Recovery from Form-Deprivation Myopia in
Ying Qiao-Grider,1,2Li-Fang Hung,1,2Chea-su Kee,1,2Ramkumar Ramamirtham,1,2and
Earl L. Smith III1,2
PURPOSE. Although many aspects of vision-dependent eye
growth are qualitatively similar in many species, the failure to
observe recovery from form-deprivation myopia (FDM) in
higher primates represents a significant potential departure.
The purpose of this investigation was to re-examine the ability
of rhesus monkeys (Macaca mulatta) to recover from FDM.
METHODS. Monocular form deprivation was produced either
with diffuser spectacle lenses (n ? 30) or by surgical eyelid
closure (n ? 14). The diffuser-rearing strategies were initiated
at 24 ? 3 days of age and continued for an average of 115 ? 20
days. Surgical eyelid closure was initiated between 33 and 761
days of age and maintained for14 to 689 days. After the period
of form deprivation, the animals were allowed unrestricted
vision. The ability of the animals to recover from treatment-
induced refractive errors was assessed periodically by retinos-
copy, keratometry, and A-scan ultrasonography. Control data
were obtained from 35 normal monkeys.
RESULTS. At the onset of unrestricted vision, the deprived eyes
of 18 of the diffuser-reared monkeys and 12 of the lid-sutured
monkeys were at least 1.0 D less hyperopic or more myopic
than their fellow eyes. The mean (diffuser ? ?4.06 D, lid-
suture ? ?4.50 D) and range (diffuser ? ?1.0 to ?10.19 D,
lid-suture ? ?1.0 to ?10.25 D) of myopic anisometropia were
comparable in both treatment groups. All 18 of these diffuser-
reared monkeys demonstrated recovery, with 12 animals ex-
hibiting complete recovery. The rate of recovery, which was
mediated primarily by alterations in vitreous chamber growth
rate, declined with age. None of the lid-sutured monkeys ex-
hibited clear evidence of recovery. Instead, 8 of the 12 lid-
sutured monkeys exhibited progression of myopia.
CONCLUSIONS. Like many other species, young monkeys are capa-
ble of recovering from FDM. However, the potential for recovery
appears to depend on when unrestricted vision is restored, the
severity of the deprivation-induced axial elongation, and possibly
the method used to produce FDM. (Invest Ophthalmol Vis Sci.
viduals normally grow in a highly coordinated manner toward
a near-emmetropic refractive state—a process called em-
metropization.1–9A large body of research has demonstrated
that the phenomenon of emmetropization proceeds in a qual-
itatively similar way in many species and that emmetropization
is a vision-dependent process that is regulated by visual feed-
back associated with the eye’s refractive state.10–23In general,
there has been a remarkable degree of agreement between the
experimental results obtained from different animal species on
the operational properties of the emmetropization process. For
example, in a truly diverse range of animals including humans,
depriving the eye of the potential for a clear retinal image
disrupts the normal emmetropization process and consistently
promotes the development of axial myopia (i.e., form-depriva-
tion myopia [FDM]).24This high degree of interspecies con-
cordance suggests that the basic mechanisms responsible for
emmetropization and phenomena such as FDM have been
conserved across species and that findings concerning vision-
dependent eye growth obtained from animals can be extrapo-
lated, at least in a qualitative sense, to humans with a relatively
high degree of confidence.
However, similar experimental strategies have not always
affected refractive development in a qualitatively similar man-
ner in all animals. When inconsistencies between species can
be attributed to known physiological differences between an-
imals, they can provide substantial insight into basic aspects of
emmetropization. Unexplained interspecies differences, how-
ever, signal potentially important evolutionary departures and
raise concerns about generalizing animal results to humans.
Consequently, identifying true interspecies differences is im-
portant, particularly when it involves animals such as monkeys,
which are considered to be very close to humans. The failure
of monkeys to recover from FDM when unrestricted vision is
restored is one such inconsistency.25,26
Recovery from FDM after the restoration of unrestricted
vision was first observed in chicks by Wallman and Adams27
and represented one of the first clear indications that em-
metropization was regulated by visual feedback. The ability to
recover from FDM has subsequently been confirmed in chicks
in several laboratories27–29and documented in another com-
monly studied animal, the tree shrew.30,31However, results in
rhesus monkeys and marmosets with FDM produced by unilat-
eral eyelid suture indicate that higher primates may not be
capable of recovering from FDM.8,25,26,32The failure of rhesus
monkeys to recover from FDM is somewhat surprising because
primates readily recover from myopia produced by rearing
with negative lenses over one or both eyes.22,23,33
There are several potential explanations for the failure to
observe recovery in rhesus monkeys with FDM. Results in
chicks indicate that the ability to recover from FDM decreases
with age.27In this respect, most of the results currently avail-
able for rhesus monkeys have come from animals that were
eonates frequently exhibit large refractive errors; how-
ever, during early development, both eyes of most indi-
From the1College of Optometry, University of Houston, Houston,
Sydney, New South Wales, Australia.
Supported by National Eye Institute Grants R01 EY03611 and P30
EY70551 and funds from the Greeman-Petty Professorship, University
of Houston (UH) Foundation.
Submitted for publication January 27, 2004; revised May 7, 2004;
accepted June 8, 2004.
