Ophthalmic & Physiological Optics ISSN 0275-5408
POINT-COUNTERPOINT In the following point-counterpoint article, acclaimed researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the editorial team provided an Introduction and Summary. By their nature, views expressed in each section of the Point-Counterpoint article are those of the authors concerned and may not reflect the views of all of the authors.
Should amblyopia be treated? Amblyopia has been treated for over 200 years but only relatively recently has the effectiveness of treatment for this common condition come under serious scrutiny. Programmes of vision screening exist for young children in most developed countries and amblyopia and the conditions thought to cause it (anisometropia, strabismus and significant refractive error) represent the main ‘targets’ of this screening. Following Snowden and Stewart-Brown’s1 call for robust evidence to describe the efficacy of amblyopia treatment, a large volume of research has been published including the results of many large-scale, multicentre studies. This research has led directly to a change in practice in a number of ways, for example a marked reduction in the numbers of hours of occlusion typically prescribed and, notably, the realisation that refractive correction (rebalancing the sensory input) alone represents a critical first element of therapy. However, despite significant strengthening in recent years of the evidence base underpinning amblyopia treatment, the question of whether the treatment of amblyopia has value is multi-faceted and it is this question which is the subject of the present point-counterpoint feature. Here, Kulp and Cotter argue that the case for treating amblyopia remains strong, whereas Connor and Clarke argue that the available evidence does not support the view that amblyopia is worth treating. Citation information: Kulp MT, Cotter SA, Connor AJ & Clarke MP. Point-Counterpoint. Should amblyopia be treated? Ophthalmic Physiol Opt 2014; 34: 226–232. doi: 10.1111/opo.12124
Point
Marjean T. Kulp The Ohio State University College of Optometry, Columbus, USA.
Susan A. Cotter Southern California College of Optometry, Marshall B. Ketchum University, Fullerton, USA.
E-mail: [email protected] E-mail: [email protected]
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Amblyopia is of significant public health concern because it is the most common cause of monocular vision loss in children, occurring in approximately 2.4% of the population.2 The damage produced by amblyopia is observed clinically as a reduction in visual acuity that is not immediately correctable despite optimal optical correction of refractive error. The nature of vision loss in amblyopia is not limited to the loss of high contrast visual acuity; abnormal contour interaction, poor accommodation, reduced contrast sensitivity, positional uncertainty, spatial distortions, abnormal eye movements, fixation instability, and suppression are also present.2–4 Functional sequelae such as reduced reading speed5 and compromised fine-motor skills6 have also been described. These impairments of visual function are expected to persist throughout life if amblyopia is left untreated. Unilateral amblyopia can preclude employment in a wide range of occupations that require good visual acuity in each eye7 and/or normal stereoacuity, such as aviation, law enforcement, military service, firefighting, dentistry, surgery, and even obtaining a commercial driver’s license.8 Individuals with untreated amblyopia are at a greater risk of becoming blind due to vision loss in the good eye.9,10 It has been reported that individuals with amblyopia have a projected lifetime risk of visual impairment or blindness of at least 1.2–3.3%, with 65% of adult amblyopes not able to continue their paid employment after losing vision in their non-amblyopic eye.10 Because treatment is more effective in younger children,11 amblyopia detection typically focuses on young children, in the form of effective vision screenings and comprehensive eye exams to detect amblyopia and its risk factors. The Vision in Preschoolers (VIP) Study Group demonstrated that preschool vision screenings with certain autorefractors and visual acuity tests can be effective in screening for amblyopia and its risk factors when used with appropriate referral criteria.12 Amblyopia screening programs have been shown to be cost-effective13 and to potentially lower the prevalence of amblyopia among older children.14 In addition, amblyopia treatment has been shown to be successful in improving visual acuity in a high percentage of children who were initially identified by screenings for amblyopia or amblyogenic risk factors.2,14 Amblyopia does not improve on its own.15 Some form of treatment must be instituted. Fortunately, visual acuity can be successfully improved and suppression ameliorated with treatment.2,15–19 In addition, gains in stereoacuity20 and accommodation,21 as well as increased cortical activation22 have been demonstrated. Treatment is usually well-tolerated,15,23,24 and the availability of a variety of treatment options allows practitioners to modify the current treatment regimen or change the treatment modality altogether if compliance issues arise.16 Treatment in older children
Should amblyopia be treated?
