|Year : 2016 | Volume
| Issue : 2 | Page : 201-207
"Combined occlusion and atropine therapy" versus "Augmented part-time patching" in children with refractory/residual amblyopia: A pilot study
Virender Sachdeva1, Vaibhev Mittal1, Varun Gupta1, Rekha Gunturu1, Ramesh Kekunnaya2, Anjali Chandrasekharan2, Preeti Patil Chabblani2, Harsha L Rao3
1 Department of Pediatric Ophthalmology, Strabismus and Neuro ophthalmology, Nimmagada Prasad Children's Eye Care Centre, L. V. Prasad Eye Institute, Visakhapatnam, India
2 Department of Pediatric Ophthalmology, Strabismus and Neuro ophthalmology, Jasti V Ramanamma Children's Eye Care Centre, L. V. Prasad Eye Institute, Hyderabad, Andhra Pradesh, India
3 Centre for Clinical Epidemiology and Biostatistics, L. V. Prasad Eye Institute, Hyderabad, Andhra Pradesh, India
|Date of Web Publication||08-Feb-2016|
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Purpose: To compare the efficacy of "combined occlusion and atropine therapy (COAT)" and "augmented part-time patching" for the treatment of unilateral refractory/residual amblyopia.
Methodology: This retrospective study evaluated children between 4 and 11 years with refractory/residual amblyopia who were treated with either additional atropine (COAT group) or increased hours of patching (augmented group). Data were collected on improvement in best-corrected visual acuity (BCVA; logarithm of the minimum angle of resolution [logMAR] units) at each follow-up visit.
Results: There were 19 children in the COAT group and 17 children in the augmented group. The baseline BCVA of the amblyopic eye was 0.79 ± 0.36 logMAR in the COAT group and 0.72 ± 0.26 logMAR in augmented group. Children were statistically significantly younger in the COAT group (6.4 ± 2.2 years) compared to the augmented group (8.6 ± 3.3 years, P = 0.02). The mean duration of follow-up was statistically significantly longer in the augmented group (20.2 COAT group; 13.9 months augmented group) (P = 0.03). Compliance was similar in both groups. LogMAR BCVA (adjusted for difference in age and baseline BCVA) was statistically significantly better in the COAT group (0.56 ± 0.04) compared to the augmented group (0.80 ± 0.04) at 3 months (P = 0.000); 6 months (COAT group, 0.50 ± 0.04 vs. augmented group, 0.74 ± 0.04; P = 0.04) and at 1 year (COAT group, 0.42 ± 0.04 vs. augmented group, 0.67 ± 0.04, P = 0.000). There was statistically significantly greater improvement in logMAR BCVA at 6 months in COAT group (0.26 ± 0.15) compared to the augmented group (0.02 ± 0.14), (P = 0.0002). Age, gender, pretreatment BCVA, duration of follow-up, or compliance to patching did not affect improvement in BCVA.
Conclusions: COAT may result in greater improvement in BCVA than augmented part-time patching in children with unilateral residual/refractory amblyopia.
