1

Refractive Development

Refractive Development: Main Parts

• Prevalence of refractive errors and changes with age.

• Factors affecting refractive development.• Operational properties of the vision-

dependent mechanisms that mediate emmetropization.

• How visual signals are transformed into biochemical signals for eye growth.

Emmetropia (ideal refractive state)

A distant object is imaged sharply on the retina when

accommodation is relaxed.

Myopia (near sighted)Image comes to a focus in

front of the retina.

Hyperopia (far sighted)Image comes to a focus behind

the retina.

2

Distribution of Refractive Errors(young adult population)

theoreticalGaussian

distribution

Major differences from random distribution:

- more emmetropes than predicted- fewer moderate errors (e.g., -2.0 D)- more high refractive errors (e.g., -6.0 D)

from Sorsby, 1957

Frequency Distributions for 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, 1957

-8 -6 -4 -2 0 2 4 6 8 10 12

Fre

quen

cy (

%)

0

10

20

30

40

Nearsighted Farsighted

Newborns(Cook & Glassgock)

Age 4-6 yrs(Kempf et al)

Newborns frequently have large optical errors, however, these errors usually disappear.

Ideal Optical Conditions

3

Age (days)

0 200 400 600

Me

an A

me

trop

ia (

D)

0

1

2

3

4

Edwards, 1991

Wood et al., 1995

Thompson (1987) from Saunders

Saunders, 1995

Gwiazda et al, 1993

Atkinson et al., 1996

Human Infants

Emmetropization occurs very rapidly. Most

infants develop the ideal

refractive error by 12-18 months.

Axial Development

Rapid Infantile phase (0-3 yrs) -- axial length increases about 6mm.Slower Juvenile phase (3-14 yrs) -- axial length increase about 1 mm.

Increase in AL counterbalanced by:

1) flatter cornea (4-5 D)2) deeper AC (0.8D)3) flatter lens (15 D)

Age Norms of Refraction(Slataper, 1950)

Age (years)

0 10 20 30 40 50 60 70 80 90

Ref

ract

ive

Err

or

(D)

0

1

2

3

4

Changes in Refractive Error with Age

Clinical population data are not very

predictive of changes on an individual basis before about 20

years. Thereafter, most people

experience the same trends.more typical

4

Age Norms of Refraction(Slataper, 1950)

Age (years)

0 10 20 30 40 50 60 70 80 90

Ref

ract

ive

Err

or (

D)

0

1

2

3

4

Acquired hyperopia due to:

1) presbyopia2) lens continues to flatten3) refractive index of lens

cortex increases

more typical

Changes in Refractive Error with Age

Age Norms of Refraction(Slataper, 1950)

Age (years)

0 10 20 30 40 50 60 70 80 90

Ref

ract

ive

Err

or (

D)

0

1

2

3

4Decrease in hyperopia

due to increase in refractive index of core of

crystalline lens.

more typical

Changes in Refractive Error with Age

Factors that Influence Refractive Development

• 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

5

Ethnic Category

Swedish British Israeli Malay Indian Eurasian Chinese

Pre

vale

nce

of M

yopi

a (%

)

0

10

20

30

40

50

60

Prevalence of myopia by ethnic category

Zadnik & Mutti, 1998

College-age samples

Myopic Parents

None One Both

0

5

10

15

from Zadnik, 1995

If both parents are myopic, the child is

4-5 times more likely to be myopic

than if neither of the child’s parents are

myopic.

Familial Inheritance Patterns

Per

cent

age

Myo

pic

Chi

ldre

n

Twin A: Refractive Error (D)

-8 -6 -4 -2 0 2 4 6 8

Tw

in B

: Re

fra

ctiv

e E

rro

r (D

)

-8

-6

-4

-2

0

2

4

6

8

Monozygotic Twins

Identical twins have very similar refractive

errors.

Sorsby et al., 1962

6

Concordance of Optical Components

Number of Individual Components1 2 3 4 5 6

Pro

cent

age

of S

ampl

e

0

20

40

60

80

100other pairs

uniovular twins

(from Sorsby et al., 1962)

Not only do twins have identical refractive errors,

their eyes have very similar dimensions.

Concordance limits:Axial length = 0.5 mm

corneal & lens power = 0.5 DAC depth = 0.1 mm

lens thickness = 0.1 mmtotal power = 0.9 D

1970 1980 1990 2000 2010

Pub

lish

ed

Pap

ers

0

20

40

60

80

Myopia and Genetics(peer-reviewed publications per year)

Occupation

1 2 3 4 5 6

Nea

rsig

hted

(pe

rcen

t)

0

5

10

15

20

25

30

35

Heavy Near Work Little Near Work

University Students

Farmers and Seamen

Tailors

Skilled workmen (butchers)

ClerksCultured people (actors & musicians)

Tscherning, 1882(Duke-Elder, 1970)

Myopia has historically been associated with nearwork.