and adults also has been shown to result in clinically significant improvements in vision.2,15,18,19 Generally, optical correction of significant refractive error is instituted initially and then followed by patching or atropine eye drops if the amblyopia does not resolve with a period of optical treatment alone.2,15,16 On average, unilateral amblyopia improves approximately three lines with spectacles alone and approximately one-third of children do not require additional treatment.2,15,16 Recent research has shown that concerns regarding potential psychosocial issues associated with children wearing spectacle corrections may be unfounded because children are just as likely to want to play with peers who wear spectacles as those without, and they perceive those who wear spectacle corrections as being slightly more honest and smarter.25 When amblyopia does not resolve with optical correction alone, further treatment with patching or atropine drops has been shown to result in meaningful improvements in amblyopic eye visual acuity with increases of approximately three to five lines on average.2,11,16 More importantly, these improvements are generally long-lasting.16,17 For example, the Pediatric Eye Disease Investigator Group recently reported average long-term visual acuity outcomes of 0.14 logMAR (approximately 20/25 or 6/7.5) at 15 years of age for children who were enrolled in a randomized clinical trial for moderate amblyopia when younger than 7 years of age.17 Amblyopic eye acuity was 20/25 (0.10 logMAR) or better in 59% and 20/20 (0.0 logMAR) or better in 34%, despite 94% of the children having not received any further amblyopia treatment between 10 and 15 years of age.17 Although generally mild, residual visual acuity deficits are common after treatment with patching and/or atropine2,16; additional novel treatment modalities such as perceptual learning18 and binocular anti-suppression treatment19 are currently being explored for evidence of improved efficacy. Treatment of amblyopia with patching or atropine has been shown to be well tolerated and without significant negative psychosocial impact or influence on the child’s overall well-being and behaviour.15,24 Cost utility analysis has found that the treatment of amblyopia in childhood results in considerable lifetime gains in quality adjusted life years (QALYs), a measure that takes into account both the duration and value of the health condition. Treatment also has been shown to be highly cost-effective in comparison to other health care interventions.26 In summary, there is a wealth of evidence that the detection and treatment of amblyopia is a valuable endeavor. Appropriate vision screening methodology for amblyopia and amblyogenic risk factors is effective12 and the efficacy of amblyopia treatment has been well-established.2,15–19 Because young children are more responsive to treatment,11 efforts to identify and treat amblyopia sooner rather than later are warranted. While older children and adults can
© 2014 The Authors Ophthalmic & Physiological Optics © 2014 The College of Optometrists Ophthalmic & Physiological Optics 34 (2014) 226–232
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also show significant improvements in amblyopic eye visual acuity with treatment,2,15,18,19 public education, the use of the best available vision screening procedures, and better access to vision care and follow up, could theoretically eliminate amblyopia as a public health concern. If childhood amblyopia is left untreated, its consequences will be felt over the affected person’s lifetime.
Counterpoint Alan J. Connor Royal Victoria Infirmary Eye Department, Newcastle upon Tyne, UK. E-mail: [email protected]
Michael P. Clarke Royal Victoria Infirmary Eye Department, Newcastle upon Tyne, UK. E-mail: [email protected]
Although occlusion therapy for amblyopia has been in use for over 200 years, it is only recently that evidence for its effectiveness has been evaluated. Many treatment trials in amblyopia have reported improvement in visual acuity, but have done so without comparison with appropriately matched control groups.27–30 These studies overestimate the benefits of treatment due to normal visual maturation, learning effects, inter-test variability and regression to the mean.31 To truly measure the effect of therapy requires a randomized control trial (RCT) with an appropriately matched ‘no treatment’ control group.32 Three papers fulfill this criterion. The first RCT 33 performed in this area studied vision screening failures and compared refractive correction and occlusion to a control group. At 1 year, the mean improvement over the control group was 0.109 logMAR. A second RCT, performed over a 12 week period, found a significant learning effect in the control group of 0.24 logMAR, but an additional 0.1 logMAR improvement was reported with 6 h per day of occlusion.27 The third RCT was powered to find 0.1 logMAR difference after 5 weeks between the occlusion and control group but only found a 0.07 logMAR difference.34 In this third paper both groups were treated after 5 weeks so it is impossible to separate if any improvement beyond 5 weeks was due to amblyopia treatment or learning effect. We can conclude from these studies that occlusion therapy does indeed improve visual acuity but the size of this improvement is modest. Even when amblyopia has been successfully treated, recurrence occurs in up to 27% of patients.35 It should be remembered that treatment (occlusion or atropine) renders the patient visually impaired during the time when the patch is worn or when the fellow eye is blurred with atropine and as a consequence compliance with treatment is poor.36 Other side effects may include local skin irritation from patching and precipitation of amblyopia in the better eye. Perhaps the most important side effects are related to induced health anxiety and unintended psychosocial impact on the child’s wellbeing.37–41 Quality of life measures in amblyopia
Amblyopia is a form of cerebral visual impairment caused by a degraded retinal image or dissimilar retinal imagery during a sensitive period of visual development.15 It affects many aspects of visual function, but clinically is typically defined as an inter-ocular difference of ≥0.2 logMAR best corrected visual acuity in the absence of any other pathology and in the presence of an amblyogenic stimulus. 228
Patient-reported quality of life measures have been used to assess the impact of amblyopia.37–41 These questionnaires may be completed by the child, the parent, or used to assess the impact of disease in adults with residual amblyopia. Quality of life tools assess the emotional, social and functional impact of amblyopia. They have highlighted strained relationships between family members, problems with social interactions, and feelings of isolation and bullying. Functional issues are also reported in terms of difficulties with specific activities of daily living as well as education
© 2014 The Authors Ophthalmic & Physiological Optics © 2014 The College of Optometrists Ophthalmic & Physiological Optics 34 (2014) 226–232
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activities. Depression, lack of self-esteem and embarrassment are also reported. It is difficult to draw any conclusions about the benefits of amblyopia treatment from these studies. Firstly, many studies have included patients with strabismic amblyopia and it may be factors relating to strabismus rather than amblyopia that affect Quality of Life. Secondly, no study has shown an improvement in a Quality of Life score that has been attributed to an improvement in amblyopia. More importantly, as these studies have included treated patients, they may highlight the adverse impact on quality of life of amblyopia treatment rather than that of the decreased visual function associated with amblyopia. Another method for assessing the impact of amblyopia involves the calculation of ‘utility’ values. Utility values can then be used to quantitatively express the benefit of amblyopia in terms of Quality Adjusted Life Years (QALYs). Utility is calculated assuming 1 year of perfect health has a value of 1 and death has a value of 0. The utility of any particular disease state then lies somewhere between 0 and 1. The value can be calculated using the time trade off method: i.e. how much life time a patient would be willing to exchange to be disease free, or by the standard gamble method, how much risk of death the patient would accept to be cured of the disease. Membrano et al.26 performed a cost utility analysis by using utility values associated with various visual acuities to quantify the improvement in quality of life with amblyopia treatment and calculated the costs associated with this. They stated that amblyopia treatment was highly cost effective resulting in a gain of 0.8 QALYs. Each QALY had an associated treatment cost of $2281. Unfortunately, the methodology they used was flawed, as they used utility values that had been calculated from a cohort of patients that lost vision in adult life, mainly due to retinal disease. When utility values have been calculated using a cohort of amblyopia patients,42 the utility values suggest the impact of amblyopia was much less and as such renders the Membrano et al. calculations invalid. The utility values calculated from amblyopia patients via the time trade off method is 0.963 (equivalent to a traded 3.7% of lifetime) and 0.9996 by the standard gamble method (equivalent to accepted risk of death of 1 in 20 000).42 Studies of cost effectiveness are highly sensitive to the utility value used with amblyopia treatment appearing much less cost effective when more appropriate utility values are used i.e. utility values which correspond to developmental loss of vision in one eye as opposed to hypothetical values derived from patients asked to speculate in relation to acquired visual reduction. In addition, the use of utility values to determine cost effectiveness has been subject to criticism. The utility value is highly subjective and individuals show large variation in how they respond to these difficult, hypothetical questions.
