Vision Research 134 (2017) 26–42

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Vision Research
journal homepage: www.elsevier.com/locate/visres

Observations on the relationship between anisometropia, amblyopia and

strabismus
Earl L. Smith III a,b,⇑, Li-Fang Hung a,b, Baskar Arumugam a,b, Janice M. Wensveen a, Yuzo M. Chino a,
Ronald S. Harwerth a
a
College of Optometry, University of Houston, TX 77204, USA
b
Brien Holden Vision Institute, Sydney, Australia

a r t i c l e i n f o a b s t r a c t

Article history: We investigated the potential causal relationships between anisometropia, amblyopia and strabismus,
Received 4 January 2017 specifically to determine whether either amblyopia or strabismus interfered with emmetropization.
Received in revised form 15 March 2017 We analyzed data from non-human primates that were relevant to the co-existence of anisometropia,
Accepted 19 March 2017
amblyopia and strabismus in children. We relied on interocular comparisons of spatial vision and refrac-
tive development in animals reared with 1) monocular form deprivation; 2) anisometropia optically
imposed by either contact lenses or spectacle lenses; 3) organic amblyopia produced by laser ablation
Keywords:
of the fovea; and 4) strabismus that was either optically imposed with prisms or produced by either sur-
Anisometropia
Emmetropization
gical or pharmacological manipulation of the extraocular muscles. Hyperopic anisometropia imposed
Hyperopia early in life produced amblyopia in a dose-dependent manner. However, when potential methodological
Myopia confounds were taken into account, there was no support for the hypothesis that the presence of ambly-
Amblyopia opia interferes with emmetropization or promotes hyperopia or that the degree of image degradation
Strabismus determines the direction of eye growth. To the contrary, there was strong evidence that amblyopic eyes
Refractive error were able to detect the presence of a refractive error and alter ocular growth to eliminate the ametropia.
Eye growth On the other hand, early onset strabismus, both optically and surgically imposed, disrupted the
emmetropization process producing anisometropia. In surgical strabismus, the deviating eyes were typ-
ically more hyperopic than their fellow fixating eyes. The results show that early hyperopic ani-
sometropia is a significant risk factor for amblyopia. Early esotropia can trigger the onset of both
anisometropia and amblyopia. However, amblyopia, in isolation, does not pose a significant risk for the
development of hyperopia or anisometropia.
Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction
In both children and laboratory animals early abnormal visual
experience can disrupt interocular alignment resulting in strabis-
mus, interfere with sensory development producing amblyopia,
and alter the course of emmetropization resulting in ametropias
in one or both eyes (see Barrett, Bradley, and Candy (2013) for a
recent detailed review). Given that each of these conditions can
themselves alter visual experience, the presence of any one of
these conditions in early childhood could potentially cause either
or both of the other two conditions. In this respect, amblyopia is
strongly associated with the presence of anisometropia and/or
strabismus during early childhood (Abrahamsson, Fabian,
⇑ Corresponding author at: University of Houston, College of Optometry, 4901
Calhoun Road, 505 J Armistead Bldg, Houston, TX 77204-2020, USA.
E-mail address: esmith@uh.edu (E.L. Smith III).
Anderson, & Sjostrand, 1990; Aurell & Norrsell, 1990; Flom &
Bedell, 1985; Ingram, Gill, & Lambert, 2003; Ingram, Lambert, &
Gill, 2009; Levi, McKee, & Movshon, 2011), which suggests, but
does not prove, that the co-occurrence of these conditions reflects
a causal relationship.
Understanding the nature of any cause and effect relationships
between strabismus, anisometropia, and amblyopia is critical for
developing the most effective detection and management strate-
gies for these early visual system abnormalities. These relation-
ships are difficult to evaluate in children because the relative
chronology of these conditions is not always obvious. This is espe-
cially true in patients with anisometropia and amblyopia because
these conditions are often first detected long after either the ani-
sometropia or amblyopia has developed (Shaw, Fielder, Minshull,
& Rosenthal, 1988; Woodruff, Hiscox, Thompson, & Smith, 1994).
In this effort, investigations involving laboratory animals, particu-
larly non-human primates, are potentially valuable because it is

http://dx.doi.org/10.1016/j.visres.2017.03.004
0042-6989/Ó 2017 Elsevier Ltd. All rights reserved.
 E.L. Smith III et al. / Vision Research 134 (2017) 26–42
possible to induce specific conditions at known ages in subjects
that are otherwise visually normal.
Unfortunately, extrapolating the existing animal data to the
human condition is complicated by a number of issues. In particu-
lar, the earlier animal research focused primarily on the effects of
visual experience on sensory (Boothe, Kiorpes, & Carlson, 1985;
Harwerth, Smith III, Boltz, Crawford, & von Noorden, 1983;
Kiorpes & Boothe, 1980; Kiorpes et al., 1987; Smith III, Harwerth,
& Crawford, 1985; von Noorden, Dowling, & Ferguson, 1970) and
oculomotor development (Quick, Tigges, Gammon, & Boothe,
1989; Tusa, Krepka, Smith, & Herdman, 1991). The potential effects
of experimental manipulations on refractive development were
often secondary aims. As a consequence, in many instances the
data on refractive development were incomplete. For example,
an animal’s refractive status was often not assessed during or at
the end of a given experimental rearing strategy. Instead the avail-
able refractive data were typically obtained later as a part of
behavioral experiments relevant to amblyopia (Harwerth, Smith,
Boltz, Crawford, & von Noorden, 1983; Smith III et al., 1985), which
ignored the potential for recovery from induced ametropias (Qiao-
Gridder, Hung, Kee, Ramamirtham, & Smith III, 2004; Smith III &
Hung, 1999). In addition, in these early studies, little effort was
given to determining the nature of any observed refractive errors
(e.g., axial dimensions and corneal power). On the other hand,
many of the early studies that focused on the effects of vision on
refractive development rarely provided data on sensory or oculo-
motor development (Crewther, Nathan, Kiely, Brennan, &
Crewther, 1988; Raviola & Wiesel, 1985). Moreover, the methods
that have been employed to manipulate the visual experience of
young animals have evolved as our understanding of potential con-
founding factors associated with these rearing strategies were dis-
covered (Hung & Smith III, 1996; Whatham & Judge, 2001b). In a
number of instances these potential confounding effects have been
ignored and the ‘‘intriguing inconsistencies” (Barrett et al., 2013)
between some early studies have obscured the nature of the rela-
tionships between anisometropia, amblyopia and strabismus.
The purpose of this investigation was to analyze the available
data from non-human primates on the effects of visual manipula-
tions on refractive development that are relevant to the relation-
ships between anisometropia, amblyopia and strabismus. In
particular, this analysis focuses on between-study inconsistencies
in refractive development that appear related to methodological
confounds that potentially masked causal relationships between
anisometropia, amblyopia and strabismus. In addition, we present
previously unpublished data, particularly on the effects of strabis-
mus on refractive development.
2. Methods
2.1. Subjects
We have included previously published data from both New-
(Marmosets, Callithrix jacchus) and Old-World primates. Results
were available for four different species of macaques (stumptail
macaques, Macaca arctoides; cynomolgus or crab-eating macaques,
Macaca fascicularis; pigtailed macaques, Macaca nemestrina; and
rhesus macaques, Macaca mulatta), with the majority of the data
coming from pigtailed and rhesus monkeys. Although some early
observations involving small numbers of monkeys suggested that
there were qualitative differences in the phenomenon of form
deprivation myopia between macaque species (e.g., the effects of
muscarinic receptor blockers on the course of form-deprivation
myopia) (Raviola & Wiesel, 1990), these potential differences have
not been observed in more recent studies (Tigges et al., 1999). As a
consequence, we have pooled data from all macaque species.
27
2.2. Rearing procedures
Our analysis, which relies primarily on interocular comparisons,
focuses on animals that were subjected to unilateral interventions
that were imposed relatively early in life and for which refractive
error and/or axial length data were reported for both the treated
and fellow untreated eyes. We included the results from studies
involving monocular form deprivation produced by surgical eyelid
closure, diffuser spectacles, diffuser contact lenses, and opaque
(‘‘black”) contact lenses. Similarly, we included the results from
animals reared with optically imposed anisometropia produced
by either contact lenses or spectacle lenses. We excluded data from
animals with experimentally induced aphakia because of potential
confounds associated with surgically removing the crystalline lens.
Data from animals with experimentally induced strabismus
were also analyzed. Ocular misalignments that were optically
imposed using prisms or produced by either surgical or pharmaco-
logical manipulation of the extraocular muscles were included.
However, animals that had undergone surgical procedures that
involved tying the eye in an extreme deviated position were
excluded (Harwerth et al., 1983; von Noorden & Dowling, 1970).
In our analysis, we have attempted to include all the relevant
data from published English-language sources in which the refrac-
tive errors and rearing histories were available for individual ani-
mals and in which at least two or more animals were studied. In
addition, we have included previously unpublished data from our
laboratory and data from animals involved in our previous studies
when relevant parameters were not included in our original publi-
cations. The rearing methods for surgical strabismus, optical stra-
bismus, form deprivation and optically imposed anisometropia
that were employed in our laboratory have been described in detail
in previous publications. In brief, surgical esotropia was induced by
shortening the medial rectus muscle combined with a tenotomy of
the lateral rectus muscle (Bi et al., 2011; Harwerth, Smith III,
Crawford, & von Noorden, 1997). These procedures, which were
performed between 20 and 120 days of age (mean = 41 ± 24 days),
produced a constant, unilateral esotropia of 10–20 degrees that
was obvious immediately after the surgery. Strabismus was opti-
cally simulated by fitting 3–4 week-old rhesus monkeys with gog-
gles that held 15 D prisms that were primarily oriented base-in in
front of each eye (the prism in front of one eye was also rotated
base-down by 15° to ensure that fusion was disrupted). The ani-
mals typically wore the prisms for durations of 4–12 weeks; subse-
quently the animals were allowed unrestricted vision (Harwerth
et al., 1983; Smith, Chino, Cheng, Crawford, & Harwerth, 1997;
Watanabe et al., 2005). Monocular form deprivation was produced
by surgical eyelid closure using procedures first employed by von
Noorden et al. (Harwerth et al., 1983; von Noorden & Dowling,
1970) or by rearing monkeys with a diffuser spectacle lens in front
of one eye and a clear, zero-powered lens in front of the fellow eye.
The diffuser spectacles consisted of a zero-powered carrier lens
that was covered with a Bangerter Occlusion Foil (Smith III &
Hung, 2000; Smith III, Hung, & Huang, 2012). We employed the
‘‘LP”, ‘‘0.1” and ‘‘0.4” occlusion foils, which were specified by the
manufacturer to reduce the visual acuities of human observers to
light perception, 20/200, and 20/50, respectively. The animals
wore the diffusers continuously from about 3 weeks of age, typi-
cally for periods ranging between 11 and 19 weeks. Both contact
lens (Hung & Smith III, 1996; Smith III, Hung, & Harwerth, 1994)
and spectacle lens rearing regimens (Hung, Crawford, & Smith III,
1995; Smith III & Hung, 1999; Smith III, Hung, & Harwerth, 1999;
Smith III et al., 1985) have been employed to optically impose ani-
sometropias. In both instances the treated eyes viewed through a
powered single-vision lens ( 3.0 to 10.0 D powers) and the fel-
low eyes were either untreated or viewed through a zero-
powered control lens. These lens-rearing procedures were also ini-
28 E.L. Smith III et al. / Vision Research 134 (2017) 26–42