7

Age in Years0 10 20 30 40

Ne

arsi

gh

ted

(p

erc

ent)

0

5

10

15

20

25

30

35

The prevalence of myopia is synchronized with the onset of formal schooling.

School Years (Jackson, 1932; Tassman, 1932)

An Epidemic of Myopia

Age (years)

6 8 10 12 14 16 18 20

Pre

vale

nce

Rat

e (%

)

0

20

40

60

80

100

Age12 Years 15 Years 18 Years

Ave

rage

Deg

ree

of M

yopi

a (D

)

0

1

2

3

419862000

Lin et al., 2004

1986

2000

1995

Taiwanese School Children

Vitale et al., 2009

An Epidemic of MyopiaNational Health and Nutrition Examination Survey data from 1971-1972 vs 1999-2004

Females Males

1971-72

1999-04

Age (yrs)Age (yrs)

Pre

vale

nce

of M

yopi

a (%

)

The prevalence of myopia is increasing too fast to reflect genetic changes; something in the environment is affecting the pattern of refractive errors.

8

Outdoor activities have a strong protective effect against myopia in children.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

High Moderate Low

High

Moderate

Low

o

Od

ds

rati

o

Rose et al., 2008

Near-work

The protective effects are not associated with exercise and they do not represent a “substitution effect” for near work. Reductions in the absolute amount of outdoor activities occur 3 years prior to the onset of myopia.

Jones et al., 2007, 2011; Rose et al., 2008; Dirani et al., 2009

Jones et al. 2007

Monkeys in Restricted Environment

Time in Restricted Environment (weeks)0 10 20 30 40 50

Ref

ract

ive

Err

or (

D)

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

(from Young, 1963)

Mean (n=12)

Mean (n=18)

Adolescent Monkeys: 4-6 years of age

Restricted environments promote myopia.

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.

Age (days)

0 50 100 150 200

0

2

4

6

8

10

Emmetropization Requires Vision

Am

etro

pia

(D)

Normal Monkeys Dark-reared Monkeys

Age (days)

Guyton et al., 1987

9

Form Deprivation MyopiaMonocularly lid-sutured

Monkey

Sherman et al., 1977

Monocularly lid-sutured Tree Shrews

Interocular Differences in Refractive Error Monocularly Form-deprived Monkeys

0 10 20 30 40 50

An

iso

met

ropi

a (D

)(d

epr

ive

d e

ye -

co

ntro

l eye

)

-16

-12

-8

-4

0

4

De

priv

ed

eye

mor

e m

yopi

c

n = 53

normal eye

Ani

som

etro

pia

(D)

(dep

rive

d ey

e –

cont

rol e

ye)

Individual Subjects

FDM is a robust, but graded phenomenon. The 2 eyes are

largely independent.

Wiesel & Raviola, 1977

deprived eye

Ametropia (D)

-15 -10 -5 0 5 10

0

10

20

30

40

50

60

70

"deprived humans"

Normal humans

Rabin et al. (1981)

Ametropia (D)

-15 -10 -5 0 5 10

Pe

rcen

tage

of C

ase

s

0

10

20

30

40

50

60

70

Normal Monkeys

Deprived Monkey Eyes

Raviola and Wiesel, 1990von Noorden and Crawford, 1978Smith et al., 1987

Monkeys Humans

Form Deprivation Myopia

-4

-2

0

-4

-2

0

Normal MonkeysTreatment PeriodRecovery PeriodEnd of Treatment

-4

-2

0

Age (days)

0 200 400 600

-4

-2

0

Recovery from Form-Deprivation Myopia

Ani

som

etro

pia

(D)

(tre

ated

eye

–co

ntro

l eye

)

0 100 200 300

Am

etro

pia

(D)

-2

0

2

4

6

8

10Monkey LIS Deprived Eye

End of Treatment

Non-Treated Eye

Age (days)

0 100 200 300

Vitr

eous

Cha

mb

er (

mm

)

8

9

10

11treatment period

10

Effects of Imposed Defocus

+9.0 D

Age (days)0 100 0 100 0 100 0 100 0 100 0 100

Am

etro

pia

(D)

-6

-4

-2

0

2

4

6

8

10

+6.0 D +3.0 D 0.0 D -3.0 D -6.0 D

ExpectedAmetropia

Binocularly Lens-Reared Monkeys

A. Treatment Period

Age (days)

0 50 100 150

Re

lativ

e V

itreo

us C

ham

ber

(mm

)

9

10

11 Positive LensesNegative Lenses

B. Recovery Period

Age (days)

100 150 200 250 300

Re

lativ

e V

itreo

us C

ham

ber

(mm

)

-0.5

0.0

0.5

1.0

1.5

Vitreous Chamber Growth

Hyperopic defocus (negative lenses) causes the eye to grow faster; myopic defocus (positive lenses) slows growth.

Lens Power (D)

-10 -5 0 5 10 15

Am

etro

pia

(D

)

-10

-5

0

5

10

Chick (Wallman & Wildsoet, 1995)

Chick (Irving et al., 1995)

Tree Shrew (Siegwart & Norton, 1993)

Monkey (Smith et al.)