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Functional impact of amblyopia The functional impact of amblyopia can be best assessed from the outcomes of population cohort studies. The Blue Mountain Eye Study reported no significant difference in employment class between the amblyopic and the non-amblyopic population.9 However, a lower number of amblyopic patients had attained university degrees. This finding may be explained by not controlling for patients with developmental and neurological disease or cognitive impairment, known risk factors for strabismus and amblyopia. A cohort study performed in the UK found no difference between amblyopes and the general population in educational attainment or employment.43 Amblyopic patients were no more likely to suffer worse general or mental health or be involved in unintended injuries or death than non-amblyopes.43 Risk of visual loss to better eye Amblyopia treatment is often justified by the need to provide a ‘backup’ eye with good vision should eye disease or trauma befall the better eye. This rationale only holds true if visual loss in the non-amblyopic eye occurs commonly. The Blue Mountains Eye Study found amblyopes were at a higher risk of visual loss than non-amblyopes but in both groups the number of patients with visual loss was small [n = 3 (11%) in the amblyopic group and n = 35 (1.7%) in normal subjects].9 A Finnish study found a higher rate of traumatic visual loss in amblyopes but this was still a rare occurrence.44 In a population of 4.5 million there were 35 cases over a 20 year period. Rahi et al.10 performed a prospective study of loss of vision (6/12 or worse) in the better eye of patients with amblyopia. Over a 2 year period 370 people in the UK with amblyopia lost vision in their better eye. Whilst the risk of visual impairment may be higher than the non-amblyopic population it must be remembered that this is a rare occurrence and in many patients the amblyopic eye may only have a mildly reduced acuity. Furthermore, most eye disease will eventually affect both eyes. Conclusion Amblyopia treatment in its current format is poorly tolerated, its effects are modest and it induces significant health anxiety and visual disability at a crucial stage of development which leads to a poorer quality of life. This is in contrast to amblyopia itself for which there is little evidence of a functional or psychosocial effect. Until significant improvements in vision can be generated by amblyopia treatment which does not, in itself, produce a significant
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impact on quality of life, it is possible to argue that amblyopia treatment is not an effective use of NHS resources. The use of spectacle correction alone to treat amblyopia by refractive adaptation is not associated with many of the
adverse side effects seen with treatment with atropine and occlusion. Screening of school age children remains worthwhile, primarily to detect children with bilateral visual impairment.
SUMMARY Brendan T. Barrett Bradford School of Optometry & Vision Science, University of Bradford, UK E-mail: [email protected] Arthur Bradley School of Optometry, Indiana University, Indiana, USA E-mail: [email protected] Kathryn J. Saunders School of Biomedical Sciences, University of Ulster, Northern Ireland, UK E-mail: [email protected]
POINTS OF SIMILARITY
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Amblyopia is a common visual condition and individuals with this condition may experience visual, functional, emotional and social difficulties. Refractive correction alone is often effective and this should represent the first step in any treatment regimen. Standard treatment methods will lead to improved visual acuity in most patients. ISSUES TO BE RESOLVED
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If the improvement achieved by refractive correction alone is factored out, how large is the visual improvement directly attributable to additional therapy (typically patching or atropine)? This issue is part of a wider debate as to what constitutes a clinically significant improvement in visual acuity. Connor and Clarke point out that only a few studies employ a randomized control group, a criticism that applies not only to more traditional forms of therapy (occlusion, atropine) but also to newer, potentially more promising treatment methods. The relative value of RCT and uncontrolled studies is clearly an important element in this debate. There is agreement that people with amblyopia are at increased risk of visual impairment throughout their lives but the number affected is small, thus questioning this reason for treating amblyopia. QALY calculations as applied to amblyopia and its treatment are contentious and do not include concerns about future visual disability due to loss of the fellow eye. Do the functional visual difficulties and psychosocial difficulties reported amongst amblyopes arise directly from the presence of amblyopia or could they be caused, at least in part, by its associated conditions (in particular strabismus) or by the treatment for amblyopia? The authors’ opinions on the recurrence of amblyopia following treatment are clearly divergent. Impact of amblyopia on education/career: while individuals with amblyopia are precluded from particular career choices, population-based cohort studies to date have failed to reveal a clear impact of amblyopia on employment class. Of course, this could be interpreted either as evidence that amblyopia has little impact, or that treatment has been successful. The issue of whether the highest level of educational attainment is affected in individuals with amblyopia is also unclear.
