Literature search
Altogether, 1892 records were retrieved from an electronic database and manual searching. After the removal of duplicated records, 1592 records were exposed for abstract screening, and 48 articles appeared to be relevant for full-text review. After full-text review, 41 articles were excluded due to various reasons. The remaining 8 articles passed the eligibility criteria, and all of them were included in qualitative and quantitative synthesis (Figure1).15, 37-39, 42-45
Characteristics of included studies
Eight randomized controlled trials with the total of 1253 participants were included. The mean age of the participants was ranged from 4.8years to 13.6years. Majority of the studies used a logMAR chart even if some of them presented the visual acuity in Snellen’s decimal and fraction (Table1).39,42
Quality assessment (Risk of bias and publication bias)
The risk of bias assessment was conducted based on the pre-specified criteria. The majority of the studies were free of allocation concealment bias (75%), random sequence generation (88%), attrition bias (88%), reporting bias (100%) and other potential bias (100%). However, a significant portion of the trials did not disclose blinding of participants (88%) and detection bias (38%) (Figure 2 and Figure 3). The supportive evidence for the author's judgment was documented (Table 2). Publication bias was evaluated for trials that compared patching with atropine. It indicated that nearly all studies appeared on the top of the funnel plot and they were symmetrically distributed with respect to the weighted mean, which was also supported by Egger’s regression intercept (Bo= -0.5; 95% CI,-2.12 to 1.09; p-value=0.3). Though publication bias is an unavoidable issue in a review article, it was not too foreboding for this review (Figure 4)
Effect of interventions
Comparison of patching interventions
Totally four clinical trials compared different spectrum of patching modalities starting from two hours patching per day to full time patching 15,38, 43,45. A total of 518 children were enrolled whose pooled mean age was 6.25 years. All studies consisted of children with amblyopia associated with either anisometropia or strabismus or mixed. Two studies conducted on children with moderate amblyopia 38, 45. The remaining two trails enrolled children with severe amblyopia 43, and mixed amblyopia (children with moderate and severe degree of amblyopia)15 . The pooled mean time that studies measured the outcome of intervention was 4 month of follow up 15, 38, 43, 45. Majority of the studies used Electronic-ETDRS chart to measure the visual acuity38, 43, 45. Overall, it is noted that there are some extent of baseline variation of enrolled participants related to cause and degree of amblyopia.
Regarding the modality of intervention, one clinical trial compared the effectiveness of 2 hours patching and 6 hours patching for moderate mixed amblyopia, and the mean baseline visual acuity of amblyopic in both groups was 0.48 Log MAR unit 38. This study reported that 79.3% of the participants from two hours patching and 76.4% of the participants from the six hours patching improved their visual acuity of the amblyopic eye by 2 ≥ log MAR lines from the baseline. The mean visual acuity improvement of amblyopic eye from the baseline was 2.4±1.34 lines in 2 hours patching group and 4±1.61 lines in 6hours patching group. The mean difference between the group is zero (MD) =0.00; 95% CI, -0.45 to 0.45). Hence, the author concluded both treatment modalities were equally effective for moderate amblyopia.
Stewart et al 45 also compared that the visual acuity improvement in the amblyopic eye in six hours and full-time patching in children with moderate amblyopia after 3.5 months of follow up. The baseline BCVA of both groups was 0.45log MAR unit. Post-treatment visual acuity improvements of amblyopic eye were 2.6±1.9 lines in six hours patching and 2.4±2.4 lines in full-time patching. The effectiveness difference was not statistically significant (MD, 0.2; 95% CI,-0.75 to 1.15). Similarly, Singh et al 15 compared the effectiveness of 2 hours patching, 4hours patching, and 6hours patching and full time patching and the baseline visual acuity of amblyopic eye were 0.67, 0.8, 0.68 and 0.76 Log MAR unit, respectively. The author reported that the four groups were matched for age, distribution of the three types of amblyopia and pre-treatment BCVA. Post-treatment visual acuity improvements of amblyopic eye from the baseline were 1.7±1.1lines in 2 hours patching, 2.6 ±1.7lines in 4hours patching, 3±1.6lines in 6 hours patching and 3.6±2.2lines, which was compared with pre-treatment visual acuity. Hence, the study showed that significant visual improvement in all four groups has been achieved. Furthermore, regardless of the severity of amblyopia, a significantly better outcome was seen when visual improvement in full time patching, six hours patching and four hours patching group were compared with two hours patching. However, statistically significant effectiveness difference between four hours, six hours and full time patching groups was not evident. This study also compared the effectiveness difference for in mild- moderate and severe amblyopia amblyopia separately. The author concluded that all grades of patching are equally effective for mild to moderate amblyopia in children. However, significantly better visual outcome was achieved in six hours and full-time group as compared to four and two hours for severe amblyopia. Both Singh et al 15 and Stewart et al 45 did not measure the success of treatment in the manner of visual acuity improvement of the amblyopic eye by 2 ≥ log MAR lines from the baseline.
