Download Observations on the effects of form deprivation on the

Observations on the Effects of Form Deprivation on
the Refractive Status of the Monkey
Earl L. Smith, III,* Ronald S. Harwerrh,* M. L. J. Crawford,t and Gunrer K. von Noorden:J:
The consistency of the refractive error alterations produced by monocular form deprivation in developing monkeys and the influence of the duration and the age at the onset of deprivation on the magnitude
of these alterations was investigated. Refractive error and axial length measurements are presented for
a group of monkeys which had one eye sutured closed for a period exceeding 18 months beginning at
various ages ranging from 26 days to 25 months. In addition, we pooled and reanalyzed refractive error
and axial length data for monocularly form-deprived monkeys from previous studies. When the
alterations in the deprived eye's refractive status are specified with respect to the fellow nondeprived
eye, the results are, with a few noteworthy exceptions, consistent between laboratories and individual
animals. In most cases, early monocular form deprivation causes the treated eye to develop a longer
axial length and to manifest a more myopic/less hyperopic refractive error than the fellow nontreated
eye. The magnitude of this deprivation-induced alteration is generally dependent on the duration and
the age at the onset of form deprivation. The earlier the deprivation is initiated and the longer it is
maintained, the greater the degree of the relative myopia produced in the deprived eye. Invest Ophthalmol Vis Sci 28:1236-1245,1987
Wiesel and Raviola1'47 have reported that form deprivation initiated early in the life of a developing
monkey causes the deprived eye to become axially
myopic. Their results were very consistent; virtually
all of their form-deprived monkeys became myopic.
Subsequently several laboratories2'8'9 reported that although neonatal lid suture did appear to disrupt the
process of emmetropization, they were not able to
confirm the consistent relationship between neonatal
form deprivation and axial myopia. In particular, the
results of von Noorden and Crawford2 are often cited
as evidence that monocular form deprivation does
not always cause the deprived eye to become myopic.
They reported that only about half of their form-deprived eyes became myopic; the remainder exhibited
hyperopic refractive errors.
To date the exact reasons for the variability in the
effects of form deprivation observed between individual animals and laboratories have not been delineated. It has often been speculated that this variability
may be due to differences in the lid fusion procedures
employed by different laboratories2'710 or that it may
simply be a by-product of the uncontrolled axial
growth associated with form deprivation.10 It is important to determine the source of this variability, as
form-deprived monkeys could potentially serve as a
useful animal model in investigations of the mechanisms which regulate the emmetropization process
and which when disrupted produce anomalies in the
eye's refractive status. In the present report we have
pooled and reanalyzed data from previous studies
Although genetic factors undoubtedly play a major
role in directing ocular development, investigations
involving a variety of mammalian species, including
humans, have suggested that a visually dependent
feedback mechanism is also involved in the regulation of eyeball growth during maturation.1"6 This vision-dependent mechanism is believed to aid in coordinating the growth of the eye's axial and optical
components so that the eye maintains an approximately emmetropic refractive condition throughout
development. Presumably this regulatory mechanism
monitors the quality or clarity of the retinal image
and adjusts the growth of the eye accordingly, because it has been consistently demonstrated that if the
potential for a clear retinal image is prevented during
development, the coordinated growth of the eye is
disrupted.1>2'4"8 There is, however, currently some
controversy concerning the type of refractive error
which is produced in young monkeys by this unregulated growth.2-7'8
From the "College of Optometry, University of Houston, Houston, Texas, the tUniversity of Texas at Houston, Sensory Sciences
Center and Department of Ophthalmology, Houston, Texas, and
the JCullen Eye Institute, Baylor College of Medicine, Houston,
Texas.
Supported in part by grants EY-03611, EY-01120, and
EY-01139 from the National Eye Institute and by BRSG grant
RR07147.
Submitted for publication: April 22, 1986.
Reprint requests: Earl L. Smith, III, College of Optometry, University of Houston, 4800 Calhoun Boulevard, Houston, TX 77004.
1236
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REFRACTIVE ERRORS IN FORM-DEPRIVED MONKEYS / Smirh er ol.