© 2014 The Authors Ophthalmic & Physiological Optics © 2014 The College of Optometrists Ophthalmic & Physiological Optics 34 (2014) 226–232
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Commentary Perhaps the most interesting of all scientific debate occurs when the same experimental literature is mined to generate two opposing positions. Our debaters, Connor, Cotter, Clarke and Kulp offer a valuable example of how the same body of research can be used to support opposing views about the value of amblyopia therapy. Part of the issue relates to efficacy and part to cost-effectiveness and value. Both sides in this debate select quite different studies to argue two sides of the same issue. Also, due to imperfections in study design, both sides of a debate can employ the same study to support opposing opinions e.g. the value of amblyopia treatment as assessed using QALY indices.26 These scenarios highlight the need for improved study designs and the application of meta-analyses to reveal overall trends. Interestingly, neither side in this debate made much of binocularity in treatment of amblyopia, which reflects the context of current practice in amblyopia treatment. However, with the recent burgeoning of interest amongst researchers and clinicians in the role of binocularity in amblyopia treatment 45 it will be fascinating to see if the emphasis in treatment changes in the future Another aspect which did not feature prominently in the debate is the issue of amblyopia severity. In mild amblyopia, the most common form of the condition, it is more difficult to reveal an improvement. Thus, the debate about both efficacy and value of amblyopia treatment must hinge, at least to some extent, on the depth of the amblyopia at the beginning of treatment. Randomized control trials for amblyopia treatment are held up by Connor and Clarke as the gold standard for assessing treatment efficacy. One wonders why so few studies of treatment efficacy have employed the routine, randomized control design? The small number of RCTs probably reflects a general clinical consensus that acuity can be successfully improved with treatment coupled with ethical concerns about the inclusion of untreated, control groups. Another aspect of the RCTs for amblyopia treatment which deserves mention relates to the complex series of activities associated with amblyopia treatment that can make these data difficult to interpret. For example, the ‘treated’ and ‘untreated’ groups in an RCT of amblyopia therapy typically undergo the same regimes (e.g. regular review by clinician, repeat testing of monocular acuities) except that only the treated group undergo, for example, patching or atropine. Connor and Clarke’s analysis indicates a broadly similar level of improvement in acuity in the ‘treated’ and ‘untreated’ groups, a finding which they interpret as evidence that patching/atropine is not very effective. Conversely, one could argue that the other
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components of the treatment regimen, aside from the patching/atropine, have an important therapeutic impact and hence that the overall treatment package (with or without patching/atropine) is effective. Thus, the RCT results showing significant improvements in the groups designated as ‘untreated’ raise important questions about which factors, such as repeat visual acuity testing, might themselves represent active components of a treatment protocol. Indeed the topic of practice also features prominently in relation to therapy for binocular disorders in the paper by Horwoord and Toor46 in the current issue.
References 1. Snowdon SK & Stewart-Brown SL. Preschool vision screening. Health Technol Assess 1997; 1: i–iv, 1–83. 2. Birch EE. Amblyopia and binocular vision. Prog Retin Eye Res 2013; 33: 67–84. 3. Levi DM. Visual processing in amblyopia: human studies. Strabismus 2006; 14: 11–19. 4. Ciuffreda KJ, Levi DM & Selenow A. Amblyopia: Basic and Clinical Aspects, Butterworth-Heinemann: Boston, 1991. 5. Stifter E, Burggasser G, Hirmann E, Thaler A & Radner W. Monocular and binocular reading performance in children with microstrabismic amblyopia. Br J Ophthalmol 2005; 89: 1324–1329. 6. O’Connor AR, Birch EE, Anderson S & Draper H. Relationship between binocular vision, visual acuity, and fine motor skills. Optom Vis Sci 2010; 87: 942–947. 7. Adams GG & Karas MP. Effect of amblyopia on employment prospects. Br J Ophthalmol 1999; 83: 380. 8. Physical qualifications for drivers. 2013, http://www.fmcsa. dot.gov/rules-regulations/administration/fmcsr/fmcsrruletext.aspx?reg=391.41, accessed 5/11/13. 9. Chua B & Mitchell P. Consequences of amblyopia on education, occupation, and long term vision loss. Br J Ophthalmol 2004; 88: 1119–1121. 10. Rahi J, Logan S, Timms C, Russell-Eggitt I & Taylor D. Risk, causes, and outcomes of visual impairment after loss of vision in the non-amblyopic eye: a population-based study. Lancet 2002; 360: 597–602. 11. Holmes JM, Lazar EL, Melia BM et al. Effect of age on response to amblyopia treatment in children. Arch Ophthalmol 2011; 129: 1451–1457. 12. Vision in Preschoolers Study Group. Preschool vision screening tests administered by nurse screeners compared with lay screeners in the vision in preschoolers study. Invest Ophthalmol Vis Sci 2005; 46: 2639–2648. 13. Rein DB, Wittenborn JS, Zhang X, Song M & Saaddine JB. The potential cost-effectiveness of amblyopia screening programs. J Pediatr Ophthalmol Strabismus 2012;49:146–155; quiz 5, 56.