Keywords: Atropine, Compliance, Occlusion Therapy, Refractory Amblyopia, Residual Amblyopia
|How to cite this article:|
Sachdeva V, Mittal V, Gupta V, Gunturu R, Kekunnaya R, Chandrasekharan A, Chabblani PP, Rao HL. "Combined occlusion and atropine therapy" versus "Augmented part-time patching" in children with refractory/residual amblyopia: A pilot study. Middle East Afr J Ophthalmol 2016;23:201-7
|How to cite this URL:|
Sachdeva V, Mittal V, Gupta V, Gunturu R, Kekunnaya R, Chandrasekharan A, Chabblani PP, Rao HL. "Combined occlusion and atropine therapy" versus "Augmented part-time patching" in children with refractory/residual amblyopia: A pilot study. Middle East Afr J Ophthalmol [serial online] 2016 [cited 2019 Aug 19];23:201-7. Available from: http://www.meajo.org/text.asp?2016/23/2/201/175892
| Introduction|| |
The current standard treatment for amblyopia is occlusion (patching) therapy. Patching involves occluding the sound eye or penalization of the sound eye, forcing the use of the amblyopic eye. If instituted early within the critical period, it helps to reestablish the synapses in ocular dominance columns in the visual cortex and lateral geniculate body from the previously amblyopic eye, thereby helping overcome the inhibitory effect of stimulation of the sound eye alone. ,, Despite successful treatment of many children using occlusion/penalization therapy, a substantial number of individuals still suffer from residual amblyopia later in life. The reported success rate with part-time/full-time occlusion therapy alone is about 86-96%. , However, in most studies the final best-corrected visual acuity (BCVA) is reported around 20/32. In Amblyopia Treatment Studies (ATSs 1 and 2A), 71-92% of the children were still left with a final BCVA of 20/32 or worse.  Factors that may lead to partial or poor response to either therapy individually are, late detection of amblyopia, initiation of therapy when the child is over 6 years old, poor compliance or a combination of these factors. , In some of these children, there may not be any improvement in BCVA or the BCVA does not improve beyond a subnormal level despite many months of compliant patching/atropine therapy alone. Treatment options for these children may include intensifying the treatment by increasing the hours of patching,  addition of atropine/patching therapy when the other was instituted alone,  additional optical penalization,  pharmacological,  and acupuncture therapy.
Studies that address the improvement in BCVA in these children with residual/refractory amblyopia are scant. A randomized controlled trial from the Pediatric Eye Disease Investigator Group (PEDIG) reported greater improvement in BCVA following increased hours of patching compared to treatment at the same number of hours of patching.  Similarly, a report by Simon et al.  observed that additional optical penalization to children who were refractory to atropine penalization alone led to improvement in BCVA in all five children.
However, in another trial, the PEDIG group (ATS 11)  found further improvement in BCVA in these children was insignificant (0.5 logarithm of the minimum angle of resolution [logMAR]; 0.0 logMAR after adjusting for the baseline visual acuity [VA]) on intensifying treatment with additional atropine to patching therapy alone. Although, the ATS 11 showed little improvement, the results were observed at 10 weeks and the study was discontinued due to slow recruitment. We have tried augmented part-time patching for patients with residual amblyopia and found slow improvement and greater emotional stress in children and parents. Hence, this study compares the results of two interventions, combined occlusion and atropine therapy (COAT) and augmented part-time patching in patients with residual/refractory amblyopia.
| Methodology|| |
This is a retrospective protocol-based nonrandomized, interventional study comprising of children with residual (anisometropic, strabismic, sensory, and mixed) amblyopia between 4 years and 11 years of age, who were treated at a tertiary eye care center. The study period was from July 1, 2011 to December 30, 2013. The study was approved by the Ethics Committee of our institution and the methods adhered to tenets of Declaration of Helsinki. Consent was received from the parents of all children for treatment and possible use of data for research. The inclusion criteria were: (a) All children diagnosed with refractory anisometropic amblyopia (i.e., anisomyopia >2.5 D; anisohyperopia and difference in cylinder of >1.5 D), sensory, strabismic, and >2.5 Dmixed amblyopia (b) BCVA in the amblyopic eye between 20/40 and 20/400 and BCVA in the better eye of 20/25; (c) very compliant (>85%) or moderately compliant (70-85%) with treatment for at least 6 months (spectacle correction along with three cycles of adequate hours of compliant occlusion therapy for 2 months each).
Children were excluded from the study if they had any organic ocular pathology, nystagmus, were intellectually challenged, were older than 12 years or <4 years, had a previous history of noncompliance with patching therapy or inadequate occlusion therapy and if the parents refused inclusion in the study.
All children underwent a comprehensive eye examination. The VA of the children was recorded using Lea symbols/logMAR charts at every visit. VA using Lea symbols was converted to the logMAR scale.
All children with anisometropic amblyopia were treated with appropriate refractive correction and then reassesed after 6-8 weeks. Children who still had subnormal VA at follow-up were treated with occlusion therapy (three cycles of compliant continuous or split hour occlusion therapy of 2 months each).
