Abstract
Background
In this systematic review, we address the question whether children and adolescents with developmental visual disorders benefit from computer-assisted visual training.
Methods
Systematic literature searches were carried out in three bibliographic databases (initial search in October 2021) and trial registries. Included were randomized controlled trials that evaluated the efficacy of computer-assisted visual training in children and adolescents with developmental visual disorders in comparison to no training, sham training, or conservative treatment.
Results
The inclusion criteria were met by 17 trials (with a total of 1323 children and adolescents) focusing on binocular or monocular computer-assisted visual training for the treatment of amblyopia. In these trials, visual training was carried out for 2 to 24 weeks, either as “stand alone” therapy or in addition to occlusion therapy. Six trials showed a statistically significant difference in favor of the visual training for the outcome “best corrected visual acuity of the amblyopic eye.” However, this difference was small and mostly below the threshold of clinical relevance of –0.05 logMAR (equivalent to an improvement of 0.5 lines on the eye chart, or 2.5 letters per line). Only few data were available for the outcomes “binocular vision” and “adverse events”; the differences between the groups were similarly small.
Conclusion
The currently available data do not permit any firm conclusions regarding the efficacy of visual training in children and adolescents with amblyopia. Moreover, treatment adherence was often insufficient and the treatment durations in the trials was relatively short. No results from randomized trials have yet been published with respect to other developmental visual disorders (refractive errors, strabismus).
Many children and adolescents suffer from developmental functional vision disorders, including amblyopia (reduced vision in one eye), eye misalignment (strabismus, squint), and refractive errors (for example, myopia and hyperopia).
Amblyopia is due to an inadequate development of the visual pathways during early childhood and is caused by uncorrected unilateral refractive errors (anisometropia) in over 60% of those affected (1). In the presence of such uncorrected refractive errors, only blurred image contours are projected onto the retina, which prevents normal development of visual acuity. Apart from refractive errors, eye misalignment can also lead to amblyopia. In order to avoid double vision from eye misalignment, the visual input from the misaligned eye is suppressed, and this in turn can lead to amblyopia.
A Dutch population-based study estimated the cumulative lifetime risk of bilateral visual impairment among individuals with unilateral amblyopia to be 18%, and 10% in the absence of amblyopia (2). Overall, the risk for bilateral visual impairment in those with unilateral amblyopia is two to three times greater than in persons without amblyopia (3). Furthermore, the worldwide prevalence of amblyopia in 2018 was estimated to be 1.8% (95% confidence interval [1.6; 1.9%]) (1). A noticeably high prevalence of 3.7% [2.9; 4.5] was found in Europe.
Because the plasticity of the nervous system deteriorates with increasing age, early treatment becomes all the more important (4). Conventional treatment of amblyopia involves occlusion of the fellow non-amblyopic eye with a special patch. Occlusion therapy, however, has its disadvantages (3, 5):
On the one hand, it can have a negative impact on personality development.
On the other, covering the non-amblyopic eye suppresses eye coordination, which can result in further visual impairments.
It is therefore understandable that research is underway into treatment approaches—based, for example, on the methods of perceptual learning (5).
Financing of these new (mostly digital) treatment methods varies: Some are only used in scientific studies, while others are available commercially (6). Digital binocular (dichoptic) vision training is one of the new methods and presents each eye with a different image component (usually during a video game): the non-amblyopic eye with contrast-reduced (out of focus) and the amblyopic eye with contrast-enhanced (focused) image components (7). The image separation required for binocular training is achieved with the use of a special pair of glasses, for example, anaglyph glasses (use of colors to separate the image), shutter glasses (coated eyeglass lenses which can alternate between transparent and opaque), or headsets (virtual reality glasses). In order to be successful at binocular training (using a video game), both eyes must perceive their respective image component and fuse the image parts.
The contrast of the image component seen by the non-amblyopic eye is increased during treatment—ideally, until fusion capability is achieved with equal contrast of both image components. There are also monocular training measures which, for example, use background stimulation (a moving sinusoidal grating) and are intended to promote neural stimulation (8, 9).
In Germany, visual training by the company Caterna Vision, based on such a procedure, was used by more than 350 ophthalmic practices and hospitals in the year 2020 (8).
In view of the large number of new treatment methods, the aim of the present systematic review, which was conducted as part of a Health Technology Assessment (HTA) report (10), was to evaluate the benefits and harms of digital vision training compared with treatment without vision training in children and adolescents with developmental vision disorders.
Methods
The protocol of this systematic review has been published in the PROSPERO register (CRD42021289044). Reporting was based on the Transparent Reporting of Systematic Reviews and Meta-Analyses (PRISMA) statement (11).
The review included randomized controlled trials in which digital vision training was used to treat children and adolescents with developmental vision disorders.
The best corrected visual acuity of the amblyopic eye was specified using the unit “logMAR”. The MAR is the minimum angle of resolution and represents the reciprocal of the visual acuity (visual acuity = 1/MAR). If the visual resolution is averaged, the logarithm is used (logMAR = log[1/visual acuity]). LogMAR values are the opposite of visual acuity values (logMAR = -log[visual acuity]).
Detailed information on the methodology and the search strategy can be found in the eMethods Section and in eTable 1. A meta-analysis was not performed due to the small number of studies per comparison, heterogeneous patient populations, differences in treatment procedures, as well as due to statistical heterogeneity.
eMethods.
Patient population
Children and adolescents with a functional developmental vision disorder who had been treated as part of a randomized controlled trial. Functional developmental vision disorders include amblyopia, refractive errors, and eye misalignment (e1, e2).
