Distribution of Refractive Errors (young adult population) Newborns frequently have large optical errors, however, these errors usually disappear.

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1 Distribution of Refractive Errors (young adult population) from Sorsby, 97 Major differences from random distribution: - more emmetropes than predicted - fewer moderate errors (e.g., -. D) - more high errors (e.g., -. D) i.e., the function is leptokurtotic. theoretical Gaussian distribution Frequency (%) Age - yrs (Kempf et al) Nearsighted Newborns (Cook & Glasscock) Farsighted Ideal Optical Conditions Newborns frequently have large optical errors, however, these errors usually disappear. Changes in Refractive Error with Age Myopia in Premature Infants Refractive Error (D) Age Norms of Refraction (Slataper, 9) more typical 7 9 Average data are not very predictive of changes on an individual basis before about years. Thereafter, most people experience the same trends. Born before weeks &/or birth weights < g; no ROP Age (weeks) Myopia associated with short axial lengths & steep corneas. Recovery primarily due to corneal flattening. Human Infants Mean Edwards, 99 Wood et al., 99 Thompson (97) from Saunders Saunders, 99 Gwiazda et al, 99 Atkinson et al., 99 Emmetropization is the process that guides ocular growth toward the optimal optical state. It occurs very rapidly; most infants develop the ideal refractive error by - months. Emmetropization is very successful. From Mayer et al., (n = ) Cycloplegic refractions in healthy, full-term children to months of age. The key point is that refraction becomes less variable and is relatively constant from about to months.

2 9% confidence limits (D)..... Net Anisometropia Howland & Sayles (97) Normal Infants n = cylinders spheres During the period of rapid emmetropization, the degree of anisometropia typically decreases (i.e., isometropization occurs). Number of Patients Prevalence of Anisometropia (Abrahamsson et al., 99) >. D new cases loss of aniso Normal Infants n= Isometropization Anisometropia is frequently transient during early development.. Axial Length (mm) Axial Length Development Gordon & Donzis Larsen, males Laren, females Zadnik et al Fledelius Axial Length Development Rapid Infantile phase (- yrs) -- axial length increases about - mm. Slower Juvenile phase (- yrs) -- axial length increases about mm. Axial Length (mm) Gordon & Donzis Larsen, males Laren, females Zadnik et al Fledelius Corneal Power (D) Corneal Development Gordon & Donzis Woodrift Zadnik et al. Corneal Power (D) Corneal Development Gordon & Donzis Woodrift Zadnik et al. Major Optical Changes: ) flatter cornea (- D) ) deeper AC (.D) ) flatter lens (- D) Anterior Chamber Depth Birth Lens Power (D) Lens Development Gordon & Donzis Zadnik et al. Lens Power (D) Lens Development Gordon & Donzis Zadnik et al. Major Optical Changes: ) flatter cornea (- D) ) deeper AC (.D) ) flatter lens (- D) AC depth increases from about. mm at birth to about. mm at years (about. D).

3 Zadnik et al., 99 Refractive Development: Early School Years Changes with Age Early School Years Age Norms of Refraction (Slataper, 9) - Corneal Power (D) Refractive Error - Zadnik et al., 99 Corneal Power (D) 7 Cornea Refractive Error (D) Axial Length (mm) 7 9 Age (yrs) From about to 7- years, the mean refractive error is quite stable & the degree of variability is low. Lens Power (D) Axial Length (mm) Axial Length Lens Power (D) 9 Lens During early adolescence, the cornea is relatively stable. The slow decrease in lens power is counterbalanced by an increase in axial length. Refractive Development: Early School Years Lens Thickness Refractive Development: Early School Years Anterior Chamber Depth Wong et al., Wong et al., Myopic Progression Myopia (percent) Prevalence of Myopia in Humans School Years Jackson, 9 Tassman, 9 Age in Years The decrease in mean refractive error between about and years is due primarily to the onset of school myopia in a small proportion of the population. Males Females Youth-Onset or Juvenile-Onset, or School Myopia For many individuals, myopic progression stops in late teenage years associated with the normal cessation of axial growth.

