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1From the Department of Optometry and Visual Science, City University, London, United Kingdom; and the 2Department of Mathematics, Imperial College London, London, United Kingdom.
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Abstract |
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METHODS. This was an intervention study consisting of three nonoverlapping phases: "Baseline", "refractive adaptation" (18 weeks of full-time spectacle wear), and "occlusion" (6 hours of patching per day, objectively monitored). Condition factors: type of amblyopia, age of participant, initial severity of amblyopia, fixation, and binocular vision status; treatment factors: refractive adaptation and occlusion (total dose [hours] and dose rate [hours per day]) were assessed for their influence on visual outcome. Visual outcome was expressed in three ways: logMAR (logarithm of the minimum angle of resolution) change, residual amblyopia, and proportion of the deficit corrected.
RESULTS. The study included 85 participants (mean age, 5.1 ± 1.4 years) with amblyopia associated with strabismus (n = 32) or anisometropia (n = 20) or associated with both anisometropia and strabismus (n = 33). Treatment factors: cumulative occlusion dose exceeding 50 hours, and dose rates 
1 hour per day resulted in (P 
0.01) lower residual amblyopia and a greater proportion of the deficit corrected. Condition factors associated with poor outcome (high residual amblyopia) were presence of eccentric fixation, severe initial amblyopia, and no binocular vision.
CONCLUSIONS. Factors influencing outcome with treatment for amblyopia are occlusion dose (the rate of delivery and cumulative dose worn), the initial severity of the amblyopia, binocular vision status, fixation of the amblyopic eye, and the age of the subject at the start of treatment.
Currently, population screening for strabismus and amblyopia is recommended in the United Kingdom between the ages of 4 and 5 years4 and in the United States between the ages of 3 and 4 years.5 Mainstream treatment for unilateral amblyopia has two principal components: refractive correction, usually by spectacles, and occlusion by patching or penalization (atropine cycloplegia) of the fellow eye. Occlusion regimens lack standardization and can range from a few minutes of patching a day to all waking hours, often continuing for many months.6 Studies that have been conducted to determine the effectiveness of treatment have had a variety of methodological constraints, to which variations in the reported success rates of 19% to 93% can be attributed.6 7 8 9 10 11 12 13 14 Recent randomized controlled trials (RCTs) with standardized protocols for visual acuity measurement have reported success rates of 
60% to 70%.15 16 17
Critical to the evaluation of therapeutic effectiveness is a valid definition of treatment outcome. On the basis that binocular vision is best promoted by equal visual input from each eye, the optimum outcome of amblyopia therapy is when the vision of the amblyopic eye equals that of the fellow eye. Calculation of residual amblyopia (interocular difference) and the proportion of the visual deficit corrected, provide measures of treatment outcome accounting for initial severity and response to treatment.18
The terminology used in MOTAS is defined as follows:
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Factors that influence outcome fall broadly into two categories: those that relate to the underlying conditions (condition factors) and those that relate to its treatment (treatment factors). Condition factors often reported to carry an independent risk of poor outcome or unsuccessful treatment are age at or near the end of the visual-sensitive period, presence of both strabismus and anisometropia, and presence of severe amblyopia.7 However, recent RCTs have suggested that age is a factor that predicts outcome only in severe compared with mild/moderate amblyopia16 17 and that the type of amblyopia is not a significant factor in determining outcome.16 17
A treatment factor most frequently quoted as influencing treatment failure is poor compliance with occlusion therapy,11 19 but until recently there has been no objective means by which to monitor compliance. However, the development of the occlusion dose monitor (ODM)20 now permits a quantitative approach, as exemplified by the Monitored Occlusion Treatment of Amblyopia Study (MOTAS) in which average compliance was found to be 50%21 —a level in accord with those reported for prescribed medicines.22 In this article, we considered objectively recorded occlusion in two ways: cumulative total dose (in hours) and dose rate (in hours per day). The purpose of the study was to identify factors that influence visual outcome in the treatment of unilateral amblyopia.
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Methods |
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The MOTAS comprised three phases: "baseline," "refractive adaptation," and "occlusion." Before study entry, all children had a full ophthalmic assessment, including cycloplegic retinoscopy, fundoscopy, fixation behavior, and assessment of binocular function. The baseline phase comprised a minimum of two consecutive visual acuity assessments to establish that the first measure of function was robust. Children who needed spectacle correction entered the refractive adaptation phase. Those who did not need spectacle correction entered the occlusion phase directly. In the refractive adaptation phase, children were instructed to wear spectacles (where prescribed) full time for 18 weeks—a period that our published research indicated would allow for all significant improvement attributable to spectacle wear to occur.24 Children remaining eligible (i.e., by still meeting the study’s operational definition of amblyopia; see the next section), entered the occlusion phase and were prescribed 6 hours of occlusion per day. Occlusion episodes were recorded to the nearest minute by an ODM.20 25 Both visual function and monitored occlusion dose were recorded at 2-week intervals until acuity ceased to improve (two reversals of visual acuity or identical measurements on three consecutive visits).23 On completion of the occlusion phase, participants returned to standard clinical care.
