Comprehensive review of amblyopia: Types and management

Abstract

The optimal method of treatment for a child depends on the patient’s age at the time of diagnosis, the onset and type of amblyopia, and the degree of compliance attainable. In deprivation amblyopia, the cause of visual impairment (e.g., cataract, ptosis) needs to be treated first, and then the disorder can be treated such as other types of amblyopia. Anisometropic amblyopia needs glasses first. In strabismic amblyopia, conventionally amblyopia should be treated first, and then strabismus corrected. Correction of strabismus will have little if any effect on the amblyopia, although the timing of surgery is controversial. Best outcomes are achieved if amblyopia is treated before the age of 7 years. The earlier the treatment, the more efficacious it is. In selected cases of bilateral amblyopia, the more defective eye must be given a competitive advantage over the comparatively good eye. Glasses alone can work when a refractive component is present, but occlusion might make the glasses work faster. The gold standard therapy for amblyopia remains occlusion of the better eye although penalization is also evidenced to achieve equal results. Pharmacotherapy has been shown to achieve suboptimal outcomes. Newer monocular and binocular therapies based on neural tasks and games are adjuncts to patching and can also be used in adults.

Amblyopia is a disorder of visual deprivation or dysfunction of the processing of visual information.[1] Von Noorden,[2] defined amblyopia as the “unilateral or bilateral decrease of best-corrected visual acuity (BCVA) caused by form deprivation, abnormal binocular interaction or both, for which no organic cause can be detected by physical examination of the eye and which in appropriate cases is reversible by therapeutic means at the appropriate time.”

A widely accepted definition of amblyopia based on visual acuity (VA) for statistical purposes is a difference of two or more Snellen’s or logarithm of the minimum angle of resolution (log MAR) lines in BCVA between the normal and amblyopic eye (in the case of unilateral amblyopia). For bilateral amblyopia, BCVA should be less than 6/12.

The prevalence of amblyopia is reported to be 1–6% in children and 1.43–5.64% in adults.[3] Patients with amblyopia have reduced reading speed, abnormal fine motor skills, and reduced stereo acuity.[4-6] Due to the failure to recognize the disease and delay in treatment, amblyopia is a very common cause of low vision even in adults.[3]

Classification of Amblyopia

For practical and clinical purposes, amblyopia is graded depending on the VA as shown in Table 1. The types of amblyopia according to the etiology are strabismic, refractive, and stimulus deprivation.

Table 1.

Types of amblyopia according to the severity

Type of amblyopia	Initial best-corrected visual acuity
Mild	20/60 or better
Moderate	20/60 to 20/100
Severe	20/100 to 20/400

Management Options

Amblyopic eye loses its function but retains its anatomic integrity. Early recognition and treatment of the problem in children can help to prevent permanent visual loss. The philosophy to treat as early as possible has led to recommendations to screen for amblyopia as soon as a child can undertake a VA measurement task.[7] Hence screening strategies should involve screening at school entry rather than at an age of 3 or 4 years as currently recommended.[8-10] Physicians should be alerted to recognize the threat of amblyopia whenever they see a unilateral squint or any child below 6 years of age who sustains an injury to the eye resulting in occlusion of the visual axis and is at risk of developing amblyopia.

The goal of amblyopia treatment is a reduction in the interocular difference in acuity. Hence, most treatment modalities are aimed at increasing monocular acuity. However, amblyopic individuals are now known to have many visual deficits beyond VA, which is the only metric assessed clinically. The other deficits include binocular and monocular losses, high-order perceptual losses, threshold elevation, fellow eye deficits, and abnormalities of visuomotor control.[11] Hence, the treatment of amblyopia is a therapeutic challenge to the ophthalmologist.

More tremendous success is achieved when therapeutic measures are instituted at the earliest as the success rates of amblyopia treatment may decline with increasing age. The recommended treatment should be based on the patient’s age, VA, compliance with previous treatment, and physical, social, and psychological status.[12] The treatment options explored for amblyopia are listed in Table 2. The Pediatric Eye Disease Investigator Group (PEDIG) was formed in 1997 to conduct clinical research on eye disorders that affect children, funded by the National Eye Institute. The primary focus was strabismus and amblyopia among children and they conducted “The Amblyopia Treatment Studies” (ATS) consisting of a series of randomized clinical trials designed to set protocols for the optimal management of amblyopia [Table 3].[13]

Table 2.