PEDIG 2003b43 compared the effectiveness of six hours patching and full time patching for treating severe amblyopia.The average baseline BCVA of amblyopic eye was 0.9 logMAR in six hour patching and 0.89 log MAR in full time patching group. This study revealed that 93% of the participants from six hours patching and 84.5% of the participants from the full-time patching improved their visual acuity of the amblyopic eye by 2 ≥ log MAR lines from the baseline. The mean visual acuity improvement after 4 month of follow up was 4.8±2.3 lines in 6 hours patching group and 4.7±2.9 lines in full time patching (MD, 0.1; 95% CI,-0.71 to 0.91).Thus the author concluded that six hours of daily patching and full-time patching are equally successful in visual acuity improvement.
Furthermore, PEDIG 2003a indicated that the incidence of reverse amblyopia was 6.5 % (6/92 cases) in 2hours and 8.9% (8/89cases) in 6 hours patching. The proportion of participants achieved good adherence was 83% for 2 hours group and 74% for 6 hours patching group38. PEDIG 2003b also reported higher reverse amblyopia in the full-time group (11%) as compared to six hours patching groups (4%). Singh et al15 and Stewart et al 45 did not report reverse amblyopia and adherence.
Overall, the finding of the four studies implies that the severity of amblyopia matters the effectiveness a certain of patching regimen. Qualitatively, the learnt-lesson is that all grades of patching, from 2 hours to full time patching, are equally effective in treating mild to moderate amblyopia. However, only 6 hours patching to full-time patching regimen are effective for severe amblyopia. Regardless of the severity of amblyopia, the effectiveness of three clinical trials that compared six-hours patching with full time patching was pooled15, 43, 45. In Singh et al 15 only participants enrolled in Six hours patching and full-time patching group was considered for meta-analysis. The weighted mean visual acuity improvement of amblyopic eye was similar for both groups. The effectiveness difference was nearly zero (MD, 0.00; 95% CI, -0.54 to 0.55), which indicates that the pooled synthesis is in agreement with the qualitative synthesis (Figure 5). Furthermore, the incidence rate of reverse amblyopia is directly related with dose of patching despite less conclusive. Therefore, these findings drive a new insight that six hours patching is an optimal choice that balances the primary and secondary outcomes of patching intervention for various degree of functional amblyopia management, particularly severe amblyopia.
Comparison of Patching with atropine
Four clinical trials compared the effectiveness of patching with atropine37, 39 42, 44. A total of 664 participants were enrolled whose pooled mean age was 9.3 years. Of them, two studies compared part-time patching (2hours patching) with atropine and they measured the visual acuity improvement at 4.25 month of follow up.39, 44. The remaining two trials compared full-time patching with atropine and the outcome was measured at 6month of follow up. 37, 42.All trials measured the visual acuity improvement as an outcome using ETDRS vision chart.
PEDIG 2002 37 studied the visual acuity improvements in full time patching and atropine group for children with moderate amblyopia associated with either anisometropia or strabismus or mixed. The baseline BCVA was 0.53 Log MAR unit. At 6month of follow up, 87% of participants in patching group and 82.5% of participants in atropine improved their visual acuity of amblyopic eye by 2≥ Log MAR lines from the baseline (RR, 1.06; 95% CI; 0.97 to 1.15).The mean visual acuity improvement of amblyopic eye was 3.16±1.6 lines in patching group and 2.84±1.6 lines in atropine group. Statistically significant betterment was seen in patching groups as compared to atropine (MD 0.32; 95% CI; 0.01 to 0.63).
Similarly, PEDIG 200839 compared the effectiveness of two hours patching with atropine penalization in children with moderate mixed amblyopia. The baseline BCVA was 0.48 Log MAR unit. At 4.25 month of follow, 45% of participants in two hour patching group and 40% in atropine improved their visual acuity of amblyopic eye by 2≥ Log MAR lines from the baseline (RR,1.14; 95%CI; 0.8 to 1.61). The mean visual acuity improvement was 1.72 ±1.56 lines in two hours group and 1.52±2.1 lines in atropine group. Significant effectiveness difference was not seen between the modalities (MD=0.2 at 95% -0.26, 0.66).
