Binocular vision therapy for the treatment of Amblyopia—A review

Abstract

Amblyopia is a monocular or binocular reduction in visual acuity that results from prolonged visual deprivation in the early years of life. It is second only to refractive error as a cause of poor vision in children. The gold standard treatment of amblyopia includes patching and, less commonly, atropine penalization and filters. These therapies are aimed at improvements in the visual acuity of the amblyopic eye alone. They have compliance and psychosocial issues and gains are accrued after prolonged periods. Experimental studies have demonstrated the presence of binocular cortical communication even in amblyopes and neural plasticity in late childhood as well as adulthood. On this basis, binocular vision therapy aimed at the stimulation of both eyes rather than forced use of the amblyopic eye was developed. Such therapies involve visual tasks designed in such a way that they can be completed only by binocular viewing. These tasks vary from simple game play using red-green glasses, to engaging 3D games and movie viewing. Preliminary data suggest that binocular vision therapy has led to lasting improvements in visual acuity and can be a useful adjunct, if not replacement, to the conventional treatment of amblyopia. In this article, we aim to describe the various binocular vision therapies and review the available literature on the same.

Amblyopia can be generally defined as a monocular (less commonly, binocular) reduction of visual acuity for which no organic cause can be found. It results from a prolonged period of inadequate visual experience during the early years of life, commonly due to one or more amblyogenic factors such as strabismus (ocular misalignment), anisometropia (refractive imbalance), or both (combined).

The global prevalence of amblyopia is 2–5% and it is second only to refractive error as the most common cause of vision loss in infants and children.[1] The functional deficits resulting from amblyopia include reduced contrast sensitivity,[2] poor spatial localization,[3] poor stereovision,[4] and foveal crowding.[5] The theoretical assumption is that amblyopia results from a mismatch between the images in each eye, such that information from the weaker eye is suppressed leading to poor visual acuity in that eye. Patching, atropine, and filters that penalize the fellow eye and “force” the monocular use of the amblyopic eye have been used to treat amblyopia for hundreds of years.[6]

Landmark clinical trials such as the Pediatric Eye Disease Investigator Group (PEDIG) trials have recommended 12 to 24 weeks of wearing prescribed optical correction as first-line treatment for amblyopia, which improves amblyopic eye acuity to normal levels in 27% to 32% of cases. This is known as “optical treatment” or “refractive adaptation.” Otherwise, patching or atropine penalization of the fellow eye is tried. Such occlusion therapies improve acuity in approximately 70% of patients by 0.2logMAR or more.[7-10] However, not all children respond to traditional therapies and patching is complicated by compliance and psychosocial issues. Studies have shown that compliance with patching averages less than 50% of the prescribed time[11,12] and gains in visual acuity (VA) are accrued after long periods. Moreover, amblyopia was seen to recur in nearly 25% of patients after discontinuation of therapy for almost a year.[13]

Children with amblyopia are known to have abnormal stereo acuity (a binocular function) and binocular summation. An imbalance of inter-ocular suppression which favors the dominant eye over the amblyopic eye during binocular viewing was demonstrated in experimental studies.[14] Therefore, amblyopia is intrinsically a binocular problem, rather than a monocular one. Studies have shown that some amount of binocular cortical communication still exists in amblyopes. Exploiting these intact neural circuits to awaken the amblyopic eye forms the basis of binocular vision therapy.[15-17] Usually, the “critical period” for the treatment of amblyopia is known to be 5–7 years but PEDIG and other trials have shown the efficacy of patching even beyond 7 years,[18,19] suggesting that cortical plasticity is seen even in late childhood. Hence, the need arises for a therapy that decreases suppression and restores binocular functions in both children and adults.

Binocular vision therapy is based on simultaneous binocular visual stimulation (dichoptic treatment) and improves overall binocular function and stereo acuity. Such therapies often involve playing computer games and watching movies on digital displays, which are more appealing and improve compliance. Binocular vision therapy includes perceptual learning and dichoptic training. This review aims at a discussion of these therapies and their recent advancements.

