An Eye-TrackingeBased Dichoptic Home

Treatment for Amblyopia

A Multicenter Randomized Clinical Trial
Tamara Wygnanski-Jaffe, MD,1,2 Burton J. Kushner, MD,3 Avital Moshkovitz, PhD,4 Michael Belkin, MD,2,5
Oren Yehezkel, PhD,4 on behalf of the CureSight Pivotal Trial Group

Purpose: Comparing visual outcomes after use of a novel binocular eye-trackingebased home treatment
(CureSight; NovaSight, Ltd) with patching.
Design: Prospective, multicenter, randomized, masked, controlled, noninferiority pivotal trial.
Participants: One hundred three children 4 to < 9 years with anisometropic, small-angle strabismic or
mixed-mechanism amblyopia were randomized 1:1 to either CureSight treatment or patching.
Methods: The CureSight treatment uses combined anaglyph glasses and an eye tracker to induce real-time
blur around the fellow eye fovea in dichoptic streamed video content. Participants used the device for 90 minutes/
day, 5 days/week for 16 weeks (120 hours). The patching group received 2 hours of patching 7 days/week (224
hours). The prespecified noninferiority margin was 1 line.
Main Outcome Measures: The primary outcome was the improvement in the amblyopic eye visual acuity
(VA), modeled with a repeated measures analysis of covariance. Secondary outcomes included stereoacuity,
binocular VA, and treatment adherence rates, analyzed by a 1-sample Wilcoxon test within each group and a 2-
sample Wilcoxon test comparing groups. Safety outcomes included the frequency and severity of study-related
adverse events (AEs).
Results: CureSight group VA improvement was found to be noninferior to patching group improvement (0.28

0.13 logarithm of the minimum angle of resolution [logMAR] [P < 0.0001] and 0.23
0.14 logMAR [P < 0.0001],
respectively; 90% confidence interval [CI] of difference, e0.008 to 0.076). Stereoacuity improvement of 0.40 log
arcseconds (P < 0.0001) and improved binocular VA (0.13 logMAR; P < 0.0001) were observed in the binocular
treatment group, with similar improvements in the patching group in stereoacuity (0.40 log arcseconds;
P < 0.0001) and binocular VA (0.09 logMAR; P < 0.0001), with no significant difference between improve-
ments in the 2 groups in either stereoacuity (difference, 0; 95% CI, e0.27 to e0.27; P ¼ 0.76) or binocular VA
(difference, 0.041; 95% CI, e0.002 to 0.085; P ¼ 0.07). The binocular treatment group had a significantly higher
adherence than the patching group (91% vs. 83%; 95% CI, e4.0% to 21%; P ¼ 0.011). No serious AEs were
found.
Conclusions: Binocular treatment was well tolerated and noninferior to patching in amblyopic children 4 to
< 9 years of age. High adherence may provide an alternative treatment option for amblyopia.
Financial Disclosure(s): Proprietary or commercial disclosure may be found after the
references. Ophthalmology 2023;130:274-285 ª 2022 by the American Academy of Ophthalmology. This is an
open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Supplemental material available at www.aaojournal.org.

Amblyopia can have a substantial impact on quality of life, Patching6), residual amblyopia, and recurrence of
with estimates of prevalence ranging from 1% to 5%. amblyopia (reported to be approximately 25% of patients),
Associated deficits involve contrast sensitivity, fixation, even after successful treatment, in addition to adverse
stereopsis, and binocularity,1e6 which may result in poor psychological effects.10e12
academic performance.7 The conventional amblyopia Over the last decade, binocular amblyopia therapy with
treatment is optical correction of the uncorrected refractive dichoptic presentation has been developed as an alterna-
error, followed by part-time monocular deprivation by tive treatment approach with the potential benefit of
patching or penalizing the fellow eye to force the visual improved adherence and better outcomes. Novel binocular
system to use the amblyopic eye.1,8,9 The limitations of this treatments with dichoptic presentation adjust the visual
treatment include poor adherence (44%e57% for stimuli between the amblyopic and fellow eye,

274 ª 2022 by the American Academy of Ophthalmology https://doi.org/10.1016/j.ophtha.2022.10.020

This is an open access article under the CC BY license (http://creativecommons. ISSN 0161-6420/22
org/licenses/by/4.0/).Published by Elsevier Inc.
 Wygnanski-Jaffe et al 
CureSight Amblyopia Treatment

