children

Article
Long-Term Efficacy of the Combination of Active Vision
Therapy and Occlusion in Children with Strabismic and
Anisometropic Amblyopia
Myriam Milla 1,2 , Ainhoa Molina-Martín 2 and David P. Piñero 2, *

1 Oftalvist, 03013 Alicante, Spain; mmilla@oftalvist.es

2 Department of Optics, Pharmacology and Anatomy, University of Alicante, 03690 Alicante, Spain;
ainhoa.molina@ua.es
* Correspondence: david.pinyero@ua.es; Tel.: +34-965903400

Abstract: This retrospective study was conducted to evaluate the efficacy of the combined treatment
of occlusion and active vision therapy in a total of 27 amblyopic children, including 14 strabismic
and 13 anisometropic cases. For such purpose, changes in distance and near visual acuity as well
as in the binocular function was evaluated during a two-year follow-up. In both amblyopia groups,
significant improvements were found in distance and near visual acuity in the non-dominant eye
(p < 0.001). In the strabismic amblyopia group, the percentage of patients with binocular function
score (BF) > 3.3 decreased significantly from a baseline value of 64.3% to a two-year follow-up value
of 7.1% (p < 0.001). In the anisometropic amblyopia group, this percentage also decreased significantly
from a baseline value of 15.4% to a two-year follow-up value of 0.0% (p < 0.001). No recurrences
were observed in the anisometropic amblyopia group, whereas recurrence occurred in two cases
of the strabismic amblyopia group after finishing the vision rehabilitation process. In conclusion,
Citation: Milla, M.; Molina-Martín, the combined approach of the treatment evaluated is efficacious for providing an improvement in
A.; Piñero, D.P. Long-Term Efficacy of visual acuity and binocular function in both anisometropic and strabismic amblyopia, which was
the Combination of Active Vision maintained over time.
Therapy and Occlusion in Children
with Strabismic and Anisometropic Keywords: amblyopia; anisometropia; occlusion therapy; patching; strabismus; stereopsis;
Amblyopia. Children 2022, 9, 1012. vision therapy
https://doi.org/10.3390/
children9071012

Academic Editors: Calvin C. P. Pang

and Eric Beyer 1. Introduction
Amblyopia is a neurological disorder that affects the development of the visual system
Received: 26 May 2022
Accepted: 6 July 2022
in early life [1–3]. Several studies have reported and listed the differences that are present
Published: 7 July 2022
between strabismic and anisometropic amblyopia [4,5], this differential behavior being an
important factor when considering the protocol for amblyopia rehabilitation. The visual
Publisher’s Note: MDPI stays neutral acuity reduced in one or both eyes is the visible part of a number of common deficits
with regard to jurisdictional claims in
such as decreased contrast sensitivity (for high frequencies in strabismic amblyopia and
published maps and institutional affil-
limitation across the frequency range in anisometropic amblyopia), slow and uneven
iations.
accommodative response, a crowding effect (stronger in strabismic), and reduced or absent
stereopsis [4–7]. However, strabismic amblyopia encompasses other problems that further
hinder the improvement of visual function. Reduced cortical control of movement due to
Copyright: © 2022 by the authors.
strabismus [8], combined with amblyopia, leads to reversals in improvement even when
Licensee MDPI, Basel, Switzerland. treatment is considered completed.
This article is an open access article The active methods of treatment were born to complement passive methods such
distributed under the terms and as occlusion or atropine in the dominant eye [9]. Active visual rehabilitation focuses on
conditions of the Creative Commons improving amblyopia by capturing the patient’s attention during the treatment period,
Attribution (CC BY) license (https:// as well as by activating the connectivity of certain cell types at the cortical level [9,10].
creativecommons.org/licenses/by/ The new approach to active visual rehabilitation methods for the treatment of amblyopia
4.0/).

Children 2022, 9, 1012. https://doi.org/10.3390/children9071012 https://www.mdpi.com/journal/children

Children 2022, 9, 1012 2 of 13

has led to the development of new protocols based on the following techniques: percep-
tual learning, dichoptic training, binocular vision therapy and virtual reality [11–14]. In
anisometropic amblyopia, according to several studies, the best option seems to be the
combination of active vision therapy and occlusion, addressing not only the improvement
of visual acuity and stereopsis, but also the rest of the visual skills reduced by this type of
amblyopia [5]. In strabismic amblyopia, active visual therapy under binocular conditions
should be performed after ensuring that bifoveal fusion is present, this being a limiting
factor for treatment with dichoptic training [4]. Furthermore, in most studies on vision
therapy in amblyopia, only a minimal part of the patients included are diagnosed with
strabismic amblyopia and, therefore, it is difficult to draw specific conclusions for this type
of amblyopia and the success of active vision therapy.
The main objective of this study was to evaluate the efficacy of the combined treatment
of occlusion and active vision therapy in both strabismic and anisometropic amblyopia
by evaluating the retrospective data collected in a pediatric ophthalmology unit of a
private hospital.

2. Materials and Methods

2.1. Patients
This retrospective study analyzed data from all patients evaluated and treated from
February 2017 to December 2021 in Oftalvist Clinic (Alicante, Spain). This study was con-
ducted in accordance with the tenets of the Declaration of Helsinki, and with the approval
of the institutional ethics committee of University of Alicante (UA-2018-03-03). Inclusion
criteria were children with strabismic and anisometropic amblyopia following a complete
program of visual rehabilitation in our institution. Exclusion criteria were a history of
other ophthalmological or systemic diseases, eccentric fixation, amblyopia fully recovered
with optical correction, previous history of amblyopia therapy, congenital cataracts, and
nystagmus. Clinically, amblyopia was defined as the presence of two conditions: one or
both eyes having a visual acuity of 6/12 or worse, and one or more lines of difference in
logMAR visual acuity between the eyes in unilateral amblyopia [4,15]. In this study, ani-
sometropic amblyopia was defined as an amblyopia associated to a significant difference in
the magnitude of refractive error between both eyes (difference ≥ 1.00 D in the equivalent
sphere between eyes and/or difference ≥ 1.50 D in astigmatism between corresponding
meridians between eyes), and without the presence of strabismus [5]. Diagnosis of strabis-
mic amblyopia was considered as the combination of amblyopia with constant strabismus
in addition to refractive error [4].

2.2. Examination Protocol

All subjects completed an ophthalmologic and optometric examination to confirm
the diagnosis of amblyopia, including autorefraction, tonometry, measurement of distance
and near LogMAR visual acuity, manifest and cycloplegic refraction (cyclopentolate 1%),
fundus exam, ocular motility test, cover test (exo- and eso-deviation were recorded by
− and +, respectively), objective evaluation of fixation behavior (microperimetry, MAIA
system, Centervue, Padova, Italy), cover test, and stereopsis. Similarly, a complete baseline
examination before vision therapy was also performed. All patients began with spectacle
correction and started an occlusion therapy according to PEDIG guidelines [16] after a
period of refractive adaptation of four to six weeks. Data from the follow-up visits were
registered and analyzed at: baseline, 15 days, one month, two months and three months
during monocular and binocular training. The evolution of the possible improvement in
binocular vision was measured with the TNO test, giving a range of values according to the
state of stereoscopic vision. The BF (binocular function score) was calculated with value 5
representing suppression, value 4 simultaneous vision or flat fusion. and from 1.6 to 3.3
(log 40 arc sec − log 2000 arc sec) the presence of stereopsis [17].
Children 2022, 9, 1012 3 of 13

Each patient performed monocular training in the amblyopic eye during three months
at home and at office. Then, by restoring part of visual acuity in the non-dominant eye, all
patients combined vision therapy with perceptual learning training.