tiated at about 3 weeks of age and the lenses were worn continu-
ously for periods ranging from 4 to 20 weeks.
We specifically delayed the onset of our optical rearing strate-
gies until 3 weeks of age because abnormal visual experience initi-
ated before 2 weeks of age frequently disrupts normal interocular
alignment producing an overt strabismus in macaque monkeys
(Quick et al., 1989). However, infant monkeys rarely develop stra-
bismus (<5%) when similar rearing procedures are initiated at
3 weeks of age or later.
III & Hung, 1999; Smith III et al., 2012). In the more recent studies,
these methods were initiated at the start of the rearing procedures
and were typically repeated at two-week intervals throughout the
optical rearing period. Thereafter, measurements were obtained at
monthly intervals for the remainder of the first year. Subsequent
measures were obtained at the onset of any behavioral experi-
ments and at approximately one-year intervals.
2.4. Spatial vision measures

2.3. Ocular biometric measures

For many of the specially reared macaques, behavioral methods
were employed to assess the effects of altered visual experience on
In general, the methods employed to make the optometric mea-
their spatial vision. Most often operant conditioning techniques
surements were similar across laboratories. Refractive errors were
and psychophysical methods were employed to assess either grat-
usually measured by retinoscopy while the animals were cyclo-
ing visual acuities or spatial contrast sensitivities. Although in
pleged and anesthetized. In some cases, refractive errors were also
some cases the behavioral assessments were obtained shortly after
obtained using autorefractors and the reported data represented
the onset of abnormal visual experience (Boothe et al., 1985;
an average of the two methods (Troilo & Nickla, 2005). Typically
Kiorpes & Boothe, 1980), we focused on measures that were typi-
cycloplegia was produced by the topical application of 1% tropi-
cally made well after the end of any optical rearing period or the
camide (e.g., Smith & Hung, 1999) or 1% cyclopentolate (e.g.,
onset of experimental strabismus (see Harwerth et al., 1983;
Smith, Harwerth, Crawford, & von Noorden, 1987; Troilo & Judge,
Kiorpes, Kiper, & Movshon, 1993; Smith et al., 1999 and
1993), sometimes in combination with 2.5% or 10% phenylephrine
Wensveen, Harwerth, & Smith III, 2003 for detailed descriptions
(e.g., Kiorpes & Wallman, 1995). In some of the earlier studies, 0.5%
of representative methods).
or 1% homatropine was employed as a cycloplegic (e.g., Wiesel &
In brief, in our laboratory, spatial contrast sensitivities were
Raviola, 1977). Ketamine was universally employed to chemically
determined for each eye by behaviorally measuring contrast detec-
restrain macaques (10–20 mg/kg), often in combination with ace-
tion thresholds for sinusoidal gratings that were electronically gen-
promazine (Bradley, Fernandes, Tigges, & Boothe, 1996; Hung
erated on displays that had low to moderate mean luminances. The
et al., 1995) or xylazine (Crewther et al., 1988). However, some
behavioral paradigm was a temporal-interval detection task. Con-
early data on young macaques were obtained without chemical
trast thresholds were measured using either a psychophysical
restraint (Crewther et al., 1988). In marmosets, Saffan (12–
descending method of limits (Harwerth et al., 1983; Smith III
18 mg/kg) was universally employed to produce anesthesia
et al., 1985) or an adaptive staircase procedure (Bi et al., 2011;
(Graham & Judge, 1999; Troilo & Judge, 1993; Troilo & Nickla,
Smith III et al., 1999). Contrast sensitivity functions were typically
2005; Troilo, Totonelly, & Harb, 2009; Whatham & Judge, 2001a;
generated from the geometric means of a minimum of 12 thresh-
Whatham & Judge, 2001b; Whatham & Judge, 2007). Inspection
old measurements for spatial frequencies between 0.25 and 16
of the results across laboratories did not reveal any systematic dif-
cy/deg in 0.1 log unit steps. The data were fitted with a double
ferences that could be attributed to either the cyclopegic or anes-
exponential function. Grating visual acuities were obtained by
thetic regimens. Moreover, given that the majority of studies
extrapolating the high spatial frequency portion of an animal’s spa-
included in this analysis employed monocular treatment strategies
tial contrast sensitivity function to a contrast sensitivity of 1.0. The
and interocular comparisons to assess treatment effects, it would
ratio of monocular grating acuities between the treated and fellow
not be expected that the above differences in cycloplegia or anes-
untreated eyes was used as a measure for the presence and depth
thesia would influence the results.
of amblyopia.
Although astigmatic errors were available for some animals, all
For the animals studied in our laboratories, all of the rearing
of the data reported here represent spherical equivalent ametro-
and experimental procedures were reviewed and approved by
pias. No corrections were made for the small eye artifact associated
the University of Houston’s Institutional Animal Care and Use
with retinoscopy (Glickstein & Millodot, 1970; Hung,
Committee and were in compliance with the National Institutes
Ramamirtham, Wensveen, Harwerth, & Smith III, 2012). Axial
of Health Guide for the Care and Use of Laboratory Animals.
dimensions were measured by A-scan ultrasonography in both
macaques and marmosets, typically employing velocity values
derived for human eyes. For macaques, when it was measured, cor- 3. Results
neal curvature was typically obtained using a commercially avail-
able keratometer and the reported measures were taken to 3.1. Does amblyopia cause hyperopia, in particular hyperopic
represent the total corneal refracting power (i.e., a relatively low anisometropia?
refractive index was employed to take into account the negative
power of the posterior corneal surface). Several strategies have The alterations in refractive errors observed in monkeys reared
been employed to measure the much steeper corneas of mar- with soft, negative-powered, extended-wear contact lenses have
mosets. Direct measures on marmosets have been obtained using been interpreted to indicate that amblyopia can promote the
custom built photokeratometers (e.g., Troilo & Judge, 1993) and development of hyperopic anisometropia. As illustrated in Fig. 1,
by extending the measurement range of commercially available which includes data from multiple laboratories (Crewther et al.,
keratometers (e.g., Whatham & Judge, 2007). An indirect method 1988; Kiorpes & Wallman, 1995; Kozma & Kiorpes, 2003; Smith
that involved assessing the changes in refractive error produced III et al., 1994), rearing infant macaques with negative-powered,
by neutralizing the refracting power of the anterior corneal surface extended-wear contact lenses can produce substantial relative
with a rigid contact lens has also been employed (e.g., Whatham & hyperopic refractive-error shifts. In general, these treatment
Judge, 2001a,b). effects were consistent between studies; 18 of the 25 contact-
The biometric methods employed in our laboratory have been lens-reared monkeys developed hyperopic anisometropias that
described in detail in previous publications (Kee, Hung, Qiao, & were greater than 0.75 D. The smaller, less consistent hyperopic
Smith III, 2003; Kee, Hung, Qiao-Grider, & Smith III, 2005; Smith shifts observed in the Crewther et al. (1988) study are likely to
 E.L. Smith III et al. / Vision Research 134 (2017) 26–42
Fig. 1. Interocular differences in refractive error (treated eye – fellow eye) for
individual macaques reared with negative-powered, soft, extended-wear contact
lenses on their treated eyes. The data were obtained at the end of the lens-rearing
period for the animals in the Crewther et al. (1988), Hung and Smith (1996) and
Smith et al. (1994) studies. The data from the Kiorpes’ lab (Kiorpes & Wallman,
1995; Kozma & Kiorpes, 2003) were obtained well after the end of the rearing
period and a long period of unrestricted vision. The fellow control eyes of the
animals from Hung & Smith III (1996), Kiorpes and Wallman (1995), Kozuma &
Kiorpes (2003), and one 6 D animal from Crewther et al. (1988) were fitted with
plano zero-powered lenses. The fellow control eyes of all the remaining monkeys
from Crewther et al. (1988) and 6 of the 8 monkeys from Smith et al. (1994) were
untreated.
reflect the fact that lens wear was started at much older ages than
in the other studies and interruptions in lens wear, which could be
as long as 10 days in duration, were common.
The hyperopic shifts found in these macaques reared with
negative-powered contact lenses are surprising because hyperopic
defocus produced by negative spectacles lenses consistently pro-
duces compensating axial myopia in every species that has been
studied in a systematic fashion (see Wallman & Winawer, 2004
and Schaeffel & Feldkaemper, 2015 for reviews). Because abnormal
visual experience can produce neural changes associated with stra-
bismus and amblyopia in a relatively short period of time (Freeman
& Olson, 1982; Olson & Freeman, 1975; Tao etal., 2014; Wang et al.,
2017; Zhang et al., 2005), certainly before the hyperopic ani-
sometropias can be observed, and because the degree of hyperopic
anisometropia was correlated with the degree of amblyopia in
contact-lens-reared monkeys, it has been argued that the ambly-
opia occurred first, which subsequently altered eye growth pro-
ducing hyperopic shifts in refractive error (Barrett et al., 2013;
Kiorpes & Wallman, 1995). In essence, this conclusion implies that
the normal emmetropizing responses to hyperopic defocus were
overridden by the presence of amblyopia. However, at the time
that these studies were conducted, accurate and reliable methods
for measuring corneal curvature were not commonly available
and, as a consequence, little is known about the effective fitting
parameters of the contact lenses that were employed in these stud-
ies (e.g., the relationship between corneal curvature and lens base
curvature), the potential optical and physical effects of contact lens
wear on refractive error, and most importantly, the nature of the
observed hyperopic errors in contact-lens-reared monkeys (e.g.,
the potential contribution of the cornea).
In this respect, it is likely that all of the data included in Fig. 1
were obtained using lenses that had base curves that were much
flatter than the corneas of the infant monkeys. For example, in
the Crewther et al. (1988) and Smith et al. (1994) studies, the base
curves of their lenses ranged between 6.4 to 6.8 mm and 6.0 to
7.0 mm, respectively. In comparison, the average corneal curvature
for infant rhesus monkeys (the species used by Smith et al.) at ages
29