Listing the treatment options for amblyopia, which are/have been tried

Refractive correction

Occlusion

Penalization

Drug therapy

Near visual exercises

Surgery to treat the cause of amblyopia

Refractive surgery

Television games/video/mobile games

Liquid crystal glasses

Opaque contact lenses

Obsolete now–pleoptics, CAM stimulator

Table 3.

Outcomes of amblyopia treatment studies

Study	Aim	Age	No. of patients	Results
ATS 1	Atropine vs. part-time patch: moderate amblyopia To compare atropine and patching for moderate amblyopia	3–7 years	419	Improvement was initially faster in the patching group, but after 6 months the difference in visual acuity (VA) between treatment groups was insignificant; 3.16 lines (patching group) vs. 2.84 lines (atropine group)
ATS 2A	Patch 6 h vs. full-time: severe amblyopia To compare 6 h vs. full-time daily occlusion for severe amblyopia	3–7 years	175	6 h of patching is equally effective as full-time patching. 86% pts in the 6-h group and 82% pts in the full-time group had improved by 3 lines from baseline.
ATS 2B	Patch 2 h vs. 6 h: moderate amblyopia To compare 2 vs. 6 h patching 2C: Spectacles but stop patch/atropine after success 1 year	3–7 years	189	6 h of patching is as effective as 2 h of patching. At 4 months, no difference in amblyopic eye acuity between groups
ATS 3	Teens: spectacles vs. atropine/patch To evaluate the effectiveness of optical correction alone vs. 2–6 h/day of patching combined with near visual activities plus atropine.	7–13 years	507	Amblyopia improves with optical correction alone in 1\4th pts (7 to 17 years), although most pts initially treated with optical correction alone will require additional treatment.
ATS 4	Atropine: weekend vs. daily; moderate amblyopia To compare daily atropine vs. weekend atropine.	3–7 years	168	Weekend atropine provides an improvement similar to that provided by daily atropine in moderate amblyopia.
ATS 5	Spectacles alone, then patch 2 h vs. spectacles Eyeglass phase study	3–7 years	84	Amblyopia improved by 77% by optical correction and resolved by 27%.
ATS 6	Patch 2 h with near vs. far activities after specs Comparing near and distance activities while patching	3–7 years	425	No difference in VA improvement between children performing near activities and distance activities during patching.
ATS 7	Bilateral refractive amblyopia; spectacles×1 year To determine improvement in binocular VA during treatment of bilateral refractive amblyopia	3–11 years	113	Bilateral refractive amblyopia improves with spectacle correction. Binocular VA of 20/25 or better was achieved by 73%
ATS 8	Atropine: full specs vs. reduced plus To compare weekend atropine augmented by a plano lens with weekend atropine alone for moderate amblyopia.	3–7 years	180	Augmentation of weekend atropine with a plano lens does not substantially improve amblyopic eye acuity.
ATS 9	Teen “ATS-1”: weekend atropine vs patch 2 h To compare patching with atropine eyedrops in the treatment of moderate amblyopia	7–12 years	193	Atropine and patching achieve similar results among older children with unilateral amblyopia.
ATS10	Bangerter filters for amblyopia A randomized trial comparing Bangerter filters vs. occlusion for the treatment of moderate amblyopia	3–10 years	186	Bangerter filters and patching were less than half a line, and there was a lower burden of treatment on the child and family, Bangerter filter treatment is a reasonable option to consider for initial treatment of moderate amblyopia
ATS11	Randomized trial to evaluate combined patching and atropine for residual amblyopia	3–10 years	55	Amblyopic eye VA improved similarly in both groups suggestive of no additional benefit of combined treatment in residual amblyopia
ATS12	Vision therapy pilot study Pilot randomized clinical trial of office-based active vision therapy for the treatment of childhood amblyopia to determine the feasibility of conducting a full-scale randomized clinical trial			16-week treatment trial of vision therapy was feasible with respect to maintaining protocol adherence; however, recruitment under the proposed eligibility criteria, necessitated by the standardized approach to vision therapy, was not successful
ATS13	Spectacles for strabismic amblyopia Non-randomized prospective trial of glasses alone for strabismic and strabismic-anisometropic amblyopia	3–7 years		The treatment effect was greater for strabismic amblyopia than for combined mechanism amblyopia
