Review Article
Clinical Medicine
Ophthalmology

Recent trends in amblyopia therapy: a review

Anupam Singh1, Sonal Dangda2, Barun Kumar3

Abstract

Amblyopia is defined as unilateral or bilateral dimness of vision caused by form vision deprivation and or abnormal binocular interaction and it is the most common cause of preventable monocular blindness in children and young and middle-aged adults. Nearly all amblyopic visual loss is reversible with timely detection and appropriate intervention. Amblyopia is an important public health problem as visual impairment is lifelong. It affects 1.0 to 5.0% of the general population and with evidence that the rate is even higher in medically underserved populations.

Various treatment modalities like refractive correction alone, patching (both full time and part time), penalization, pharmacological therapy have been tried, but which one is the best is still to be proved.

Refractive correction alone improves visual acuity in one third of patients with anisometropic amblyopia.

In occlusion therapy, the fixating eye is prevented from taking part in the act of vision so that the patient is forced to use the amblyopic eye. In addition it removes the inhibitory stimuli to the amblyopic eye that arise from the stimulation of the fixating eye.

Penalization is a therapeutic technique performed by optically defocusing the eye having better vision by using cycloplegia (pharmacological penalization) or by altering the eyeglass lens (optical penalization) to cause decreased vision in the non-amblyopic eye.

Various drugs have been tried however carbidopa levodopa has been tried extensively in western world as well as in India. Recent trends indicate some role for active home vision exercises in amblyopia. Home vision exercises are very commonly advised to the patients but without much research in this aspect of therapy. The Amblyopia treatment study (ATS), however, has resumed interest in the active home vision exercises. Among the various activities forming the spectrum of near activities, video games using television is an interesting modality in view of better compliance. This article will illustrate various modalities of amblyopia therapy, recent trends in this field along with review of literature.

Keywords:amblyopia occlusion therapy, penalization, pharmacological treatment of amblyopia

Author and Article Information

1) Department of Ophthalmology, All India Institute of Medical Sciences (AIIMS) Rishikesh, India
2) Department of Ophthalmology, Guru Nanak eye Centre, MAMC New Delhi, India.
3) Department of Medicine (Cardiology), Swami Rama Himalayan University, Dehradun, India.

RecievedDec 15 2014 AcceptedMar 25 2015 PublishedApr 30 2015

CitationSingh A, Dangda S, Kumar B (2015) Recent trends in amblyopia therapy: a review. Science Postprint 1(2): e00048. doi:10.14340/spp.2015.04R0003.

Copyright©2014 The Authors. Science Postprint published by General Healthcare Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 2.1 Japan (CC BY-NC-ND 2.1 JP) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

FundingNone

Competing interestNothing to be disclosed.

Corresponding authorAnupam Singh

AddressOphthalmology Department, AIIMS Rishikesh, Uttarakhand, India, 249203.

E-mail dr.anupamsingh@gmail.com

Peer reviewersKe-Hung Chien1 and Reviewer B

1 MD, Department of Ophthalmology, Tri-Service General Hospital, Taipei, Taiwan, R.O.C.

Introduction

Amblyopia is defined as unilateral or bilateral dimness of vision caused by form vision deprivation and or abnormal binocular interaction 1. This is the most common cause of preventable monocular blindness in children and young and middle-aged adults 2. Nearly all amblyopic visual loss is reversible with timely detection and appropriate intervention 3. Various treatment modalities (refractive correction alone 4-8, patching 9-21, penalization 22-32, pharmacological therapy 33-42) have been tried.

Recent trends indicate some role for active home vision exercises 43, 44 which have been popular in the past as well 11, 45-47, but without much research in this aspect of therapy, especially clinical trials with randomization and control groups. The Amblyopia treatment study (ATS), however, has highlighted this aspect of therapy in its recent trials 8, 20, 21, 44, 48–50.

Efforts have also been made to utilize television in providing some form of amblyopia therapy, like modification of antisuppression exercises 51, stripe therapy 52. This article will illustrate various modalities of amblyopia therapy along with recent trends.