consequently reducing interocular suppression.13e20 New Participants

approaches that quantify the degree of interocular sup-
Participants diagnosed with amblyopia were recruited prospec-
pression, tested on large samples of patients with ambly- tively from the outpatient clinics of the participating centers. Par-
opia, demonstrated a direct relationship between the ticipants were enrolled beginning August 18, 2020; the last
strength of suppression and the depth of amblyopia.19 participant completed the 16-week visit on February 15, 2022. The
Dichoptic therapy has shown promise in pilot key entry criteria were amblyopia associated with small-angle
studies15e18 and has been evaluated in randomized strabismus, anisometropia, or both (a combined mechanism) in
controlled trials (RCTs)14,21e26 with mixed results. The children 4 to younger than 9 years, with a best-corrected visual
efficacy of dichoptic therapy was demonstrated success- acuity (BCVA) of 20/32 to 20/100 in the amblyopic eye, a fellow
fully in a few large multicenter RCTs performed versus eye BCVA of 20/40 or better for those 4 to 5 years of age, and a
continued spectacle correction.14,21,24,26,27 However, to BCVA of 20/32 or better for those between 5 and 7 years of age,
the best of our knowledge, no previous multicenter, with an interocular difference of 2 lines or more. Strabismus was
limited to tropia of 5 prism diopters or less measured by the
long-term RCT that compared dichoptic therapy with simultaneous prism and cover test at near fixation or heterophoria
patching found dichoptic therapy to be either noninferior up to 10 prism diopters measured by the prism alternate cover test.
or superior to patching. The need for stronger evidence to Participants were required to have stable visual acuity (VA) in their
support the use of binocular treatment as an alternative for best refractive correction before enrollment, defined as wearing the
currently accepted therapies has been recognized by the same glasses for 16 weeks or more or until 2 consecutive VA
American Academy of Ophthalmology.28 CureSight measurements in the amblyopic eye 8 weeks apart did not change
(NovaSight, Ltd) is a novel investigational digital by > 1 line. Anisometropia was defined as an interocular differ-
dichoptic device for binocular home treatment of ence of at least 1.00 diopter in spherical equivalent, at least 1.50
amblyopia based on passive watching of video content. diopters in astigmatism, or both. Both treatment-naive and previ-
The treatment algorithm blurs the central vision of the ously treated patients (i.e., patching, atropine penalization) were
allowed. The list of inclusion and exclusion criteria is presented in
nonamblyopic (fellow) eye in real time using continuous Table 1.
gaze tracking and is less obtrusive than conventional
patching. This approach is designed to encourage
adherence by allowing an unlimited choice of streamed CureSight System
video content that caters to a child’s preference for an CureSight is an eye-trackingebased system designed to treat
enjoyable home treatment. No limitations are imposed amblyopia under dichoptic conditions that incorporates eye-gaze
on which websites or streaming content can be used for tracking and separation of streamed visual stimuli presented on a
training, as long as the link for the specific website is monitor into 2 separate digital channels, one for each eye (the
included in the device and is not blocked through the CureSight device was an investigational device when this study
parental control function by the guardians. A monitoring was performed and received a Food and Drug Administration
center remotely tracks adherence and offers technical clearance based on the outcomes of this study [identifier, K221375;
September 29, 2022]). The treatment task consists of passively
support and advice with respect to adherence as needed. watching streamed video content presented by the system accord-
After the initial results from a single-arm pilot study that ing to the child’s personal preference from the web links approved
showed significant improvements in amblyopic eye acuity by the parents. The main components of the system include the
and stereoacuity,29 the visual outcomes after use with the following: (1) a computer with an 11.6-inch monitor used for
CureSight device were evaluated in a multicenter RCT for stimulus presentation, (2) an eye tracker that allows the continuous
16 weeks compared with part-time daily patching in chil- tracking of each eye gaze position, (3) anaglyph glasses worn
dren 4 to younger than 9 years with amblyopia associated during the treatment to separate stimuli presented to each eye (Fig
with anisometropia, small-angle strabismus, or both. 1), and (4) proprietary software that uses the eye-tracking data to
blur the central vision area of the visual stimuli presented to the
nonamblyopic eye to encourage the brain to use the sharp, high-
Methods resolution information from the amblyopic eye’s center of vision.
The diameter and magnitude of the blur are adjusted automatically
during treatment according to the VA of each eye, as measured at
Study Design
periodic follow-up visits at the clinic and registered on the Cure-
The study was a prospective, multicenter, randomized (1:1), Sight cloud portal. Worse amblyopic eye distance VA and greater
evaluator-masked controlled trial conducted at 6 academic and differences in VA between eyes result in greater blur amplitudes
community sites in Israel (Goldschleger Eye Institute, Sheba and greater diameters being applied. The system includes a Health
Medical Center, Tel Hashomer; Kaplan Medical Center, Rehovot; Insurance Portability and Accountability Acte and General Data
Maccabi Healthcare; Rambam Health Care Campus, Haifa; Shaare Protection Regulationecompliant cloud web application that al-
Zedek Medical Center, Jerusalem; and Soroka University Medical lows an eye care provider and the dedicated monitoring center to
Center, Beer Sheva). The study was placed on a national registry track the child’s adherence and to intervene or provide technical
(identifier, MOH_2020-08-10_009227; available at: https:// support when needed.
my.health.gov.il/CliniTrials/Pages/MOH_2020-08-10_009227.
aspx) and listed on ClinicalTrials.gov (identifier, NCT05185076). Procedure
The study adhered to the tenets of the Declaration of Helsinki,
institutional review board or ethics committee approval at all Each participant was assigned randomly to either the binocular
participating sites, and the parents or guardians of study partici- treatment group or the control patching group using a permuted
pants provided written informed consent before any study block design stratified by site with a 1:1 allocation ratio.
procedures. Randomization was conducted by the principal investigator or

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Table 1. Eligibility Criteria

