Distribution of Refractive Errors Refractive Development ...voi.opt.uh.edu/VOI/emmetropization...

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1

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.

Distribution of Refractive Errors (young adult population)

Major differences from random

distribution:

- more emmetropes than predicted

- fewer moderate errors (e.g., -2.0 D)

- more high errors (e.g., -6.0 D)

i.e., the function is leptokurtotic.

from Sorsby, 1957

theoretical

Gaussian

distribution

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

Fre

qu

en

cy (

%)

0

10

20

30

40

Nearsighted Farsighted

Newborns (Cook & Glasscock)

Age 4-6 yrs (Kempf et al)

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

Ideal Optical Conditions

Age Norms of Refraction

(Slataper, 1950)

Age (years)

0 10 20 30 40 50 60 70 80 90

Refr

active E

rror

(D)

0

1

2

3

4

Changes in Refractive Error with Age

more typical

Average data are

not very predictive

of changes on an

individual basis

before about 20

years. Thereafter,

most people

experience the

same trends.

Age (weeks)

Am

etr

op

ia (

D)

Myopia in Premature Infants

Born before 32 weeks &/or birth

weights < 1500 g; no ROP

Myopia associated with short axial lengths & steep corneas.

Recovery primarily due to corneal flattening. Age (days)

0 200 400 600

Mean A

metr

opia

(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 is

the process that

guides ocular growth

toward the optimal

optical state. It

occurs very rapidly;

most infants develop

the ideal refractive

error by 12-18

months.

2

Age (years)

0 1 2 3 4 5

95

% c

on

fid

en

ce

lim

its (

D)

0.0

0.2

0.4

0.6

0.8

1.0

cylinders

spheres

n = 360Normal Infants

Net Anisometropia

Howland & Sayles (1987) During the period of

rapid emmetropization,

the degree of

anisometropia typically

decreases (i.e.,

“isometropization”

occurs).

Age (years)

0 1 2 3 4

Nu

mb

er

of P

atie

nts

0

10

20

30

40

>1.0 D

new cases

loss of aniso

Prevalence of Anisometropia(Abrahamsson et al., 1990)

n=310

Normal Infants

“Isometropization”

Anisometropia

is frequently

transient during

early

development.

Rapid Infantile phase (0-3 yrs) -- axial length increases about 5-6 mm.

Slower Juvenile phase (3-14 yrs) -- axial length increases about 1 mm.

Axial Length Development

Age (years)

0 1 2 3

Axia

l Le

ng

th (

mm

)

14

16

18

20

22

Gordon & Donzis

Larsen, males

Laren, females

Zadnik et al

Fledelius

Axial Length Development

Age (years)

0 5 10 15 20 25 30

Axia

l L

en

gth

(m

m)

14

16

18

20

22

24

Gordon & Donzis

Larsen, males

Laren, females

Zadnik et al

Fledelius

Corneal Development

Age (years)

0 1 2 3

Co

rne

al P

ow

er

(D)

42

44

46

48

50

52

54

56

Gordon & Donzis

Woodrift

Zadnik et al.

Corneal Development

Age (years)

0 5 10 15 20 25 30

Co

rne

al P

ow

er

(D)

42

44

46

48

50

52

54

56

Gordon & Donzis

Woodrift

Zadnik et al.

Major Optical Changes:

1) flatter cornea (6-8 D)

2) deeper AC (0.8D)

3) flatter lens (12-15 D)

Anterior Chamber Depth

AC depth increases from about 2.4 mm at birth

to about 3.5 mm at 3 years (about 0.8 D).

Birth

Lens Development

Age (years)

0 1 2 3

Le

ns P

ow

er

(D)

20

25

30

35

40

45

Gordon & Donzis

Zadnik et al.

Lens Development

Age (years)

0 5 10 15 20 25 30

Len

s P

ow

er

(D)

15

20

25

30

35

40

45

Gordon & Donzis

Zadnik et al.

Major Optical Changes:

1) flatter cornea (6-8 D)

2) deeper AC (0.8D)

3) flatter lens (12-15 D)

3


(Slataper, 1950)

Age (years)

0 10 20 30 40 50 60 70 80 90

Refr

active E

rror

(D)

0

1

2

3

4

4 6 8 10 12 14

Corn

eal P

ow

er

(D)

41

42

43

44

45

46

47

4 6 8 10 12 14

Am

etr

opia

(D

)

-1

0

1

2

Age (years)

4 6 8 10 12 14

Axia

l Length

(m

m)

21

22

23

24

25

Age (years)

4 6 8 10 12 14

Lens P

ow

er

(D)

18

19

20

21

22

23

24

Age (yrs)

From about 2 to 7-8

years, the mean refractive

error is quite stable & the

degree of variability is low.

Zadnik et al., 1993

Changes with Age

4 6 8 10 12 14

Co

rne

al P

ow

er

(D)

41

42

43

44

45

46

47

4 6 8 10 12 14

Am

etr

op

ia (

D)

-1

0

1

2

Age (years)

4 6 8 10 12 14

Axia

l L

en

gth

(m

m)

21

22

23

24

25

Age (years)

4 6 8 10 12 14

Le

ns P

ow

er

(D)

18

19

20

21

22

23

24

Refractive Development: Early School Years

Refractive Error

Lens Axial Length

Cornea

Zadnik et al., 1993

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 Anterior Chamber Depth

Wong et al., 2010

Refractive Development: Early School Years Lens Thickness

Wong et al., 2010

Refractive Development: Early School Years Anterior Segment

Larsen, 1971

Age in Years

0 10 20 30 40

Myo

pia

(p

erc

en

t)

0

5

10

15

20

25

30

35

Jackson, 1932

Tassman, 1932

Prevalence of Myopia in Humans

School Years

The decrease in

mean refractive error

between about 8 and

20 years is due

primarily to the onset

of “school” myopia in

a small proportion of

the population.

4

Males

Myopic Progression

“Youth-Onset” or

“Juvenile-Onset”, or

“School” Myopia

Females

For many individuals,

myopic progression

stops in late teenage

years…associated with

the normal cessation of

axial growth.

Myopic Progression (D/year)

-1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4

Pro

port

ion

of S

am

ple

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Males

Females

Annual Rate of Myopic Progression

Rate varies

considerably between

individuals. Average =

-0.40 to -0.6 D/yr

(before age 15 yrs)

The earlier the onset of myopia…the higher the rate

of progression and the final degree of myopia.

