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Amblyopia treatment beyond the critical period.

INTRODUCTION

Amblyopia has been defined as the condition in which 'the patient sees nothing and the practitioner very little.' (1) This play on words conveys information that amblyopia is characterised by reduced visual acuity (usually monocular, infrequently bilaterally), (2) despite optimal optical correction and the absence of any pathology, past or present. In fact, the reduction in visual acuity is not the only abnormality of the eye since amblyopia almost always co-exists with strabismus, anisometropia or both. (2) Indeed, some definitions suggest that unless there is strabismus or anisometropia, any reduction in best corrected visual acuity should be treated with real suspicion because the reduction may not in fact be due to amblyopia. (2)

As with any disorder, the prevalence of amblyopia depends on precisely how it is defined. For example, if the criterion for the visual acuity deficit is any reduction below 'normal' in either eye, amblyopia will be found to be highly prevalent. However, if amblyopia is only diagnosed when there is a minimum reduction relative to normal of, for example, two lines of letters, or a difference in visual acuity between the eyes of say two or more lines, the prevalence will naturally be much lower. (3) Estimates place the prevalence of amblyopia between 0.8% and 3.3%, depending on the population studies and the definition adopted. (4)

Amblyopia is described as a developmental disorder of vision. This reflects the fact that if you don't become amblyopic in early childhood, it is not a condition you will acquire later. In the same way that humans are immune to developing amblyopia once a certain age has been reached, (5) there was until quite recently a strongly-held belief that the opportunity to treat amblyopia was also very time-restricted. Animal studies in which visual deficits caused by artificially generated strabismus or anisometropia were found to be largely reversible provided the treatment commenced early in the animal's life; adult animals with amblyopia from early life were found to be much less treatable, and frequently untreatable. (6) This is the well-known concept of the 'critical period', denoting a fixed and relatively brief duration in early life when things can go wrong in visual development and similarly, when the opportunity exists to put them right. A useful analogy to describe this thinking is the way cement sets on the building site: the surface is vulnerable until the cement has solidified. The animal research which generated the clinical dogma that only young children are at risk from amblyopia and that when it has been found, it needs to be dealt with early, was instrumental in the establishment of school vision screening programmes in the United Kingdom (and in many other parts of the developed world). As well as identifying significant refractive errors and reduced vision, the aim of school vision screening is to identify amblyopia so that treatment can start without delay. (7)

Although there were always dissenters to the view that amblyopia had to be treated early (some from the research community, but mainly clinicians who claimed that they had evidence that amblyopia was treatable in adulthood), the overwhelmingly accepted view was that seven or eight years represented the upper age limit for treating amblyopia. (8) It now turns out that the dissenters were correct and that the clinical thinking of the past was wrong in many key respects. The purpose of this article is to summarise recent developments relating to amblyopia treatment, specifically in relation to the treatability beyond the early years and to highlight the implications for the optometrist in practice.

TRADITIONAL APPROACHES TO AMBLYOPIA TREATMENT

The condition we call amblyopia was documented around the year 900 but amblyopia treatment only began in earnest around two hundred years ago. (2) Since treatment began, some very interesting and surprising treatment approaches have been tried, including reverse occlusion where the weaker eye was occluded. The thinking here was that covering the weaker eye might prevent the abnormal pattern of visual behaviour (such as when the visual axes are misaligned in strabismus) from becoming engrained. Reverse occlusion never gained credibility outside of the research lab. (2)

From the time when amblyopia therapy was first attempted to this day, the main treatment approach consists of optimal refractive correction combined with some means of giving the signal from the weaker eye an advantage over its fellow. (2) Sometimes this takes the form of atropine sulphate eye drops instilled to the better eye to prevent this eye from accommodating, thereby ensuring that the weaker eye had to be relied upon during close work. Alternatively and more commonly, the fellow eye is occluded on a part-time (or rarely, a full-time) basis. So the traditional approach to treatment could be summarised as follows: spectacles and patching up until the age of seven or eight, after which spectacles will likely still be needed but refractive correction won't deliver any further amblyopia therapy; similarly patching is not effective beyond this age cutoff (see Figure 1). Until relatively recently, there was little to challenge this position.