Perceptual Learning

Introduced in 1963 by Eleanor Gibson,[20] perceptual learning is an application of the old proverb—Practice makes perfect. It involves practicing recognition of repeated visual stimuli. These stimuli may be in the form of Vernier acuity, Gabor detection, positional discrimination, letter identification in noise, position discrimination in noise, and contrast detection.[21] The first such device was the Cambridge Visual Stimulator (CAM), in which patients view high-contrast rotating sine-wave gratings with the amblyopic eye.[22] With technological advancements, a number of interactive perceptual learning software became available. In an early study, Polat et al.[23] reported gains in visual acuity when subjects participated in a learned trial of Gabor signals. A reduction in lateral inhibition pathways in the brain forms the neural basis for this improvement as reported by Maniglia et al.[24] Another study with amblyopic children aged 7–10 years also showed improved visual performance with a positional acuity task.[25] Many small studies involving positional discrimination, Snellen’s acuity, and contrast sensitivity in amblyopic children showed success.[25,26]

Adult amblyopes have also shown increased contrast sensitivity, improvement in VA and letter-recognition tasks, and reduction of the crowding effect via repetition of visual tasks. Chung et al.[27] observed a significant reduction in contrast thresholds of the amblyopic eye for identifying contrast-defined letters. Zhou et al.[28] found similar results, with improvements in VA lasting for up to a year.

Successful patching takes very long to show results, whereas most studies on perceptual learning use brief periods of training. Li et al.[29] showed that severe amblyopia requires about 50 hours (≈35,000 trials) to yield a five-fold improvement in performance, with a transfer of learning from the amblyopic to the dominant eye. Huang et al.[30] theorized that perceptual training improves contrast sensitivity by the exclusion of external noise and reduction of the internal noise in the visual system of amblyopes, in whom this mechanism is more robust than normal adults. Ding et al.[31] demonstrated recovery of stereopsis following perceptual learning with stereoscopic gratings. Improvements in contrast sensitivity, sensitivity of motion detection, and VA have been noted in as early as 10 days.[32] Improvements in the phenomenon of crowding were demonstrated by Chung et al.[33] and Hussain et al.[34] Eleven subjects with anisometropic or ametropic amblyopia were trained to judge depth and improvements in their stereovision were seen over 10 to 13 sessions.[35] These results show that the mature amblyopic brain is surprisingly malleable, and warrant more intensive treatment methods for adult amblyopia. Also, contrary to earlier belief that improvements with perceptual learning are limited to specific visual tasks, this improvement is durable and generalized.[36] Singh et al. compared combined monocular video game play (1 hour) and occlusion therapy (6 hours/day) to occlusion alone (6 hours/day) in a cohort of 68 children with anisometropic amblyopia. Significant improvement in VA in the combined group was noted after 1 and 3 months.[37]

Ooi et al. described a binocular “push–pull” protocol based on perceptual learning, where the improvement is achieved with an emphasis on the total inhibition of the stronger eye while forcing excitation of the amblyopic eye, using fixation targets of varying contrasts. The effects of this exercise last for 4 months even after training ends, suggesting long-term changes in cortical plasticity.[38] Even monocular visual perception training leads to binocular function gains.[39,40]

Although a promising therapy, the limitations of perceptual learning are the small size of these studies, lack of long-term follow-ups, limited visual tasks that cannot be reproduced in novel situations, and lack of home-based therapy.

Dichoptic Training

Dichoptic training is a visual training process involving the presentation of independent stimuli to each eye simultaneously and the integration of the two stimuli under binocular viewing conditions. The contrast or quality of the image presented to the amblyopic eye is higher than the fellow eye. Gradually, the contrast difference between the two eyes is reduced, potentially to a point where no difference is seen. VA gains follow improvements in binocularity and contrast sensitivity. This is unlike perceptual learning tasks in which one identical stimulus is presented to both eyes simultaneously or under monocular viewing conditions.