Definition of amblyopia

Amblyopia has been defined in a variety of ways in ophthalmology literature. The word amblyopia has been derived from the Greek words, “Amblyos” and “ops” meaning dull vision 1. It was first described by Hippocrates in 4,000 BC. One of the most succinct definition has been attributed to von Graefe, who defined amblyopia as the condition in which observer sees nothing and patient very little 53. Von Noorden has clinically defined amblyopia as unilateral or bilateral reduction in best-corrected visual acuity caused by form vision deprivation and/or abnormal binocular interaction, without a visible organic cause commensurate with this visual loss. This significant reduction in corrected central visual acuity is labelled to visual acuity less than 6/12 in bilateral amblyopia and a difference of two or more lines between normal and abnormal eye in unilateral amblyopia 1. This is correctable if appropriate measures are applied at appropriate time 3. In addition to this, changes have been described in other functions as well, like contrast sensitivity, colour vision, motion processing and magnocellular to parvocellular processing. Whether, the above abnormalities pose difficulties in everyday visual perceptions in amblyopic patients is an important unresolved question 54. However, amblyopia till date remains a diagnosis of exclusion.

Prevalence

Amblyopia is an important public health problem as visual impairment is lifelong 2. It affects 1.0 to 5.0% of the general population 1, 55–58 and with evidence that the rate is even higher in medically underserved populations. [This part was concealed because of the plagiarism concern which was reported by a reader. Science Postprint is making an inquiry for the author about this matter (update:11/27/2015). ].

The results of the ALSPAC and Israeli childhood amblyopia studies quoted earlier suggest that early screening for and treatment of conditions that predispose amblyopia reduce the prevalence of amblyopia in school-aged children 58.

This highlights the fact that the process is non linear and correction within and up to 2 years of age “window” was required for optimum correction 61.

Risk factors

Various risk factors have been described for occurrence of amblyopia. These include family history of amblyopia or strabismus, childhood cataract or glaucoma, premature birth of less than 30-weeks gestation or 1,500 g, and delayed visual or neurological maturation of unclear etiology 62.

It occurs four times more frequently in premature children 63, 64 and six times more commonly in children with delayed milestones 65. Socioeconomic factors significantly influence the age of presentation of amblyopia in anisometropic but not in strabismic amblyopia 66. It is usually caused by abnormal visual experiences early in life resulting from strabismus, anisometropia, or bilateral refractive errors, or visual deprivation.

Pathophysiology of amblyopia

The oldest concept of pathophysiology of amblyopia is that it is a result of disuse: amblyopia ex anopsia; this term has now been discarded 1.

[This part was concealed due to the plagiarism concern which was reported by a reader. Science Postprint takes appropriate action for this matter (update:11/04/2015). ]

Diagnostic criteria

[This part was concealed because of the plagiarism concern which was reported by a reader. Science Postprint is making an inquiry for the author about this matter (update:11/27/2015). ]

Etiological classification of amblyopia 89

[This part was concealed because of the plagiarism concern which was reported by a reader. Science Postprint is making an inquiry for the author about this matter (update:11/27/2015). ]

Management

[This part was concealed due to the plagiarism concern which was reported by a reader. Science Postprint takes appropriate action for this matter (update:11/04/2015). ]. In 1935, Gifford reported from Chicago that he had been unable to obtain cooperation for prolonged occlusion treatment for most of the cases of amblyopia and that even in those who cooperated the results of therapy were disappointing 92. Sattler deserves credit for reintroducing occlusion treatment 93.

The rationale for treatment of amblyopia highlights the fact that an important health hazard exists in that the sound eye can become diseased or injured. A population based study found a 2.7 relative risk of such impairment in the better eye of amblyopes 94.

In managing amblyopia, the goal is to improve visual acuity by using two basic strategies. The first is to present a clear retinal image to the amblyopic eye by eliminating causes of visual deprivation and correcting visually significant refractive errors. The second strategy is to make the patient use the amblyopic eye. The recommended treatment should be based on the patient’s age, visual acuity, compliance with previous treatment and physical, social and psychological status 62.