RENEWED RESEARCH INTEREST IN AMBLYOPIA TREATMENT

In 1997, a report by Snowden and Stewart-Brown, (910) commissioned by the NHS, produced huge shockwaves because it concluded that while there was at the time a strong belief that amblyopia treatment works there was 'no evidence that treatment is either effective or necessary.' (10) What followed has been an explosion in the volume of research conducted on the topic of amblyopia treatment, examining questions such as: what duration of patching is needed? Is atropine more or less effective than patching? Is patching therapy more effective when combined with near tasks? The research findings in response to all of these questions are beyond the scope of this article. However, other questions posed that have direct relevance here include: should refractive correction be worn until all of its benefits are identified before starting additional therapy, for example, patching?

Can amblyopia be treated in older children and adults?

As is often the case, when research on a new or controversial topic initially appears in the literature it is often in the form of published case studies. In one such case study of the treatment of amblyopia in an adult, Anita Simmers and Lyle Gray (both based in Glasgow Caledonian University) reported the case of a 30-year-old strabismic amblyope. (11) This individual had received orthoptic therapy including patching in early childhood. They reinstated patching in adulthood and, as a result, demonstrated substantial improvement in visual function--LogMAR visual acuity improved from +0.55 (Snellen -6/24) to +0.20 (-6/9). The patient's motivation for patching in adulthood stemmed from a desire to qualify for a HGV driving licence. There have been many other reports of improvement in amblyopic eye function amongst adults following the onset of age-related pathology, in particular macular disease. (12) Prior to the appearance of several of such case studies, Wick and colleagues had published the results of a study which they titled Anisometropic amblyopia: is the patient ever too old to treat?and in which they conducted a retrospective study of 19 patients aged from six to 49 years. (13) In addition to patching, they included 'active vision therapy to develop monocular acuity and improve binocular visual function.' They concluded 'following a sequential management plan for treatment of anisometropic amblyopia can yield substantial long-lasting improvement in visual acuity and binocular function for patients of any age.' And in 1991, Ciuffreda and colleagues in their book entitled Amblyopia: basic and clinical aspects stated that 'the end of the period for susceptibility does not mark the end of the period during which treatment may result in improved visual function.' They also added 'rather, for many cases of functional amblyopia, some degree of residual plasticity remains present well into adulthood.' (2)

While early studies were certainly important, their clinical implications mostly fell on deaf ears in the sense that there was little or no sign that they were finding their way into the clinical setting. It was the 1997 report by Snowdon and Stewart-Brown, (9) that prompted something of a revolution in relation to the nature and scale of the studies on the effectiveness of amblyopia therapy, and it is this research which has already had a significant clinical impact and which will, one suspects, continue to alter clinical practice in the future.

As an example of the 'new age' amblyopia treatment studies, Michael Clarke and colleagues in Newcastle included 177 children and successfully compared visual outcomes in children receiving both patching and spectacles with another group who received spectacles only, and crucially to a third group who received neither spectacles nor patching. (14) Other large-scale studies conducted in the UK includes research by the Fielder-Moseley-Stewart group in London. (15,16) In the US, the Pediatric Eye Disease Investigator Group (PEDIG) was established. This collaborative network of researchers and clinicians established protocols and paradigms for the large-scale, multi-centred study of a large number of research questions in strabismus, amblyopia and other eye disorders affecting children. The PEDIG group has published extensively and the interested reader can visit their website (bit.ly/1Gcvsz4) for much more information; for example, it is possible to download the publications themselves and even the spreadsheets containing anonymised results for individual participants, and many of their studies are available to view.