corresponding to the onset of lens wear was only 5.46 mm (Qiao-
Grider, Hung, Kee, Ramamirtham, & Smith III, 2007) and the cor-
neal radii of the age-equivalent cynomolgus monkeys used by
Crewther et al. were generally steeper than those of rhesus mon-
keys (4.8 to 5.4 mm (Kiely et al., 1987)). The base curvatures of
the contact lenses employed by the Kiorpes’ lab (Kiorpes &
Wallman, 1995; Kozma & Kiorpes, 2003) were not reported. How-
ever, at the time that these studies were conducted, it would have
been difficult to get an extended-wear lens with a large enough
overall diameter to fit under both eyelids of an infant monkey
(about 11–13 mm) with a base curve that matched the anterior
corneal radius. Thus, it is very likely that all of the data in Fig. 1
were obtained using relatively flat contact lenses. This is significant
because flat-fitting contact lenses can produce significant corneal
flattening in infant monkeys (Whatham & Judge, 2001b).
The data shown in Fig. 2 suggest that alterations in corneal
shape contributed significantly to the hyperopic shifts observed
in the contact-lens-reared monkeys described above. Panel 2A
shows longitudinal refractive-error data for the fellow control eyes
of infant rhesus monkeys that wore extended-wear contact lenses
that had zero refracting power (Hung & Smith III, 1996). The trea-
ted eyes of these monkeys were fit with contact lenses that had
nominal refracting powers of either +3 or 3 D. The lens materials
and dimensions were comparable to those worn by the monkeys
included in Fig. 1 from Smith et al. (1994). Panels B and C show
the average interocular differences in refractive error and corneal
power plotted as a function of age for marmosets reared with
monocular soft, zero-powered, extended-wear contact lenses on
their treated eyes; their fellow eyes were untreated (Whatham &
Judge, 2001b). The lenses worn by the marmosets were made of
materials comparable to those employed with macaques and, like
the lenses worn by the macaques, the base curves were about
0.5 mm flatter than the average anterior corneal radius of age-
matched marmosets (Troilo & Judge, 1993). The key finding in
Fig. 2 is that the zero-powered lenses produced significant hyper-
opic shifts in both macaques and marmosets. For the macaques in
panel A, the ‘‘treated” eyes of these monkeys, which were fitted
with either +3 and 3 D lenses, also developed comparable degrees
of hyperopia. Most importantly, as illustrated in panel C, the aver-
age reductions in corneal power associated with contact lens wear
could account for the relative hyperopic shifts observed in the trea-
ted eyes. Thus, it seems likely that lens-induced decreases in cor-
neal power contributed to the relative hyperopia shown in Fig. 1.
However, it is also possible that, as with orthokeratology or corneal
reshaping therapy (Kang & Swarbrick, 2011), the central corneal
flattening produced by contact lens wear in infant monkeys was
associated with a relative increase in peripheral corneal power. If
that was the case, the resulting relative peripheral myopic defocus,
which would likely increase with the degree of central corneal flat-
tening, would have provided a strong visual signal to slow ocular
growth and produce hyperopic shifts in much the same way that
orthokeratology is effective in slowing myopia progression in chil-
dren (Cho & Cheung, 2012) and that optically imposed peripheral
myopia produces central hyperopic shifts in animals (Liu &
Wildsoet, 2011; Liu & Wildsoet, 2012; Arumugam, Hung, To,
Sankaridurg, & Smith III, ARVO Abstract 5512, 2016).
In support of the idea that the hyperopia observed in monkeys
reared with contact lenses on an extended wear basis was due to
confounding corneal side-effects, when steps were taken to elimi-
nate lens-induced changes in corneal power, predictable compen-
sating refractive changes were observed in response to the
imposed defocus produced by negative- and positive-powered
contact lenses. First, using marmosets Whatham and Judge
(2001b) demonstrated that reducing the duration of zero-
powered, soft-contact-lens wear from 24 to 8 h per day eliminated
the corneal flattening produced by continuous daily wear. More
30 E.L. Smith III et al. / Vision Research 134 (2017) 26–42
Fig. 2. Effects of zero-powered, soft, extended-wear contact lenses on refractive development. (A) Longitudinal refractive errors for the fellow ‘‘control” eyes of individual
rhesus monkeys that were fitted with zero-powered contact lenses (Hung & Smith III, 1996). The treated eyes of these monkeys were fitted with either +3 or 3 D contact
lenses. Mean (±SEM) interocular differences (treated eye – fellow eye) in refractive error (B) and corneal power (C) plotted as a function of age for marmosets reared with
zero-powered lenses on the treated eyes (Whatham & Judge, 2001b). The fellow control eyes were untreated. In all plots, the filled and open symbols represent data obtained
during and after the lens-rearing period, respectively.
importantly, they (Whatham & Judge, 2001a) and Troilo et al.
(2009) subsequently demonstrated that when lens wear was
restricted to the daytime hours, marmosets reared with powered
contact lenses made of the same materials and physical dimen-
sions as the zero-powered lenses exhibited compensating ocular
growth in response to the induced defocus. Specifically, the relative
hyperopia produced by negative-powered contact lenses acceler-
ated ocular growth producing axial myopia; positive-powered con-
tact lenses reduced axial growth resulting in relatively hyperopia.
It is important to note that the data shown in Fig. 1 were
obtained at different times relative to the end of the contact lens
rearing period. For example, the Smith et al. (1994) data were
obtained at the end of the contact lens rearing period. And like
the monkeys (Hung & Smith III, 1996) and marmosets (Whatham
& Judge, 2001b) represented in Fig. 2, these lens-reared monkeys
demonstrated substantial recovery from the induced hyperopic
ametropias following restoration of unrestricted vision. On the
other hand, most of the available data from the Kiorpes lab were
obtained several years after the end of contact-lens-rearing period
(Kiorpes & Wallman, 1995; Kozma & Kiorpes, 2003). The duration
of lens wear in the Kiropes lab was also much longer (e.g., about
230–320 days of age versus 90–120 days of age), which may have
minimized any potential recovery. Nevertheless, the available data
show that there were some similarities in the course of the refrac-
tive changes between these studies. For example, Kiropes and
Wallman (1995) reported during the contact-lens-rearing period
that several animals developed large bilateral hyperopic errors,
but none of the animals exhibited large anisometropias (Note how-
ever, that end-of-treatment data were not available for most ani-
mals). However, several animals in this study developed
substantial hyperopic anisometropias well after unrestricted vision
was restored. Kozma and Kiorpes (2003) reported that although 3
of their 4 contact-lens-reared monkeys exhibited at least 2 D of
hyperopic anisometropia during the lens rearing period (absolute
refractive errors were not reported), after about 2.5 to 4 years of
unrestricted vision, their lens-reared animals exhibited substantial
hyperopic anisometropias that ranged from 4.75 D to 8.50 D. In the
cases where the data are available, the animals that eventually
manifested large hyperopic anisometropias exhibited large bilat-
eral hyperopic errors during the rearing period (Kiorpes &
Wallman, 1995). The hyperopic anisometropias appeared to
develop well after the treatment period because the non-
amblyopic eyes exhibited emmetropizing responses while the
treated amblyopic eyes maintained their high degrees of hyper-
opia, possibly because these animals had small degrees of unde-
tected strabismus (see below).
The confounding effects of contact lens wear on refractive
development may have also contributed to the relationship
reported by Kiorpes and Wallman (1995) between the degree of
amblyopia and the final hyperopic anisometropias that were man-
ifest at the time the behavioral experiments were conducted.
Fig. 3A, which includes data for macaques reared with contact
lenses (open symbols) and those in which an anisometropia was
induced using spectacle lenses (filled symbols), illustrates that
for the higher degrees of optically imposed anisometropia (i.e.,
9 and 10 D), the degree of amblyopia was similar for animals
reared with spectacles and contact lenses. And although there
was substantial inter-subject variability in the degree of ambly-
opia, the range and depth of amblyopia observed in our lab and
by the Kiorpes’ lab were comparable. In addition, for animals
reared with spectacle lenses, there was a strong relationship
between the degree of optically imposed anisometropia at the start
of the experimental rearing period and the interocular acuity ratio
(r2 = 0.57; p < 0.0001). Thus, as observed in humans (Barrett et al.,
2013; Granet, Christian, Gomi, Branuelos, & Castro, 2006; Levi
et al., 2011; Weakley, 1999), the degree of experimentally induced
amblyopia in monkeys appears to be related to the degree of
hyperopic anisometropia experienced early in life (Smith III et al.,
1999).
However, as shown in Fig. 3B, in contrast to the results obtained
in some contact-lens-reared monkeys, for the spectacle-lens-
reared animals there was no relationship between the degree of
amblyopia and the degree of anisometropia exhibited at the time
when the behavioral data were obtained (r2 = 0.04; p = 0.37). At
the end of the lens-rearing period, the spectacle-lens-reared mon-
keys typically showed either no interocular differences in refrac-
tive error or varying degrees of compensating myopic
anisometropia, which subsequently decreased in magnitude fol-
lowing the restoration of unrestricted vision (see Fig. 7 below).
As a consequence, at the time the behavioral experiments were
performed, the majority of spectacle-lens-reared animals showed
relatively small degrees of myopic anisometropia. These results
emphasize that amblyopia does not necessarily promote the devel-
opment of hyperopia.
3.2. Does the severity of image degradation determine the direction of
refractive change?
Comparisons of the results between early studies of form-
deprived animals have led to the conclusion that the severity of
retinal image degradation determines the direction of refractive
change (Barrett et al., 2013; Kiorpes & Wallman, 1995). This idea
has been taken as support for the hypothesis that moderate
degrees of amblyopia produced by relatively mild reductions in
retinal image quality, like those observed in the contact lens stud-
ies summarized in Figs. 1, promote the development of hyperopia
 E.L. Smith III et al. / Vision Research 134 (2017) 26–42 31