ATS14	Levodopa pilot study A pilot study of levodopa dosage as a treatment for residual amblyopia	8–18 years		The results suggested that levodopa/carbidopa therapy for residual amblyopia in older children and teenagers is well tolerated and may improve visual acuity. There was a suggestion of partial regression of the improvement in VA after treatment was discontinued.
ATS15	Increasing patching for amblyopia Randomized trial of increasing patching for amblyopia	3–8 years	169	More improvement in VA after 10 weeks compared with continuing 2 h daily.
ATS16	Augmenting atropine treatment for amblyopia, the effectiveness of adding a plano lens (a lens without any prescription) to weekend atropine treatment after a patient’s VA has stabilized but amblyopia is still present.	3–8 years	73	At the primary outcome or later visit when the best-measured VA was observed,(more than 10 weeks) the mean amblyopic-eye improvement from baseline was 1.9 lines with the plano lens and 0.8 lines with atropine only. The results were not statistically significant.
ATS17	Levodopa for residual amblyopia Compare the efficacy and safety of oral levodopa and patching versus oral placebo and patching at 18 weeks, after 16 weeks of treatment followed by a 2-week taper of oral medication.	7–12 years	139	At 18 weeks, amblyopic-eye VA improved from randomization by an average of 5.2 letters in the levodopa group and by 3.8 letters in the placebo group. Not statistically significant.
ATS18	Multicentric RCT to compare VA improvement in children with amblyopia treated with a binocular iPad game vs. part-time patching. Participants were randomly assigned to either 16 weeks of a binocular iPad game prescribed for 1 hour a day (190 participants; binocular group) or patching of the fellow eye prescribed for 2 h a day (195 participants; patching group).	5–13 years	385	At 16 weeks, mean amblyopic-eye VA improved 1.05 lines in the binocular group and 1.35 lines in the patching group. VA improvement with this particular binocular iPad treatment was not as good as with 2 hours of prescribed daily patching.
ATS18	RCT to compare VA improvement in teenagers with amblyopia treated with a binocular iPad game versus part-time patching. Participants were randomly assigned to treatment for 16 weeks of either a binocular iPad game prescribed for 1 h per day (N=40) or patching of the fellow eye prescribed for 2 h per day (N=60)	13–17 years	100	Mean amblyopic eye VA improved from baseline by 3.5 letter in the binocular group and by 6.5 letters in the patching group. Improvement in amblyopic eye VA with the binocular iPad game used in this study was not found to be better than patching and was possibly worse.
ATS19	Excimer laser surgery for anisometropic amblyopia To compare the efficacy and safety of surgical treatment (PRK) versus non-surgical treatment of anisometropic amblyopia in children who have failed conventional treatment due to non-compliance or non-response.			Closed but no data available
ATS20	Binocular Dig Rush game treatment for amblyopia To compare the efficacy of 1 h/day of binocular game play 5 days per week plus spectacle correction with spectacle correction only for the treatment of amblyopia in children	4–13 years	320	Finished but not yet published
ATS21	Evaluation of accommodative behavior in children with and without amblyopia The proposed pilot study will determine whether children with amblyopia have significant accommodative behavior deficits and if so, which accommodative tests should be required for eligibility to maximize enrollment of children with accommodative deficits in any future RCT. This pilot study is also designed to determine the practicality of using Nott retinoscopy in lieu of “accepted standard” instrument-based methods by determining if Nott retinoscopy has sufficient sensitivity and specificity to detect abnormal accommodative behavior (amplitude, accuracy, and variability) for use in determining eligibility in a future RCT. The proposed pilot study will evaluate three accommodative behaviors (amplitude, accuracy, and variability) using both Nott retinoscopy and the accepted standard instrument-based method for each behavior (Grand			Recruiting
	Seiko autorefractor for amplitude and accuracy and the Power Ref 3 for variability).
ATS22	To determine whether simultaneous treatment with spectacles and patching has an equivalent VA outcome compared with sequential treatment, first with spectacles alone, followed by patching (if needed), for previously untreated amblyopia in children 3 to <13 years of age. If found to be equivalent, the study will also evaluate whether child and parent HRQOL outcomes are superior with sequential treatment versus simultaneous treatment.	3<7 years 7<13 years		Recruiting

