Study protocol for a randomized controlled trial using VISIONARY, a dichoptic Gabor patch video game, to improve visual function in children with amblyopia

doi:10.21203/rs.3.rs-3772007/v1

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Study protocol

Study protocol for a randomized controlled trial using VISIONARY, a dichoptic Gabor patch video game, to improve visual function in children with amblyopia

https://doi.org/10.21203/rs.3.rs-3772007/v1

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Background: Conventional treatment for amblyopia, involving occlusion and penalization of the dominant eye, does not always lead to effective outcomes and is associated with a high risk of recurrence and non-compliance. In this article, we present a protocol for a randomized controlled trial to evaluate the safety and clinical efficacy of Visionary, a novel computer-based therapy that uses dichoptic Gabor patches and band-filtered noise to treat amblyopia in the patient’s home.

Methods: Our aim is to recruit a total of 120 children with amblyopia, aged 4–12 years, from the Paediatric Ophthalmology Unit at the Merida Hospital in Badajoz (Spain). The children will be divided into two groups according to whether or not they have previously undergone treatment involving occlusion or penalization of the dominant eye: 60 participants with no history of occlusion or penalization treatment will be assigned to Group A (GA), while Group B (GB) will consist of 60 participants who have previously received treatment with an occlusion dose > 32 weeks in mild or moderate amblyopia or > 48 weeks in severe amblyopia.

In GA, the participants will be randomly assigned to either an experimental subgroup (GA-E) or a control subgroup (GA-C). Members of the GA-E group will be prescribed home therapy using computer-based exercises (Visionary); members of the GA-C group will be prescribed occlusion according to Pediatric Eye Disease Investigation Group (PEDIG) protocols.

In GB, all participants will receive occlusion according to PEDIG protocols, and all will be prescribed home therapy using Visionary. In the experimental subgroup (GB-E), the computer will adjust the training spatial frequency of the Gabor patch, taking into account the user’s visual acuity (VA); while in the control subgroup (GB-C), the spatial frequency will remain low, irrespective of the patient’s VA.

Visual function assessments will be carried out prior to the intervention and every three weeks thereafter; changes in best corrected visual acuity (BCVA) at distance will be the primary outcome measure under consideration. Stereoacuity and patient compliance will also be assessed.

Discussion: The Visionary system based on dichoptic Gabor patches was originally conceived as a serious game to provide vision training to amblyopic children by combining the concepts of perceptual learning, dichoptic training, and gamification in the home environment. We hope that this novel approach may lead to greater improvements in vision performance in amblyopic children, as a substitute for occlusion treatment in novel amblyopia or as an adjunct treatment option in persistent amblyopia.

Trial registration: This protocol was registered with ClinicalTrials.gov (NCT06150391) on 29^th of November 2023.

amblyopia

visual acuity

perceptual learning

occlusion

Gabor patch

Amblyopia

Amblyopia is a common neurodevelopmental abnormality that results in physiological alterations of the visual pathways and impaired vision in one eye or, less commonly, in both.¹ Disruption of normal visual development early in life may lead to perceptual, oculomotor and clinical abnormalities such as fixation instability, anomalous retinal correspondence, and lack of stereoacuity.¹ Amblyopia has a prevalence of around 2–4% in children and is associated with refractive error (anisometropia or isometropia) and strabismus.²

The Pediatric Eye Disease Investigator Group (PEDIG) has produced several studies that evaluate the most effective therapies for amblyopia. The gold standard treatment prescribed for this condition combines spectacle correction of the refractive error with penalization and/or occlusion of the dominant eye,³ the main outcomes of which are summarized in the following points: ⁴

i. although between 73 and 90% of patients experience some improvement in their visual acuity with this treatment, around 50% fail to achieve normal VA;

ii. only 28% of patients with amblyopia associated with anisometropia experience improved stereoacuity, while in cases associated with strabismus the outcomes are even worse;

iii. significantly, 25% of patients for whom treatment is initially successful experience a subsequent regression of VA.

In addition, Buckle et al.⁵ analysed the results of applying PEDIG protocols to amblyopic patients in a hospital to determine a “real-life” benchmark for treatment outcomes in clinical practice. Although the outcomes in terms of VA were similar to those previously obtained with PEDIG protocols, they found a plateau time of 32 weeks for mild amblyopia and 48 weeks for severe amblyopia.

For all of these reasons, in the last decades there has been a substantial increase in research into novel treatment approaches aimed at improving VA, acquiring binocular fusion, reducing interocular suppression and improving stereoacuity through home-based exercises that are based on the perceptual learning paradigm, can engage children as well as adults, and use gamification and remote compliance monitoring to improve the patient’s adherence to treatment.

