conditions of myopia (top) and hyperopia (bottom). In the top left-side panel (Fig. 23.10A), it can be seen that, for myopic eyes, the image shell for distance objects tends to be flatter (relative hyperopic defocus) than the surface of the retina.126,127 When traditional minus lens visual correction is prescribed, there is clear central vision but an increase in the relative peripheral defocus, which further increases in magnitude with increasing eccentricity (Fig. 23.10B).128,129 This situation provides a strong stimulus for myopic ocular growth.130,131 This relation is reversed for hyperopia (Fig. 23.10 bottom panel). Thus, both the model and clinical research suggest that conventional visual correction with glasses and contact lenses may increase myopia progression.

As shown in the top right panel (Fig. 23.10C), the goal of an optimal peripheral treatment strategy is to provide clear distance vision with a concurrent increase in the curvature of the image shell to provide stimuli that reduce visually driven axial growth (i.e., myopic rather than the traditional hyperopic retinal defocus). For the hyperopic patient, correction that increases the stimuli to visually driven ocular growth by creating a relative hyperopic peripheral image defocus would tend to help the patient “outgrow” hyperopia (Fig. 23.10F). These corrections, which include specially designed spectacle lenses, OK, and/or bifocal contact lenses, are a significant departure from the traditional negative (for myopia) or positive (for hyperopia) powered lenses. Traditional spectacle correction, which although providing clear distance vision, typically provides an inappropriate peripheral retinal signal to visually directed ocular growth.132,133


Spectacle Lenses for Myopia Control

As pointed out earlier, any visual correction which provides appropriate peripheral stimuli should affect visually driven axial growth. However, successful development of spectacle lenses that have an effect on myopia progression has been elusive. This is probably a result of eye movement behind the spectacle lenses. To affect visually driven axial growth, a spectacle lens must provide clear central distance vision with a coexisting change in the curvature of the peripheral image shell to provide stimuli to alter visually driven axial growth. In the presence of a stable peripheral correction (e.g., contact lens correction where the lens moves with the eye), this can be readily achieved. However, with spectacle correction, the eye moves behind a fixed lens and there are significant amounts of time where the ocular gaze is through a peripheral portion of the lens, which probably reduces the benefit of the peripheral stimuli in the lens designed to reduce visually driven axial growth.

Notwithstanding the difficulties presented by eye movement, spectacle lenses are being designed to reduce the relative strength of visually driven axial growth and decrease myopia progression. Sankaridurg et al134 studied a spectacle lens designed to reduce peripheral hyperopic defocus. Asian children (n = 210) with myopia (−0.75 to −3.50 D sphere) were randomized to a double-masked study. Primary and secondary outcome measures were changes in central cycloplegic autorefraction and eye AL, respectively. For the entire group, there were no statistically significant differences in the rates of progression. However, in 100 younger children (6 to 12 years) with parental history of myopia, there was 30% less (−0.68 ± 0.47 D; p = 0.038) myopia progression compared with control spectacles (−0.97 ± 0.48 D).

Lam et al designed a Defocus Incorporated Multiple Segments (DIMS) spectacle lens that contains multiple areas of midperipheral myopic defocus surrounding a central optical zone that corrects the distance refractive error.135 In a randomized double-masked study of 160 Asian children (age 8 to 13, myopia from −1.00 to −5.00 D), they found that the DIMS spectacle lens decreased myopia progression by 59% and AL progression by 60%.


Orthokeratology and Multifocal Soft Contact Lenses

Clinical trials have not shown that conventional contact lenses (neither soft nor rigid gas permeable [RGP]) slow myopia progression.136,137 However, as described later, both OK and multifocal soft CLs can provide relative peripheral myopic defocus (relative plus power in the visual periphery) compared to the central correction. According to the model, this peripheral plus creates a “stop signal” for visually directed growth, which should result in an accompanying decrease in myopia progression.