Marmoset (Whatham & Judge, 2001)

Emmetropization: Effective Operating Range

Moderate powered treatment lenses

produce predictable changes in refractive

error in many species.

11

B. Effective Emmetropization Range

Effective Refractive Error (D)

-8 -4 0 4 8 12

Cha

nge

in R

efr

activ

e E

rror

(D

)

-12

-8

-4

0

4

r ² = 0.76

Effective Operating Range for EmmetropizationMonkeys vs Humans

Monkeys Humans

Large refractive errors produce unpredictable growth – possibly these eyes have faulty emmetropization mechanisms.

ove

r n

ext

6 m

on

ths

Optically Imposed AnisometropiaInterocular Differences in Refractive Error

Philips, 2005Monovision correction

Age (days)0 50 100 150

Ani

som

etro

pia

(D)

(tre

ate

d e

ye -

fello

w e

ye)

-3

-2

-1

0

1Treated eye = -3.0 D lensFellow eye = Plano lens

Monkeys Humans

Regulation of refractive development is largely independent in the two eyes.

Age (monkey years)

0 1 2 3 4 5

Age (human years)

0 4 8 12 16 20

Axi

al L

eng

th (

mm

)

12

14

16

18

20

22

24

Normal MonkeysGordon & Donzis Larsen, malesLaren, femalesZadnik et alFledeliusTreated Monkeys

Late-Onset Form Deprivation

Onset ofJuvenileMyopia

12

Age (years)

2 4 6 8

Vitr

eous

Cha

mbe

r (m

m)

(tre

ated

eye

- fe

llow

eye

)

0.0

0.5

1.0

1.5

Age (Human Years)

8 16 24 32

Individual Subjects

1 2 3 4 5 6 7 8

Ani

som

etro

pia

(D)

(fel

low

eye

- tr

eate

d ey

e)

0

1

2

3

4

5

6Vitreous Chamber Depth Anisometropia

(End of Treatment)

Late Onset Form Deprivation

Adult Onset Myopic Progression

Age (years)

20-25 25-30 30-35 35-40 40-45

Pro

port

ion

Pro

gres

sing

(%

)

0

10

20

30

40

50

60

Bullimore, 1998

Progression = >0.75 D over 5 years

Population of contact lens wearers.

Daily Exposure History

Hours of the Light Cycle

0 2 4 6 8 10 12

Form DeprivationUnrestricted Vision

Continuous FD

1 hr

2 hr

4 hr

Treatment period:onset: 24 3 days

duration: 120 17 days

Temporal Integration Properties of Emmetropization

n=6

n=7

n=7

n=4

13

p y p

Hours of Unrestricted Vision

0 2 4 6 8 10 12

Ani

som

etro

pia

(D)

(fel

low

eye

- tr

eate

d ey

e)

0

1

2

3

4

5

6

7

n = 6

n = 7

n = 4

n = 7

n = 14

1 hour of unrestricted vision reduces the degree

of FDM by over 50%.

4 months of age

Temporal Integration Properties of Emmetropization

Hours of Unrestricted Vision

0 2 4 6 8

Re

lativ

e M

yop

ia

-0.25

0.00

0.25

0.50

0.75

1.00 FDM Chicks (Napper et al., 1995)-5 D Lens Tree Shrew (Shaikh et al., 1999)-10 D Lens Chick (Schmid & Wildsoet, 1999)FDM Monkeys

Brief periods of unrestricted

vision counterbalance long periods of

form deprivation in multiple species.

FDM: Compliance Effects

Effects of Brief Periods of Unrestricted Vision on Lens Compensation

Daily Exposure History

Hours of the Light Cycle

0 2 4 6 8 10 12

-3 D LensesUnrestricted Vision

n=6

n=6

Treatment period:onset: 24 3 daysduration: 115 8 days

Macaca mulatta

14

Effects of 1 hour of vision through plano lenses on compensation for –3 D lenses.

Age (days)

0 30 60 90 120 150

Am

etro

pia

(D

)

-2

0

2

4

6

Normal Monkeys1-hr Plano LensesContinuous -3 D Lenses

Am

etr

opia

(D

)

-2

0

2

4

+2.45 D

-0.68 D

+2.63 D

End of Treatment Averages

Hours of the Light Cycle

0 2 4 6 8 10 12

-3 D LensesUnrestricted Vision

Am

etr

op

ia (

D)

-2

0

2

4

-3 D continuous Normals1 hr plano lens

Diopter HoursRelative to Controls

+36 D-hrs / day

+33 D-hrsper day

“0” D-hrs

• Temporal integration factors reduce the likelihood that the eye will become myopic due

to near work.

• Current measures of visual experience are not adequate.