The various treatment modalities are refractive correction alone 4-8, occlusion therapy 9-21, penalization 22-32, drug therapy 33-42, home vision therapy 8, 20, 21, 44, 48–50, surgery 95 to treat the cause of amblyopia. Others described in the past were pleoptics 96, 97, Cambridge stimulator (CAM stimulator) 98 and red filter 99; they are outdated nowadays. Although a large magnitude of studies have been done on above mentioned treatment modalities, none of them has been found foolproof. The paediatric eye disease investigator group (PEDIG) was formed in 1997 to facilitate research in amblyopia and strabismus and have given various recommendations in the treatment of amblyopia 100.

Refractive correction

An essential component in amblyopia treatment is to provide high spatial frequency image content to the amblyopic eye. The child’s prescription thus needs to be accurate to begin with, and has to be changed according to refractive status later on. To the extent that refraction if inadequate, treatment efficacy is reduced. Because refraction is difficult in infants and young children, there may be a bias towards better outcome in older children, even if they are neutrally less plastic, since they are more cooperative and hence can be more accurately refracted than young children 61.

[This part was concealed because of the plagiarism concern which was reported by a reader. Science Postprint is making an inquiry for the author about this matter (update:11/27/2015). ]

The effectiveness of refractive correction alone in treating children with previously untreated strabismic amblyopia, even in the absence of anisometropia was highlighted by Stewart et al 6. This was supported by results of ATS 5 7. Although the above reports show that refractive correction alone results in improved vision, it is generally held that majority will need an additional treatment 8.

Following guidelines (Table 1) are followed for prescription of eye glasses in young children 86.

Table 1 Followed guideline for prescription of eye glasses in young children 86

Occlusion

There is neither a substitute nor a shortcut to full time occlusion in treatment of amblyopia despite recent recommendations of amblyopia study group.

In occlusion therapy, the fixating eye is prevented from taking part in the act of vision so that the patient is forced to use the amblyopic eye. In addition it removes the inhibitory stimuli to the amblyopic eye that arise from the stimulation of the fixating eye 1.

Eyes can be occluded in a variety of ways. On the basis of light transmission two types of occlusion are available.

  • Total occlusion—Involves complete blocking of both form vision and light. This includes the followings:
    • Direct skin patch
      • Commercially available, hypoallergenic patches
      • Patching with cotton pad and 2 inch-wide micropore
    • Spectacles patched with paper and tape
    • Doyne’s occluder
    • Pirate patches
    • Extended wear occlusive contact lenses 101
  • Partial occlusion—There is incomplete blockage of light transmission and can be used only in mild amblyopia, or for maintenance therapy.
    • Colourless nail varnish over spectacles
    • Layer of semi—transparent membranes of various densities over the spectacles

The occlusion schedule prescribed by von Noorden as following Table 2.

Table 2 The occlusion schedule by von Noorden

When to stop occlusion?: Occlusion can be stopped when the visual acuity becomes equal in both the eye; when there is true alternation of fixation; there is no visual improvement after three to six months of occlusion despite good compliance.

What to examine during follow up: Visual acuity of both eyes on the same chart after five to ten minutes of acclimitization, fixation pattern, presence of occlusion amblyopia.

Reports have described the effect of patching to be optimal within the first 6 months of wear and in terms of occlusion duration, maximum improvement occurs in response to 400 hours of occlusion 9.

Success rate varies from 30–92% in various studies reported in literature 10-16. The variation in success rate is due to various factors like patient selection, treatment durations, age, definition of amblyopia used in the study and type of amblyopia.

[This part was concealed because of the plagiarism concern which was reported by a reader. Science Postprint is making an inquiry for the author about this matter (update:11/27/2015). ]

Penalization

Penalization is a therapeutic technique performed by optically defocusing the eye having better vision by using cycloplegia (pharmacological penalization) or by altering the eyeglass lens (optical penalization) to cause decreased vision in the non amblyopic eye. Penalization has the advantage of being cosmetically acceptable, but it does not inhibit the abnormal binocular interaction, which is the essential cause for amblyopia. It rarely decreases the vision of the good eye to levels less than that of amblyopic eye and therefore, its indications are limited 22. These include moderate amblyopia in unco-operative patients, anisometropic amblyopia, and maintenance therapy after improvement with occlusion, occlusion failures and occlusion nystagmus.