ATS=Amblyopia treatment study. RCT=Randomized clinical study. VA=Visual acuity

Refractive correction

Refraction is the most fundamental part of the treatment of amblyopia to create a clear foveal image in the non-dominant eye. Hence, it is mandatory to carry out proper refraction and prescribe adequate optical correction in every case of amblyopia. Refraction must be performed objectively with full cycloplegia. In younger children atropine ointment 1% should be used thrice a day for 3 days before their visit. In older children (>8 years), use cyclopentolate (1%, two drops at 15 min intervals) and perform retinoscopy after 30–40 min of instillation. Age-appropriate tests for the estimation of logMAR VA, followed by age-appropriate prescription of glasses should be performed. The age-appropriate guidelines for prescribing glasses should be followed to avoid amblyopia due to uncorrected refractive errors.

For anisometropic amblyopia, the first step is to provide an age-appropriate refractive correction. It is important to correct the objectively determined anisometropia because the subjective response may make the determination of the appropriate power difficult. The type and degree of anisometropia, and the patient’s age and level of VA should be considered when choosing the best treatment plan for the patient. High degrees of hyperopia and astigmatism in newborns are known to improve considerably by 1 year of age. Therefore, it is reasonable to wait until the age of 1 year to prescribe glasses correcting anisometropia that could potentially cause amblyopia. The amblyopia treatment study-ATS-5 was performed to evaluate the effectiveness of refractive correction in moderate amblyopia, and it was concluded that amblyopia resolved in 27% and there was an improvement of more than two lines in 77% of patients with refractive correction only.[14] Glasses alone have been proven to improve VA up to 18 weeks of initiating spectacles alone.[15] We can try a refractive correction or adaptation for 4–6 weeks before moving on to patching and other therapies. For bilateral ametropic amblyopia, spectacle correction is the first line of treatment. Spectacle correction alone improves binocular VA in bilateral refractive amblyopia as per the recommendations of ATS 7.[16]

Refractive correction alone resulted in a significant improvement in acuity not only in patients with pure anisometropic amblyopia but also in children with strabismic amblyopia.[17]

Occlusion

Occlusion or patching of the better eye is still considered the gold standard for amblyopia therapy. It forces the patient to use an amblyopic eye and it also inhibits “inhibitory impulses” arising from a sound eye. The success rate of occlusion therapy varies from 30%–92% in various reports. However, variability exists in the number of hours prescribed to treat amblyopic patients. The variation in success rate is also due to other factors such as patient selection, treatment duration, age, the definition of amblyopia used in the study, and type of amblyopia. The preferable and advisable patch is a direct skin patch. Another option can be a self//home made with 2” micropore tape. Spectacle with an opaque patch or Doayne’s occluder and contact lens occluder are other less recommended options.

The amblyopia treatment studies were initiated to address some important questions regarding the duration of patching. ATS 2A compared full-time patching (all waking hours) and part-time patching (6 h patching/day) in severe amblyopia (20/100–20/400) in children of 3–7 years of age.[18] It concluded that 6 h of daily patching and full-time patching are alike treating severe amblyopia in children of 3–7 years of age. ATS 2B compared patching for 2 h and 6 h in the treatment of moderate amblyopia. It was concluded that in moderate amblyopia, 2 h patching gives similar results to 6 h of patching, and prescribing a greater number of hours does not seem to have significantly beneficial effects during the first 4 months of treatment. A lot of studies still describe full-time patching[19,20] despite the recommendations of ATS, as they are fearful of poor visual outcomes with reduced patching hours. Additionally in ATS, compliance was not measured objectively and it is quite possible that patients who were prescribed full-time patching averaged 6 h and those prescribed 6 h averaged 2 h patching. It is pertinent to mention here that recording of VA of both eyes with the same chart and similar physical conditions is mandatory. The patient must be given 5–10 min time to the occluded eye for acclimatization.

Occlusion can be stopped if the VA in both eyes becomes equal, or the fixation becomes fully alternating, or when there is no further improvement despite 3–6 months of patching. The patching regimen is considered a failure if there is no visual improvement after 3–6 months of compliant patching or no improvement after at least three intervals of full-time occlusion therapy. It is recommended to always taper patching with part-time occlusion of the normal eye (3–4 h per day) or alternately patching both eyes. There are various disadvantages of occlusion therapy, which include occlusion amblyopia, that is, diminution of vision in the seeing “occluded” eye, cosmetic blemish as the patch may be cosmetically unacceptable to children, allergic skin rash, and recurrence. One-fourth of successfully treated amblyopic patients experience a recurrence within the first year of treatment. Hence, when the child reaches a point where he/she is ready for a cessation of treatment, patching hours should be weaned before treatment is stopped. The risk of recurrence is inversely correlated with age. Regression is seen in 14% of cases per year (nearly 25% recur after the first year post-therapy) and hence the need for maintenance therapy along with careful monitoring. In patients with intense patching (6–8 h per day), recurrence is more common when the treatment is not tapered than when treatment was reduced to 2 h per day before cessation as proven in a study.[21] When at any visit, amblyopia recurs, it is advisable to patch it two to three times at a higher level than when the amblyopia recurred, and when the acuity recovers again, a still slower tapering is advised. Patients with untreated strabismus may be prone to develop recurrence. Hence, realignment of the visual axis is a must. It should be preferably performed within 6 months of completion of amblyopia therapy.