No. 8
1237
Table 1. Characteristics of the monkey subjects
Refractive error
Subjects
Age at onset*
Eye\
8104
62 days
REf
LE
8024
92 days
REt
8114
118 days
Pre-treatment
LE
REt
LE
8021
153 days
REt
LE
L33O
184 days
REt
LE
L332
242 days
L322
309 days
L420
366 days
REt
LE
REt
LE
REt
LE
L260
558 days
L244
770 days
+0.75 DS
+ 1.75 DS
+ 1.75 DS
+ 1.75-0.50 X 180
+0.75 DS
+0.75 DS
+2.75 DS
+2.75 DS
REt
LE
L264
L266
L48§
13623§
30 days
(24 months)*
26 days
(24 months)*
30 days
(60 days)*
33 days
(14 days)*
REt
LE
RE
LEt
RE
LEt
REt
-3.25 DS
-2.25 DS
+ 3 . 7 5 - 1.00 X 90
+ 3 . 7 5 - 1.00 X 90
+0.75
+0.75
LE
REt
LE
* The duration of deprivation was 18 months for all subjects except for
subjects L264, L266, L48, and 13623. For these subjects the duration of
deprivation is given in parentheses under the age at onset.
and present new data in an attempt to identify important experimental variables. The results demonstrate that when fundamental experimental variables
are taken into account, the refractive error alterations
produced by long-term monocular form deprivation
in developing monkeys are, with a few notable exceptions, consistent and that the discrepancies previously noted between laboratories are more apparent than real.
Materials and Methods
All of the procedures used in this investigation
conform to the ARVO Resolution on the Use of Animals in Research. Twelve rhesus monkeys (Macaca
mulatto) were used as subjects. Unilateral form deprivation was produced by surgically fusing the eyelids
of one eye using the procedures described by von
Noorden et al.11 The age at the onset of monocular
form deprivation was varied from animal to animal
and ranged from 26 days to 25 months of age. The
duration of the form deprivation for this group of
animals was in excess of 18 months for each animal
(see Table 1). A brief report of some of the psycho-
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Post-treatment
+ 2 . 5 0 - 1.25 X 180
+4.00 DSt
-8.25 DS
+0.75 DS
- 2 . 0 0 - 2 . 0 0 X 135
+ 3 . 5 0 - 1.00 X 180
+2.50-0.50 X 180
+ 5 . 5 0 - 1.00 X 180
- 5 . 5 0 - 0 . 5 0 X 180
+0.25-0.50 X 180
- 2 . 5 0 - 1.00 X 120
+0.25 DS
- 3 . 0 0 - 2 . 5 0 X 180
+ 1.50- 1.00 X 180
-1.25 DS
+ 1.50- 1.00 X 180
- 1 . 5 0 - 1.50 X 135
0.00 DS
-8.00 DS
-5.50 DS
+1.50-0.50X45
-0.50-2.50X180
-4.00-0.50 X 180
- 0 . 5 0 - 1.00X45
-8.50 DS
-2.00 - 2.00 X 090
0.00 DS
+6.00-3.00 X 180
Axial
length
18.8 mm
18.2 mm
21.8 mm
19.3 mm
20.5 mm
19.6 mm
18.8 mm
18.6 mm
19.7 mm
18.4 mm
19.5 mm
18.8 mm
20.0 mm
18.4 mm
19.1 mm
18.5 mm
19.4 mm
18.6 mm
21.5 mm
20.9 mm
18.7 mm
19.8 mm
19.8 mm
19.8 mm
20.1 mm
19.0 mm
18.2 mm
17.5 m m
t Indicates the deprived eye.
% DS = dioptric sphere.
§ Refractive errors previously reported in ref. 9.
physical effects of form deprivation in these animals
has been presented.12
At the end of the treatment period, the palpebral
fissure was re-established, the refractive status of each
eye was determined by retinoscopy and with an objective infrared optometer (Bausch & Lomb Ophthalmetron, Rochester, NY), and the axial lengths
were measured by A-scan ultrasonography (Sonometric DBR 310, Huntington, WV). To obtain the measurements the animals were anesthesized with ketamine hydrochloride (10 mg/kg IM) and cycloplegia
was produced by the topical application of 2 drops of
1 % cyclopentolate hydrochloride. The optometer was
aligned on the pupillary axis and a minimum of three
readings were taken for each eye. The optometer was
repositioned and refocused between measurements.
The optometer provided, in graphic form, an estimate of the refractive error for essentially every meridian of the eye. A basic spectacle correction was
derived from the optometer readings and was subsequently refined by retinoscopy. Retinoscopy was performed with a streak retinoscope and hand-held trial
lenses. For the axial length measurements, several
drops of a topical anesthetic (proparacaine hydro-
1238
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / Augusr 1987
chloride, 0.5%) were instilled in the eye and the ultrasound probe (10 MHz crystal) was placed in direct
contact with the geometrical center of the cornea with
care being taken not to indent the corneal surface.
The position of the probe was adjusted to maximize
the echoes from the posterior lens surface and the
vitreal-retinal interface. It was assumed that the velocity of ultrasound in the monkey's eye was the same
as that measured in the human eye. The distance
between the crystal artifact and the echo from the
vitreal-retinal interface was considered to represent
the axial length of the eye and was measured to the
nearest tenth of a millimeter.