2.3. Active Vision Therapy

The training procedure was performed both in the home and the office settings, but
always under the professional supervision of the same optometrist (M.M.). All patients
underwent a program of personalized visual exercises according to age and cognitive
level. Figure 1 shows a diagram explaining the type of procedures used in the vision
therapy program. The rehabilitative protocol followed in our center in amblyopia began
with an intensive training of the monocular visual function, including the accommodative
response, ocular motility and spatial localization, all of which are affected in amblyopia [17].
Occlusion was remained in this initial stage of treatment as an additional method of
monocular treatment (passive), following the PEDIG guidelines [16]. Once the patient
reached a visual acuity of 20/30 in the amblyopic eye, occlusion was stopped and binocular
training was initiated, as the cortical integration of images can be facilitated without a very
significant worsening of the non-amblyopic eye. Occlusion was not prescribed if the visual
acuity in the amblyopic eye was better than 20/30. In strabismic amblyopia cases, the
correction of the deviation with surgery or prisms (if normal retinal correspondence was
presence and the deviation was 12 prism diopters or below) was required before initiating
the binocular training [18]. A weekly or biweekly training session at the office of around
30–45 min was performed with an additional daily home exercise routine of approximately
20–30 min. This part of the treatment was successfully performed by all patients. As
traditional exercises, such as flippers or printed sheets of tests, were used, it was impossible
to check the exact compliance of the treatment. A successful outcome was achieved when
obtaining a 1% frequency of tropia provided that diplopia is noticed at these times and up
to five prism diopters was required to be worn in spectacles (Flom’s criteria) [19].
Once finished the monocular training, binocular training was initiated with traditional
tools, such as a Brock cord or anaglyphs, following the same program of visits and home
exercises of monocular training. This binocular stimulation was performed until achieving a
gross stereopsis of 480 arc sec, with stimulation of fine stereopsis afterwards with 20–30 min
of home exercises using the specialized software Visionary (Visionarytool, Gijón, Spain).
The use of this software has been demonstrated to be effective for improving the level of
stereoacuity in amblyopes [20]. If fine stereopsis was present after monocular training, this
specialized software was used directly. The treatment stopped once achieving a stereopsis
level of 120 arc sec or one year after performing active training without improving from
gross stereopsis or not achieving it. All patients use the Visionary software as a maintenance
method (20 min of training) for six months after finishing the rehabilitation program. The
optical correction was maintained during the follow-up if it was needed to maintain good
visual acuity and the alignment.
Recurrence was defined as a 0.2 or more logMAR loss of visual acuity according to
Walsh et al. [21]. No recurrences were observed in the anisometropic amblyopia group,
whereas recurrence occurred in two cases of the strabismic amblyopia group after finishing
the vision rehabilitation process. In these two cases, the binocular stimulation was initiated
again, fully recovering the visual loss at the end of the follow-up.

2.4. Statistical Analysis

Statistical analysis of the results was done using the SPSS program v.19.0.0 for Win-
dows (SPSS Inc., Chicago, IL, USA). Analysis of normality by Kolmogorov-Smirnov test
revealed that most of the parameters did not follow a normal distribution, so, accordingly
non-parametric tests were applied. The Friedman test was used to assess the statistical
significance of differences in the anisometropic and strabismic groups between consecutive
visits, with a post-hoc comparison by pairs using the Wilcoxon test adjusted with the
Bonferroni correction. Concerning percentage, differences between baseline and last visit
Children 2022, 9, 1012 4 of 13

were evaluated with the McNemar test. Differences were considered to be statistically
significant when the associated p-value was <0.05. The results reported in were those
Children 2022, 9, x FOR PEER REVIEW 4 of 16
obtained once the period of refractive adaptation was finished and therefore changes were
due to the combination of active (training) and passive therapy (occlusion) of amblyopia.

Figure 1. Diagram showing the type of vision therapy performed in the current study.
Figure 1. Diagram showing the type of vision therapy performed in the current study.
Children 2022, 9, 1012 5 of 13

As the sample of patients recruited was small, the statistical power associated to
each change that was found to be statistically significant was calculated a posteriori using
the software PS Power and Sample Size Calculations Version 3.0 (Vanderbilt University,
Nashville, TN, USA). This software allows for the performing of a calculation of the statisti-
cal power associated with different types of statistical tests using the method described by
Dupont and Plummer [22]. The statistical power was calculated for changes in distance
BCVA and BF.

3. Results
A total of 27 patients were analyzed, 14 were strabismic amblyopes and 13 were ani-
sometropic amblyopes. The mean age in the strabismic amblyopia group was 11.0 ± 2.7 years
(range, 7–16 years), whereas in the anisometropic amblyopia group it was 11.0 ± 2.6 years
(range, 8–18 years).

3.1. Sample Size Calculations

Table 1 shows the statistical power calculations for the anisometropic and strabismic
amblyopia groups associated with the analysis of changes at the end of follow-up compared
to the baseline conditions in distance BCVA and BF. As shown, the statistical power
associated to distance BCVA and BF changes in both strabismic and anisometropic groups
were over 95.0%.

Table 1. Statistical power calculations associated with the analysis of changes in distance BCVA
and BF for the strabismic and anisometropic groups. Abbreviations: α, Type I error probability
(probability that we will falsely reject the null hypothesis; δ, difference between means; σ, standard
deviation of difference in the response of matched pairs; n, number of subjects; SP, statistical power.
BCVA, best corrected visual acuity; BF, binocular function score.

α δ σ n SP
Strabismic amblyopia
Distance BCVA 0.05 −0.21 0.16 14 99.2%
BF 0.05 −1.27 1.20 14 95.2%
Anisometropic amblyopia
Distance BCVA 0.05 −0.26 0.16 13 99.8%
BF 0.05 −0.67 0.56 13 97.3%

3.2. Strabismic Amblyopia

Table 2 reports the data obtained according to the non-amblyopic and amblyopic eye
and according to visits to the office (initial, 15 days, 30 days, 60 days, 90 days, one year
and years years). In addition, the evolution of binocular vision results in terms of cover
test and BF was provided. The analysis of BCVA and NVA (best corrected visual acuity
and near vision visual acuity) outcomes revealed the presence of no statistically significant
changes (p = 0.73 and p = 0.11, respectively) in the non-amblyopic eyes as the treatment
progressed, even at one and two years of follow-up. However, in the analysis of amblyopic
eyes, significant improvements were observed for both BCVA and NVA (p < 0.01). In the
comparison by pairs, statistically significant differences were found in BCVA between the
first visit and the rest of visits after one month of combined treatment (p = 0.02). In the NVA
analysis, according to the analysis by pairs, statistically significant differences were only
found between the results obtained at the visit after 90 days of combined treatment and
after one year of follow-up with respect to the initial visit (p = 0.02 and p = 0.04, respectively).
In terms of cycloplegic and subjective refraction, no statistically significant changes were
observed between visits in both the non-amblyopic and amblyopic eyes (p > 0.05).
Children 2022, 9, 1012 6 of 13