The appearance of a constant manifest deviation after occlusion in a child who does not have strabismus or only intermittent deviation is also seen. Repka et al. found that patching and atropine penalization are infrequently associated with the development of significant strabismus. This investigation showed 14% of 161 previously orthotropic children developed micro strabismus; however, only five (3%) developed strabismus greater than eight prism diopters.[22]

Occlusion in bilateral amblyopia

There is no standard treatment for these patients, and outcomes of patching have not been well described. A recent comparative study stated that primary occlusion provides no further benefit to spectacle alone, nor does it hinder final VA improvement in the stronger eye in these groups of patients. It is recommended that these patients should be treated with glasses alone, with the addition of patching or atropine to correct any residual interocular difference, when the VA reaches 20/30 or better in at least one eye.[16,23]

Adult amblyopia

Though amblyopia is best treated in early childhood, it can be treated at any age but becomes progressively difficult at a later age. The ATS 3 analyzed the effectiveness of treatment in children aged 7 to 17 years. They recruited 507 patients in this age group and concluded that for patients aged 13 to 17 years, 2 to 6 h of patching per day with near visual activities may improve when amblyopia has not been previously treated but is of little benefit if amblyopia was previously treated with patching.[24]

Simultaneous or sequential patching

Based on amblyopia treatment studies by Pediatric Eye Disease Investigator Group (PEDIG), many pediatric eye care providers currently treat amblyopia first with optical correction alone expecting at least 25–40% of cases of anisometropic, strabismic, or combined-mechanism amblyopia to resolve with no further treatment needed. For those with residual amblyopia after such optical treatment, part-time patching or atropine is often prescribed, and this overall treatment approach could be termed “sequential.” Nevertheless, even after sequential optical and patching treatment, approximately 50% of children with anisometropic, strabismic, or combined mechanism amblyopia have residual or recurrent amblyopia.

Simultaneous treatment

Some clinicians prescribe spectacles and patching (or atropine) together at the initiation of treatment; this approach could be termed “simultaneous.”

There are several advantages to sequential treatment. A proportion of children with amblyopia will never need patching. Amblyopic eye VA in children that do not completely resolve with spectacles alone is often better at the commencement of patching, and therefore subsequent patching is likely easier for the child and parents. This in turn may be better for the overall quality of life of parents and the child. “Simultaneous” treatment may also have the overall superior VA outcomes because the child is younger at the commencement of patching and the rate of improvement may be faster. A current trial by the PEDIG group will try to answer which approach is better.[25]

Penalization

Penalization implies optically defocusing the dominant eye pharmacologically by cycloplegics or optically treating amblyopia in the other eye. Atropine is the most commonly used penalizing agent as a 1% drop to the healthy eye. It blocks the parasympathetic innervations of the pupil and ciliary muscle, causing pupillary dilatation and loss of accommodation. The blurring that occurs is greater in eyes with hypermetropic refractive errors because accommodation can no longer correct blur. It does not inhibit abnormal binocular interaction. It can be tried in moderate amblyopia in uncooperative patients, in occlusion failures, or in those allergic to patches. The ATS 1 trial was initiated with the aim to address whether occlusion or atropine penalization is the best initial treatment for moderate amblyopia (20/40–20/100) in children 3–7 years of age. Atropine or patching for 6 months produced a similar improvement in amblyopia 2 years after treatment.[26] After the follow-up at 2 years of age, it was reported that improved VA was maintained although residual amblyopia was common.[27] Patching has a potential advantage of a more rapid improvement in VA and possibly a slightly better acuity outcome, whereas atropine has the potential advantage of easier administration and lower cost. However, Kushner pointed out that the importance of a faster response in the patching group should not be minimized as this meant fewer visits to the ophthalmologist and the associated costs and inconvenience.[28] However, there are certain drawbacks of ATS; thus, before applying these conclusions in the Indian scenario, we have to keep in mind the following limitations of ATS as pointed out by Lambert.[29] The strict inclusion criteria hampered the study by including a limited number of patients. Ethnic variations in treatment always remains a factor; thus, the results cannot be generalized to other countries. ATS 1 did not answer the effect of atropine on fusion and stereopsis as the patients were under the effect of the drug at the time of final examination. Simon et al.[30] compared full-time atropine, intermittent atropine, and optical penalization in strabismic amblyopia and found that all three forms of penalization produced a statistically significant mean reduction in amblyopia (1.7–2.7 logMAR lines) and a mean improvement in binocularity. A comparison between combined pharmacological and optical penalization with atropine penalization alone showed the improvement to be similar in both groups.[31] The PEDIG compared daily atropine to weekend atropine for moderate amblyopia in a randomized clinical trial in 168 patients. The study concluded that weekend atropine provides an improvement in VA of a magnitude similar to that of improvement provided by daily atropine in treating amblyopia in the 3–7 years age group.[32] Antuna and Johnson combined atropinization of the fixating eye with miotics instilled at bedtime in the amblyopic eye of hypermetropic children who were non-compliant to complete occlusion.[33]