4 Percent Myopic Adult Onset Myopia Classifications of Myopia Vitale et al 9 % of myopes become myopic after 7 yrs 97 to to to 7 yrs to yrs to yrs Age Group to yrs to yrs Grosvenor, 97 Congenital = present at birth & persists through infancy. Youth-onset = occurs between years and early teens. Early adult-onset = occurs between & years Late adult-onset = occurs after years. Annual Rate of Myopic Progression Age of Onset vs. Degree of Myopia From Goss, 99 Proportion of Sample Males Females Rate varies considerably between individuals. Average = -. to -. D/yr (before age yrs) Myopic Progression (D/year) The earlier the onset of myopia the higher the rate of progression and the final degree of myopia. Axial Nature of Myopia.. Predictability of Refractive Errors at Age - Years The rate of myopic progression is highly correlated with the rate of axial elongation. Proportion of Sample > >. Refractive Error Distributions for Children at - years who develop: Myopia >. D Emmetropia -.9 to +.99 D Hyperopia >. D >. From Goss, 99 From Hirsch, 9

5 Refractive Error (D) Changes in Refractive Error with Age Age Norms of Refraction (Slataper, 9) Acquired hyperopia due to: ) presbyopia ) lens continues to flatten ) refractive index of lens cortex increases Lens Development - Mass The crystalline lens continues to grow throughout life. more typical 7 9 Weale, 9 Acquired Hyperopia Changes in Refractive Error with Age Vitreous Chamber Young adult ( yrs) =. mm Mature adult ( yrs) =.7 mm Ooi & Grosvenor, 99 Refractive Error (D) Age Norms of Refraction (Slataper, 9) Decrease in hyperopia due to increase in refractive index of core of crystalline lens. more typical 7 9 Prevalence of Astigmatism (young adult population) Astigmatism Axis vs Spherical Ametropia Young Adult Population Mandel et al., Percentage of Population Astigmatism is the most common ametropia. The magnitude is, however, usually relatively small..... > Amount of Astigmatism (D)

6 Prevalence of Astigmatism: Infants Marked levels of astigmatism are common in young infants -- due primarily to corneal toricity. Prevalence of Astigmatism (> D) in Human Infants Prevalence (%) Santonastaso, 9 Howland et al., 97 Mohindra et al., 97 Atkinson et al., 9 Fulton et al., 9 Gwiazda et al., 9 Edwards, 99 Saunders, 99. Atkinson et al. 9 Age (weeks) Longitudinal Changes in Astigmatism Almost every infant shows a decrease in astigmatism during early infancy. Early astigmatism may not be very predictive of astigmatism later in life. Axis of Astigmatism: Infants Right eye astigmatism at 9 months of age (n =, Cambridge, UK). W-t-R astigmatism predominates. Atkinson et al. 9 from Ehrlich et al., 997 Change in Axis of Astigmatism Change in Corneal Power & Astigmatism W-t-R A-t-R With age the prevalence of W-t-R decreases & there is a concomitant increase in A-t-R. Most of the changes occur after about years of age and occur at a rate of about. D every years. After age years, the cornea gets progressively steeper. The reduction in the radius of curvature is greater for the horizontal meridian. oblique age in decades Bennett & Rabbetts, 99 Bennett & Rabbetts, 99