Table 2. Median [range], mean ± SD and (min-max) of the different variables evaluated in non-amblyopic (0) and amblyopic (1) eyes in the strabismic amblyopia
group from the previous visit to 15 days, 30 days, 60 days and 90 days of treatment. Similarly, data of the one and two-year follow-up after completion of treatment
were also added.
Median [IQ]
Previous 15 Days 1 Month 2 Months 3 Months 1 Year Post Avt 2 Years Post Avt
Mean ± SD

(Range) 0 1 0 1 0 1 0 1 0 1 0 1 0 1 p (0) p (1)

Distance BCVA 0.00 [0.03] 0.19 [0.30] 0.00 [0.02] 0.11 [0.19] 0.00 [0.01] 0.07 [0.09] 0.00 [0.02] 0.03 [0.06] 0.00 [0.01] 0.02 [0.08] 0.00 [0.02] 0.02 [0.03] 0.00 [0.02] 0.02 [0.05]
(logMAR) 0.03 ± 0.06 0.25 ± 0.17 −0.01 ± 0.09 0.17 ± 0.15 −0.00 ± 0.11 0.08 ± 0.06 0.01 ± 0.01 0.05 ± 0.05 0.01 ± 0.05 0.05 ± 0.07 0.01 ± 0.02 0.03 ± 0.03 0.00 ± 0.03 0.04 ± 0.05 0.73 <0.001
(0.00–0.15) (0.05–0.52) (−0.30–0.10) (0.00–0.52) (−0.30–0.22) (0.00–0.19) (0.00–0.05) (0.00–0.15) (−0.08–0.15) (0.00–0.22) (0.00–0.07) (0.00–0.10) (−0.08–0.05) (0.00–0.19)

Near BCVA 0.00 [0.10] 0.20 [0.23] 0.00 [0.10] 0.15 [0.20] 0.00 [0.02] 0.10 [0.20] 0.00 [0.10] 0.10 [0.12] 0.00 [0.10] 0.00 [0.12] 0.00 [0.02] 0.00 [0.10] 0.00 [0.00] 0.00 [0.10]
(logMAR) 0.03 ± 0.11 0.26 ± 0.20 0.03 ± 0.09 0.16 ± 0.13 0.01 ± 0.08 0.10 ± 0.10 0.01 ± 0.06 0.08 ± 0.10 −0.01 ± 0.06 0.03 ± 0.10 −0.01 ± 0.05 0.02 ± 0.06 0.01 ± 0.03 0.06 ± 0.08 0.11 <0.001
(0.30–0.40) (0.00–0.70) (−0.10–0.20) (−0.10–0.30) (−0.10–0.20) (0.00–0.30) (−0.10–0.10) (−0.10–0.30) (−0.10–0.10) (−0.10–0.20) (−0.10–0.10) (−0.10–0.10) (0.00–0.10) (0.00–0.30)

3.00 [2.25] 4.94 [2.88] 3.00 [2.25] 4.94 [2.88] 3.00 [2.25] 4.94 [2.88] 3.00 [2.25] 4.94 [2.63] 2.94 [2.67] 4.75 [3.00] 2.94 [3.19] 5.13 [3.28] 2.88 [4.00] 5.00 [2.88]
Cycloplegic
3.23 ± 1.83 4.12 ± 2.63 3.23 ± 1.83 4.12 ± 2.63 3.25 ± 1.86 4.08 ± 2.71 3.21 ± 1.87 4.10 ± 2.68 3.26 ± 1.90 4.11 ± 2.70 3.18 ± 1.94 4.13 ± 2.73 3.23 ± 2.18 4.11 ± 3.05 0.74 0.93
refraction (D)
(0.50–6.63) (−2.38–7.38) (0.50–6.63) (−2.38–7.38) (0.25–6.63) (−2.38–7.38) (0.25–6.63) (−2.25–7.38) (0.50–6.63) (−2.25–7.38) (0.50–6.88) (−2.25–7.63) (0.38–6.75) (−3.38–7.50)

Subjective refraction 2.37 [3.06] 4.31 [3.38] 2.86 [3.06] 4.31 [3.72] 2.75 [3.06] 4.25 [3.06] 2.75 [2.78] 4.31 [3.16] 2.50 [3.44] 4.38 [3.41] 2.63 [3.44] 4.63 [3.38] 2.50 [3.75] 4.50 [3.19]
(D) 2.64 ± 2.13 3.55 ± 2.96 2.71 ± 2.13 3.60 ± 3.00 2.80 ± 2.04 3.55 ± 2.81 2.72 ± 1.97 3.61 ± 2.66 3.02 ± 2.00 3.72 ± 2.68 3.04 ± 2.04 3.82 ± 2.69 3.13 ± 2.38 3.74 ± 3.06 0.02 0.93
(−0.38–6.63) (−3.00–7.50) (−0.38–6.63) (−3.00–7.50) (0.00–6.63) (−3.00–7.50) (−0.13–6.63) (−2.63–7.00) (0.00–6.63) (−2.38–7.00) (0.00–6.50) (−2.38–7.25) (−0.50–6.75) (−3.25–7.25)

Distance Cover Test 3.00 [10] 3.00 [10] 2.25 [10] 3.75 [11] 2.25 [8] 0.00 [6] 0.00 [7]
(prism diopters) 5.14 ± 10.21 5.14 ± 10.21 3.89 ± 8.40 4.00 ± 10.13 2.18 ± 7.49 1.29 ± 7.09 2.64 ± 4.92 <0.001
(−17–25) (−17–25) (−17–16) (−25–16) (−20–10) (−20–10) (−8–10)

Near Cover Test 7.75 [10] 7.75 [11] 7.50 [11] 6.50 [8] 4.75 [9] 4.25 [9] 6.75 [10]
(prism diopters) 7.50 ± 11.47 8.50 ± 11.67 6.32 ± 10.27 5.75 ± 9.94 3.99 ± 7.88 4.07 ± 8.46 6.89 ± 6.82 0.45
(−25–25) (−25–25) (−25–16) (−25–16) (−19–15) (−19–19) (−8–18)

4.00 [2.47] 4.00 [2.73] 4.00 [2.50] 2.60 [1.70] 2.60 [0.68] 2.30 [0.75] 2.30 [0.33]
BF 3.79 ± 1.30 3.76 ± 1.33 3.62 ± 1.29 2.96 ± 1.09 2.29 ± 1.08 2.54 ± 0.75 2.52 ± 0.77 0.002
(1.60–5.00) (1.60–5.00) (1.60–5.00) (1.60–5.00) (1.51–5.00) (1.80–5.00) (1.70–5.00)
Children 2022, 9, 1012 7 of 13

The evolution of binocular vision was recorded by improvements in the BF. At the
first visit, of the 14 patients with strabismic amblyopia, nine of them had suppression
or simultaneous vision, with only five showing some degree of gross stereopsis without
reaching bifoveal fixation. After three months of combined treatment (occlusion and active
visual therapy), only two patients maintained the state of binocular suppression, nine
patients achieved some degree of gross binocular vision, and only two achieved random
stereopsis. After one and two years of follow-up, the results obtained after treatment were
maintained, with only one patient with suppression and 13 patients with some degree of
Children 2022, 9, x FOR PEER REVIEW 9 of 16
gross binocular vision or random stereopsis (Figure 2). The percentage of patients with
BF > 3.3 decreased significantly from a baseline value of 64.3% to a two-year follow-up
value of 7.1% (p < 0.001).