Atropine, instilled as 1% ointment or one drop daily, is the most frequently used cycloplegic. It was first used by Worth in 1903 23. Its efficacy has since then been demonstrated in various studies 24-27 and in recent randomised control trials 28 conducted by PEDIG, 74% patients showed either a visual acuity better than 20/30 or an improvement of 3 or more lines. Of late the interest has arisen in the various regimens of atropine which can be prescribed. The ATS 4, studying 168 patients younger than 7 years with moderate amblyopia, found that weekend atropine provides an improvement in visual acuity of a magnitude similar to that of daily atropine, with 53% in weekend group and 47% in daily group improving by 2.4 lines at the end of 4 months 29.

When the sound eye is hypermetropic, the penalisation effect can potentially be augmented by prescribing less than full correction of the sound eye, effectively blurring its vision for near as well as distance fixation.

Simon et al. compared full-time atropine, intermittent atropine, and optical penalization in strabismic amblyopia and found that all three forms of penalization produced statistically significant mean reduction in amblyopia (1.7–2.7 logMAR lines) and a mean improvement in binocularity 26.

However, other studies (Tejender et al. 30 and Noorden et al. 31) concluded optical penalisation to be less effective than pharmacological penalisation.

A comparison between combined pharmacological and optical penalisation with atropine penalization alone showed the improvement to be similar in both the groups 32.

Despite all benefits, its major disadvantages include potential side effects due to systemic absorption of drug, allergic reaction and cost. Active inhibition of amblyopic eye by better eye is not inhibited. Also a concern about the use of prolonged unilateral cycloplegia for treatment of amblyopia, has been the potential for producing adverse effect on progression of refractive error by inducing changes in spherical equivalent of sound eye in hypermetropic patients, but this has not been substantiated by the amblyopia treatment study 103.

Comparison between atropine penalization and occlusion

The ATS 1 was initiated to address whether occlusion or atropine penalization is the best initial treatment for moderate amblyopia (20/40–20/100). It was undertaken between April 1999 and April 2001 and 419 patients were enrolled at 47 sites across United States of America 104. Improvement from baseline to 6 months was 3.16 lines in the patching group and 2.84 lines in atropine group. In the patching group 15% achieved their maximum improvement (3 lines) by 5 weeks and 52% by 16 weeks 16, whereas in the atropine group it was 7% by 5weeks and 46% by 16 weeks 28. Hence a faster response with patching than atropine was noted.

In both the groups, the amblyopia treatment index indicated that the initial month of treatment was usually well tolerated by the child as well as the parent. However, atropine was a more acceptable treatment than patching overall and also on 3 ATI subscales, namely adverse effects, treatment compliance, and social stigma 105.

Kushner pointed that the importance of a faster response in the patching group should not be minimised as this meant fewer visits to the ophthalmologist and the associated costs and inconvenience. Also as noted by him, if the visual acuity criteria are changed to 20/25 patching showed 40% result as compared to 28% with atropine 106.

Effect of amblyopia treatment on ocular deviation

Prognostic factors

Success of occlusion therapy depends upon several factors which should be kept in mind while treating amblyopia.

Age: The maximum age for attempting amblyopia treatment has been an important unresolved question among paediatric eye care professionals. It has been reported that success rate of amblyopia treatment may decline with increasing age 79. The response to treatment is more rapid and the visual outcome better in younger children.

Type of amblyopia: Earlier evidence suggested that strabismic amblyopia is taxonomically different and more difficult condition than anisometropic amblyopia and in keeping with such a difference, most studies report best to worst ranking of anisometropic, strabismic, and combined for visual acuity outcome at the end of treatment 9, 61. However ATS reports no difference in response to treatment whether the amblyopia was classified as strabismic, anisometropic, or both 28.

Pretreatment visual activity: If comparatively good, improves patients’ compliance to occlusion, hence visual prognosis is better. However, initial poor vision does not necessarily mean a poorer prognosis 86.

Type of occlusion: Conventional full time occlusion is preferred over part time and partial occlusion 86.