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14. Williams C, Northstone K, Harrad RA, Sparrow JM & Harvey I. Amblyopia treatment outcomes after screening before or at age 3 years: follow up from randomised trial. BMJ 2002; 324: 1549. 15. Holmes JM & Clarke MP. Amblyopia. Lancet 2006; 367: 1343–1351. 16. Repka MX & Holmes JM. Lessons from the amblyopia treatment studies. Ophthalmology 2012; 119: 657–658. 17. Barnhardt CN, Repka MX, Kraker RT & Group PEDI. A randomized trial of atropine versus patching for treatment of moderate amblyopia: follow-up at 15 years of age. Optom Vis Sci 2013; 90:E-abstract 130643. 18. Levi DM & Li RW. Improving the performance of the amblyopic visual system. Philos Trans R Soc Lond B Biol Sci 2009; 364: 399–407. 19. Hess RF, Mansouri B & Thompson B. A new binocular approach to the treatment of amblyopia in adults well beyond the critical period of visual development. Restor Neurol Neurosci 2010; 28: 793–802. 20. Wallace D, Lazar E, Melia M et al. Stereoacuity in children with anisometropic amblyopia. J AAPOS 2011; 15: 455–461. 21. Ciuffreda KJ & Rumpf D. Contrast and accommodation in amblyopia. Vision Res 1985; 25: 1445–1457. 22. Zhai J, Chen M, Liu L et al. Perceptual learning treatment in patients with anisometropic amblyopia: a neuroimaging study. Br J Ophthalmol 2013; 97: 1420–1424. 23. Hrisos S, Clarke MP & Wright CM. The emotional impact of amblyopia treatment in preschool children: randomized controlled trial. Ophthalmology 2004; 111: 1550–1556. 24. Choong YF, Lukman H, Martin S & Laws DE. Childhood amblyopia treatment: psychosocial implications for patients and primary carers. Eye (Lond) 2004; 18: 369–375. 25. Walline JJ, Sinnott L, Johnson ED, Ticak A, Jones SL & Jones LA. What do kids think about kids in eyeglasses? Ophthalmic Physiol Opt 2008; 28: 218–224. 26. Membreno JH, Brown MM, Brown GC, Sharma S & Beauchamp GR. A cost-utility analysis of therapy for amblyopia. Ophthalmology 2002; 109: 2265–2271. 27. Awan M, Proudlock FA & Gottlob I. A randomized controlled trial of unilateral strabismic and mixed amblyopia using occlusion dose monitors to record compliance. Invest Ophthalmol Vis Sci 2005; 46: 1435–1439. 28. Pediatric Eye Disease Investigator Group. Treatment of anisometropic amblyopia in children with refractive correction. Ophthalmology 2006; 113: 895–903. 29. Pediatric Eye Disease Investigator Group. A randomized trial of patching regimens for treatment of moderate amblyopia in children. Arch Ophthalmol 2003; 121: 603–611. 30. Pediatric Eye Disease Investigator Group. A randomized trial of prescribed patching regimens for treatment of severe
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POINT-COUNTERPOINT In the following point-counterpoint article, acclaimed researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the editorial team provided an Introduction and Summary. By their nature, views expressed in each section of the Point-Counterpoint article are those of the authors concerned and may not reflect the views of all of the authors.
Should amblyopia be treated? Amblyopia has been treated for over 200 years but only relatively recently has the effectiveness of treatment for this common condition come under serious scrutiny. Programmes of vision screening exist for young children in most developed countries and amblyopia and the conditions thought to cause it (anisometropia, strabismus and significant refractive error) represent the main ‘targets’ of this screening. Following Snowden and Stewart-Brown’s1 call for robust evidence to describe the efficacy of amblyopia treatment, a large volume of research has been published including the results of many large-scale, multicentre studies. This research has led directly to a change in practice in a number of ways, for example a marked reduction in the numbers of hours of occlusion typically prescribed and, notably, the realisation that refractive correction (rebalancing the sensory input) alone represents a critical first element of therapy. However, despite significant strengthening in recent years of the evidence base underpinning amblyopia treatment, the question of whether the treatment of amblyopia has value is multi-faceted and it is this question which is the subject of the present point-counterpoint feature. Here, Kulp and Cotter argue that the case for treating amblyopia remains strong, whereas Connor and Clarke argue that the available evidence does not support the view that amblyopia is worth treating. Citation information: Kulp MT, Cotter SA, Connor AJ & Clarke MP. Point-Counterpoint. Should amblyopia be treated? Ophthalmic Physiol Opt 2014; 34: 226–232. doi: 10.1111/opo.12124
Point
Marjean T. Kulp The Ohio State University College of Optometry, Columbus, USA.
Susan A. Cotter Southern California College of Optometry, Marshall B. Ketchum University, Fullerton, USA.