Disclosure: Y. Qiao-Grider, None; L.-F. Hung, None; C.-s. Kee,
None; R. Ramamirtham, None; E.L. Smith III, None
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked “advertise-
ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Earl L. Smith III, University of Houston,
College of Optometry, 505 J Davis Armistead Building, Houston, TX
2The Vision CRC, The University of New South Wales,
Investigative Ophthalmology & Visual Science, October 2004, Vol. 45, No. 10
Copyright © Association for Research in Vision and Ophthalmology
deprived for relatively long periods of time and were perhaps
beyond the critical period for recovery when unrestricted
vision was restored.25,26It is also possible that lid-suture sur-
gery, the most common method used to produce form depri-
vation in monkeys, produces complications, possibly optical in
nature, that interfere with the eye’s ability to compensate for
optical defocus after eyelid reopening. In this respect, tree
shrews with FDM produced by eyelid suture fail to recover,
whereas those with FDM produced by diffuser lenses do re-
cover.30,31,34,35The purpose of this study was to re-examine
the ability of rhesus monkeys to recover from FDM. Based on
promising preliminary observations in both marmosets (Troilo
D, et al. IOVS 2000;41:ARVO Abstract 691; Troilo D, et al. IOVS
2002;43:ARVO E-Abstract 186) and rhesus monkeys,13we con-
centrated our studies on relatively young rhesus monkeys that
had FDM produced by wearing diffuser spectacle lenses over
MATERIALS AND METHODS
Longitudinal measures of refractive error were obtained from 44 rhe-
sus monkeys (Macaca mulatta) that experienced monocular form
deprivation. All our experimental monkeys were subjects in previous
studies of either refractive or sensory development and as a group have
a somewhat mixed history.13,22–24,33,36–38A beneficial consequence of
these different treatment histories is that as a group our experimental
subjects exhibited a range of refractive errors from essentially em-
metropia to more than ?10 D of FDM.
Monocular form deprivation was imposed on experimental mon-
keys by either eyelid surgery or with diffuser spectacle lenses. For the
majority of treated animals (n ? 30), form deprivation was produced
by fitting the infant monkeys with helmets that held a diffuser specta-
cle lens in front of one eye and a clear plano lens in front of the fellow
eye. The helmet-rearing procedure, which has been described in detail
in a previous study,23was initiated at 24 ? 3 days of age and continued
for an average of 115 ? 20 days. The amount of form deprivation
varied among helmet-reared animals using either different strength
diffuser lenses37or by allowing the animals short periods of unre-
stricted vision each day during the treatment period.38At the end of
the treatment period, the helmets and diffusers lenses were removed,
and the animals were allowed unrestricted vision.
Monocular form deprivation was produced in 14 animals by surgi-
cally closing the eyelids of one eye using the procedures described by
von Noorden et al.39The onset of lid closure varied between monkeys
from 33 to 761 days of age in a systematic manner. Although the
duration of eyelid closure ranged from 14 to 689 days, for 12 of these
14 lid-sutured monkeys, the duration of deprivation was at least 540
days. The other two lid-sutured monkeys experienced durations of 14
and 31 days, beginning at 38 and 60 days of age, respectively. At the
end of the treatment period, the palpebral fissure was surgically re-
established and the animals were allowed unrestricted vision.
Control data for the first 2 years of life were obtained from 17
normal monkeys that were reared with unrestricted vision. In addition,
control data for the helmet-rearing procedures were obtained for three
monkeys that were reared wearing helmets that held plano spectacle
lenses in front of both eyes. The onset and duration of helmet wear for
the plano control monkeys were equivalent to those for the diffuser-
reared monkeys. Refractive-error data for the normal and the plano-
lens–reared infants have been reported previously.22,23,33,40,41Fifteen
normal monkeys that were obtained as adolescents provided control
data for the later juvenile period of refractive development.
During the recovery period, many of the treated and control mon-
keys were used as subjects in psychophysical studies of spatial and/or
binocular vision. These experiments were initiated when the monkeys
were at least 540 days of age and required the animals to perform
behavioral detection tasks for approximately 2 hours each day. The
details of these studies have been described previously.42–45
Refractive development and in particular the changes in refraction that
occurred after the period of form deprivation were assessed using
measurement methods that have been described in detail previ-
ously.22,23,33,41For the helmet-reared monkeys and the young control
animals, refractive error, corneal curvature, and the eye’s axial dimen-
sions were measured at 2- to 4-week intervals throughout the obser-
vation period. To make these measurements, cycloplegia was induced
with 2 drops of topically applied 1% tropicamide. The animals were
anesthetized with intramuscular injections of ketamine hydrochloride
(20 mg/kg) and acepromazine maleate (0.2 mg/kg) and topically in-
stilled 0.5% tetracaine hydrochloride. The spherical-equivalent, spec-
tacle-plane refractive corrections were determined by retinoscopy.
The reported data represent the average from two independent ob-
servers. The mean radius of curvature of the cornea along the eye’s
pupillary axis was determined with a hand-held keratometer (Alcon
Auto-keratometer; Alcon Systems Inc., St. Louis, MO). The eye’s axial
dimensions, particularly vitreous chamber depth, were measured by
A-scan ultrasonography using an instrument with a focused, 7-MHz
transducer (Image 2000; Mentor, Norwell, MA). The reported axial
dimensions represent the average of 10 individual readings obtained
using a weighted average velocity for ultrasound of 1550 m/sec.