The pretreatment refractive errors for some of the
subjects were determined by retinoscopy at the time
that form deprivation was initiated. These refractive
errors are reported in Table 1, but, because these
measurements were obtained for a relatively small
number of monkeys, the data were not considered
when the effects of form deprivation were evaluated.
Nevertheless, comparisons between pre- and posttreatment refractions within this group of monkeys
support the conclusions drawn below from posttreatment comparisons between deprived and nondeprived eye populations.
In order to examine the consistency of the effects of
form deprivation on the monkey's refractive status
and to aid in the investigation of the effects of several
experimental variables on these induced refractive
error alterations, we have attempted to pool all of the
data for individual monocularly lid-sutured monkeys
that are available in the current literature. Therefore,
we have included in this paper data from previous
studies by Wiesel and Raviola,1'7 von Noorden and
Crawford,2 Harwerth et al,9 and Thorn et al.8 In addition we report axial length measurements for two
monocularly lid-sutured monkeys for which refractive error data were published previously.9
Results
Effects on Refractive Status
The deprivation schedule, the spectacle plane refractive errors specified in minus cylinder notation,
and the axial lengths for each eye of the experimental
subjects are shown in Table 1. The effects of lid suture on the monkeys' deprived eyes are illustrated in
Figure 1 where the interocular differences in refractive error, expressed in diopters, are shown for each
subject. The plotted values were obtained by subtracting the spherical equivalent refractive error correction for the nondeprived eye from the deprived
eye's correction. Therefore, points plotted above the
dashed line indicate that the deprived eye was more
myopic/less hyperopic than the nondeprived eye.
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Vol. 28
For comparison purposes data previously reported
from our laboratories2'9 and from the laboratories of
Wiesel and Raviola1 have also been included in Figure 1. Only data for monkeys which were deprived
during the first 2 years of life are shown. The filled
symbols in the data from the study by von Noorden
and Crawford2 represent animals which had undergone reverse-suture procedures. This reverse-suture
procedure included an initial period of monocular
eyelid suture that was terminated by opening the initially deprived eye and suturing closed the initially
open eye. Within this population of monkeys, the
durations of the deprivation periods for the first and
second sutured eyes varied from animal to animal.
Nevertheless, for these reverse-sutured animals the
initially sutured eye was considered the "treated" eye;
the eye which was subsequently closed during the
reverse suturing procedures was designated as the
"control" eye.
Primarily due to procedural differences, one must
be cautious when pooling data between laboratories.
Nevertheless the data in Figure 1 illustrate several
points. First, when the refractive error alterations in
the deprived eyes of the monocularly lid-sutured
monkeys (open symbols) are specified with respect to
the nontreated control eyes, the effects of form deprivation are consistent. With two exceptions, one animal from the study by Harwerth et al9 and one
animal from this study, monocular lid suture
always caused the deprived eye to become relatively
more myopic/less hyperopic than the nontreated
control eye.
A second point illustrated by Figure 1 is that the
majority of the animals included in the report by von
Noorden and Crawford2 had been reverse sutured.
The inclusion of reverse-sutured animals probably
contributed to the apparent discrepencies between
their results and those reported by Wiesel and Raviola.1 One of the primary advantages of employing
unilateral lid suture procedures is that the nondeprived eye provides an "in animal" control for a
number of potentially critical experimental variables.
Employing reverse-suture procedures confounds interocular comparisons and, as shown in Figure 1, results in a substantial degree of variability in the interocular differences in refractive error. When it is considered that the duration of deprivation was often
different for the two eyes of these reverse-sutured
monkeys and that with reverse-suture procedures the
age at the onset of deprivation is different for the two
eyes, it is not surprising that interocular comparisons
of refractive errors in these animals did not yield
consistent results.
Although Figure 1 demonstrates that monocular
lid suture almost always causes the deprived eye to
No. 8
1239
REFRACTIVE ERRORS IN FORM-DEPRIVED MONKEYS / Smith er ol.
INTEROCULAR REFRACTIVE ERROR DIFFERENCES
MONOCULARLY FORM-DEPRIVED MONKEYS
1
-14.0 -
Age at onset <24 months
O
O MONOCULAR LID
SUTURE
-12.0 -
•
Fig. 1. Interocular spherical equivalent refractive
error differences (diopters)
for individual form-deprived monkeys (deprived
eye correction - nondeprived eye correction). Data
from three previous studies1-2-9 are also included.
Only data for monkeys
which were deprived by 2
years of age are shown. The
open andfilledsymbols represent monocularly lid-sutured and reverse lid-sutured monkeys, respectively. With two exceptions,
the data for the monocularly deprived monkeys are
plotted above the dashed
zero line, indicating that
form deprivation caused the
deprived eye to become
more myopic/less hyperopic than the nondeprived
eye.