Age of Onset vs. Degree of Myopia

From Goss, 1998

Axial Nature of Myopia

From Goss, 1998

The rate of myopic

progression is highly

correlated with the

rate of axial

elongation.

Ametropia (D)

-0.5 0.0 0.5 1.0 >1.5

0.0

0.2

0.4

-0.5 0.0 0.5 1.0 >1.5

Pro

po

rtio

n o

f S

am

ple

0.0

0.2

0.4

-0.5 0.0 0.5 1.0 >1.5

0.0

0.2

0.4

Predictability of Refractive

Errors at Age 13-14 Years

From Hirsch, 1964

Refractive Error Distributions

for Children at 5-6 years who

develop:

Myopia >0.50 D

Emmetropia -0.49 to +0.99 D

Hyperopia >1.0 D

Congenital = present at birth & persists through infancy.

Youth-onset = occurs between 6 years and early teens.

Early adult-onset = occurs between 20 & 40 years

Late adult-onset = occurs after 40 years

Classifications of Myopia

Grosvenor, 1987

5

McBrien & Adams, 1997

Early Adult Onset Myopia

Examples of adult onset myopia associated with

a change in occupation.

Adult Progression

Adult Onset

McBrien & Adams, 1997

Change in refractive

error for myopic

subjects following

onset of microscopy

career. 48% of

myopes showed

myopic changes

>0.37 D (i.e., myopic

progression).

Median age = 29.7 years

Early Adult Onset Myopia


(Slataper, 1950)

Age (years)

0 10 20 30 40 50 60 70 80 90

Refr

active E

rror

(D)

0

1

2

3

4


more typical

Acquired hyperopia due

to:

1) presbyopia

2) lens continues to flatten

3) refractive index of lens

cortex increases

Weale, 1982

Lens Development - Mass

The crystalline lens

continues to grow

throughout life.

Vitreous Chamber

young adult (22 yrs) = 16.14 mm

Mature adult (54 yrs) = 15.7 mm Ooi & Grosvenor, 1995

Acquired Hyperopia


(Slataper, 1950)

Age (years)

0 10 20 30 40 50 60 70 80 90

Refr

active E

rror

(D)

0

1

2

3

4

more typical


Decrease in hyperopia

due to increase in

refractive index of core of

crystalline lens.

6

Prevalence of Astigmatism(young adult population)

Amount of Astigmatism (D)

0.0 0.5 1.0 1.5 >2

Perc

enta

ge o

f P

opula

tion

0

10

20

30

40

50

Astigmatism is

the most common

ametropia. The

magnitude is,

however, usually

relatively small.

Astigmatism Axis vs Spherical Ametropia Young Adult Population

Mandel et al., 2010

Prevalence of Astigmatism: Infants

Atkinson et al. 1980

Marked levels of

astigmatism are

common in young

infants -- due

primarily to corneal

toricity.

Age (weeks)

0 10 20 30 40 50

Pre

va

lence

(%

)

0

20

40

60

80

100

Santonastaso, 1930

Howland et al., 1978

Mohindra et al., 1978


Fulton et al., 1980

Gwiazda et al., 1984

Edwards, 1991

Saunders, 1995

.Prevalence of Astigmatism (>1 D)

in Human Infants

Atkinson et al. 1980

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.

from Ehrlich et al., 1997

Right eye

astigmatism at 9

months of age (n =

143, Cambridge,

UK). W-t-R

astigmatism

predominates.

Axis of Astigmatism

7

Change in Axis of Astigmatism

Bennett & Rabbetts, 1989

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 35 years of age

and occur at a rate of

about 0.25 D every 10

years.

age in decades

A-t-R

oblique

W-t-R

Bennett & Rabbetts, 1989

Change in Corneal Power & Astigmatism

After age 35 years, the

cornea gets

progressively steeper.

The reduction in the

radius of curvature is

greater for the

horizontal meridian.

My Eyelash

About 200 microns

Distribution of Refractive Errors (young adult population)

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

theoretical

Gaussian

distribution

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, 1978

Nature of Refractive Errors

Not all emmetropic eyes

are alike.

Ks = 39.0 – 47.6 D

Lens = 15.5 – 23.9 D

AC = 2.5 – 4.2 mm

AL = 22.3 – 26.0 mm

Ametropic eyes between

-4 D and +6 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.

emmetropes ametropes

from Sorsby, 1978

8

Factors that influence refractive state

• 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

Ethnic Category

Swedish British Israeli Malay Indian Eurasian Chinese

Pre

vale

nce o

f M

yopia

(%

)

0

10

20

30

40

50

60

Prevalence of Myopia in Different Ethnic Groups

Myopic Parents

None One Both

Pe

rcent

Childre

n M

yopic

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 Intrapair Correlations for Refractive Error Monozygotic vs Dizygotic Twins (Dirani et al., 2006)

Monozygotic Twins Dizygotic Twins

r = 0.82 r = 0.36

Twin 1 Ametropia (D) Twin 1 Ametropia (D)

Tw

in 2

Am

etr

op

ia (

D)

Twin A: Refractive Error (D)

-4 -2 0 2 4 6 8

Tw

in B

: R

efr

active E

rror

(D)

-4

-2

0

2

4

6

8

(Sorsby et al., 1962)

Identical twins have very

similar refractive errors.

Evil twin? Good twin?

