- Email: [email protected]
Clinical trial of patching versus atropine penalization for the treatment of anisometropic amblyopia in older children
Clinical trial of patching versus atropine penalization for the treatment of anisometropic amblyopia in older children Vimla Menon, MS, Gadaginamath Shailesh, MD, Pradeep Sharma, MD, and Rohit Saxena, MD PURPOSE METHODS
RESULTS
CONCLUSIONS
To compare conventional patching therapy with atropine penalization in the treatment of anisometropic amblyopia. Prospective, randomized, institution-based clinical trial of patching versus atropine penalization in patients aged 8-20 years. Patients received either conventional, full-time patching, or atropine penalization. Fifty-seven patients were enrolled, with visual acuity ranging from 6/12 to 6/60 in the amblyopic eye. Twenty-nine patients received conventional full-time patching; 28 received atropine penalization. At 6 months, visual acuity improved by 2.38 lines in the conventional patching group and 2.34 lines in the atropine group ( p ⫽ 0.889). The speed of visual recovery was faster in the patching group (3.7 months) than in the atropine group (4.7 months; p ⫽ 0.013). There was significant improvement in near vision and contrast sensitivity in both groups, but improvement in the patching group was significantly better than in the atropine group. No patient had reduced visual acuity in the unaffected eye. Redness of eyes was observed more in the atropine group than in the patching group. Treatment tended to be better-accepted by parents and patients in the atropine group, but not significantly more. In patients aged 8-20 years with anisometropic amblyopia, both patching and atropine therapy improved visual acuity. Although recovery was faster with patching, the 2 modalities of treatment appeared to be equally effective. ( J AAPOS 2008;12:493-497)
O
cclusion therapy with patching of the unaffected eye has been the mainstay of amblyopia treatment.1 Opinions vary regarding the optimal number of hours of patching.1 Poor adherence to recommended treatment is often cited as the major problem with occlusion treatment, along with skin irritation and psychological problems.2 Even with part-time patching, clinicians have resorted to varying durations of patching.3,4 Pharmacological penalization offers an alternative treatment for amblyopia which, in addition to being perceived as cosmetically more acceptable, cannot be undermined by the child.5,6 To the best of our knowledge, there have been only 2 prospective, comparative studies of patching versus atropine penalization, both of which have included both strabismic and anisometropic forms of amblyopia.2,7 Anisometropic amblyopia has a better prognosis than other types of amblyopia and can show response to treatment in older age groups.8-12 Anisometropic amblyopia usually remains undetected until the child’s eyes are examined at
Author affiliations: Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India Submitted January 22, 2007. Revision accepted March 24, 2008. Published online June 5, 2008. Reprint requests: Dr. G. M. Shailesh, MD, #485, Administrative Block, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, India. (email: [email protected]). Copyright © 2008 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2008/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2008.03.006
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school.13 Cobb et al14 found that age at presentation had no effect on the final visual outcome, and children with anisometropic amblyopia should be treated regardless of age. We undertook this prospective study to compare the effectiveness of conventional full-time patching versus pharmacological penalization with atropine in anisometropic amblyopia in the age group of 8 to 20 years.
Methods A prospective, randomized clinical trial was conducted on 57 patients with anisometropic amblyopia attending the squint clinic of the Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Science, New Delhi. Informed consent for participation in the study was obtained for all subjects as well as prior approval from the Institutional Review Committee. Inclusion criteria were anisometropic hypermetropia of more than 1 diopter (D), intereye visual acuity difference of ⱖ3 logMAR lines, visual acuity in sound eye of ⬎6/9, and visual acuity of amblyopic eye between 6/12 and 6/60. Exclusion criteria included myopia, more than 2 months of amblyopia therapy in the past 2 years, and a known skin reaction to patches or allergy to atropine. Patients were divided into 2 main treatment groups: a patching group (P), which received full-time conventional patching, and an atropine group (A), which received penalization with atropine. Stratified randomization was used to place patients in these 2 groups, which were further divided into 2 subgroups, depending on the visual acuity of patients at presentation (Patching 1 [P-1] and Atropine 1 [A-1], with moderate amblyopia of visual acuity
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FIG 1. Randomization of patients into two treatment groups and their subgroups. n: number of patients; VA: Snellen visual acuity; P-1: Patching 1 group; P-2: Patching 2; A-1: Atropine 1; A-2: Atropine 2. 6/60 to 6/24; Patching 2 [P-2] and Atropine 2 [A-2], with mild amblyopia and visual acuity of 6/18 to 6/12; Figure 1). A detailed history and ocular examination of anterior and posterior segments was conducted to rule out any organic cause of vision loss. Retinoscopy using 2% homatropine eye drops was performed, and spectacles were prescribed. A detailed orthoptic evaluation was also performed. Visual acuity was recorded under an adequately illuminated background, with proper spectacles worn for 4 to 6 weeks after refraction. A Snellen visual acuity testing chart was used to record visual acuity at a distance of 6 m. An Early Treatment Diabetic Retinopathy Study (ETDRS) chart was also used to record the visual acuity in logMAR (minimum angle of resolution) values from a distance of 4 m in both eyes separately. Near vision with point system ( printer’s type) was recorded and later converted into decimal notation. Contrast sensitivity was recorded using a Pelli-Robson chart (Clement Clarke International Ltd., Harlow, UK) at a distance of 1 m, each eye being tested separately and later together. Stereoacuity was quantified using TNO test (Lameris Instrumenten, Utrecht, the Netherlands). Plus lenses were used to record near acuity in the atropinized eye during follow-ups.