-10.0
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Wiesel &
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(1977)
become relatively more myopic than the nondeprived eye, the results plotted in Figure 2 indicate that
in a number of instances the deprived eye did not
develop an absolute myopia. Figure 2 illustrates refractive error frequency distributions for three different monkey populations. The histogram in panel A
shows the refractive error distribution for normal
macaque monkeys obtained by Young.13 This population consisted primarily of adolescent and adult
macaque monkeys (Macaca mulatta and Macaca nemistrina); both wild and laboratory-reared animals
are included in the distribution. The histograms
shown in panels B and C of Figure 2 represent data
for the nondeprived and deprived eyes, respectively,
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i
Von Noorden &
Crawford (1978)
i
i
HARWERTH
NORMAL
et al. (1983) CONTROLS
SMITH
U of H
et aL
(RIGHT - LEFT)
of monocularly lid-sutured monkeys. Again, data for
monocularly deprived monkeys have been pooled
from several studies.2'7'9
The refractive error distribution for the normal
monkeys in panel A demonstrates all of the essential
characteristics observed in refractive error distributions for the general human population.14 The distribution is basically leptokurtic with the great majority
of animals demonstrating either no refractive error or
a small degree of hyperopia.
The refractive error distribution for the lid-sutured
monkeys' nondeprived eyes (panel B) appears to be
broader than the distribution for the normal monkeys. In particular there appears to be a higher preva-
1240
INVESTIGATIVE OPHTHALMOLOGY & VI5UAL SCIENCE / August 1987
"•SET"
Vol. 28
lence of moderate degrees of hyperopia than observed
in the normal population. This higher prevalence of
hyperopia can be attributed, in part, to the fact that
some of these animals were very young (less than 3
months of age) at the time the refractive error measurements were obtained. Although the data suggest
that the refractive error distribution for the nondeprived eyes may not be entirely normal, a larger number of monocularly lid-sutured monkeys must be examined before any firm conclusions can be made
concerning the status of the nondeprived eyes.
The distribution of refractive errors for the lid-sutured monkeys' deprived eyes (panel C) indicates that
the majority of the deprived eyes developed an absolute myopic refractive error. However, as originally
pointed out by von Noorden and Crawford,2 some of
the deprived eyes clearly exhibit hyperopic refractive
errors. In some, but certainly not in all cases (see
subjects 8104 and 8021 in Table 1), these hyperopic
refractive errors were observed in relatively young
animals.
The refractive error distribution for the deprived
eyes also illustrates the high degree of variability
characteristic of refractive errors in lid-sutured eyes.
Figures 3 and 4 demonstrate that much of this rather
large range of refractive errors can be attributed primarily to basic procedural differences between animals and laboratories, specifically the age at the time
of lid suture and the duration of lid suture.
Figure 3 illustrates the relationship between the age
at the onset of the form deprivation and the magnitude of the interocular refractive error difference in
r—I «-«».. u.
n
n
inJ" H - rtAJI n11
MONOCULARL.V FORM-DEPRIVEO MONKEYS
i
REFRACTIVE ERRORS (DIOPTRIC SPHERICAL EQUIVALENTS)
Fig. 2. Refractive error frequency distributions for normal and
monocularly lid-sutured monkeys. The distribution for normal
adult macaque monkeys (A) has been replotted from an investigation by Young. 13 Data for the nondeprived (B) and deprived eyes
(C) of monocularly lid-sutured monkeys from three previous studies 2 7 9 have been combined with the data from this investigation.
Only data for monkeys which were deprived by 2 years of age are
shown. The data from Raviola and Wiesel's study7 were obtained
from a histogram with 2-diopter bin widths (their Fig. 1). To make
their data compatible with the format of the histogram illustrated
above, the individual refractive errors in their histogram were
sorted into 1-diopter groups centered on the nearest odd diopter.
This sorting process undoubtedly contributed to the apparent absence of data for nondeprived eyes in the +2.0 diopter refractive
error category (B). The distribution for the deprived eyes (C) demonstrates the range of refractive errors produced by neonatal lid
suture and illustrates that some deprived eyes exhibit a hyperopic
refractive error.
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Fig. 3. Interocular refractive error differences (diopters) for
monoculary lid-sutured monkeys (deprived eye correction — nondeprived eye correction) plotted as a function of the age (days) at
the onset of form deprivation. Data from three previous studies1'2'9
are also shown. Only data for monkeys that were deprived for a
duration of 2 months or longer have been included. The magnitude
of the interocular refractive error difference decreases as the age at
the onset of deprivation is increased.
1241
REFRACTIVE ERRORS IN FORM-DEPRIVED MONKEYS / Smirh er ol.