Intervention
The study intervention involved vision training requiring regular and attentive participation from those involved, with instruction provided by appropriately qualified medical staff (specialized in the field of ophthalmology). This included, for example, binocular or monocular and computer-supported interactive training measures, based on the methods of perceptive learning, as well as eye movement exercises. Vision training used in combination with standard therapy (conventional treatment, for example, eyeglass lenses or occlusion) was possible. Measures to modify vision habits (for example, involving light exposure or leisure activities), experimental optic interventions (such as, special eyeglass lenses or contact lenses, for example), and pharmacotherapy methods were excluded as study interventions.
Comparative treatment
No treatment, sham treatment, standard treatment (conventional treatment such as optical correction or occlusion therapy), and surgical or drug interventions were allowed as comparative treatments.
Endpoints
The following patient-relevant endpoints were considered for the systematic review:
vision (for example, visual acuity, binocular vision, refraction value, strabismus angle);
headache and dizziness;
health-related quality of life;
health-related social and educational functioning level (for example, stigmatization and school failure);
adverse events.
Subjective endpoints, such as health-related quality of life and health-related symptoms were only included if they were recorded using valid measuring tools (for example, with validated scales).
Literature search
The literature search was performed using the PRESS (Peer Review of Electronic Search Strategies) criteria (e3) by a search specialist. A systematic literature review was conducted in bibliographic databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, time of the search 10/2021) and trial registries (U.S. National Institutes of Health: ClinicalTrials.gov, and World Health Organization [WHO] International: Clinical Trials Registry Platform Search Portal, time of the search: 12/2021). Furthermore, reference lists of retrieved review articles were screened, and author enquiries were made. The search strategy for the database Medline is accessible in eTable 1.
Selection process of the studies
In an initial selection step, the identified literature references were screened using their title and abstract to decide which of them could be classified as reliably relevant, taking into account the predefined inclusion and exclusion criteria. The full texts of studies classified as potentially relevant were then read to determine their final inclusion or exclusion (full text screening). The whole selection process was conducted by two reviewers independently of each other (CS, ET).
Data extraction and risk of bias assessment
Data extraction from published studies was carried out by one author (ET) and checked by a second author (CS). The following information was extracted from the studies: details of patient characteristics, details about the intervention, the comparative treatment, and information about the reported endpoints. The risk of bias was assessed using the Cochrane methods (e4).
Statistical analysis
The treatment effect for each continuous endpoint (such as visual acuity, measured on a continuous scale) was provided as mean difference (MD) of the average change in value (between baseline and follow-up values between the treatment arms), including the 95% confidence interval (CI).
For the MD of the endpoint “best corrected visual acuity of the amblyopic eye”, which is specified in the unit logMAR in the present systematic review, a negative sign indicates an effect in favor of the intervention. A positive sign, on the other hand, indicates an effect in favor of the control treatment. For the MD of the endpoint “binocular vision”, which is specified in the unit angle-seconds, a positive sign indicates an effect in favor of the intervention and a negative sign in favor of the control treatment.
The effect estimator for dichotomous endpoints (events that do, or do not, affect the patient, for example, adverse events) was reported as the relative risk (RR) together with the respective 95% CI.
In addition to the comparison of the results of the individual studies, meta-analyses with random effects as well as sensitivity analyses and the investigation of effect modifiers had been planned, provided that the methodological requirements had been met. But since a (very) high degree of heterogeneity (I² >70%) was evident, even within small subgroups, an aggregate data meta-analysis of the results of the primary studies was dispensed with.
eTable 1. Search strategy in the Medline database.
| Ovid MEDLINE(R) 1946 to October 27, 2021, Ovid MEDLINE(R) Epub Ahead of Print October 27, 2021, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations October 27, 2021 | |
| # | Searches |
| A. Intervention | |
| 1 | Video Games/ |
| 2 | Learning/ |
| 3 | Computers, handheld/ |
| 4 | or/1–3 |
| 5 | Vision, binocular/ |
| 6 | Visual acuity/ |
| 7 | Visual perception/ |
| 8 | or/5–7 |
| 9 | and/4,8 |
| 10 | ((vision* or vergence* or occlusion* or orthoptic* or (pencil adj1 push* adj1 up*)) adj3 therap*).ti,ab. |
| 11 | (perceptual adj3 learning*).ti,ab. |
| 12 | ((training* or game* or video* or ipad* or learning*) and (binocular* or visual activit* or visual acuit* or vernier acuit* or visual function* or visual task* or dichoptic*)).ti,ab. |
| 13 | or/9–12 |
| B. Population | |
| 14 | exp pediatrics/ |
| 15 | (infan* or newborn* or new-born or perinat* or neonat* or baby or baby* or babies or toddler* or minors or minors* or boy or boys or boyfriend or boyhood or girl* or kid or kids or child or child* or children* or schoolchild* or schoolchild or adolescen* or juvenil* or youth* or teen* or under*age* or pubescen* or pediatric* or paediatric* or peadiatric* or prematur* or preterm*).af. |
| 16 | (school child* or school*).ti,ab. |
| 17 | or/14–16 |
| A + B | |
| 18 | and/13,17 |
| C Study type | |
| 19 | randomized controlled trial.pt. |
| 20 | controlled clinical trial.pt. |
| 21 | (randomized or placebo or randomly or trial or groups).ab. |
| 22 | drug therapy.fs. |
| 23 | or/19–22 |
| Human volunteers | |
| 24 | exp animals/ not exp humans/ |
| 25 | 23 not 24 [CHSS-sensitivity-maximizing version] |
| A + B + C | |
| 26 | and/18,25 |
| Publication type | |
| 27 | (animals/ not humans/) or comment/ or editorial/ or exp review/ or meta analysis/ or consensus/ or exp guideline/ |
| 28 | hi.fs. or case report.mp. |
| 29 | or/27–28 |
| 30 | 26 not 29 |
| Publication language | |
| 31 | 30 and (english or german or multilingual or undetermined).lg. |
Results
Search
The Figure presents the selection process of the studies. The full texts from 49 of 1303 references were reviewed, of which 17 trials (19 references [12–30]) that exclusively assessed digital vision training for amblyopia met the inclusion criteria.