Figure
Figure 2. Binocularfunction
2. Binocular function (BF)
(BF)score
scoreevolution
evolutionof strabismic amblyopia
of strabismic group group
amblyopia from the previous
from the previous
visit to 15 days, 30 days, 60 days and 90 days of treatment, as well as at one and two years after the
visitcompletion
to 15 days, 30 days, 60
of treatment. days and 90 days of treatment, as well as at one and two years after the
completion of treatment.
3.3. Anisometropic Amblyopia
Concerning the the
Table 3 shows type of deviation,
results only the
obtained from oneanalysis
case ofinexotropia
the groupwas included while the
of anisometropic
restamblyopes.
of the cases were
In the esotropias. The
non-amblyopic eyes,case of exotropia
no statistically (17 prism
significant diopters
changes at distance
were found in and
BCVA diopters
25 prism between visits (p = showed
at near) 0.20). In contrast, significantof
an improvement differences wereat
BF from 2.60 found in NVA
baseline (p at the
to 1.80
end= of
0.01).
the However,
follow-up, after
thisthe Bonferroni
being correction
the case with the of highest
paired comparisons,
post-therapy noBF
statistically
of the sample.
significant differences were found between pairs of visits (p > 0.05). There was only a trend
3.3.inAnisometropic
non-amblyopicAmblyopia
eyes to a slight improvement in NVA after treatment compared to base-
line. In amblyopic
Table 3 shows eyes, statistically
the results significant
obtained fromchanges were observed
the analysis in both of
in the group BCVA and
anisometropic
NVA results (p < 0.05). According to the analysis by pairs in BCVA, differences between
amblyopes. In the non-amblyopic eyes, no statistically significant changes were found in
visits were found to be significant when comparing the 15 and 30-day visits of combined
BCVA between visits (p = 0.20). In contrast, significant differences were found in NVA
treatment and the one-year and two-year follow-up with respect to the initial (p = 0.02) in
(p =all0.01).
cases.However, after the Bonferroni
Likewise, differences correction
were statistically of paired
significant comparisons,
between no statistically
the 15-day visit and
significant differences were found between pairs of visits (p > 0.05).
the two-year follow-up (p = 0.02) as well as between the first month's visit with respect There was
to only a
two-year
trend follow-up (p =eyes
in non-amblyopic 0.04).toIna the NVA
slight analysis by pairs
improvement in NVAin non-amblyopic
after treatment eyes, no
compared to
significant
baseline. differences eyes,
In amblyopic between visits weresignificant
statistically found. Finally, subjective
changes wereand cycloplegic
observed re- BCVA
in both
andfraction did not(p
NVA results show statistically
< 0.05). According significant
to thechanges
analysisduring the in
by pairs follow-up
BCVA, (p > 0.05).
differences between
The initial status of the 13 patients with anisometropic
visits were found to be significant when comparing the 15 and 30-day visits amblyopia was as follows:
of combined
two patients
treatment and had flat fusion and
the one-year or simultaneous vision, four
two-year follow-up had respect
with gross stereopsis, and seven
to the initial (p = 0.02) in
had random fine stereopsis. After the evolution of combined occlusion and vision therapy,
all cases. Likewise, differences were statistically significant between the 15-day visit and
11 patients achieved fine stereopsis and only two coarse stereopsis. After the evolution
theand
two-year follow-up (p = 0.02) as well as between the first month’s visit with respect
follow-up of one and two years after the end of the treatment, the results of the BF
to two-year
value were maintained (p
follow-up = 0.04).
(Figure In the
3), with NVAmajority
the great analysis by pairsachieving
of patients in non-amblyopic
fine stere- eyes,
no oacuity with bifoveal fixation and three patients still having gross stereopsis. Theand
significant differences between visits were found. Finally, subjective percent-
cycloplegic
age of patients
refraction did notwith
show BF statistically
> 3.3 decreased significantly
significant from aduring
changes baseline value
the of 15.4%(pto>a0.05).
follow-up
two-year follow-up value of 0.0% (p < 0.001).
Children 2022, 9, 1012 8 of 13

Table 3. Median [range], mean ± SD and (min-max) of the different variables evaluated in non-amblyopic (0) and amblyopic (1) eyes in the anisometropic amblyopia
group from the previous visit to 15 days, 30 days, 60 days and 90 days of treatment. Similarly, data of the one and two-year follow-up after completion of treatment
were also added.
Median [IQ]
Previous 15 Days 1 Month 2 Months 3 Months 1 Year Post Avt 2 Years Post Avt
Mean ± SD

(Range) 0 1 0 1 0 1 0 1 0 1 0 1 0 1 p (0) p (1)

Distance BCVA 0.00 [0.02] 0.22 [0.32] 0.00 [0.00] 0.07 [0.13] 0.00 [0.00] 0.02 [0.05] 0.00 [0.00] 0.02 [0.01] 0.00 [0.00] 0.01 [0.02] 0.00 [0.00] 0.01 [0.02] 0.00 [0.04] 0.00 [0.01]
(logMAR) 0.01 ± 0.06 0.26 ± 0.17 0.01 ± 0.03 0.12 ± 0.10 −0.00 ± 0.02 0.04 ± 0.03 −0.01 ± 0.02 0.05 ± 0.08 −0.01 ± 0.02 0.03 ± 0.06 0.00 ± 0.01 0.02 ± 0.02 −0.02 ± 0.04 −0.00 ± 0.02 0.2 <0.001
(−0.08–0.15) (0.10–0.60) (0.00–0.10) (0.00–0.35) (−0.08–0.02) (0.02–0.10) (−0.08–0.00) (0.00–0.30) (−0.08–0.00) (0.00–0.22) (0.00–0.02) (0.00–0.07) (−0.08–0.02) (−0.08–0.02)

Near BCVA 0.00 [0.10] 0.20 [0.20] 0.00 [0.05] 0.10 [0.25] 0.00 [0.00] 0.00 [0.10] 0.00 [0.05] 0.00 [0.15] −0.10 [0.10] 0.00 [0.10] 0.00 [0.10] 0.00 [0.10] −0.10 [0.10] 0.00 [0.10]
(logMAR) −0.01 ± 0.08 0.16 ± 0.18 −0.01 ± 0.05 0.06 ± 0.12 0.00 ± 0.00 0.04 ± 0.06 −0.02 ± 0.04 0.01 ± 0.09 −0.05 ± 0.05 −0.04 ± 0.06 −0.04 ± 0.05 −0.03 ± 0.05 −0.05 ± 0.05 −0.05 ± 0.05 0.01 <0.001
(−0.10–0.20) (−0.10–0.60) (−0.10–0.10) (−0.10–0.20) (0.00–0.00) (0.00–0.20) (−0.10–0.00) (−0.10–0.20) (−0.10–0.00) (−0.10–0.10) (−0.10–0.00) (−0.10–0.00) (−0.10–0.00) (−0.10–0.00)