Optical penalization for distance, adding plus correction to cycloplegic refraction in the sound eye is a useful alternative to occlusion for treating amblyopia. Recently, Tejeder and O’galler[34] compared the efficacy of penalization methods in moderate amblyopia and concluded that atropine penalization may be considered more effective than optical penalization. Combined optical and atropine penalization (COAT) for the treatment of strabismic and anisometropic amblyopia is also an effective treatment method when occlusion therapy fails initially. One more trial by the PEDIG comparing atropine to atropine plus a Plano lens for the sound eye as a treatment for amblyopia in children 3–6 years of age was carried out with the aim to compare the effectiveness and safety of weekend atropine augmented with a plano lens for a sound eye versus weekend atropine alone for moderate amblyopia. It was concluded that as an initial treatment for moderate amblyopia, the augmentation of weekend atropine use with a plano lens did not substantially improve amblyopic eye vision when compared with weekend atropine use alone.[31]

Pharmacotherapy

In light of the current limitations in conventional treatment modalities and the serious consequences of residual amblyopia, a diverse array of pharmacological agents has been tried in amblyopia treatment over the last century. In the past, there was experimentation with many drugs, starting from strychnine, oxygen, alcohol, and propranolol.[35-40] Other targeted therapies such as bicuculline and exogenous nerve growth factor[41] were also tried, but none with significant and durable effects.

Levodopa

Because dopamine plays an important role in both retinal neurotransmission and central visual processing, its precursor levodopa, which can freely cross the blood–brain barrier, has been widely evaluated in various human studies on amblyopia. It is used in combination with carbidopa in a ratio of 4:1 (levodopa: carbidopa). The exact site of action of levodopa is not known. Because the plasticity of the visual system during the sensitive period is dependent on inputs from non-adrenergic neurons, levodopa either extends or reactivates the visual system’s sensitive period of neural plasticity. Hence, visual deprivation decreases dopamine concentration. Peripheral dopa decarboxylases in the gut, kidneys, and liver, and decreases their oral bioavailability. The addition of carbidopa inhibits the peripheral conversion of levodopa to dopamine, thereby increasing its availability in the central nervous system.

Different studies have used different doses of levodopa. Although some have used relatively higher doses (61–132 mg/kg/day) for shorter periods (1 day to 1 week),[42,43] others have used much lower doses (1.5 mg/kg/day) for a longer duration (7 weeks).[44-46] A pilot study comparing two doses of levodopa (0.51 v/s 0.76 mg/kg thrice a day) along with 2 h daily patching showed a + 4(±4) letters improvement in the lower dose group compared to + 6(±6) letters improvement in the higher dose group. Adverse effects were more commonly noted in the higher dose group although none were serious.[47] The study on the efficacy of lower doses concluded that levodopa/carbidopa, at an average of 0.48 to 0.12 mg/kg, is efficacious and has lower side effects.[48] A study by Dadeya[46]et al. evaluated the role of levodopa/carbidopa in the treatment of amblyopia and concluded that there was more than two lines of improvement in visual acuity, especially in children younger than 8 years of age.

Although many studies have shown that treatment with levodopa leads to improvement in visual acuity, scotoma, and even visually evoked potentials,[46,49,50] some have found this improvement to regress after discontinuing treatment.[44,47] However, a large trial by PEDIG reported no clinically or statistically meaningful improvement in vision with levodopa in their study conducted on 139 (7 to 12-year) children with residual amblyopia.[51] These findings were corroborated by Bhartiya et al.[52] who further reported an increased risk of occlusion amblyopia with levodopa. There are a lot of side effects with this drug combination, and a high-protein diet with adequate dosing is recommended to counteract these.

Citicoline (Cytidine 5’-diphosphocholine or CDP-choline)

Citicoline is a complex organic molecule that acts as an intermediate in the biosynthesis of cell membrane phospholipids, increases brain metabolism, and has been shown to increase norepinephrine and dopamine levels in the central nervous system. In light of these neuro-modulatory properties, it has been tried in ocular conditions such as amblyopia and glaucoma.