E-mail: [email protected] E-mail: [email protected]
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Amblyopia is of significant public health concern because it is the most common cause of monocular vision loss in children, occurring in approximately 2.4% of the population.2 The damage produced by amblyopia is observed clinically as a reduction in visual acuity that is not immediately correctable despite optimal optical correction of refractive error. The nature of vision loss in amblyopia is not limited to the loss of high contrast visual acuity; abnormal contour interaction, poor accommodation, reduced contrast sensitivity, positional uncertainty, spatial distortions, abnormal eye movements, fixation instability, and suppression are also present.2–4 Functional sequelae such as reduced reading speed5 and compromised fine-motor skills6 have also been described. These impairments of visual function are expected to persist throughout life if amblyopia is left untreated. Unilateral amblyopia can preclude employment in a wide range of occupations that require good visual acuity in each eye7 and/or normal stereoacuity, such as aviation, law enforcement, military service, firefighting, dentistry, surgery, and even obtaining a commercial driver’s license.8 Individuals with untreated amblyopia are at a greater risk of becoming blind due to vision loss in the good eye.9,10 It has been reported that individuals with amblyopia have a projected lifetime risk of visual impairment or blindness of at least 1.2–3.3%, with 65% of adult amblyopes not able to continue their paid employment after losing vision in their non-amblyopic eye.10 Because treatment is more effective in younger children,11 amblyopia detection typically focuses on young children, in the form of effective vision screenings and comprehensive eye exams to detect amblyopia and its risk factors. The Vision in Preschoolers (VIP) Study Group demonstrated that preschool vision screenings with certain autorefractors and visual acuity tests can be effective in screening for amblyopia and its risk factors when used with appropriate referral criteria.12 Amblyopia screening programs have been shown to be cost-effective13 and to potentially lower the prevalence of amblyopia among older children.14 In addition, amblyopia treatment has been shown to be successful in improving visual acuity in a high percentage of children who were initially identified by screenings for amblyopia or amblyogenic risk factors.2,14 Amblyopia does not improve on its own.15 Some form of treatment must be instituted. Fortunately, visual acuity can be successfully improved and suppression ameliorated with treatment.2,15–19 In addition, gains in stereoacuity20 and accommodation,21 as well as increased cortical activation22 have been demonstrated. Treatment is usually well-tolerated,15,23,24 and the availability of a variety of treatment options allows practitioners to modify the current treatment regimen or change the treatment modality altogether if compliance issues arise.16 Treatment in older children
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and adults also has been shown to result in clinically significant improvements in vision.2,15,18,19 Generally, optical correction of significant refractive error is instituted initially and then followed by patching or atropine eye drops if the amblyopia does not resolve with a period of optical treatment alone.2,15,16 On average, unilateral amblyopia improves approximately three lines with spectacles alone and approximately one-third of children do not require additional treatment.2,15,16 Recent research has shown that concerns regarding potential psychosocial issues associated with children wearing spectacle corrections may be unfounded because children are just as likely to want to play with peers who wear spectacles as those without, and they perceive those who wear spectacle corrections as being slightly more honest and smarter.25 When amblyopia does not resolve with optical correction alone, further treatment with patching or atropine drops has been shown to result in meaningful improvements in amblyopic eye visual acuity with increases of approximately three to five lines on average.2,11,16 More importantly, these improvements are generally long-lasting.16,17 For example, the Pediatric Eye Disease Investigator Group recently reported average long-term visual acuity outcomes of 0.14 logMAR (approximately 20/25 or 6/7.5) at 15 years of age for children who were enrolled in a randomized clinical trial for moderate amblyopia when younger than 7 years of age.17 Amblyopic eye acuity was 20/25 (0.10 logMAR) or better in 59% and 20/20 (0.0 logMAR) or better in 34%, despite 94% of the children having not received any further amblyopia treatment between 10 and 15 years of age.17 Although generally mild, residual visual acuity deficits are common after treatment with patching and/or atropine2,16; additional novel treatment modalities such as perceptual learning18 and binocular anti-suppression treatment19 are currently being explored for evidence of improved efficacy. Treatment of amblyopia with patching or atropine has been shown to be well tolerated and without significant negative psychosocial impact or influence on the child’s overall well-being and behaviour.15,24 Cost utility analysis has found that the treatment of amblyopia in childhood results in considerable lifetime gains in quality adjusted life years (QALYs), a measure that takes into account both the duration and value of the health condition. Treatment also has been shown to be highly cost-effective in comparison to other health care interventions.26 In summary, there is a wealth of evidence that the detection and treatment of amblyopia is a valuable endeavor. Appropriate vision screening methodology for amblyopia and amblyogenic risk factors is effective12 and the efficacy of amblyopia treatment has been well-established.2,15–19 Because young children are more responsive to treatment,11 efforts to identify and treat amblyopia sooner rather than later are warranted. While older children and adults can
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also show significant improvements in amblyopic eye visual acuity with treatment,2,15,18,19 public education, the use of the best available vision screening procedures, and better access to vision care and follow up, could theoretically eliminate amblyopia as a public health concern. If childhood amblyopia is left untreated, its consequences will be felt over the affected person’s lifetime.