The following provides a brief summary of publications that relate to our topic of interest here, the treatment of amblyopia beyond the critical period:

* Treatment of amblyopia in children aged seven to 17. (17) In 2005, the PEDIG group published a study, conducted at 49 different clinical sites, of over 500 amblyopic children aged from seven to 17 and in whom amblyopic eye visual acuity ranged from 6/12 to 6/120. Some of the children had been treated for their amblyopia but none had received any treatment (other than spectacles) in the previous month, or in more than one of the previous six months. The study compared visual acuity outcomes in an 'optical correction only' group with a second 'optical correction and treatment' group (note: interestingly, this terminology implies that optical correction is not part of the 'treatment'; although many would disagree with this view, it will not be discussed further here). Children were randomly allocated to one of these two groups. Treatment consisted of two to six hours per day of patching combined with near activities (playing on a hand-held games console) for at least one hour per day. Children in the 7-12 age range also received atropine sulphate every day, which the older children did not receive. Children were classified as 'responders' if the visual acuity improved by a minimum of two lines, and the proportion of responders was compared in the younger and older children. In the younger (7-12 year old children), patching and near activities more than doubled the proportion of children who were responders--25% of the spectacles-only group responded, but 53% of the children in the spectacles-plus-treatment group were responders. By contrast, in the older children, 23% and 25% were classed as responders in the spectacles-only and spectacles-plus-treatment groups, respectively. Crucially, however, they found that in the older, but previously untreated children, the results were very similar to the younger children. In these children, 20% of the spectacles-only were responders compared to 47% of the spectacles-plus-treatment group. No such difference existed between previously treated versus previously untreated children in the younger age group. The authors reported no adverse effects of treatment (in particular no case of diplopia following treatment) and on the basis of these findings, they concluded that in seven to 12-year-olds, optical correction and treatment (patching, atropine, near activities) stands a good chance of being successful even if treatment had been previously undertaken.

In the older age group, refractive correction alone was all that was needed if treatment had previously been tried but, importantly, attempting full-treatment was justified if it hadn't.

* In another randomised-controlled trial by PEDIG, the effectiveness of atropine and patching was compared in older children (seven to 12-year-olds) (18) In this study, 193 children received either weekend atropine or patching for two hours per day. Our interest here is less about which of the two treatment methods is the more effective, and more in terms of whether either treatment can be effective in children who are older than those traditionally considered treatable. In fact, after the 17 weeks of the trial, there was a mean improvement of around eight letters (close to two lines) for both the patching and atropine groups. Interestingly, this study also found evidence for improvements in stereopsis as well as visual acuity.

* In November 2011, the PEDIG group published another paper, which is highly relevant to the topic being considered here. (19) The paper is important because it featured a meta-analysis of data from four randomised-controlled trials. Meta-analysis is a means for combining the results across studies, thus offering increased confidence about treatment effectiveness and hence a greater ability to identify trends. The PEDIG analysis took the following factors into account: baseline visual acuity, spherical-equivalent refractive error of the amblyopic eye, the type of amblyopia (anisometropic or strabismic), whether prior treatment for amblyopia had been undertaken, the study treatment and protocol. Age was categorised into three ranges: three to less than five years, five to less than seven years and seven to less than 13 years. The main finding of this meta-analysis was that children aged seven to less than 13 years were significantly less responsive to treatment than younger age groups. However, they stressed that there was still an overall improvement with treatment in the older children and that, although the average treatment response is smaller in children seven to less than 13 years than in the younger children, some children aged seven to 12 years showed a dramatic response to treatment. They were unable to identify whether the reason for such big discrepancies in the response to treatment amongst older children had to do with treatment compliance, since occlusion dose monitors used in some studies, were not a feature of the studies considered in this analysis. Interestingly, and contrary to previous studies, the results of this meta-analysis did not identify 'prior treatment' as a statistically significant determinant of treatment response in the older children. Overall the authors concluded that 'it seems reasonable to offer treatment to even older teenagers (for example, up to the age of 17 years) because we are currently unable to predict which patients will or will not respond'. (19)

* Are the gains in visual acuity achieved in older children maintained once treatment has ceased? Indeed, it seems as though they are maintained. In yet another PEDIG study, the visual acuity improvement that arose during amblyopia treatment was sustained in most seven to 12-year-old children for at least one year (the period for which they were longitudinally followed) after discontinuing treatment, although spectacle wear was continued. (20)

