The purpose of amblyopia treatment is to decrease visual stimulus to the sound eye, increase use of the amblyopic eye, and thus improve visual acuity (VA).1 Patch therapy has been the most universally employed method. However, side effects such as local irritation and allergy, impaired binocularity during treatment, and psychological stress due to cosmetic issues can occur.2,3 For patients showing such side effects or poor compliance, alternative therapy must be considered. Alternative therapy is also necessary for patients showing no improvement after 6 months of treatment, which is the minimum treatment duration for patch therapy.4–6
Among the available substitute therapies, atropine penalization is generally used as a secondary treatment option and is known to be similar to patch therapy. The advantage of atropine penalization is that it allows stimulation of binocular function while concurrently treating the amblyopic deficit. Atropine penalization reduces high spatial frequency input to the better eye, which appears to be essential to restoring high-spatial frequency VA function in the amblyopic eye. Additionally, atropine penalization maintains low-spatial frequency input to the better eye, therefore maintaining binocularity.7,8 However, because it can cause side effects, it is not usually considered as a primary treatment. Some countries consider it as a secondary treament.9,10
Most completed studies on the effect of atropine penalization have reported only long-term results for patients treated with daily atropine. To our knowledge, there have been no reports on short-term results of intermittent atropine penalization or the factors associated with treatment success.7,11–13 The purpose of our study was to evaluate the efficacy of 1% atropine treatment administered twice a week for 4 months in children with amblyopia for whom patch therapy had failed due to low effect or low compliance and to identify the factors associated with treatment success.
Patients and Methods
This investigation followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Seoul National University Hospital. The design of this retrospective observational case series study and patient enrollment procedures are summarized in Figure 1. Sixty-eight patients with amblyopia who visited the Seoul National University Hospital between January 1, 2011, and December 31, 2015, were screened for eligibility.
Design of the retrospective observational case series study.
Only patients with amblyopia who had undergone patch therapy for at least 6 months and for whom that treatment had failed were included. Daily patching therapy was prescribed from between 2 hours and full-time patching. Patch therapy failure was defined as treatment discontinuation due to low compliance or low effect. The patients were treated with one drop of 1% atropine in the sound eye twice per week for 4 months. The interval between atropine dosing was 3 or 4 days. The patients were instructed to stop using atropine if side effects occurred and to visit a clinic for possible reversion to patch therapy. Excluded patients were those who had any systemic or ocular disease (excluding anisometropia or strabismus) possibly affecting their VA or those who were uncooperative with respect to VA determination.
Seven of the 68 patients were excluded due to exclusion criteria and 6 patients did not want atropine treatment. Subsequently, a total of 55 patients received intermittent atropine penalization treatment. Ten of the 55 patients were excluded because they did not use or stopped using the atropine eye drops for no definite reason. Four patients stopped using the atropine eye drops due to side effects. Ultimately, 41 patients were included in our study and their medical records were analyzed retrospectively.
Amblyopia was defined as an inter-eye difference in best corrected visual acuity (BCVA) of at least 2 logarithm of the minimum angle of resolution (logMAR) lines. Based on the cause of amblyopia, the eyes were classified as either anisometropic amblyopic, strabismic amblyopic, or combined anisometropic/strabismic amblyopic. Anisometropic amblyopia was defined as amblyopia with anisometropia of inter-eye spherical equivalent differences of at least 1.00 diopter (D) and/or inter-eye astigmatism differences of at least 1.00 D. Strabismic amblyopia was defined as amblyopia on alternate cover testing of esotropia of at least 5 prism diopters (PD), exotropia of at least 10 PD, hypertropia of at least 5 PD, or a history of strabismus surgery. Combined anisometropic/strabismic amblyopia was defined as amblyopia in the presence of both anisometropia and strabismus. Treatment success was defined as a final BCVA improvement of two logMAR lines relative to the baseline BCVA at the start of atropine penalization in the amblyopic eye.