Figure.
Study selection according to the PRISMA flow diagram
PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Study characteristics
The key characteristics of the 17 randomized trials are included in eTable 2, stratified by intervention (binocular or monocular training) and comparative treatment. Binocular training was assessed in 11 trials (N = 1138 participants) (12–22) and monocular training in six trials (N = 185 participants) (23–28). Occlusion therapy was used in six trials as the only comparative treatment (12–17). In the other trials, vision training was compared with no training (16, 18–20, 23, 24) or with sham training (21, 22, 25–28).
eTable 2. Study characteristics.
| Study | Country |
N
randomized |
Treatment groups | Patient characteristics | |||||
| Intervention | Comparison | Average age (SD), years | Previous treatment, %*1 | Cause of amblyopia | |||||
| I | CG | I | CG | ||||||
| Binocular training versus no training (in each case, without additional occlusion) | |||||||||
| Holmes (20) | USA | 138 | Video game wearing anaglyph glasses, 1 hr/day, 5 days/week, 8 weeks | Optic correction | 9.6 (1.6) | 9.6 (1.5) | 94 | 97 | Anisometropia, strabismus |
| Xiao (19) | USA | 105 | Movies wearing VR glasses, 1 hr/day, 6 days/week, 12 weeks | Optic correction | 6.2 (1.0) | 6.0 (1.1) | 84 | 74 | Anisometropia, strabismus |
| Binocular training versus no training (in each case, with additional occlusion) | |||||||||
| Rajavi (18) | Iran | 50 | Video game wearing anaglyph glasses, 0.5 hrs/day, 5 days/week, 4 weeks + occlusion | Occlusion | 6.3 (2.0) | 5.1 (1.6) | 44 | n.s. | Anisometropia |
| Yao (16)*2 | China | 67 | Video game wearing anaglyph glasses, 0.75 hrs/day, daily, 12 weeks + occlusion | Occlusion | 6.2 (2.5) | 6.0 (2.3) | 28 | 21 | Anisometropia |
| Binocular training versus sham training (in each case, without additional occlusion) | |||||||||
| Herbison (22) | Australia | 51 | Video game wearing shutter glasses, 0.5 hrs/day, 1 day/week, 6 weeks | Placebo game: without dichoptic component | 6.0 (1.3) | 5.6 (1.1) | 77 | 72 | Anisometropia, strabismus |
| Gao (21) | Australia, NZ, China, Canada | 62 | Video game wearing anaglyph glasses, 1–2 hrs/day, daily, 6 weeks | Placebo game: without dichoptic component | 12.5 (1.5) | 11.8 (1.5) | n.s. | n.s. | Anisometropia, strabismus |
| Binocular training versus occlusion | |||||||||
| Holmes (12) | USA | 385 | Video game wearing anaglyph glasses, 1 hr/day, daily, 16 weeks | Occlusion | 8.4 (1.8) | 8.6 (2.0) | 76 | 79 | Anisometropia, strabismus |
| Manh (13) | USA | 100 | Video game wearing anaglyph glasses, 1 hr/day, daily, 16 weeks | Occlusion | 14.3 (1.1) | 14.3 (1.1) | 77 | 88 | Anisometropia, strabismus |
| Rajavi (14) | Iran | 38 | Video game wearing anaglyph glasses, 0.5 hrs/day, 5 days/week, 4 weeks | Occlusion | 6.5 (2.0) | 7.6 (1.6) | 94 | 67 | Anisometropia, strabismus |
| Birch (15) | USA | 48 | Video game wearing anaglyph glasses, 1 hr/day, 5 days/week, 2 weeks | Occlusion | 6.7 (1.8) | 7.0 (1.8) | 58 | 58 | Anisometropia, strabismus |
| Yao (16)*2 | China | 74 | Video game wearing anaglyph glasses, 0.75 hrs/day, daily, 12 weeks | Occlusion | 6.5 (2.8) | 6.0 (2.3) | 31 | 21 | Anisometropia |
| Rajavi (17) | Iran | 58 | Video game wearing VR glasses, 1 hr/day, 5 days/week, 4 weeks | Occlusion | 6.7 (1.9) | 7.6 (1.7) | n.s. | n.s. | Anisometropia, strabismus |
| Monocular training versus no training (in each case, without additional occlusion) | |||||||||
| Iwata (23) | Japan | 46 | Video game, 0.5 hrs/day, 2 days/week, 24 weeks | Optic correction | 4.8 (1.2) | 4.9 (1.1) | 0 | 0 | Anisometropia |
| Monocular training versus no training (in each case, with additional occlusion) | |||||||||
| Dadeya (24) | India | 40 | Video game, 0.5 hrs/day, 1 day/week, 12 weeks + occlusion | Occlusion | 6.0 (1.0) | 5.8 (1.2) | 0 | 0 | Anisometropia, strabismus |
| Monocular training versus sham training (in each case, with additional occlusion) | |||||||||
| Bau (25) | Germany | 15 | Video game with background stimulation, 0.75 hrs/day, 5 days/week, 4 weeks + occlusion | Placebo game: without background stimulation + occlusion | 6.0 (n.s.) | 6.8 (n.s.) | 0 | 0 | Anisometropia, strabismus |
| Jukes (28) | UK | 20 | Video game, 1.0 hr/day, daily, 7 weeks + occlusion | Close work + occlusion | 4.4 (1.3) | 4.1 (1.8) | 0 | 0 | Anisometropia, strabismus |
| Kämpf (26) | Germany | 14 | Video game with background stimulation, 0.75 hrs/ Tag, 5 days/week, 2 weeks + occlusion | Placebo game: without background stimulation + occlusion | 7 (n.s.) | 9 (n.s.) | 100 | 43 | Anisometropia, strabismus |
| Yeh (27) | Taiwan | 30 | Picture drawing on a tablet with background stimulation, 0.25 hrs/day, 5 days/week, 24 weeks + occlusion | Placebo: Picture drawing on a tablet without background stimulation + occlusion | 5.5 (0.4) | 5.4 (0.3) | n.s. | n.s. | Anisometropia |
I, intervention group; n.s., not specified; NZ, New Zealand; SD, standard deviation; hr, hour; UK, United Kingdom; CG: comparative group.