SUMMARY OF RESEARCH FINDINGS

In summary, the effectiveness of treatment does seem to decline with age. However, the research supports the view that treatment can still be effective beyond the age that was previously thought to represent the upper age limit, the so-called 'critical period'. The effectiveness of treatment in older children and adults appears to depend to some extent on whether or not previous treatment was undertaken (that is treatment that was offered and complied with). Studies have generally found that the response to treatment is poorer in older children, and in those who have previously undertaken amblyopia therapy compared to those who had not previously been treated. While the treatment of older children is effective but on average, less effective than in young children, in some older children it produces dramatic improvements. Although there are concerns about the possibility of treatment generating diplopia (particularly in strabismic amblyopes), studies have consistently found that amblyopia therapy in older children is safe and that its effects are long lasting. The results of large-scale studies seem to indicate that strabismic amblyopia responds just as well to treatment when compared to anisometropic amblyopia. (17) Some useful summaries of the clinical findings from the recently published randomised amblyopia treatment trials have appeared in the literature. (23,24)

CLINICAL IMPLICATIONS FOR OPTOMETRISTS

One very prominent element from research studies that has already found its way into the clinical setting relates to cessation of the practice whereby patching therapy, for example, was initiated at the same time as spectacles were issued. Following many demonstrations in the clinical research literature that spectacles alone represent an effective (and in some cases, a complete) therapy for amblyopia, (21,22) it is now standard clinical practice to wear optical correction for at least 16 weeks or longer, until stable visual acuity is demonstrated before any other therapy is initiated. (25) This holds no matter how poor the visual acuity, and similarly it does not depend on the age of the patient or the type (anisometropic or strabismic) of amblyopia.

Practitioners are supported by guidelines from their professional bodies. The 2012 Preferred Practice Patterns (PPP) on Amblyopia issued by the American Academy of Ophthalmology (AAO) lists Highlighted Findings and Recommendations for Care. (4) There it states that there is 'good evidence' that 'patching may be effective in older children and teenagers, particularly if they have not previously been treated'. This document also states 'all children with amblyopia should be offered an attempt at treatment regardless of age, including those in later childhood.' Interestingly, the 2002 PPP guidelines issued by the AAO listed an upper age limit for amblyopia treatment of 10 years; this no longer appears.

Here in the UK, the College of Optometrists guidelines on Principles of Examining and Managing Patients with an Anomaly of Binocular Vision are less specific and could perhaps better reflect current evidence. In guideline A187 (Amblyopia and Patching) it states that 'If you treat a patient with patching you should have up-to-date knowledge and skills on this topic.' Guideline A190 ('When to refer') includes the statement 'you should be aware of the critical period for amblyopia development and ensure prompt treatment.'

Thus, there is no specific mention of the fact that age is no longer considered to be a barrier to treatment.

Amblyopia management does raise some potential risk factors from a legal perspective and has been a feature of fitness to practise cases in the past. As with all clinical conditions, optometrists need to ensure that their decisions are based on, and supported by, up-to-date clinical evidence and where such evidence may not exist, to conform with the 'accepted wisdom'. A failure to refer for possible amblyopia treatment because 'the critical period is over' obviously represents a scenario that could land an optometrist in difficulty as a result of the fact that the clinical thinking in this area has altered so dramatically in the relatively recent past.

SHOULD ALL AMBLYOPES, IRRESPECTIVE OF AGE, NOW BE REFERRED OR TREATED?

The answer to this question is clearly no. However, you should check with your local hospital eye service (HES) to ask their advice. The author contacted several of his ophthalmology and orthoptist colleagues in the Yorkshire region about how they wished local optometrists to respond to developments in amblyopia referral patterns. Broadly speaking there was a consensus that older amblyopia patients should only be referred to the HES if they had not previously been treated by occlusion or atropine penalisation. Some said that children up to the age of 17 could be referred, whereas others suggested a cutoff of 12-13 years. HES colleagues were keen to stress that, as well as having had no prior patching/ penalisation treatment, older children should only be referred provided they and/or their parents actually want to undergo treatment and understand something about what the treatment will involve. A number of my HES colleagues felt that optometrists should also be mentioning the potential risks of treatment (for example, possibility of no response to treatment, diplopia) to older children and their parents before referral is initiated.

It is therefore important that this topic is discussed in some detail with local HES colleagues. Indeed, for clarity and legal protection, it would be advisable to document the outcome of these discussions.