Patching Protocol Full-time patching of the sound eye using Micropore tape (3M, St. Paul, MN) attached to a piece of opaque oval paper was alternated between the sound eye and amblyopic eye, the ratio being 6:1 (ie, patching of the sound eye for 6 days followed by patching of the amblyopic eye for 1 day). We routinely followed a protocol for patching in our center based on the age of the patient: 2:1 for 2 years and older, 3:1 for 3 years, and so on through 6:1 for 6 years and older. In cases in which a skin allergy to the eye patch developed, it was replaced by Doyne’s occluder/ Opticlude (Nexcare, 3M).
Atropine Protocol Penalization with atropine entailed administering a drop of 1% atropine sulfate daily into the conjunctival fornix of the unaffected eye, with punctal occlusion by finger pressure to prevent any systemic absorption of atropine from nasal mucosa. Excess
atropine drops on the skin were wiped away to prevent allergic reactions. Patients and parents were informed about the side effects of atropine. Because a significant penalization effect is present for only a day or so, daily atropine was prescribed.15 The frequency of atropine drops was reduced when visual acuity reached the desired level, or if there was no improvement in visual acuity for 3 months, at which point a minimum twice weekly regimen was adopted. If an allergy to atropine occurred, it was replaced by 2% homatropine eye drops twice daily.
Follow-up Schedule Patients were followed monthly for 6 months, after which they received a final evaluation. Any patient missing more than 2 follow-up examinations was excluded. The following parameters were recorded after 6 months in the patching group and 2 weeks after stopping the eye drops in the atropine group: (1) visual function with Snellen distance visual acuity, ETDRS visual acuity, near vision, and contrast sensitivity; (2) orthoptic evaluation; (3) stereoacuity by TNO test; (4) adverse effects; and (5) compliance. Children unable to appreciate the minimal stereoacuity chart on TNO were arbitrarily assigned a stereoacuity value of 960 arcsec for statistical calculations. Visual acuity was checked at 6 months as well as at 6 months and 2 weeks, but no regression in the improved distance visual acuity in those 2 weeks was observed. A standardized questionnaire was not used. The main adverse effects were itching of eyes in the patching group and redness of eyes in the atropine group. Compliance was graded as good ( patching not missed on any day of 1-month follow-up) and average ( patching not done for one day or more in a month).
Statistical Analysis Data analysis was performed with the use of Stata 8.0 computer software (StataCorp LP, College Station, TX) as follows. Descriptive statistics were expressed as mean plus or minus SD (continuous variables) or number and percentage (categorical variables) as appropriate. The Student’s t-test was used to compare mean difference in the 2 major groups. A paired t-test was then used to compare baseline and follow-up measurements within the groups. Parametric one-way analysis of variance was used to compare mean difference
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FIG 2. Overall distribution of age in 57 patients from 8 to 20 years. of measurements among the groups, with Bonferroni post-hoc analysis for pairwise comparison and repeated measures analysis of variance to compare the mean difference in the follow-up values between groups. Categorical variables according to group were assessed by means of 2 testing. Stereoacuity was evaluated using nonparametric tests. A p-value of less than 0.05 was considered statistically significant. Both patching and atropine groups were compared for various parameters; their corresponding subgroups were also analyzed. Although the sample size was larger than previously published studies, we did not perform sample size calculations in advance of our study, as we were aware in advance that we would be recruiting as many patients as possible over a period of three years in a single center. The power of the study for the final visual acuity by ETDRS was found to be 6% at the end our clinical trial. A sample size of 1,750 per group would have been needed to obtain a statistical power of 80%.
Results Sixty-three patients with anisometropic amblyopia were enrolled. Because of incomplete follow-up after their second visit, 6 patients (9%, 3 from each group) were excluded and were considered treatment failures in the study. Long distances and travel time were the reasons for lack of follow-up in these patients. Fifty-seven patients completed the 6-month follow-up, with 29 in the patching group and 28 in atropine group. Comparisons were made between the patching and atropine groups and their corresponding subgroups, ie, P-1 with A-1 and P-2 with A-2. No significant difference in age (Figure 2) or gender between the 2 groups or any of the corresponding subgroups was observed. The difference in refractive error was statistically higher in the patching group ( p ⫽ 0.027, Table 1). Visual acuity was measured by both ETDRS (Table 2 and Figure 3) and Snellen chart (Table 1). Visual acuity significantly improved from baseline to 6 months in both the patching and atropine groups and their subgroups.
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Visual acuity at baseline and at each follow-up visit at one month intervals, including 6 months, was the same between the atropine and patching groups, indicating no significant difference in response to the treatment. ETDRS visual acuity improved in both groups (Figure 3), with minimal difference between groups (Table 2). Snellen visual acuity also improved in both groups from baseline to 6-month follow-up. Visual acuity improved by 2.38 lines in the Patching group and 2.34 lines in the Atropine group using ETDRS logMAR values, which was statistically not significant between the groups ( p ⫽ 0.889, Table 1). Best visual acuity was attained in 3.7 months in the patching group and more slowly (4.7 months) in the atropine group ( p ⫽ 0.013, Table 1). Near vision improved significantly in both groups after treatment ( p ⬍ 0.001). Between groups, baseline near visual acuity was comparable ( p ⫽ 0.754), but after 6 months treatment, the patching group improved significantly more ( p ⫽ 0.039) than the atropine group (Table 1). Contrast sensitivity and stereoacuity were not significantly different between groups at baseline or at the 6-month follow-up visit (Table 1). Compliance was assessed during each follow-up by questioning patients and parents. There was a trend toward a preference for atropine (Table 1) that was not statistically significant ( p ⫽ 0.537). Redness of the eyes was seen significantly more frequently in the atropine group (Table 1). There was trend toward more itching around the eyes in the patching group that was not significant. Only one patient in the atropine group developed recurrent redness at the end of 6 months follow-up, for which atropine was discontinued and patching was prescribed at the parent’s request.