*1 Previous treatment with occlusion and/or other form of amblyopia treatment.
*2 Yao (16) is a 3-armed trial and is presented twice in the table.
The trials were conducted in Europa, North America, Asia, and Australia. Treatment duration ranged between two and 24 weeks, and the average age of the study population varied between 4.3 and 14.3 years. In four trials, only children with an initial diagnosis were treated. In the other trials, the proportion of cases which had undergone previous treatment was between 21 and 97%. Children with amblyopia due to anisometropia alone were examined in four trials. Training was conducted in three trials on an outpatient basis and in 14 trials at home.
The best corrected visual acuity of the amblyopic eye
Data for the endpoint “best corrected visual acuity of the amblyopic eye” are presented in the Table, stratified according to intervention and comparative treatment.
Table. Best corrected visual acuity of the amblyopic eye.
| Trial | Age (years) | Longest follow-up (weeks) | LogMAR visual acuity*1 at start of trial, mean (SD) | Change compared with start of trial (SD)*2 | MD [95% CI] or p-value*3 | ||
| I | CG | I | CG | ||||
| Binocular training versus no training (without additional occlusion) | |||||||
| Holmes (20) | 7–12 | 8 | 0.50 (n.s.) | 0.52 (n.s.) | −0.05 (n.s.) | −0.05 (n.s.) | −0.00 (p = 0.71) |
| Xiao (19) | 4–7 | 12 | 0.54 (0.21) | 0.50 (0.19) | −0.18 (0.16) | −0.09 (0.14) | −0.10 [−0.16; −0.04] |
| Binocular training versus no training (with additional occlusion) | |||||||
| Rajavi (18) | 3–10 | 4 | 0.34 (0.14) | 0.33 (0.17) | −0.17 (0.14) | −0.06 (0.08) | −0.11 [−0.17; −0.0.5] |
| Yao (16)*4 | 3–13 | 12 | 0.51 (0.25) | 0.46 (0.23) | −0.30*5 (0.21) | −0.28 (0.23) | −0.02 [−0.14; 0.10] |
| Binocular training versus sham training (without additional occlusion) | |||||||
| Herbison (22) | 4–8 | 10 | 0.49 (0.17) | 0.50 (0.20) | −0.07*5 (0.03) | −0.06*5 (0.02) | −0.01 [−0.08; 0.06] |
| Gao (21)*6 | 7–12 | 6 | 0.54 (0.17) | 0.54 (0.19) | −0.05 (0.13) | −0.11 (0.13) | 0.06 [−0.02; 0.14] |
| 13–17 | 0.62 (0.10) | 0.56 (0.18) | −0.06 (0.07) | −0.05 (0.08) | −0.01 [−0.08; 0.06] | ||
| Binocular training versus occlusion | |||||||
| Holmes (12) | 5–12 | 16 | 0.52 (0.17) | 0.48 (0.16) | −0.11 (0.15) | −0.14 (0.13) | 0.03 [0.00; 0.05] |
| 5–6 | 0.53 (0.19) | 0.45 (0.13) | −0.19*5 (0.18) | −0.20*5 (0.14) | 0.01 [−0.06; 0.08] | ||
| 7–12 | 0.51 (0.17) | 0.50 (0.17) | −0.08*5 (0.12) | −0.11*5 (0.11) | 0.03 [<0.00; 0.06] | ||
| Manh (13) | 13–16 | 16 | n.s. | n.s. | −0,07 (0,36) | −0.13 (0.04) | 0.06 [−0.04; 0.16] |
| Rajavi (14) | 3–10 | 4 | 0.29 (0.22) | 0.23 (0.13) | −0.08 (0.09) | −0.09 (0.09) | 0.01 [−0.05; 0.07] |
| Birch (15) | 4–10 | 2 | 0.48 (0.17) | 0.49 (0.15) | −0.15 (0.08) | −0.07 (0.08) | −0.08 [−0.13; −0.03] |
| Yao (16)*4 | 3–13 | 12 | 0.49 (0.29) | 0.46 (0.23) | −0.18*5 (0.23) | −0.28*5 (0.23) | +0.10 [−0.01; 0.21] |
| Rajavi (17)*7 | 4–10 | 4 | 0.30 (0.03) | 0.40 (0.03) | −0.07 (0.02) | −0.08 (0.01) | +0.01 [−0.00; 0.02] |
| Monocular training versus no training (without additional occlusion) | |||||||
| Iwata (23) | 3–8 | 24 | 0.25 (0.09) | 0.24 (0.08) | −0.30 (k. A.) | −0.19 (k. A.) | −0.11 (p <0.0001) |
| Monocular training versus no training (with additional occlusion) | |||||||
| Dadeya (24)*8 | 4–10 | 12 | 0.89 (0.16) | 0.84 (0.19) | −0.43 (0.16) | −0.30 (0.16) | −0.13 [−0.20; −0.03] |
| Monocular training versus sham training (with additional occlusion) | |||||||
| Bau (25) | 4–10 | 4 | 0.84 (0.32) | 0.71 (0.23) | −0.22 (0.21) | −0.20 (0.16) | −0.02 [−0.20; 0.16] |
| Jukes (28) | 2–7 | 7 | 0.59 (0.30) | 0.71 (0.25) | −0.15*5 (0.18) | −0.18*5 (0.12) | +0.03 [−0.11; 0.18] |
| Kämpf (26)*9 | 6–14 | 2 | n.s. | n.s. | n.s. | n.s. | n.s. (p = 0.11) |