The general methods used to assess refractive development in the
lid-sutured monkeys and the older control animals were similar to
those described earlier with the following exceptions. Cycloplegia was
induced with topically applied 1% cyclopentolate instead of tropicam-
ide. No attempts were made to measure corneal curvature. Total axial
length was measured with an A-scan system with a 10-MHz transducer
(DBR 310; Sonometric, Huntington, WV). It was not possible, how-
ever, to obtain the dimensions of the vitreous chamber alone with this
instrument. The reported axial lengths represent the mean of three to
five individual readings. Of the 12 monkeys that exhibited myopic
anisometropias larger than ?1.0 D, the first measurements were ob-
tained immediately after eyelid opening for six of these monkeys. For
the other six lid-sutured monkeys, their initial measurements were
obtained from 40 to 367 days after eyelid opening (i.e., there was a
period of unrestricted vision before the first measurement). Subse-
quent measurements for the lid-sutured animals were made at less
frequent intervals than with the diffuser-reared animals.
All the rearing and experimental procedures were approved by The
University of Houston’s Institutional Animal Care and Use Committee
and were in compliance with the ARVO Statement for the Use of
Animals in Ophthalmic and Vision Research and the National Institutes
of Health Guide for the Care and Use of Laboratory Animals.
Two-sample t-tests were used to compare the data from treated and
normal monkeys. Paired student t-tests were used to examine intero-
cular differences and for before-after comparisons in individual ani-
mals. Due to the low number of subjects, a nonparametric test (the
Mann-Whitney test) was used to compare the anisometropic and axial
length changes between the lid-sutured monkeys that were allowed
unrestricted vision before the first measurement and those that were
assessed immediately after eyelid opening. The relationship between
the rate of recovery and the magnitude of the experimentally induced
refractive errors was determined by nonlinear regression analysis. All
the analyses were executed on computer (Minitab, rel. 12.21; Minitab
Inc., State College, PA; and SPSS software, ver. 8.0; SPSS Inc., Chicago,
To evaluate axial growth, a locally weighted regression scatter plot
smoothing method (LOESS) was used to generate developmental
curves for overall axial length and vitreous chamber growth rates in
normal monkeys. LOESS is a nonparametric smoothing algorithm that
allows data to be expressed in a trend without initial mathematical
3362 Qiao-Grider et al.
IOVS, October 2004, Vol. 45, No. 10
assumptions. LOESS was most applicable for our monkey data because
the data were irregularly spaced and there were variable numbers of
observations at each point in time.46The LOESS analysis was con-
ducted on computer (S-plus 6 software; Insightful Corp., Seattle, WA).
Recovery in Diffuser-Reared Monkeys
The monocular form deprivation associated with our various
diffuser-rearing regimens disrupted emmetropization in the
deprived eyes of most of the treated animals, resulting in an
interocular imbalance in refractive errors with the treated eyes
typically becoming more myopic or less hyperopic than the
nontreated eyes. Although monocular manipulations have
been shown to alter refractive development in both the treated
and untreated eyes of infant monkeys,22,23,33,37these intero-
cular effects are relatively small, and consequently we consid-
ered the degree of anisometropia exhibited by the treated
animals to represent the amount of FDM. At the end of the
treatment period, the treated eyes of 18 of the 30 diffuser-
reared monkeys were at least 1.0 D more myopic or less
hyperopic than their fellow, nontreated eyes. The range of
myopic anisometropias in this subgroup of treated monkeys
varied from ?1.0 to ?10.19 D (mean ? ? 4.06 ? 2.77 D; Fig.
As shown in Figure 1A, at least some recovery from FDM
was subsequently observed in all 18 of the diffuser-reared
monkeys that had ?1.0 D of FDM at the end of the treatment
period. In 12 of these 18 monkeys, the magnitude of myopic
anisometropia had decreased to less than 1.0 D by the end of
the observation period, which varied in duration from 126 to
1366 days. Within this group of animals, the decrease in aniso-
metropia varied from 0.69 to 7.50 D. As illustrated by Fig. 1B,
the recovery was due to a hyperopic shift in the refractive state
of the treated eyes, and in some cases, a myopic shift in the
refractive state of the fellow eyes. The six monkeys that had
residual anisometropic errors that were greater than 1.0 D at
the end of the observation period tended to be the animals that
showed high amounts of FDM at the start of the recovery
period. For example, four of these six monkeys had at least
?5.0 D of FDM at the start of the recovery period. However, as
will be shown later in this section, it is likely that more
complete recovery would have been observed in these mon-
keys if we had increased the duration of the observation pe-
The consistency and systematic nature of the recovery pro-
cess are emphasized in Figures 2 and 3, which illustrate the
longitudinal changes in anisometropia that occurred during the
treatment (filled symbols) and recovery periods (open sym-
bols) for the 18 diffuser-reared monkeys that developed signif-
icant amounts of FDM. Figure 2 shows individual plots for each
of the 13 diffuser-reared monkeys that had less than ?5.0 D of
FDM. At some point during the recovery period, the anisome-
tropia for each of these animals fell within the range of ani-
sometropias observed in control monkeys (thin solid lines),
which demonstrates how successful the recovery process was
in infant monkeys. The data for the five monkeys that showed
severe FDM (?5.50 to ?10.19 D) are superimposed in a single
plot in Figure 3. Complete recovery was observed for one of
these monkeys, although it required approximately 1500 days
of unrestricted vision. The other four monkeys included in
Figure 3 were observed for a shorter period and showed
incomplete recovery. However, considering that the recovery
data for all the animals in Figure 3 appear to follow a similar
time trajectory, it seems reasonable to speculate that given
longer observation periods, more of these monkeys would
have shown complete recovery.