Dr. Y. Chino

Monozygotic Twins Concordance of Optical Components

Number of Individual Components

1 2 3 4 5 6

Pro

ce

nta

ge o

f S

am

ple

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 D

AC depth = 0.1 mm

lens thickness = 0.1 mm

total power = 0.9 D

9

Locus Location Study Myopia Severity

MYP1 Xq28 Schwartz et al, 1990 -6.75 to -11.25 D

MYP2 18p11.31 Young et al, 1998 -6.00 to -21 D

MYP3 12q21-q23 Young et al, 1998 -6.25 to -15 D

MYP4 7q36 Naiglin et al, 2002 Avg = -13.05 D

MYP5 17q21-q22 Paluru et al, 2003 -5.50 to -50 D

Genetic Loci for Myopia 1990-2003

Genetic Loci for Myopia 2005 to 2009

Locus Location Study Myopia Severity

MYP6 22q12 Stambolian et al, 2004 -1.00 D or lower

MYP7 11p13 Hammond et al, 2004 -12.12 to +7.25 D

MYP8 3q26 Hammond et al, 2004 -12.12 to +7.25 D

MYP9 4q12 Hammond et al, 2004 -12.12 to +7.25 D

MYP10 8p23 Hammond et al, 2004 -12.12 to +7.25 D

MYP11 4q22-q27 Zhang et al, 2005 -5 to -20 D

MYP12 2q37.1 Paluru et al, 2005 -7.25 to -27 D

MYP13 Xq23-q25 Zhang et al, 2006 -6.00 to -20 D

MYP14 1p36 Wojcechowski et al, 2006 Avg = -3.46 D

MYP15 10q21.1 Nallasamy et al, 2007 Avg = -7.04

MYP16 5p15.33-p15.2 Lam et al,2008 -7.13 to -16.68 D

MYP? 1q41 Klein et al, 2007 Range of Errors

MYP? 7p21 Klein et al, 2007 Range of Errors

MYP? 22q11.23-12.3 Klein et al, 2007 Range of Errors

MYP? 7p15 Ciner et al, 2008 Avg = -2.87 D

MYP? 3q26 Andrew et al, 2008 -20 to +8.75 D

MYP? 20q11.23-13.2 Ciner et al, 2009 Avg = -4.39 D

MYP? 9q34.11 Li et al, 2009 <-5.00 D

MYP? 15q14 Solouki et al, 2009 Range of Errors

MYP? 15q25 Hysi et al, 2009 Range of Errors

Occupation

1 2 3 4 5 6

Ne

ars

igh

ted

(p

erc

en

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.

Age in Years0 10 20 30 40

Nears

ighte

d (

pe

rcen

t)

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)

Myopia & Intelligence

IQ Score

<80 81-96 97-103 104-111 112-127 >127

Pro

po

rtio

n o

f M

yo

pe

s (

%)

0

5

10

15

20

25

30

Myopia & Education

Years of Education

<8 9 10 11 >12

0

5

10

15

20

25

Significant Associations in Myopia

An Epidemic of Myopia

Age (years)

6 8 10 12 14 16 18 20

Pre

va

len

ce

Ra

te (

%)

0

20

40

60

80

100

Age

12 Years 15 Years 18 Years

Ave

rag

e D

eg

ree

of

Myo

pia

(D

)

0

1

2

3

4

1986

2000

Lin et al., 2004

1986

2000

1995

Taiwanese School Children

The prevalence and average degree of myopia is

increasing rapidly over time.

10

Vitale et al., 2009

An Epidemic of Myopia National 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 o

f M

yopia

(%

)

The prevalence of myopia is increasing too fast to reflect genetic changes;

something in the environment is affecting the pattern of refractive errors.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

High Moderate Low

High

Moderate

Low

near-work

outdoor

Od

ds

ra

tio

Multivariable-Adjusted Odds for Myopia

Outdoor activities have a strong

protective effect against myopia.

Mitchell et al., 2006

Monkeys in Restricted Environment

Time in Restricted Environment (weeks)

0 10 20 30 40 50

Refr

active E

rror

(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.

Human days

0 200 400 600 800

Age (days)

0 50 100 150 200

0

2

4

6

8

10

Emmetropization Requires Vision A

me

tro

pia

(D

)

Normal Monkeys Dark-reared Monkeys

Age (days)

Guyton et al., 1987

normal eye deprived eye

Chronic Image Degradation Causes Myopia Monocularly Form-Deprived Monkeys

Wiesel & Raviola, 1977

The potential for a clear retinal image is essential for

normal refractive development.

Vitreous Chamber Growth

Age (months)

0 10 20 30

Vitre

ou

s C

ha

mb

er

(mm

)

8

10

12

14

deprived eye

fellow eye

Lagomorpha

Carnivora

Rodentia

New World

Old World

Tree

Shrews

Marsupialia

FDM occurs in a wide variety of animals.

Vertebrata

Aves

Terrestrial

vertebrates Placental

mammals

Primates Human

11

Form-deprivation Myopia

Ametropia (D)

-15 -10 -5 0 5 10

0

10

20

30

40

50

60

70

"deprived humans"

Normal humans

Rabin et al. (1981)

Form-deprivation Myopia in Humans

Ametropia (D)

-15 -10 -5 0 5 10

Pe

rce

nta

ge

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

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.

Form-Deprivation Myopia

-4

-2

0

-4

-2

0

Normal Monkeys

Treatment Period

Recovery Period

End of Treatment

-4

-2

0

Age (days)

0 200 400 600

-4

-2

0

-9

-6

-3

0

-9

-6

-3

0

Anis

om

etr

opia

(D

)(T

reate

d E

ye -

Contr

ol E

ye)

-9

-6

-3

0

Age (days)

0 200 400 600

-9

-6

-3

0

Recovery from Form-Deprivation Myopia

Anis

om

etr

opia

(D

) (t

rea

ted

eye

– c

on

tro

l eye

)

0 100 200 300

Am

etr

op

ia (

D)

-2

0

2

4

6

8

10Monkey LIS Deprived Eye

End of Treatment

Non-Treated Eye

Age (days)

0 100 200 300

Vitre

ou

s C

ha

mb

er

(mm

)

8

9

10

11treatment period

Emmetropization is guided by optical defocus. Optically imposed refractive errors produce predictable refractive-

error changes.

Imposed Myopia: To

compensate, the eye must

become more hyperopic.

Imposed Hyperopia: To

compensate, the eye must

become more myopic.

Positive Treatment

Lens

Negative Treatment

Lens

Lens Compensation in Monkeys

+9.0 D

Age (days)

0 100 0 100 0 100 0 100 0 100 0 100

Am

etr

op

ia (

D)

-6

-4

-2

0

2

4

6

8

10

+6.0 D +3.0 D0.0 D -3.0 D -6.0 D

Expected

Ametropia

RE vs. Age for Binocularly Lens-Reared Monkeys

Age (days)0 50 100 150

Vitre

ou

s C

ha

mb

er

Le

ng

th (

mm

)

9

10

11Positive Lenses

Negative Lenses

Negative lenses cause the eye to grow faster;

positive lenses reduce growth.

Lens Power (D)

-20 -10 0 10 20 30

Am

etr

opia

(D

)

-15

-10

-5

0

5

10

15

20

25

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.