7 My Eyelash Distribution of Refractive Errors (young adult population) Major differences from random distribution: - more emmetropes than predicted - fewer moderate errors (e.g., -. D) - more high refractive errors (e.g., -. D) theoretical Gaussian distribution About microns from Sorsby, 97 Frequency Distributions for Individual Ocular Components Since the distribution of refractive errors is leptokurtic, there can not be free association between individual components. Highest correlation is typically found between refractive error and axial length. from Sorsby, 97 Nature of Refractive Errors emmetropes ametropes from Sorsby, 97 Not all emmetropic eyes are alike. Ks = D Lens =..9 D AC =.. mm AL =.. mm Ametropic eyes between - D and + D frequently have individual ocular components that fall within the range for emmetropic populations. With larger ametropias, one component, typically axial length, falls outside the range for emmetropia. Factors that influence refractive state Prevalence of Myopia in Different Ethnic Groups Genetic Factors ethnic differences in the prevalence of refractive errors familial inheritance patterns monozygotic twins candidate genes Environmental Factors humans: epidemiological studies of prevalence of myopia lab animals: restricted environments lab animals: altered retinal imagery Prevalence of Myopia (%) Swedish British Israeli Malay Indian Eurasian Chinese Ethnic Category 7

8 Percent Children Myopic Twin Familial Inheritance Patterns from Zadnik, 99 None One Both If both parents are myopic, the child is - times more likely to be myopic than if neither of the child s parents are myopic. Intrapair Correlations for Refractive Error Monozygotic vs Dizygotic Twins (Dirani et al., ) Monozygotic Twins r =. r =. Dizygotic Twins Myopic Parents Twin Twin Twin B: Refractive Error (D) - Monozygotic Twins (Sorsby et al., 9) Evil twin? Dr. Y. Chino Good twin? Identical twins have very similar refractive errors. Procentage of Sample Concordance of Optical Components (from Sorsby et al., 9) uniovular twins other pairs Not only do twins have identical refractive errors, their eyes have very similar dimensions. Concordance limits: Axial length =. mm corneal & lens power =. D AC depth =. mm lens thickness =. mm total power =.9 D Twin A: Refractive Error (D) Number of Individual Components Myopia and Genetics (peer-reviewed publications per year) Genetic Loci for Myopia 99- Published Papers Locus Location Study Myopia Severity MYP Xq Schwartz et al, to -. D MYP p. Young et al, to - D MYP q-q Young et al, to - D MYP 7q Naiglin et al, Avg = -. D MYP 7q-q Paluru et al, -. to - D

9 Genetic Loci for Myopia to 9 Locus Location Study Myopia Severity Genetic Factors & Myopia Schuman et al., MYP q Stambolian et al, -. D or lower MYP7 p Hammond et al, -. to +7. D MYP q Hammond et al, -. to +7. D MYP9 q Hammond et al, -. to +7. D MYP p Hammond et al, -. to +7. D MYP q-q7 Zhang et al, - to - D MYP q7. Paluru et al, -7. to -7 D MYP Xq-q Zhang et al, -. to - D MYP p Wojcechowski et al, Avg = -. D MYP q. Nallasamy et al, 7 Avg = -7. MYP p.-p. Lam et al, -7. to -. D MYP? q Klein et al, 7 Range of Errors MYP? 7p Klein et al, 7 Range of Errors MYP? q.-. Klein et al, 7 Range of Errors MYP? 7p Ciner et al, Avg = -.7 D MYP? q Andrew et al, - to +.7 D MYP? q.-. Ciner et al, 9 Avg = -.9 D MYP? 9q. Li et al, 9 <-. D MYP? q Solouki et al, 9 Range of Errors MYP? q Hysi et al, 9 Range of Errors Variations in amino acid sequences at MYP (Xq) appear to influence the degree of myopia. Myopia has historically been associated with nearwork. Nearsighted (percent) University Students Clerks Cultured people (actors & musicians) Tailors Skilled workmen (butchers) Farmers and Seamen Heavy Near Work Little Near Work Occupation Tscherning, (Duke-Elder, 97) Nearsighted (percent) The prevalence of myopia is synchronized with the onset of formal schooling. School Years (Jackson, 9; Tassman, 9) Age in Years Proportion of Myopes (%) Significant Associations in Myopia Myopia & Intelligence Myopia & Education < >7 < 9 > IQ Score Years of Education Prevalence Rate (%) An Epidemic of Myopia 9 Lin et al., Taiwanese School Children 99 Average Degree of Myopia (D) 9 Years Years Years Age The prevalence and average degree of myopia is increasing rapidly over time. 9