Inspection of the data in Figures 2 and 3 suggests that the
rate of recovery and the time required for complete recov-
ery varied systematically with the initial degree of FDM. To
quantify the rate of recovery we used a nonlinear regression
analysis to fit the following logarithmic function to the
anisometropia data obtained during the recovery period for
each monkey: y ? a ? b ln(x); where y and x represent the
amount of anisometropia and the number of days since
unrestricted vision was restored, respectively, and a and b
represent scaling coefficients. As illustrated in Figure 4A,
which shows the calculated functions for three representa-
tive animals, this log function provided a good fit (P ? 0.01)
to the data for 16 of the 18 monkeys and an adequate fit for
the remaining two animals. With a logarithmic function like
this, the rate of recovery can best be described by the slope
or first derivative of the logarithmic function. The first de-
rivative of y ? a ? b ln(x) (i.e., dy/dx) is b/x. Therefore, b
is proportional to the rate of recovery; specifically b in-
creases as the rate of recovery gets faster. Figure 5B illus-
trates that the coefficient b, hence the rate of recovery, was
significantly correlated with the magnitude of anisometropia
at the start of the recovery period (r2? 0.93; P ? 0.001). It
is also clear from the first derivative of this function (dy/
dx ? b/x) that the rate of recovery decreased with time
during the recovery process.
correction (treated eye minus fellow eye) in the 18 diffuser-reared
monkeys that exhibited at least 1 D of FDM at the end of the treatment
period. Also shown is the degree of anisometropia at the end of the
recovery period. All the monkeys exhibited a decrease in the degree of
FDM during the recovery period. (B) Changes in refractive error that
occurred during the recovery period in the same 18 monkeys. In both
plots, the monkeys are arranged according to the magnitude of aniso-
metropia at the end of the treatment period.
(A) Interocular differences in spectacle-plane refractive
IOVS, October 2004, Vol. 45, No. 10
Recovery from Myopia 3363
of the treatment period. Data were obtained during the treatment (F) and recovery (E) periods, respectively. (?) The end of the treatment period
and the restoration of unrestricted vision. Solid thin lines: data from the normal monkeys (right eye minus left eye). At some point during the
recovery period, all the treated monkeys showed anisometropic errors that fell within the range of normal monkeys.
Degree of anisometropia plotted as a function of age in the 13 monkeys that exhibited between ?1.00 and ?5.00 D of FDM at the end
After the recovery from FDM, many of the diffuser-reared
animals represented in Figure 2 subsequently maintained the
resulting isometropia over very long observation periods (e.g.,
monkeys TIA, NEL, and LIS). However, it is interesting that
some animals did not remain isometropic after the initial re-
covery from FDM. For example, in monkey QUI, after it recov-
ered from approximately ?3.0 D of FDM, a relative hyperopia
developed in the originally form-deprived eye. In contrast,
monkey MAR’s deprived eye became relatively myopic again
after a successful recovery from ?4.40 D of FDM. However, as
shown in Figure 5, many of the 12 diffuser-reared monkeys in
which less than 1.0 D of FDM developed during the treatment
period also failed to maintain isometropia throughout the ob-
servation period (e.g., monkeys SAW, NIN, and MIG). Thus, the
initial degree of FDM does not appear to influence the long-
term stability of the balance of refractive errors between the
The recovery from FDM in the diffuser-reared monkeys
came about primarily because there was a dramatic decrease
in the vitreous chamber growth rates of the deprived eyes
after removal of the diffuser lenses. However, the recovery
process, and particularly the reduction in myopic anisome-
tropia, were also influenced by alterations in the vitreous
chamber growth rates in the nontreated eyes. Figure 6,
which shows data for two representative monkeys, illus-
trates the two basic recovery patterns that we observed.
After the onset of unrestricted vision, vitreous chamber
growth in the deprived eyes of both monkeys virtually
halted, and the deprived eyes subsequently exhibited rela-
tive hyperopic shifts in refractive error as a consequence of
reductions over time in the refracting powers of the cornea
and crystalline lens (Qiao Y, et al. IOVS 2000;41:ARVO
Abstract 693). However, the changes in the nontreated eye’s
vitreous chamber growth rate depended on the nontreated
eye’s absolute refractive error. Nontreated eyes that were
less hyperopic than normal (e.g., monkey JAS) showed a
decrease in vitreous chamber growth and relative hyperopic
shifts in refractive error after the onset of unrestricted vi-
sion. In contrast, nontreated eyes with relatively high de-
grees of hyperopia (e.g., monkey LIS) showed an increase in
vitreous chamber growth rate and a subsequent reduction in
hyperopia. Consequently, the initial growth changes in both
the treated and nontreated eyes contributed to the observed
changes in the degree of myopic anisometropia.