Fig. 3. Grating acuity versus anisometropia in lens-reared macaques. (A) Interocular grating acuity ratios (treated eye/fellow eye) plotted as a function of the degree of
optically imposed anisometropia (treated eye – fellow eye) during the treatment period for individual animals. The black and white symbols represent monkeys reared with
spectacle and extended-wear contact lenses, respectively. The grey symbols represent normal monkeys reared with unrestricted vision. (B) Interocular grating acuity ratios
plotted as a function of the degree of anisometropia that existed at the time that the behavioral data were obtained for individual monkeys. These animals were reared with
either 3, 6, or 9 D spectacle lenses in front of their treated eyes and plano lenses in front of their fellow control eyes. In panel A, the data represented by the open circles
were from the Kiorpes’ lab at New York University (NYU) (Kiorpes & Wallman, 1995; Kozma & Kiorpes, 2003). The other data were from Smith III et al. (1997, 1985; 1999) and
Tao et al. (2014) at the University of Houston (UH) or were previously unpublished.

(Barrett et al., 2013; Kiorpes & Wallman, 1995). However, method-
ological confounds are probably responsible for the different pat-
tern of results observed in animals that were form-deprived
using different optical devices.
Fig. 4 shows the interocular differences in refractive error
obtained from individual monocularly form-deprived macaques.
Because the degree of form-deprivation myopia is influenced by
the age of onset and the duration of deprivation (Smith III,
Harwerth, Crawford, & von Noorden, 1987; Smith III, Harwerth,
Crawford, & von Noorden, 1988), only data from animals that
underwent a single, early manipulation (e.g., no animals that
underwent reverse occlusion) and for which the duration of
form-deprivation was longer than 30 days are included. As illus-
trated in Fig. 4A, surgical eyelid closure, a common procedure
employed in early studies and that severely limits spatial vision,
consistently produced relative myopia in the treated eye. In 40 of
the 43 animals that had monocular eyelid closure, the treated
eye was more myopic/less hyperopic than the fellow control eye.
Similarly, 24 of the 26 monkeys that were form-deprived using dif-
fuser spectacle lenses developed relative myopia in their treated
eyes (Fig 4B). The least consistent results were obtained using con-
tact lenses to produce form deprivation (Fig 4C). While 8 of the 10
monkeys reared with black occluder contact lenses, which virtually
eliminated spatial vision, developed form-deprivation myopia, all 5
monkeys reared with diffuser contact lenses exhibited relative
hyperopia in their treated eyes. Because the diffuser contact lenses
employed by Bradley et al. (1996) only reduced contrast sensitivity
by about 1 log unit over a range of medium to high spatial frequen-
cies, it was concluded that mild form deprivation, i.e., those manip-
ulations that primarily affect high spatial frequencies and foveal
vision, produce a different pattern of results than severe depriva-
tion, which affects vision across the retina and a larger range of
spatial frequencies.
However several concerns raise doubts about this hypothesis.
As in the studies described above, the contact lenses that were
employed in the form-deprivation experiments had base curva-
tures that were substantially flatter than the corneas of infant
monkeys. For example, the initial base curvatures were 7 mm for
the contact lenses employed by the Emory lab (Fernandes,
Tigges, Tigges, Gammon, & Chandler, 1988; Gammon, Boothe,
Chandler, Tigges, & Wilson, 1985), which were well over 1 mm flat-
ter than the corneas of infant rhesus monkeys (Qiao-Grider et al.,
2007). Thus, as with defocusing contact lenses, it is possible that
the contact lenses used to produce form deprivation altered cor-
neal topography in a manner that led either directly or indirectly
to hyperopic shifts. This was especially the case for the diffuser
contact lenses, which were made from a low oxygen permeable
material (Bradley et al., 1996). As a consequence the diffuser con-
tacts were likely to have a higher modulus than the previously
used high-water-content lenses and more likely to impact corneal
curvature.
Unfortunately relatively little is known about the effects of
either eyelid closure or contact lens wear on corneal shape in
macaques, primarily because most early studies did not measure
corneal parameters. Bradley et al. (1996) used a keratometer to
assess corneal power at the end of the diffuser contact-lens-
rearing period and reported that the treated-eye corneas of 4 of
the 5 monkeys reared with diffuser contact lenses were flatter than
the corneas of their fellow eyes (although the average difference
did not reach statistical significance). Unfortunately the keratome-
ters that were commonly used in clinical settings at that time
required active patient fixation and consequently it was difficult
to obtain reproducible results in infant macaques (Crewther
et al., 1988).
There is, however, clear evidence in marmosets that corneal
changes can directly mask myopic changes produced by form
deprivation. Fig. 5 compares the refractive changes observed in
marmosets reared with monocular lid closure versus those reared
wearing diffuser spectacles. As observed in macaques (Fig. 4B),
form deprivation produced by diffuser spectacles (panel 5B) con-
sistently produced axial myopia (Troilo & Nickla, 2005). Interest-
ingly, with short durations of lid closure, the treated eyes
32 E.L. Smith III et al. / Vision Research 134 (2017) 26–42
Fig. 4. Interocular differences in refractive error (treated eye – fellow eye) obtained
at the end of the treatment period for individual macaques reared with monocular
form deprivation produced by eyelid closure (A), diffuser spectacle lenses (B), and (C)
black opaque contact lenses or diffuser contact lenses. The published data in panel A
were unpublished (dark red) or obtained from Harwerth et al. (red, 1983), Smith et al.
(green, 1987), Wiesel and Raviola (cyan, 1977), Raviola and Wiesel (dark green, 1990),
Tigges, Tigges, Fernandes, Eggers, and Gammon (grey, 1990), and von Noorden and
Crawford (dark cyan, 1978). In panel B, the data were obtained from Smith and Hung
(2000) and Smith et al. (2012). In panel C, the data were obtained from Irving,
Callender, and Sivak (1991), Tigges et al. (1999), and Bradley et al. (1996).
exhibited hyperopia relative to their fellow control eyes whereas
with longer durations the treated eyes exhibited relative myopic
errors (panel 5A) (Troilo & Judge, 1993). However, the refractive
error measures in the lid-closure experiments were confounded
by reductions in corneal power. If the degree of corneal flattening
is taken into account even the short durations of lid closure pro-
duced relative myopic shifts (green bars in 5A). The fact that vitre-
ous chamber depth and relative myopic shifts continued to take
place once unrestricted vision was restored may also reflect cor-
neal changes. In particular, the relatively flat cornea and the result-
ing relative hyperopic refractive errors that existed at the onset of
unrestricted vision would serve as a stimulus for myopic growth in
the treated eyes. In addition, as suggested by the available recovery
data (Troilo & Judge, 1993), as the cornea returned to its normal
shape following lid opening, the resulting increase in power would
produce large relative, myopic shifts in refractive errors.
The idea that contact lens wear somehow contributed to the
hyperopia observed in monkeys reared with diffuser contact lenses
is also supported by the observation that form deprivation pro-
duced in monkeys with diffuser spectacle lenses consistently
results in axial myopia (Fig. 4B) (Smith III & Hung, 2000; Smith
III et al., 2012). The data illustrated in Fig. 4B were obtained with
three different strengths of spectacle diffusers that produced
reductions in spatial vision in humans that ranged from essentially
light perception (the ‘‘LP” diffusers reduced image contrast by
nearly 3.0 log units at 2 c/deg) to a visual acuity of about 20/50
(the ‘‘0.4” diffusers reduced image contrast by about 0.5 log units
at 2 c/deg) (Smith III & Hung, 2000) and encompassed the degree
of image degradation produced by the contact lens diffusers
employed by Bradley et al. (1996). The degree of form-
deprivation myopia varied with the degree of image degradation
(i.e., as in chickens form-deprivation myopia is a graded phe-
nomenon (Bartmann & Schaeffel, 1994)), but all of the animals
reared with the weakest diffuser spectacles developed myopia. In
addition behavioral experiments confirmed that all of the
diffuser-reared monkeys were amblyopic and the degree of ambly-
opia varied from severe to mild; the average interocular grating
acuity ratios (treated eye/fellow eye) ranged from 0.09 to 0.26 to
0.68 for the monkeys reared with the strongest, intermediate and
weakest spectacle diffusers, respectively (Smith III, Hung, &
Harwerth, 2000).
Based on the results in Fig. 4B, it is reasonable to suppose that
the diffuser contact lenses employed by Bradley et al. (1996) pro-
duced lesser amounts of axial elongation than the black occluding
contact lenses used by Tigges et al. (1999) and Irving, Callender,
and Sivak (1991). Given that both the black occluding and diffuser
contact lenses were likely to produce corneal flattening, possibly
with the diffuser lenses producing greater effects due to the more
rigid nature of the lens materials, it can be argued that the reduc-
tions in corneal power produced by the diffuser contact lenses
were sufficient to mask the milder axial myopic effects associated
with the milder image degradation produced by the diffusers rela-
tive to the black occluding contact lenses.
Observations of refractive errors in children have also been
taken as support for the hypothesis that the severity of image
degradation determines the direction of refractive-error change.
In this respect, Nathan, Kiely, Crewther, and Crewther’s (1985) ret-
rospective analysis of refractive errors in children with various
ocular diseases is frequently cited as evidence that visual manipu-
lations that are restricted to the fovea or that only affect high spa-
tial frequencies promote hyperopia (Barrett et al., 2013; Kiorpes &
Wallman, 1995). Nathan et al. (1985) observed that those children
who had ocular diseases that affected peripheral vision or periph-
eral plus central vision had refractive errors that were significantly
more myopic than normal children or children with conditions
that primarily affected central vision. These results have been gen-
 E.L. Smith III et al. / Vision Research 134 (2017) 26–42 33