Early reports of dichoptic training used this concept in a clinic-based setting with adult amblyopes[41-44] and demonstrated the potential for amblyopia treatment beyond the critical period. Hess et al.[41] showed significant improvements in amblyopic eye VA and stereo acuity in nine adults (four of whom had prior patching treatment).

To shift therapy from a clinic-based task to a home-based one, the design had to be more user-friendly. An iPod display with a lenticular overlay (a textured screen that produces images with a perception of depth, for example, holograms) allowed for viewing the dichoptic stimuli was designed, but required stable head positioning. Although successful, it is challenging to use.[45] A transition from the lenticular design to anaglyphic (red-green dichoptic) images using red-green glasses overcame this limitation, so that it could be used by young children and unsupervised patients.[46]

Binocular iPod-Based Therapy

Some early binocular approaches to amblyopia, such as the I-BiT[47] and “Push-Pull” system,[38] were aimed at the recovery of fusion and re-establishment of binocular vision. Hess et al.[42] developed a dichoptic contrast balancing system for amblyopic adults in 2010, where complementary stimuli were given to balance the contrast between the amblyopic and the normal eye such that completion of the given visual task could be done only by binocular integration. As improvements in the VA of the amblyopic eye were seen, an adaptation of this system using a falling blocks (Tetris) video game on an Apple iPod was developed.[43] In this game, a second-generation iPod with a lenticular screen overlay and the Tetris block game was used. The lenticular screen uses alternate rows of pixels aligned at an angle such that the blocks are visible to only one eye at a time. The amblyopic eye receives a display at a higher contrast, whereas the normal fixing eye, at a lower contrast. Simultaneous viewing with both eyes is required to play the game. The degree of progressive reduction in the inter-ocular contrast helps to quantify improvements in suppression. Out of 10 subjects, nine showed this improvement in 2 weeks by engaging in 1 to 3 hours of play per day, while six showed improvements in stereopsis. This pilot study targeted binocular function as opposed to patching which is only directed at the amblyopic eye. Moreover, the dose–response relationship was much shorter (36 hours) compared to patching and the technique was effective even for middle-aged adults.

The BRAVO study was a randomized placebo-controlled multicenter trial of 108 participants aged 7 years or older with anisometropic and/or strabismic amblyopia. In this trial, a falling-blocks game on a fifth-generation iPod touch device viewed through red/green anaglyphic glasses was used as a home-based treatment for 6 weeks.[48] However, primary results after 6 weeks did not show improvements as expected.[49] Poor compliance, dose-continuity effects, or a failure of the particular method could be the possible causes.

Interactive Binocular Treatment (I-BiT)

An interactive binocular treatment (I-BiT) system was developed to treat amblyopia using dichoptic stimuli presented via virtual reality (VR) game play or movie watching.[50] This was software specifically designed to appeal to children and improve compliance. It involves the dichoptic presentation of videos (such as short films) or simple video games (such as a collection of coins) with the background presented to both eyes and foreground elements presented only to the amblyopic eye. This ensures that the amblyopic eye of the patient is preferentially stimulated during treatment.

Results of early I-BiT studies were promising, showing improvement in VA of both pediatric and adult patients.[47,50,51] With advancements in 3D viewing technology, the use of shutter glasses in video games was introduced, where the glasses lighten and darken in synchrony with the monitor, but faster than the user can perceive.[52]

A randomized controlled trial by Herbison et al.[53] compared the effect of 3 h (30 min per week) of dichoptic videos versus dichoptic video games versus non-dichoptic (control) video games on amblyopic eye visual acuity in 75 children aged 4–8 years. All the subjects in the three groups were given shutter glasses to present the dichoptic stimuli but in the control group, the same image was sent to both eyes. Authors found much smaller gains in visual acuity (mean 0.07LogMAR) with no difference between treatment groups. However, this study had limitations in that the majority of the participants in the trial had received previous patching treatment (76%) and their potential for visual acuity improvement was limited. Furthermore, the period of therapeutic intervention per week as well as the total treatment duration (3 hours) was very short. Lastly, the study included strabismic amblyopes without any mechanism to compensate for the angle of deviation.