All patients underwent a complete ophthalmic examination including anterior and posterior segments to rule out any organic cause of vision impairment. Retinoscopy with 1% cyclopentolate eye drops was performed and spectacles were prescribed as needed. A dilated fundus examination was performed to rule out macular disease, which can affect VA. Refractive errors as measured by cycloplegic refraction were recorded as spherical equivalents. Age, cause of amblyopia, pretreatment BCVA at the time of starting atropine penalization in the amblyopic eye, age at the start of eyeglass prescription, age at the start of patch therapy, type of refraction, type of strabismus, and cause of patch therapy failure were all analyzed and compared between two groups: the failure and success groups. Duration, compliance with, and total amount of patch therapy were also evaluated. Calculating the “total amount of patch therapy” is a new method of evaluating the effect of atropine penalization on VA improvement. We introduced it because patients had different durations and degrees of compliance for each inter-visit interval. It was defined as the sum of all visits' examination data for “patch therapy duration (months) × compliance (%).” Pretreatment BCVA, posttreatment BCVA, and improvement of BCVA in the amblyopic eye were also evaluated. Any side effects were identified by questioning the patients' guardians regarding the occurrence of ocular symptoms such as congestion, glare, skin irritation, and systemic symptoms such as dryness of the mouth or skin, facial rash, sleeplessness, drowsiness, or other discomforts.
Statistical analyses were undertaken with SPSS software (version 18; SPSS Inc., Chicago, IL). A P value less than .05 was considered statistically significant. Comparisons of the failure and success groups' clinical characteristics were performed using the independent t and Mann–Whitney U tests for continuous variables and the chi-square and Fisher's exact tests for categorical variables. Tests of normality of distribution of continuous data were done using the Shapiro–Wilk test. In normally and non-normally distributed data, the independent t and Mann–Whitney U tests were used, respectively. In categorical variables analysis, the chi-square and Fisher's exact tests were used according to the sample size.
Of the 41 patients, 18 were boys and 23 were girls. Twenty-one of the 41 patients (51.2%) showed treatment success, and 20 (48.8%) showed treatment failure. The mean ± standard deviation (SD) ages in the failure and success groups were 6.05 ± 1.40 and 5.10 ± 1.52 years, respectively. The success group had a statistically significantly younger age (P = .044). The median (interquartile range) pretreatment BCVAs of the amblyopic eyes in the failure and success groups were 0.30 ± 0.20 and 0.50 ± 0.20 logMAR, respectively. The success group showed a statistically significantly worse pretreatment BCVA than that of the failure group (P = .001). None of the other factors (eg, age at the start of eyeglass prescription, age at the start of patch therapy, or duration, compliance with, and total amount of patch therapy) showed any statistically significant differences between the groups (Table 1).
Comparison of Continuous Factors Between Atropine Penalization Failure and Success Groups
The cause of amblyopia was anisometropia (17 cases), strabismus (15 cases), or both (9 cases). There were no statistically significant differences between those groups. Patients were either hyperopic (33 cases) or myopic (8 cases) with no statistically significant differences. The cause of patch therapy failure was low compliance (20 cases) or no effect (21 cases) with no statistically significant differences (Table 2).
Comparison of Discrete Factors Between Atropine Penalization Failure and Success Groups
The mean ± SD final BCVAs in the amblyopic eyes in the failure and success groups were 0.21 ± 0.16 and 0.22 ± 0.17 logMAR, respectively. The mean ± SD VA improvements in the two groups were 0.09 ± 0.08 and 0.28 ± 0.13 logMAR, respectively (Table 3).
Changes of Visual Acuity After Atropine Penalization
We evaluated the effect of short-term intermittent atropine penalization in children with amblyopia for whom patch therapy had failed and analyzed the factors associated with treatment success. Our results showed that a younger age and poor pretreatment VA in the amblyopic eye were associated with the success of atropine penalization treatment. With regard to the proper amblyopia treatment period, it is known to be helpful to begin early.4,14–16 Although the significant period for VA development is known to be between the ages of 7 and 8 years, several studies have reported that amblyopia treatment can be effective even in patients aged 9 to 10 years.4,14–16 Clarke et al.17 reported that, until the age of 5 years, the time of treatment did not affect the final VA in amblyopic eyes. Our study's finding of an association of younger age with treatment success is consistent with Yu and Choi's10 results, which reported mean failure and success group ages of 9.53 and 7.42 years, respectively, and which noted a younger age in the success group than in the failure group. In our study, the patients' mean age was younger than in Yu and Choi's investigation. However, we also showed that improvement of VA is anticipated in patients of a younger age.
In our study, in addition to a younger age, poor pretreatment VA in the amblyopic eye was also associated with the success of atropine penalization treatment. Although several studies have reported similar results to ours, there are also studies that have reported the opposite result. Such studies mentioned that VA in the amblyopic eye might be lower than that in the sound eye after the application of atropine eye drops; therefore the effect of atropine penalization treatment may be weaker or absent.10,18 Our patients showed an average VA of 0.4 logMAR in the amblyopic eye and only a small number of patients showed severe amblyopia. Thus, we assume that there is a low possibility that the VA in the amblyopic eye was lower than that in the sound eye after the application of atropine eye drops.