INTEROCULAR REFRACTIVE ERROR DIFFERENCES
MONOCULARLY FORM-DEPRIVED MONKEYS
DURATION OF DEPRIVATION (DAYS)
Fig. 4. Interocular refractive error differences (diopters) for
monoculary lid-sutured monkeys (deprived eye correction - nondeprived eye correction) plotted as a function of the duration of
deprivation (days). Data from three previous studies129 are also
shown. Only data for monkeys which were lid-sutured before 6
weeks of age are presented. The magnitude of the interocular refractive error difference increases as the duration of deprivation is
increased.
INTEROCULAR AXIAL LENGTH DIFFERENCES
MONOCULARLY DEPRIVED MONKEYS
1
Cont rol)
>1.20
©
1
1
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1.12
O
1.10
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1.08
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-
O
0
O
a
0
a
JGTHS
monocularly lid-sutured monkeys. The interocular
refractive error difference in diopters (deprived eye
correction — nondeprived eye correction) is plotted as
a function of the subjects' ages at the onset of deprivation. Data have been pooled from several studies, but
only monkeys which were deprived for a minimum
duration of 2 months are represented. With two exceptions (one animal deprived at 30 days of age in the
study by Harwerth et al9 and one animal deprived at
26 days of age in this study), the data appear to follow
a lawful relationship between the age at onset and the
magnitude of the induced refractive error. The correlation coefficient of a linear regression analysis of the
data from only the subjects which manifested a relative myopia in their deprived eyes indicates that there
is a significant relationship (r = 0.65; df = 19; P
< 0.01) between the log of the age at onset and the
magnitude of the differences in refractive error between the deprived and control eyes. The earlier the
lid suture is initiated, the greater the magnitude of the
induced refractive error. However, it must be emphasized that this conclusion only holds for subjects
that developed a relative myopia in their deprived
eyes.
The influence of the duration of monocular form
deprivation on the magnitude of the induced refractive error is illustrated in Figure 4. The interocular
differences in refractive error (deprived eye correction - control eye correction) are plotted as a function of the duration of monocular deprivation. Data
are illustrated for monkeys which were form deprived
before 6 weeks of age; the different symbols represent
individual animals from different laboratories.
Again, with the exception of the two animals noted
above (the animals deprived for 22 and 24 months),
the data indicate that the magnitude of the relative
myopia induced in the deprived eyes increased as a
function of the duration of deprivation. If the two
animals which failed to develop a relative myopia in
their treated eyes are excluded from the analysis,
there is a significant relationship between the log of
the duration of the deprivation and the magnitude of
the interocular differences in refractive error (r
= -0.65;df= 10; P< 0.05).
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Effects on Axial Length
Form deprivation in developing monkeys has also
been reported to produce alterations in the eye's axial
length.1'81516 The nature of the axial length alterations produced by monocular form deprivation is
illustrated in Figure 5, where the interocular differences in axial length are expressed for individual animals as the ratio of axial lengths between the deprived
and nondeprived eyes. The data included in Figure 5
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O INDIVIDUAL
ANIMALS
THORN ET AL.
Wlatal A
(1982)
Ravlola (1977)
•
SMITH ET AL. CONTROLS RE/CE
GROUP MEAN
Ravlola & Wle««l (1985)
Fig. 5. Interocular axial length ratios (deprived eye/nondeprived
eye) for monocularly form-deprived monkeys. Individual data
from three previous studies178 have also been included. Only animals which were deprived before 2 years of age are represented. In
comparison to their nondeprived eyes, the great majority of monkeys (23 of 26 animals) exhibited longer axial lengths for their
deprived eyes.
1242
INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / Augusr 1987
AXIAL LENGTH vs. REFRACTIVE ERROR
• WIESEL AND RAVIOLA ( 1 9 7 7 )
• SMITH •• at
+ PREDICTED
1.02
1.04
1.09
1.08
1.10
1.12
1.14
1.16
1.18
1.20
1.22
AXIAL LENGTH RATIOS (DEPRIVED/CONTROL)
Fig. 6. Interocular refractive error differences (diopters; deprived
eye correction - nondeprived eye correction) plotted as a function
of the interocular axial length ratios (deprived eye/nondeprived
eye) for individual monocularly form-deprived monkeys. Data
from the study by Wiesel and Raviola1 have also been included.
Only animals that were deprived before 2 years of age and that
manifested a relative myopia in their deprived eyes are represented.
The solid line was derived from a least-squares linear regression
analysis of the data. The broken line represents the predicted relationship between the interocular refractive error differences and the
interocular axial length ratios (see the text for details). The agreement between the predicted and the experimental data indicate
that the deprivation-induced refractive error alterations are axial in
nature.
were pooled from three laboratories and represent
only animals which were deprived before 2 years
of age.