12

A. End of Treatment

Spectacle Lens Power (D)

-8 -4 0 4 8 12

Refr

active E

rro

r (D

)

-8

-4

0

4

8B. Effective Emmetropization Range

Effective Refractive Error (D)

-8 -4 0 4 8 12

Cha

ng

e in R

efr

active E

rro

r (D

)

-12

-8

-4

0

4

r ² = 0.76r ² = 0.85

Effective Operating Range for Emmetropization Monkeys vs Humans

Monkeys Humans

Large refractive errors produce unpredictable growth –

possibly these eyes have faulty emmetropization

mechanisms.

Age (days)

0 50 100 150

0

2

4

6

0 50 100 150

Am

etr

opia

(D

)

-2

0

2

4

Plano Lens

0 50 100 150

-2

0

2

4

6

Positive Lens

Negative Lens

Optically Imposed Anisometropia

RE = -3.0 D lens

LE = Plano lens

RE = +3.0 D lens

LE = Plano lens

RE = Positive lenses

LE = Negative lenses

Regulation of refractive development is largely

independent in the two eyes.

Can optical defocus predictably alter

refractive development in children? -Optically Imposed Anisometropia-

Interocular Differences in Ref Error Subjects: n = 13

11-year-old myopic children

Treatment: Monovision CLs

-Dominant eye corrected for

distance.

-Fellow eye uncorrected or

corrected to maintain <2.0 D

aniso.

Results:

Distance corrected eye

progressed 0.36 D more than

the fellow eye.

Philips, 2005

Age (days)

0 300 600 900 1200A

me

tro

pia

(D

)

0

1

2

3

4

5Control

Treated

Untreated

Incre

ase

in

Myo

pia

(D

/yr)

0.0

0.2

0.4

0.6

0.8

1.0

Optimal Rx

OverminusedRx

Goss, 1984


Can defocus/spectacles predictably alter

refractive development in children?

Infants

Age (days)

0 300 600 900 1200

Am

etr

opia

(D

)0

1

2

3

4

5Control

Treated

Untreated

Incre

ase

in

Myo

pia

(D

/yr)

0.0

0.2

0.4

0.6

0.8

1.0

Optimal Rx

OverminusedRx

Goss, 1984


Adolescent Children

Why is there little evidence that spectacles alter human refractive

development? Faulty Emmetropization; Humans vs. Monkeys; Age;

Compliance (temporal Integration); Spatial Integration of Visual Signals

Age (days)

0 300 600 900 1200

Me

an

Am

etr

op

ia (

D)

-2

0

2

4

Edwards, 1991

Wood et al., 1995

Thompson (1987) from Saunders

Saunders, 1995



controls

treated hyperopes

untreatead hyperopes

Additions from Atkinson et al., 1996

- Faulty Emmetropization

- Humans vs. Monkeys

- Age

- Compliance

Can spectacles predictably alter

refractive development in children?

Age (monkey years)

0 1 2 3 4 5

Age (human years)

0 4 8 12 16 20

Axia

l Length

(m

m)

12

14

16

18

20

22

24

Normal Monkeys

Gordon & Donzis

Larsen, males

Laren, females

Zadnik et al

Fledelius

Treated Monkeys

Age Effects: Are vision dependent

mechanisms only active early in life?

Onset of

Juvenile

Myopia

13

Age (years)

2 4 6 8

Vitre

ous C

ham

ber

(mm

)(t

reate

d e

ye -

fello

w e

ye)

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

Anis

om

etr

opia

(D

)(f

ello

w e

ye -

tre

ate

d e

ye)

0

1

2

3

4

5

6

Vitreous Chamber Depth Anisometropia(End of Treatment)

Late Onset Form Deprivation

Daily Exposure History

Hours of the Light Cycle

0 2 4 6 8 10 12

Form Deprivation

Unrestricted 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

Brief daily periods of unrestricted vision

counterbalance long daily periods of form deprivation.

Hours of Unrestricted Vision

0 2 4 6 8 10 12

Vitre

ous C

ham

ber

(mm

)(t

reate

d e

ye -

fello

w e

ye)

0.0

0.2

0.4

0.6

0.8

n = 6

n = 7

n = 4

n = 7n = 14

Hours of Unrestricted Vision

0 2 4 6 8 10 12

An

isom

etr

op

ia (

D)

(tre

ate

d e

ye -

fello

w e

ye)

0

1

2

3

4

5

6

7

n = 6

n = 7

n = 4

n = 7n = 14

4 months of age

Refractive Error Vitreous Chamber

Temporal Integration Properties

Daily Exposure History


0 2 4 6 8 10 12

-3 D Lenses

Unrestricted Vision

n=6

n=6

Treatment period:

onset: 24 3 days

duration: 115 8 days

Effects of Brief Periods of Unrestricted Vision on

Compensation for Binocular Negative Lenses

Lens Compensation for Continuous -3D Lenses

Am

etr

op

ia (

D)

-2

0

2

4

+2.45 D

-0.68 D

Age (days)

0 30 60 90 120 150

Am

etr

opia

(D

)

-2

0

2

4

6

8 Normal Monkeys

Continuous -3 D Lenses

End of Treatment

Averages

Effects of 1 hour of vision through plano

lenses on compensation for –3 D lenses.

Age (days)

0 30 60 90 120 150

Am

etr

op

ia (

D)

-2

0

2

4

6

Normal Monkeys

1-hr Plano Lenses

Continuous -3 D Lenses

Am

etr

op

ia (

D)

-2

0

2

4

+2.45 D

-0.68 D

+2.63 D

End of Treatment

Averages

14

Implications for Nearwork


0 2 4 6 8 10 12

-3 D Lenses

Unrestricted Vision

Am

etr

op

ia (

D)

-2

0

2

4

-3 D continuous

Normals

1 hr plano lens

Diopter Hours Relative to Controls

+36 D-hrs / day

+33 D-hrs

per day

“0” D-hrs

•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.

What visual system mechanisms are involved in

transforming a visual signal into a biochemical

signal for growth?

Afferent Components

e.g., “blur detector”

Efferent Components

e.g., accommodation

diffuser

FDM used as a tool to determine

what components are important.

Form-deprived Primates

Treatment Strategies

1 2 3 4 5

Degre

e o

f M

yopia

(D

)

0

2

4

6

8

10 destriate (monkey)optic n. section (monkey)TTX (tree shrew)ciliary ganglion (monkey)Sup. cervical ganglion (monkey)

FDM does NOT require:

1) the visual signal to leave the

eye

2) sympathetic or

parasympathetic inputs to the

eye.