Campos et al.[53] reported statistically significant improvement in VA in both amblyopic and sound eyes with citicoline (1000 mg I/M for 15 days) in older children beyond the plastic period of the visual system, which remained stable for at least 4 months after stopping the treatment. Another study observed a significant improvement in visual acuity, contrast sensitivity, and visual evoked potential in young adult amblyopic patients (mean age 24.8 years) with the use of citicoline. However, despite these promising results, a major drawback of the study was its small sample size (10 patients).[54]

Owing to the similar bioavailability of the drug with the oral route and ease of administration, most studies now employ citicoline through the oral route. Prabha and Lahre[55] found improvement in VA and refractive status in patients of myopic amblyopia of age group 5–30 years before and after administration of oral citicoline (500 mg daily for 12 weeks). Narula et al.,[56] in their study, to see the effectiveness of the addition of citicoline to patching, included 30 patients who were randomly divided into two groups. Both the groups received patching therapy for 6 months or until a plateau was reached. Then, in phase 2, group I received citicoline plus patching, and group II continued to receive only patching. They found that the improvement in VA with citicoline plus patching was significantly more than that with patching alone. Similar findings were echoed by Pawar et al.[57] in their study in both younger (<7 years of age) and older (>7 years of age) subjects.

Selective serotonin reuptake inhibitors (SSRIs)

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), used commonly as an antidepressant, is now being tried in the treatment of amblyopia as it increases extracellular serotonin and noradrenaline. Animal studies have shown that fluoxetine restores ocular dominance plasticity and stimulates visual function even in adult amblyopic animals.[58] However, studies on human subjects have shown variable results. Although a phase 2 multicenter trial comparing fluoxetine with a placebo for the treatment of amblyopia showed no added benefit of the drug,[59] another similar study showed a higher magnitude of improvement in VA in the fluoxetine group.[60] Other SSRIs such as citalopram have also been tried but have shown no added benefits.[61]

Donepezil

The neurotransmitter acetylcholine is known to facilitate plasticity in animal models by increasing the levels of acetylcholine in the cortex while animals were passively exposed to the stimulus. Donepezil, a reversible cholinesterase inhibitor, is thereby being tried in the treatment of amblyopia. Human studies have shown donepezil to improve perceptual learning in healthy subjects, with its effects lasting for months even after discontinuation of the therapy.[62,63] However, no such benefit was observed in a pilot study conducted on nine amblyopic patients, wherein donepezil was found to neither improve nor speed up perceptual learning in adult amblyopes and it was observed that it may even halt learning and transfer related to a crowding task.[64]

In conclusion, more randomized trials with larger sample sizes and longer periods of follow-up are required to substantially prove or disprove the benefits of these drugs.

Binocular simulation and games

It has been shown that loss of binocularity is one of the defining features of amblyopia; therefore, the focus of research in this area has shifted from monocular interventions that involve patching of the fellow eye to approaches that directly target binocular visual function and as the primary therapeutic step. This has led to increased interest in the development of amblyopia treatments that directly address binocular dysfunction by promoting binocular vision and reducing inhibitory interactions within the visual cortex. These therapies are based on monocular and binocular stimulation.

Perceptual learning is based on the principle that repeated practice can influence neural plasticity by improving performance on sensory tasks.[65] Many studies demonstrated this repetitive practice-based learning as the most effective method to improve acuity and contrast detection.[66] Amramov et al. have studied stimuli involving detecting and localization near threshold Gabor patches with a spatial frequency close to the cut-off and varying orientation in video games.[67] The approach is based on monocular training, which consists of tasks, whereas the dominant eye is occluded, the aim is that the amblyopic eye is stimulated. It has been seen that contrast sensitivity improves when grating patterns are used, more specifically those frequencies near the cutoff frequency.[68,69] Perceptual learning has been shown to improve VA in even adult amblyopes in various studies.[70]

The other treatment approach for amblyopia is dichoptic therapy, which works to reduce suppression and improve binocular function using the presentation of different information to each eye. In this method, children with amblyopia are trained on tasks in which reduced contrast images are presented to the sound eye, whereas higher contrast images are presented to the amblyopic eye to balance the ocular input and overcome interocular suppression. The stimuli presented to both eyes need to be combined to complete the task. Over time, the treatment is hypothesized to extend the contrast range over which binocular fusion can occur until it includes images of the same contrast in each eye (comparable to natural viewing). Hess et al.[69] examined the potential of treating amblyopic adults using the mobile game. In this study, the dichotic mobile game Tetris was used on iPod to treat 14 amblyopic patients aged 13 to 50 years. The dichoptic video game treatment was conducted at home, and visual function was assessed before and after treatment. On this basis, they concluded that the home-based dichoptic iPod mobile game approach represents a viable treatment for adults with amblyopia. Birch et al.[71] also did a similar study to find the effectiveness of a novel home-based binocular amblyopia treatment. They treated children (4–12 years of age) who wore anaglyphic glasses to play binocular games on an iPad platform for 4 h/w for 4 weeks. They concluded that binocular iPad treatment rapidly improved visual acuity, and VA was stable for at least 3 months following the cessation of treatment.