Inclusion criteria
The participants met all of the following inclusion criteria to be eligible for the study:
1. Age 4 to < 9 years, male and female
2. Amblyopia associated with strabismus, anisometropia, or both (untreated or previously treated) meeting 1 of the following conditions:
 Newly diagnosed amblyopia (no prior treatment)
 Prior amblyopia treatment must have been discontinued with no treatment administered for a minimum of 8 wks before the screening visit
a. Criteria for strabismic amblyopia (at least 1 of the following must be met):
 The presence of heterotropia on examination at distance or near fixation (with or without optical correction; up to 5 PD by SPCT
at near fixation)
 A documented history of strabismus that is no longer present
b. Criteria for anisometropia (at least 1 of the following criteria must be met):
  1.00-D difference between eyes in SE
  1.50-D difference in astigmatism between the corresponding meridians in the 2 eyes
c. Criteria for a combined-mechanism amblyopia (both of the following criteria must be met):
 Criteria for strabismus
  1.00-D difference between eyes in a SE or  1.50-D difference in astigmatism between the corresponding meridians in the 2 eyes
3. Refractive error correction (based on a cycloplegic refraction completed within the previous 7 mos) if any of the following are true*:
 Hypermetropia of  2.50 D by SE
 Myopia of the amblyopic eye of  0.50 D
 Astigmatism of  1.00 D
 Anisometropia of > 0.50 D
a. Spectacle-prescribed instructions in reference to the cycloplegic refraction must have been completed within the previous 7 months:
 SE must be within 0.50 D of fully correcting the anisometropia
 SE must not be undercorrected by > 1.50 D SE, and a reduction in the plus sphere must be symmetric in both eyes
 The cylinder power in both eyes must be within 0.50 D of fully correcting the astigmatism
 The axis must be within
10 if the cylinder power is  1.00 D and within
5 if the cylinder power is > 1.00 D
 Myopia must not be undercorrected by > 0.25 D or overcorrected by > 0.50 D SE, and any change must be symmetrical in both eyes
b. Spectacle correction meeting the above criteria must be adhered to:
 For at least 16 wks or until distance VA stability is documented (defined as < 0.1 logMAR change by the same testing method measured on 2
consecutive examinations at least 8 wks apart)
 For determining VA stability (nonimprovement)y:
 The first of 2 measurements may be made (1) in the current spectacles, or (2) in trial frames with or without cycloplegia, or (3) without correction
(if a new correction is prescribed)
 The second measurement must be made without cycloplegia in corrected spectacles that have been worn for at least 8 wks
4. VA, measured in each eye without cycloplegia in the current spectacle correction (if applicable) within 7 days before randomization using the Lea
symbol per ATS VA protocol for children younger than 7 yrs and the E-ETDRS VA protocol for children 7 yrs of age or older on a study-approved
device displaying single surrounded optotypes was as follows:
a. VA in the amblyopic eye of 20/32 to 20/100 inclusive
b. Best-corrected fellow eye VA meeting the following criteria:
 If 4 yrs of age, 20/40 or better by Lea symbols per ATS protocol
 If 5 yrs of age or older, 20/32 or better by ATS HOTV using LEA symbols for age younger than 7 yrs and Lea numbers for age older than 7 yrs
c. Interocular difference of  2 logMAR lines (Lea symbols per ATS protocol)
5. Heterotropia with a near deviation of < 5 PD (measured by SPCT) in habitual correction (angles of ocular deviation of > 4 PD are not allowed
because the large magnitudes of the deviation would compromise successful alignment of the dichoptic stimuli)z
6. Passing a dedicated 10-minute in-clinic performance ability test to assure suitable eye-tracking performance
7. Patients and families eligible for clinic visits during the course of the study
8. Patients in general good health and able, as per investigator determination, to comply with the study visits and protocol procedures, to wear refractive
correction, and who have access to wireless internet service at home that is able to support the CureSight treatment (loaned by the sponsor)
9. A signed and dated informed consent form
10. Parents and participants understand, and are willing to comply with, the study procedures and are available for the duration of the study
Exclusion criteria
Individuals with any of the following characteristics were excluded from the study:
1. Myopia > e6.00 D SE in either eye
2. Known skin reactions to patch or bandage adhesives
3. Any other condition that could be a potential cause for reduced BCVA according to the investigator
4. Severe developmental delay that would interfere with treatment or evaluation (in the opinion of the investigator); patients with mild speech delay or
reading or learning disabilities, or both, are not excluded
5. History of low adherence with amblyopia treatment, as assessed informally by the investigator
6. Patients who do not wear their spectacles (as assessed by investigator)
7. A history of light-induced seizures
8. Wearing rigid gas permeable contact lenses
9. Any reported anatomic ocular anomaly (e.g., a small lens opacity, a myelinated nerve fiber layer)
10. Previous intraocular or refractive surgery
11. Any condition that prevents the patient from completing a continuous treatment for 45 to 90 minutes daily while seated in front of a near screen,
which includes children who do not like or cannot watch TV or movies for > 60 minutes every day according to the parent’s report
12. Heterophoria with a total near deviation of  10 PD (measured by PACT)

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ATS ¼ Amblyopia Treatment Study; BCVA ¼ best-corrected visual acuity; D ¼ diopter; E-ETDRS ¼ electronic Early Treatment for Diabetic Retinopathy
Study; logMAR ¼ logarithm of the minimum angle of resolution; PACT ¼ prism alternate cover test; PD ¼ prism diopter; SE ¼ spherical equivalent;
SPCT ¼ simultaneous prism and cover test; VA ¼ visual acuity.
*Patients with cycloplegic refractive errors that do not fall within the requirements noted for spectacle correction may be given spectacles at the in-
vestigator’s discretion but must follow the study-specified prescribed guidelines, as detailed elsewhere in the table.
y
Because this determination was a prestudy procedure, the method of measuring VA was not mandated.
z
Heterotropia of  5 PD at near, as measured by SPCT, was allowed for inclusion in the study (although the protocol text reads < 5 PD). This is specified
correctly in the study definition for strabismic amblyopia in criterion 2a.

study coordinator at each site using the secure electronic data enrollment was used throughout the study, regardless of the age
capture, web-based computer software. Allocation concealment at follow-up. Stereoacuity was assessed using the Randot Pre-
was achieved by keeping the randomization sequences hidden. school Stereoacuity test (Stereo Optical Co, Inc) at near (0.4 m).
Examiners who performed primary outcome measurements were A simultaneous prism and cover test and prism alternate cover
masked to the treatment group assignments at all follow-up visits. test were used to measure the ocular alignment. Adherence was
Patients assigned to the binocular treatment group were pre- monitored objectively by analyzing the treatment logs of screen
scribed the CureSight home treatment for 90 minutes per day, 5 gaze as recorded by the eye tracker for the binocular treatment
days per week for 16 weeks for a total of 120 hours. At the group and was calculated using the guardians’ manual self-
beginning of each session, a positioning algorithm automatically reported logs for the patching group. At the end of treatment
guided the child to sit at the optimal position for treatment (at a (16 weeks), visiting patients’ treatment satisfaction was assessed
viewing distance of approximately 60 cm). As soon as optimal using a questionnaire.
positioning was achieved, a brief eye-tracking calibration was
performed. Patients assigned to the patching control group were Outcomes
instructed to wear an adhesive patch (Ortopad; Pietrasanta Pharma)
over the fellow eye for 2 hours per day, 7 days per week for 16 The primary effectiveness outcome was defined as the mean
weeks (for a total of 224 hours). improvement from baseline in amblyopic eye VA to week 16 in
Outcome assessments were performed at weeks 4, 8, 12, and 16 both study groups (a noninferiority of no more than 0.10 logMAR).
(
1 week). Outcome measures comprised the Amblyopia Treat- Secondary and additional outcomes included the change from
ment Study diplopia assessment and a symptom survey (5-question baseline to week 16 in the stereoacuity test score, the amblyopic
ocular symptom survey from the Amblyopia Treatment Study eye near VA, the binocular VA, and the binocular near VA. Safety
Miscellaneous Testing Procedures Manual30); masked examiners was evaluated by the frequency, severity, and causality of adverse
performed distance VA and stereoacuity testing. events (AEs). Adverse events were captured using a protocol-
Monocular and binocular VA testing was performed using defined questionnaire of parents and participants for diplopia,
CTS software (M&S Technologies). Participants 7 years of age or headaches, and eye strain and the examination data for new or
older underwent VA assessment by the electronic Early Treat- worsening heterotropia (an increase of  10 prism diopters from
ment for Diabetic Retinopathy Study (E-ETDRS) protocol31 baseline), worsening of VA in either eye (a decrease of  2 lines
using Lea numbers optotype, whereas participants 4 to younger from baseline), and seizures. The mean change in the fellow eye
than 7 years of age were assessed by the HOTV protocol31 BCVA from baseline to week 16 also was compared between
using Lea symbols optotype.32 The same VA protocol used at groups.