CURRENT TRENDS AND POSSIBLE FUTURE DEVELOPMENTS

In this article, results from studies in which amblyopia treatment effectiveness has been studied in older children have been summarised. Mostly, these studies have featured fairly traditional treatment approaches. What has not been mentioned so far is that there are many different groups around the world examining new and alternative ways to promote recovery from amblyopia. (26,27) Many of these newer approaches have, at their core, an attempt to develop binocularity. This obviously contrasts with occlusion therapy, which has as its main aim the improvement in amblyopic eye visual acuity. Binocular approaches to treatment involve leaving both eyes open but balancing the input to the two eyes, (28-30) such that the weaker eye gets a higher contrast signal relative to its fellow and they feature a dichotic viewing arrangement whereby certain elements of the visual display can only be seen by the amblyopic eye. These treatment approaches are likely to appeal more than the passive methods, such as patching, to patients of all ages because the time commitment per day is generally lower and because they involve game playing. (31) In one such treatment method, the game of Tetris is played. (32) The dropping blocks are visible to one eye and the blocks assembled on the bottom of the display can only be seen by its fellow (see Figure 3). Other, much more radical approaches to amblyopia treatment include the possibility that in the future, pharmacological substances will be available to inject into the visual system so as to re-start the critical period. (33,34) Also, recent animal studies indicate that sustained periods of complete darkness (for example, 10 days), can reboot the critical period allowing for a fast and complete recovery of amblyopic eye acuity in kittens. (35) While the latter experimental approaches are clearly of academic interest only for now, whatever form amblyopia treatment takes in the future, the onus will remain with the optometrist to ensure that patterns of advice and referral and possibly treatment are rooted in good clinical research evidence. The available evidence now clearly shows that amblyopia treatment should be considered in children of all ages.

// REFLECTIVE LEARNING

Having completed this CET exam, consider whether you feel more confident in your clinical skills--how will you change the way you practice? How will you use this information to improve your work for patient benefit?

KEY POINTS

* Spectacles alone represent an integral part of amblyopia treatment

* Once acuity has ceased improving with spectacles, and a minimum of 16 weeks of wearing them has elapsed, additional therapies, such as patching, may need to be initiated

* Optometrists should establish the approach for managing older amblyopes with local HES colleagues and document the outcome of these discussions

* Practitioners should be aware of their responsibility to patients by managing cases of amblyopia based on and supported by up-to-date clinical evidence

* The available evidence now clearly shows that amblyopia treatment should be considered in children of all ages

* Recent animal studies have identified methods for rebooting the critical period to achieve fast and complete recovery of amblyopic eye acuity in kittens.

Course code: C-39117 Deadline: 6 February 2015

LEARNING OBJECTIVE

To be able to explain to patients about the implications of amblyopia (Group 1.2.4)

To understand the advice from professional bodies relating to the management of amblyopia (Group 2.2.3)

To be able to manage patients with amblyopia appropriately (Group 8.1.2)

Exam questions

Under the enhanced CET rules of the GOC, MCQs for this exam appear online at www.optometry.co.uk/cet/exams. Please complete online by midnight on February 6, 2015. You will be unable to submit exams after this date. Answers will be published on www.optometry.co.uk/cet/exam-archive and CET points will be uploaded to the GOC every two weeks. You will then need to log into your CET portfolio by clicking on 'MyGOC' on the GOC website (www.optical.org) to confirm your points.

1 CET POINT

What factors should a practitioner consider when treating a 13-year-old child with amblyopia who seldom wears their spectacles? The purpose of this article is to acquaint the practitioner with recent research on the topic of amblyopia treatment in older children and to highlight how thinking is changing.

References

Visit www.optometry.co.uk/clinical, click on the article title and then on 'references' to download

ABOUT THE AUTHOR

Brendan Barrett is professor of visual development at the University of Bradford where he is the module leader for refraction and refractive error and also teaches on the binocular vision module.

He is currently an external examiner for the undergraduate ophthalmic dispensing programme at Glasgow Caledonian University. His research interests include amblyopia, vision and sport, and vision and reading.
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Title Annotation:CET: AMBLYOPIA
Author:Barrett, Brendan
Publication:Optometry Today
Geographic Code:4EUUK
Date:Jan 10, 2015
Words:4141
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