Orthokeratology

OK (also sometimes called corneal refractive therapy—CRT) is a nonsurgical vision treatment with RGP contact lenses (usually worn overnight) that are specially designed to reshape the curvature of the cornea; myopia is the most commonly treated condition, although sometimes hyperopia and astigmatism are also treated. Change in refraction is achieved by:



  • horizontal peripheral movement (displacement) of corneal epithelial cells138,139 created when the midperipheral-bearing area of the lens creates a seal and reverse pressure, along with a


  • change in the curvature of the central cornea caused by mechanical flattening.


OK, which provides a “wow factor” by rapidly reducing the need for daily wearing of glasses or contact lenses, is most effective when there is moderate (−1.25 to −4.00 D) myopia and larger pupils. It is more difficult to achieve success with lower (probably because of the smaller amount of midperipheral plus induced) or higher myopia (inability to achieve the targeted prescription).140,141,142 Dropout rates are around 20%; however, patients who continue OK have been found to be more satisfied than children fit with traditional contact lenses.143 VA improvement is excellent with most patients achieving 20/20 and over 90% achieving 20/30 unaided acuity during the day when lenses are not worn.144

Refractive changes are not permanent with OK. The refractive error will return when OK lens wear is discontinued and, to maintain acceptable daytime vision, a retainer lens must be worn indefinitely. The amount of time a retainer lens must be worn is determined by the stability of the OK result—it could be as little as one time per week or as often as every other night.

OK was shown, in a retrospective study of 253 children ages 6 to 18, to slow myopia progression up to 0.5 D per year.145 And, in a 1-year crossover design study, Swarbrick et al146 compared the results of conventional rigid gas-permeable (RGP) and OK lens treatment of 26 Asian myopic children (aged 11 to 17). Each subject wore an overnight OK lens in one eye and a conventional RGP lens during the daytime in the other. The lenseye combinations were reversed after 6 months and lens wear was continued for another 6 months. After the first 6 months, the average AL of the eye wearing the RGP lens had increased by 0.04 mm; the OK-treated eye showed no change. When lens-eye combinations were reversed, the OK-treated eye showed no change in AL; the conventional RGP-treated eye demonstrated a mean increase of 0.09 mm in AL.

Other prospective clinical trials used AL and wash-out cycloplegic measurements to demonstrate that OK tends to slow the progression of myopia by about 40%.140,147,148 There are also data supporting the additive effects of optically correcting myopic children with OK in conjunction with low dosages of atropine. In a 1-year study, “OK and atropine” subjects increased AL by 0.09 mm,149 whereas “OK only” subjects increased AL by 0.19 mm. According to the model, this additive effect occurs because OK and atropine influence different “stop mechanisms” for myopia progression.


Soft Contact Lenses with Plus Periphery (Soft Multifocal with Center-Distance Design)

There is also interest in treatment of myopia progression using soft lenses designed with a distance center and midperipheral plus, a combination that results in optics analogous to those produced during OK treatment.150,151,152 The model suggests that center-distance soft multifocal contact lenses may have better success than OK when there is less than −2.00 D of myopia. This has been shown during OK treatment of smaller amounts of myopia where OK effectiveness on myopia control is decreased,140 presumably because of the fact that the smaller amount of myopia being treated provides an insufficient peripheral inhibition signal to retinal growth.

The concept is that the peripheral plus of the multifocal contact lens needs to be strong enough to have a significant inhibitory effect on myopia progression. The optimum soft multifocal with center-distance design includes smaller central optic zones and a larger stronger peripheral plus lens stimulating retinal area to cause greater slowing of myopia progression. In general, the bifocal addition should be no less than +2.50, tending toward the strongest add power that does not impair clear distance vision.

Aller et al153 used an Acuvue center-distance bifocal soft contact lens in treatment of myopic patients with near esophoria and, after 1 year, achieved almost 70% reduction in myopia progression. The high incidence of near esophoria among myopic patients increases applicability of this finding (see discussion later in this chapter).

Paune et al154 allocated children who had myopic progression after 1 year of traditional (contact lens or spectacle) correction to one of three groups:



  • 1. distance center and plus mid-periphery (DC/+MP) multifocal soft contact lenses,


  • 2. OK, or


  • 3. Single vision glasses (SVG).

