core myopia lecture 2016 dab - opt.uh.edu
TRANSCRIPT
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.