Implications for Nearwork

Age (days)0 50 100 150

Am

etro

pia

(D)

-2

0

2

4

6

8

10

0 50 100 150

Am

etro

pia

(D)

-2

0

2

4

6

8

10

Effects of Simultaneous Defocus

Dual-Focus Lenses +3 D / plano

-3 D / planoTse et al. 2007

15

Age (days)0 50 100 150

Am

etro

pia

(D)

0

2

4

6

8

Normals

+3 D Full Field

+3D / Pl

0

2

4

6

8

Myopic Defocus vs Unrestricted Vision+3 D / Plano Lenses

Longitudinal Refractive Error End of Treatment

Refractive development was dominated by the positive-poweredportion of the lens.

Age (days)

0 50 100 150

Am

etro

pia

(D)

-2

0

2

4

6

8

Normals

-3D Full Field

-3D / Pl

-2

0

2

4

6

8

Hyperopic Defocus vs Unrestricted Vision-3 D / Plano Lenses

Longitudinal Refractive Error End of Treatment

Refractive development was dominated by the zero-powered portion of the lens.

Area Ratio (+3:pl)

Controls "18:82" "25:75" "33:66" "50:50" FF +3D

Am

etro

pia

(D)

0

2

4

6

Even when the positive portion of the lens is 4.5 times smaller than the plano portion, the eye develops hyperopia.

Myopic Defocus vs Unrestricted Vision+3 D / Plano Lenses

+3 single vision

Normals

Baskar Arumugam; Li-Fang Hung; Chi-ho To; Brien A Holden; Earl L Smith Invest Ophthalmol Vis Sci; 2015; 56(7); 2169

16

Main Points• Emmetropization occurs very quickly.• The potential for a clear retinal image is

essential for normal emmetropization• In many species, including higher primates,

emmetropization is regulated by optical defocus.– Vision-dependent mechanisms are active into adulthood.

– Temporal integration factors severely constrain the effects of visual experience.

– The least hyperopic focus plan is usually the target for emmetropization.

What visual system mechanisms are involved in transforming a visual signal into a biochemical signal for growth?

Afferent Componentse.g., “blur detector”

Efferent Componentse.g., accommodation

diffuser

FDM used as a tool to determine what components are important.

0

2

4

6

8

10 destriate optic n. sTTX (treeciliary gaSup. cerv

FDM does NOT require:1) the visual signal to leave the

eye

2) sympathetic or parasympathetic inputs to the

eye.

Form-Deprivation Myopia

Raviola & Wiesel, 1985Norton et al., 1994

Deg

ree

of

Myo

pia

(D)

The vision-dependent mechanisms that

dominate refractive development are located

in the eye.

17

Temporal Field Nasal Field-45 -30 -15 0 15 30 45

Am

etr

opi

a (

D)

-6

-4

-2

0

2

4Fellow Eye

Treated Eye

Eccentricity (deg)

Hemi-field Form-Deprivation in Monkeys

Nasal-Field DiffuserClear Plano Lens

MKY 368

Control Eye

Treated Eye

NasalTemporal

Vitreous Chamber DepthNasal-Field Form Deprivation

Control Eye

Treated Eye

N

N

T

T

Temporal Field Nasal Field

Eccentricity (deg)

-45 -30 -15 0 15 30 45

Am

etro

pia

(D)

1

2

3

4

Treated Eye

Fellow Eye

Hemi-Field Optical DefocusMonocular -3 D Nasal Field

Treated vs. Fellow Eyes

N = 8-3DPlano Plano

18

T45ºN45º

0º

MKY 383

Control Eye

Treated Eye

Treated Eye

T

N

N

T

Control Eye

NasalTemporal

Vitreous Chamber DepthNasal-Field -3 D Defocus

Local Retinal Mechanisms

Afferent

Efferent

•The mechanisms that mediate the effects of visual experience on eye

growth are located largely within the eye and operate in a spatially restricted

manner.

• Global mechanisms (e.g., accommodation or IOP) are unlikely to play a primary role in refractive development.

Central vs. Peripheral Vision

Because resolution acuity is highest at the fovea and decreases rapidly with eccentricity, it has been

assumed that central vision dominates refractive development.

Cone Density vs. Eccentricity

From Rodieck, 1998

fovea

19

Visual signals from the fovea are not essential for:

• Emmetropization• Form deprivation myopia• Recovery from induced refractive errors• Lens compensation

Insights from Studies of Laboratory Animals

Age (days)

0 100 200 300

Ani

som

etro

pia

(D)

(tre

ate

d e

ye -

fello

w e

ye)

-2

-1

0

1

2

Normal MonkeysLasered Monkeys

Age (days)0 100 200 300

Am

etro

pia

(D)

0

2

4

6Control MonkeysTreated EyeFellow Eye

Mky ZAK

Laser

Laser

Foveal ablation does not alter the time course, efficiency or target refractive error of emmetropization, i.e., foveal signals are not

essential for normal refractive development.

n = 5

Interocular Differences

Unrestricted Vision

+An intact fovea is notessential for normal

emmetropization.

An intact fovea is notessential for Form

Deprivation Myopia.