An I-BiT system redesigned for home use is under trial which can deliver a daily treatment dose and adjust for the angle of deviation in strabismic eyes. The trial will involve treatment-naive anisometropic, strabismic, and mixed amblyopes aged 3.5 to 12 years of age.[54]

Binocular iPad-Based Therapy

Video games have varied demands and immersive visual experiences for the player, hence the potential to improve visual performance in amblyopia. But studies using dichoptic iPad therapy have shown mixed results. By translating the Hess Falling Blocks game onto an iPad, Birch and colleagues conducted a small study on children aged 4–12 years playing this game wearing red-green anaglyphic glasses for 4 hours/week over 4 weeks and saw significant improvement in amblyopic eye logMAR acuity.[46] Another study by Li et al. in preschool children confirmed dose–response relationship in the improvement in VA of the amblyopic eye. Children completing 8 total hours of game play during the 4-week study had significantly greater improvement than those playing 0–4 hours.[55]

In 2015, PEDIG conducted the first large-scale, multicenter randomized controlled trial comparing the effectiveness of 1 hour/day, 7 day/week binocular game play to 2 hours/day patching in children <13 years. The same regimen was examined in children aged 13 to <17 years. Results in the younger cohort showed similar improvements in both types of treatment at 16 weeks. However, poor compliance in the binocular game group was seen.[56] The older cohort (13 to <17 years) results were similar with compliance being similarly poor.[57] Gao et al. compared 1 hour of home-based, dichoptic falling-blocks video game play to a placebo game in participants older than 7 years, including adults. No significant difference in the VA of the groups was seen after 6 weeks of treatment. They found no difference in age effect, type of amblyopia, or impact of prior occlusion treatment.[49] Another comparative study with 28 children, who were randomized to either binocular game treatment or patching, showed after 2 weeks that the binocular iPad game was more efficacious than patching in treating amblyopia. However, the period of the study was too short.[58] More recently, a study of 48 children aged 4 to 10 years, either patched or playing a contrast rebalanced dichoptic game (Dig Rush), showed a larger improvement after 2 weeks for the game group than for the patched group.[59] Children with moderate amblyopia and orthotropia had more VA improvement than those with severe amblyopia. So did children who spent more time playing the binocular game.

Many of the studies may not have shown the expected improvements in the VA but these studies have several limitations. Most of the earlier trials were small-scale studies which are inherently subject to placebo effects, Hawthorne effects, regression toward the mean, and selection bias. Secondly, it is important to carefully align the images to the two eyes, which is critical for binocular combination with strabismus, but some of the trials did not do so. Finally, non-compliance may be a problem, even though this is ironic. Even the most immersive games may not be stimulating enough to be played for 1–2 hours for several days in a week, whereas a number of activities can be performed with a patch over the eye.

Perhaps, more work in the field of passive dichoptic movie viewing, smartphone games, and head-mounted virtual reality games could solve compliance issues.

In a study by Roy et al.,[60] a new smartphone-based dichoptic video game play (2 hours/day) was compared to occlusion therapy (6 hours/day). At 3 months, VA and contrast sensitivity was significantly better in the smartphone video game group with improvements in near stereo acuity seen only in this group.

Dichoptic Training Using Head-Mounted Display

Head-mounted VR displays have also shown preliminary evidence to suggest improvement in both VA and stereo acuity in adults,[61] so has video game play.[62,63] Vedamurthy et al.[62] demonstrated retention of VA and stereo acuity after 2 months. Continuously evolving technology will help to present dichoptic stimuli in more engaging and interactive platforms, thereby improving effectiveness and compliance.