Children with stimulus deprivation amblyopia (congenital/developmental cataract, ptosis) were reassesed after appropriate surgical treatment (standard lens aspiration, primary posterior capsulotomy, anterior vitrectomy, posterior chamber intraocular lens implantation for cataract or ptosis surgery), and visual rehabilitation. Children with subnormal VA underwent occlusion therapy.
Children with strabismus after comprehensive eye examination were given a spectacle correction and/or surgical treatment (as needed) and were assesed for the improvement in BCVA, whereas with subnormal VA were given occlusion therapy.
Duration of occlusion therapy was based on the severity of amblyopia: 2 h/day for mild (BCVA 20/40-20/60), 4 h/day for moderate (BCVA 20/60-20/100), and 6 h/day patching for severe amblyopia (BCVA <20/100) along with 2 h of near vision tasks. Compliance to occlusion therapy was recorded using a patching calendar method. Compliance was assessed by using the patching calendar method. At every follow-up visit, the hours of patching and compliance were calculated and patients were categorized as low compliance (<70% of prescribed patching duration), moderate compliance (70-85%), and highly compliant patients (>85% prescribed patching duration).
Children whose BCVA did not improve with complaint amblyopia (highly or moderately compliant) were treated by one of the two methods. They were either prescribed additional atropine eye drops twice weekly in the sound eye "COAT" (COAT group) or "augmented number of hours of patching" (augmented group). Traditionally, the practice at our institute was to treat these children with augmented part-time patching, however, from 2011 onward, the authors' tried COAT for these children. In the COAT group, all children were continued on the number of hours of part-time patching, i.e., (mild amblyopia: 2 h/day; moderate amblyopia: 4 h/day and severe amblyopia: 6 h/day) whereas in augmented group, for all children with moderate and severe amblyopia were given at least 6 h of part-time patching These children were followed at 3 months intervals for the improvement in BCVA.
The main outcome measures were the improvement in BCVA between the group at the 6 months and 1 year follow-up visit. The Shapiro-Wilk test was used to evaluate the distribution of the continuous parameters and all the BCVA parameters at follow-up. These parameters were normally distributed. The unpaired t-test was used to evaluate the difference in BCVA parameters between the two groups at follow-up. Analysis of covariance models adjusted for the difference in age and baseline BCVA were used to calculate the mean BCVA as well as the mean improvement in BCVA at the 3 and 6 month follow-up visits. The associations between improvement in BCVA and baseline factors such as age, gender, baseline BCVA, compliance to patching and the group were evaluated with a multivariate regression model. Statistical analyses were performed using commercial software (Stata version 12.0, StataCorp., College Station, TX, USA). A P < 0.05 was considered statistically significant.
| Results|| |
A total of 36 children met the inclusion criteria. Of these, 19 children were treated with COAT (COAT group) and 17 were treated with "augmented part-time patching" (augmented group). [Table 1] summarizes the baseline characteristics of the two groups. Children were statistically significantly younger in the COAT group (6.4 ± 2.2 years vs. 8.6 ± 3.3 years, respectively, P = 0.02) [Table 1]. Both groups had a similar number of the children with anisometropic, strabismic, and stimulus deprivation amblyopia [Table 1]. Mean duration of follow-up was statistically significantly greater in the augmented group (20.2 months vs. 13.9 months, P = 0.03) [Table 1]. Compliance with treatment was similar in both groups.
|Table 1: Baseline characteristics of children with amblyopia who were treated with two different therapies|
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[Table 2] presents the BCVA and improvement in BCVA in the amblyopic eye at different time points. The mean baseline BCVA in the amblyopic eye at presentation after spectacle correction or strabismus/cataract surgery was 0.96 ± 0.36 and 1.05 ± 0.35 logMAR in the COAT group and augmented group, respectively. Mean BCVA as well and the improvement in BCVA was significantly higher in the COAT group compared to the augmented group at all follow-up periods (P < 0.05, all comparisons) [Table 2] and [Figure 1].