Cyploplegic refraction 1.88 [1.56] 4.38 [7.00] 2.00 [1.56] 4.38 [6.81] 1.88 [1.56] 4.38 [6.81] 1.88 [1.94] 4.38 [7.00] 2.00 [2.13] 3.25 [6.75] 2.00 [2.31] 3.63 [7.75] 2.00 [2.75] 3.38 [8.88]
(D) 2.21 ± 1.60 2.71 ± 4.10 2.22 ± 1.60 2.74 ± 4.06 2.19 ± 1.56 2.70 ± 4.00 2.31 ± 1.71 2.75 ± 4.02 2.27 ± 1.73 2.50 ± 3.92 2.11 ± 1.70 2.32 ± 4.53 1.89 ± 1.88 2.13 ± 4.58 0.59 0.31
(−0.50–6.25) (−4.25–8.00) (−0.50–6.25) (−4.25–8.00) (0.00–6.25 (−4.25–7.88) (0.00–6.25) (−4.25–7.88) (0.00–6.25) (−4.25–7.88) (−0.50–5.50) (−5.75–7.63) (5.50–6.50) (−6.00–7.13)

Subjective refraction 1.25 [1.13] 3.50 [6.25] 1.00 [1.00] 2.50 [6.38] 1.13 [1.00] 4.00 [6.38] 1.13 [1.25] 3.00 [6.25] 1.25 [1.50] 3.75 [6.19] 1.50 [2.00] 2.63 [6.81] 1.38 [2.00] 2.38 [7.31]
(D) 1.44 ± 1.48 2.29 ± 3.86 1.45 ± 1.47 2.13 ± 3.89 1.45 ± 1.44 2.22 ± 3.94 1.55 ± 1.49 2.06 ± 3.94 1.54 ± 1.51 2.11 ± 3.99 1.62 ± 1.49 1.90 ± 4.11 1.51 ± 1.61 1.49 ± 4.17 0.9 <0.001
(−0.25–5.50) (−4.38–7.50) (−0.25–5.50) (−4.50–7.50) (−0.25–5.50) (−4.50–7.38) (−0.25–5.50) (−5.00–7.38) (−0.25–5.50) (−5.13–7.38) (−0.25–5.25) (−5.38–7.25) (−1.00–5.00) (−5.50–7.00)

Distance Cover Test 0.00 [0] 0.00 [0] 0.00 [0] 0.00 [0] 0.00 [0] 0.00 [0] 0.00 [0]
(prism diopters) −0.69 ± 1.80 −0.62 ± 1.56 −0.86 ± 0.83 0.23 ± 0.83 −0.38 ± 1.39 −0.38 ± 1.39 0.00 ± 0.00 0.04
(−6–0) (−5–0) (0–3) (0–3) (−5–0) (−5–0) (0–0)

Near Cover Test 0.00 [2.8] 0.00 [3.3] 0.00 [0] 0.00 [0] 0.00 [5] −4.00 [4] 0.00 [2]
(prism diopters) 0.15 ± 3.78 0.23 ± 3.85 −0.62 ± 3.50 −0.62 ± 3.50 −1.69 ± 3.64 −2.62 ± 2.76 −1.23 ± 2.52 0.04
(−10–4.5) (−10–4.5) (−10–6) (−10–6) (−8–4) (−8–0) (−8–0)

2.30 [0.50] 2.10 [0.66] 2.00 [0.69] 2.00 [0.44] 2.08 [0.59] 1.80 [0.14] 1.80 [0.00]
BF 2.52 ± 0.69 2.43 ± 0.75 2.19 ± 0.64 2.01 ± 0.34 2.06 ± 0.33 1.89 ± 0.33 1.85 ± 0.26 <0.001
(1.80–4.00) (1.70–4.00) (1.60–4.00) (1.40–2.70) (1.60–2.70) (1.51–2.70) (1.70–2.70)
Children 2022, 9, 1012 9 of 13

The initial status of the 13 patients with anisometropic amblyopia was as follows: two
patients had flat fusion or simultaneous vision, four had gross stereopsis, and seven had
random fine stereopsis. After the evolution of combined occlusion and vision therapy,
11 patients achieved fine stereopsis and only two coarse stereopsis. After the evolution and
follow-up of one and two years after the end of the treatment, the results of the BF value
were maintained (Figure 3), with the great majority of patients achieving fine stereoacuity
Children 2022, 9, x FOR PEER REVIEW 12 of 16
with bifoveal fixation and three patients still having gross stereopsis. The percentage of
patients with BF > 3.3 decreased significantly from a baseline value of 15.4% to a two-year
follow-up value of 0.0% (p < 0.001).

Figure 3. Binocular function (BF) score evolution of anisometropic amblyopia group from the pre-
Figure 3. Binocular function (BF) score evolution of anisometropic amblyopia group from the
vious visit to 15 days, 30 days, 60 days and 90 days of treatment, as well as at one and two years
previous visit to 15 days, 30 days, 60 days and 90 days of treatment, as well as at one and two years
after completion of treatment.
after completion of treatment.
4.
4. Discussion
Discussion
In
Inthe
thecurrent
currentseries,
series,aacombined
combinedtreatment
treatment of ofocclusion
occlusion and andactive
activevision
visiontherapy
therapyhashas
been shown to improve the visual function in both anisometropic
been shown to improve the visual function in both anisometropic and strabismic amblyopia, and strabismic ambly-
opia, demonstrating
demonstrating thatapproach
that this this approachmay be may be a and
a good goodintegral
and integral
optionoption to provide
to provide a visuala
visual rehabilitation
rehabilitation in amblyopia.
in amblyopia. Although Although some studies
some studies have demonstrated
have demonstrated the ability theofability
patch-
of
ingpatching of providing
of providing some improvements
some improvements in stereopsis
in stereopsis and contrast
and contrast sensitivity sensitivity [23–
[23–25], there
25], there are other options in terms of active visual training that
are other options in terms of active visual training that have also been shown to provide have also been shown to
provide an effective rehabilitation of the binocular function of
an effective rehabilitation of the binocular function of amblyopia, including perceptual amblyopia, including per-
ceptual
learninglearning
training,training, accommodative
accommodative and binocular
and binocular functionfunction
stimulationstimulation [4,5]. How-
[4,5]. However, this
ever,
does this
not does
meannot thatmean that this
this active active
vision vision is
therapy therapy is a substitute
a substitute for patchingfor patching [26].
[26]. Indeed,
Indeed,
previousprevious
experiences experiences
have shown have theshown
benefitthe benefit
of the of the combination
synergistic synergistic combination
of patching and of
patching and vision
vision therapy, leading therapy, leading to
to satisfactory satisfactory
results, even inresults, even treated
those cases in thoseunsuccessfully
cases treated
unsuccessfully
only with patching only with patching
[18,27]. Likewise, [18,27]. Likewise, the
the difference difference
between between
the course the treatment
of the course of
the treatment and
in strabismic in strabismic
anisometropicand anisometropic
amblyopia hasamblyopia been also has been also demonstrated,
demonstrated, with a slower
with a slower
recovery recovery
and the and theofachievement
achievement less degree of of binocular
less degree of binocular
vision visionamblyopia.
in strabismic in strabis-
mic amblyopia.
This was not a comparative study to confirm if vision therapy is better than patching, as
in allThis was not
patients botha treatments
comparative werestudy
usedto inconfirm if visionDifferent
combination. therapy is better than
previous patching,
investigations
as in all patients both treatments were used in combination. Different previous investiga-
have already demonstrated the efficacy and indications of patching or vision therapy
tions have already demonstrated the efficacy and indications of patching or vision therapy
to treat amblyopia [4,5,14,16,23–25,28–41]. However, the results of the combination of
to treat amblyopia
treatments in amblyopia [4,5,14,16,23–25,28–41].
are still scarce [18,27]. However, the results
In the current study, of the combination
a retrospective of
analysis
treatments in amblyopia
of the long-term results of areour
stillclinical
scarce practice
[18,27]. In is the currentby
provided study,
clearlya retrospective
differentiating anal-
the
ysis of the long-term results of our clinical practice is provided by clearly differentiating
the results of anisometropic and strabismic amblyopic patients and filtering the cases in-
cluded, ensuring that none of them had previous ocular surgeries, occlusion or vision
therapy treatments. From our perspective, the report of the results of amblyopia treat-
ments in the long term in order to confirm the recurrence rate and potential predicting
Children 2022, 9, 1012 10 of 13