Step 1: Step 2:
Anaglyph color conversion Central blur illustration
Large diameter, high amplitude Small diameter, low amplitude
Fellow eye channel

Amblyopic eye Fellow eye

channel channel

Amblyopic eye channel

Figure 1. Diagram showing binocular treatment setup. Step 1: Streamed visual stimuli is converted into 2 anaglyph separate channels, blue for the
amblyopic eye and red for the fellow eye, and are presented superimposed. Step 2: Illustration of the blurred fellow eye channel (red) central visual area, a
high-diameter blur area with a high amplitude blur (left) and a small-diameter blur area with a low blur amplitude (right). The amblyopic eye channel is not
affected by the blur.

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Statistical Analyses The treatment group-by-site interaction was evaluated as well

for assessment of the ability to be pooled, which confirmed that the
The statistical analysis plan was established a priori. The sample primary outcome data could be pooled across sites (Table S2,
size for the study was calculated for the primary effectiveness end available at www.aaojournal.org). Secondary end points were
point. A sample size of 90 patients was calculated (45 per arm) to analyzed with a 1-sample t test or a 1-sample Wilcoxon test for
test the null hypothesis with 90% power at a 1-sided 5% level of within-group comparisons and a 2-sample t test sample or a 2-
significance based on a t test of the noninferiority using a pre- sample Wilcoxon test to compare groups, depending on data dis-
specified noninferiority margin of e0.1 logMAR, assuming a dif- tribution. Analyses were performed using SAS software version,
ference between the groups of zero (0) and a standard deviation 9.4 (SAS Institute, Inc).
(SD) of 0.16 logMAR. After adjusting for an approximately 20% Stereoacuity was measured in current correction. For analysis,
dropout, a total of up to 114 (57 per arm) patients were to be nil stereoacuity measurements were scored as 10 000 arc
recruited. We planned to use a sample size adaptive design seconds.33
(promising zone approach), which allowed for 1 interim analysis One interim analysis was planned after 90% of the original
after approximately 80 patients were recruited into the study. Based sample size was randomized to the study and had completed the
on the conditional power at the interim analysis (of the primary end 16-week follow-up period, in addition to those patients who were
point), the study either would continue to the originally planned terminated from the study early. The interim analysis included an
sample size if the results were favorable, would stop for futility if analysis of the primary efficacy end point and allowed for early
the results were unfavorable, or would increase the sample size to cessation of the study only for futility. The interim analysis was
the maximum sample size of 200 patients or the recalculated value, performed in December 2021 by the independent external statis-
whichever was lower, if the results were promising. Following this tician, who was contracted solely for this purpose, and consisted of
principle does not inflate the type I error. the data from 87 patients. Based on the conditional power for the
The overall a level for this study was 5%. The primary end primary outcome at the interim analysis, the data monitoring
point was be tested with a 1-sided 95% confidence interval (CI). committee and the unmasked independent statistician recom-
All other tests were tested at a 5% level of significance using 2- mended continuing the trial with the original sample size planned
tailed tests, except for the treatment-by-site interaction that was for 90 patients, without the need to increase the sample size
tested at a significance level of 15%. The hierarchy approach was adaptively. The data monitoring committee report with the decision
adopted for the primary and secondary end points to control a type to proceed to the original sample size of 90 patients was signed on
I error resulting from multiple end point testing. Thus, the primary January 2, 2022. Final database lock was performed on February
end point was analyzed first, and only if it was successful were the 24, 2022, with 95 evaluable patients.
secondary end points analyzed. Safety analyses were performed on
the intention-to-treat (ITT) population, and effectiveness analyses
were performed on the modified ITT (mITT) population, which Results
was prespecified in the protocol to consist of all randomized pa-
tients who also retrospectively met the inclusion criteria of the Between August 18, 2020, and February 15, 2022, 103 children
protocol; effectiveness analyses also were performed on the ITT with amblyopia were randomized to 1 of 2 treatment groups:
and per-protocol sets as sensitivity analyses. The improvement binocular treatment (n ¼ 51) and patching (n ¼ 52; Fig 2). Ninety-
from baseline in amblyopic eye VA (in LogMAR) to 16 weeks was five of the 103 participants had available 16-week outcome data
compared between the treatment groups using repeated measures and were included in the primary analysis. The groups were similar
analysis of covariance (SAS MIXED procedure; SAS Institute, in age (binocular treatment group, 6.6
1.3 years; patching group,
Inc). The model included the following fixed effects: treatment 6.9
1.4 years). Fifty percent of the overall participants were
group, visit (4, 8, 12, and 16 weeks as a categorical variable), and female. Those who had not received prior patching treatment or
the treatment group-by-visit interaction term, which is the param- atropine penalization were evenly distributed (51%). Most partic-
eter of interest. Baseline amblyopic eye VA, age (as a continuous ipants had a diagnosis of anisometropic amblyopia (92%). Table 3
variable), and site (as a categorical random effect) were entered as summarizes the demographics and baseline characteristics overall
covariates. Baseline amblyopic eye VA was entered as a contin- and per group.
uous variable so that the potential for colinearity problems would
be minimized. No differential dropout occurred between the Primary Effectiveness Outcomes (mITT
treatment groups; thus, any missing data at the 16-week time point Population)
most likely can be considered missing at random. Because
likelihood-based repeated measures analysis of variance also is an At baseline, the mean
SD amblyopic eye VAs in the binocular
imputation method, for this evaluation, no other method of impu- and patching treatment groups were 0.37
0.15 logMAR and 0.37
tation of missing data was considered beyond the model estimates.
0.14 logMAR, respectively. The mean
SD improvement from
The principal statistical analysis was a comparison between the baseline at 16 weeks was 0.28
0.13 logMAR in the binocular
treatment groups, derived from the visit-by-treatment group inter- treatment group (P < 0.0001) and 0.23
0.14 logMAR in the
action term from the model. The adjusted mean (least squares [LS] patching group (P < 0.0001; Fig 3).
mean) improvement from baseline in amblyopic eye VA at the 16- The study met its primary effectiveness end point of non-
week visit was estimated from the model interaction term per group inferiority of improvement in amblyopic eye VA in the binocular
(with 2-sided 95% CIs) and for the difference between the groups treatment group compared with the patching group. At 16 weeks,
(CureSight minus patching), which was presented with 1-sided the LS mean change from baseline was 0.26 logMAR (standard
95% CI (equivalent to 2-sided 90% CI), which was used as the error, 0.02 logMAR) in the binocular treatment group and 0.23
prespecified method for testing the noninferiority hypothesis. The logMAR (standard error, 0.02 logMAR) in the patching group
null hypothesis was rejected if the lower limit of the 1-sided 95% (Table S4, available at www.aaojournal.org). The difference
CI of the LS mean difference in amblyopic eye VA between the between groups in LS mean improvement from baseline at 16
treatment groups (binocular treatment minus patching) at week 16 weeks was 0.034 logMAR (90% CI, e0.008 to 0.076 logMAR;
was more than the noninferiority margin fixed at e0.10 logMAR. Table S4), fulfilling the success criterion of noninferiority in