| Yeh (27) | 4–8 | 24 | 0.35 (0.06) | 0.28 (0.03) | −0.27 (0.04) | n.s. | n.s. (p <0.05) |
I, intervention group; n.s., not specified; CI, confidence interval; logMAR, logarithm of the minimum angle of resolution; MD, mean difference; SD, standard deviation; CG, comparative group; vs., versus
Values in bold indicate a statistically significant effect.
*1 MAR denotes the “Minimum Angle of Resolution” (smallest visual angle below which 2 points are still perceived separately) and represents the reciprocal of the visual acuity (visual acuity = 1/MAR). If the visual acuity is averaged, then the logarithm (log) is used (logMAR = log[1/visual acuity]). LogMAR values are therefore opposite of visual acuity values (logMAR = -log[visual acuity]). For comparability of the visual acuity data: 0.1 logMAR corresponds to 1 line or 5 letters on the eye chart.
*2 If not otherwise stated, intention-to-treat (ITT) analysis
*3 Mean difference (MD) in logMAR: - (minus) sign: in favor of intervention; + (plus) sign: in favor of controls. p-value only stated if no 95% CI calculable.
*4 Yao (16) is a 3-armed study and is presented twice in the Table.
*5 Only those individuals were evaluated who participated in the final examination.
*6 Adults were also included in the trial by Gao (21); visual acuity, however, is reported by age stratification.
*7 Without providing numerical values, Rajavi (17) reports that, after adjusting for baseline visual acuity, the intervention group performed better by 10, although the change was not significant. The effect size and CI reported in the table refer to self-calculated, unadjusted values.
*8 In der trial by Dadeya (24) the clinical relevance level of -0.05 logMAR was exceeded after 9 weeks: MD -0.15, 95% CI [-0.24; -0.06].
*9 Kämpf (26) conducted an ANOVA test with repeated measurements and reported the p-value.
Vision training versus no training
When binocular vision training is compared with no training, then two out of four trials treating three- to ten-year-old children demonstrated effects in favor of the intervention: mean difference [MD] in logMAR: -0.10; [-0.16; -0.04] and -0.11; [-0.17; -0.05], respectively. The effect estimators of the two other trials which treated three- to thirteen-year-olds pointed in the same direction (in favor of the intervention), although the group difference was not statistically significant. The two trials on monocular training also demonstrated a statistically significant superiority of digital training: MD in logMAR: –0.11; 95% CI not calculable; [0.0001; -0.04] and –0.13; [-0.20; –0.03], respectively. It is not possible to deduce from the available data whether additional occlusion therapy enhanced the effect of the digital intervention.
Vision training versus sham training
The two trials which compared binocular training with sham training did not find any statistically significant group differences: MD in logMAR: –0.01; [0.08; -0.06] and 0.06; [-0.02; 0.14], respectively. One of four trials reported a statistically significant effect in favor of vision training in four- to eight-year-olds for monocular training. Due to an absence of numerical values, however, it is not possible to estimate in which area this improvement lies. One of the trials without a significant effect also failed to report any numerical values. The MD in logMAR of the two others was -0.02 and 0.03, with a 95% confidence interval of [-0.20; 0.16] and [-0.11; 0.18], respectively.
Vision training versus occlusion therapy
One of six trials demonstrated a significant difference in favor of binocular training in four- to ten-year-olds: MD in logMAR: –0.08; [-0.13; –0.03]. The effect estimators were in favor of the occlusion therapy in the other five trials which covered a wide age range (three- to sixteen-year-olds).