results of anisometropic and strabismic amblyopic patients and filtering the cases included,
ensuring that none of them had previous ocular surgeries, occlusion or vision therapy
treatments. From our perspective, the report of the results of amblyopia treatments in the
long term in order to confirm the recurrence rate and potential predicting factors for this
situation is especially interesting. The results from our series must be confirmed in future
prospective comparative studies, including randomized clinical trials confirming whether
the combined treatment option provides a significant benefit over the prescription of a
single treatment, occlusion or vision therapy.
The group of strabismic amblyopia in the current series showed improvements in
distance and near visual acuity as well as in the binocular function scoring. The recov-
ery of visual acuity occurred mainly during the first two to three months, whereas the
improvement of the binocular function began at three months and was therefore a later
change. This could be explained due to the sequence of treatment in these cases, including
an initial active and passive monocular stimulation, and the initiation of a binocular phase
once the monocular recovery was significant (around 0.2 logMAR). This phase could be
initiated then after two to three months or more of treatment. Binocular vision training
should be considered as the final part of the treatment in strabismic amblyopia and should
always confirm if a bifoveal fixation was possible (no sensorial adaptations present) [4].
Molina-Martin et al. [18] evaluated the results of the combination of passive and active
treatment for the management of amblyopia in esotropic subjects with accommodative
component. These authors refracted all subjects under cycloplegia and treated them with
occlusion (passive therapy), as in the current series. After a period of adaptation, subjects
not achieving orthotropia with the optical correction performed an active vision therapy
(full-time prismatic correction and subsequent fusional vergence therapy), the performance
of surgery in larger angles (>12 prism diopters) being necessary [18]. A similar protocol
was followed in the current series, but it should be considered that exotropias were also
included in which the optical correction has a minimal effect on ocular alignment. With the
protocol mentioned, Molina-Martin et al. [18] found that all subjects acquired stereoacuity
equal or better than 800”, besides a significant visual acuity improvement. In our series,
there was a small portion of patients (7.1%) remaining with suppression despite experienc-
ing a visual acuity improvement. As mentioned, our series included large angle constant
exotropia cases as well as non-accommodative esotropias, and some of them may have a
worse prognosis. It should be considered that the significant changes detected in the ocular
deviation in our cases of strabismic amblyopia over time was mainly due to the reduction
or elimination of some tropias with surgery.
The group of anisometropic amblyopia responded very favorably to both active vision
therapy and binocular control in the early phases of the treatment, with the achievement of
stereopsis by all patients. This suggests that the prognosis of an efficacious visual rehabili-
tation with the combined treatment described is better in anisometropic amblyopia. This is
consistent with previous research showing significant differences in the neural mechanism
of both types of amblyopia, with significant differences in interhemispheric functional con-
nectivity [42–44]. Indeed, more limited outcomes of dichoptic or binocular therapies have
been reported in those samples of amblyopes including a relevant proportion of strabismic
amblyopes [45]. Although more studies are needed, it is important to consider this when
explaining to patients or parents the prognosis of the treatment of their amblyopia or the
amblyopia of their children. As shown, the achievement or improvement of stereopsis in
anisometropic amblyopia seems to be a common finding among studies [46], but depending
on the specific features of each case, this may be not be possible in strabismic amblyopia.
A careful analysis of each case of strabismic amblyopia must be performed in the clinical
setting to select the most appropriate patient management, combining, in most of cases,
passive and active therapies.
In the last years, a great variety of studies have shown the outcomes of active vision
therapy under dichoptic environments in most of the cases in amblyopia, specially asso-
ciated to anisometropia [28–40]. However, few studies have investigated the potential of
Children 2022, 9, 1012 11 of 13

combining both patching and vision therapy. Our research group published the results
of a retrospective study demonstrating the benefit of a combined therapy of perceptual
learning-based visual training and patching in children with moderate to severe amblyopia
who did not recover vision with patching alone or had poor patching compliance [27]. We
found a significant improvement in visual acuity and contrast sensitivity at one month after
initiating treatment, with a stability of the outcomes during an 18-month follow-up. In our
series, a stability of the outcomes achieved was also found during a two-year follow-up,
confirming that this combined approach of treatment in amblyopia also promotes the
absence of recurrences. Indeed, it should be considered that approximately one fourth of
successfully treated amblyopic children with patching experience a recurrence within the
first year of treatment [47]. Tang et al. [48] conducted a retrospective case series evaluating
the results of patching for amblyopia management in Hong Kong, finding a recurrence rate
of 7% and 46% in children with moderate and severe amblyopia, respectively.
The main limitation of the current study was its retrospective nature without the
inclusion of a control group. Therefore, the results of the study must be considered with
caution, and future randomized clinical trials should be conducted to confirm the outcomes
presented here. Despite this limitation, to our knowledge, this is the series with the longest
follow-up evaluating the results obtained with the combination of passive and active vision
therapy in anisometropic and strabismic amblyopia. Furthermore, another strength of
the study is that the same clinician performed all the evaluations as well as the active
vision therapy sessions, minimizing the potential variability associated to the participation
of different examiners. The use of a treatment protocol adapted to the peculiarities of
each case can be considered as an additional limitation of the study, as the number of
vision therapy sessions or hours of patching prescribed were not the same in all cases.
However, we consider that the treatment in amblyopia must be customized according
to the existing visual limitations, the presence of risk factors of a poor outcome, and the
patient’s motivation and ability to follow the treatment plan. Furthermore, the compliance
of the treatment can be considered as an additional limitation due to the impossibility of
estimating it, as most home exercises were traditional exercises, such as flippers or printed
sheets of tests, whose performance at home is impossible to be controlled. This may explain
some variability among individuals in the time required to achieve a successful outcome.
Finally, a BF score was used that was initially designed based on the Randot Preschool
Stereoacuity Test (RPST) and the Randot Butterfly tests [17]. In contrast, due to technical
limitations, the TNO test was used in our series. This may be considered as a limitation
due to the difference of these tests with the TNO test, although the potential effect of this
fact seems to be limited, considering that the first three pages of the TNO test are screening
and provide a disparity of around 1900 arc sec, and the Randot Butterfly test measures up
to 2000 arcsec.

5. Conclusions
The combination of patching and active vision therapy is an efficacious approach for
achieving an improvement in visual acuity and binocular function in anisometropic and
strabismic amblyopia. However, the recovery achieved seems to be faster in anisometropic
amblyopia, with a slower recovery of the binocular function in strabismic amblyopia if
bifoveal fixation is ensured. Similarly, the results obtained were maintained during a two-
year follow-up without recurrences. These results should be confirmed in future controlled
clinical trials.