Study Participants
Children were recruited from two London hospitals between January 2000 and December 2001. Eligibility criteria were 3 to 8 years of age, anisometropia and/or strabismus, an interocular acuity difference of at least 0.1 logMAR (e.g., 20/20; 20/25, logarithm of the minimum angle of resolution), and no history of previous occlusion therapy, ocular disease, or learning difficulties.23 Written parental consent was a prerequisite for enrollment. The study was administered according to the Helsinki Declaration II and approved by Hillingdon and St. Mary’s Hospital NHS Trusts’ Local Research Ethics Committees.
Outcome Measures
Assessment of Visual Function.
The primary visual outcome was logMAR visual acuity. Three logMAR visual acuity charts were used: ETDRS (Early Treatment Diabetic Retinopathy Study; Precision Vision Ltd., Aurora, CO), crowded (Keeler Ltd., Windsor, UK), and uncrowded (Keeler Ltd.).26 Standard protocols for visual acuity testing were used and were scored by letter. The chart used depended on the reading ability of the child and was generally age dependent. The visual acuity test used at the first study session for each individual was used throughout the study period; however, when children were able to perform a more difficult test, it was added to their test battery.
Factors Influencing Outcome.
Factors assessed for their possible influence on visual outcome were classified into condition and treatment factors. Condition factors included: type of amblyopia, age at treatment, initial severity of amblyopia, fixation, and binocular vision status (Table 1) . Treatment factors include the relative contributions of refractive adaptation and occlusion, and occlusion specific factors: total dose (in hours) and dose rate (in hours per day).
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Statistical Analysis
The Kruskal-Wallis one-way analysis of variance (ANOVA) on ranks was conducted to test for significant differences in final visual outcome for study participants according to their age, type of amblyopia, initial severity, fixation, binocular vision, and occlusion dose. Multiple hypothesis testing demanded a stringent P < 0.01 for rejection of the null hypothesis. The statistical power of the analyses ranged from 0.6 to 0.9, to detect a 0.20 difference in logMAR units between groups (for ranges of n = 17–37; 
= 0.01). Data are in mean logMAR units (range), unless stated otherwise.
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Results |
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1.50 Ds bilateral hypermetropia, 1.50 Ds bilateral myopia, 0.75 Dc bilateral astigmatism and/or anisometropia 1.00 Ds)23 and underwent full refractive adaptation. In the refractive adaptation phase, visual acuity in amblyopic eyes improved from 0.65 ± 0.41 (1.6–0.14) to 0.43 ± 0.37 (1.3 to –0.08)—an improvement of 0.22 ± 0.18 (0.0–0.6). In the refractive adaptation phase, visual acuity in fellow eyes improved from 0.15 ± 0.13 (0.30 to –0.10) to 0.07 ± 0.07 (0.2 to –0.14)—an improvement of 0.08 ± 0.08 (0.0–0.16). After refractive adaptation, 13 study participants no longer had amblyopia, according to the study definition.
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The overall improvement (including both refractive adaptation and occlusion phases) of visual acuity increased significantly with decreasing age: under 4 years (n = 23), 0.57 ± 0.32 (0.05–1.475); 4 to 6 years (n = 34), 0.44 ± 0.34 (0–1.55); older than 6 years (n = 28), 0.24 ± 0.18 (0–92; P < 0.0001). After age had been accounted for (two-way ANOVA to account for interactions), the change in visual acuity (log units) was not significantly different (P = 0.03) for amblyopia associated with anisometropia (n = 21; 0.28 ± 0.20; 0–0.75), strabismus (n = 32; 0.39 ± 0.34; 0.05–1.55), or both (n = 32; 0.46 ± 0.32; 0.08–1.475).
Visual Outcome
Residual amblyopia was nil in 30%, within <0.1 logMAR of the fellow eye in 57%, <0.2 logMAR in 69%, <0.4 logMAR in 83%, and <0.6 logMAR in 90%. The proportion of deficit corrected was full in 30% of participants, 75% to <100% in 24%, 50% to <75% in 23%, and 25% to <50% in 13%; whereas in 10%, <25% of the amblyopic deficit was corrected.