Age (days)0 50 100 150

Am

etro

pia

(D)

-4

-2

0

2

4

6 Control MonkeysTreated Eye

Control Eye

Diffuser

+

-10

-8

-6

-4

-2

0

2

End of Treatment

An

iso

met

rop

ia (

D)

20

0 100 200 300 400 500

Am

etro

pia

(D)

-4

-2

0

2

4

6

8

Control MonkeysRight EyeLeft Eye

Age (days)

0 100 200 300 400 500

Vitr

eou

s C

ham

ber

(mm

)

8

9

10

11

12

Mky MIT

Laser

An intact fovea is not essential for the recovery from induced myopia.

0 50 100 150 200 250 300 350

Am

etro

pia

(D)

0

2

4

6

Control MonkeysRight EyeLeft Eye

Age (days)

0 50 100 150 200 250 300 350

Vitr

eou

s C

ham

ber

(m

m)

8

9

10

11

12

Mky LAU

Laser

An intact fovea is not essential for the recovery from induced hyperopia.

An intact fovea is not essential for lens compensation.

Age (days)0 50 100 150

Am

etr

opia

(D

)

-9

-4

-2

0

2

4

6

Controls

Laser Contro

ls

-3 D full field

-3 D + laser

-9

-4

-2

0

2

4

6Treated Eyes

-3.0 D lenses

End of Treatment

21

When conflicting signals exist between the central and

peripheral retina, peripheral visual signals can dominate

central refractive development.

• Peripheral form deprivation

Insights from Studies of Laboratory Animals

Clear Vision

Form Deprived

Form Deprived

Peripheral form deprivation alters central refractive

development.

Subjects (n = 12)4 mm = 24 deg 8 mm = 37 deg

14 mmvertex

entrancepupil

Diffuser lenses(4 or 8 mm apertures)

Am

etro

pia

(D

)

-6

-4

-2

0

2

4

6

Normals

4 mm

8 mm

Peripheral Form Deprivation: End of Treatment

Normals = +2.39 ± 0.92 DTreated = +0.01 ± 2.27 D Ametropia (D)

-6 -4 -2 0 2 4

Vitr

eous

Cha

mb

er (

mm

)

9

10

11

Refractive Error Vitreous Chamber

22

Competing Regional Myopic & Hyperopic Defocus

Tse & To, 2011

Controlled the proportion of the field that was exposed to

+10 D of defocus versus -10 D of

defocus.

Am

etropi

a (D

)

-10

-5

0

5

10100% +10 D

100% -10 D

50% +10 D 50% -10 D

25% +10 D 75% -10 D

40% +10 D 60% -10 D

33% +10 D 67% -10 D

Competing Regional Myopic & Hyperopic Defocus

Tse & To, 2011 (chick)

As the proportion of the retina receiving positive defocus increased relative to that receiving negative defocus, the refraction shifted in

the hyperopic direction.

Can peripheral refractive errors alter central refractive development?

• Some observations from human studies are in agreement with the hypothesis that peripheral hyperopia is a risk factor for myopia.

23

Myopes

Emmetropes

Hyperopes

Rel

ativ

e P

erip

hera

l Ref

ract

ion

(D)

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

Mutti et al., 2000

The pattern of peripheral refraction varies with the central refraction. Myopes typically exhibit relative hyperopia in the periphery, whereas

hyperopes show relative myopia in the periphery.

Central vs. 30 deg Nasal

Association between Central & Peripheral Refraction

Children

Temporal Eccentricity

Millodot, 1981

Adults

Ref

ract

ive

Err

or (

D)

Peripheral Hyperopia Precedes Myopia in Children

Became-myopic

Emmetropes

Mutti et al., 2007

Children who became myopic showed more peripheral hyperopia 2 years before the onset of myopia.

Relative to Onset (years)

Onset of Myopia

Can relative peripheral hyperopia promote central myopia?

• However, evidence from human and animal studies indicate that the relationship between peripheral hyperopia and central myopia is complex and not necessarily causal in nature.

24

“Prolate” Shaped Eyes Are More Likely to Exhibit Myopia Progression

Ch

ang

e in

Cen

tral

Am

etro

pia

Relative Peripheral Eye Length

Schmid, 2011

Children age 7-11 years. RPEL measured 20 deg from fovea.

However, the predictive effects of eye shape were

only significant for the temporal retina (r = 0.21, p

=0.049).

The effects of hyperopic defocus may vary with

locations….the temporal retina appears to be more sensitive than the nasal

retina.More prolate More oblate

Correlations between relative peripheral hyperopia and axial myopia are weak.

Mutti et al., 2011

VariableChange in Foveal Refractive

ErrorChange in AL

Coefficient P Coefficient P

Average RPR −0.024 0.020 0.0015 0.77

RPR at interval start

0.012 0.19 0.0058 0.22

Age 0.033 0.034 0.046 <0.0001

Sex −0.090 <0.0001 −0.024 0.030

Relative peripheral hyperopia is associated with greater myopia progression. However, RPR accounts for a very small

degree of the variance.

