COMMENTARY |
Recent Advances in the Treatment of Amblyopia
Children’s Hospital of Philadelphia
University of Pennsylvania School of Medicine
Philadelphia, PA 19104
Jaeb Center for Health Research
Tampa, FL 33647
Department of Ophthalmology
Mayo Clinic College of Medicine
Rochester MN 55905
Wilmer Institute
Johns Hopkins University School of Medicine
Baltimore, MD 21287
Abbreviations: PEDIG, Pediatric Eye Disease Investigator Group • logMAR, logarithm of the minimal angle of resolution
In 1997, the Pediatric Eye Disease Investigator Group (PEDIG) was formed to conduct clinical research in eye disorders that affect children.1,2 The primary focus of PEDIG involves studies that can be conducted through simple protocols with limited data collection and implemented by both university-based and community-based pediatric eye care practitioners as part of their routine practice. As of October 1, 2003, 135 investigators at 97 sites in North America have participated in at least 1 PEDIG study.
A major focus of PEDIG has been the evaluation of different treatment modalities for amblyopia (the Amblyopia Treatment Study). Amblyopia was selected for study because it is the most common cause of monocular visual impairment in children and young and middle-aged adults,3,4 and opinions vary on the appropriate treatment regimens. Three randomized trials have been completed thus far, and 3 trials and 2 observational studies are currently in progress.
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ATROPINE VERSUS PATCHING FOR MODERATE AMBLYOPIA |
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 TOP ATROPINE VERSUS PATCHING FOR... TWO VERSUS SIX HOURS...SIX HOURS VERSUS FULL-TIME...ONGOING AND FUTURE PROTOCOLSCONCLUSIONSREFERENCES |
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The first PEDIG amblyopia trial compared patching of the sound eye versus instillation of atropine drops in the sound eye as treatments for moderate amblyopia (20/40 to 20/100) in children 3 to 7 years old.5–9 Amblyopia was due to unequal refractive error, strabismus, or both. Atropine blurs the vision in the sound eye through its cycloplegic effect that can last, at least partially, for up to 14 days. The group of children randomized to atropine treatment received 1 drop of 1% atropine in the sound eye daily; if by 4 months acuity had not reached 20/30 or improved from baseline by
3 lines, then any far-sighted correction in the spectacle lens of the sound eye was removed to augment the effect of the atropine. The patching group was initially prescribed daily patching for a minimum of 6 hours up to all waking hours at investigator discretion; if by 4 months acuity had not reached 20/30 or improved from baseline by 3 lines, then full-time patching was required if not prescribed already. Visual acuity was measured in this protocol, as well as in other protocols involving children in this age group, by using a standardized testing procedure that we developed for testing visual acuity of preschool children.10 The acuity test, which has been computerized,11 presents single letters (H, O, T, and V) with surrounding crowding bars using a testing algorithm that has been developed to produce a reliable measure of acuity in young children and at the same time minimizing testing time. We currently use this method of visual-acuity testing in all our study protocols involving children in this age range.
Between April 1999 and April 2001, 419 patients were enrolled at 47 clinical sites. The average age of the patients was 5.3 years. The mean visual acuity in the amblyopic eye at enrollment was 
20/63, with a mean difference in acuity between eyes of 4.4 lines. The cause of the amblyopia was strabismus in 38% patients, anisometropia (difference in refractive error between eyes) in 37%, and both strabismus and anisometropia in 24%.
The primary outcome examination at 6 months was completed by 96% of the 419 patients. Visual acuity in the amblyopic eye improved substantially from baseline in both groups (mean improvement of 3.16 lines in the patching group and 2.84 lines in the atropine group). Improvement initially was faster in the patching group (particularly if full-time patching was prescribed initially), but after 6 months, the difference in acuity between treatment groups was small and clinically inconsequential (mean difference at 6 months: 0.034 logMAR * [approximately one-third of a line]). At 6 months, 79% of the patching group and 74% of the atropine group had acuity in the amblyopic eye that was 20/30 or better and/or had improved from baseline by 3 lines.