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relation to control participants within a margin of e0.1 logMAR. Safety Outcomes (ITT Population)
These findings were consistent in the per-protocol and ITT pop-
ulations as well (Table S4). Amblyopic eye VA demonstrated a No serious AEs and no unanticipated AEs occurred in the study.
statistically significant improvement in both treatment groups Nonserious AEs were reported in 27% of patients (14/51) in the
from baseline at weeks 4, 8, 12, and 16 (P < 0.001). binocular treatment group and 27% of patients (14/52) in the
patching group. The most commonly reported AEs were related to
pathogens and allergies that are not related to the study (Table 8).
Secondary Effectiveness Outcomes (mITT Two of 51 patients (3.9%) in the binocular treatment group and 5
Population) of 52 patients (9.6%) in the patching group experienced AEs that
possibly were related to the treatment procedure. Most AEs were
At baseline, the median stereoacuity was 2.3 log arcseconds for mild, and all were resolved without sequelae. Other theoretical
both groups. At week 16, the median stereoacuity was 1.78 log risks of a digital dichoptic system, such as diplopia, eye strain,
arcseconds for the binocular treatment group and 2.0 log arc- and seizures, were not reported in the binocular treatment group.
seconds for the patching group (Fig 4). At 16 weeks, the binocular No significant linear trend was found for change in the VA of
treatment was associated with a median improvement in the Randot the fellow eye for the type of treatment, CureSight or patching (P
stereoacuity of 0.40 log arcsecond (range, e0.65 to 1.78 log > 0.05 at all visits, CochraneArmitage trend test). At week 16, 3
arcseconds; P < 0.0001, Wilcoxon 1-sample test; Table S5). The participants in the patching group showed a worsening of fellow
improvement from baseline to week 16 was also significant in eye VA of > 1 line, as opposed to no participants in the binocular
the patching group (P < 0.0001), with a median improvement of treatment group.
0.40 log arcsecond (range, e0.60 to 1.95 log arcseconds) and no
significant difference between the groups in the magnitude of
change (difference, 0 log arcseconds; 95% CI, e0.27 to 0.27 log Discussion
arcsecond; P ¼ 0. 76). As observed from the upper quartile
(quartile 3), at week 16, 75% of the participants showed a
Randot stereoacuity of better than 2.3 log arcseconds in the We report that the novel digital, binocular eye-track-
binocular treatment group and 2.6 log arcseconds in the patching ingebased home treatment device was as effective as
group. patching as a treatment for amblyopia stemming from
In addition, at 16 weeks, mean
SD binocular VA had anisometropia, small-angle strabismus, or both in an
improved significantly from baseline by 0.13
0.09 logMAR in evaluator-masked multicenter RCT. The mean amblyopic
the binocular treatment group (P < 0.0001, 1-sample t test); eye distance VA improvement from the binocular treatment
however, the difference between the groups was not statistically was 2.8 lines over 16 weeks. Importantly, the benefit was
significant (difference, 0.041 logMAR; 95% CI, e0.002 to 0.085 seen in both age subgroups (4 to < 7 years and 7 to < 9
logMAR; P ¼ 0.07). A significant improvement also was observed
years), with the advantage of significantly higher adherence
at weeks 4 through 12 (P ¼ 0.0001 at week 4; P < 0.0001 at other
visits). A significant improvement from baseline also was observed rate for the binocular treatment users compared to patching.
at weeks 8 through 16 in the patching group (P < 0.0001), by 0.09 The improvement in the control patching group observed

0.12 logMAR at week 16, whereas the change from baseline at in this study is comparable with what has been reported in
week 4 did not reach statistical significance (P ¼ 0.13). the literature for 2-hour patching in a similar age group.8,9,34
The percentage of patients with a 2-line or more improve-
ment in the binocular treatment group was 79% (34/43 pa-
Additional Effectiveness Outcomes (mITT
tients) versus 61% (30/49 patients) in the patching group.
Population) Although this difference was not statistically significant
Subgroup analysis did not reveal significant differences in the (P ¼ 0.0635, Fisher exact test), the improvement in the
primary end point of improvement in amblyopic eye VA by the binocular treatment group seems to be higher than what was
baseline covariates of the age group (4 to < 7 years, 7 to < 9 observed with patching group. Table S9 (available at
years), the type of amblyopia, previous amblyopia treatment, or the www.aaojournal.org) presents the distribution of line
baseline VA levels (< 0.3 logMAR, from 0.3 to 0.5 logMAR, > change from baseline in amblyopic eye VA in each
0.5 logMAR). treatment group for weeks 4 through 16 for the mITT set.
At the 16-week visit, the proportion of participants with 2 lines
Note that the distribution of subjects in our study was
or more improvement from baseline in amblyopic eye VA was
79% (34/43) in the binocular treatment group and 61% (30/49) in even between younger children aged 4 to < 7 years and
the patching group, with no significant difference between the slightly older children aged 7 to < 9 years and between
groups (difference, 17.9%; 95% CI, e0.43% to 36.1%; P ¼ those who had not received previous amblyopia treatment.
0.0635, chi-square test; Fig 5; Table S6, available at Although some studies23,24 have associated a younger age
www.aaojournal.org). and no prior treatment with a better outcome from
At 16 weeks, the regimen adherence (as determined by the total amblyopia therapy, we did not observe any statistically
treatment time) of the binocular treatment group was significantly significant effect of age and prior amblyopia therapy in
greater than that of the patching group (median adherence, 91%; this study. One of the differences in the baseline
range, 33%e137%) in the binocular treatment group and 83% characteristics in this study compared with other binocular
(range, 22%e130%) in the patching group (difference, 8%; 95%
treatment RCTs24e26 is the interocular difference criterion
CI, e4% to 21%; P ¼ 0.0114). In addition, 88% of parents re-
ported satisfaction with the CureSight therapy and believed that of 2 logMAR lines or more (vs.  3 logMAR lines). The
this treatment therapy had greater ease of use. The mean adherence improvement from baseline in the subset with a 3-line or
in the binocular treatment group also was greater than that of the more interocular difference (about 60% of the study pa-
patching group: 93% versus 78% (Fig S6 and Table S7, available tients) was 3.1 (
1.6) lines in the binocular treatment group
at www.aaojournal.org). and 2.6 (
1.4) lines in the patching group, reflecting the