Counterpoint Alan J. Connor Royal Victoria Infirmary Eye Department, Newcastle upon Tyne, UK. E-mail: [email protected]
Michael P. Clarke Royal Victoria Infirmary Eye Department, Newcastle upon Tyne, UK. E-mail: [email protected]
Although occlusion therapy for amblyopia has been in use for over 200 years, it is only recently that evidence for its effectiveness has been evaluated. Many treatment trials in amblyopia have reported improvement in visual acuity, but have done so without comparison with appropriately matched control groups.27–30 These studies overestimate the benefits of treatment due to normal visual maturation, learning effects, inter-test variability and regression to the mean.31 To truly measure the effect of therapy requires a randomized control trial (RCT) with an appropriately matched ‘no treatment’ control group.32 Three papers fulfill this criterion. The first RCT 33 performed in this area studied vision screening failures and compared refractive correction and occlusion to a control group. At 1 year, the mean improvement over the control group was 0.109 logMAR. A second RCT, performed over a 12 week period, found a significant learning effect in the control group of 0.24 logMAR, but an additional 0.1 logMAR improvement was reported with 6 h per day of occlusion.27 The third RCT was powered to find 0.1 logMAR difference after 5 weeks between the occlusion and control group but only found a 0.07 logMAR difference.34 In this third paper both groups were treated after 5 weeks so it is impossible to separate if any improvement beyond 5 weeks was due to amblyopia treatment or learning effect. We can conclude from these studies that occlusion therapy does indeed improve visual acuity but the size of this improvement is modest. Even when amblyopia has been successfully treated, recurrence occurs in up to 27% of patients.35 It should be remembered that treatment (occlusion or atropine) renders the patient visually impaired during the time when the patch is worn or when the fellow eye is blurred with atropine and as a consequence compliance with treatment is poor.36 Other side effects may include local skin irritation from patching and precipitation of amblyopia in the better eye. Perhaps the most important side effects are related to induced health anxiety and unintended psychosocial impact on the child’s wellbeing.37–41 Quality of life measures in amblyopia
Amblyopia is a form of cerebral visual impairment caused by a degraded retinal image or dissimilar retinal imagery during a sensitive period of visual development.15 It affects many aspects of visual function, but clinically is typically defined as an inter-ocular difference of ≥0.2 logMAR best corrected visual acuity in the absence of any other pathology and in the presence of an amblyogenic stimulus. 228
Patient-reported quality of life measures have been used to assess the impact of amblyopia.37–41 These questionnaires may be completed by the child, the parent, or used to assess the impact of disease in adults with residual amblyopia. Quality of life tools assess the emotional, social and functional impact of amblyopia. They have highlighted strained relationships between family members, problems with social interactions, and feelings of isolation and bullying. Functional issues are also reported in terms of difficulties with specific activities of daily living as well as education
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activities. Depression, lack of self-esteem and embarrassment are also reported. It is difficult to draw any conclusions about the benefits of amblyopia treatment from these studies. Firstly, many studies have included patients with strabismic amblyopia and it may be factors relating to strabismus rather than amblyopia that affect Quality of Life. Secondly, no study has shown an improvement in a Quality of Life score that has been attributed to an improvement in amblyopia. More importantly, as these studies have included treated patients, they may highlight the adverse impact on quality of life of amblyopia treatment rather than that of the decreased visual function associated with amblyopia. Another method for assessing the impact of amblyopia involves the calculation of ‘utility’ values. Utility values can then be used to quantitatively express the benefit of amblyopia in terms of Quality Adjusted Life Years (QALYs). Utility is calculated assuming 1 year of perfect health has a value of 1 and death has a value of 0. The utility of any particular disease state then lies somewhere between 0 and 1. The value can be calculated using the time trade off method: i.e. how much life time a patient would be willing to exchange to be disease free, or by the standard gamble method, how much risk of death the patient would accept to be cured of the disease. Membrano et al.26 performed a cost utility analysis by using utility values associated with various visual acuities to quantify the improvement in quality of life with amblyopia treatment and calculated the costs associated with this. They stated that amblyopia treatment was highly cost effective resulting in a gain of 0.8 QALYs. Each QALY had an associated treatment cost of $2281. Unfortunately, the methodology they used was flawed, as they used utility values that had been calculated from a cohort of patients that lost vision in adult life, mainly due to retinal disease. When utility values have been calculated using a cohort of amblyopia patients,42 the utility values suggest the impact of amblyopia was much less and as such renders the Membrano et al. calculations invalid. The utility values calculated from amblyopia patients via the time trade off method is 0.963 (equivalent to a traded 3.7% of lifetime) and 0.9996 by the standard gamble method (equivalent to accepted risk of death of 1 in 20 000).42 Studies of cost effectiveness are highly sensitive to the utility value used with amblyopia treatment appearing much less cost effective when more appropriate utility values are used i.e. utility values which correspond to developmental loss of vision in one eye as opposed to hypothetical values derived from patients asked to speculate in relation to acquired visual reduction. In addition, the use of utility values to determine cost effectiveness has been subject to criticism. The utility value is highly subjective and individuals show large variation in how they respond to these difficult, hypothetical questions.
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Functional impact of amblyopia The functional impact of amblyopia can be best assessed from the outcomes of population cohort studies. The Blue Mountain Eye Study reported no significant difference in employment class between the amblyopic and the non-amblyopic population.9 However, a lower number of amblyopic patients had attained university degrees. This finding may be explained by not controlling for patients with developmental and neurological disease or cognitive impairment, known risk factors for strabismus and amblyopia. A cohort study performed in the UK found no difference between amblyopes and the general population in educational attainment or employment.43 Amblyopic patients were no more likely to suffer worse general or mental health or be involved in unintended injuries or death than non-amblyopes.43 Risk of visual loss to better eye Amblyopia treatment is often justified by the need to provide a ‘backup’ eye with good vision should eye disease or trauma befall the better eye. This rationale only holds true if visual loss in the non-amblyopic eye occurs commonly. The Blue Mountains Eye Study found amblyopes were at a higher risk of visual loss than non-amblyopes but in both groups the number of patients with visual loss was small [n = 3 (11%) in the amblyopic group and n = 35 (1.7%) in normal subjects].9 A Finnish study found a higher rate of traumatic visual loss in amblyopes but this was still a rare occurrence.44 In a population of 4.5 million there were 35 cases over a 20 year period. Rahi et al.10 performed a prospective study of loss of vision (6/12 or worse) in the better eye of patients with amblyopia. Over a 2 year period 370 people in the UK with amblyopia lost vision in their better eye. Whilst the risk of visual impairment may be higher than the non-amblyopic population it must be remembered that this is a rare occurrence and in many patients the amblyopic eye may only have a mildly reduced acuity. Furthermore, most eye disease will eventually affect both eyes. Conclusion Amblyopia treatment in its current format is poorly tolerated, its effects are modest and it induces significant health anxiety and visual disability at a crucial stage of development which leads to a poorer quality of life. This is in contrast to amblyopia itself for which there is little evidence of a functional or psychosocial effect. Until significant improvements in vision can be generated by amblyopia treatment which does not, in itself, produce a significant
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impact on quality of life, it is possible to argue that amblyopia treatment is not an effective use of NHS resources. The use of spectacle correction alone to treat amblyopia by refractive adaptation is not associated with many of the
adverse side effects seen with treatment with atropine and occlusion. Screening of school age children remains worthwhile, primarily to detect children with bilateral visual impairment.