In another pilot study,[61] adult participants were invited to play two computer games with a dichoptic setting, using a VR head-mounted device Oculus Rift (Oculus, Menlo Park, CA, USA) twice a week, over a period of 4 weeks in total. The majority of the participants demonstrated significant improvement in VA of the amblyopic eye as well as stereopsis. This is in agreement with previous dichoptic training studies and confirms the hypothesis of residual cortical plasticity. This study had several limitations such as a small sample size, short follow-up, and absence of a control group; with the added challenge of adult amblyopes having received some form of treatment for amblyopia, thereby making comparison difficult. Table 1 summarizes the major clinical studies on binocular vision therapy in amblyopia.

Table 1.

Summary of the major clinical studies conducted to evaluate the use of binocular vision therapy for the treatment of amblyopia.

Author (year)	Patients	Treatment	Results	Follow-up
Waddingham et al.50 (2006)	6	VR* based I-BiT system	Mean improvement in VA* of 13 letters (3.25 lines on Keeler LogMAR chart)	4 weeks
Cleary et al.47 (2009)	12	I-BiT system	Mean improvement in high-contrast VA of 0.177 log units	3-18 months
Hess et al.42 (2010)	9	Dichoptic motion stimuli (moving dots) detection task	Improvements in VA (P<0.008) and stereopsis (P=0.012)	2-6 weeks
Hess et al.43 (2012)	10	iPod binocular Tetris game	Nine of 10 participants showed improvements in amblyopic eye VA (P=0.008). Six of 10 participants showed an improvement in stereo sensitivity (P=0.028)	6-36 h of training
Li et al.44 (2013)	18	Head-mounted Tetris video game	Improvement in VA (P<0.0001) and stereoacuity (P=0.02)	3 months
Herbison et al.51 (2013)	10	I-BiT system based video- game and video watching	67% of those who completed the treatment showed a clinically significant improvement of 0.125 LogMAR units or more	6 weeks
Hess et al.17 (2014)	14	Home-based iPod binocular video game	Improvements in VA (0.11±0.08 logMAR) and stereopsis (0.6±0.5 log units).	30-40 days
Li et al.55 (2014)	75	Binocular iPad games	Mean VA improved from 0.47±0.03 to 0.39±0.03 logMAR at 4 weeks. No change in stereoacuity.	4 weeks
Vedamurthy et al.62 (2015)	38	Dichoptic custom-made action video game	VA improved on average by 0.14 logMAR (28%) in the game group	40 h
Vedamurthy et al.63 (2015)	23	Dichoptic custom-made first person shooter action video game (Unreal Tournament)	Improvements in Gabor target’s resolution by a factor of ≈2.6, inter-ocular suppression reduced by a factor of 1.6	40 h
Birch et al.46 (2015)	50	Binocular iPad games	Improvement in mean VA from 0.43±0.03 to 0.34±0.03 logMAR, no change in stereoacuity	4 weeks
Herbison et al.53 (2016)	75	I-BiT and non i-BiT games	Improvements in VA by 0.07 logMAR	6 weeks
Holmes et al.56 (2016)	385	Binocular iPad games vs patching	Mean VA improved 1.05 lines in the binocular group and 1.35 lines in the patching group	16 weeks
Ziak et al.61 (2017)	17	Oculus Rift VR head mounted display (Oculus VR)	Improvements in VA from 0.58±0.35 to 0.43±0.38 logMAR (P<0.01). Mean stereoacuity changed from 263.3±135 to 176.7±152.4 s of arc (P<0.01)	8 sessions in 1 month
Bossi et al.65 (2017)	22	Balanced binocular viewing therapy (BBV)	Improvement in VA of 0.27 logMAR	8-24 weeks
Gao et al.49 (2018)	115	iPod based Tetris game	Improvement in mean logMAR VA of 0.02	6 weeks
Manh et al.57 (2018)	100	Binocular iPad games vs patching	Mean VA improved from baseline by 3.5 letters in the binocular group and by 6.5 letters in the patching group	16 weeks
Brown et al.54 (2019)	40	I-BiT system based video- game and video watching	Ongoing trial	Ongoing trial
Birch et al.59 (2020)	48	Binocular iPad games (DigRush) vs patching	At 2-weeks, a larger improvement in VA was found with binocular game compared with patching (0.15 vs. 0.07 logMAR)	2 weeks
Gopal et al.66 (2020)	35	Magnocellular stimulation device Orthoptek (Carditek Pvt. Ltd., Bangalore, India)	Improvements in mean logMAR from 0.31±0.34 and 0.32±0.44 to 0.08±0.12 and 0.07±0.12 posttreatment in the right eye and left eye, respectively and improved stereopsis in 97%	1 year
Roy et al.60 (2022)	55	Smartphone-based dichoptic video game vs patching	Improvements in contrast sensitivity from 1.41±0.20 and 1.38±0.20 in the video game and patching groups, respectively, to 1.74±0.18 and 1.61±0.21 (P<0.001 for both). Near stereoacuity significantly improved only in the video game group (P=0.006).	3 months