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 Ophthalmology Volume 130, Number 3, March 2023

Figure 2. Consolidated Standards of Reporting Trials diagram of the trial. PI ¼ principal investigator; VA ¼ visual acuity.

Table 3. Demographics and Baseline Characteristics

Characteristic Treatment Group (n [ 51) Control Group (n [ 52)

Age (yrs) 6.63
1.34 6.94
1.43
Sex
Male 28/51 (54.90) 23/52 (44.23)
Female 23/51 (45.10) 29/52 (55.77)
Amblyopic eye
Right eye 17/51 (33.33) 25/52 (48.08)
Left eye 34/51 (66.67) 27/52 (51.9)
Type of amblyopia
Refractive 46/51 (90.20) 49/52 (94.23)
Strabismic 0/51 (0.0) 0/52 (0.0)
Both combined 5/51 (9.8) 3/52 (5.77)
Prior amblyopia treatment
None 24/51 (47.06) 26/52 (50.00)
Patching 26/51 (50.98) 26/52 (50.00)
Atropine plus patching 1/51 (1.96) 0/52 (0.0)
Binocular treatment 0/51 (0.0) 0/52 (0.0)
Prior strabismus surgery 0/51 (0.0) 0/52 (0.0)
Duration in current correction (mos)
Within the last 6 mos 32/51 (62.75) 33/52 (63.46)
More than 6 mos 19/51 (37.25) 19/52 (36.54)
Cycloplegic refraction spherical equivalent (diopters)
Amblyopic eye 3.87
3.51 4.70
3.39
Fellow eye 2.20
1.77 3.29
2.12
Baseline best-corrected visual acuity (logMAR)
Amblyopic eye 0.370
0.144 0.36
0.14
Fellow eye 0.053
0.11 0.043
0.11

logMAR ¼ logarithm of the minimum angle of resolution.

Data are presented as no./total no. (%) or mean
standard deviation.

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 Wygnanski-Jaffe et al 
CureSight Amblyopia Treatment

0.40 100 Binocular treatment

Binocular treatment
Patching
AEDVA change from Baseline

0.28 Patching 79

Improvement ≥2 Lines (%)

80
0.22 0.23 0.23 63 61
(Mean+SE)

0.2
0.18 60
51
0.20 48
0.12 0.15
39 36
40

20
20

n=45 n=46 n=44 n=47 n=44 n=46 n=43 n=49 n=45 n=46 n=44 n=47 n=44 n=46 n=43 n=49
0.00 0
Week 4 Week 8 Week 12 Week 16 Week 4 Week 8 Week 12 Week 16
Follow-Up Visit Follow-Up Visit
Figure 3. Bar graph showing the change in amblyopic eye distance visual Figure 5. Bar graph showing the proportion of participants with
acuity (AEDVA) from the baseline at each follow-up visit at 4, 8, 12, and improvement of 2 lines or more in amblyopic eye visual acuity at each
16 weeks for participants in the binocular treatment group compared with follow-up visit.
the patching group (modified intention-to-treat population).

for stereoacuity in the literature on conventional patching

ability to reduce a 3-line interocular difference in VA and therapy and the newer binocular approaches have been
thereby increase the potential for binocularity. Importantly, inconsistent, with some studies reporting a tendency for
both groups improved similarly until week 12. At week 16, improvement35e37 and others reporting no demonstrable
the binocular treatment group continued to demonstrate a improvement.15,22,23,26
significant improvement (P ¼ 0.0003), whereas the patching Adherence plays a key role in amblyopia treatment
group had reached a plateau (P ¼ 0.62; Table S10, available effectiveness, with higher regimen adherence being associ-
at www.aaojournal.org). This suggests the potential for ated with greater amblyopic eye VA gains.38 Poor adherence
further improvement with longer binocular treatment with patching is a significant risk factor affecting the child’s
periods in the VA of the amblyopic eye. Future studies final VA outcome.38e40 It is estimated that only 50% of
are needed to explore the value of longer treatment caregivers achieve the recommended patching times for
durations for maximum benefit from the investigated their children.41 Despite the closely monitored boundaries of
binocular treatment. a clinical study, the adherence with patching was similar to
The improvement in amblyopic eye VA was coupled that of the binocular treatment group only at the initial
with significantly improved stereopsis and binocular VA, follow-up times. The significantly greater adherence to the
possibly demonstrating a positive effect of treatment on binocular treatment regimen at week 16 (median, 91% for
binocular interaction. These improvements were achieved binocular treatment vs. 83% for patching [Table S11,
progressively over the study period in both groups. available at www.aaojournal.org]) demonstrates the
Improvement in stereoacuity was observed in the binocular sustained benefit of this treatment in maintaining
treatment group, both in the previous single-arm pilot adherence throughout the assigned treatment period. In
study29 and in the current evaluator-masked RCT. Results addition, unlike the subjective reporting of the adherence
with patching that was recorded by subjective logbook
entries by the guardians, the adherence monitoring for
2.5 CureSight was monitored accurately by using the eye-
Binocular treatment
tracking data, and only the actual screen watching time
Stereo Acuity (Log Arcsecomds,

2.3 2.3 2.3 Patching

was considered in calculating adherence. If the patient’s eye
gaze was not on the screen or if the patient was not wearing
the treatment glasses, the treatment was stopped, the patient
Median)