Figure 7 summarizes the changes in vitreous chamber
growth rates that occurred at the onset of the recovery period
for all 18 monkeys that had developed significant amounts of
FDM. In 16 of these 18 treated animals, the deprived eyes (Fig.
7A) showed a reduction in vitreous chamber growth rate in
response to the restoration of unrestricted vision. For most
monkeys, the treated-eye growth rates during the initial recov-
ery period were near zero, indicating a complete cessation of
axial elongation. For the nontreated eyes (Fig. 7B), the changes
in vitreous chamber growth rates were generally smaller and
five monkeys that exhibited more than ?5.00 D of FDM at the end of
the treatment period. Small solid and open symbols: data obtained
during the treatment and recovery periods, respectively. Large open
symbols: the end of the treatment period and the restoration of unre-
stricted vision. Solid thin lines: data from the normal monkeys (right
eye minus left eye). Some degree of recovery was observed in all five
monkeys and the time course for recovery was similar in all animals.
Degree of anisometropia plotted as a function of age in the
representative monkeys. Solid lines fit to the data are the logarithmic functions described in the text. (B) Recovery index (i.e., the first derivative
of the functions shown in A) plotted as a function of the initial degree of anisometropia. Recovery rate from FDM was dependent on the initial
anisometropia (P ? 0.001).
Relationship between the initial degree of FDM and the rate of recovery. (A) Longitudinal changes in anisometropia in three
IOVS, October 2004, Vol. 45, No. 10
Recovery from Myopia3365
the direction of the growth changes correlated with the non-
treated eyes’ absolute refractive state (r2? 0.619, P ? 0.001).
In addition to the alterations in vitreous chamber growth
rate, a small, but statistically significant, part of the recovery
from myopic anisometropia could be attributed to corneal
changes. At the end of the treatment period, the corneas of the
deprived eyes were, on average, 0.37 D steeper than those of
the nontreated eyes (Fig. 8A; paired t-test, P ? 0.005), which
contributed in part to the myopic anisometropia observed in
the 18 diffuser-reared monkeys that showed significant
amounts of FDM. However, at the end of the recovery period,
these interocular differences in corneal power had diminished
and were no longer significant (Fig. 8B, mean difference ?
0.08 D, paired t-test, P ? 0.425).
Absence of Recovery from FDM in
Monocular form deprivation produced by surgical eyelid clo-
sure consistently disrupted refractive development in the
treated eyes, resulting in a relative myopic shift in the deprived
eye’s refractive state. Twelve of the 14 lid-sutured monkeys,
including the two animals that experienced the shorter periods
of deprivation, demonstrated relative myopic anisometropia
that was ? ?1.0 D and the mean and range of myopic aniso-
metropia in this group of lid-sutured monkeys (mean ?
?4.45 ? 2.90 D; range ? ?1.00 to ?10.25 D) was comparable
to that in the diffuser-reared monkeys described earlier (two-
sample t-test, P ? 0.67). Because there were no significant
differences in the anisometropic changes (end of the observa-
tion period minus beginning of the observation period) that we
observed in monkeys that were and were not allowed unre-
stricted vision before the first measurement (Mann-Whitney
test, treated eye P ? 1.00; nontreated eye P ? 0.42), the data
for all 12 monkeys were pooled. In contrast to the diffuser-
reared monkeys, there was little evidence of recovery from
FDM in our lid-sutured monkeys. As illustrated in Figure 9, the
myopic anisometropia exhibited by these lid-sutured monkeys
was well outside the range of the anisometropia observed in
normal monkeys; but, more important, there was no clear
indication of a systematic reduction in the degree of anisome-
tropia over time. Despite average recovery periods that were
485 ? 192 days in length, the average decrease in anisometro-
treatment period. See Figure 3 for details.
Anisometropia plotted as a function of age in the 12 diffuser-reared monkeys that exhibited less than ?1.0 D of FDM at the end of the
3366 Qiao-Grider et al.
IOVS, October 2004, Vol. 45, No. 10
pia that occurred during the observation period was only
0.44 ? 1.54 D (range ? ?2.25 to ?3.25 D), which was not
significantly different from zero (Fig. 10A, one-sample t-test;
P ? 0.16).
Also contrary to expectations, both the deprived and non-
treated eyes of these lid-sutured monkeys tended to become
more myopic during the recovery period. As shown in Figure
10B, 8 of 12 deprived eyes and all the nontreated eyes exhib-
Ametropia plotted as a function of age. Thin solid lines: data from the control monkeys. (C, D) Interocular difference in vitreous chamber depth
plotted as a function of age. (E, F) Vitreous chamber growth rates plotted as a function of age. Small dots and the broken line represent right eye
data from the control animals. The growth rate data for the deprived monkeys represent the average of the last three measurements at the end of
the treatment period and the first three measurements after the onset of unrestricted vision. The key to symbols in the top panels applied to all panels.