Discussion Most studies that have evaluated amblyopia treatment are retrospective,16 and only a few have compared patching with atropine penalization. Some prospective studies have been limited by smaller sample size.7,16 To the best of our knowledge, there is no prospective study comparing patching treatment with atropine penalization exclusively in older patients (aged 8 years and older) with anisometropic amblyopia. One potential confounding factor was the significantly greater difference in refractive error in the patching group. This was not associated with any difference between groups in the improvement of visual acuity, as corroborated by the PEDIG study.17 However, it is possible that if the patching group had more severe anisometropia, a superior response to patching compared with atropine would have been masked. One study13 reported a better prognosis for treatment in patients with anisometropia ⬍4 D. One fourth of the patients in a recent PEDIG study18 showed improvement in visual acuity by optical correction alone; meanwhile, another study19 reported resolution of amblyopia in nearly half of the 60 anisometropes treated with spectacle correction alone. Although we allowed 6 weeks for the refractive adaptation
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Table 1. Baseline and 6 months posttreatment characteristics in amblyopic eye Various parameters Mean age ( years) ⫾ SD Mean refractive error ⫾ SD (diopters) Snellen VA* Baseline 6 months Lines of VA improvement (ETDRS logMAR value) mean ⫾ SD Speed of visual acuity recovery (months) Near vision (decimal notation) Baseline 6 months Contrast sensitivity (log units) Baseline 6 months Stereo acuity (arcsec) Baseline 6 months Compliance Average Good Side effects to therapy Itching† Present Absent Redness Present Absent
Patching group (n ⫽ 29)
Atropine group (n ⫽ 28)
p-value
13.53 ⫾ 4.01 ⫹4.24 ⫾ 1.66
13.75 ⫾ 3.66 ⫹3.29 ⫾ 1.47
0.833 0.027
0.221 ⫾ 0.09 0.462 ⫾ 0.15 ( p ⬍ 0.001) 2.38 ⫾ 1.19
0.228 ⫾ 0.10 0.446 ⫾ 0.21 ( p ⬍ 0.001) 2.34 ⫾ 1.14
0.805 0.752
3.79 ⫾ 1.44
4.71 ⫾ 1.27
0.013
0.27 ⫾ 0.17 0.44 ⫾ 0.08 ( p ⬍ 0.001)
0.26 ⫾ 0.17 0.38 ⫾ 0.12 ( p ⬍ 0.001)
0.754 0.039
1.40 ⫾ 0.26 1.58 ⫾ 0.09 ( p ⫽ 0.0017)
1.37 ⫾ 0.22 1.52 ⫾ 0.15 ( p ⫽ 0.0006)
0.649 0.07
755.5 ⫾ 319.7 746.8 ⫾ 353.3
780 ⫾ 296.6 677.1 ⫾ 325.3
0.781 0.388
11 18
12 16
0.537
8 21
5 23
0.381
2 27
8 20
0.031
0.889
*Visual acuity in decimal notation. †Skin allergy; p-values in brackets show changes within the group from baseline to 6 months. ETDRS: Early Treatment Diabetic Retinopathy Study; SD: standard deviation.
Table 2. ETDRS visual acuity (logMAR units) in the subgroups (mean ⫾ standard deviation) Subgroups
Baseline
1 Month
2 Months
3 Months
4 Months
5 Months
6 Months
P-1 A-1 P-2 A-2
0.77 ⫾ 0.10 0.79 ⫾ 0.17 0.51 ⫾ 0.15 0.49 ⫾ 0.16
0.66 ⫾ 0.12 0.69 ⫾ 0.17 0.41 ⫾ 0.19 0.39 ⫾ 0.15
0.60 ⫾ 0.11 0.63 ⫾ 0.17 0.40 ⫾ 0.16 0.34 ⫾ 0.17
0.57 ⫾ 0.10 0.62 ⫾ 0.17 0.37 ⫾ 0.16 0.33 ⫾ 0.16
0.53 ⫾ 0.11 0.59 ⫾ 0.17 0.35 ⫾ 0.16 0.32 ⫾ 0.16
0.53 ⫾ 0.10 0.57 ⫾ 0.18 0.37 ⫾ 0.14 0.30 ⫾ 0.16
0.50 ⫾ 0.11 0.56 ⫾ 0.17 0.34 ⫾ 0.15 0.25 ⫾ 0.13
p-values were not significant in the subgroups comparison at each month of follow-up. ETDRS: Early Treatment Diabetic Retinopathy Study; P-1: Patching Group 1; P-2: Patching Group 2; A-1: Atropine Group 1; A-2: Atropine Group 2.