Author Contributions: Conceptualization. M.M., D.P.P. and A.M.-M.; methodology. M.M., D.P.P.
and A.M.-M.; formal analysis. M.M., D.P.P. and A.M.-M.; investigation. M.M., D.P.P. and A.M.-M.;
resources. D.P.P.; data curation. M.M., D.P.P. and A.M.-M.; writing—original draft preparation.
M.M.; writing—review and editing. D.P.P. and A.M.-M.; supervision, D.P.P. and A.M.-M.; project
administration. D.P.P.; funding acquisition. D.P.P. All authors have read and agreed to the published
version of the manuscript.
Children 2022, 9, 1012 12 of 13

Funding: The author David P Piñero has been supported by the Ministry of Economy, Industry and
Competitiveness of Spain within the program Ramón y Cajal, RYC-2016-20471. The rest of authors
did not receive external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki. and approved by the Ethics Committee of the University of Alicante (protocol code
UA-2018-03-03 and 03/03/2018).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare that they have no conflicts of interest.

References
1. Scheiman, M.M.; Hertle, R.W.; Kraker, R.T.; Beck, R.W.; Birch, E.E.; Felius, J.; Holmes, J.M.; Kundart, J.; Morrison, D.G.; Repka,
M.X.; et al. Patching vs. atropine to treat amblyopia in children aged 7 to 12 years: A randomized trial. Arch. Ophthalmol. 2008,
126, 1634–1642. [PubMed]
2. Hu, B.; Liu, Z.; Zhao, J.; Zeng, L.; Hao, G.; Shui, D.; Mao, K. The global prevalence of amblyopia in children: A systematic review
and meta-analysis. Front. Pediatr. 2022, 10, 819998. [CrossRef] [PubMed]
3. Barrett, B.T.; Bradley, A.; McGraw, P.V. Understanding the neural basis of amblyopia. Neuroscientist 2004, 10, 106–117. [CrossRef]
[PubMed]
4. Milla, M.; Piñero, D.P. Characterization. passive and active treatment in strabismic amblyopia: A narrative review. Int. J.
Ophthalmol. 2020, 13, 1132–1147. [CrossRef] [PubMed]
5. Hernández-Rodríguez, C.J.; Piñero, D.P. Active Vision Therapy for Anisometropic Amblyopia in Children: A Systematic Review.
J. Ophthalmol. 2020, 2020, 4282316. [CrossRef]
6. Ulrich, K.; Palmowski-Wolfe, A. Comparing three different contrast sensitivity tests in adults and in children with and without
amblyopia. Klin. Mon. Augenheilkd. 2019, 236, 434–437. [CrossRef]
7. Mohammadi, A.; Hashemi, H.; Mirzajani, A.; Yekta, A.; Jafarzadehpur, E.; Valadkhan, M.; Khabazkhoob, M. Contrast and
spatial frequency modulation for diagnosis of amblyopia: An electrophysiological approach. J. Curr. Ophthalmol. 2019, 31, 72–79.
[CrossRef]
8. Niechwiej-Szwedo, E.; Colpa, L.; Wong, A.M.F. Visuomotor behaviour in amblyopia: Deficits and compensatory adaptations.
Neural. Plast. 2019, 2019, 6817839. [CrossRef]
9. Suttle, C.M. Active treatments for amblyopia: A review of the methods and evidence base. Clin. Exp. Optom. 2010, 93, 287–299.
[CrossRef]
10. Miller, J.R.; Cibis, L. Clinical results with active amblyopia treatments. Am. Orthopt. J. 1960, 10, 28–32. [CrossRef]
11. Dosher, B.; Lu, Z.L. Visual perceptual learning and models. Ann. Rev. Vis. Sci. 2017, 15, 343–363. [CrossRef]
12. Levi, D.M.; Li, R.W. Perceptual learning as a potential treatment for amblyopia: A mini-review. Vis. Res. 2009, 49, 2535–2549.
[CrossRef]
13. Kraus, C.L.; Culican, S.M. New advances in amblyopia therapy I: Binocular therapies and pharmacologic augmentation. Br. J.
Ophthalmol. 2018, 102, 1492–1496. [CrossRef]
14. Žiak, P.; Holm, A.; Halička, J.; Mojžiš, P.; Piñero, D.P. Amblyopia treatment of adults with dichoptic training using the virtual
reality oculus rift head mounted display: Preliminary results. BMC Ophthalmol. 2017, 17, 105. [CrossRef]
15. West, S.; Williams, C. Amblyopia. BMJ Clin. Evid. 2011, 2011, 0709.
16. Pediatric Eye Disease Investigator Group; Wallace, D.K.; Lazar, E.L.; Holmes, J.M.; Repka, M.X.; Cotter, S.A.; Chen, A.M.; Kraker,
R.T.; Beck, R.W.; Clarke, M.P.; et al. A randomized trial of increasing patching for amblyopia. Ophthalmology 2013, 120, 2270–2277.
[CrossRef]
17. Webber, A.L.; Wood, J.M.; Thompson, B.; Birch, E.E. From suppression to stereoacuity: A composite binocular function score for
clinical research. Ophthalmic Physiol. Opt. 2019, 39, 53–62. [CrossRef]
18. Molina-Martín, A.; Martín-González, S.; Illarramendi-Mendicute, I.; Portela-Camino, J.A. Combined passive and active treatment
in strabismic amblyopia with accommodative component. Clin. Exp. Optom. 2020, 103, 885–894. [CrossRef]
19. Flom, M.C. The prognosis in strabismus. Am. J. Optom. Arch. Acad. Optom. 1958, 35, 509–514. [CrossRef]
20. Portela-Camino, J.A.; Martín-González, S.; Ruiz-Alcocer, J.; Illarramendi-Mendicute, I.; Garrido-Mercado, R. A random dot
computer video game improves stereopsis. Optom. Vis. Sci. 2018, 95, 523–535. [CrossRef]
21. Walsh, L.A.; Hahn, E.K.; LaRoche, G.R. The method of treatment cessation and recurrence rate of amblyopia. Strabismus 2009, 17,
107–116. [CrossRef]
22. Dupont, W.D.; Plummer, W.D. Power and sample size calculations: A review and computer program. Control. Clin. Trials 1990,
11, 116–128. [CrossRef]
23. Chinn, R.N.; Michalak, S.M.; Shoshany, T.N.; Bishop, K.; Staffa, S.J.; Hunter, D.G. Effect of sequential and simultaneous patching
regimens in unilateral amblyopia. Am. J. Ophthalmol. 2022, 233, 48–56. [CrossRef]
Children 2022, 9, 1012 13 of 13