SUMMARY Brendan T. Barrett Bradford School of Optometry & Vision Science, University of Bradford, UK E-mail: [email protected] Arthur Bradley School of Optometry, Indiana University, Indiana, USA E-mail: [email protected] Kathryn J. Saunders School of Biomedical Sciences, University of Ulster, Northern Ireland, UK E-mail: [email protected]
POINTS OF SIMILARITY
• • •
Amblyopia is a common visual condition and individuals with this condition may experience visual, functional, emotional and social difficulties. Refractive correction alone is often effective and this should represent the first step in any treatment regimen. Standard treatment methods will lead to improved visual acuity in most patients. ISSUES TO BE RESOLVED
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If the improvement achieved by refractive correction alone is factored out, how large is the visual improvement directly attributable to additional therapy (typically patching or atropine)? This issue is part of a wider debate as to what constitutes a clinically significant improvement in visual acuity. Connor and Clarke point out that only a few studies employ a randomized control group, a criticism that applies not only to more traditional forms of therapy (occlusion, atropine) but also to newer, potentially more promising treatment methods. The relative value of RCT and uncontrolled studies is clearly an important element in this debate. There is agreement that people with amblyopia are at increased risk of visual impairment throughout their lives but the number affected is small, thus questioning this reason for treating amblyopia. QALY calculations as applied to amblyopia and its treatment are contentious and do not include concerns about future visual disability due to loss of the fellow eye. Do the functional visual difficulties and psychosocial difficulties reported amongst amblyopes arise directly from the presence of amblyopia or could they be caused, at least in part, by its associated conditions (in particular strabismus) or by the treatment for amblyopia? The authors’ opinions on the recurrence of amblyopia following treatment are clearly divergent. Impact of amblyopia on education/career: while individuals with amblyopia are precluded from particular career choices, population-based cohort studies to date have failed to reveal a clear impact of amblyopia on employment class. Of course, this could be interpreted either as evidence that amblyopia has little impact, or that treatment has been successful. The issue of whether the highest level of educational attainment is affected in individuals with amblyopia is also unclear.
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Commentary Perhaps the most interesting of all scientific debate occurs when the same experimental literature is mined to generate two opposing positions. Our debaters, Connor, Cotter, Clarke and Kulp offer a valuable example of how the same body of research can be used to support opposing views about the value of amblyopia therapy. Part of the issue relates to efficacy and part to cost-effectiveness and value. Both sides in this debate select quite different studies to argue two sides of the same issue. Also, due to imperfections in study design, both sides of a debate can employ the same study to support opposing opinions e.g. the value of amblyopia treatment as assessed using QALY indices.26 These scenarios highlight the need for improved study designs and the application of meta-analyses to reveal overall trends. Interestingly, neither side in this debate made much of binocularity in treatment of amblyopia, which reflects the context of current practice in amblyopia treatment. However, with the recent burgeoning of interest amongst researchers and clinicians in the role of binocularity in amblyopia treatment 45 it will be fascinating to see if the emphasis in treatment changes in the future Another aspect which did not feature prominently in the debate is the issue of amblyopia severity. In mild amblyopia, the most common form of the condition, it is more difficult to reveal an improvement. Thus, the debate about both efficacy and value of amblyopia treatment must hinge, at least to some extent, on the depth of the amblyopia at the beginning of treatment. Randomized control trials for amblyopia treatment are held up by Connor and Clarke as the gold standard for assessing treatment efficacy. One wonders why so few studies of treatment efficacy have employed the routine, randomized control design? The small number of RCTs probably reflects a general clinical consensus that acuity can be successfully improved with treatment coupled with ethical concerns about the inclusion of untreated, control groups. Another aspect of the RCTs for amblyopia treatment which deserves mention relates to the complex series of activities associated with amblyopia treatment that can make these data difficult to interpret. For example, the ‘treated’ and ‘untreated’ groups in an RCT of amblyopia therapy typically undergo the same regimes (e.g. regular review by clinician, repeat testing of monocular acuities) except that only the treated group undergo, for example, patching or atropine. Connor and Clarke’s analysis indicates a broadly similar level of improvement in acuity in the ‘treated’ and ‘untreated’ groups, a finding which they interpret as evidence that patching/atropine is not very effective. Conversely, one could argue that the other
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components of the treatment regimen, aside from the patching/atropine, have an important therapeutic impact and hence that the overall treatment package (with or without patching/atropine) is effective. Thus, the RCT results showing significant improvements in the groups designated as ‘untreated’ raise important questions about which factors, such as repeat visual acuity testing, might themselves represent active components of a treatment protocol. Indeed the topic of practice also features prominently in relation to therapy for binocular disorders in the paper by Horwoord and Toor46 in the current issue.
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