before starting treatment, optical correction alone as a treatment modality should be kept in mind. Speed of visual recovery (mean of time duration taken to attain maximum stable vision in each group) was faster in the patching group than in the atropine group, but the difference in mean visual acuity at the end of 6 months was minimal. Similar observations were made in the PEDIG study,2 with patching group showing more rapid improvement. Kushner17 believed that if treatment success can be attained in less than than 6 months, then this spare an additional three to four visits to a doctor’s office, thus reducing inconvenience, expense, and frustration. The patching group showed significant improvement in near visual acuity over the atropine group at the end of 6 months. Although near vision was not measured until 2 weeks after atropine drops were discontinued, it is still pos-
sible that a residual cycloplegic effect impaired near visual acuity. Contrast sensitivity and stereoacuity also improved from baseline to 6-month follow-up in both the groups, with no significant difference in improvement between the groups and their corresponding subgroups. In a study done by Koskela and Hyvarinen,20 contrast sensitivity at intermediate frequencies was found to be the most sensitive indicator of disturbances in the vision of dominant eye and improvement of the vision in the amblyopic eye. They recommended that contrast sensitivity be measured regularly during the treatment of amblyopia. Stereoacuity in both groups did not reach normal values. No patients in the atropine group had systemic side effects. Only transient local side effects were noticed in both the groups. Compliance rates were also comparable. Most pa-
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FIG 3. Trend in the improvement of visual acuity (ETDRS log units) in patching and atropine groups from baseline to the 6-month follow-up period. (Eb: baseline visual acuity; E1: visual acuity at 1 month; E6: visual acuity at 6 months).
tients and parents appeared to prefer atropine penalization over patching as a modality of treatment for cosmetic and psychological reasons, but this did not achieve statistical significance. The impact of patching and atropine treatment on child and family was similar to that found in PEDIG21 study. Visual acuity improved in all age groups from 8 to 20 years (Figure 2). A superior treatment outcome in anisometropic amblyopes over 15 years of age has also been reported by Sen et al.13 A recent PEDIG trial22 also reported improvement in visual acuity in older children and adolescents aged 10-18 years. In conclusion, we believe that atropine and patching are equally effective in the treatment of anisometropic amblyopia in patients aged 8-20 years. The response to therapy is more rapid in patching patients, and there is a suggestion that near acuity may improve more in patients treated with patching. Literature Search The authors conducted a MEDLINE (PubMed) search for the dates 1966 to 2007 using the following terms: anisometropic amblyopia, atropine penalization, and occlusion therapy. Only articles published in English language were considered. References 1. von Noorden GK. Binocular vision and ocular motility: Theory and Management of Strabismus. 5th ed. St. Louis (MO): Mosby-Year Book Inc; 1996. p. 512-20. 2. Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs. patching for treatment of moderate amblyopia in children. Arch Ophthalmol 2002;120:268-78.
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3. Hiscox F, Strong N, Thompson JR, Minshull C, Woodruff G. Occlusion of amblyopia. A comprehensive survey of outcome. Eye 1992;6:300-304. 4. Olson RJ, Scott WE. A practical approach to occlusion therapy for amblyopia. Semin Ophthalmol 1997;12:161-5. 5. von Noorden GK, Milam JB. Penalization in the treatment of amblyopia. Am J Ophthalmol 1979;88:511-8. 6. Repka MX, Gallin PF, Scholz RT, Guyton DL. Determination of optical penalization by vectografic fixation reversal. Ophthalmology 1985;92:1584-6. 7. Foley-Nolan A, McCann A, O’Keefe M. Atropine penalization vs. occlusion as the primary treatment for amblyopia. Br J Ophthalmol 1997;81:54-7. 8. Wick B, Wingard M, Cotter S, Scheiman M. Anisometropic amblyopia: Is the patient ever too old to treat? Optometry Vision Sci 1992;69:866-78. 9. Vereecken EP, Brabant P. Prognosis for vision in amblyopia after the loss of the good eye. Arch Ophthalmol 1984;102:220-4. 10. Kivlin JO, Flynn JT. Therapy of anisometropic amblyopia. J Pediatr Ophthalmol Strabismus 1981;18:47-56. 11. Mintz-Hittner HA, Fernandez KM. Successful amblyopia therapy initiated after age 7 years: Compliance cures. Arch Ophthalmol 2000;118:1535-41. 12. Oliver M, Neumann R, Chaimovitch Y, Gotesman N, Shimshoni M. Compliance and results of treatment for amblyopia in children more than 8 years old. Am J Ophthalmol 1986;102:340-5. 13. Sen DK. Results of treatment of anisohypermetropic amblyopia without strabismus. Br J Ophthalmol 1982;66:680-4. 14. Cobb CJ, Russell K, Cox A, MacEwen CJ. Factors influencing visual outcome in anisometropic amblyopes. Br J Ophthalmol 2002;86: 1278-81. 15. Arnold RW, Gionet E, Hickel J, Owen M, Armitage MD. Duration and effect of single-dose atropine: Paralysis of accommodation in penalization treatment of functional amblyopia. Binocul Vis Strabismus Q 2004; 19:81-6. 16. Simons K, Gotzler KC, Vitale S. Penalization vs. part-time occlusion and binocular outcome in treatment of strabismic amblyopia. Ophthalmology 1997;104:2156-60. 17. Pediatric Eye Disease Investigator Group. A comparison of atropine and patching treatments for moderate amblyopia by patient age, cause of amblyopia, depth of amblyopia, and other factors. Ophthalmology 2003;110:1632-8. 18. Pediatric Eye Disease Investigator Group. Randomized trial of treatment of amblyopia in children aged 7 to 17 years. Arch Ophthalmol 2005;123:437-47. 19. Chen PL, Chen JT, Tai MC, Fu JJ, Chang CC, Lu DW. Anisometropic amblyopia treated with spectacle correction alone: Possible factors predicting success and time to start patching. Am J Ophthalmol 2007;143:54-60. 20. Koskela PU, Hyvarinen L. Contrast sensitivity in amblyopia. Effect on occlusion. Acta Ophthalmol 1986;64:386-90. 21. Pediatric Eye Disease Investigator Group. Impact of patching and atropine treatment on the child and family in the amblyopia treatment study. Arch Ophthalmol 2003;121:1625-32. 22. Pediatric Eye Disease Investigator Group. A prospective, pilot study of treatment of amblyopia in children 10 to ⬍18 years old. Am J Ophthalmol 2004;137:581-3.