Progressing myopes (P) have less myopic/more hyperopic peripheral refractions than non-progressing myopes (NP).

Correlations between peripheral refraction and progression

Faria-Ribeiro et al., 2012

25

Form deprivation produces prolate growth.

Central Myopia and Relative Peripheral Hyperopia.

Treated Eye

Control Eye

Treated Eye Control Eye

In form deprivation, relative peripheral hyperopia does not contribute to the central axial myopia. Instead, the peripheral

hyperopia is a consequence of prolate growth.

Can relative peripheral hyperopia promote central myopia?

• Although a causal relationship in humans has not been clearly established, animal studies have demonstrated that relative peripheral hyperopic defocus can promote the onset and progression of central axial myopia.• Relative peripheral myopia can slow axial

growth.

Can peripheral hyperopic defocus produce central axial myopia?

Field of View (n=8)unrestricted = 6.8 deg

mixed focus = 30.5 deg

Unrestricted

MultifocalZone

Always Defocused

-3.0 D spectacle lenses(6 mm apertures)

26

Age (days)0 50 100 150

Am

etr

opi

a (

D)

-4

-2

0

2

4

6

contro

ls

-3 D fu

ll field

-3 D perip

hery

Am

etr

opi

a (D

)-4

-2

0

2

4

6

.

Peripheral Hyperopic Defocus-3 D lenses with 6 mm apertures

Average Sph EquivalentControls = +2.49 ± 0.99 D

-3 D full field = -0.68 ± 1.82 D-3 D periphery = +0.37 ± 2.31 D

Peripheral myopic defocus can produce central axial hyperopia.

Liu and Wildsoet, 2010

Peripheral myopic defocus has a stronger effect on central refractive error than myopic defocus in the central retina.

+5 D

0.0 D

Center Zone Diameter

Peripheral myopic defocus can produce central axial hyperopia.

Lenses with positive radial power profiles promote axial hyperopia. Moreover, Guthrie et al. (2011) found that positive power in periphery

can counteract central hyperopic defocus.

Cha

nge

in A

met

ropi

a(D

)

Tepelus et al., 2012Eccentricity (deg)

Lens

Pow

er (

D)

SphEquivalentt

27

1) ocular growth and the refractive state of the eye are regulated by defocus.

2) vision-dependent changes in eye growth are mediated by local acting mechanisms.

3) visual signals from the fovea are not essential for vision-dependent growth

4) visual signals from the periphery can dominate central refractive development.

5) peripheral hyperopia can produce central myopia --- peripheral myopia can produce central hyperopia.

Animal models tell us that:

Traditional negative spectacles produce relative peripheral hyperopia.

Myopic Adults

Corrected

Uncorrected

Tabernero & Schaeffel, 2009

Ch

ange

in R

elat

ive

PR

E (

D)

Lin et al., 2010

Myopic Children

Absolute Peripheral Defocus (mean SD)Children wearing glasses (SVLs or PALs)

SVL(n=43)

30° Superior -0.38 0.97 D

30°Temporal

+0.46 0.80 D

Central-0.32 ± 0.29 D

30°Nasal

+0.32 0.65 D

20° Inferior -0.53 0.87 D

PAL(n=41)

30° Superior -1.95 1.03 D

30°Temporal -0.08 0.87 D

Central-0.61 ± 0.42 D

30°Nasal

-0.35 0.63 D

20° Inferior -0.62 0.87 D

Berntsen et al. 2013

Progressive addition lenses caused more myopic defocus than single vision lenses in three of the four peripheral locations measured.

28

Myopic children wearing PALs or SVLs(Absolute Peripheral Defocus)

Myopic defocus on the superior and temporal retina was associated with slower foveal myopia progression in children

regardless of whether randomized to wear PALs or SVLs

-1.25

-1.00

-0.75

-0.50

-0.25

0.00

0.25

Baseline Year 1

Ad

just

ed

Myo

pia

Pro

gre

ssio

n (

Dio

pte

rs)

Hyperopic Superior Defocus

Myopic Superior Defocus

‐0.38 D (n=67)

‐0.65 D (n=17)

p = 0.001

-1.25

-1.00

-0.75

-0.50

-0.25

0.00

0.25

Baseline Year 1

Ad

just

ed

Myo

pia

Pro

gre

ssio

n (

Dio

pte

rs)

Hyperopic Temporal Defocus

Myopic Temporal Defocus

‐0.34 D (n=36)

‐0.51 D (n=48)

p = 0.01

Berntsen et al. 2013

Peripheral Treatment Strategy

• Treatment strategies that take peripheral vision into consideration

are more likely to be successful than those that do not.

• Can provide optimal distance vision at the fovea and a peripheral

visual signal to slow myopia (regardless of etiology).

• Can improve peripheral visual performance.

• Can be implemented via all traditional correction modalities (i.e., spectacles, contact lenses,

orthokeratology, refractive surgery).

Emmetropization Model

Norton, 1999

Key points: 1. Ocular growth regulated by retinal responses to optical image. 2. Accommodation, by its influence on retinal

image quality, plays an indirect role in emmetropization.