For all 3 causes of amblyopia (strabismus, anisometropia, and combined mechanism), as well as in subgroups based on patient age and baseline acuity in the amblyopic eye, the effect of each treatment seemed consistent with the effect in the overall group. Both treatments were well tolerated, although atropine had a statistically significant higher degree of acceptability based on a parental questionnaire. More patients in the atropine group than in the patching group had reduced acuity in the sound eye at 6 months, although this finding did not persist with additional follow-up.
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TWO VERSUS SIX HOURS DAILY PATCHING FOR MODERATE AMBLYOPIA |
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TOPATROPINE VERSUS PATCHING FOR...TWO VERSUS SIX HOURS...SIX HOURS VERSUS FULL-TIME...ONGOING AND FUTURE PROTOCOLSCONCLUSIONSREFERENCES |
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This protocol compared 2 vs 6 hours of daily patching of the sound eye as treatments for moderate amblyopia (20/40 to 20/80) in children 3 to 7 years old.13 The study was conducted to resolve the debate as to whether a minimal amount of prescribed daily patching might be a sufficient treatment for amblyopia. Between May 2001 and May 2002, 189 patients were enrolled at 35 sites. The average age of the patients was 5.2 years. The mean visual acuity in the amblyopic eye at enrollment was
20/63, with a mean difference in acuity between eyes of 4.1 lines. The cause of the amblyopia was strabismus in 40% patients, anisometropia in 33%, and both strabismus and anisometropia in 27%.
The primary outcome examination at 4 months was completed by 96% of the 189 patients. Visual acuity in the amblyopic eye improved substantially from baseline to 4 months in both groups (mean improvement of 2.4 lines in each group). At 4 months, there was no difference in amblyopic eye acuity between groups (mean difference at 4 months: 0.001 logMAR [<1 letter]), and 62% of patients in each group had acuity in the amblyopic eye that was 20/30 or better and/or had improved from baseline by 3 lines. For all 3 causes of amblyopia (strabismus, anisometropia, and combined mechanism), as well as in subgroups based on patient age and baseline acuity in the amblyopic eye, the effect of each treatment seemed consistent with the effect in the overall group. This study was not designed to determine the maximum effect of amblyopia treatment, and for many of these patients treatment was continued. Nevertheless, these data suggest that prescribing a greater number of hours of patching does not seem to have a significant beneficial effect during the first 4 months of treatment. In addition, based on an examination at 5 weeks, there did not seem to be a benefit to the greater number of hours of prescribed patching on the rate of improvement.
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SIX HOURS VERSUS FULL-TIME DAILY PATCHING FOR SEVERE AMBLYOPIA |
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TOPATROPINE VERSUS PATCHING FOR...TWO VERSUS SIX HOURS...SIX HOURS VERSUS FULL-TIME...ONGOING AND FUTURE PROTOCOLSCONCLUSIONSREFERENCES |
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This protocol, which was conducted in parallel with the patching protocol for moderate amblyopia, compared 6 hours versus full-time (all or all but 1 waking hour) prescribed daily patching of the sound eye as treatments for severe amblyopia (20/100 to 20/400) in children 3 to 7 years old.14 As with the moderate amblyopia protocol, this study was conducted to determine whether greater intensity of patching had merit in the treatment of amblyopia. Between May 2001 and March 2003, 175 patients were enrolled at 32 sites. The average age of the patients was 4.8 years. The mean visual acuity in the amblyopic eye at enrollment was
20/160, with a mean difference in acuity between eyes of 7.8 lines. The cause of the amblyopia was strabismus in 27% patients, anisometropia in 34%, and both strabismus and anisometropia in 38%.
The primary outcome examination at 4 months was completed by 90% of the 175 patients. Visual acuity in the amblyopic eye improved substantially from baseline to 4 months in both groups (mean improvement of 4.8 lines in the 6-hour group and 4.7 lines in the full-time group). At 4 months, there was no difference in amblyopic eye acuity between groups (mean difference at 4 months: 0.03 logMAR [1 letter]); 86% of patients in the 6-hour group and 82% of patients in the full-time group had acuity in the amblyopic eye that had improved from baseline by 3 lines from baseline. For all 3 causes of amblyopia (strabismus, anisometropia, and combined mechanism), as well as in subgroups based on patient age and baseline acuity in the amblyopic eye, the effect of each treatment seemed consistent with the effect in the overall group. Based on an examination at 5 weeks, there did not seem to be a benefit to the greater number of hours of prescribed patching on the rate of improvement.