Form-Deprivation Myopia

From Raviola & Wiesel, 1985;

Norton et al., 1994

Deg

ree

of

Myop

ia (

D)

The vision-dependent

mechanisms that regulate

refractive development

are located in the eye

Hemi-Retinal Form Deprivation

Temporal Field Nasal Field

-45 -30 -15 0 15 30 45

Am

etr

opia

(D

)

-6

-4

-2

0

2

4Treated Eye

Fellow Eye

Selectively depriving a

portion of the retina

restricts the refractive

changes to the deprived

areas.

Hemi-Field Diffuser

Clear Lens

Horizontal section viewed from below.

Treated Eye Fellow Eye

MKY KIM 364

Temporal Field Nasal FieldEccentricity (deg)

-40 -20 0 20 40

IOD

Vitre

ous C

ham

ber

(mm

)

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

IOD

Refr

active E

rror

(D)

-8

-7

-6

-5

-4

-3

-2

-1

0

Vitreous Chamber

Refraction

Hemi-field Form-Deprivation in Monkeys

Interocular Differences

Hemi-Field vs Full-Field Form Deprivation Evidence for Local Mechanisms

MKY 343

Full-Field Form Deprivation

Control Eye

Treated Eye

Nasal Temporal

MKY 368

Nasal-Field Form Deprivation

Control Eye

Treated Eye

Nasal Temporal

15


Eccentricity (deg)

-45 -30 -15 0 15 30 45

An

iso

me

tro

pia

(D

)(t

reate

d e

ye -

fello

w e

ye)

-2

-1

0

1

Controls

-3 Nasal Field


Eccentricity (deg)

-45 -30 -15 0 15 30 45

Am

etr

opia

(D

)

1

2

3

4

Treated Eye

Fellow Eye

Hemi-Field Optical Defocus Monocular -3 D Nasal Field

Treated vs. Fellow Eye

N = 8 -3D

Plano Plano

T45º N45º

0º

MKY 383

Treated Eye

T

N

Control Eye

Treated Eye

Nasal-Field Optical Defocus Local Retinal Mechanisms

N

T

Control Eye Nasal Temporal

Local Retinal

Mechanisms

Afferent

Efferent

• The mechanisms that mediate the

effects of visual experience on eye

growth are located largely within the

eye and act in a regionally selective

manner.

• Global mechanisms (e.g., the act of

accommodation) are unlikely to play a

primary role in refractive development.

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)

Retinal

Components

Norton, 1999

• Acetylcholine (M1 or M4 receptors)

• Dopamine (Acs)

• Gulcagon (Acs)

• Vasoactive Intestinal Peptide (Acs)

• Nicotine (Antagonist effects)

Atropine and FDM

Chronic atropinization prevents

FDM in some species of monkeys.

16

Neurochemical Transmission in

the Parasympathetic System

Atropine produces cycloplegia by blocking the action of

acetylcholine on muscarinic receptors in ciliary muscle.

Cholinergic Receptor Subtypes

M1 CNS, nerves

M2 Heart, smooth muscle, ciliary muscle

M3 Smooth muscle, exocrine glands, ciliary muscle

M4 CNS, nerves

M5 CNS, ciliary muscle

Atropine blocks all

muscarinic receptor

subtypes.

Effects of Muscarinic Agents

Treatment Regimen

Inte

rocula

r D

iffe

rence (

mm

)

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 sites

4-DAMP - smooth muscle

pirenzepine - neural ganglia

Form-deprived Eyes

Refr

active E

rro

r C

han

ge

(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

Perc

ent C

hange

-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

0.0

0.5

1.0

1.5

2.0

2.5

3.0

High Moderate Low

High

Moderate

Low

near-work

outdoorO

dd

s r

ati

o

Protective effects are not associated with exercise nor do

they represent a “substitution effect” for near work.

Outdoor activities have a strong protective effect against myopia.

Mitchell et al., 2006

High ambient light levels retards the development of form-

deprivation myopia in chicks.

Ashby et al., 2009

Control Eyes

Form-Deprived Eyes

15000 lux

Form-Deprived Eyes

50 & 500 lux

High Light Levels & Experimental Myopia

17

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 Lens

15,000 lux

-7 D Lens

500 lux

Ashby et al., 2009

High Light Levels & FDM Longitudinal Anisometropia

Normal Lighting ~ 350 lux

High Ambient Lighting 18,000 – 25,000 lux

Age (days)

0 50 100 150

An

iso

me

tro

pia

(D

)(t

reate

d e

ye -

fe

llow

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

Normal

FD+Normal Light

FD+High Light

Am

etr

opia

(D

)

-10

-5

0

5

10

IOD Vitreous Chamber (mm)(treated eye - fellow eye)

-0.5 0.0 0.5 1.0 1.5 2.0

Anis

om

etr

opia

(D

)(t

rea

ted

eye

- fe

llow

eye

)

-12

-10

-8

-6

-4

-2

0

2

4

High Light Levels & FDM End of Treatment

Refractive Error IOD RE vs IOD VC

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

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

18

Choroidal Mechanisms Changes in choroid thickness move the retina toward the

appropriate focal point.

from Wallman et al., 1995

normal chick chick recovering

from induced myopia

Scleral

Components

Norton, 1999

• bFGF & TGF beta (growth factors)

• For a myopic 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-beta

1e-14 1e-13 1e-12 1e-11 1e-10 1e-9 1e-8 1e-7

Axia

l le

ngth

Diffe

rence (

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. Myopic defocus reduces the degree of scleral catabolism.

Scleral Changes with FDM

Guggenheim & McBrien, 1996

Decorin is the major proteoglycan in the marmoset sclera. The rate

of proteoglycan synthesis is reduced in the posterior pole of FDM.

Rada et al., 2000

Scleral Changes with FDM 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

19

Physical Changes

Norton, 1999

• Increase / decrease in scleral creep rate

• Axial vitreous chamber depth

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.

Siegwart & Norton, 1995

Scleral Changes with FDM

Vitale et al., 2009

Females Males

1971-72

1999-04

Age (yrs) Age (yrs)

Pre

vale

nce o

f M

yopia

(%

)

The prevalence of myopia is increasing too fast to reflect genetic changes;

something in the environment is affecting the pattern of refractive errors.