2.0 2.0 2.0 2.0 2.0 was alerted, and the pause time was not calculated as
2
treatment time. Holmes et al23 found that the adherence
1.8 1.8 could be reduced substantially, even in the case of
binocular treatment with iPad (Apple, Inc) games, when
the viewed content was repetitive for children. Because
n=49 n=49 n=45 n=46 n=43 n=47 n=44 n=46 n=43 n=49 our treatment offers children the choice of unlimited
1.5
streamed visual content to keep them engaged and
Baseline Week 4 Week 8 Week 12 Week 16
treatment is tailored individually, along with continued
Follow-Up Visit support from the monitoring center, the adherence to
Figure 4. Bar graph showing the change in stereoacuity (Randot preschool treatment likely will remain high even outside the rigor of
test) in arcseconds from baseline and at follow-up visits at 4, 8, 12, and 16 a clinical study.
weeks for participants in the binocular treatment group compared with the The subjective satisfaction questionnaire also matched
patching group (modified intention-to-treat population). the objective measure of adherence, with 88% of parents

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 Ophthalmology Volume 130, Number 3, March 2023

Table 8. Incidence of Adverse Events Observed in the Study Intervention

Difference between Groups

(Binocular minus Patching) in Percentage of Participants
Adverse Event Binocular Treatment (n [ 51) Patching (n [ 52) (95% CI)
Diplopia 0% (0%e0.05%)
No. (%) of participants 0 (0.0) 0 (0.0)
No. of events 0 0
95% CI 0%e6.98% 0%e6.85%
New heterotropia e3.85% (e9.07% to 1.38%)
No. (%) of participants 0 (0.0) 2 (3.85)
No. of events 0 2
95% CI 0%e6.98% 0.47%e13.21%
Worsening heterotropia 1.96% (0%e10.45%)
No. (%) of participants 1 (1.96) 0 (0)
No. of events 1 0
95% CI 0%e10.45% 0%e6.85%
Worsening of VA
Amblyopic eye 3.92% (0.48%e13.46%)
No. (%) of participants 2 (3.92) 0 (0)
No. of events 2 0
95% CI 0.48%e13.46% 0%e6.85%
Fellow eye e1.92% (e10.26% to e0.05%)
No. (%) of participants 0 (0) 1 (1.92)
No. of events 0 1
95% CI 0%e6.98% 0.05%e10.26%
Headache e3.77% (e12.76% to 5.22%)
No. (%) of participants 2 (3.92) 4 (7.69)
No. of events 2 5
95% CI 0.48%e13.46% 2.14%e18.54%
Eye strain 0% (0%e0.05%)
No. (%) of participants 0 (0) 0 (0)
No. of events 0 0
95% CI 0%e6.98% 0%e6.85%
Skin irritation 0% (0%e0.05%)
No. (%) of participants 0 (0) 0 (0)
No. of events 0 0
95% CI 0%e6.98% 0%e6.85%
Seizures 0% (0%e0.05%)
No. (%) of participants 0 (0) 0 (0)
No. of events 0 0
95% CI 0%e6.98% 0%e6.85%
Pathogens and allergies 6.11% (e7.49% to 19.71%)
No. (%) of participants 9 (23.53) 6 (11.54)
No. of events 12 6
95% CI 8.4%e30.87% 4.35%e23.44%
Othery e3.84% (e13.21% to e0.47%)
No. (%) of participants 0 (0) 2 (3.85)
No. of events 0 2
95% CI 0%e6.98% 0.47%e13.21%
Overall 0.53% (e16.66% to 17.71%)
No. (%) of participants 14 (33.33) 14 (30.77)
No. of events 17 16
95% CI 15.20%e41.74% 15.57%e41.02%

CI ¼ confidence interval; VA ¼ visual acuity.

Participants may experience > 1 adverse event. Negative point estimates of the difference between groups indicate that the adverse event was observed more
commonly in the control group than in the treatment group.
y
The adverse events categorized as “other” in the continued glasses group were uncharacteristic anger attack and syncope.

reported being either very satisfied or satisfied with the beneficial option in young children whose resistance to
CureSight system as a treatment for amblyopia (Table S11 wearing a patch, resulting from psychological and sensory
available at www.aaojournal.org). Most parents answered factors, could adversely affect the treatment.20,22
favorably to questions regarding adherence (including the The safety profile of the reported binocular treatment is
ability to track adherence data on the system), the ease of comparable with the standard of care patching of the non-
use, and satisfaction. Hence, our treatment also may be a amblyopic eye. Headaches associated with the binocular

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 Wygnanski-Jaffe et al 
CureSight Amblyopia Treatment

treatment showed a lower incidence (4%) than in the conservative noninferiority limit should have been
patching (8%). Other notable risks, including diplopia, eye considered, and we intend to use such margins when
strain, and seizures, were not observed. planning future studies.
The current study has several limitations that should be
considered. Most patients had anisometropic amblyopia
(90% of the patients in this study vs. 50%e60% in com- Conclusions
parable RCTs23,26). Although the amblyopia-type subgroup
analysis showed no significant difference in the groups, To the best of our knowledge, this is the only successful
further generalizability confirmation to strabismic and multicenter RCT to demonstrate the effectiveness of a dig-
mixed amblyopia populations should be explored. ital dichoptic amblyopia therapy delivered through passive
Moreover, future studies are needed to evaluate the impact video watching requiring no gaming skills compared with
of dosing on the rapidity of visual improvement and its the gold standard of patching therapy. The evaluated novel
durability and the effect of subgroups on treatment binocular treatment was found to be noninferior to patching
effectiveness compared with other binocular treatments. after a 16-week trial period and was associated with higher
Tropia was limited to no more than 5 prism diopters. regimen adherence rates and parent preferences. Stereopsis
Finally, using a subjective self-logging compliance diary and binocular visual acuity also improved significantly,
by the guardians of the patching group was another limita- despite a twofold shorter overall treatment time than with
tion in our study because evidence is ample for over- patching. Hence, it is reasonable that this approach to
estimating compliance in this type of patching amblyopia treatment represents a safe, engaging, and
monitoring.42,43 personalized alternative to patching. Whether this binocular
In the current study, we used a noninferiority margin of treatment can apply for other forms of amblyopia and to
1 line (0.1 logMAR), which is more than that used in the older children and adults is yet to be investigated.
other noninferiority studies, with more conservative limits
of either 0.05 or 0.075 logMAR. As shown in Table S4, if Acknowledgments
we had performed the statistical comparison using either The authors thank Gregg T. Lueder for serving as the safety officer
of the more conservative noninferiority margins, the for the study and Lisa Deutsch, PhD, and Netanel Deutsch, MA,
study conclusions would have been the same. the study biostatisticians (Biostats Statistical Consulting, Ltd,
Nevertheless, in retrospect, we believe that a more Maccabim, Israel).