|Figure 1: Distribution of the visual acuity of the amblyopic eye of children who were treated with two different therapies. BCVA: Best-corrected visual acuity, BCVA_PP: Best-corrected visual acuity of the amblyopic eye after 6 months of patching therapy, BCVA_ 3 mo: Best-corrected visual acuity of the amblyopic eye at 3 months of COAT/ augmented patching, BCVA_ 6 mo: Best-corrected visual acuity of the amblyopic eye at 6 months of COAT/ augmented patching; BCVA_COAT_1 year: Best-corrected visual acuity of the amblyopic eye at the last follow-up. Combined occlusion and atropine therapy group underwent combined occlusion and atropine therapy, augmented group received augmented number of hours of patching|
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|Table 2: Distribution of the adjusted best-corrected visual acuity in children with amblyopia who were treated with two different therapies at 3 months and 6 months follow-up|
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Distribution of best-corrected visual acuity over follow-up visits
[Figure 1] presents the distribution of BCVA at the different follow-up for both groups. The mean BCVA (adjusted for the difference in baseline age and BCVA) was significantly higher in the COAT group at the 3 months and 6 months follow-up visits (mean difference = 0.24 logMAR, P = 0.000). A similar difference was also observed at 1 year follow-up (mean difference = 0.25 logMAR, P = 0.000).
Improvement in best-corrected visual acuity after additional intervention over follow-up visits
The improvement in BCVA was greater in COAT group at all follow-up visits (P < 0.05, all comparisons) [Table 2] and [Figure 1]. At 3-month follow-up, a 2 or more line improvement in BCVA occurred in 60% and 10.7% of patients in COAT groups and augmented group, respectively (P = 0.001). At 6-month follow-up, the number of patients gaining more than two lines of VA was also statistically significantly greater in the COAT groups (79%) compared to the augmented group (40%) (P = 0.02). At 1-year follow-up, a similar number of patients showed an improvement between groups (COAT group 84.2% vs. augmented group, 88.2%, P = 0.34). The average improvement was statistically significantly greater in the COAT group (3.3 lines) compared to the augmented group (0.88 lines, P = 0.0001) [Figure 2].
|Figure 2: Distribution of final visual acuity 1 year after treatment of the amblyopic eye of children who were treated with two different therapies|
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At 3 months, the compliance rate was 82% in the COAT group and 72% in the augmented group (P > 0.05). At 6 and 12 months, compliance with therapy was similar in between groups (COAT, 84% vs. 88.2%, augmented group; P = 0.63).
The results of the multivariate analysis evaluating the factors associated with the improvement in BCVA at 1 year are presented in [Table 3]. Improvement in BCVA at 1 year in the entire cohort of patients was not significantly affected by age, gender, compliance to treatment [[Table 3]; P < 0.05]. The treatment group was the only factor that affected the improvement in BCVA. Children in the COAT group had a greater improvement in the BCVA by about 0.23 logMAR as compared to the augmented group at 6 months follow-up. Multivariate analysis showed similar results at 3 and 6 months follow-up.
|Table 3: Results of the multivariate analysis showing the influence of age, gender, baseline best-corrected visual acuity, compliance to patching and the group on improvement in best-corrected visual acuity at 6 months follow-up|
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| Discussion|| |
Despite successful treatment of many children using occlusion or penalization therapy, a substantial number of individuals continue to suffer from amblyopia later in life. This may be due to failure of early detection, lack of response to the original treatment, acuity loss following cessation of treatment, or only partial correction of amblyopia. Despite equal success rates with atropine or occlusion therapy, ATS 1 reported that the mean BCVA in the amblyopic eye was 20/32 or 1.8 lines worse than the nonamblyopic eye. 
Various reports from the PEDIG group suggest that 71-92% children with amblyopia will still have a BCVA < 20/32.  To address the question of residual amblyopia, PEDIG in a prospective, randomized, multicentre clinical trial, evaluated the effectiveness of increasing daily patching from 2 to 6 h in children (3-8 years) with stable residual amblyopia (20/32-20/160) due to strabismus or anisometropia.  Patients were randomly assigned to continue 2 h of daily patching or to increase patching time to 6 h/day. The authors reported that after 10 weeks of randomization, the BCVA of the amblyopic eye improved an average of 1.2 lines in the 6 h COAT group and 0.5 line in the 2 h group (95% confidence interval [CI]: 0.3-1.0; P = 0.002). Hence, they recommended that when VA of an amblyopic eye stops improving with 2 h of daily patching, increasing the daily patching dosage to 6 h results in greater improvement in VA.  However, increasing the dose to 6 h of patching may lead to increased emotional stress on the child.