RESULTS
CONCLUSIONS
To compare conventional patching therapy with atropine penalization in the treatment of anisometropic amblyopia. Prospective, randomized, institution-based clinical trial of patching versus atropine penalization in patients aged 8-20 years. Patients received either conventional, full-time patching, or atropine penalization. Fifty-seven patients were enrolled, with visual acuity ranging from 6/12 to 6/60 in the amblyopic eye. Twenty-nine patients received conventional full-time patching; 28 received atropine penalization. At 6 months, visual acuity improved by 2.38 lines in the conventional patching group and 2.34 lines in the atropine group ( p ⫽ 0.889). The speed of visual recovery was faster in the patching group (3.7 months) than in the atropine group (4.7 months; p ⫽ 0.013). There was significant improvement in near vision and contrast sensitivity in both groups, but improvement in the patching group was significantly better than in the atropine group. No patient had reduced visual acuity in the unaffected eye. Redness of eyes was observed more in the atropine group than in the patching group. Treatment tended to be better-accepted by parents and patients in the atropine group, but not significantly more. In patients aged 8-20 years with anisometropic amblyopia, both patching and atropine therapy improved visual acuity. Although recovery was faster with patching, the 2 modalities of treatment appeared to be equally effective. ( J AAPOS 2008;12:493-497)
O
cclusion therapy with patching of the unaffected eye has been the mainstay of amblyopia treatment.1 Opinions vary regarding the optimal number of hours of patching.1 Poor adherence to recommended treatment is often cited as the major problem with occlusion treatment, along with skin irritation and psychological problems.2 Even with part-time patching, clinicians have resorted to varying durations of patching.3,4 Pharmacological penalization offers an alternative treatment for amblyopia which, in addition to being perceived as cosmetically more acceptable, cannot be undermined by the child.5,6 To the best of our knowledge, there have been only 2 prospective, comparative studies of patching versus atropine penalization, both of which have included both strabismic and anisometropic forms of amblyopia.2,7 Anisometropic amblyopia has a better prognosis than other types of amblyopia and can show response to treatment in older age groups.8-12 Anisometropic amblyopia usually remains undetected until the child’s eyes are examined at
Author affiliations: Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India Submitted January 22, 2007. Revision accepted March 24, 2008. Published online June 5, 2008. Reprint requests: Dr. G. M. Shailesh, MD, #485, Administrative Block, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, India. (email: [email protected]). Copyright © 2008 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2008/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2008.03.006
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school.13 Cobb et al14 found that age at presentation had no effect on the final visual outcome, and children with anisometropic amblyopia should be treated regardless of age. We undertook this prospective study to compare the effectiveness of conventional full-time patching versus pharmacological penalization with atropine in anisometropic amblyopia in the age group of 8 to 20 years.
Methods A prospective, randomized clinical trial was conducted on 57 patients with anisometropic amblyopia attending the squint clinic of the Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Science, New Delhi. Informed consent for participation in the study was obtained for all subjects as well as prior approval from the Institutional Review Committee. Inclusion criteria were anisometropic hypermetropia of more than 1 diopter (D), intereye visual acuity difference of ⱖ3 logMAR lines, visual acuity in sound eye of ⬎6/9, and visual acuity of amblyopic eye between 6/12 and 6/60. Exclusion criteria included myopia, more than 2 months of amblyopia therapy in the past 2 years, and a known skin reaction to patches or allergy to atropine. Patients were divided into 2 main treatment groups: a patching group (P), which received full-time conventional patching, and an atropine group (A), which received penalization with atropine. Stratified randomization was used to place patients in these 2 groups, which were further divided into 2 subgroups, depending on the visual acuity of patients at presentation (Patching 1 [P-1] and Atropine 1 [A-1], with moderate amblyopia of visual acuity
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FIG 1. Randomization of patients into two treatment groups and their subgroups. n: number of patients; VA: Snellen visual acuity; P-1: Patching 1 group; P-2: Patching 2; A-1: Atropine 1; A-2: Atropine 2. 6/60 to 6/24; Patching 2 [P-2] and Atropine 2 [A-2], with mild amblyopia and visual acuity of 6/18 to 6/12; Figure 1). A detailed history and ocular examination of anterior and posterior segments was conducted to rule out any organic cause of vision loss. Retinoscopy using 2% homatropine eye drops was performed, and spectacles were prescribed. A detailed orthoptic evaluation was also performed. Visual acuity was recorded under an adequately illuminated background, with proper spectacles worn for 4 to 6 weeks after refraction. A Snellen visual acuity testing chart was used to record visual acuity at a distance of 6 m. An Early Treatment Diabetic Retinopathy Study (ETDRS) chart was also used to record the visual acuity in logMAR (minimum angle of resolution) values from a distance of 4 m in both eyes separately. Near vision with point system ( printer’s type) was recorded and later converted into decimal notation. Contrast sensitivity was recorded using a Pelli-Robson chart (Clement Clarke International Ltd., Harlow, UK) at a distance of 1 m, each eye being tested separately and later together. Stereoacuity was quantified using TNO test (Lameris Instrumenten, Utrecht, the Netherlands). Plus lenses were used to record near acuity in the atropinized eye during follow-ups.