Endpoint binocular vision
eTable 3 contains data on the endpoint “binocular vision”.
eTable 3. Binocular vision.
| Trial | Age (years) | Longest follow-up (weeks) | Log angle-seconds at start of trial, mean (SD) | Change compared with start of trial (SD)*1 |
MD [95% CI]
or p-value *2 |
||
| I | CG | I | CG | ||||
| Binocular training versus no training (without additional occlusion) | |||||||
| Holmes (20) | 7 – 12 | 8 | Randot Preschool Stereoacuity Test, Butterly Test: no difference | ||||
| Xiao (19) | 4 – 7 | 12 | 3.3 (0.6) | 3.1 (0.8) | -0.0 (0.6) | -0.1 (0.5) | Titmus Test: +0.1 [−0.2; +0.3] |
| Binocular training versus no training (with additional occlusion) | |||||||
| Yao (16)*3 | 3–13 | 12 | 2.8 (0.8) | 2.5 (0.6) | 0.6 (0.7)*4 | 0.2 (0.4)*4 | Titmus Test: +0.4 [+0.1; +0.7] |
| Binocular training versus sham training (without additional occlusion) | |||||||
| Herbison (22) | 4 – 8 | 10 | Frisby Test: no statistical difference between the groups | ||||
| Binocular training versus occlusion | |||||||
| Holmes (12) | 5 – 12 | 16 | 3.3 (–)*5 | 2.9 (−)*5 | 0.0 (n.s.)*4 | 0.0 (n.s.)*4 | Randot Preschool Stereoacuity Test, Butterly Test: no difference |
| Manh (13) | 13 – 16 | 16 | n.s. | n.s. | 0.0 (n.s.)*4 | 0.0 (n.s.)*4 | Randot Preschool Stereoacuity Test, Butterly Test: no difference |
| Rajavi (14) | 3 – 10 | 4 | 2.6 (1.8) | 3.5 (2.5) | 0.3 (n.s.)*4 | 0.0 (n.s.) | Titmus Test: no difference |
| Birch (15) | 4 – 10 | 2 | 4.0 (2.9; 4.0)*5 | 4.0 (2.6; 4.0)*5 | 0.0 (n.s.) | 0.0 (n.s.) | Randot Preschool Stereoacuity Test, Butterly Test: no difference |
| Yao (16)*3 | 3 – 13 | 12 | 2.7 (0.7) | 2.5 (0.6) | 0.4 (0,8) | 0.2 (0.4) | Titmus Test: +0.2 [−0.1; +0.5] |
| Monocular training versus sham training (with additional occlusion) | |||||||
| Bau (25) | 4 – 10 | 4 | Titmus Test, Bagolini Test: no statistically significant difference between the groups | ||||
I: intervention group; n.s.: not specified; CI: confidence interval; MD: mean difference; SD: standard deviation; CG: comparative group; vs.: versus. Values in bold indicate a statistically significant effect.
*1 If not otherwise stated, intention-to-treat (ITT) analysis.
*2 Mean difference in log angle-seconds: + (plus) sign, in favor of intervention; – (minus) sign, in favor of control. p-value only stated if no 95% CI calculable.
*3 Yao (16) is a 3-armed trial and is presented twice in the table.
*4 Only the data of individuals analyzed who participated in the final examination.
*5 Median and interquartile range (if stated in the publication).
Vision training versus no training
One of three trials demonstrated a significant effect in favor of binocular training in three- to thirteen-year-olds: MD in log angle-seconds: +0.38; [+0.06; +0.70]. One of the two trials without a significant difference did not publish any explicit data. The effect estimator of the other trial was +0.10; [–0.19; +0.34].
Vision training versus sham training
Altogether, two trials (without providing numerical values) reported that no group differences were found for binocular vision.
Vision training versus occlusion therapy
Group differences were found in none of the five trials. One study stated an effect estimator: MD in log angle-seconds: +0.20; [–0.10; +0.50].
Adverse effects
Adverse outcomes, such as double vision, asthenopia (eyestrain) and headache, dizziness, increased blinking, or nightmares were reported in seven studies (eTable 4). However, these events only occurred occasionally, and it is not to be expected that digital training is associated with an increased risk of adverse events.
eTable 4. Adverse events.
| Adverse event | Trial | Intervention | Comparison | Intervention vs. comparison | ||||
|
N
evaluated |
n
with event |
(%) |
N
evaluated |
n
with event |
(%) | RR [95% CI]) | ||
| Double vision | Herbison (22) | 26 | 1 | (4) | 24 | 0 | (0) | 2.78 [0.12; 65.08] |
| Holmes (12) | 182 | 16 | (9) | 188 | 7 | (4) | 2.36 [0.99; 5.60] | |
| Holmes (20)*1 | 67 | 2 | (3) | 69 | 0 | (0) | 5.15 [0.25; 105.26] | |
| Manh (13) | 39 | 2 | (5) | 56 | 2 | (4) | 1.44 [0.21; 9.76] | |
| Xiao (19) | 51 | 0 | (0) | 54 | 1 | (2) | 0.35 [0.01; 8.46] | |
| Asthenopia and headache | Xiao (19) | 51 | 4 | (8) | 54 | 1 | (2) | 4.24 [0.49; 36.64] |
| Decreased visual acuity (amblyopic eye) | Herbison (22) | 26 | 0 | (0) | 25 | 2 | (8) | 0.19 [0.01; 3.82] |
| Xiao (19) | 56 | 2 | (4) | 54 | 4 | (7) | 0.48 [0.09; 2,52] | |
| Rajavi (18) | 25 | 0 | (0) | 25 | 0 | (0) | not calculable | |
| Decreased visual acuity (dominant eye) | Xiao (19) | 51 | 2 | (4) | 54 | 0 | (0) | 4.82 [0.24; 98.24] |
| Newly diagnosed strabismus*2 | Holmes (12) | 182 | 16 | (9) | 188 | 11 | (6) | 1.50 [0.72; 3.15] |
| Holmes (20) | 67 | 9 | (13) | 69 | 9 | (13) | 1.03 [0.44; 2.40] | |
| Manh (13) | 39 | 3 | (8) | 56 | 3 | (5) | 1.44 [0.31; 6.75] | |
| Xiao (19) | 51 | 3 | (6) | 54 | 3 | (6) | 1.06 [0.22; 5.01] | |
| Nausea or dizziness | Xiao (19) | 51 | 1 | (2) | 54 | 0 | (0) | 3.17 [0.13; 76.16] |