Another study (ATS 11) by PEDIG reported results of a randomized trial to determine whether an intensive final push with additional atropine therapy can improve VA in children with residual amblyopia.  The study  included amblyopic (anisometropic and strabismus) children between 3 and 10 years of age who showed no improvement in BCVA in the amblyopic eye between two consecutive visits at least 6 weeks apart while patching 6 h/day or using daily atropine. Subjects were randomized into an intensive group that was treated with 6 h of prescribed daily patching combined with daily atropine and a weaning group that whose current treatment was reduced for 4 weeks with 2 h of prescribed daily patching or once-weekly atropine followed by spectacles alone if required. This study  reported that the improvement in VA in the amblyopic eye averaged 0.5 logMAR line in both groups (treatment group difference in mean logMAR lines adjusted for baseline VA = 0.0; 95% CI, −0.7 to +0.7). After adjusting for gender, cause of amblyopia, refractive error in the amblyopic eye, and VA testing method results were similar.  Hence, the study  was stopped on recommendations of the Data and Safety Monitoring Committee because of slow recruitment and a conditional power analysis indicating that the study was unlikely to find a statistically significant benefit of intensive treatment if the study continued.
However, despite the previous report  there are some reports  of an improvement in BCVA in all patients following the addition of combined optical and atropine therapy penalization in children refractory to atropine alone.
Unlike the ATS 11,  our study showed that COAT therapy may be useful in children with refractory/residual amblyopia. This may be due to the slow improvement expected in these patients while ATS 11 looked at the improvement in BCVA at 10-week follow-up. This is also indicated by the observation that there is a further improvement in children with prolonged treatment even at 1 year in COAT group in the current study.
The PEDIG group reported good outcomes with increased patching in children (aged 3-8 years) with stable residual amblyopia (20/32-20/160) after 2 h of daily patching for at least 12 weeks.  They increased the duration of patching from 2 h to 6 h/day and found that after adjustment for the BCVA at randomization, the improvement of two or more lines occurred in 40% of participants patched for 6 h versus 18% of those who continued to patch for 2 h (P = 0.003). 
Similar to this PEDIG report,  our practice pattern was to ensure good compliance to patching and increase the duration of patching. However, it was always associated with a greater emotional stress and mixed compliance rate despite repeated counseling. Based on these previous reports,  we designed a comparative study comparing COAT and augmented patching.
The present study included patients with refractory amblyopia due to various etiologies despite compliant patching therapy. We also included only patients aged between 4 and 11 years, as it would have been difficult to assess the improvement in VA, patching and compliance in younger children. In addition, in children older than 11 years, the response to patching therapy may be slower.
Although the current study was comparative, it was nonrandomized as it was designed as an attempt to study the beneficial effect in the entire cohort of children with refractory amblyopia. Similar to the experience of slow recruitment in ATS 11, we carried out a nonrandomized study to initially study the effect of the combined treatment and extend it to a randomized controlled trial if there is a reported benefit of treatment.
We included children who had poor vision despite compliant patching therapy (refractory amblyopia) and children who had a partial improvement despite compliant patching therapy for at least 6 months (residual amblyopia). All patients prior to administration of COAT therapy/augmented part-time patching therapy had been followed up for at least 6 months duration.
Patients in the COAT group were slightly younger (6.4 vs. 8.6 years) and there were more boys in the augmented part-time patching group. However, it was not clinically significant and the overall distribution of age overlapped for most of the patients in both groups. This is notable as previous studies have reported that age >6 years is a significant risk factor for failure of amblyopia therapy. ,
In the current study, initially, BCVA was slightly better in the COAT group (0.09 logMAR or 4.5 letters), but this difference was not statistically significant (P = 0.41). In addition, patients in the augmented group gained more VA after initial patching alone. Thus, at the onset of the current study, residual amblyopia was slightly worse in the COAT group (BCVA: 0.79 logMAR) than the augmented group (0.72 logMAR), but this 3-letter difference was not statistically significant (P > 0.05). Despite the small differences in the baseline age and BCVA and the small sample size, we adjusted the BCVA and lines of improvement in the two groups at different follow-up periods.