Patching Protocol Full-time patching of the sound eye using Micropore tape (3M, St. Paul, MN) attached to a piece of opaque oval paper was alternated between the sound eye and amblyopic eye, the ratio being 6:1 (ie, patching of the sound eye for 6 days followed by patching of the amblyopic eye for 1 day). We routinely followed a protocol for patching in our center based on the age of the patient: 2:1 for 2 years and older, 3:1 for 3 years, and so on through 6:1 for 6 years and older. In cases in which a skin allergy to the eye patch developed, it was replaced by Doyne’s occluder/ Opticlude (Nexcare, 3M).
Atropine Protocol Penalization with atropine entailed administering a drop of 1% atropine sulfate daily into the conjunctival fornix of the unaffected eye, with punctal occlusion by finger pressure to prevent any systemic absorption of atropine from nasal mucosa. Excess
atropine drops on the skin were wiped away to prevent allergic reactions. Patients and parents were informed about the side effects of atropine. Because a significant penalization effect is present for only a day or so, daily atropine was prescribed.15 The frequency of atropine drops was reduced when visual acuity reached the desired level, or if there was no improvement in visual acuity for 3 months, at which point a minimum twice weekly regimen was adopted. If an allergy to atropine occurred, it was replaced by 2% homatropine eye drops twice daily.
Follow-up Schedule Patients were followed monthly for 6 months, after which they received a final evaluation. Any patient missing more than 2 follow-up examinations was excluded. The following parameters were recorded after 6 months in the patching group and 2 weeks after stopping the eye drops in the atropine group: (1) visual function with Snellen distance visual acuity, ETDRS visual acuity, near vision, and contrast sensitivity; (2) orthoptic evaluation; (3) stereoacuity by TNO test; (4) adverse effects; and (5) compliance. Children unable to appreciate the minimal stereoacuity chart on TNO were arbitrarily assigned a stereoacuity value of 960 arcsec for statistical calculations. Visual acuity was checked at 6 months as well as at 6 months and 2 weeks, but no regression in the improved distance visual acuity in those 2 weeks was observed. A standardized questionnaire was not used. The main adverse effects were itching of eyes in the patching group and redness of eyes in the atropine group. Compliance was graded as good ( patching not missed on any day of 1-month follow-up) and average ( patching not done for one day or more in a month).
Statistical Analysis Data analysis was performed with the use of Stata 8.0 computer software (StataCorp LP, College Station, TX) as follows. Descriptive statistics were expressed as mean plus or minus SD (continuous variables) or number and percentage (categorical variables) as appropriate. The Student’s t-test was used to compare mean difference in the 2 major groups. A paired t-test was then used to compare baseline and follow-up measurements within the groups. Parametric one-way analysis of variance was used to compare mean difference
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FIG 2. Overall distribution of age in 57 patients from 8 to 20 years. of measurements among the groups, with Bonferroni post-hoc analysis for pairwise comparison and repeated measures analysis of variance to compare the mean difference in the follow-up values between groups. Categorical variables according to group were assessed by means of 2 testing. Stereoacuity was evaluated using nonparametric tests. A p-value of less than 0.05 was considered statistically significant. Both patching and atropine groups were compared for various parameters; their corresponding subgroups were also analyzed. Although the sample size was larger than previously published studies, we did not perform sample size calculations in advance of our study, as we were aware in advance that we would be recruiting as many patients as possible over a period of three years in a single center. The power of the study for the final visual acuity by ETDRS was found to be 6% at the end our clinical trial. A sample size of 1,750 per group would have been needed to obtain a statistical power of 80%.
Results Sixty-three patients with anisometropic amblyopia were enrolled. Because of incomplete follow-up after their second visit, 6 patients (9%, 3 from each group) were excluded and were considered treatment failures in the study. Long distances and travel time were the reasons for lack of follow-up in these patients. Fifty-seven patients completed the 6-month follow-up, with 29 in the patching group and 28 in atropine group. Comparisons were made between the patching and atropine groups and their corresponding subgroups, ie, P-1 with A-1 and P-2 with A-2. No significant difference in age (Figure 2) or gender between the 2 groups or any of the corresponding subgroups was observed. The difference in refractive error was statistically higher in the patching group ( p ⫽ 0.027, Table 1). Visual acuity was measured by both ETDRS (Table 2 and Figure 3) and Snellen chart (Table 1). Visual acuity significantly improved from baseline to 6 months in both the patching and atropine groups and their subgroups.
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Visual acuity at baseline and at each follow-up visit at one month intervals, including 6 months, was the same between the atropine and patching groups, indicating no significant difference in response to the treatment. ETDRS visual acuity improved in both groups (Figure 3), with minimal difference between groups (Table 2). Snellen visual acuity also improved in both groups from baseline to 6-month follow-up. Visual acuity improved by 2.38 lines in the Patching group and 2.34 lines in the Atropine group using ETDRS logMAR values, which was statistically not significant between the groups ( p ⫽ 0.889, Table 1). Best visual acuity was attained in 3.7 months in the patching group and more slowly (4.7 months) in the atropine group ( p ⫽ 0.013, Table 1). Near vision improved significantly in both groups after treatment ( p ⬍ 0.001). Between groups, baseline near visual acuity was comparable ( p ⫽ 0.754), but after 6 months treatment, the patching group improved significantly more ( p ⫽ 0.039) than the atropine group (Table 1). Contrast sensitivity and stereoacuity were not significantly different between groups at baseline or at the 6-month follow-up visit (Table 1). Compliance was assessed during each follow-up by questioning patients and parents. There was a trend toward a preference for atropine (Table 1) that was not statistically significant ( p ⫽ 0.537). Redness of the eyes was seen significantly more frequently in the atropine group (Table 1). There was trend toward more itching around the eyes in the patching group that was not significant. Only one patient in the atropine group developed recurrent redness at the end of 6 months follow-up, for which atropine was discontinued and patching was prescribed at the parent’s request.