Relationship between the degree of anisometropia and vitreous chamber growth in two representative diffuser-reared monkeys. (A, B)
IOVS, October 2004, Vol. 45, No. 10
Recovery from Myopia3367
ited relative myopic changes in refractive error over the obser-
vation period. There was a substantial amount of variability
between subjects in terms of the amount of myopic progres-
sion, but the average refractive-error changes were signifi-
cantly myopic for both the deprived (?1.27 ? 1.98 D, one-
sample t-test, P ? 0.024) and nontreated eyes (?1.94 ? 1.81 D,
one-sample t-test, P ? 0.0017).
During the recovery period, the myopic shifts observed in
both eyes of the monocularly lid-sutured monkeys were asso-
ciated with increases in axial length. In Figure 11, axial length
is plotted as a function of age for the right eyes of normal
monkeys (thin lines) and for the deprived (Fig. 11A) and
nontreated eyes (Fig. 11B) of the lid-sutured monkeys. As
expected, the axial lengths of many of the deprived eyes fell
outside the range of axial lengths in the normal monkeys.
However, inspection of the data reveals that the slopes of the
treated and nontreated eyes’ functions were also steeper than
normal. To quantify these increases in ocular growth, we
calculated the axial growth rates by dividing the total change in
axial length during the entire recovery period by the length of
the recovery period. Both the deprived and nontreated eyes
exhibited significantly faster than normal growth rates (two-
sample t-test, deprived eyes, P ? 0.012; nontreated eyes; P ?
0.006). However, the axial growth rates for the deprived and
nontreated eyes were not significantly different (paired t-test,
P ? 0.50), which is consistent with our observation that the
at least ?1.0 D of FDM at the end of the treatment period. Data show growth rates at the [F] end of the treatment period (average of the last three
measurements) and at the (E) beginning of the recovery period (average of the first three measurements).
Vitreous chamber growth rates for the deprived (A) and nontreated, fellow eyes (B) of all 18 diffuser-reared monkeys that exhibited
for the interocular differences in cor-
neal power obtained at the end of
the treatment (A) and recovery peri-
ods (B) for the 18 diffuser-reared
monkeys in which at least ?1.0 D of
FDM developed. At the end of the
treatment period, the corneas of the
deprived eyes were ?0.37 D more
powerful than those of the nonde-
prived eyes (P ? 0.005). At the end
of the recovery period, there were
no significant interocular differences
in corneal power (P ? 0.425).
3368Qiao-Grider et al.
IOVS, October 2004, Vol. 45, No. 10
amount of myopic anisometropia found in a given animal did
not change significantly during the recovery period.
Our main findings were that infant rhesus monkeys with axial
myopia produced by image-degrading diffuser lenses consis-
tently recovered from FDM after the onset of unrestricted
vision, whereas adolescent rhesus monkeys with FDM pro-
duced by surgical eyelid closure failed to show any signs of
recovery, even with prolonged postdeprivation observation
periods. This pattern of results is in agreement with previous
observations on the reversibility of FDM in mammals. For
example, previous studies have reported that lid-sutured rhe-
sus monkeys,36,47tree shrews,30,35and marmosets8,32failed to
recover from FDM after the termination of eyelid closure.
However, it has been shown that tree shrews31and marmosets
(Troilo D, et al. IOVS 2000;41:ARVO Abstract 691; Troilo D, et
al. IOVS 2002;43:ARVO E-Abstract 186), like our rhesus mon-
keys, are capable of recovering from FDM produced by diffuser
The ocular changes responsible for the recovery from FDM
in our diffuser-reared monkeys were qualitatively similar to
those observed in rhesus monkeys during the recovery from
myopia induced by defocusing lenses.22,23,33In both cases, the
onset of unrestricted vision, which was accompanied by myo-
pic defocus for distant targets, caused a dramatic decrease in
the deprived eye’s vitreous chamber growth rate. The deprived
eye’s absolute refractive state became less myopic and more
hyperopic over time because of a concomitant decrease in the
eye’s total refracting power. Ignoring the small additional de-
crease in corneal power observed in the deprived eyes
(mean ? 0.37 D), there were no systematic interocular differ-
ences in the corneal and lenticular changes observed in our
monocular diffuser-reared animals during the recovery period
(i.e., the normal reductions in corneal and lenticular refracting
power were not altered by the recovery process).48Thus, data
from normal animals should provide an indication of the rela-
tive contributions of the crystalline lens and cornea to the
recovery from myopia and an approximation of the limits to
the degree of recovery that is possible. For example, from
approximately 115 days of age (the average age at which
unrestricted vision was restored), corneal power normally de-
creases in an exponential fashion by approximately 2 D over
the next 500 days. Over this same period, crystalline lens
power normally decreases by approximately 7 D (Qiao Y, et al.
IOVS 2000;41:ARVO Abstract 693). Consequently, the eyes of
115-day-old infant monkeys have the potential to recover from
approximately 9 D of axial FDM and the changes in the de-
prived eye’s total refracting power will be dominated by mat-
urational changes in the crystalline lens, with decreases in
corneal power playing a smaller but significant role. Whether
recovery in a young monkey is complete depends in large part
on the eye’s absolute axial length at the end of the period of
deprivation. The potential for complete recovery is substan-
tially reduced if a deprived eye obtains an axial length that is
greater than that of a normal adult. In this respect, at the end
of the treatment period the deprived eyes of our diffuser-reared
monkeys were longer than those of age-matched control mon-
keys, but were still shorter than the eyes of normal adults, and
all these treated monkeys exhibited complete recovery (Fig.