*VR – Virtual reality, VA – Visual acuity. †Studies include various age groups

Knox et al.[64] also utilized a head-mounted device that allows prolonged dichoptic stimulation. Participants were asked to play a simple game. It was noted that children with small angles or no squint benefited the most from this treatment in terms of VA and stereo acuity. Hence, the need for distinction between different types of amblyopia. Fig. 1a and b shows two types of head-mounted VR devices. Fig. 2 shows the VR game display as seen by the patient.

Figure 1.

(a) Oculus all-in-one VR headset with game handle, (b) VR headset in use

Figure 2.

Game play as seen by the patient wearing the headset

Balanced Binocular Viewing Therapy

A new approach to the binocular treatment of amblyopia has been described by Bossi et al.[65] which they have named “balanced binocular viewing therapy.” This involves watching 3D, dichoptic movies while wearing shutter glasses, combined with an interactive game that aims to measure suppression. This technique has demonstrated promising results (significant improvements in VA of the amblyopic eye and increased stereo acuity in patients with some baseline stereo acuity). While the treatment period varied between 8–24 weeks, compliance was good.

Magnocellular Stimulation

Recently, Santhan Gopal et al.,[66] in a pilot study, used Orthoptek (Magnocellular Stimulator OMS; Carditek Pvt. Ltd., Bangalore) in 35 patients and noted improvements in logMAR as well as stereopsis in both anisometropic and strabismic amblyopia. This device is based on the principle that repeated stimulation of the M (magnocellular) cells of the peripheral retina during saccadic movements causes stimulation of the V1 area of the occipital cortex via top-down impulses, which in turn improves spatial resolution. This method has shown long-lasting improvements in amblyopia regardless of age.

Conclusion

The time-tested approaches for the treatment of amblyopia include refractive correction, and visual stimulation of the amblyopic eye by covering the dominant eye, either by means of patching or pharmacological blurring with atropine. Recently, binocular treatment approaches have evolved in an attempt to improve compliance and binocular function. These novel strategies are based on simultaneous binocular visual stimulation (dichoptic treatment) and aim not only to improve VA in the amblyopic eye but also to promote binocular function and stereo acuity. With technological advancements, newer and appealing treatments involving VR games and watching movies on digital displays have been developed. Although binocular visual therapy in both adults and children has shown promising results, some RCTs have shown very small effects on visual acuity, failing to demonstrate their non-inferiority over standard treatments. There are discrepancies in study designs—non-uniform testing protocols, small sample sizes, enrolment of participants from different age groups, and different amblyopia types, with confounding factors such as prior occlusion treatment and patient compliance. Better outcome measures such as hand-eye coordination, and quality of life to more fully assess the effects of treatment can be added to the studies which are underway. If not a replacement, these treatments, which are still evolving, can be a useful adjunct to conventional therapies and help overcome the worldwide burden of amblyopia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.