Fig. 5. Interocular differences in refractive error (treated eye – fellow eye) for monocularly formed-deprived marmosets. (A) Mean (±SD) anisometropia obtained at the end of
the treatment period for marmosets reared with monocular eyelid closure. Data are shown for 4 different treatment groups; the average onset age and duration of treatment
for each group are shown in the symbol legend (from Troilo and Judge (1993)). The green bars represent the mean anisometropias after compensating for the average
treatment-induced flattening of the anterior corneal surface. To make this adjustment, we assumed that the fellow control eyes had anterior corneal radii equivalent to
normal, age-matched marmosets and used the growth-curve equation for age-related corneal changes in Troilo and Judge (1993) to calculate the corneal power of the fellow
control eyes using an assumed refractive index of 1.333. Using the interocular differences in corneal curvature reported by Troilo and Judge (1993), we then calculated the
refracting power of the treated eye cornea and adjusted the measured anisometropia by the interocular differences in anterior corneal power. (B) End-of-treatment
anisometropias for individual marmosets reared with diffuser spectacle lenses over their treated eyes; their fellow control eyes were untreated. The data are from Group 1 in
Troilo and Nickla (2005).

eralized to mean that visual deprivation regimens that primarily

Fig. 6. Interocular differences in refractive error (treated eye – fellow eye) obtained
from individual monkeys that had undergone monocular foveal ablation and
subsequently allowed unrestricted vision (red boxes) and normal control monkeys
(green boxes, n = 34). The laser ablations were performed at 3 weeks of age and the
data were collected at biweekly or monthly intervals over the next 1–2 years. The
horizontal lines in the box plots represent the medians, the bottoms and tops of the
boxes represent the 25th and 75th percentiles, respectively. The whiskers that
extend vertically from the tops and bottoms of the boxes represent the 90th and
10th percentiles, respectively. The diamond symbols represent outliers. The
majority of data were taken from Smith et al. (2007); some results were previously
unpublished.
affect the fovea result in hyperopia while deprivation regimens
that affect the periphery result in myopia. Since the visual acuity
deficits in amblyopia are largely confined to the central visual field
(Hess & Jacobs, 1979; Sireteanu & Fronius, 1981), these observa-
tions in children with ocular disease have been taken as support
for the idea that the presence of amblyopia promotes hyperopia
(Barrett et al., 2013; Kiorpes & Wallman, 1995). However, it is
important to note that in Nathan et al.’s study, the average refrac-
tive error observed in children with conditions that primarily
affected central vision was not significantly different from that in
age-matched normal children. Moreover, experimentally produc-
ing selective central visual field abnormalities does not promote
the development of hyperopia in infant monkeys. In Fig. 6, box
plots of the interocular differences in refractive error are shown
for individual monkeys that had the macular area of one eye
ablated with a thermal laser at about 3 weeks of age and were sub-
sequently allowed unrestricted vision. The data were obtained over
a 1–2 year observation period. In contrast to the hypothesis that
foveal abnormalities promote hyperopia, the refractive errors in
the laser-treated eyes were on average slightly more myopic than
their fellow eyes, reflecting in part the fact that the retinas in the
lasered eye were thinner than those of their fellow eyes (Smith
III et al., 2007).
3.3. Does amblyopia interfere with emmetropization?
In children, anisometropia, especially hyperopic anisometropia,
can develop long after a diagnosis of strabismic amblyopia, espe-
34 E.L. Smith III et al. / Vision Research 134 (2017) 26–42

Fig. 7. Recovery from experimentally induced ametropias in amblyopic macaques. Interocular differences in refractive error (treated eye – fellow eye) plotted as a function of
age for individual monkeys reared with monocular diffuser spectacles (A, from Qiao-Grider et al. (2004) and unpublished), monocular negative-powered, extended-wear
contact lenses (B, from Smith et al. (1994)), and monocular powered spectacle lenses (C, from Smith and Hung (1999) and unpublished). All of these monkeys had
behaviorally confirmed amblyopia in their treated eyes. The mean (SD), median and range of interocular grating acuity ratios are 0.24 ± 0.22, 0.15, and 0.04 to 0.66 for the
animals in panel A; 0.50 ± 0.24, 0.49, and 0.23 to 0.80 for the animals in panel B; and 0.58 ± 0.23, 0.66, and 0.17 to 0.89 for the animals in panel C. In panel D (from Smith et al.
(2005) and unpublished), refractive error is plotted as a function of age for individual animals that were reared with binocular peripheral form deprivation produced by
diffuser spectacles. At the end of the period of form deprivation, the fovea of the represented eye was ablated with a thermal laser and the animals were allowed unrestricted
vision. The green box plot to the right in panel D represents the ametropias over an equivalent period of time for age-matched normal monkeys. In all plots, the first symbol of
each individual function represents the onset of unrestricted vision and the recovery period. (For interpretation of the references to colour in this figure legend, the reader is
referred to the web version of this article.)

cially esotropic amblyopia. As summarized by Barret et al. (2013),
longitudinal studies of children at risk for strabismus
(Abrahamsson, 1992; Aurell & Norrsell, 1990) and those of children
following the onset of strabismus (Birch, Stager Sr, Wang, &
O’Connor, 2010; Lepard, 1975; Nastri, Caccia Perugini, Savastano,
Polezell, & Sbordone, 1984) support a four-component model for
the development of strabismic amblyopia with anisometropia
(Note that this model is not intended to apply to individuals with
congenital esotropia). Specifically, first the emmetropization pro-
cess fails to reduce moderate to high degrees of hyperopia that
exist early in life. Next, presumably driven by accommodative-
convergence demands, children who maintain high hyperopic
errors develop esotropia. The subsequent onset of a unilateral fix-
ation pattern leads to amblyopia. Anisometropia then develops as
the fixating eye exhibits a late and slow emmetropization while
the hyperopia in the amblyopic eye fails to decrease or actually
increases in some cases. Late developing anisometropia has also
been observed in monkeys with experimentally induced strabismic
amblyopia (Kiorpes & Wallman, 1995) and high degrees of bilateral
hyperopia (Smith III et al., 1999).
The failure of emmetropization in the non-fixating eyes in eso-
tropic amblyopes could be a consequence of the strabismus, the
amblyopia or a combination of the strabismus and amblyopia. Evi-
dence for emmetropizing responses in monkeys with experimen-
tally induced amblyopia supports the idea that strabismus is the
critical element in the failure of emmetropization in these deviat-
ing eyes. Fig. 7 illustrates the ability of amblyopic monkeys to
recover from refractive errors induced by a variety of early optical
rearing strategies. Only animals that appeared to be orthotropic
and exhibited at least 1 D of axial anisometropia (panels A–C) or
obvious axial ametropias (panel D) were included in the figure.
Like emmetropization in normal untreated animals, the recovery
from experimentally induced refractive errors is a vision-
dependent process that is regulated by optical defocus (Wallman
& Winawer, 2004). In panels A–C, the interocular differences in
refractive error are plotted as a function of age for individual ani-
mals that were reared with either monocular spectacle diffusers
(A), monocular powered contact lenses (B) or monocular powered
spectacle lenses (C). All of these animals had behaviorally con-
firmed functional amblyopia in their treated eyes (Smith III et al.,
 E.L. Smith III et al. / Vision Research 134 (2017) 26–42 35