Like the alterations in refractive error described
above, when the effects of form deprivation on the
deprived eye's axial length are specified with respect
to the nondeprived eye's axial length, the results are
fairly consistent. In all but three of the animals for
which data are available (23 of 26 monkeys), the axial
length of the deprived eye was longer than that for the
nondeprived eye. The relatively shorter axial lengths
observed by Thorn et al8 in two of their monocularly
form-deprived monkeys suggest that these animals,
like the two exceptions noted above in Figure 1, had
developed a relative hyperopia in their deprived eyes.
However, the axial length measurements for these
monkeys were obtained through their fused eyelids;
their refractive errors were not measured.
Other studies71516 in which axial length data for
populations of deprived monkeys are reported (the
data for individual monkeys were not available) also
indicate that form deprivation results in a consistent
increase in the deprived eye's axial length relative to
that for nondeprived control eyes. Therefore, these
results, when considered together with the individual
data shown in Figure 5, indicate that monocular form
deprivation almost always causes the deprived eye to
Downloaded From: http://iovs.arvojournals.org/ on 05/12/2017
Vol. 28
develop a longer axial length than the nondeprived
control eye.
The relationship between the axial length and refractive error alterations produced by neonatal form
deprivation is shown in Figure 6. The interocular refractive error differences in diopters (deprived eye nondeprived eye) are plotted as a function of the interocular axial length ratios (deprived eye/nondeprived eye) for individual animals from two laboratories. Only animals which manifested a relative myopia in their deprived eyes are represented. The solid
line was derived from a least-squares linear regression
analysis of the data. The broken line represents the
predicted relationship between the interocular refractive error differences and the interocular ratios of
axial length. The predicted values are based on the
assumptions that the nondeprived eye had a 19-mm
axial length and was emmetropic (the optics of the
eye were represented by a single spherical refracting
surface 1.32 mm behind the cornea), and that the
interocular refractive error differences were due exclusively to alterations in the deprived eye's axial
length, more specifically to alterations in the depth of
the vitreous chamber (ie, the cornea, lens and intraocular fluids were assumed to be unaffected by form
deprivation).
The data demonstrate that, for this selective subset
of animals, there is a significant relationship between
the interocular differences in refractive error and the
interocular ratios of axial length (r = 0.87; df = 15; P
< 0.01). Moreover, there is good agreement between
the experimental data and the predicted relationship
between axial length and refractive error. Therefore,
these data support the conclusion by Raviola and
Wiesel7 that the deprivation-induced refractive error
alterations shown in Figure 1 are axial in nature.
Because of the clear association between the alterations in refractive error and axial length, it would be
expected that the magnitude of the axial length alterations would also be dependent on the age at the
onset of form deprivation and the duration of the
deprivation. Figure 7 illustrates the relationship between the magnitude of these axial length alterations
and the age at the onset of deprivation. The interocular axial length ratios for individual monkeys monocularly deprived for a minimum of 2 months are
plotted as a function of the age at onset. Data have
been pooled from three different laboratories.1'8
A linear regression analysis of all of the data in
Figure 7 indicates that there is not a significant correlation between the magnitude of the induced axial
length changes and the age at the onset of deprivation
(r = -0.09). If, however, the three subjects that failed
to develop longer axial lengths in their deprived eyes
(two monkeys from the study by Thorn et al8 and one
No. 8
1243
REFRACTIVE ERRORS IN FORM-DEPRIVED MONKEYS / Smirh er QI.
from the present study) are excluded from the analysis, there is a significant correlation between the interocular axial length ratios and the age at the onset of
deprivation (r = -0.48; df = 19; P < 0.05). Within
the subset of our population that demonstrated a relative axial elongation in their deprived eyes, the earlier
the age at the onset of deprivation, the greater the
interocular difference in axial length.
The effects of the duration of deprivation on interocular axial length ratios (deprived eye/nondeprived
eye) in monocularly form-deprived monkeys are
shown in Figure 8. Data for monkeys which were
deprived before 6 weeks of age have been pooled from
three different laboratories.1'8 When all of the data are
considered, the correlation between the duration of
deprivation and the induced axial length anomaly is
not significant (r = -0.19). Even when the data for
the three subjects which failed to develop longer axial
lengths in their deprived eyes are excluded from the
analysis, the interocular axial length ratios are not
significantly correlated with the duration of deprivation. In light of the significant relationship observed
between the magnitude of the induced refractive
error and the duration of deprivation (Fig. 4), it is
somewhat surprising that an analysis of the axial
length data suggests that the duration of deprivation
does not influence the magnitude of the axial length
alterations. However, the animal populations that
provided the data for Figures 4 and 8 were not identical. In particular, Figure 8 includes axial length data
from the study by Thorn et al.8 Since in their study
the axial length measurements were obtained through
the monkeys' fused eyelids, the refractive errors for
these animals were not available. If the data reported
by Thorn et al8 are also excluded from the analysis,
there is a tendency for the animals which were treated
for the longer durations to exhibit the larger interocular axial length ratios and the correlation between
these ratios and the duration of deprivation approaches statistical significance (r = 0.54).
