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Stability of Visual Acuity Improvement Following Discontinuation of Amblyopia Treatment in Children Aged 7 to 12 Years
Pediatric Eye Disease Investigator Group*
Arch Ophthalmol. 2007;125(5):655-659.
ABSTRACT
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Objective To assess the stability of visual acuity improvement during the first year after cessation of amblyopia treatment other than spectacle wear in children aged 7 to 12 years.
Methods At the completion of a multicenter randomized trial during which amblyopia treated with patching and atropine improved by at least 2 lines on the electronic Early Treatment of Diabetic Retinopathy Study testing protocol, 80 patients aged 7 to 12 years were followed up while not receiving treatment (other than spectacle wear) for 1 year.
Main Outcome Measure Ten letters or more ( 2 lines) worsening of visual acuity (measured using the electronic Early Treatment of Diabetic Retinopathy Study testing protocol) during the year following treatment discontinuation.
Results During the year following cessation of treatment, the cumulative probability of worsening visual acuity (2 lines) was 7% (95% confidence interval, 3%-17%); 82% of patients maintained an increase in visual acuity of 10 letters or more compared with their visual acuity before starting treatment.
Conclusion Visual acuity improvement occurring during amblyopia treatment is sustained in most children aged 7 to 12 years for at least 1 year after discontinuing treatment other than spectacle wear.
Trial Registration clinicaltrials.gov Identifier: NCT00094692
INTRODUCTION
Although amblyopia can be improved with different therapies, including patching1-3 and topical atropine,1, 4 there are few prospective studies on the course of visual acuity after such treatment has been discontinued. The literature consists of retrospective studies5-8 with small sample sizes, variable lengths of follow-up, and/or heterogeneous patient populations, as well as a prospective study9 of younger children. These studies have reported widely varying estimates of regression risk following treatment discontinuation of 6%,5 9%,10 24%,9 27%,8 33%,11 60%,7 and 67%.6
We conducted a randomized trial of 507 patients aged 7 to 17 years, 67% of whom had moderate amblyopia (20/40 to 20/80), and 33% of whom had severe amblyopia (20/100 to 20/400) and measured visual acuity using the electronic Early Treatment Diabetic Retinopathy Study (ETDRS) testing protocol. We previously reported that, among 404 children aged 7 to 12 years, treatment with spectacle wear plus patching and atropine produced greater improvement than spectacle correction alone (53% vs 25% improved 2 lines, P<.001 by Fisher exact test).12 Among 103 patients aged 13 to 17 years, we reported overall that treatment with spectacle wear plus patching was no better than spectacle wear alone (25% vs 23% improved 2 lines, P =.47 by Fisher exact test), although a subgroup analysis suggested a possible treatment effect in patients whose amblyopia had not been previously treated (47% vs 20% improved 2 lines).12 Most patients whose visual acuity improved while receiving treatment in both age groups were left with a residual visual acuity deficit. Patients whose visual acuity improved 2 lines or more during treatment with spectacle wear, patching, and atropine continued treatment until their visual acuity stopped improving. At that time, all treatment except spectacle wear was discontinued, and patients were followed up for 1 year to determine whether visual acuity improvement was sustained. Hereinafter, we report results from the year following treatment discontinuation. The present analysis was limited to patients aged 7 to 12 years at treatment initiation because a treatment effect had been seen in subjects aged 13 to 17 years only when analyzed using secondary outcome measures (eg, maximum visual acuity improvement) or in some subgroups (eg, previously untreated patients) and because only a few patients in the group aged 13 to 17 years continued follow-up after treatment discontinuation.
METHODS
PARTICIPANTS
The study, supported through a cooperative agreement with the National Eye Institute of the National Institutes of Health, was conducted by the Pediatric Eye Disease Investigator Group at 49 clinical sites. The protocol and informed consent forms were approved by institutional review boards. The parent or guardian of each study patient gave written informed consent, and each patient gave assent to participate. The details and results of the randomized trial have been published in a separate article12 and are only partially described herein.