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ONGOING AND FUTURE PROTOCOLS |
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TOPATROPINE VERSUS PATCHING FOR...TWO VERSUS SIX HOURS...SIX HOURS VERSUS FULL-TIME...ONGOING AND FUTURE PROTOCOLSCONCLUSIONSREFERENCES |
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Ongoing Amblyopia Treatment Study protocols include 3 randomized trials and 2 observational studies. The randomized trials include a comparison of 1) daily versus weekend-only atropine for moderate amblyopia (20/40 to 20/80) in children 3 to <7 years old, 2) patching with or without atropine versus a control group (spectacle correction only) in children 7 to 17 years old, and 3) 2 hours of patching a day versus a control group (spectacle correction only) for moderate amblyopia in children 3 to <7 years old. The trial of amblyopia treatment for 7- to 17-year-olds was preceded by a pilot observational study that demonstrated that visual-acuity improvement was possible with treatment of amblyopia in this age group.15 For use in the randomized trial in older children (trial 2 above), we developed and validated a computerized letter visual-acuity test.16,17
In addition to the randomized trials, 2 observational studies are underway, one to determine the recurrence rate of amblyopia when treatment is discontinued in children 3 to <8 years old and another to evaluate the resolution rate of anisometropic amblyopia using spectacle correction alone in 3- to <7-year-olds. We also are conducting a long-term follow-up study of the children enrolled in the atropine-patching study to assess vision at 10 years of age. A randomized trial is being planned to assess whether performing eye-hand coordination activities during patching of the sound eye enhances the effect of occlusion therapy.
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CONCLUSIONS |
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Thus far, we conclude from our studies that both atropine and patching are effective treatments for moderate amblyopia in children in the age range of 3 to <7 years old and that the initial choice of treatment regimen can be made by the eye care provider and the parents. When patching is prescribed, 2 hours of daily patching is as effective for moderate amblyopia as prescribing 6 hours of daily patching. For severe amblyopia, prescribing 6 hours of daily patching is just as effective in improving visual acuity as prescribing more intensive patching regimes. It must be kept in mind that these results refer to the intensity of patching that was prescribed and not to the actual amount of patching that occurred. Additional work, however, is needed to determine whether these regimens can attain maximum improvement in visual acuity that is sustained when treatment is discontinued.
ON BEHALF OF THE PEDIATRIC EYE DISEASE INVESTIGATOR GROUP
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ACKNOWLEDGMENTS |
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This work was supported by the National Eye Institute Cooperative Agreement EY11751.
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FOOTNOTES |
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Received for publication Dec 8, 2003; Accepted Dec 22, 2003.
Address correspondence to Graham E. Quinn, MD, MSCE, Division of Pediatric Ophthalmology, Children’s Hospital of Philadelphia, One Children’s Center, Philadelphia, PA 19104. E-mail: quinn{at}email.chop.edu
* logMAR refers to the logarithm of the minimal angle of resolution, a method of measuring letter or symbol visual acuity in which each smaller line is 0.1 logMAR unit smaller than the line before. For example, 20/20 = 0.0 logMAR, 20/25 = 0.1 logMAR, etc.12 
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REFERENCES |
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- National Eye Institute Office of Biometry and Epidemiology. Report on the National Eye Institute’s Visual Acuity Impairment Survey Pilot Study. Washington, DC: Department of Health and Human Services; 1984
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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G. E. Quinn, R. W. Beck, M. X. Repka, J. M. Holmes, and on Behalf of Pediatric Eye Disease Investigator Gr The Pediatric Eye Disease Investigator Group Report May Be Too Optimistic About Efficacy of Treatment: In Reply Pediatrics, November 1, 2004; 114(5): 1366 - 1367. [Full Text] [PDF]
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