Perceptual learning

Perceptual learning (PL) is loosely defined as long-term changes in perception that result from practice or experience.⁶ In visual PL, the preferred stimulus is the Gabor patch;⁷ the frequency and contrast of the Gabor patch is adjusted to enable stimulation of the amblyopic eye.^8–10 Polat (2004, 2009) and others have demonstrated that amblyopic stimulation is selective.¹¹ Learning with low frequency Gabor patches does not transfer to high frequency, that is, visual acuity does not improve. On the other hand, stimulation that uses high frequency Gabor patches does lead to improved low frequency contrast sensitivity and visual acuity. In 2008, Chen et al.¹² obtained improvements in visual acuity in anisometropic patients (both adults and children) as a result of PL training with Gabor patches, and proposes an intervention protocol whereby PL is used as an adjunct to occlusion, for the purpose of reducing the time required to recover VA (120 hours/logMAR line).¹³

Dichoptic training

Baker et al. (2007) suggested that the mechanisms responsible for combining the information received by the two eyes are intact in patients with amblyopia.¹⁴ Despite the imbalance in the visual system, interocular balance in the primary visual cortex can be achieved by reducing the contrast^15,16 or luminance¹⁷ of the dominant eye to produce a binocular response; and binocular imbalance can be assessed in a number of different ways.^18–20 Subsequent studies have confirmed this hypothesis: the binocular neural architecture is intact but suppressed in amblyopia, and suppression may be the cause rather than the consequence of amblyopia. ⁴

The primary aim of novel treatments should be to reduce/minimize suppression.⁴. The key idea of so-called dichoptic training is to provide different stimuli to each eye, attenuating or eliminating the dominant eye signal²¹ to guarantee amblyopic eye perception.²² Initial laboratory studies seemed to confirm this approach.^23,24,25 Later, clinical trials made use of gamification to improve patient compliance, by inserting dichoptic elements into videogames^26–31 or films.^32–34

In terms of VA and stereoacuity, these treatments produced inconsistent results: in some cases, better or similar to those obtained by optical refraction, with^30,26 and without occlusion;^28,35 but worse in others,^29,36,37 for reasons which are unclear.³⁸

Notwithstanding, dichoptic therapy has never, to our knowledge, produced results superior to those obtained using a passive therapy protocol in isolation, according to large, randomized clinical trial studies comparing the two strategies.³⁹

Dichoptic Gabor patches and band-filtered noise

The shortcoming of dichoptic training is that it ignores the frequency-contrast content of the images presented to the patient. The absence of any monitoring of the frequency-contrast content of the two different images might explain the contradictory results obtained with this approach. One possible solution to the problem is the dichoptic demasking training proposed by Liu XY and Zhang JY (2018, 2019, 2021).^40–43 Here, the patient must identify the differences in contrast between two Gabor patches, of known frequency, presented to the amblyopic eye; at the same time, a band-filtered noise pattern is presented to the dominant eye. In this way, as previously stated, the contrast sensitivity perception at different frequencies of the amblyopic eye will improve, and at the same time anti-inhibition channels against fellow eye signal will be strengthened. Preliminary results have shown improvements in stereoacuity, amblyopic eye contrast sensitivity, and amblyopic eye tolerance to dominant eye noise contrast.

Hypothesis and aims

We hypothesize that, in patients with no history of previous occlusion or penalization treatment, VA will improve with Visionary treatment (half an hour per day, five days per week), leading to results similar to those produced by occlusion treatment according to PEDIG protocols (two hours per day for mild and moderate amblyopia, or six hours for severe amblyopia) after about two months (significant difference between groups P < 0.05).

In patients with persistent amblyopia, we hypothesize that the use of Visionary as an adjunct to occlusion will significantly improve VA, in comparison with the occlusion and Visionary placebo subgroup.

Study design

To test both hypotheses, we intend to conduct a small-scale randomized controlled trial (RCT) involving 120 children with amblyopia, aged 4–12 years. The children will be divided into two groups according to whether or not they have previously undergone treatment involving occlusion or penalization of the dominant eye: 60 participants with no history of occlusion or penalization treatment will be assigned to Group A (GA), while Group B (GB) will consist of 60 participants who have previously received treatment with an occlusion dose > 32 weeks in mild or moderate amblyopia or > 48 weeks in severe amblyopia.