In this study, the cause of amblyopia was found to not be associated with treatment success. Recently, several large-scale prospective studies have noted that the effect of atropine penalization treatment did not differ based on the cause of amblyopia.2,5,19–22 Kim and Choi12 reported that there were no differences in the pharmacotherapeutic effect of atropine based on the cause of amblyopia. We also evaluated the cause of the failure of patch therapy as a possible factor related to treatment success and it was not associated. There were patients who experienced patch therapy failure despite their good compliance, insinuating that there are different mechanisms of atropine penalization and patch therapy improvement. As Repka and Ray18 noted, unlike patch therapy, atropine penalization does not absolutely diminish visual stimulus, but instead blurs images and decreases spatial frequency. Eventually, it will change the dominant eye from a sound eye to an amblyopic eye. We considered that the patients for whom patch therapy had failed due to no improvement of VA despite compliance and a long-duration treatment period may have experienced different mechanisms.
Where our study differs from previous studies is in its more detailed analysis of the factors potentially associated with treatment success. Specifically, we separately evaluated duration, compliance with, and total amount of patch therapy. Additionally, we evaluated patients 4 months after the initial administration of atropine eye drops. Atropine penalization therapy is known to require a longer treatment time than patch therapy. Most of the previous studies on atropine penalization have analyzed patients treated daily for at least 1 year.4,10,18,23,24 However, to the best of our knowledge, no other study has investigated for a set period such as 4 months and our results indicated that 4-month intermittent atropine penalization therapy can improve VA.
Atropine penalization treatment has usually been administered daily based on the duration of its effect. Arnold et al.25 reported that visual blurring lasted less than 48 hours and that a significant penalization effect was present for only one day. Therefore, daily atropine use should be prescribed for penalization.25 However, there also have been several intermittent atropine penalization treatment studies and they reported an improvement of VA.11–13 Notably, there have been reports that intermittent atropine penalization treatment compared with daily treatment improved compliance.10,18 In the current study, we found that approximately half of the patients for whom patching therapy had failed showed treatment success after twice weekly atropine penalization treatment. This implies that if patients cannot undergo daily atropine penalization therapy, due to either adverse side effects or insufficient compliance, intermittent atropine penalization therapy can be considered.
Similar to the current study, Yu and Choi10 evaluated the effect of intermittent atropine penalization for patients with amblyopia for whom patch therapy had failed and concluded that approximately 80% of patients showed success. The relevant statistics were as follows: average VA: 0.3 logMAR; average age: 7.8 years; average treatment duration: 7.5 months. Unlike the current study, however, they did not analyze the factors associated with treatment success and for a set period. The success rate in our study was lower than in Yu and Choi's, perhaps due to differences in patient age, pretreatment VA in amblyopic eyes, and treatment duration.
In our study, 14 patients were excluded: 10 who did not take or stopped taking atropine eye drops for no definite reason and 4 who stopped due to side effects such as glare, skin irritation, and facial rash. Atropine treatment is known to have a higher rate of compliance than patch therapy because it is easy to administer in the form of eye drops and children do not suffer stress due to cosmetic issues. Although several side effects of atropine have been reported, most of them are mild ocular (eg, glare or skin irritation) rather than severe systemic.2,7,10,12 Severe systemic side effects did not arise in our study.
This study has several limitations. First, it is a retrospective study and has a relatively small number of patients. A retrospective observational case series may be limited by selection and attrition bias, and by not masking of observers and participants leading to performance and detection bias. Thus, further prospective and large-scale investigations are needed.
Second, no case showed severe systemic side effects in our study, but that does not mean that it is impossible for systemic side effects to occur. Therefore, when clinicians administer atropine for the treatment of amblyopia, caution is always needed. Finally, the study was not powered to allow any significance testing and findings from these tests must be interpreted with caution.
Approximately half of the amblyopic children showed treatment success after 4-month intermittent atropine penalization treatment. Specifically, these were individuals of a younger age or who had shown poor pretreatment VA in amblyopic eyes. Given the fact that a significant portion of patients showed treatment success with a relatively short-duration intermittent treatment, clinicians should attempt intermittent atropine penalization in cases in which patch therapy has failed.