Type of occluder: An adhesive skin patch is preferable. Improper occlude might compromise prognosis 86.

Type of fixation: Amblyopes with foveal fixation respond more than those with eccentric fixation 86.

Refractive correction: If refractive correction is not proper, the efficacy of treatment is reduced 86.

Previous treatment: Some studies report no effect of previous treatment on amount of visual acuity improvement; others report that a new treatment outcome may simply constitute re-establishment of the previous regimen’s outcome, thus compromising maintenance 54.

Compliance: Patient compliance which has been a major concern in the treatment of amblyopia. Compliance is often compromised because the child may not like the patch, eyeglasses, or drops, or using the amblyopic eye 62. The reported compliance with patching varies between 49% and 87% 61.

Recurrence

One fourth of successfully treated amblyopic patients experience a recurrence within the first year of treatment. An important finding was that when 2 hours of daily patching was stopped, the recurrence risk was low, in contrast to when 6 to 8 hours of daily patching was stopped abruptly without weaning. 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 107.

There was no statistically significant increased risk of recurrence with being male vs. female, white vs non-white, age at diagnosis, increased age at cessation of treatment, longer duration of treatment, or inter-ocular difference at the time of diagnosis. Unexpectedly, the risk of recurrence was noted very similar between those who were orthotropic, microtropic (1–8 prism diopters (pd)) and heterotropic (>8 pd) and also similar between those patients who had excellent stereopsis, moderate stereopsis, coarse stereopsis or no measurable stereopsis. The risk was higher with better amblyopic eye visual acuity at the time of cessation of patching, when greater improvement was seen during previous treatment, or any previous recurrence 108.

Pharmacological Therapy

Drug therapy for amblyopia is a wish dream for all of us. Various drugs have been tried however carbidopa levodopa has been tried extensively all over world.

Past efforts to treat amblyopia medically have experimented with substances like oxygen 33, alcohol 34, propranolol 35, bicuculline 36, exogenous nerve growth factor 37 but none were successful in terms of clinical applicability and effectiveness.

More recently there have been attempts based on catecholamines, which appear to either extend or reactivate the visual system’s sensitive period of neural plasticity. Catecholamine based medical treatment has been demonstrated to improve vision in amblyopic eyes. Presumably because it stimulates both eyes, it does not produce reverse amblyopia 61.

The pioneering work, in children, in this field was done by Leguire and co-workers. They found that one hour after drug ingestion, Snellen visual acuity, contrast sensitivity and pattern VERs temporarily improved but started to decrease 5 hours after drug ingestion 38. They were of the opinion that the combination of levodopa-carbidopa and occlusion improves visual function more than levodopa-carbidopa alone in amblyopic children 39. Average dose levels of 0.95/0.24 mg kg-1 and 1.94/0.49 mg kg-1 of levodopa/carbidopa were found to be well tolerated and efficacious at temporarily improving visual acuity in amblyopic eyes of children 40. The study on efficacy of lower doses concluded that levodopa/carbidopa, at an average of 0.48/0.12 mg kg-1 is efficacious and has lower side effects 41.

Study by Dadeya et al. evaluate the role of levodopa/carbidopa in the treatment of amblyopia and concluded that there was more than two lines improvement in visual acuity, especially in children younger than eight years of age 42.

Citicoline (cytidine 5’-diphosphocholine) used in a dose of 1,000 mg I.M. for 15 days, without any amblyopia therapy to patients aged 9–37 years (mean 16.6 years), caused a temporary improvement in visual acuity without any side effects 109.

Pleoptics Therapy

In the 1940s, Bangerter, coined the term pleoptics, which is derived from Greek words—pleion meaning more and optikos for eyesight 96. His method involves dazzling of the eccentrically fixating area with bright lights while protecting the fovea with a disc projected on to the fundus, followed by intermittent stimulation of the macula. Treatment is given under direct observation using a modified Gullstrand ophthalmoscope (pleoptophor) and is continued until the central scotoma diminishes and fixation becomes central.