Discussion Most studies that have evaluated amblyopia treatment are retrospective,16 and only a few have compared patching with atropine penalization. Some prospective studies have been limited by smaller sample size.7,16 To the best of our knowledge, there is no prospective study comparing patching treatment with atropine penalization exclusively in older patients (aged 8 years and older) with anisometropic amblyopia. One potential confounding factor was the significantly greater difference in refractive error in the patching group. This was not associated with any difference between groups in the improvement of visual acuity, as corroborated by the PEDIG study.17 However, it is possible that if the patching group had more severe anisometropia, a superior response to patching compared with atropine would have been masked. One study13 reported a better prognosis for treatment in patients with anisometropia ⬍4 D. One fourth of the patients in a recent PEDIG study18 showed improvement in visual acuity by optical correction alone; meanwhile, another study19 reported resolution of amblyopia in nearly half of the 60 anisometropes treated with spectacle correction alone. Although we allowed 6 weeks for the refractive adaptation
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Table 1. Baseline and 6 months posttreatment characteristics in amblyopic eye Various parameters Mean age ( years) ⫾ SD Mean refractive error ⫾ SD (diopters) Snellen VA* Baseline 6 months Lines of VA improvement (ETDRS logMAR value) mean ⫾ SD Speed of visual acuity recovery (months) Near vision (decimal notation) Baseline 6 months Contrast sensitivity (log units) Baseline 6 months Stereo acuity (arcsec) Baseline 6 months Compliance Average Good Side effects to therapy Itching† Present Absent Redness Present Absent
Patching group (n ⫽ 29)
Atropine group (n ⫽ 28)
p-value
13.53 ⫾ 4.01 ⫹4.24 ⫾ 1.66
13.75 ⫾ 3.66 ⫹3.29 ⫾ 1.47
0.833 0.027
0.221 ⫾ 0.09 0.462 ⫾ 0.15 ( p ⬍ 0.001) 2.38 ⫾ 1.19
0.228 ⫾ 0.10 0.446 ⫾ 0.21 ( p ⬍ 0.001) 2.34 ⫾ 1.14
0.805 0.752
3.79 ⫾ 1.44
4.71 ⫾ 1.27
0.013
0.27 ⫾ 0.17 0.44 ⫾ 0.08 ( p ⬍ 0.001)
0.26 ⫾ 0.17 0.38 ⫾ 0.12 ( p ⬍ 0.001)
0.754 0.039
1.40 ⫾ 0.26 1.58 ⫾ 0.09 ( p ⫽ 0.0017)
1.37 ⫾ 0.22 1.52 ⫾ 0.15 ( p ⫽ 0.0006)
0.649 0.07
755.5 ⫾ 319.7 746.8 ⫾ 353.3
780 ⫾ 296.6 677.1 ⫾ 325.3
0.781 0.388
11 18
12 16
0.537
8 21
5 23
0.381
2 27
8 20
0.031
0.889
*Visual acuity in decimal notation. †Skin allergy; p-values in brackets show changes within the group from baseline to 6 months. ETDRS: Early Treatment Diabetic Retinopathy Study; SD: standard deviation.
Table 2. ETDRS visual acuity (logMAR units) in the subgroups (mean ⫾ standard deviation) Subgroups
Baseline
1 Month
2 Months
3 Months
4 Months
5 Months
6 Months
P-1 A-1 P-2 A-2
0.77 ⫾ 0.10 0.79 ⫾ 0.17 0.51 ⫾ 0.15 0.49 ⫾ 0.16
0.66 ⫾ 0.12 0.69 ⫾ 0.17 0.41 ⫾ 0.19 0.39 ⫾ 0.15
0.60 ⫾ 0.11 0.63 ⫾ 0.17 0.40 ⫾ 0.16 0.34 ⫾ 0.17
0.57 ⫾ 0.10 0.62 ⫾ 0.17 0.37 ⫾ 0.16 0.33 ⫾ 0.16
0.53 ⫾ 0.11 0.59 ⫾ 0.17 0.35 ⫾ 0.16 0.32 ⫾ 0.16
0.53 ⫾ 0.10 0.57 ⫾ 0.18 0.37 ⫾ 0.14 0.30 ⫾ 0.16
0.50 ⫾ 0.11 0.56 ⫾ 0.17 0.34 ⫾ 0.15 0.25 ⫾ 0.13
p-values were not significant in the subgroups comparison at each month of follow-up. ETDRS: Early Treatment Diabetic Retinopathy Study; P-1: Patching Group 1; P-2: Patching Group 2; A-1: Atropine Group 1; A-2: Atropine Group 2.
before starting treatment, optical correction alone as a treatment modality should be kept in mind. Speed of visual recovery (mean of time duration taken to attain maximum stable vision in each group) was faster in the patching group than in the atropine group, but the difference in mean visual acuity at the end of 6 months was minimal. Similar observations were made in the PEDIG study,2 with patching group showing more rapid improvement. Kushner17 believed that if treatment success can be attained in less than than 6 months, then this spare an additional three to four visits to a doctor’s office, thus reducing inconvenience, expense, and frustration. The patching group showed significant improvement in near visual acuity over the atropine group at the end of 6 months. Although near vision was not measured until 2 weeks after atropine drops were discontinued, it is still pos-
sible that a residual cycloplegic effect impaired near visual acuity. Contrast sensitivity and stereoacuity also improved from baseline to 6-month follow-up in both the groups, with no significant difference in improvement between the groups and their corresponding subgroups. In a study done by Koskela and Hyvarinen,20 contrast sensitivity at intermediate frequencies was found to be the most sensitive indicator of disturbances in the vision of dominant eye and improvement of the vision in the amblyopic eye. They recommended that contrast sensitivity be measured regularly during the treatment of amblyopia. Stereoacuity in both groups did not reach normal values. No patients in the atropine group had systemic side effects. Only transient local side effects were noticed in both the groups. Compliance rates were also comparable. Most pa-
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FIG 3. Trend in the improvement of visual acuity (ETDRS log units) in patching and atropine groups from baseline to the 6-month follow-up period. (Eb: baseline visual acuity; E1: visual acuity at 1 month; E6: visual acuity at 6 months).