| Increased eye twitching | Xiao (19) | 51 | 1 | (2) | 54 | 0 | (0) | 3.17 [0.13; 76.16] |
| Nightmares | Xiao (19) | 51 | 1 | (2) | 54 | 0 | (0) | 3.17 [0.13; 76.16] |
| Conjunctivitis | Herbison (22) | 26 | 0 | (0) | 24 | 0 | (0) | not calculable |
| Skin irritation (due to occlusion) | Dadeya (24) | 20 | 3 | (15) | 20 | 2 | (10) | 1.50 [0.28; 8.04] |
| Holmes (12) | 182 | 0 | (0) | 188 | 3 | (2) | 0.15 [0.01; 2.84] | |
| Manh (13) | 39 | 0 | (0) | 56 | 1 | (2) | 0.47 [0.02; 11.36] | |
| Xiao (19) | 51 | 1 | (2) | 54 | 0 | (0) | 3.17 [0.13; 76.16] | |
| Yao (16) | 22 | 0 | (0) | 30 | 1 | (3) | 0.45 [0.02; 10.54] | |
CI, confidence interval; RR, relatives risk; vs., versus
*1 Holmes (20) reports of double vision occurring more than once per week. The data refers to the measurement time point of 4 weeks.
*2 Newly diagnosed strabismus and worsening of pre-existing eye deviation by >10 prism diopters.
Risk of bias
The risk of bias was rated as low in one trial (21) and high in 16 trials. Studies in which vision training was compared with no training or occlusion generally do not allow blinding of treatment. Therefore, it cannot be excluded that, to an uncertain degree, the study results are due to the awareness of the study population and the study staff of the respective intervention. In addition, there is uncertainty about adherence to the training plan (compliance). For example, deviations are reported in up to 87% of cases. Furthermore, it remains uncertain whether the children and adolescents wore the glasses, which are required for image separation, all the time and how often their eyes wandered from the screen. Details of the risk-of-bias assessment are shown in eTable 5.
eTable 5. Risk of bias.
| Trial | Bias from | |||||
| randomization process | deviations from intended intervention*1 | missing endpoint data | measurement of the endpoint | selective reporting | Total | |
| Binocular training versus no training (without additional occlusion) | ||||||
| Holmes (20) | low | high*2 | low | low | low | high |
| Xiao (19) | low | high*2 | low | low | low | high |
| Binocular training versus no training (with additional occlusion) | ||||||
| Rajavi (18) | low | high*2 | low | high*6 | low | high |
| Yao (16) | some concerns*3 | high*2 | high*4 | low | low | high |
| Binocular training versus sham training (without additional occlusion) | ||||||
| Herbison (22) | some concerns*3 | high*2 | high*4 | low | low | high |
| Gao (21) | low | some concerns | low | low | low | low |
| Binocular training versus occlusion | ||||||
| Holmes (12) | low | high*2 | low | low | low | high |
| Manh (13) | low | high*2 | low | high*6 | low | high |
| Rajavi (14) | low | high*2 | high*4 | high*6 | low | high |
| Birch (15) | some concerns*3 | high*2 | low | high*6 | low | high |
| Yao (16) | some concerns*3 | high*2 | high*4 | low | low | high |
| Rajavi (17) | low | high*2 | high*4 | high*6 | low | high |
| Monocular training versus no training (without additional occlusion) | ||||||
| Iwata (23) | some concerns*3 | high*2 | low | high*6 | some concerns*7 | high |
| Monocular training versus no training (with additional occlusion) | ||||||
| Dadeya (24) | some concerns*3 | high*2 | low | high*6 | some concerns*7 | high |
| Monocular training versus sham training (with additional occlusion) | ||||||
| Bau (25) | some concerns*3 | some concerns | some concerns*5 | low | some concerns*7 | high |
| Jukes (28) | some concerns*3 | high*2 | high*4 | low | some concerns*7 | high |
| Kämpf (26) | some concerns*3 | some concerns | some concerns*5 | low | some concerns*7 | high |
| Yeh (27) | some concerns*3 | some concerns | low | low | low | high |
*1 In general, there are uncertainties about adherence to the allocated training plan and implementing the treatment. For example, deviations from the training plan are reported in up to 87% of cases (Manh [13]). It also remains uncertain with binocular training whether the children and adolescents actually wore the anaglyph glasses, which are used for image separation during digital training, during the training or how often the eyes of the trainees wandered from the screen (due to distraction or lack of concentration).
*2 No blinding of trial participants.
*3 Although the studies are reported as randomized, information on the generation of the randomization sequence is missing or insufficiently precise, or it remains unclear whether randomization was carried out in a blinded manner.
*4 Missing results data due to dropouts.
*5 Missing information about whether all randomized/included individuals participated, including in the final examinations.
*6 The individual who registered the endpoint was not blinded. As this is a subjective assessment procedure (measurement of visual acuity or binocular vision), it cannot be ruled out that the result was influenced by awareness of which intervention the study participants received.