There are two reasons why the data from the paper
by Thorn et al,8 when included in the above analysis,
appear to mask the influence of the duration of deprivation on the magnitude of the induced axial length
changes. First, in two of their monkeys, lid suture
caused the deprived eye to become shorter than the
nondeprived eye. Thesefindings,although atypical of
the population of monocularly deprived monkeys as
a whole, are important because they indicate clearly
that form deprivation does not always result in the
development of an abnormally long axial length. Like
the two animals noted in Figure 1 which failed to
develop a relative myopia in their deprived eyes,
there does not appear to be anything significant in the
history of these two animals which would explain
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AXIAL LENGTH DIFFERENCES VS AGE AT ONSET
• THORN .1.1(1082)
• TION OP DEPRIVATION 2 2 MONTHS
• SMITH .1 al
1-
AGE AT ONSET (DAYS)
Fig. 7. Interocular axial length ratios (deprived eye/nondeprived
eye) plotted as a function of the age (days) at the onset of deprivation for monocularly lid-sutured monkeys. Data from two previous
studies18 have also been included. Only animals which were deprived for a minimum of 2 months are shown. Four of the six
monkeys from the study by Thorn et al8 underwent bilateral lid
closure for short periods of time (4 to 12 days) prior to the opening
of one eye and the commencement of monocular form deprivation.
Since interocular comparisons were employed to assess the effects
of form deprivation, the ages at which the lids of the "control" eye
were parted were considered the ages at the onset of deprivation for
these subjects.
AXIAL LENGTH DIFFERENCES VS. DURATION
• THORN at a l l I sail
8 „
• SMITH .1 at
AGE AT ONSET S • WEEKS
DURATION OF DEPRIVATION (DAYS)
Fig. 8. Interocular axial length ratios (deprived eye/nondeprived
eye) plotted as a function of the duration of the deprivation in days.
Data from two previous studies1'8 have also been included. Only
animals which were deprived before 6 weeks of age are represented.
1244
INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / Augusr 1987
why they failed to develop longer axial lengths in
their deprived eyes. Second, when axial length measurements are taken through fused lids, it may not
always be possible to accurately identify the position
of the anterior pole of the cornea. Therefore, if the
estimates of axial length included some portion of the
eyelids, the measured axial lengths would be artificially long. Since the effects of form deprivation on
the axial dimensions of the eye are restricted essentially to the vitreous chamber, interocular axial length
differences expressed as ratios derived from axial
length measurements which included some portion
of the eyelids would be smaller in absolute terms than
if the ratios were based on the true distance between
the anterior pole of the cornea and the retina. Possibly that is why the interocular axial length ratios reported by Thorn et al8 are, in general, smaller than
those reported by other laboratories for monkeys deprived for equivalent periods of time.
Discussion
The results demonstrate that monocular form deprivation initated early in the life of a developing
monkey disrupts the normally regulated growth of
the eye. When the effects of this unregulated growth
on the deprived eye's refractive status are specified
with respect to that of the fellow nondeprived eye, the
nature of the resulting refractive error alteration is
very consistent. In almost every case (43 out of 47
cases; combined totals from this study and refs. 6-9;
the group data in refs. 15 and 16 also support this
consistent relationship), monocular form deprivation
causes the treated eye to develop a longer axial length
and/or to manifest a more myopic/less hyperopic refractive error than the nontreated eye. Furthermore,
the magnitude of this relative axial myopia is dependent on the duration and the age at the onset of deprivation. However, even when the obvious experimental variables are taken into account, a small proportion of form-deprived animals fail to develop
anomalous refractive errors, and in some cases these
exceptions exhibit refractive error and axial length
changes which indicate that form deprivation caused
the treated eye to become relatively more hyperopic.
At the present time these exceptions cannot be explained, but the existence of these exceptions supports the concept that multiple factors are involved in
the pathogenesis of experimentally induced refractive
errors.
The apparent failure of some laboratories to confirm the consistent relationship between neonatal
form deprivation and induced axial myopia can be
attributed in part to the difficulty of establishing appropriate controls. If relatively short periods of deprivation are employed so that the magnitude of the
induced refractive anomaly is small, the normal in-
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Vol. 28
tersubject variability of refractive errors can mask the
alterations produced by form deprivation. If, for example, an animal had a moderate hyperopic refractive error prior to form deprivation, the alterations in
the deprived eye's refractive status may not be sufficient to result in an absolute myopia. Normal intersubject variability in refractive errors becomes a particularly critical factor when interocular comparisons
of refractive errors for a given subject are not practical or not employed (eg, when reverse suture procedures are used) and when monkeys are employed as
subjects, because usually relatively small numbers of
subjects are used. The results presented in this study
confirm the advantages of using unilateral form deprivation procedures which allow small treatment-related alterations to be detected by interocular comparisons between the deprived and nondeprived eyes.