Footnotes and Disclosures

Originally received: July 12, 2022. MD (SI), Alexandra Goz, MD (SI), Haia Katz, MD (SI), Anabel Bazov (C),
Final revision: October 18, 2022. Chaim Nissen (E), Gabriel Avraham (E), and Emad Borsha (E); Maccabi
Accepted: October 18, 2022. Healthcare Service, Tel Aviv, Israel (n ¼ 18): Idit Keynann, MD (I), Tali Aviv
Available online: October 26, 2022.Manuscript no. OPHTHA-D-22-01256. (E), Nathalie Corcos (C), and Keren Roll (E); Rambam Medical Center, Haifa,
1
Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel. Israel (n ¼ 14): Eedy Mezer, MD (I), Vered Brucker (E), and Meital Abecassis
2 (C); Shaare Zedek Medical Center, Jerusalem, Israel (n ¼ 9): Ronen Rabino-
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
3
vich, MD (I), Eran Laster (E), Ronit Politi (E), and Hila Givoni (C); Soroka
Department of Ophthalmology and Visual Sciences, University of Wis- Medical Center, Beer Sheva, Israel (n ¼ 5): Ahed Amitirat, MD (I), Chiya
consin, Madison, Wisconsin. Robert Barrett, MD (SI), Adelina Zioni (E), Katty Kuperman (C), and Yael
4
NovaSight, Ltd, Airport City, Israel. Crocus (clinical study manager). The number of patients enrolled at each site is
5 noted in parentheses and personnel are listed as: investigator (I), subinvestigator
Goldschleger Eye Research Institute, Sheba Medical Center, Tel
Hashomer, Israel. (SI), coordinator (C), and masked examiner (E).
Disclosure(s): Supported by NovaSight Ltd., Airport City, Israel. The sponsor or funding
All authors have completed and submitted the ICMJE disclosures form. organization participated in designing the study; conducting it; data man-
The author(s) have made the following disclosure(s): T.W.-J.: Scientific agement; data analysis; interpreting the data; and preparation, review, and
advisor and Equity owner e NovaSight Ltd. approval of the manuscript.
B.J.K.: Scientific advisor and Equity owner e NovaSight Ltd. HUMAN SUBJECTS: Human subjects were included in this study. The
Institutional Review Board/Ethics Committees at Sheba Medical Center,
A.M.: Employee and Equity owner e NovaSight Ltd.
Kaplan Medical Center, Maccabi Healthcare, Rambam Health Care
M.B.: Scientific advisor and Equity owner e NovaSight Ltd.; Patent e 16/ Campus, Shaare Zedek Medical Center, and Soroka University Medical
334666 (“Screening, Diagnosing, Assessing, Monitoring and Treating Eye Center approved the study. All research adhered to the tenets of the
Diseases and Visual Impairments Using Eye Tracking”) Declaration of Helsinki. Both the parents and/or guardians of all partici-
O.Y.: Employee and Equity owner e NovaSight Ltd.; Patent e 16/334666 pants provided informed consent.
(“Screening, Diagnosing, Assessing, Monitoring and Treating Eye Diseases No animal subjects were included in this study.
and Visual Impairments Using Eye Tracking”)
Author Contributions:
CureSight Pivotal Trial Group (sites are listed in order by number of participants
Conception and design: Wygnanski-Jaffe, Kushner, Moshkovitz, Belkin,
enrolled into the study): Sheba Medical Center, Ramat Gan, Israel (n ¼ 36):
Yehezkel
Abraham Spierer, MD (I), Tamara Wygnanski-Jaffe, MD (SI), Nethanel Zitzer
(E), Dan Cohen (E), Ahuva Shpigelman (E), Maoz Hadash (E), Ilya Ortenberg Analysis and interpretation: Wygnanski-Jaffe, Kushner, Moshkovitz, Bel-
(E), and Rinat Cohen (C); Kaplan Medical Center, Rehovot, Israel (n ¼ 21): kin, Yehezkel
Hana Leib, MD (I), Majd Arow, MD (SI), Reut Parness, MD (SI), Luba Rodov, Data collection: Wygnanski-Jaffe, Moshkovitz, Yehezkel

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 Ophthalmology Volume 130, Number 3, March 2023
Obtained funding: N/A; No additional funding was received. Keywords:
Overall responsibility: Wygnanski-Jaffe, Kushner, Moshkovitz, Belkin, Amblyopia, Binocular treatment, Dichoptic treatment, Eye tracking,
Yehezkel Stereopsis.
Abbreviations and Acronyms: Correspondence:
AE ¼ adverse event; BCVA ¼ best-corrected visual acuity; Oren Yehezkel, PhD, 1 Hayarden Street, Airport City 7019801, Israel.
CI ¼ confidence interval; ITT ¼ intention-to-treat; logMAR ¼ logarithm E-mail: oren.yehezkel@gmail.com.
of the minimum angle of resolution; LS ¼ least squares; mITT ¼ modified
intention-to-treat; RCT ¼ randomized controlled trial; SD ¼ standard de-
viation; VA ¼ visual acuity.

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Pictures & Perspectives

Pseudo-Horner Syndrome in Infancy

A 2-month-old girl presented with ptosis of the right upper and lower eyelids, mild miosis (without dilation lag) of the right pupil, and
apparent enophthalmos of the right eye (Fig A). Concern for Horner syndrome led to magnetic resonance imaging (MRI) of the head, neck,
and chest, with MRI angiography of the head and neck (all interpreted as normal). Later review of axial orbital MRI showed enophthalmos
of the right eye with greater kinking of the right optic nerve (Fig B). Horner syndrome is known to produce apparent enophthalmos.
Conversely, congenital enophthalmos with physiologic anisocoria can produce a pseudo-Horner syndrome (Magnified version of Fig A-B is
available online at www.aaojournal.org).

MICHAEL C. BRODSKY, MD
Department of Ophthalmology and Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota

Footnotes and Disclosures

Supported in part by Mayo Clinic, Rochester, MN. The funding organization had no role in the design or conduct of this research.

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