(in mammals)

29

Retinal Components

Norton, 1999

• Acetylcholine (M1 or M4 receptors)• Dopamine (Acs)• Gulcagon-Insulin (Acs)• Vasoactive Intestinal Peptide (Acs)• Nicotine (Antagonist effects)

Atropine Treatment for Myopia

Months

0 5 10 15 20 25 30

Myo

pic

Pro

gre

ssio

n (

D)

-1

0

1

2

3

4Controls (0.5% tropicamide)

0.5% atropine

0.25% atropine

0.1% atropine

Shih et al., 1999

N = 200Ages = 6-13 years- 42-61% of treated children showed nomyopic progression

- 8% of control group show no progression.

Myo

pic

Pro

gre

ssio

n (D

)

0.0

0.5

1.0

1.5

2.0

Control Eyes Treated Eyes

Axi

al E

long

atio

n (m

m)

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

Control Eyes Treated Eyes

Atropine in the Treatment of Myopia Study“The Atom Study”

Randomized, double-masked study of 6- to12-year-old myopic children. Monocular 1% topical atropine vs. placebo

Year two results.Chua et al., 2006

n = 346

30

Key IssuesAre the effects permanent?

Is there a rebound phenomenon?

End of Treatment

Tong et al., 2009

Treated Eye Control Eye

Long-term Effects of Atropinization

Chronic atropine can produce permanent alterations in the neuropharmacology of intraocular muscles and pupil size

(amplitude of accommodation, acc-convergence interactions?).

Adult cat treated with 1% atropine in the right eye from 4 weeks to 4 months of age.

Atropine in the Treatment of Myopia Study 2“The Atom 2 Study”

Duration of Treatment

1%

0.01%

0.5%

0.1%

Placebo

Effects of Atropine Dose on Myopia Progression

31

Atropine Concentration (%)

0.01 0.1 1

Red

uctio

n in

Myo

pia

Pro

gre

ssio

n (%

)

0

20

40

60

80

100

120

Kelly et al., 1975Chou et al., 1997Shih et al., 1999Kenedy et al., 2000Syniuta & Isenberg, 2001Lee at el., 2006Fang et al., 2010Chia et al., 2011

Effects of Atropine Concentration

Atropine and FDM

Chronic atropinization can prevent FDM in monkeys.

Atropine

0.01% atropine slows myopic change in refractive error and has minimal rebound effect after ceasing treatment.

Higher concentrations have greater rebound after stopping treatment.

Chia et al. Ophthalmology 2016;123:391-9Treatment No Treatment

32

Atropine

Does 0.01% atropine slow axial growth?

Chia et al. Am J Ophthalmol 2014;157:451-7 e1

Neurochemical Transmission in the Parasympathetic System

Atropine produces cycloplegia by blocking the action of acetylcholine on muscarinic receptors in ciliary muscle.

Receptor Subtypes

M1 CNS, nervesM2 Heart, smooth muscle, ciliary muscleM3 Smooth muscle, exocrine glands, ciliary muscleM4 CNS, nervesM5 CNS, ciliary muscle

Atropine blocks all muscarinic receptor

subtypes.

33

Effects of Muscarinic Agents

Treatment Regimen

Inte

rocu

lar

Diff

ere

nce

(m

m)

0.0

0.1

0.2

0.3

0.4

on Form-deprivation Myopia(Stone et al.)

MD control

MD + atropine

MD + pirenzepine (M1)MD + 4 DAMP (smooth muscle)

Blocking actions:atropine - all muscarinic sites4-DAMP - smooth musclepirenzepine - neural ganglia

Atropine and pirenzepine are effective in preventing FDM in tree shrews. Other

selective muscarinic antagonists (M2,

gallamine; M3, P-f-HHSid) were not effective in

blocking FDM. Hence, the M1 receptor appears to

have potential therapeutic value. M1 blockers do not eliminate accommodation.

McBrien et al., 2000

Tree Shrew: Pirenzepine & FDM

Form-deprived Eyes

Ref

ract

ive

Err

or

Cha

nge

(D

)

-6

-5

-4

-3

-2

-1

0

1

(from Iuvone et al., 1991)

MD alone

MD + apomorphine (dop. agonist)

MD + apo + haloperidol (D antagonist)

Form-deprived Monkeys

Pe

rce

nt C

han

ge

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

(from Iuvone et al., 1989)

Dopamine DOPAC Tyros. Hydroxylase

Retinal dopamine is involved in FDM

34

Jones et al. 2007 – Prospective Cohort Rose et al. 2008 – Cross-Sectional Sample

Increased time outdoors prior to becoming myopic is protective against myopia onset

Jones-Jordan et al., 2012

It is not clear that time outdoors slows the annual rate of myopia progression once a child

is myopic

Extra outdoor time at school slowed myopic shift in non-myopic eyes, but did not

significantly slow progression in myopic eyes (Wu et al. 2013)

35

High ambient light levels retards the development of form-deprivation myopia in chicks.