Due to the success of the earliest studies on binocular games and amblyopia, subsequent randomized trials were performed to compare the efficacy of patching. Binocular treatment of amblyopia using video games (BRAVO) has been performed to compare the effectiveness of a binocular video game with a placebo video game for improving visual function.[72] This study was a randomized controlled trial with 115 participants aged 7 to 55 years of age. The result indicated that binocular video games did not improve visual outcomes more than placebo video games in older children and adults, mainly because of poor compliance with games. Another randomized controlled trial conducted by Manh et al.[73] compared VA improvement in 100 children aged 13–17 years randomly assigned to treatment for 16 weeks of either a binocular iPad game prescribed for 1 h per day (N = 40) or patching of the fellow eye prescribed for 2 h per day (N = 60). Adherence data from the iPad device indicated only 13% of participants completed more than 75% of the prescribed treatment. Holmes et al.[48] conducted a randomized controlled trial on 138 children between 7 and 12 years of age with amblyopia, in which participants were randomly assigned to treatment for 8 weeks with the dichoptic binocular Dig Rush iPad game (prescribed for 1 h per day for 5 days per week) plus spectacle wear if needed (n = 69) or continued spectacle correction alone if needed (n = 69). No difference in letter scores was observed between groups when the analysis was repeated after 8 weeks of treatment. For the binocular group, adherence data from the iPad indicated that slightly more than half of the participants (58% and 56%) completed more than 75% of the prescribed treatment by the 4^th and 8^th-week visits, respectively. Hence, larger trials concluded the inferiority of binocular games mainly due to low compliance.

Park et al.,[74] in a retrospective study, also considered television games as a sort of near activity along with a variety of other activities and not considered it exclusively. Jeon et al.[75] showed improvement in one or both eyes on a wide variety of tasks including acuity, spatial contrast sensitivity, and sensitivity to global motion. In a study conducted by Li et al.,[76] the effect of playing video games, while patched, on adults with amblyopia were studied. They reported that patients tended to recover vision much faster than was expected from the results of conventional occlusion therapy in childhood amblyopia. Television was found to be of utility in administering amblyopia therapy.[77]

All therapies seem to provide a similar consistent improvement in VA of 0.1–0.2 logMAR.

Other treatment options/augmentation of therapy

Near-visual activities are often prescribed during patching for amblyopia based on the assumption that those activities stimulate the visual system.[78] Due to the lack of rigorous studies using randomized control trial methods, with masking and standardization of VA assessment, their significance remained controversial. Park et al.[74] from Korea in a retrospective study published in 2008 highlighted the importance of near visual activities with part-time patching (6 h) in treating children (mean age 4.86 years) with anisometropic, strabismic, or combined amblyopia (both moderate and severe). A randomized control trial, that is, ATS 6 was then conducted between February 2005 and June 2007. Near activities included arts and crafts, counting up close, board games, card games, computer games, video games, homework, stacking coins, a string of beads, writing, reading, and activity books. Distance activities included active physical games, counting at distance, general outdoor games, and watching television at a distance of 6 m. At 8 weeks, however, the investigators did not notice any difference in VA improvement between children who performed common near activities and those who performed distance activities during patching treatment for amblyopia. This finding was in contrast to the results of a previous randomized pilot study and also to several case series reporting the effect of near activities or activities involving eye–hand coordination in the treatment of amblyopia.[21,79,80]

Conclusion

The keys to treatment success of amblyopia are younger age at detection/treatment, optimum refractive correction, and compliance with treatment. With the cessation of amblyopia treatment, there is a risk of recurrence. Careful and prolonged follow-up during the amblyogenic years is needed for all children previously treated for amblyopia to prevent a recurrence. Generally, the younger the amblyopes are treated, better the likelihood of improvement. Occlusion of the better eye is the gold standard treatment in children under 7 years of age. In cases of recurrent or residual amblyopia in older children and adults, supplementation with binocular therapies is the way forward.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.