24. Scaramuzzi, M.; Murray, J.; Nucci, P.; Shaikh, A.G.; Ghasia, F.F. Fixational eye movements abnormalities and rate of visual acuity
and stereoacuity improvement with part time patching. Sci. Rep. 2021, 11, 1217. [CrossRef]
25. Rajavi, Z.; Sabbaghi, H.; Amini Sharifi, E.; Behradfar, N.; Kheiri, B. Comparison between patching and interactive binocular
treatment in amblyopia: A randomized clinical trial. J. Curr. Ophthalmol. 2019, 31, 426–431. [CrossRef]
26. Pineles, S.L.; Aakalu, V.K.; Hutchinson, A.K.; Galvin, J.A.; Heidary, G.; Binenbaum, G.; VanderVeen, D.K.; Lambert, S.R. Binocular
treatment of amblyopia: A report by the American Academy of Ophthalmology. Ophthalmology. 2020, 127, 261–272. [CrossRef]
27. Hernández-Rodríguez, C.J.; Fukumitsu, H.; Ruiz-Fortes, P.; Soto-Negro, R.; Merino-Suárez, M.; Piñero, D.P. Efficacy of perceptual
learning-based vision training as an adjuvant to occlusion therapy in the management of amblyopia: A pilot study. Vision 2021, 5,
15. [CrossRef]
28. Xiao, S.; Angjeli, E.; Wu, H.C.; Gaier, E.D.; Gomez, S.; Travers, D.A.; Binenbaum, G.; Langer, R.; Hunter, D.G.; Repka, M.X.
Luminopia Pivotal Trial Group. Randomized controlled trial of a dichoptic digital therapeutic for amblyopia. Ophthalmology 2022,
129, 77–85. [CrossRef]
29. Huang, Y.T.; Lin, H.J.; Liao, W.L.; Tsai, Y.Y.; Hsieh, Y.C. Effects of vision therapy on bilateral amblyopia unresponsive to
conventional treatment: A retrospective comparative study. Children 2022, 9, 205. [CrossRef]
30. Manny, R.E.; Holmes, J.M.; Kraker, R.T.; Li, Z.; Waters, A.L.; Kelly, K.R.; Kong, L.; Crouch, E.R.; Lorenzana, I.J.; Alkharashi, M.S.;
et al. Pediatric Eye Disease Investigator Group. A randomized trial of binocular Dig Rush game treatment for amblyopia in
children aged 4 to 6 years. Optom. Vis. Sci. 2022, 99, 213–227.
31. Jost, R.M.; Hudgins, L.A.; Dao, L.M.; Stager, D.R., Jr.; Luu, B.; Beauchamp, C.L.; Hunter, J.S.; Giridhar, P.; Wang, Y.Z.; Birch, E.E.
Randomized clinical trial of streaming dichoptic movies versus patching for treatment of amblyopia in children aged 3 to 7 years.
Sci. Rep. 2022, 12, 4157. [CrossRef] [PubMed]
32. Xiao, S.; Gaier, E.D.; Wu, H.C.; Angjeli, E.; Nuth, P.L.; Bohra, L.I.; Miller, A.M.; Mazow, M.L.; Stout, A.U.; Morse, C.L.; et al. Digital
therapeutic improves visual acuity and encourages high adherence in amblyopic children in open-label pilot study. J. AAPOS
2021, 25, 87.e1–87.e6. [CrossRef] [PubMed]
33. Pang, P.C.K.; Lam, C.S.Y.; Hess, R.F.; Thompson, B. Effect of dichoptic video game treatment on mild amblyopia—A pilot study.
Acta Ophthalmol. 2021, 99, e423–e432. [CrossRef] [PubMed]
34. Raveendran, R.N.; Krishnan, A.K.; Thompson, B. Reduced fixation stability induced by peripheral viewing does not contribute to
crowding. J. Vis. 2020, 20, 3. [CrossRef]
35. Birch, E.E.; Jost, R.M.; De La Cruz, A.; Kelly, K.R.; Beauchamp, C.L.; Dao, L.; Stager, D., Jr.; Leffler, J.N. Binocular amblyopia
treatment with contrast-rebalanced movies. J. AAPOS 2019, 23, 160.e1–160.e5. [CrossRef]
36. Jia, W.; Lan, F.; Zhao, X.; Lu, Z.L.; Huang, C.B.; Zhao, W.; Li, M. The effects of monocular training on binocular functions in
anisometropic amblyopia. Vis. Res. 2018, 152, 74–83. [CrossRef]
37. Mezad-Koursh, D.; Rosenblatt, A.; Newman, H.; Stolovitch, C. Home use of binocular dichoptic video content device for treatment
of amblyopia: A pilot study. J. AAPOS 2018, 22, 134–138.e4. [CrossRef]
38. Bossi, M.; Tailor, V.K.; Anderson, E.J.; Bex, P.J.; Greenwood, J.A.; Dahlmann-Noor, A.; Dakin, S.C. Binocular therapy for childhood
amblyopia improves vision without breaking interocular suppression. Investig. Ophthalmol. Vis. Sci. 2017, 58, 3031–3043.
[CrossRef]
39. Li, S.L.; Reynaud, A.; Hess, R.F.; Wang, Y.Z.; Jost, R.M.; Morale, S.E.; De La Cruz, A.; Dao, L.; Stager, D., Jr.; Birch, E.E. Dichoptic
movie viewing treats childhood amblyopia. J. AAPOS 2015, 19, 401–405. [CrossRef]
40. Birch, E.E.; Li, S.L.; Jost, R.M.; Morale, S.E.; De La Cruz, A.; Stager, D., Jr.; Dao, L.; Stager, D.R., Sr. Binocular iPad treatment for
amblyopia in preschool children. J. AAPOS 2015, 19, 6–11. [CrossRef]
41. Agervi, P.; Kugelberg, U.; Kugelberg, M.; Zetterström, C. Two-year follow-up of a randomized trial of spectacles plus alternate-day
patching to treat strabismic amblyopia. Acta Ophthalmol. 2013, 91, 678–684. [CrossRef]
42. Wong-Kee-You, A.M.B.; Wei, H.; Hou, C. Feature counting under dichoptic viewing in anisometropic and strabismic amblyopia.
Transl. Vis. Sci. Technol. 2020, 9, 13. [CrossRef]
43. Liang, M.; Xie, B.; Yang, H.; Yin, X.; Wang, H.; Yu, L.; He, S.; Wang, J. Altered interhemispheric functional connectivity in patients
with anisometropic and strabismic amblyopia: A resting-state fMRI study. Neuroradiology. 2017, 59, 517–524. [CrossRef]
44. Agrawal, R.; Conner, I.P.; Odom, J.V.; Schwartz, T.L.; Mendola, J.D. Relating binocular and monocular vision in strabismic and
anisometropic amblyopia. Arch. Ophthalmol. 2006, 124, 844–850. [CrossRef]
45. Herbison, N.; MacKeith, D.; Vivian, A.; Purdy, J.; Fakis, A.; Ash, I.M.; Cobb, S.V.; Eastgate, R.M.; Haworth, S.M.; Gregson, R.M.;
et al. Randomised controlled trial of video clips and interactive games to improve vision in children with amblyopia using the
I-BiT system. Br. J. Ophthalmol. 2016, 100, 1511–1516. [CrossRef]
46. Boniquet-Sanchez, S.; Sabater-Cruz, N. Current management of amblyopia with new technologies for binocular treatment. Vision
2021, 5, 31. [CrossRef]
47. Holmes, J.M.; Beck, R.W.; Kraker, R.T.; Astle, W.F.; Birch, E.E.; Cole, S.R.; Cotter, S.A.; Donahue, S.; Everett, D.F.; Hertle, R.W.; et al.
Pediatric Eye Disease Investigator Group. Risk of amblyopia recurrence after cessation of treatment. J. AAPOS 2004, 8, 420–428.
48. Tang, E.W.; Li, B.C.; Yeung, I.Y.; Li, K.K. Occlusion therapy in amblyopia: An experience from Hong Kong. Hong Kong Med. J.
2014, 20, 32–36. [CrossRef]