After 2 years, there was a reduction in myopic progression of 43% and 67% for the DC/+MP and OK-treated subjects compared with the SVG wearers. AL growth was decreased by 27% and 38% in the DC/+MP and OK groups, compared with the SV group. These results are similar to meta-analysis of eight studies (587 subjects), which indicted that distance centered multifocal soft contact lens designs slowed myopia progression by more than 30% and axial elongation by more than 31% over 24 months.155

Turnbull et al156 executed a retrospective case series analysis of 110 myopic subjects and determined that OK and multifocal soft lens treatment equally slowed myopic progression: OK treatment progression of −1.17 D per year before treatment was reduced to −0.09 D per year after treatment; multifocal soft contact lens progression of −1.15 D per year before treatment was reduced to −0.10 D per year after treatment. With a smaller (32 case) retrospective analysis, Cooper et al157 reported that a center-distance soft multifocal contact lens slowed
myopic progression of the right eye from −0.85 D per year before treatment to −0.04 D per year after treatment and for the left eye from −0.90 D before treatment to −0.04 D per year after treatment.

Walline et al158 compared children (n = 40) fit with soft multifocal center-distance contact lenses (Proclear Multifocal “D”; +2.00 D add) to a historical age-matched control group of single vision soft contact lens wearers. For the single vision contact lens wearers, myopia progression after 2 years was −1.03 ± 0.06 D and for the soft multifocal contact lens wearers, it was −0.51 ± 0.06 D (p = 0.0001). The mean axial elongation was 0.41 ± 0.03 mm for the single vision and 0.29 ± 0.03 mm for soft multifocal contact lens wearers (p = 0.0016).


Side Effects and Safety of OK and Soft Multifocal Contact Lenses

As with any contact lens wear, proper cleaning and hygiene is mandatory for either OK or soft multifocal lens wear. Assuming proper care, all contact lenses are quite safe; however, there is a potential risk of microbial keratitis (MK). Generally, OK lenses have been found to be safer than other types of contact lenses, although all types of contact lenses have a higher incidence of MK than the incidence of 1.4 per 10,000 (1.4/10 K) in noncontact lens wearers. The rate of OK-associated MK is 7.7/10 K, which is lower than the 11.9/10 K in silicone hydrogel daily wearers, and 25.4/10 K in soft contact lens extended wear (where the greatest incidence of MK occurs).159 The incidence of MK is similar for soft multifocal and single vision soft lenses. Perhaps because of care differences, the incidence of MK is lower for younger children, higher for teenagers, and then lower again for adults who are treated with OK.160

The relative safety of OK lens wear is influenced by the fact that the lenses are typically worn during sleep (8 to 10 hours/day) rather than the 160 continuous hours that weekly extended wear lenses are worn. Corneal infiltrates, which only occasionally occur with OK lens wear, can be minimized using hydrogen peroxide solutions and careful design of the mid-periphery of the lens so that there is enough tear film exchange to prevent the lens from becoming too tight. OK lenses are more oxygen permeable than soft lenses and biofilm does not readily stick to the smooth surface of the lens. The majority of infections that do occur can be treated with aggressive antimicrobial therapy. There are very few cases of vision loss (0.4/10 K), although infection that results from Acanthamoeba or Fusarium can result in significant corneal damage and concurrent severe vision loss.161

The most significant complaints from OK patients are discomfort from the lenses and halos secondary to spherical aberration (which reduces contrast sensitivity and VA).162 Soft lens wearers complain of dryness and fluctuating vision more often than discomfort.


Rebound Effect

Cho and Cheung163 evaluated the response when OK lenses were discontinued by comparing AL in two patient groups. Group 1 wore OK lenses for 24 months, discontinued lens wear and wore single vision spectacles for 7 months, and then resumed OK lens wear for another 7 months. Group 2 was a spectacle-wearing control group. Suspending OK lens wear resulted in more rapid increase in AL compared to subjects wearing spectacles. Axial elongation decreased after resumption of OK.

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Apr 13, 2020 | Posted by in OPHTHALMOLOGY | Comments Off on Development and Management of Refractive Error: Binocular Vision-Based Treatment

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