Visual Outcome: Condition Factors
The distribution of participants by type of amblyopia was categorized according to the condition factors age, initial severity of amblyopia, fixation, and binocular vision status (Table 4) . Of the participants with eccentric fixation, 76% had mixed-type amblyopia and 24% had strabismus. A summary of residual amblyopia and proportion of deficit corrected according to condition factors is shown in Table 5 .
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Age.
Residual amblyopia was not significantly different (P = 0.30) as a function of age: <4 years (n = 23; 0.13 ± 0.16; 0–0.58), 4 to 6 years (n = 28; 0.21 ± 0.23; –0.02–0.8), and >6 years (n = 23; 0.23 ± 0.28; 0–0.98). The proportion of the deficit corrected was not significantly different (P = 0.11) as a function of age: <4 years (0.80 ± 0.24; 0.04–1.0), 4 to 6 years (0.62 ± 0.33; 0.08–1.14), and >6 years (0.61 ± 0.33; 0.04–1.14). Although when outcome is considered by overall change in visual acuity, age is a factor (described earlier).
Severity of the Amblyopic Deficit.
Participants were subcategorized according to the severity of their initial amblyopic deficit (mild, <0.3 logMAR; moderate, 0.3–0.6 logMAR; and severe, >0.6 logMAR). Residual amblyopia differed significantly (P < 0.001) between the mild and severe group and the moderate and severe group: mild, 0.04 ± 0.06 (0.0–0.16); moderate, 0.14 ± 0.14 (0–0.58); and severe, 0.35 ± 0.30 (–0.02–0.98). However, the proportion of the deficit corrected was not significantly different (P = 0.06) as a function of severity: mild, 0.78 ± 0.30 (0–1.0); moderate, 0.66 ± 0.31 (0.04–1.16); and severe, 0.58 ± 0.34 (0.07–1.14).
Fixation of the Amblyopic Eye.
Participants with eccentric fixation had significantly greater residual amblyopia (P < 0.0001) than did those with central fixation: residual amblyopia, 0.36 ± 0.29 (0–0.98) versus 0.13 ± 0.18 (–0.02–0.70). However, the proportion of deficit corrected was not significantly different (P = 0.03): proportion of deficit corrected 0.53 ± 0.27 (0.07–1) versus 0.69 ± 0.34 (0–1.14).
Binocular Status.
Participants were subcategorized according to their binocular function status (binocular, motor fusion and/or stereopsis; and nonbinocular: no stereopsis, no fusion; Table 1 ). Nonbinocular participants had significantly greater residual amblyopia (P = 0.0001) than did binocular participants: residual amblyopia, 0.31 ± 0.30 (0.0–0.98) versus 0.13 ± 0.15 (–0.02–0.68). However, the mean proportion of deficit corrected was not significantly different (P = 0.31): 0.63 ± 0.33 (0.04–1.0) versus 0.66 ± 0.33 (0–1.16).
Visual Outcome: Treatment Factors
Cumulative Dose.
Residual amblyopia was significantly greater (P = 0.0009) in those who had less than 50 hours of occlusion: 0–49 hours, 0.42 ± 0.20; and 50 hours, 0.23 ± 0.25; Fig. 1A ). The proportion of deficit corrected was significantly less (P = 0.01) in those who had less than 50 hours of occlusion: 0–49 hours, 0.37 ± 0.35; 50 hours, 0.74 ± 0.26; Fig. 1B ).
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0.5 h/d: 0.11 ± 0.17 (similar residual amblyopia for all dose rates 0.5–6 h/d; Fig. 2A ). The proportion of deficit corrected was significantly less (P = 0.01) in study participants wearing occlusion for less than 1 hour per day: <1 hour, 0.52 ± 0.35; 1 h/d, 0.74 ± 0.26 (similar proportion of deficit corrected for all dose rates 1 h/d to 6 h/d; Fig. 2B ).
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Discussion |
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In current practice, dose rates prescribed range from 10 min/d to all waking hours.8 13 16 17 18 28 For the first time we have been able to quantify outcome in terms of the actual dose: dose rate and cumulative dose worn to achieve best outcome. Actual dose rates exceeding 1 h/d contribute to successful outcomes. Therefore, low compliance—less than 17% of the prescribed 6-h/d dose is likely to be associated with poor outcome. This suggests that occlusion regimens of 
1 h/d (actual dose hours) would have similar effects on outcome as moderate amounts—a finding that has also emerged from a recent randomized trial of 2 versus 6 h/d prescribed occlusion for moderate amblyopia.16 However, care should be exercised when prescribing small doses, as compliance is on average half the dose prescribed.