The nature of the ocular changes that underlie the recovery
from FDM in our diffuser-reared monkeys is also qualitatively
similar to that which occurs during recovery from FDM in tree
shrews and chickens. For example, in the first study to docu-
ment recovery from FDM in chickens, Wallman and Adams27
found that unrestricted vision produces a dramatic and selec-
tive cessation of vitreous chamber growth, whereas the rest of
the eye appears to continue to grow normally. Recovery is
correction (treated eye minus fellow eye) for the lid-sutured monkeys
that manifest at least ?1.0 D of FDM at the end of the treatment period.
(B) Changes in refractive error that occurred during the recovery
period. In both plots, the monkeys are arranged according to the
magnitude of anisometropia at the end of the treatment period.
(A) Interocular differences in spectacle-plane refractive
for the 12 lid-sutured monkeys that had at least ?1.0 D of FDM. Thin
lines: represent the data from the normal animals. Filled symbols:
monkeys that were examined immediately after eyelid opening. Open
symbols: monkeys that were allowed unrestricted vision after eyelid
opening and before the first measurement.
The degree of anisometropia plotted as a function of age
IOVS, October 2004, Vol. 45, No. 10
Recovery from Myopia3369
complete when the optical components of the eye catch up
with the deprivation-induced axial elongation. Siegwart and
Norton31observed a similar recovery pattern in myopic tree
shrews. Because of anatomic differences between the eyes of
chickens, tree shrews, and monkeys, it is likely that there are
differences in the relative contributions of the lens and cornea
to the power changes that occur during recovery from FDM,
but the general strategy appears to be the same across species.
It has been documented in monkeys22,36,49and several
other species18,20,35,50–52that monocular form deprivation can
alter the course of emmetropization in the fellow nontreated
eyes resulting in atypical refractive errors in both eyes. In the
present study, we found that growth changes in the nontreated
eyes also contributed to the isometropization process during
the recovery from FDM. Therefore, when the degree of recov-
ery from FMD is measured by interocular differences in refrac-
tive error, refractive changes in the nontreated eye can either
speed up or delay recovery, depending on the nontreated eye’s
absolute refractive error. It is interesting that the nontreated
eyes showed clear evidence of recovery toward more normal
refractive errors after the onset of unrestricted vision in the
treated eye, even though the refractive errors in many of the
nontreated eyes were relatively stable for some time before the
end of the treatment period. This pattern of results suggests
that the stimulus for abnormal growth in the fellow nontreated
eye was maintained throughout the period of form deprivation.
Although the recovery process in our diffuser-reared mon-
keys was very successful, the recovery was not permanent in
all monkeys. Instead, the eyes of some animals overshot
isometropia and subsequently hyperopic anisometropia devel-
oped, whereas in others myopic anisometropia redeveloped.
The instability in the balance of refractive errors in the two
eyes suggests that the early period of form deprivation may
have permanently compromised the processes that normally
maintain isometropia, possibly reflecting plasticity-related al-
terations in the visual system. In this respect, observations in
both humans53–56and monkeys33,36,45,57–60have suggested
that the presence of amblyopia may interfere with the ability of
the eye to grow in a manner that would compensate for
chronic optical defocus and subsequent behavioral experi-
ments (Smith EL III, et al. IOVS 2003;44:ARVO E-Abstract
3188)45demonstrated that the deprived eyes of many of our
diffuser-reared monkeys were amblyopic. However, there was
no clear-cut relationship between the degree of amblyopia and
the long-term stability of the refractive errors in our diffuser-
reared monkeys. Possibly the observed instability reflects dif-
ferences in the binocular vision status of our animals. In this
respect, infant monkeys with experimentally induced strabis-
mus frequently have anisometropia that develops well after the
onset of the strabismus and in the absence of amblyopia.43
However, because many aspects of ocular growth appear to be
regulated by mechanisms within the eye itself,11,47,61–64it is
not clear how amblyopia and/or anomalous binocular vision,
which are not believed to be associated with retinal abnormal-
ities, would directly influence the eye’s response to optical
defocus. It is possible, however, that over long periods of time
interocular misalignments and/or slight interocular asymme-
tries in accommodation associated with unilateral fixation pref-
erences could produce chronic interocular asymmetries in
retinal image quality that would result in differential interocu-
Given the very consistent recovery observed in our diffuser-
reared monkeys, why did virtually all of our animals that were
form deprived by eyelid closure fail to recover from FDM?
Because there was a substantial amount of overlap in the
function of age for the treated (A) and
nontreated, fellow (B) eyes of the 10
lid-sutured monkeys for which longitu-
dinal axial length data were available.
Thin lines: right eye data from the 10
normal animals for which longitudinal
axial length data were available. Filled
symbols: monkeys that were exam-
ined immediately after eyelid opening;
open symbols: monkeys that were al-
lowed unrestricted vision before the
first measurement after eyelid open-
ing. There were no statistically signifi-
cant differences (Mann-Whitney test,
treated eye, P ? 0.59; nontreated eye
P ? 0.75) in the axial length changes
between the monkeys that were mea-
and those that had some unrestricted
vision before the first measurement af-
ter eyelid opening.