In GA, the children will be randomly assigned to either an experimental subgroup (GA-E) or a control subgroup (GA-C). Patients in the GA-E subgroup will be prescribed home therapy using Visionary computer-based exercises for half an hour per day, five days per week, for 12 weeks. Patients in the GA-C subgroup will be prescribed occlusion according to PEDIG protocols: two hours for mild and moderate amblyopia, or six hours for severe amblyopia.

In GB, all the children will receive occlusion treatment according to PEDIG protocols, and all will be prescribed home therapy using Visionary. In the experimental subgroup (GB-E), the computer will automatically adjust the training spatial frequency of the Gabor patch, taking into account the user’s visual acuity (moving towards higher frequencies as soon as VA improves); while in the control subgroup (GB-C), the spatial frequency will remain low, irrespective of the child’s VA.

Importantly, those participants with horizontal deviations of 10 to 25 prism diopters will be assigned to experimental or treatment subgroups following an independent randomization, to ensure a similar number of these patients in both subgroups. A Fresnel prism over the dominant eye will be used to compensate deviation.

Study overview

The facility in which the children will be recruited, and the study visits carried out, is the Paediatric Ophthalmology Unit of the Merida Hospital in Badajoz (Spain). Recruitment will be carried out over a period of 12 months (December 2023 to December 2024).

The sample will be made up of children with amblyopia, aged 4–12 years, with amblyopia defined as BCVA ≤ 0.8 in decimal units or > two lines of difference between both eyes). Volunteers with strabismus will be included if horizontal deviation is < 25 prism diopters and vertical deviation is ≤ 2 prism diopters. In addition, subjects with nystagmus, ocular pathology or cognitive delay will be excluded.

Children who meet the inclusion criteria and whose parents and minor sign the informed consent will participate in the study.

Five complete visual evaluations will be conducted before and after the intervention (Fig. 1). The first and second of these will take place (1) prior to commencement of the study, to collect baseline data, and (2) upon completion of the treatment, to collect outcome data. Three follow-up visits to assess the stability of the results will then be conducted: (3) at three months, (4) at six months, and (5) at twelve months after completion.

Complete visual evaluations will include the following: BCVA (logarithmic VA chart in ETDRS format) using Sifi MAV vision tester (SIFI SpA, Catania, Italy); monocular cover-uncover test and alternate cover test, using accommodative stimuli (VA 20/30 Snellen); refractive error by autorefraction under cycloplegia (cyclopentolate 1%; Topcon model TRK 1P), following PEDIG guidelines;³ evaluation of the anterior and posterior segment; and stereoacuity, measured with the Randot Preschool Stereoacuity Test (Stereo Optical, Inc., Chicago, USA), a random dot stereogram that measures global stereopsis (or cyclopean stereopsis) and contains no monocular cues. All the evaluations will be carried out in the same examination room using an illumination of 120 cd/m².

During the intervention, basic visual function assessments will be carried out at three-weekly intervals, with changes in distance BCVA being the primary outcome measure under consideration. Stereoacuity and patient compliance will also be assessed.

Group GA protocol

Patients without previous occlusion or penalization treatment are included in GA (Fig. 2).

Children assigned to the GA-E subgroup will be prescribed home therapy using Visionary computer-based exercises for half an hour per day, five days per week, for 12 weeks. Visionary software will automatically adjust the target frequencies according to the participant’s current BCVA at three-weekly intervals. In the same way, the software will also adjust Gabor patch frequency contrast to match the patient’s contrast sensitivity thresholds.

Children assigned to the GA-C subgroup will be prescribed occlusion according to PEDIG protocols: two hours for mild and moderate amblyopia, or six for severe amblyopia.

Where BCVA fails to improve by at least two lines in two consecutive visits (six weeks), the patient in question will be moved from one subgroup to the other.

Group GB protocol

Patients with a history of occlusion or penalization treatment (persistent amblyopia) are included in GB (Fig. 3).

All volunteers will receive occlusion treatment according to PEDIG protocols; they will also be prescribed home therapy using Visionary. The difference between the subgroups lies in the configuration of the Visionary software.

In the GB-E subgroup, Visionary target frequencies will be adjusted automatically according to current BCVA at three-weekly intervals.

In the GB-C subgroup, however, Visionary target frequencies will remain low, irrespective of the patient’s VA.

Where BCVA fails to improve at least two lines in two consecutive visits (six weeks), the patient assigned to GB-C will be moved to GB-E (but not in the other direction).

Double-blind study

The RCT is designed as a double-blind study. Ophthalmologists at the Paediatric Ophthalmology Unit of the Merida Hospital will select patient volunteers that meet the inclusion criteria, assigning the patients selected to GA or GB according to their previous treatment history. All patients will be given an eye patch, a compliance calendar, anaglyph glasses, Visionary instructions, and a Fresnel prism as required. The same ophthalmologists will be responsible for the final and post-treatment visual evaluations.