1985; Smith III et al., 1999; Smith III et al., 2000; Tao et al., 2014).
The average (±SD) interocular grating acuity ratios (treated eye/fel-
low eye) for the monkeys in panels A, B, and C, were 0.24 ± 0.22,
0.50 ± 0.24 and 0.58 ± 0.23, respectively. In panel D, the absolute
ametropias are shown for 5 animals that developed large binocular
refractive errors in response to optically induced defocus. At the
end of the lens-rearing period, an organic amblyopia was produced
in one eye of each of these animals by laser ablation of the fovea
(Smith III, Kee, Ramamirtham, Qiao-Grider, & Hung, 2005).
Inspection of the data in all four plots in Fig. 7 reveals that fol-
lowing the onset of unrestricted vision (the first data point for each
animal; in essence when the eyes were confronted with the optical
effects of the induced refractive errors) there were consistent, sys-
tematic reductions in the experimentally induced refractive errors.
Every animal included in Fig. 7 exhibited an emmetropizing
response despite the presence of amblyopia. For the animals with
relative myopia, the subsequent hyperopic shifts were associated
with a reduction in the axial elongation rates of the amblyopic
eyes. For the animals with relative hyperopia in their amblyopic
eyes, the relative myopic shifts were primarily associated with a
relative increase in the amblyopic eyes’ axial elongation rate
(Qiao-Gridder et al., 2004; Smith III & Hung, 1999; Smith III
et al., 1994; Smith III et al., 2005).
3.4. Does strabismus interfere with emmetropization?
Numerous studies in children have found that strabismus, par-
ticularly esotropia, frequently precedes the onset of anisometropia,
particularly hyperopic anisometropia, which suggests that strabis-
mus can alter emmetropization and is a trigger for anisometropia
(Abrahamsson, 1992; Aurell & Norrsell, 1990; Barrett et al., 2013;
Lepard, 1975; Nastri et al., 1984). However, as described above,
prior to the onset of strabismus many children who eventually
manifest anisometropia also exhibit moderate to high degrees of
hyperopia early in life, which suggests that the operational proper-
ties of the emmetropization mechanisms in these individuals may
be different from those in the average child. If that is the case, the
subsequent anisometropic errors could be the result of individual
limitations in the mechanisms responsible for emmetropization.
In addition, refractive development in children with strabismus

Fig. 8. Frequency distributions of refractive errors from the right eyes of normal control monkeys (A, from Qiao-Grider et al. (2007) and previously unpublished), the fellow
and deviating eyes of monkeys with surgically or neurotoxin induced esotropia (B and C, respectively, from Kiropes and Wallman (1995), Kozma and Kiorpes (2003),
Harwerth et al. (1997) and previously unpublished), and the right and left eyes of monkeys reared with optically induced strabismus (D and E, respectively, from Smith et al.
(1997), Watanabe et al. (2005), and Wensveen, Harwerth, and Smith (2001), Wensveen, Smith, Hung, and Harwerth (2011)). Only data from macaques are shown. Only the
refractive errors that were obtained at the oldest ages for each subject were included. The prism-rearing procedures for the monkeys in panels D and E were initiated at 3–
4 weeks of age. For the esotropic monkeys in panels B and C, the strabismus was induced before 4 months of age.

Fig. 9. Interocular differences in refractive error (deviating eye – fixating eye) for individual monkeys reared with experimentally induced strabismus. The left panel (A)
includes macaques with naturally occurring esotropia (Kiorpes & Boothe, 1981; Wong, Burkhalter, & Tychsen, 2005) and those with esotropia induced by extraocular muscle
surgeries (Harwerth et al., 1997; Kiorpes & Wallman, 1995; Kozma & Kiorpes, 2003) and previously unpublished) or by botulinum injections (Kiorpes & Wallman, 1995). The
experimental esotropias were induced or observed before 4 months of age. The right panel (B) includes macaques (Smith et al. (1997); Watanabe et al., 2005; Wensveen,
Harwerth, & Smith III, 2001; Wensveen, Smith III, Hung, & Harwerth, 2011) and marmosets (Whatham & Judge, 2007) reared with optically imposed strabismus. The onset of
prism rearing was 3–4 weeks of age for both macaques and marmosets. In both plots, only the refractive errors that were obtained at the oldest ages for each subject were
included. The dotted lines in both graphs represent the ±2 standard deviations from the mean anisometropia in normal monkeys.
36 E.L. Smith III et al. / Vision Research 134 (2017) 26–42

could possibly be influenced by any optical corrections that are
worn. In this respect, data from ‘‘normal” laboratory animals with
experimentally induced strabismus can shed light on the relation-
ship between strabismus and anomalous refractive errors.
To date, Kiorpes and Wallman (1995) have provided the most
accessible data set on the effects of esotropia on refractive develop-
ment in macaques and Whatham and Judge (2007) have provided
the most complete data set on prism-reared monkeys. The results
of both studies are in agreement with the idea that strabismus can
alter emmetropization. This conclusion is supported by the pooled
data included in Fig. 8, which shows the refractive-error frequency
distributions for normal macaques (panel A) and macaques reared
with either surgically induced esotropia (panels B and C) or opti-
cally simulated strabismus (panels D and E). In panels B and C, only
data from animals that had the esotropia surgically induced prior
to 4 months of age were included. Animals that underwent surgical
procedures that produced extremely large esotropic deviations and
that may have restricted eye movements were excluded (e.g.,>50
prism diopters (Harwerth et al., 1983; von Noorden & Dowling,
1970)). For the animals represented in panels D and E, the prism-
rearing procedures employed to optically simulate a strabismus
were initiated at 3–4 weeks of age and were maintained for a min-
imum of 4 weeks. The data from the normal monkeys were
obtained at an average of 544 ± 513 days of age (range: 145 to
1871 days of age). For the animals with experimental strabismus,
the data are shown for the oldest ages available, which ranged
from 129 to 4495 days of age for the surgical esotropes
(mean = 1747 ± 1041 days) and 97 to 1529 days of age for the
macaques with optically induced strabismus (mean = 623 ±
548 days).
Inspection of the frequency distributions in Fig. 8 reveals that in
comparison to normal monkeys, the refractive errors were more
variable in macaques with experimental strabismus. In comparison
to normal controls, the population of strabismic monkeys exhib-
ited both larger myopic and hyperopic ametropias. In particular,
despite the fact that the data from the strabismic animals were
obtained at older ages, both eyes of macaques with either surgi-
cally or optically induced strabismus were more likely than the
controls to exhibit moderate to high degrees of hyperopia. While
only one control animal exhibited a hyperopic ametropia over +5
D, 9 of the 50 deviating eyes in the esotropic monkeys and 9 of
the 38 eyes in the prism-reared monkeys (right and left eye data
combined) had hyperopic errors larger than +5.0 D.
In Fig. 9, the interocular differences in refractive error are
shown for individual esotropic macaques with either natural or
experimentally induced esotropia and for individual prism-reared
monkeys (both macaques and marmosets (Whatham & Judge,
2007)). A key feature of the figure is that monkeys with experimen-

Fig. 10. Refractive development in normal macaques (left) and macaques reared with surgically (Harwerth et al., 1997; Kiorpes & Wallman, 1995; Kozma & Kiorpes, 2003,
and previously unpublished) and neurotoxin induced esotropia (Kiorpes & Wallman, 1995) (right). In the top plots (A and B), refractive error is plotted as a function of age for
the right or deviating eyes of individual monkeys. The bottom plots (C and D) show the interocular differences in refractive error (right or deviating eye – left or fellow eye)
plotted as a function of age.
 E.L. Smith III et al. / Vision Research 134 (2017) 26–42 37

tally induced strabismus exhibited significant degrees of ani-
sometropia. The results were consistent between laboratories with
20 of the 50 esotropic monkeys and 11 of the 23 prism-reared
monkeys exhibiting anisometropias that were more than 2 stan-
dard deviations away from the mean anisometropia for normal
monkeys (mean = 0.03; SD = 0.44 D). For the esotropic popula-
tion, the deviating eyes were consistently more hyperopic than
their fellow eyes (+2.59 ± 2.65 D versus + 1.38 ± 2.12 D; T = 4.56,
P < 0.0001) and the average degree of hyperopic anisometropia
was significantly larger than that observed in normal monkeys
(+1.25 ± 1.91 D versus 0.01 ± 0.42 D; T = 4.42, P < 0.0001). For
the prism-reared monkeys, knowledge of which eye was the pre-
ferred fixating eye (if there was one) was not consistently available
for the macaques. Regardless, for both the esotropic monkeys
(1.38 ± 1.77 D; T = 4.42; P < 0.0001) and the monkeys reared with
optically induced strabismus (1.17 ± 116 D; T = 3.80; P = 0.001),
the average absolute degree of anisometropia was significantly lar-
ger than that observed in normal monkeys (0.24 ± 0.24 D).
As illustrated in Fig. 10, the alterations in refractive develop-
ment produced by experimental esotropia often continued to take
place well after the early stages of emmetropization. Refractive
errors (top) and the interocular differences in refractive error (bot-
tom) are plotted as a function of age for individual normal controls
(left) and for esotropic macaques (right). In contrast to the normal
monkeys that generally showed systematic reductions in hyper-
opia (i.e., emmetropization) and in the variability of refractive
errors between subjects and between the two eyes of a given ani-
mal over time, the range of deviating-eye refractive errors and the
degree of anisometropia observed in the esotropic subject group
increased with age. In particular, many of deviating eyes main-
tained moderate to high degrees of hyperopia throughout the
observation period (i.e., these eyes did not exhibit emmetropiza-
tion). In many of these cases, the fixating eyes underwent
emmetropization and as a consequence there was an increase in
anisometropia, primarily hyperopic anisometropia, in the esotropic
animals that was particularly obvious after about 100 days of age.
Unfortunately, little data is available concerning the nature of
the refractive errors in monkeys reared with experimentally
induced strabismus. Whatham and Judge (2007) found that for
two prism-reared marmosets with relatively large anisometropias,
the interocular differences in refractive error were associated with
interocular differences in vitreous chamber depth. Kiorpes and
Wallman (1995) reported vitreous chamber data for 3 esotropic
monkeys; in each case the deviating eyes were more hyperopic
and exhibited shorter vitreous chamber depths. However, only
one of these esotropic monkeys had an anisometropia greater than
1.0 D. In Fig. 11A, the degree of anisometropia (deviating eye – fel-
low eye ametropia) is plotted as a function of the interocular differ-

Fig. 11. Nature of ametropias in macaques with surgically and optically induced esotropia. In panels A and B, interocular differences in refractive error (treated or right eye –
fellow or left eye) are plotted as function of interocular differences in vitreous chamber depth (treated or right eye – fellow or left eye) for monkeys with experimentally
induced esotropia and optically imposed strabismus, respectively. In panel C interocular differences in vitreous chamber depth are shown as a function of interocular
differences in corneal power for monkeys with experimentally induced esotropia (deviating eye – fellow eye). The small solid symbols in each plot represent normal control
monkeys. The control data were not included in the regression calculations.