The remaining two clinical trials investigated the effectiveness of patching and atropine in treating severe and mixed amblyopia 42, 44. PEDIG 200944 compared two hours patching with atropine in children with severe amblyopia. The baseline BCVA was 0.95 Log MAR unit. After 17weeks of treatment, 54% in two hours patching group and 40% in atropine improved visual acuity of the amblyopic eye by 2≥ log MAR lines from the baseline (RR,1.35; 95% CI; 0.61 to 2.81). The visual acuity of amblyopic eye was improved by 1.8 ±1.3 lines in two hours patching and 1.5± 2.1 lines in atropine group. Both modalities produced similar improvement, (MD 0.3, at 95% CI, -0.86 to 1.46). One trial studied the treatment outcome of full time patching and atropine in children with mixed anisometropic amblyopia 42.The baseline BCVA was nearly 0.64 log MAR units in both groups. At 6month of follow up, the visual acuity of amblyopic eye of improved by 2.38 ±1.19 lines in patching group and 2.34 ±1.14 lines in atropine from the baseline. Statistically significant difference between the modalities was not found (MD=0.04, at 95% CI -0.56 to 0.64).
Three trails reported incidence of developing reverse of amblyopia 37, 39, 44. PEDIG 2002 37 reported that 1.4% of participants in patching and 8.7% in atropine groups have developed reverse amblyopia. The variation was statistically significant (RR, 0.16; 95% CI; 0.05 to 0.55). Likewise, PEDIG 200944 revealed a single case of reverse amblyopia from atropine group but no cases from patching (RR, 0.5; 95% CI; 0.02 to 11.42). PEDIG 2008 reported that there was no incidence of reverse amblyopia in both groups39. The combined incidence of developing reverse amblyopia was lower by 19% for patching groups as compared to atropine (RR, 0.19; 95% CI: 0.06, 0.57). With regard to adherence, 83% of the participants from patching group and 96% from atropine group achieved the level of good adherence 37. Even though majority of the participants from both intervention were within the level of good adherence, it was noted that atropine is statistically favorable (RR, 0.87, 95% CI; 0.81 to 0.93). Similarly, PEDIG 2008 reported that 84 % of the participants from atropine group and 80% of participants from patching (RR 0.95, 95% CI; 0.82 to 1.09) 39. However, Menon et al 2008 found that adherence was slightly better in patching (62%) than atropine group (57%) but it was not statistically significant variation (RR, 1.09, 95% CI; 0.71 to 1.67). 42
Therefore, regardless of the severity of amblyopia, the two hours patching and atropine produces similar visual acuity improvement. Even though the degree and significance of visual acuity improvement seems slightly better in full time patching as compared to atropine, it is inconclusive. Hence, the quantitative synthesis may resolve the controversy, in which the pooled estimate indicated that patching was statistically favorable to atropine (MD, 0.25 lines; 95% CI, 0.01 to 0.48) (Figure 6). Besides, the weighted estimate of improving visual acuity in the amblyopic eye by ≥2 log MAR lines was better in patching group (74.1%%) than atropine (67.2% ) (RR, 1.08; 95% CI, 0.98 to 1.18). On the other hand, the incidence of developing reverse amblyopia was lower in patching groups as compared to atropine (RR, 0.19; 95% CI: 0.06, 0.57). Even if there was disagreement between the authors, the pooled estimate of adherence is better in atropine, (RR, 0.9; 95% CI, 0.84 to 0.96) (Figure 7).
Moderator variables and Subgroup analysis
Severity of amblyopia, the cause of amblyopia, a dose of patching and age of the participants were considered as moderator variables. The pooled mean visual acuity between part-time (2hours patching) patching and atropine was 0.21 lines (95% CI,-0.21 to 0.64), which was not significantly different. Similarly, for trials that compared full time patching with atropine, the mean post-treatment visual acuity different was 0.26 lines (95% CI, -0.02 to 0.54), which was not also significant(Figure 6).37,42 Hence, the effectiveness difference between patching and atropine was not explained by the variation of the patching dose. The Meta-regression analysis showed that the effectiveness difference for patching and atropine did not associate with age (B0=-0.03; α=0.5; p=0.4) (Figure 8). Regardless of the cause of amblyopia, Singh et al found that part-time patching and full-time patching can produce a similar visual outcome for mild to moderate amblyopia. However, in severe amblyopia, six hours and full-time occlusion treatment were significantly more effective than two hours occlusion15. It was also noted that there was no significant difference between 6 hours and full time patching for severe amblyopia. Furthermore, PEDIG 2003a indicated that the mean visual acuity improvement in strabismus, anisometropic, and mixed amblyopia was similar for both modalities.40