The Quality Control Area of the Merida Hospital will randomly allocate GA and GB patients into treatment or control subgroups and will be responsible for the custody of documentation and the final statistical analysis.

Members of the Visionary team, including optometrists and technical advisors will communicate directly with patients about the treatment (occlusion or Visionary software, or both), resolving any questions or queries by email or telephone.

Optometrists at the Paediatric Ophthalmology Unit of the Merida Hospital will oversee BCVA and stereoacuity measurements during the treatment. This data will be communicated to the Quality Control Area at Merida Hospital as well as to the Visionary team.

Sampling

Hypothetical sample size calculation was performed using the GRANMO online platform (https://www.imim.es/ofertadeserveis/software-public/granmo/), establishing a minimum difference in BCVA at distance to be detected in both groups before and after treatment of 0.15 logMAR, with a loss percentage of 10%, and a common standard deviation (SD) of 0.195 logMAR. Statistical power was set at 80%, using a bilateral χ² test for two independent samples and a signification level of 5%. Based on this, a sample size of 30 patients per group would be required. Hence the complete sample will consist of 120 subjects.

Intervention

The software intended to be used in this study is Visionary (www.visionarytool.com), a software product certified by the European Union as a Class I (low risk) medical device that complies with the health and safety requirements of European Regulation MDR 2017/745. Visionary’s intended use is the treatment of amblyopia (anisometropic, strabismic or mixed) and non-strabismic binocular problems such as convergence insufficiency. Visionary has been designed as an adjunct to vision therapy according to PEDIG protocols, which recommend initial correction of the refractive defect, in addition to occlusion of the dominant eye for between two and six hours each day. Visionary should be used under the supervision of a competent specialist responsible for the patient’s diagnosis.

The activities included in Visionary are grouped into exercises to produce improvement in three areas: VA, using Gabor patches; stereo acuity, using random dot clouds; and eye movements and vergence ranges. In this study, only the first group of exercises are used. The gamified exercises are called Frisbee Hunt, Balloon Buster, Cookie Crunch, The Big Race, and Crossing the River.

All exercises are designed for Windows computers with an internet connection. Patient compliance and results from each session are saved in the cloud, enabling the remote control of data and subsequent detailed analysis and evaluation of patient progress.

If the patient’s BCVA is lower than 0.4 decimal VA, occlusion of the dominant eye during the exercise is mandatory to avoid crosstalk perception with the fellow eye. Otherwise, the patient will wear anaglyph glasses with the red filter over the amblyopic eye to unify criteria.

Gabor patches are presented to the amblyopic eye within an otherwise binocular scene. The patient’s task is to identify the direction of the patch (horizontal, 45°, vertical or 135°). The Gabor patch will vary automatically in size and frequency, according to the patient’s current VA (see Table 1). The software will automatically adjust the target Gabor patch contrast to the patient’s perception threshold, continuously recalculating in response to previous in-game responses. Even so, for each trial, the Gabor patch contrast will randomly deviate a little around the patient’s threshold, looking for a constant patient success ratio of 70% to increase motivation.

Table 1

Visionary VA exercises configuration: BCVA of amblyopic eye; Gabor patch size; Gabor patch frequency; patch/anaglyph glasses; and band-filtered noise.
BCVA [decimal]	Gabor size [degrees]	Frequency [cpd]	Patch/Anaglyph	Band-filtered noise
0.08	5	1; 2	Patch	No
0.1	5	1; 2	Patch	No
0.125	5	1; 2; 4	Patch	No
0.16	5	1; 2; 4	Patch	No
0.2	5	1; 2; 4	Patch	No
0.25	5	1; 2; 4	Patch	No
0.33	3	2; 4; 8	Patch	No
0.4	3	2; 4; 8	Anaglyph	No
0.5	2	4; 8; 12	Anaglyph	No
0.63	1.5	8; 12; 16	Anaglyph	Yes
0.8	1	12; 16; 24	Anaglyph	Yes
1.0	1	12; 16; 24	Anaglyph	Yes

In patients whose BCVA is lower than 0.63 decimal VA, the dominant eye is stimulated with a medium grey tone in the area where the amblyopic eye sees the Gabor patch (Fig. 4). Once the patient achieves a BCVA ≥ 0.63 decimal VA, band-filtered noise to the same peak frequency as the Gabor patch is shown to the dominant eye in some trials. The contrast of the band-filtered noise is adjusted to the maximum tolerable, i.e., the maximum value that does not affect the contrast sensitivity threshold calculated for that frequency.