10 Prevalence of Myopia (%) Odds ratio An Epidemic of Myopia National Health and Nutrition Examination Survey data from vs 999- Outdoor activities have a strong protective effect against myopia. Females Males Mitchell et al., 97-7 Age (yrs) 999- Age (yrs) Vitale et al., 9 The prevalence of myopia is increasing too fast to reflect genetic changes; something in the environment is affecting the pattern of refractive errors High Moderate Low near-work Low Moderate High Multivariable-Adjusted Odds for Myopia outdoor Refractive Error (D) Restricted environments promote myopia Monkeys in Restricted Environment Mean (n=) (from Young, 9) Adolescent Monkeys: - years of age Mean (n=) Time in Restricted Environment (weeks) Monkeys reared in restricted visual environments develop myopia. Avoids many of the confounding variables in human studies -- in particular self selection. Attributed to excessive accommodation. Insights from Studies of Laboratory Animals Refractive development is regulated by visual feedback associated with the eye s refractive state. Basic Observations: Emmetropization Form-deprivation myopia Recovery from form-deprivation myopia Optically imposed defocus Emmetropization Requires Vision Normal Monkeys Dark-reared Monkeys Chronic Image Degradation Causes Myopia Monocularly Form-Deprived Monkeys normal eye deprived eye Vitreous Chamber Growth Human days Guyton et al., 97 Wiesel & Raviola, 977 Vitreous Chamber (mm) Age (months) The potential for a clear retinal image is essential for normal refractive development. deprived eye fellow eye

11 Anisometropia (D) (treated eye control eye) Aves FDM occurs in a wide variety of animals. Vertebrata Marsupialia Terrestrial vertebrates New World Tree Shrews Placental mammals Rodentia Old World Primates Lagomorpha Human Carnivora Percentage of Cases Form-Deprivation Myopia Form-deprivation Myopia Monkeys Humans 7 Raviola and Wiesel, 99 von Noorden and Crawford, 97 Smith et al., 97 Normal Monkeys Deprived Monkey Eyes "deprived humans" Normal humans Rabin et al. (9) FDM occurs in a wide variety of animals -- including humans-- which suggests that the mechanisms responsible for FDM are probably fundamental to ocular development. The potential for a clear retinal image is essential for normal emmetropization. Recovery from Form-Deprivation Myopia Normal Monkeys - Treatment Period Recovery Period - End of Treatment - Monkey LIS Deprived Eye Non-Treated Eye End of Treatment Emmetropization is guided by optical defocus. Optically imposed refractive errors produce predictable refractiveerror changes. Positive Treatment Lens Imposed Myopia: To compensate, the eye must become more hyperopic. ays) Vitreous Chamber (mm) - treatment period 9 Negative Treatment Lens Imposed Hyperopia: To compensate, the eye must become more myopic Lens Compensation in Monkeys +9. D RE vs. Age for Binocularly Lens-Reared Monkeys +. D Expected Ametropia +. D. D -. D -. D Vitreous Chamber (mm) 9 Vision-Induced Ametropias Are Axial in Nature Negative Lenses Positive Lenses - Lens-Reared Monkeys r =. n = - 9 Vitreous Chamber (mm)