The most obvious advantage of employing unilateral
deprivation procedures is that the nontreated eye
provides an "in animal" control for a number of important and previously recognized variables that influence an animal's refractive status (eg, genetic factors, the housing environment, age, etc.).71317
Probably the best way to evaluate the effects of
monocular form deprivation on the developing animal's refractive status would be to compare interocular refractive error differences before and after the
period of form deprivation. Unfortunately, pretreatment refractive error measurements have only been
reported for a small number of animals. In most investigations, including this study, it is assumed that
prior to form deprivation the refractive errors for the
monkey's two eyes are equal. It should be noted,
however, that some of our monkeys (eg, subjects
L330 and L244) exhibited a small, but significant,
anisometropia prior to the onset of form deprivation.
It is likely that if pre-treatment differences in refractive error were systematically taken into account, the
degree of variability between animals would be further reduced and the effects of pertinent experimental
variables would be more obvious.
A characteristic of the refractive error alterations
produced by neonatal form deprivation is that the
amount of relative myopia manifested by monkeys
varies substantially from individual to individual.
Since the techniques which have been most commonly used to deprive a monkey of form vision (eg,
lid suture) are unrefined from an optical point of
view, the associated alterations in the retinal image
are difficult to accurately specify and are likely to
vary to some degree from animal to animal. As a
result, it has been speculated often that much of the
individual variability in the magnitude of these induced refractive errors is due to inconsistencies in the
nature of the anomalous visual input produced by
these techniques.2710 The results presented in Figures
No. 8
REFRACTIVE ERRORS IN FORM-DEPRIVED MONKEYS / Smith et ol.
3, 4, 7, and 8 indicate, however, that differences in
the duration and the age at the onset of deprivation
are responsible for much of the individual variability
in the magnitude of the induced refractive error.
There are indications in the literature that the duration and the age at the onset of form deprivation are
important experimental variables in determining the
magnitude of the induced refractive error anomaly.
Raviola and Wiesel7 have reported that when the lids
of a monocularly lid-sutured monkey are opened, the
subsequent axial growth rate of the deprived eye is
identical to that of the nondeprived eye. Since the
unregulated excessive axial growth was only observed
when the eyes were lid-sutured, the magnitude of the
resulting refractive error alterations would be dependent on the duration of the deprivation. Several laboratories1'2 have reported previously that form deprivation initiated in adolescent or mature monkeys did
not cause the deprived eye to develop an anomalous
refractive error. These observations suggest that a
sensitive period exists for the effects of form deprivation on the monkey's refractive status and imply that
age at the onset of deprivation would influence the
magnitude of the induced refractive anomaly. Sommers et al,15 however, did not observe a clear relationship between the age at the onset of form deprivation and the magnitude of the axial length alterations.
The apparent discrepency between their results and
those reported in this study can most likely be attributed to differences in the range of ages considered and
the number of animals analyzed. Whereas Sommers
et al15 varied the age at the onset of deprivation from
7 to 81 days, in the present study we analyzed all of
the available data for monocularly deprived monkeys, which provided a range of ages between 1 day
and 25 months.
It has been repeatedly demonstrated that the refractive errors produced by form deprivation are associated with alterations in the eye's axial dimensions.1<4'7'81516 The clear relationship between the interocular differences in refractive error and axial
length illustrated in Figure 5 for monocularly deprived monkeys corroborates the axial nature of the
induced refractive anomalies. It has been previously
reported that form deprivation does not affect corneal curvature, the depth of the anterior segment, or
the thickness of the lens.7 The alterations in the deprived eye's axial dimensions appear to be limited to
changes in the depth of the vitreous chamber.78 The
close agreement between the experimental data and
the predicted relationship between the refractive
error and axial length alterations shown in Figure 5
supports the concept that the induced refractive
errors are the result of an increase in the depth of the
vitreous chamber.
By pooling data from several laboratories it has
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1245
been possible to demonstrate that the refractive errors
produced by form deprivation are influenced by several experimental variables. It is likely that other experimental parameters associated with form deprivation also affect the genesis of these refractive anomalies. Nevertheless, the overall consistency in the
refractive anomalies reported by different laboratories indicate that these induced alterations are robust,
and strengthens the use of the form-deprived monkey
as a model for studying the emmetropization process
and the pathogenesis of refractive errors.
Key words: myopia, form deprivation, monkey, refractive
error, axial length
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