Cuppers used a different approach which was based on re-establishing the physiological superiority of the fovea over the retinal periphery. This is done by an ingenious application of afterimages elicited by a modified ophthalmoscope (Euthyscope), which has projectable black discs of various sizes. While the fovea is protected with the black mark, the retinal periphery is dazzled with bright light 97. The negative afterimage is enhanced by flickering of room illumination. This is complemented by fixation exercises with Haidinger brushes (coordinator).

Both these methods, however, are time consuming, requires, elaborate instrumentation and a regular follow up. It requires the cooperation of an intelligent patient (therefore useful for older than 5 years old) and the duration of therapy requires is earlier.

Although the practical importance of pleoptics has faded and is no longer practiced, Bangerter and Cuppers deserve credit for rejuvenating interest in therapy of amblyopia.

CAM Vision Stimulator

A considerable practical and theoretical interest was generated by initial reports from Addenbrooke's Hospital and the Physiological Laboratory, University of Cambridge, in the late 1970s of a new treatment for amblyopia, popularly known as CAM stimulator. [This part was concealed because of the plagiarism concern which was reported by a reader. Science Postprint is making an inquiry for the author about this matter (update:11/27/2015). ]

Red Filter Treatment 99

[This part was concealed because of the plagiarism concern which was reported by a reader. Science Postprint is making an inquiry for the author about this matter (update:11/27/2015). ]

Surgery

Recently Astle et al. have described that LASIK is an effective surgical alternative to improve visual acuity in anisometropic children, who are unable to tolerate conventional amblyopia treatment or in whom this therapy fails 95. This should be used as a last resort in desperate cases only.

Near visual activities

Near visual activities are often prescribed during patching for amblyopia based on the assumption that those activities stimulate the visual system 44.

A number of uncontrolled case series during the middle and later half of twentieth century have suggested a benefit to prescribing near activities 45-47 but the question has not been rigorously studied. The major proponents of these at that time were Francois and James 45, Callahan and Berry, and von Noorden and colleagues. They incorporated tracing pictures, completing puzzles, colouring small symbols on exercise sheets for one hour a day during occlusion. Watson and colleagues also described playing a visually demanding game while patched.

Garzia summarised findings of earlier studies on effects of vision therapy for amblyopia in patients who failed occlusion therapy 110. A variety of different vision therapy approaches were used ranging from hand-eye activities from tracing to colouring pictures. While the reviewed report suggests that active vision therapy can successfully treat a wide range of patients of all ages, the studies were limited by small sample size, lack of comparison or control group, poorly defined patient selection criteria, probable patient selection bias and lack of standardisation of both treatment and success criteria.

[This part was concealed because of the plagiarism concern which was reported by a reader. Science Postprint is making an inquiry for the author about this matter (update:11/27/2015). ]
These included trials in the amblyopia treatment study 2 comparing patching regimes in moderate and severe amblyopia 20, 21, those in the amblyopia treatment study 3 evaluating the benefit of treatment in 10-18 years old patients through a pilot study 48 and then again in the main study having 7–17 years old subjects 8, and also in trial evaluating two hours of daily patching 51. In each of these studies incorporating different doses of patching, combined with near visual activities, successful results in terms of improvement in visual acuity in most children was achieved. It, however, remained unclear as to how much of this benefit could be attributed to near visual activities vis-a-vis patching 44.

Role of television

Television has always been a very popular mode of entertainment and its popularity refuses to die down. As a matter of fact, it has in the past, found utility in administering amblyopia therapy.

[This part was concealed due to the plagiarism concern which was reported by a reader. Science Postprint takes appropriate action for this matter (update:11/04/2015). ] They reported that engaging the child in a visually demanding task, while part time patching rather than the stripes helped improvement in vision 52.

Conclusions

At the end we conclude that amblyopia is still an unsolved problem for ophthalmologists. The modalities of treatment are subject to patient and clinician preference. The best modality of treatment is still to be explored in future.

Author contributions

Conceived and designed the work: Singh A, Dangda S
Acquired the data: Dangda S
Analyzed and/or interpreted the data: Kumar B
Drafted the work: Singh A, Dangda S
Revised and approved the work: Kumar B
All authors approved the final version to be published.

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