Fig. 12. (A) Interocular ratio of grating acuities (deviating eye/fellow eye) plotted as a function of the deviating eye’s ametropia and (B) interocular difference in refractive
error (deviating eye – fellow eye) for individual monkeys with esotropia. See the legend for Fig. 9 for the sources of the data.
38 E.L. Smith III et al. / Vision Research 134 (2017) 26–42
ences in vitreous chamber depth for esotropic macaque monkeys.
There was a significant negative correlation with the more hyper-
opic deviating eyes having relatively short vitreous chambers
(P = 0.04). However for this population of esotropic monkeys,
which does not include many of the esotropic monkeys with high
degrees of anisometropia, the interocular differences in vitreous
chamber only explained 13% of the variance in the degree of ani-
sometropia. The resulting correlation was much weaker than that
typically observed in monkeys with vision-induced refractive
errors (Arumugam, Hung, To, Holden, & Smith III, 2014; Qiao-
Grider, Hung, Kee, Ramamirtham, & Smith III, 2010; Smith III
et al., 2012). In contrast, in the prism-reared macaques, the
observed anisometropias were strongly correlated with interocular
differences in vitreous chamber depth (Fig. 11B; r2 = 0.77). Inter-
estingly, in the sample of esotropic monkeys included in Fig. 11A,
there was a significant correlation between the interocular differ-
ences in corneal power, which were larger than those observed
in normal monkeys, and the interocular differences in vitreous
chamber depth. Many of these monkeys also showed obvious
increases in the corneal and refractive astigmatism of their devi-
ated eyes 2–4 weeks after the surgical procedures; however, these
astigmatic errors usually decreased rapidly with time.
In addition to alterations in the emmetropization process, many
of the esotropic monkeys also developed amblyopia. As shown in
Fig. 12A, the degree of amblyopia was not related to the deviating
eye’s refractive error at the time the behavioral measurements
were performed (r2 = 0.012; P = 0.21). However as observed in stra-
bismic children with anisometropia (Flom & Bedell, 1985; Flom &
Neumaier, 1966), monkeys with significant degrees of ani-
sometropia were more likely to be amblyopic (Fig. 12B). There
was a significant negative correlation in the interocular grating
acuity ratio and the degree of hyperopic anisometropia (r2 = 0.62;
P < 0.0001).
4. Discussion
4.1. The relationship between anisometropia and amblyopia
One of the main conclusions of this study is that experimental
rearing strategies that exert physical pressure/force on the fragile
corneas of infant monkeys are likely to alter corneal curvature, typ-
ically reducing corneal power and resulting in hyperopic shifts in
refractive error. In particular, as noted most clearly in studies of
marmosets (Troilo & Judge, 1993; Troilo, Nickla, Wildsoet, &
Rada, 1999; Whatham & Judge, 2001a; Whatham & Judge,
2001b), the evidence indicates that surgical eyelid closure and
even soft, high-water-content contact lenses that are worn on a
continuous-wear basis can alter corneal curvature in infant mon-
keys. As a consequence, the hyperopic errors commonly found in
amblyopic monkeys that were reared with negative-powered con-
tact lenses (Kiorpes & Wallman, 1995; Smith III et al., 1994) cannot
be taken as strong support for the hypothesis that amblyopia pro-
duces hyperopia or hyperopic anisometropia.
The corneal side-effects of continuous-wear contact lenses also
appear to have masked the axial myopia produced by form depri-
vation in some experiments (Bradley et al., 1996). When method-
ological confounds are avoided, depriving the retina of the
potential for a clear retinal image promotes unregulated axial elon-
gation and myopia, as first noted by Schaeffel and Howland (1988).
The degree of image degradation influences the rate and degree of
ametropia, but not the direction of refractive-error change
(Bartmann & Schaeffel, 1994; Smith III & Hung, 2000). There was
no evidence that either foveal abnormalities or mild degrees of
image degradation that primarily impact central vision promote
axial hyperopia. Moreover, neither functional nor organic ambly-
opia prevents the eye from detecting the presence of a refractive
error and initiating compensating changes in axial elongation
rates. Specifically, the presence of amblyopia does not override
emmetropizing responses to either hyperopic or myopic defocus.
There was no evidence that amblyopia, per se, prevented
emmetropization.
On the other hand, as previously observed in both macaques
(Hung et al., 1995; Smith III et al., 1985; Smith III et al., 1999;
Tao et al., 2014) and marmosets (Graham & Judge, 1999; Troilo
et al., 2009; Whatham & Judge, 2001a), the results obtained using
spectacle lens strategies to impose hyperopic anisometropia or
contact lens regimens that were specifically designed to avoid cor-
neal alterations demonstrate that chronic hyperopic defocus con-
sistently produces compensating axial myopia in the defocused
eye. Moreover, imposed hyperopic anisometropias can produce
amblyopia and the degree of amblyopia is strongly correlated with
the magnitude of imposed hyperopic anisometropia that an animal
experiences early in life (Smith III et al., 1985; Smith III et al., 1999;
Tao et al., 2014). Thus, the results from animals experiments pro-
vide strong support for the concept that uncorrected hyperopic
anisometropia promotes the development of amblyopia in young
children and that the depth of amblyopia will increase with the
degree of hyperopic anisometropia, an association that is well
established in children (Barrett et al., 2013; Granet et al., 2006;
Levi et al., 2011; Weakley, 1999). However, it is important to note
that in children the degree of anisometropia that was present
when the amblyopia first developed was typically unknown.
4.2. The relationship between anisometropia and strabismus
A consistent finding was that strabismus experimentally
induced early in life, via a variety of methods, can interfere with
emmetropization resulting in anomalous ametropias, both hyper-
opic and myopic, and higher than normal amounts of ani-
sometropia. The fact that abnormally high degrees of
anisometropia were found in both optical and surgical rearing
strategies suggests that factors associated with the interruption
of binocular fusion and the normal binocular fixation pattern trig-
gered the anisometropia, i.e., the anisometropic errors were not
simply a consequence of the altered eye movements associated
with the surgical procedures.
With surgically induced esotropia, where it is likely that animals
adopted a unilateral fixation pattern relatively soon after the proce-
dure, the deviating eyes of many animals failed to undergo
emmetropization and maintained moderate degrees of hyperopia.
Many of these animals manifested hyperopic anisometropias well
after the onset of strabismus as the fixating eyes underwent
emmetropization (Kiorpes & Wallman, 1995). This pattern of
refractive-error changes is qualitatively similar to the four-
component model for the development of strabismic amblyopia
with anisometropia that evolved from longitudinal studies of chil-
dren and described above (Barrett et al., 2013). In both humans
and animal models, the esotropia is manifest in the presence of
moderate to high degrees of bilateral hyperopia. In children, the rel-
atively high degrees of hyperopia appear to reflect a failure in the
emmetropization process prior to the onset of strabismus, whereas
in experimental esotropia, the strabismus is induced at an early age
before emmetropization can run its course. In children a unilateral
fixation preference evolves over time, possibly triggered by sighting
preferences. With surgical esotropia, the resulting anomalous eye
movements, particularly immediately after the procedure, and the
presence of astigmatism in the deviating eye are likely to influence
an animal’s fixation preference and promote the development of a
unilateral fixation pattern. The amblyopia presumably arises in
the deviating eye as a consequence of chronic interocular suppres-
sion and reductions in retinal image quality that come about
 E.L. Smith III et al. / Vision Research 134 (2017) 26–42
because the plane of accommodation is controlled by the fixating
eye. In both humans and monkey models, the hyperopic ani-
sometropia develops because the fixating eye exhibits an
emmetropizing reduction in hyperopia. In this respect, the results
from animals provide support for the four-component model and
emphasize that it is the onset of strabismus that promotes both
the development of amblyopia and anisometropia. The fact that
imposed hyperopic anisometropia consistently promotes the devel-
opment of amblyopia in animal models also supports the argument
that the more severe amblyopia typically found in esotropic chil-
dren and monkeys with hyperopic anisometropia comes about
because the effects of unilateral strabismus and hyperopic defocus
both facilitate the development of amblyopia.
4.3. How does strabismus produce hyperopic anisometropia?
A large body of research demonstrates that ocular growth and
refractive development are regulated by visual feedback associated
with the eye’s effective refractive error, in essence optical defocus
(Schaeffel & Feldkaemper, 2015; Smith III, Hung, & Arumugam,
2014; Wallman & Winawer, 2004). The vision-dependent mecha-
nisms that regulate ocular growth normally mediate the phe-
nomenon of emmetropization, but they can also contribute to the
development of common refractive errors, like juvenile onset myo-
pia. The operational performance properties of these mechanisms
determine the extent and manner in which visual experience can
influence eye growth and, in particular, the effects of strabismus
on refractive development. In this respect, it is important to note
that although various manipulations of the neural inputs to and
from the eye have been shown to influence some of the effects of
vision on refractive development (Shih, Fitzgerald, & Reiner,
1994; Troilo, 1987), the mechanisms that dominate refractive