Ashby et al., 2009

Control Eyes

Form-Deprived Eyes15000 lux

Form-Deprived Eyes50 & 500 lux

High Light Levels & Experimental Myopia

High light levels slow the rate of compensation for negative lenses. The effect is blocked by dopamine antagonist.

High Light Levels & Experimental Myopia

Control Eyes

-7 D Lens15,000 lux

-7 D Lens500 lux

Ashby et al., 2009

High Light Levels & FDMLongitudinal Anisometropia

Normal Lighting~ 350 lux

High Ambient Lighting~ 25,000 lux

Age (days)

0 50 100 150

Ani

som

etr

opia

(D

)(t

reat

ed e

ye -

fel

low

eye

)

-12

-10

-8

-6

-4

-2

0

2

4

Age (days)

0 50 100 150-12

-10

-8

-6

-4

-2

0

2

4

n = 18 n = 8

36

Dopamine Antagonist & High Light Levels

Spiperone, a dopamine antagonist, blocks the protective effects of high ambient lighting on form-deprivation myopia.

Ashby & Schaeffel, 2010

High Light Levels and Animal Myopia

Filled symbol = treated eye Open symbol = control eye(rhesus monkeys)

High light levels prevent FDM, but have no effect on lens induced myopia – mechanisms not identical

Smith et al. 2012 Smith et al. 2013

Activity Markers in Amacrine Cells

Glucagon amacrine cells are more abundant than

dopaminergic Acs. Tested for visual regulation of

several transcription factors. Conditions that stimulate axial elongation decrease ZENK synthesis (basically glucagon activity) whereas conditions that reduce axial growth up-regulate ZENK.

Glucagon AC exhibit sign of defocus information.

Seltner & Stell, 1995

37

Choroidal Components

Norton, 1999

• Choroidal Retinoic Acid• Choroidal Thickness

Choroidal Retinoic Acid Synthesis: Mediator of Eye Growth?

Evidence in chicks: 1) the choroid can convert retinol to all-

trans retinoic acid at a rapid rate. 2) Visual conditions that

increase ocular growth produce a sharp decrease in retinoic acid synthesis. 3) Visual conditions

that slow ocular growth produce an increase in RA synthesis. 4)

application of RA to cultured sclera inhibits proteoglycan production at physiological

concentrations.Mertz et al., 2000a

Choroidal MechanismsChanges in choroid thickness move the retina toward the

appropriate focal point.

from Wallman et al., 1995

normal chick chick recovering from induced myopia

38

Scleral Components

Norton, 1999

• bFGF & TGF beta (growth factors)• For a myopic growth stimulus:

• Decrease proteoglycan synthesis• Decrease sulfated GAGs• Increase gelatinolytic enzymes

Daily Dose of bFGF (g)1e-10 1e-9 1e-8 1e-7

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Daily Dose of TGF-beta1e-14 1e-13 1e-12 1e-11 1e-10 1e-9 1e-8 1e-7

Axi

al le

ngth

Diff

eren

ce (

mm

)

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

MD and bFGF MD and TGF-beta and bFGF

Biochemical "stop" and "go" Signals

Rhorer and Stell, 1994

(basic Fibrobast Growth Factor) (Transforming Growth Factor Beta)

Possible growth factors involved in FDM

bFGF = basic fibroblast growth factor. TGF-beta = transforming growth factor beta. The broad dose response curve suggests that more than

one type of FGF receptor is involved.

Matrix metalloproteinase (MMP-2) appears to be the major gelatinolytic enzyme in the tree shrew sclera. Form deprivation increases catabolism in

the sclera. Hyperopic defocus reduces the degree of scleral catabolism.

Tree Shrew ScleraGuggenheim & McBrien, 1996

39

Decorin is the major proteoglycan in the marmoset sclera. The rate of proteoglycan synthesis is reduced in the posterior pole of FDM.

Marmoset Sclera

Rada et al., 2000

Scleral Changes with FDM(posterior thinning)

McBrien & Gentle, 2003

Scleral thinning occurs very rapidly in response to onset of myopia development – due to a loss of tissue (i.e., not simply stretch).

Form-deprived Tree Shrew

Physical Changes

Norton, 1999

• Increase / decrease in scleral creep rate• Axial vitreous chamber depth

40

The scleras from eyes that are undergoing myopic axial elongation exhibit higher than normal creep rates. During recovery from FDM the scleral creep rates fell

below normal values. During both emmetropization and the development of refractive errors, vision-dependent alterations in the extracellular matrix may

alter the mechanical properties of the fibrous sclera making it more distensible.

Myopic Tree Shrew Sclera Siegwart & Norton, 1995

Conclusions

• Vision-dependent mechanisms are active well into adult life.

• Operational properties are not always intuitive. Consequently the clinical implications of animal studies are not always obvious.

• The ocular cascade that transforms visual signals into biochemical signals for growth is complex and can be influenced in a variety of ways.