12 . Emmetropization: Effective Operating Range Effective Operating Range for Emmetropization Monkeys vs Humans Lens Power (D) Chick (Wallman & Wildsoet, 99) Chick (Irving et al., 99) Tree Shrew (Siegwart & Norton, 99) Monkey (Smith et al.) Marmoset (Whatham & Judge, ) Moderate powered treatment lenses produce predictable changes in refractive error in many species.. Change in Refractive Error (D) Monkeys B. Effective Emmetropization Range r ² = Effective Refractive Error (D) Mutti et al. () Humans Large refractive errors produce unpredictable growth possibly these eyes have faulty emmetropization mechanisms. - RE = -. D lens LE = Plano lens Optically Imposed Anisometropia RE = +. D lens LE = Plano lens - RE = Positive lenses LE = Negative lenses Positive Lens Negative Lens Plano Lens Regulation of refractive development is largely independent in the two eyes. Anisometropia (D) Optically Imposed Anisometropia Interocular Differences in Refractive Error Monkeys Treated eye = -. D lens Fellow eye = Plano lens - Humans Philips, Monovision correction Humans and monkeys respond in a similar manner to imposed defocus. Insights from Studies of Laboratory Animals Vision-dependent mechanisms that regulate refractive development are active well into early adult life. Basic Observations: FDM myopia and anisometropic compensation in mature animals. Phenomenon of adult onset myopia and adult progression in humans. Axial Length (mm) Age Effects: Are vision dependent mechanisms only active early in life? Age (human years) Onset of Juvenile Myopia Age (monkey years) Normal Monkeys Gordon & Donzis Larsen, males Laren, females Zadnik et al Fledelius Treated Monkeys

13 Vitreous Chamber (mm) (treated eye - fellow eye).... Late Onset Form Deprivation Vitreous Chamber Depth Age (Human Years) Anisometropia (D) (fellow eye - treated eye) Anisometropia (End of Treatment) 7 Individual Subjects Early Adult Onset Myopia McBrien & Adams, 997 Adult Onset Adult Progression Examples of adult onset myopia associated with a change in occupation. Insights from Studies of Laboratory Animals When the eye is presented with two different focal plans viewed sequentially, refractive development is dominated by the least hyperopic / most myopic focus. Interrupted Lens Compensation Treatment period: onset: days duration: 7 days Temporal Integration Properties of Emmetropization n= n=7 n=7 n= Daily Exposure History Continuous FD hr hr hr Hours of the Light Cycle Form Deprivation Unrestricted Vision Temporal Integration Properties: Similarities Between Species Effects of Brief Periods of Unrestricted Vision on Compensation for Binocular Negative Lenses Anisometropia (D) (treated eye - fellow eye) 7 n = n = 7 Refractive Error n = 7 n = months of age n = Vitreous Chamber (mm) (treated eye - fellow eye)..... Vitreous Chamber n = n = 7 n = 7 n = n = n= n= Daily Exposure History - D Lenses Unrestricted Vision Hours of Unrestricted Vision Hours of Unrestricted Vision Hours of the Light Cycle Brief daily periods of unrestricted vision counterbalance long daily periods of form deprivation. Treatment period: onset: days duration: days

14 - Lens Compensation for Continuous -D Lenses Normal Monkeys Continuous - D Lenses 9 - End of Treatment Averages +. D -. D - Effects of hour of vision through plano lenses on compensation for D lenses. Normal Monkeys -hr Plano Lenses Continuous - D Lenses 9 End of Treatment Averages +. D +. D - -. D - Implications for Nearwork - D continuous Normals hr plano lens D-hrs + D-hrs per day + D-hrs / day Diopter Hours Relative to Controls - D Lenses Unrestricted Vision Hours of the Light Cycle Visual signals that increase axial growth and those that normally reduce axial growth are not weighed equally. To stimulate axial growth, a myopiagenic visual stimulus must be present almost constantly. Insights from Studies of Laboratory Animals When the eye is presented with two different focal plans viewed simultaneously, refractive development is dominated by the least hyperopic / most myopic focus. Dual Power Lenses Effects of Simultaneous Defocus Dual-Focus Lenses Tse et al. 7 Vitreous Chamber (mm) D / plano MKY. Normal Monkeys Right Eye +D/pl Left Eye +D/pl Myopic Defocus vs Unrestricted Vision + D / Plano Lenses Longitudinal Refractive Error End of Treatment Normals + D Full Field +D / Pl Refractive development was dominated by the positivepowered portion of the lens.

15 Hyperopic Defocus vs Unrestricted Vision - D / Plano Lenses Longitudinal Refractive Error End of Treatment - - Normals -D Full Field -D / Pl Refractive development was dominated by the zeropowered portion of the lens.