Why Worry About Myopia? Ocular Sequelae of Myopia

(Curtin, 1985)

Posterior

Subcapsular Cataract 2 to 5 X

Idiopathic Retinal

Detachment 4 to 10 X

Open-Angle Glaucoma 2.2 X

Chorioretinal

Degeneration

Health ConcernsHealth Concerns

Myopia is the 7th leading cause of legal blindness in the U.S.A. (Zadnik, 2001).

The second highest cause of blindness in India (Edwards, 1998).

Myopic retinal degeneration is the second highest cause of low vision in asians (Yap et al., 1990).

The idea that something about near

work causes myopia has dominated

thinking for centuries.

Theoretical basis for traditional therapy

- Increased IOP

- Excessive convergence &/or accommodation

- Gravity & posture

Duke-Elder, 1970

Levinson, 1919

20

Jensen, 1991

Subject Groups

IOP > 17 mmHG IOP < 17 mmHG

Myop

ic P

rog

ressio

n (

D/y

ear)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7Controls

Timolol

Timolol Treatment for Myopia

Timolol was effective

in lowering IOP.

However there was

not a significant

effect on the rate of

myopic progression.

Control Treated

Degre

e o

f M

yopia

(D

)

-40

-30

-20

-10

0

Control Treated

Rela

tive A

xia

l E

longation (

mm

)

0.0

0.5

1.0

1.5

2.0

Control

0.5% Timolol BID

Schmidt & Wildsoet, 2000

Timolol and Form-Deprivation Myopia

Timolol was effective in lowering IOP in young chicks (between 18 &

27%). However there was not a significant effect on the rate of

myopic progression for either form deprivation or negative lenses.

Atropine Treatment for Myopia

Months

0 5 10 15 20 25 30

Myopic

Pro

gre

ssio

n (

D)

-1

0

1

2

3

4

Controls (0.5% tropicamide)

0.5% atropine

0.25% atropine

0.1% atropine

Shih et al., 1999

N = 200

Ages = 6-13 years - 42-61% of treated

children showed no

myopic progression

- 8% of control group

show no progression.

Myop

ic P

rog

ressio

n (

D)

0.0

0.5

1.0

1.5

2.0

Control Eyes Treated Eyes

Axia

l E

lon

ga

tio

n (

mm

)

-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

Atropine TherapyAtropine Therapy

ShortShort--term sideterm side--effects:effects:

––photophobia & blurred visionphotophobia & blurred vision

––cycloplegia (need for reading cycloplegia (need for reading glasses)glasses)

––potential light damage to retinapotential light damage to retina

––potential elevations in IOPpotential elevations in IOP

––potential systematic reactionspotential systematic reactions

21

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?).

Control Binocularly

Treated

Adult cat treated with 1% atropine in both eyes

from 4 weeks to 4 months of age.

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.

Key Issues Are the effects permanent?

Is there a rebound phenomenon?

End of Treatment

Tong et al., 2009

Pirenzepine Trials

• Safety and efficacy of 2% PRZ ophthalmic

gel in myopic children: Years 1 & 2 (Siatkowski et al., 2003 & 2004, ARVO)

• US Phase II Trial.

– 8- to 12-year old children (n=174); mean age = 9.9 yrs

– -0.75 to -4.00 D myopia; mean = -2.04

0.9 D

– Treated with 2% PRZ or placebo BID for 2 years

PIRZ Placebo

Myop

ic P

rogre

ssio

n (

D/y

ea

r)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

PIRZ bid PIRZ qd Placebo

0.0

0.2

0.4

0.6

0.8

1.0

Pirenzepine: Efficacy for Pediatric Myopia Year-One Results

Asia Study U.S. Study

N = 353 N = 174

Siatkowski et al., 2003 (ARVO) Tan et al., 2003 (ARVO)

Pirenzepine: Efficacy for Pediatric Myopia Year-Two Results

PIRZ Placebo

Myo

pic

Pro

gre

ssio

n (

D)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8 U.S. Study

N = 174

Siatkowski et al., 2008

Proportion ≥ 0.75 D PIR = 37%

PLC = 68%

Dropouts 12% of PIR subjects

0% of PLC group

Common adverse events eyelid gel residue, blurred near

vision, and asymptomatic

conjunctival reactions.

22

Pirenzepine Trials

• Other Questions: – What are the mechanisms and sites of action

of PRZ? (Optimal drug & deliver system?)

– How do you identify patients who will benefit?

– How long do you need to treat the patient?

– Are the effects permanent?

– Are partial effects acceptable?

– Is it safe during pregnancy?

– Are there long-term side effects? Percentage Change in Progression (%)

-30 -20 -10 0 10 20 30 40

BFs / PALs

Under- Correction


Hasebe et al., 2008

Fulk et al., 2000

Edwards et al., 2002

Chung et al., 2002

Adler & Millodot, 2006

Decrease Increase

Percentage Change in Progression (%)

Designed to decrease the level of accommodation during near work

and/or to influence the quality of foveal vision (e.g., to reduce hyperopic defocus associated with a lag of accommodation).

Traditional Optical Treatment Strategies

for Myopia Progression

New Hopes for

Optical Interventions Emmetropization: Basic Operating Properties

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

1. Visual signals from the fovea are

not essential for:

• Emmetropization

• Form deprivation myopia

• Recovery from induced refractive errors

• Lens compensation


Experimental Manipulations

Monocular Foveal Ablation &

1) unrestricted vision

2) form deprivation

3) recovery from induced errors

4) hyperopic defocus (neg. lenses)

Photoreceptor

Layer

Treated Eye

Fellow Eye

Are visual signals

from the fovea

essential for vision-

dependent growth?

23

An intact fovea is not essential for

normal emmetropization.

Age (days)

0 100 200 300

Anis

om

etr

opia

(D

)(t

rea

ted

eye

- f

ello

w e

ye

)

-2

-1

0

1

2

Normal Monkeys

Lasered Monkeys

Age (days)

0 100 200 300

Am

etr

opia

(D

)

0

2

4

6Control Monkeys

Treated Eye

Fellow 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

An intact fovea is not

essential for Form

Deprivation Myopia.