Dose–response appears to plateau beyond 100 cumulative hours generating on average no further treatment gains. We were able to analyze the occlusion dose (worn) required for optimum outcomes. In a previous study documenting cumulative prescribed hours rather than dose actually worn,13 investigators concluded that no benefit was observed after 400 hours of occlusion, and inspection of their data reveals little benefit (5%–10% of total improvement) beyond 200 prescribed hours.
Children with eccentric fixation were found to have considerably greater residual amblyopia than those with central fixation, as documented previously.13 29 However, the proportion of deficit improvements gained are independent of eccentric fixation, suggesting that the amblyopic component of the deficit has responded, and the visual deficit remaining is dependent on the physiological consequence of using an eccentric point of fixation.
Initial severity of amblyopia is a prognostic factor of outcome.6 In our study, those with severe amblyopia (defined as >0.6 logMAR) had significantly greater residual amblyopia than did those with lesser degrees of amblyopia. However, there was no difference with respect to the proportion of the deficit corrected in this group (an analysis that was independent of initial severity). Although it is perhaps not surprising that those with severe amblyopia had greater residual amblyopia, since they had farther to improve, it is intriguing that the proportion of the deficit corrected was independent of initial severity, with average values being similar for each group. This may suggest that a proportion of the deficit is correctable. This matter needs further clarification with more detailed psychophysical testing revealing second-order deficits as well as larger numbers of patients, to increase the power and certainty of the results.
Overall, type of amblyopia was not shown to be a significant factor affecting outcome. However, the presence of eccentric fixation that was predominantly present in those with mixed amblyopia (58% of mixed amblyopia, 22% of strabismic amblyopia, and 0% of anisometropic amblyopia) is a significant factor indicative of poor outcome. Assessment of fixation although subjectively determined appears to be informative.
Although it is a long-held clinical belief that amblyopia therapy is more successful during early visual development,9 30 the evidence is equivocal. Indeed, Hiscox et al.6 and others15 16 31 32 33 34 reported no significant difference in the effectiveness of occlusion treatment commencing at any time between 3 and 7 years of age. Cobb et al.34 studied the age range up to 12 years with children with anisometropic amblyopia and found no age effect. However, others7 17 have demonstrated greater gains in visual acuity in those younger than 5 years. We have provided further evidence that age is a factor in the effectiveness of occlusion; however, this is not without caveat, as the effect depends on the manner in which outcome is expressed. Age is a factor when considering simple change in visual acuity; however, if outcome by residual amblyopia and proportion of deficit corrected are considered, the effect of age ceases to be significant. In this analysis, children older than 6 years had significantly milder initial amblyopia than did the other two age groups, therefore limiting the possible change in visual acuity. Defining outcome by residual amblyopia and proportional amblyopia eliminates this bias. Therefore, in the majority of children, age was not a factor in obtaining optimum outcome. Pediatric Eye Disease Investigator Group (PEDIG) studies have reported significant age-dependent outcomes only when the initial amblyopia was severe. This may suggest that the effective timing of treatment could be influenced by the nature of the amblyopic deficit.35
The presence of binocular vision appeared to be a prognostic factor for favorable outcome; however, it had no influence on the proportion of the deficit corrected. This finding may reflect the onset and severity of the deficit.
Because of the relatively small number of participants when divided into groups, the analysis of the data was limited to one factor at a time and therefore did not benefit from interaction analysis between factors. However, this is the first study that has been able to interpret the effect of occlusion compliance throughout a whole course of occlusion with respect to outcome.
In summary, factors influencing outcome with treatment for amblyopia are occlusion dose (the rate of delivery and cumulative dose worn), the initial severity of the amblyopia, binocular vision, fixation of the amblyopic eye, and the age of the subject at the start of treatment. These findings enable clinicians to discuss how the components of treatment (spectacle wear and occlusion) contribute to outcome and the likely prognosis based on the child’s clinical characteristics. Increasing evidence suggests that small doses of occlusion are as beneficial as substantial or maximum doses.
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Acknowledgements |
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Footnotes |
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Submitted for publication March 21, 2005; revised April 26, 2005; accepted July 25, 2005.
Disclosure: C.E. Stewart, None; A.R. Fielder, None; D.A. Stephens, None; M.J. Moseley, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Catherine E. Stewart, Department of Optometry and Visual Science, City University, CM466, Tait Building, Northampton Square, London EC1V 0HB, UK; c.e.stewart{at}city.ac.uk.
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