Axial length plotted as a
monkeys that had at least 1 D of FDM, plotted as a function of age
(solid lines). The earliest point for each function represents the onset
of unrestricted vision. The dashed line is the LOESS growth curve for
the normal monkeys. At the end of the period of deprivation, most of
these diffuser-reared monkeys had axial lengths that were longer than
those in age-matched control animals but still shorter than those in
normal adult monkeys.
Axial length of the deprived eyes of the 18 diffuser-reared
3370Qiao-Grider et al.
IOVS, October 2004, Vol. 45, No. 10
degree of amblyopia observed in our lid-sutured and diffuser-
reared monkey populations (Smith EL III et al. IOVS 2003;44:
ARVO E-Abstract 3188),44it is unlikely that differences in the
degree of amblyopia limited the ability of our lid-sutured mon-
keys to recover. There are, however, several possible explana-
tions. It seems likely that differences in the absolute degree of
deprivation-induced axial elongation and the age of onset for
unrestricted vision contributed significantly to the disparities
between our diffuser-reared and lid-sutured animals. In partic-
ular, most of the lid-sutured monkeys were much older at the
onset of unrestricted vision (average ? 701 ? 362 days, rang-
ing from 52–1326 days) than the diffuser-reared monkeys (av-
erage ? 139 ? 20 days, ranging from 107–176 days). Although
hyperopic defocus can still produce appropriate compensating
refractive changes in monkeys at these ages,67it is likely that
the animals’ fixation behavior combined with the way in which
recovery from myopia occurs are limiting factors in this case. If
the monkeys had fixated with their originally deprived eyes,
then the nontreated eyes would have experienced hyperopic
defocus, which could have resulted in myopic growth in the
nontreated eyes and an equalization of refractive errors in the
two eyes. However, because the originally deprived eyes were
frequently amblyopic,44,65,66it is most likely that the non-
treated, fellow eyes dominated fixation and accommodation
during the recovery period and hence the originally deprived
eyes would experience chronic myopic defocus. Because re-
covery associated with myopic defocus depends on the normal
reductions in the eye’s refracting power,48an animal’s ability
to recover decreases exponentially with age and presumably
ceases when the cornea and lens have reached their adult
dimensions. In this respect, many of the deprived eyes of our
lid-sutured monkeys had axial lengths that were outside the
range of our adult control monkeys before the onset of unre-
stricted vision (Fig. 11). Given how eyes recover from axial
myopia, the absolute axial lengths of these eyes greatly re-
duced the potential for recovery, regardless of the effects of
the resultant myopic defocus on axial growth. However, two
of the monkeys that had significant amounts of FDM were
lid-sutured from 38 and 60 days of age for periods of 14 and 31
days, respectively, and were very likely to have had axial
lengths that were shorter than a normal adult. It is interesting
that these monkeys demonstrated ?1.0- to ?1.5-D increases in
myopia in the treated eye during the postdeprivation observa-
tion period. The data from these two animals suggest that the
age of onset of unrestricted vision and the eye’s absolute axial
length may not be the only limiting factors for recovery from
In both tree shrews30,31,34,35,68and marmosets (Troilo D et
al. IOVS 2000;41:ARVO Abstract 691; Troilo D, et al. IOVS
2002;43:ARVO E-Abstract 186),8,32equating the duration of
deprivation and the age at the onset of unrestricted vision does
not eliminate the disparity in the ability to recover between
animals form deprived by diffuser lenses versus those deprived
by surgical eyelid closure. Even when the absolute axial
lengths of the treated eyes are well within the normal adult
range, eyes that experience form deprivation by lid suture do
not recover.8,35Consequently, it is likely that additional factors
contributed to the absence of recovery in our lid-sutured mon-
keys. Eyelid suture has been shown to alter corneal shape in
tree shrews30,35and we have noted by simple inspection that,
on eyelid opening, the corneal light reflex in our previously
lid-sutured monkeys was often irregular. Although we do not
know how long these corneal shape changes persisted, it is
plausible that early eyelid suture produces permanent alter-
ations in corneal shape that could alter the aberrant structure
of the eye in a way that results in a mild degree of image
degradation. Because image degradation can produce axial
myopia in adolescent monkeys69and the mechanisms respon-
sible for FDM are sensitive to even small reductions in image
quality,37this scenario could explain why the treated eyes of
our lid-sutured monkeys failed to recover, but instead contin-
ued to exhibit faster than normal rates of axial elongation. In
this respect, the progressive myopic changes found in the
nontreated, fellow eyes of our lid-sutured monkeys could re-
flect interocular influences of abnormal visual experience sim-
ilar to those observed in young animals.
In conclusion, young rhesus monkeys, like young chicks,28
tree shrews,31and marmosets (Troilo D, et al. IOVS 2000;41:
ARVO Abstract 691; Troilo D, et al. IOVS 2002;43:ARVO E-Ab-
stract 186), can recover from the axial myopia produced by
early monocular form deprivation. Although the timing of the
period of form deprivation and the severity of the induced axial
elongation are likely to influence the potential for recovery, it
is clear that the ability to recover from FDM is a common
phenomenon in young animals. This interspecies congruence
enhances the likelihood that human eyes behave in a similar
fashion and that human eyes also have the ability to alter their
growth in response to optical defocus in a manner that elimi-
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