*7 No information on the planned endpoints are available (neither study protocol nor study registry entry available).
Discussion
Whereas conventional amblyopia therapy is usually integrated as part of everyday life, the actual technique used for vision training often determines whether the procedures are used at home or a visit to the outpatient clinic is needed. Vision training often requires many sessions, and the organizational effort can be quite demanding if it is conducted on an outpatient basis. A transfer to the home setting is therefore of advantage. However, such a transfer can only be successful if the available equipment allows it and if the children are supported when using the devices and games. Yet the present review shows that compliance issues often develop (eTable 5). Younger children in particular experienced concentration difficulties. With adolescents, on the other hand, it was often a question of boredom because the video games offered are inferior to the innovative computer game genres (10). Apart from the lack of compliance, there is also a heightened risk awareness in the parents with regard to digital treatment methods. It is therefore understandable that the use of digitally supported forms of treatment for children and adolescents is approached critically (31). The decision-making process should therefore involve the following elements:
● Treatment benefits: Although individual trials have shown a statistically significant effect in favor of vision training, it cannot be assumed that the measured differences are of any clinical relevance. For example, the upper and lower limits (95% CI) of the measured MDs for the best corrected visual acuity of the amblyopic eye were -0.03 logMAR (improvement of about +0.3 lines on the eye chart) and -0.20 logMAR (+2.0 lines), respectively. If the published value of -0.05 logMAR (+0.5 lines) is used as the non-inferiority limit for visual acuity (12), then only one study managed to exceed this threshold value (24): The lower and upper limits of the measured MDs after nine weeks were –0.06 logMAR (+0.6 lines) and –0.24 logMAR (+2.4 lines), respectively. A lack of any effect when comparing vision training with sham training could be due to the comparative intervention: For example, in binocular training, different contrast elements were not incorporated into the sham training, but the children still wore image-separating glasses. In monocular training, the background stimulation used for neural stimulation was dispensed with in the sham intervention. It therefore cannot be ruled out that the sham training has the same effect as the intervention which the studies examined. If vision training is compared with occlusion therapy, then—with the exception of one trial (15)—no statistically significant effects were identified in favor of vision training. On the contrary, the effect estimators were in favor of occlusion therapy. Little study data is available for binocular vision, and only one trial (16) demonstrated any benefit in favor of digital treatment. When interpreting the results, it must also be taken into account that, although the stereo tests used (for example, the Titmus test) are suitable for recognizing deficits, they are not good at quantifying thresholds (32). From the heterogeneous study pool available, it was also not possible to deduce whether the age of the children or the form of amblyopia could possibly have an impact on the treatment effect.
● Treatment costs: The average total cost of conventional amblyopia treatment per patient for the first year of treatment is between 606 and 646 euros (10). Except for a personal contribution of about 92 euros, these costs are reimbursed by the statutory health insurance system. Since digital training methods have so far only been used as a supplement to conventional treatment in Germany, these costs are incurred with each amblyopia treatment. If the vision training is provided by Caterna Vision as concomitant therapy, then the overall costs are increased by 380 euros per person. The costs for Caterna vision training, which is limited to three months, are only covered by certain health insurance funds within the scope of selective contracts. Apart from Caterna vision training, the insurance funds do not otherwise reimburse vision training (10).
Ethical aspects: The vulnerability of the population also plays a role in the decision-making process (10). A too-early exposure to digital media has its risks and can lead to increased media consumption. Furthermore, health games fall under the category “Serious computer games” because video games are used as both recreation and a therapeutic measure. “Gaming disorder” as defined in the ICD-11 is also recognized by the WHO as an official disease.
Apart from the present article, other systematic reviews (33–35) have also been published in recent years. The conclusions of these articles are comparable with the present results, and the authors point out that, at the moment, replacement of conventional therapy by digital therapies cannot be recommended. Furthermore, another randomized study was published in 2022 which assessed Caterna vision training (36). This study included 37 children from the Russian Federation, some with bilateral amblyopia or pathological alterations of the fundus. This patient population did not fulfill the inclusion criteria of the present review, so the trial was not included in the results section. Although the study authors concluded that the children of the intervention group demonstrated a significantly better monocular visual acuity after ten days of treatment as compared with controls, it does not appear that the differences found in this trial are of any clinical relevance either. Other randomized studies published since the last literature search also suggest no clinically relevant effects of digital vision training (for example, 37, 38).
Conclusions
Overall, the available studies do not allow a conclusive statement on the benefits and harms of vision training in children and adolescents with amblyopia. Apart from the marginal effect and often absent compliance, it must be considered that the duration of treatment in the trials was set at a few weeks and does not really reflect the results of amblyopia treatment, which often lasts for some years. It was also not possible to deduce from the heterogeneous study pool available whether children with amblyopia due to anisometropia achieve better results than children with amblyopia caused by strabismus or whether the age of the children had an impact on the effect of treatment. Such results would be particularly important for estimating whether certain patient populations would possibly benefit from such treatment.
Acknowledgments
Acknowledgments
We would like to thank Ms Carolin Wolf (orthoptist at the Freiburg Eye Clinic) for her specialist expertise.
Funding
This systematic review is part of a Health Technology Assessment (HTA) and was financed by the Institute for Quality and Institute for Quality and Economic Efficiency in Health Care (HTA-21–03).
Translated from the original German by Dr. Grahame Larkin, MD.
Footnotes
Conflict of interest statement
The authors confirm that there are no conflicts of interest.
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