Age (days)

0 50 100 150

Am

etr

opia

(D

)

-4

-2

0

2

4

6 Control Monkeys

Treated Eye

Control Eye

Diffuser

+

Age (days)

0 50 100 150

Anis

om

etr

opia

(D

)(t

rea

ted

eye

- f

ello

w e

ye

)

-6

-4

-2

0

2

4

Control Monkeys

Treated Monkeys

-10

-8

-6

-4

-2

0

2

End of Treatment

An

iso

metr

op

ia (

D)

0 50 100 150 200 250 300 350

Am

etr

op

ia (

D)

0

2

4

6

Control Monkeys

Right Eye

Left Eye

Age (days)

0 50 100 150 200 250 300 350

Vitre

ou

s C

ha

mb

er

(mm

)

8

9

10

11

12

Mky LAU

Laser

An intact fovea is not essential for the recovery from

induced hyperopia.

0 100 200 300 400 500

Am

etr

op

ia (

D)

-4

-2

0

2

4

6

8

Control Monkeys

Right Eye

Left Eye

Age (days)

0 100 200 300 400 500

Vitre

ou

s C

ha

mb

er

(mm

)

8

9

10

11

12

Mky MIT

Laser

An intact fovea is not essential for the recovery from

induced myopia.

-3.0 D lenses

Controls

-3 D

full f

ield

-3 D

perip

hery

-3 D

+ la

ser

Am

etr

opia

(D

)

-10

-8

-4

-2

0

2

4

6

.

Age (days)

0 50 100 150

Am

etr

opia

(D

)

-10

-8

-4

-2

0

2

4

6

.

An intact fovea is not essential for lens

compensation.

Treated Eyes

2. When conflicting signals exist

between the central and

peripheral retina, peripheral

visual signals can dominate

central refractive development.

• Peripheral form deprivation

• Peripheral hyperopic defocus


24

Clear Vision

Form Deprived

Am

etr

op

ia (

D)

-6

-4

-2

0

2

4

6

Normals

4 mm

8 mm

Form Deprived

Peripheral form

deprivation produces

central myopia.

Diffuser lenses

(4 or 8 mm apertures) Peripheral hyperopic defocus produces

central axial myopia.

-3.0 D spectacle lenses

(6 mm apertures)

Age (days)

0 50 100 150

Am

etr

opia

(D

)

-4

-2

0

2

4

6

contro

ls

-3 D

full f

ield

-3 D

perip

hery

Am

etr

opia

(D

)

-4

-2

0

2

4

6

.

Peripheral myopic defocus can produce

central axial hyperopia in chickens.

Liu and Wildsoet, 2010

Peripheral myopic defocus has a very strong effect on central

refractive error development.

In monkeys... • Peripheral form deprivation and peripheral hyperopic

defocus can produce axial myopia at the fovea, even in the presence of unrestricted central vision.

• Photoablation of the fovea does not:

– interfere with normal emmetropization.

– prevent recovery from induced refractive errors.

– prevent form-deprivation myopia.

– compensation to imposed hyperopic defocus

Impact of peripheral vision

Peripheral vision can have a substantial influence on foveal refractive development in primates.

Refractive error varies with eccentricity. The visual signal for eye

growth varies with eccentricity.

Central vs. Peripheral Refractive Error

Corrected Myopic Eye

Image shell Myopes

Emmetropes

Hyperopes

Rela

tive P

erip

he

ral R

efr

actio

n (

D)

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

.

Mutti et al., 2000

Myopes typically exhibit relative hyperopia in the periphery,

whereas hyperopes show relative myopia in the periphery.

Central vs.

30 deg Nasal

Central vs. Peripheral Refraction Children

Temporal Eccentricity

Millodot, 1981

Adults

Refr

active E

rror

(D)

25

Adapted from Wallman, 2004


Oblate

(hyperopic)

Prolate

(myopic)

Spherical

(emmetropic)

from Hoogerheide, Rempt, & Hoogenboom, 1971

Pe

rce

nta

ge

of S

am

ple

0

20

40

60

80

100

Pattern of Peripheral Refractive Error

peripheral hyperopia peripheral myopia

Shift in Central Rx vs. Peripheral Rx

Young adults with

peripheral hyperopia are

more likely to exhibit

myopic Rx shifts during

pilot training.

Myopic Changes

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)

The total number of neurons is

much higher in the periphery.

Spatial summation favors

the periphery.

Uncorrected

Myope

“Corrected”

Myope

Image Shell

As a consequence of eye shape

and/or aspheric optical

surfaces, myopic eyes may

experience significant defocus

across the visual field,

regardless of the refractive state

at the fovea.

Should we correct peripheral refractive errors?

Optimal Correction?

Traditional Spectacle Lenses Increase

Peripheral Hyperopia

Myopic Adults

Corrected

Uncorrected

Tabernero & Schaeffel, 2009

Ch

an

ge i

n R

ela

tive P

RE

(D

)

Lin et al., 2010

Myopic Children

26

Possible Implementation Strategies

• Contact lenses

• Spectacle lenses

• Orthokeratology

• Corneal refractive surgery

Pre-treatment

14-days Ortho K

Peripheral treatment strategies

can provide optimal distance

correct at the fovea and provide an

anti-myopia growth signal in the

periphery.

from Charman et al., 2006


-60 -40 -20 0 20 40

BFs / PALs

Under- Correction

Spectacles

Decrease Increase

Contact Lenses

Executive BF

BF Contact Lenses

OrthoK Cho et al., 2005

Walline et al., 2009

Cheng et al., 2010 Antise & Philips, 2010

Sankaridurg et al., 2010 Holden et al., 2010

Peripheral Components

Central vs. Peripheral Treatment Strategies


-60 -40 -20 0 20 40

Peripheral Treatment Strategies

MYOVISION – SPECTACLE PROGRAM (Sankaridurg et al., 2010)

• Chinese children 6-12 years of age

• Three treatment lens designs vs traditional SV spectacles

Radius (mm)

0 5 10 15 20 25 302.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

Lens shape

Radius (mm)

0 5 10 15 20 25 300.0

0.5

1.0

1.5

2.0

2.5

3.0

Front Surface Astigmatism

Tangential (black) & Sagittal (magenta) Curvature

Mean crown curvature = 3.40 D [@12 mm = 3.55 D]Mean marginal curvature = 4.37 D (@ 22.5 mm)

RMSPE Astigmatism

+/-30 deg eye rotation

Radius (mm)

0 5 10 15 20 25 302.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

Front Surface Mean Power

MyoVision Lens: Teaser Design

Tan Power for Static Eye

Type I

Rotationally

Symmetrical

Radius (mm)