- Kaye SB, Chen SI, Price G, et al. Combined optical and atropine penalization for the treatment of strabismic and anisometropic amblyopia. J AAPOS. 2002;6:289–293. doi:10.1067/mpa.2002.127920 [CrossRef]
- Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for treatment of moderate amblyopia in children. Arch Ophthalmol. 2002;120:268–278. doi:10.1001/archopht.120.3.268 [CrossRef]
- Holmes JM, Beck RW, Kraker RT, et al. Pediatric Eye Disease Investigator Group. Impact of patching and atropine treatment on the child and family in the amblyopia treatment study. Arch Ophthalmol. 2003;121:1625–1632. doi:10.1001/archopht.121.11.1625 [CrossRef]
- Moon CS, Jin YH. Timing of amblyopia therapy in pure anisometropic amblyopia. Journal of the Korean Ophthalmological Society. 1998;39:185–192.
- Oh DE, Lim KH. Efficacy of occlusion therapy in amblyopia: type, depth and timing of amblyopia. Journal of the Korean Ophthalmological Society. 2003;44:2850–2856.
- Chang HR, Hong SH, Huh DW. The clinical outcomes of occlusion for monocular amblyopia in children more than 8 years. Journal of the Korean Ophthalmological Society. 2003;44:1146–1152.
- Simons K, Stein L, Sener EC, Vitale S, Guyton DL. Full-time atropine, intermittent atropine, and optical penalization and binocular outcome in treatment of strabismic amblyopia. Ophthalmology. 1997;104:2143–2155. doi:10.1016/S0161-6420(97)30048-7 [CrossRef]
- Simons K, Gotzler KC, Vitale S. Penalization versus part-time occlusion and binocular outcome in treatment of strabismic amblyopia. Ophthalmology. 1997;104:2156–2160. doi:10.1016/S0161-6420(97)30047-5 [CrossRef]
- North R, Kelly ME. Atropine occlusion in the treatment of strabismic amblyopia and its effect upon the non-amblyopic eye. Ophthalmic Physiol Opt. 1991;11:113–117. doi:10.1111/j.1475-1313.1991.tb00209.x [CrossRef]
- Yu DK, Choi MY. The efficacy of intermittent atropine penalization in amblyopic children who have failed patching therapy. Journal of the Korean Ophthalmological Society. 2005;46:1167–1174.
- Medghalchi AR, Dalili S. A randomized trial of atropine vs patching for treatment of moderate amblyopia. Iran Red Crescent Med J. 2011;13:578–581.
- Kim YH, Choi MY. The prospective comparison of the efficacy of intermittent atropine penalization and part-time occlusion therapy. Journal of the Korean Ophthalmological Society. 2008;49:958–966. doi:10.3341/jkos.2008.49.6.958 [CrossRef]
- Lee K, Chae JB, Choi MY. Comparison of part-time occlusion therapy and intermittent atropine penalization therapy for amblyopic children of school age. Journal of Korean Ophthalmological Society. 2010;51:259–265. doi:10.3341/jkos.2010.51.2.259 [CrossRef]
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Comparison of Continuous Factors Between Atropine Penalization Failure and Success Groupsa
|Factor||Failure Group (n = 21)||Success Group (n = 20)||P|
|Age (y)||6.05 ± 1.40||5.10 ± 1.52||.044b|
|Pretreatment BCVA (logMAR)||0.30 ± 0.20||0.50 ± 0.20||.001c|
|Age at start of eyeglass prescription (y)||3.67 ± 1.65||3.10 ± 1.65||.279b|
|Age at start of patch therapy (y)||3.81 ± 1.63||3.55 ± 1.67||.618b|
|Duration of patch therapy (mo)||19.38 ± 10.71||15.15 ± 8.55||.171b|
|Compliance with patch therapy (%)||56.43 ± 34.17||58.75 ± 37.34||.836b|
|Total duration of patch therapy (mo)||75.67 ± 45.58||53.77 ± 33.11||.089b|
Comparison of Discrete Factors Between Atropine Penalization Failure and Success Groups
|Factor||Failure Group (n = 21)||Success Group (n = 20)||P|
|Type of classification||1.000a|
|Type of refraction||.066a|
|Type of strabismus||.474a|
|Cause of patch therapy failure||.879b|
| No effect||11||10|
Changes of Visual Acuity After Atropine Penalizationa
|Visual Acuity||Failure Group (n = 21)||Success Group (n = 20)||Total (N = 41)|
|Posttreatment BCVA (logMAR)||0.21 ± 0.16||0.22 ± 0.17||0.22 ± 0.16|
|Improvement of BCVA (logMAR)||0.09 ± 0.08||0.28 ± 0.13||0.18 ± 0.14|