development are located entirely within the eye (Wallman &
Winawer, 2004), can extract the sign of defocus from visual signals
(Fischer, McGuire, Schaeffel, & Stell, 1999; Zhong, Ge, Smith III, &
Stell, 2004), do not require accommodation to produce
emmetropizing responses (Schaeffel, Troilo, Wallman, &
Howland, 1990; Schmid & Wildsoet, 1996), and they operate in a
local, regionally selective manner (Smith III et al., 2009; Smith III,
Hung, Huang, & Arumugam, 2013; Smith III et al., 2010;
Wallman, Gottlieb, Rajaram, & Fugate-Wentzek, 1987). For exam-
ple, hemi-field form deprivation produces regional increases in vit-
reous chamber depth and myopia that are restricted to the treated
part of the retina, even if the optic nerve has been surgically sec-
tioned (Troilo, Gottlieb, & Wallman, 1987).
Given that the underlying neural abnormalities for strabismus
and amblyopia are in the visual cortex (Bi etal., 2011; Kumagami,
Zhang, Smith III, & Chino, 2000; Mori, Matsurra, Zhang, Smith III,
& Chino, 2002; Movshon et al., 1987; Shooner et al., 2015; Smith
III, Chino, Cheng, Crawford, & Harwerth, 1997; Spengpiel &
Blakemore, 1996), the retina and subcortical afferent pathways
being functionally unaffected, it is not clear how the presence of
strabismus or amblyopia could directly influence refractive devel-
opment. However, alterations in visual experience associated with
strabismus that is secondary to high bilateral hyperopia could
influence refractive development in both the fixating and deviating
eyes leading to hyperopic anisometropia. We recognize that the
following discussion is speculative, but there currently is not a uni-
versally accepted explanation for the pattern of refractive changes
that occur in children with bilateral hyperopia who subsequently
development strabismus, a unilateral fixation pattern, and hyper-
opic anisometropia.
First, alterations in visual experience may contribute to the late
onset of emmetropization in the fixating eye. It has been observed
that orthotropic monkeys (Smith III & Hung, 1999; Smith III et al.,
1999) and children (Mutti et al., 2009) with high bilateral hyper-
39
opia do not consistently accommodate to overcome their hyper-
opic errors, presumably to reduce the drive to accommodative
convergence and the demand on fusional divergence. Given that
these eyes experience chronic hyperopic defocus, which is a strong
stimulus for axial elongation, it is not known why these eyes
remain hyperopic. A reasonable explanation is that the
emmetropization process in these eyes is not operating as effi-
ciently as in the average eye. It has also been speculated that the
failure to accommodate for these high hyperopic errors somehow
prevents or interferes with the emmetropization (Mutti et al.,
2009; Smith III & Hung, 1999). In this respect, the onset of strabis-
mus, by removing constraints on accommodation, would presum-
ably allow the fixating eye to accommodate more frequently or
more accurately, which could somehow initiate emmetropization.
Given that accommodation is consensual in primates, it seems
unlikely that it is the physical act of accommodating that is the
critical trigger, otherwise it would be expected that emmetropiza-
tion would be initiated in both the fixating and deviating eyes.
Similarly, it seems likely that the parasympathetic inputs to the
choroid, which could affect the overall gain of the emmetropiza-
tion process, are also consensual in nature. On the other hand, in
monkeys, treatment lenses that impose high hyperopic ametropias
that fall outside the operating range of the emmetropization pro-
cess fail to consistently initiate compensating ocular growth in
otherwise normal animals (Smith III & Hung, 2000; Smith III
et al., 1999). It is possible that large optical errors mask the ability
of the emmetropization process to identify the sign of defocus.
Improved accommodative function in the fixating eye could reduce
the optical error to within the effective operating range of the
emmetropization process, promoting axial elongation.
The relatively slow time course of emmetropization typically
observed in fixating eyes of hyperopic esotropes could reflect a
compromised emmetropization process or age-related reductions
in the potential rate of axial elongation. However, we have previ-
ously observed that the untreated eyes of monkeys reared with sev-
ere form deprivation emmetropize more slowly and tend to be
more hyperopic than normal binocular monkeys (Smith III, Hung,
Kee, & Qiao, 2002). Possibly, the slower emmetropizing responses
in ‘‘monocular” hyperopes reflect the fact that their accommoda-
tion may be more accurate than normal. It has been argued that
optical defocus associated with under accommodation or errors of
accommodation promotes the normal reduction in hyperopia that
occurs during emmetropization (Norton & Siegwart, 1995;
Wallman, 1993). As the degree of hyperopia is reduced and the
eye approaches emmetropia, there is a time-averaged improve-
ment in the clarity of the retinal image that slows down ocular
growth resulting in the maintenance of emmetropia. If this scenario
is correct, it is possible that the slow rate of emmetropization in the
fixating eyes came about because the onset of strabismus, by elim-
inating constraints associated with accommodative convergence
and the maintenance of fusion, actually increased the accuracy of
accommodation in the fixating eye in a time-averaged manner. As
a result, in comparison to normal monkeys, the fixating eyes of ani-
mals with unilateral esotropia would experience better overall
image quality and/or longer periods of clear vision, which could
slow emmetropization or result in the premature cessation of the
normal emmetropization process.
It can be speculated that defocus signals may also contribute to
the stability of hyperopia in the deviating eyes of hyperopic esotro-
pic individuals. In particular, several behaviors and viewing condi-
tions could produce relative myopic focusing errors in the
deviating eye, which is a potent signal to suppress axial elongation
(Wallman & Winawer, 2004). First, highly hyperopic eyes are rela-
tively oblate in shape and, as a consequence can exhibit substantial
amounts of relative peripheral myopia (Hung, Ramamirtham,
Huang, Qiao-Grider, & Smith III, 2008; Li et al., 2015; Millodot &
40 E.L. Smith III et al. / Vision Research 134 (2017) 26–42
Lamont, 1974; Mutti, Sholtz, Friedman, & Zadnik, 2000). For an indi-
vidual with a constant esotropic deviation, the image of the fixation
point (i.e., the object plane in focus in the fellow eye) would be dis-
placed into the retinal periphery and myopically defocused (assum-
ing symmetrical refractive errors and/or if both eyes are optimally
corrected). This is significant because visual signals from the periph-
ery can dominate axial elongation and central refractive develop-
ment (Smith III, 2011; Smith III et al., 2005; Smith III et al., 2007).
In this scenario, because the degree of relative peripheral myopia
generally increases with eccentricity (at least along the horizontal
meridian) (Millodot, 1981; Millodot & Lamont, 1974), it would be
expected that these stop signals would be greater in individuals with
larger degrees of esotropia. In agreement with this idea, larger
emmetropizing responses have been observed in the amblyopic
deviating eyes of individuals with smaller ocular misalignments
(Kulp et al., 2012). During nearwork, depending on the size of the
object of regard and the angle of deviation, the fovea of the deviating
eye could also receive images that are myopically defocused. It is
important to note that even short periods of myopic defocus can
override much longer exposure periods to visual signals that nor-
mally increase axial elongation (Kee et al., 2007; Norton, Siegwart,
& Amedo, 2006; Winawer & Wallman, 2002; Winawer, Zhu, Choi,
& Wallman, 2005; Zhu, Winawer, & Wallman, 2003). So multiple
brief exposures to myopic defocus could be sufficient to prevent
emmetropization in hyperopic deviating eyes.
Face turns, head tilts, and posture, especially during near tasks,
could also result in substantial amounts of myopic defocus in the
deviating eye (Charman, 2011). Patients often develop anomalous
head postures to maximize visual acuity (Havertape & Cruz,
1998), increase the field of view (Goltz, Steinbach, & Gallie,
1997), or to maintain binocularity (Hiatt & Cope-Troupe, 1978),
which can be eliminated by the appropriate optical correction or
simply occluding the fellow eye. For example, functionally monoc-
ular individuals often rotate their heads around the vertical axis
away from the fixating eye in order to center and effectively
enlarge their visual field,(Goltz et al., 1997). If this behavior takes
place at near, the distance between the fixation plane and deviat-
ing eye will be increased. While this may only represent a 3–
4 cm backward displacement, for short reading distances or for
children who combine a face rotation with a head tilt favoring
the fixating eye, this could result in substantial amounts of myopic
defocus across the retina (Charman, 2011). Unfortunately relative
little is known about anomalous head positions and reading pos-
tures in strabismic children that otherwise have normal eye move-
ments. Compensating postural attitudes are a well-recognized
adaptation in individuals with non-comitant strabismus (Duke-
Elder, 1973). However, the frequency of anomalous head postures
is lower in concomitant unilateral esotropia with high hyperopia
because the onset of suppression and/or amblyopia eliminates
diplopia and confusion.
Regardless of whether or not the above speculations are correct,
defocus is the visual signal that regulates refractive development
and it makes sense that efforts should be made to determine the
potential role of defocus in the pattern of refractive changes
observed in strabismic amblyopes.
Proprietary interests
None of the Authors.
Financial support
This work was supported by NIH Grants EY-03611 and EY-
07551 and funds from the Brien Holden Vision Institute and the
UH Foundation.
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