0 5 10 15 20 25 302.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

Lens shape

Radius (mm)

0 5 10 15 20 25 300.0

0.5

1.0

1.5

2.0

2.5

3.0

Front Surface Astigmatism

Tangential (black) & Sagittal (magenta) Curvature

Mean crown curvature = 3.40 D [@8 mm = 3.55 D]Mean marginal curvature = 5.42 D (@ 25 mm)

RMSPE Astigmatism


Radius (mm)

0 5 10 15 20 25 303.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Front Surface Mean Power

MyoVision Lens: Design 19 (Teaser Spline)

Mean Power for Static Eye

16:52 25-07-07Saulius Varnas, R&D AustraliaCarl Zeiss Vision

Type II

Rotationally

Symmetrical

Radius (mm)

0 5 10 15 20 25 302.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

Radius (mm)

0 5 10 15 20 25 303.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Front Surface Mean CurvatureVertical (blue) & Horizontal (magenta) Meridians

Lens shape

Front Surface:w = 136.5 t = 0 j = 176.67m = 0 n = 0.000002p = 3.83a=1.0b=1.35

Radius (mm)

0 5 10 15 20 25 300.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

Front Surface AstigmatismVertical (blue) & Horizontal (magenta) Meridians

Tangential (black) & Sagittal (magenta) Curvature Along the H. Meridian


RMSPE Astigmatism



MyoVision Lens: Design 15 (Optimised)

Surface Tan Power

D=80 mm


Type III

Rotationally

Asymmetrical

Anti-Myopia Spectacles 12-month results

Children 6-12 years-old with 1 or 2 myopic parents

(-0.97

0.48D vs -0.68

0.48D, p = 0.03)

Pro

gre

ssio

n (

D)

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Traditional

Spectacles

Type III

Spectacles Radius (mm)

0 5 10 15 20 25 302.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

Radius (mm)

0 5 10 15 20 25 303.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Front Surface Mean CurvatureVertical (blue) & Horizontal (magenta) Meridians

Lens shape

Front Surface:w = 136.5 t = 0 j = 176.67m = 0 n = 0.000002p = 3.83a=1.0b=1.35

Radius (mm)

0 5 10 15 20 25 300.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

Front Surface AstigmatismVertical (blue) & Horizontal (magenta) Meridians

Tangential (black) & Sagittal (magenta) Curvature Along the H. Meridian


RMSPE Astigmatism



MyoVision Lens: Design 15 (Optimised)

Surface Tan Power

D=80 mm


Type III, Vertical

Type III

Horizontal


-60 -40 -20 0 20 40


Anti-Myopia Contact Lenses (Holden et al., 2010)

• Chinese children 7-14 years of age

• Rotationally symmetric CL vs traditional SV spectacles

-1.00

-0.50

0.00

0.50

1.00

1.50

2.00

2.50

3.00

-40 -30 -20 -10 0 10 20 30 40

SPL Group AMCL Group

Nasal Temporal

Anti-Myopia Contact Lenses 6- and 12-month results

all children 7 to 14 years of age

• 34% reduction in myopia (p < 0.05)

• 33% reduction in axial length (0.41 ± 0.21 mm, n = 45 vs 0.21 ± 0.16 mm, n = 40)

Spherical Equivalent Axial Length

27

*

• 49% reduction in myopia (p=0.03)

• 49% reduction in axial length (0.41 ± 0.21mm vs 0.21 ± 0.16mm)

Traditional

Spectacles

Anti-Myopia

CLs

12 months results

Anti-Myopia Contact Lenses Children with Parental Myopia (60% of sample)


-60 -40 -20 0 20 40


Executive Bifocals (Cheng et al., 2010)

• Progressing myopic, Chinese children (8-13 years, n = 135)

• Exec BFs with or without 6∆ BI prism vs. traditional SV spectacles

• 55% reduction in myopia (p=0.001)

• 35% reduction in axial length (0.40 ± 0.04 mm vs 0.62 ± 0.04 mm, p < 0.001)

Executive Bifocals

Cheng et al., 2010

Archives of Ophthalmology


-60 -40 -20 0 20 40


Simultaneous Bifocal Contact Lenses (Phillips & Anstice et al., 2010)

• Children (11-14 years, n = 40)

• Concentric multifocal (+2.00 D Add) vs. SV CL in a monocular cross-over

design

•Treatment Duration = 8 months

Simultaneous Bifocal CLs

Refractive Error Axial Length

Per

cent

age

Red

uctio

n (%

)

-80

-60

-40

-20

0


-60 -40 -20 0 20 40


Overnight Orthokeratology (Cho et al., 2005 & Walline et al., 2009)

from Charman et al., 2006

http://i.ehow.co.uk/images/a05/2u/9n/concentric-rings-bifocal-contact-lenses-800X800.jpg

28

Re

lative

Am

etr

op

ia (

D)

Refractive Errors Changes with Ortho-K

from Clark et al., 2008

Myopia Progression & Corneal Re-shaping LORIC Study

Ortho-K children (mean age = 9.6 yrs, n = 35) vs SV spectacles. CRAYON

study reported similar results (i.e., about 50% reduction over two years).

Ongoing Ortho-K Studies: ROMIO (Cheung & Cho), MCOS

(Santodomingo et al), Japan (Kakita et al), Sydney (Swarbrick et al.)

from Cho et al., 2005

Key Practical Points

Peripheral treatment strategies: • should be initiated as early as practical.

– It is likely that optical treatment strategies only slow progression.

– Should not be limited to children

• will be of greatest benefit for individuals destined to develop high degrees of myopia. – Need to develop better methods to identify fast progressors.

• will probably be most effective when implemented via contact lenses. – More aggressive treatment zones than SV spectacles.

Key Issues

• Do the treatment effects “saturate”? – e.g., COMET study

Myopic Progression

PALs

SV


Key Issues

• Is it possible to prevent the onset of myopia?

Nature of Refractive Errors

Not all emmetropic eyes

are alike.

Ks = 39.0 – 47.6 D

Lens = 15.5 – 23.9 D

AC = 2.5 – 4.2 mm

AL = 22.3 – 26.0 mm

Ametropic eyes between

-4 D and +6 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.

emmetropes ametropes

from Sorsby, 1978

Distribution of Refractive Errors Refractive Development ...voi.opt.uh.edu/VOI/emmetropization...

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