The present study suggests that the COAT led to greater improvement than augmented part-time patching after adjusting for these differences. Notably, a slight worsening was noted in the augmented group followed by a steady improvement in this group. Alternately, a continuous improvement was noted in the COAT group even at 1 year. This improvement was always greater in COAT group than the augmented group. We postulate that since patients with refractory amblyopia may experience slow improvement in BCVA; these patients may they derive sustained benefit from additional intervention.
Various factors can influence the outcomes of patching therapy. Arikan et al.  reported that baseline VA, age at initiation of treatment and type of occlusion (full time, part time, or minimal) correlated to final VA (P = 0.000, P = 0.035, P = 0.012, respectively). They  found that initial VA was the only factor associated with the final VA in the subtypes of amblyopia that were investigated (P < 0.05). Hussein et al.  showed that there was an increased risk of poor outcomes with amblyopia therapy in patients above 6 years old at the onset of treatment, the presence of astigmatism >1.5 D in the amblyopic eye, poor compliance with treatment and initial VA in the amblyopic eye of 20/200 or worse. They did not report strabismus, type of refractive error, or the difference in the refractive power between the two eyes as a significant risk factor for treatment failure.
We evaluated the effect of with multivariate analysis. We found that there was no clinical or statistically significant effect on improvement of BCVA due to age, gender, refractive error, postpatching BCVA of the amblyopic eye and compliance to treatment in both groups. The only significant factor that influenced improvement in BCVA was the treatment arm, COAT versus augmented patching. However, due to the small sample sizes, the results of the multivariate analyses should be interpeted with caution.
Although we hypothesized that COAT may lead to better compliance than augmented part-time patching therapy, compliance to the patching therapy was only slightly better in split hours patching group during the initial 3 months. However, at 6-month and 1-year follow-up, compliance to patching was slightly greater in the augmented group. This might be attributable to the greater determination of the parents and repeated counseling sessions.
In the current study, compliance to patching was measured on the basis of the patching calendar method and not the electronic monitored dose occluders as advocated in the Monitored Dose Treatment of Amblyopia Study (MOTAS).  The current study was not designed to observe the difference in the compliance to the patching hours accurately. These issues can be addressed in a prospective, randomized clinical trial.
We believe that the greater compliance at 3 months in the COAT group and the combined mechanism of occlusion and penalization may have led to greater and faster improvement in BCVA in COAT than augmented part-time patching.
There were no significant adverse effects to treatment in either group. In the COAT group, 2 out of 19 children reported an initial blurring of near vision and inability to perform schoolwork. However, over time these two children were able to continue to perform schoolwork.
Despite being a novel study in addressing a very important question of further interventions for refractory or residual amblyopia, the study has some limitations. The limitations include the nonrandomized, nonmasked design with a heterogeneous population comprised of children with varying etiologies. In addition, the sample size was small in both groups and the groups were not matched. Hence, we adjusted for even small baseline differences in the patching group.
| Conclusion|| |
The current study suggests that COAT may be more beneficial than augmented part-time patching in children who have refractory/residual unilateral amblyopia due to anisometropia, strabismus, stimulus deprivation, or mixed mechanism. While further randomized, multicenter studies are needed to confirm the results, ophthalmologists may consider using this information for the benefit of their patients.
The authors would like to acknowledge the contribution of the following:
- Dr. Abhishek C. Bawdekar (ophthalmologist, L. V. Prasad Eye Institute, GMRV Campus, Visakhapatnam); Ms. Chukka Vani (Optometrist, L. V. Prasad Eye Institute, GMRV Campus, Visakhapatnam): Towards the collection of patient data/contributing to the management of the patient
- Ms. Akhila Acharya for help toward English editing of the revised manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]