tients and parents appeared to prefer atropine penalization over patching as a modality of treatment for cosmetic and psychological reasons, but this did not achieve statistical significance. The impact of patching and atropine treatment on child and family was similar to that found in PEDIG21 study. Visual acuity improved in all age groups from 8 to 20 years (Figure 2). A superior treatment outcome in anisometropic amblyopes over 15 years of age has also been reported by Sen et al.13 A recent PEDIG trial22 also reported improvement in visual acuity in older children and adolescents aged 10-18 years. In conclusion, we believe that atropine and patching are equally effective in the treatment of anisometropic amblyopia in patients aged 8-20 years. The response to therapy is more rapid in patching patients, and there is a suggestion that near acuity may improve more in patients treated with patching. Literature Search The authors conducted a MEDLINE (PubMed) search for the dates 1966 to 2007 using the following terms: anisometropic amblyopia, atropine penalization, and occlusion therapy. Only articles published in English language were considered. References 1. von Noorden GK. Binocular vision and ocular motility: Theory and Management of Strabismus. 5th ed. St. Louis (MO): Mosby-Year Book Inc; 1996. p. 512-20. 2. Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs. patching for treatment of moderate amblyopia in children. Arch Ophthalmol 2002;120:268-78.
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3. Hiscox F, Strong N, Thompson JR, Minshull C, Woodruff G. Occlusion of amblyopia. A comprehensive survey of outcome. Eye 1992;6:300-304. 4. Olson RJ, Scott WE. A practical approach to occlusion therapy for amblyopia. Semin Ophthalmol 1997;12:161-5. 5. von Noorden GK, Milam JB. Penalization in the treatment of amblyopia. Am J Ophthalmol 1979;88:511-8. 6. Repka MX, Gallin PF, Scholz RT, Guyton DL. Determination of optical penalization by vectografic fixation reversal. Ophthalmology 1985;92:1584-6. 7. Foley-Nolan A, McCann A, O’Keefe M. Atropine penalization vs. occlusion as the primary treatment for amblyopia. Br J Ophthalmol 1997;81:54-7. 8. Wick B, Wingard M, Cotter S, Scheiman M. Anisometropic amblyopia: Is the patient ever too old to treat? Optometry Vision Sci 1992;69:866-78. 9. Vereecken EP, Brabant P. Prognosis for vision in amblyopia after the loss of the good eye. Arch Ophthalmol 1984;102:220-4. 10. Kivlin JO, Flynn JT. Therapy of anisometropic amblyopia. J Pediatr Ophthalmol Strabismus 1981;18:47-56. 11. Mintz-Hittner HA, Fernandez KM. Successful amblyopia therapy initiated after age 7 years: Compliance cures. Arch Ophthalmol 2000;118:1535-41. 12. Oliver M, Neumann R, Chaimovitch Y, Gotesman N, Shimshoni M. Compliance and results of treatment for amblyopia in children more than 8 years old. Am J Ophthalmol 1986;102:340-5. 13. Sen DK. Results of treatment of anisohypermetropic amblyopia without strabismus. Br J Ophthalmol 1982;66:680-4. 14. Cobb CJ, Russell K, Cox A, MacEwen CJ. Factors influencing visual outcome in anisometropic amblyopes. Br J Ophthalmol 2002;86: 1278-81. 15. Arnold RW, Gionet E, Hickel J, Owen M, Armitage MD. Duration and effect of single-dose atropine: Paralysis of accommodation in penalization treatment of functional amblyopia. Binocul Vis Strabismus Q 2004; 19:81-6. 16. Simons K, Gotzler KC, Vitale S. Penalization vs. part-time occlusion and binocular outcome in treatment of strabismic amblyopia. Ophthalmology 1997;104:2156-60. 17. Pediatric Eye Disease Investigator Group. A comparison of atropine and patching treatments for moderate amblyopia by patient age, cause of amblyopia, depth of amblyopia, and other factors. Ophthalmology 2003;110:1632-8. 18. Pediatric Eye Disease Investigator Group. Randomized trial of treatment of amblyopia in children aged 7 to 17 years. Arch Ophthalmol 2005;123:437-47. 19. Chen PL, Chen JT, Tai MC, Fu JJ, Chang CC, Lu DW. Anisometropic amblyopia treated with spectacle correction alone: Possible factors predicting success and time to start patching. Am J Ophthalmol 2007;143:54-60. 20. Koskela PU, Hyvarinen L. Contrast sensitivity in amblyopia. Effect on occlusion. Acta Ophthalmol 1986;64:386-90. 21. Pediatric Eye Disease Investigator Group. Impact of patching and atropine treatment on the child and family in the amblyopia treatment study. Arch Ophthalmol 2003;121:1625-32. 22. Pediatric Eye Disease Investigator Group. A prospective, pilot study of treatment of amblyopia in children 10 to ⬍18 years old. Am J Ophthalmol 2004;137:581-3.