We believe that this approach combines the best current scientific evidence on perceptual learning and dichoptic treatment.

Data analyses plan

The Quality Control Area of the Merida Hospital will oversee the data analysis plan, in which descriptive analysis of all data will be provided, including means and standard deviations or medians for continuous variables and proportions for categorical variables.

Variables will be assessed for distribution normality (skewness and kurtosis). If the sample follows a parametric distribution, the data will be analysed according to different statistical tests including the student T, analysis of variance (ANOVA) and multiple linear regression. On the other hand, if the sample follows a non-parametric distribution, the data will be analysed using the Mann-Whitney U test, the chi-square test, the Kruskal-Wallis H test, and other non-parametric methods. This analysis will be blind.

Dissemination plan

The objective will be to disseminate the results of the study as widely as possible due to its potential relevance for the clinical practice of treating this group of patients. It will be presented to the scientific community through high-impact, peer-reviewed journals. In addition, pertinent communications will be presented at national and international ophthalmology and optometry congresses.

This RCT adds to the long list of studies that have evaluated the efficacy of so-called dichoptic training in amblyopia.^15–26 Gabor patches,^8,9,12 even dichoptic Gabor patches, have been used in amblyopia treatment before now.^29–32

But, to our knowledge, this will be the first time that gamified home training using dichoptic Gabor patches has been tested. The story behind the exercises (the adventures of a dog training to take part in a canine championship) and the remote tracking via a web system is designed to improve attention, compliance and adherence, the main problems pointed out in previous studies.³⁸ Patching compliance has also been identified as a major handicap in standard protocols, insofar as an electronic occlusion dose monitor is not available.¹³ Following ideas expounded in previous studies, parents will be given a physical calendar to track each participant’s compliance with day-to-day occlusion and performance of exercises.^44–46

Moreover, previous studies using a dichoptic approach have not differentiated between treatment doses for untreated and persistent amblyopia. The hypothesis that untreated amblyopia will respond to PL exercises with comparable results to those obtained from patching has been put forward by several researchers.^38,47 Cases of persistent amblyopia, where patching has reached the “plateau” value, might also benefit from the PL treatment used as an adjunct to occlusion.

ANOVA

Analysis of variance

BCVA

best corrected visual acuity

Group A

GA-C

Group A control subgroup

GA-E

Group A experimental subgroup

Group B

GB-C

Group B control subgroup

GB-E

Group B experimental subgroup

PEDIG

Pediatric Eye Disease Investigation Group

Perceptual learning

RCT

randomized controlled trial

visual acuity

Ethics approval and consent to participate

This study follows the principles of the Declaration of Helsinki and was approved (CEI 046/23) by the Research Ethics Committee of the Gerencia del Area de Salud de Badajoz (Avenida de Huelva nº8, 2ª Pl. - 06005 Badajoz, Spain, [email protected]) on 21^st of July 2023.

Prior to participation, trained research staff will obtain written informed consent from the patient or the patient’s parents or legal guardians depending on whether the patient is older or younger than 16 years of age.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

MPB and EAM declare that they have no competing interests. Authors TCG, SMG and JPC declare having received fees from VisionaryTool, S.L. for different works as consultors. Authors SMG and JPC declare holding stocks of VisionaryTool, S.L.

Funding

The Merida Hospital (Mérida, Extremadura, Spain) has founded the costs of the study.

Authors' contributions

JPC wrote the initial draft of the study design. MPB, TCG, EAM, SMG and JPC participated in the study design review. All authors read and approved the final manuscript.

Acknowledgements

Ignacio Fermoselle-Moreno, Optometrist at the Servicio de Oftalmología at Hospital de Mérida; and Fernando Arnau-Carda, Quality Coordinator at Área de Salud de Mérida.

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Competing interest reported. MPB and EAM declare that they have no competing interests. Authors TCG, SMG and JPC declare having received fees from VisionaryTool, S.L. for different works as consultors. Authors SMG and JPC declare holding stocks of VisionaryTool, S.L.

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Study protocol for a randomized controlled trial using VISIONARY, a dichoptic Gabor patch video game, to improve visual function in children with amblyopia

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Abstract

Figures

Background

Amblyopia

Perceptual learning

Dichoptic training

Dichoptic Gabor patches and band-filtered noise

Material and methods

Hypothesis and aims

Study design

Study overview

Group GA protocol

Group GB protocol

Double-blind study

Sampling

Intervention

Data analyses plan

Dissemination plan

Discussion

Abbreviations

Declarations

References

Additional Declarations

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