The major eligibility criteria for the randomized trial included age 7 to 17 years (as noted earlier, only the group aged 7 to 12 years is included in this analysis), amblyopia due to strabismus and/or anisometropia, no amblyopia treatment other than spectacles in the prior month and no more than 1 month of amblyopia treatment in the prior 6 months, best-corrected amblyopic eye visual acuity between 20/40 and 20/400 inclusive, best-corrected sound eye visual acuity of 20/25 or better, and no ocular cause for reduced visual acuity.
Patients were randomly assigned to a control group that received optical correction only (if needed) or to a treatment group that received optical correction (if needed) plus additional treatment consisting of patching and atropine in patients aged 7 to 12 years and patching alone in patients aged 13 to 17 years. Patching treatment consisted of 2 to 6 hours of daily patching of the sound eye with 1 hour of near visual activities to be performed during patching; atropine treatment consisted of daily atropine application in the sound eye. Treatment was continued until there was no further improvement at 2 consecutive 6-week follow-up visits. At the time of patching and atropine treatment discontinuation, patients in the treatment group whose amblyopic eye had improved 10 letters or more entered a 1-year observation phase after discontinuing all treatment except spectacle wear.
During the observation phase, follow-up visits were performed at 3 months, 6 months, and 1 year. At each visit, distance visual acuity was measured in each eye without cycloplegia and with appropriate refractive correction using the electronic Early Treatment Diabetic Retinopathy Study testing protocol.13 If amblyopic eye visual acuity had decreased 10 letters or more since the time of treatment discontinuation, the testing was repeated. If a refractive correction had not been performed within the prior 6 months, it was completed before retesting visual acuity.
During the 1-year observation phase, no treatment was to be prescribed unless amblyopic eye visual acuity had worsened 10 letters or more (as already described), in which case restarting treatment was at investigator discretion. One patient restarted treatment at the 13-week visit in the absence of a documented visual acuity loss and did not return for subsequent follow-up visits; for the analysis, this patient was not considered to have worsened 10 letters or more and was censored at 13 weeks.
STATISTICAL ANALYSIS
The primary study outcome was a worsening of amblyopic eye visual acuity by 10 letters or more. We chose a 10-letter (2-line) decrease as the criterion for worsening of visual acuity based on data that demonstrated that a change of 10 letters or more is unlikely to result from measurement variability.13 The 1-year cumulative probability of visual acuity worsening of 10 letters or more and a 95% confidence interval were computed using the Kaplan-Meier product-limit method.
Frequency distributions and descriptive statistics for assessing change in visual acuity over time were calculated for the patients who completed the study, defined as completing 1 year of follow-up or experiencing a decrease in visual acuity of 10 letters or more. For any patient who experienced a worsening of 10 letters or more at a visit before 1 year, that visual acuity (before the reinstitution of treatment) was carried forward as the 1-year visual acuity.
Data from the patients who completed the study were used to estimate the probability of worsening 10 letters or more among those who did not complete the study. Based on the amount of visual acuity change since treatment cessation that was present at the last completed visit for each patient not completing the study, a corresponding risk was assigned equal to the risk among patients completing the study who had a similar amount of change in visual acuity at the same time point. For patients with no follow-up visits, a risk was assigned equal to the risk among patients who had completed the study and who had similar baseline visual acuity.
RESULTS
BASELINE CHARACTERISTICS
At the time of enrollment in the randomized trial, the mean ± SD age of 80 patients was 9.3 ± 1.5 years (age range, 7.1-12.9 years), the mean ± SD visual acuity was 0.58 ± 0.24 logarithm of the minimum angle of resolution (approximately 20/80), and 57 patients (71%) had visual acuity between 20/40 and 20/80 inclusive. The mean ± SD visual acuity improvement from the start of treatment to the time of treatment discontinuation was 17 ± 8 letters (3.4 ± 1.6 lines), ranging from 10 to 58 letters (2.0-11.6 lines). At the time of treatment discontinuation, 36 patients (45%) had visual acuity in the amblyopic eye of 20/25 or better, 27 patients (34%) had 20/32 to 20/40, 11 patients (14%) had 20/50 to 20/80, and 6 patients (8%) had 20/100 or worse. Additional characteristics of the cohort are given in Table 1.
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Table 1. Baseline Demographic and Clinical Characteristic*
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VISIT COMPLETION
Sixty-seven patients (84%) completed the study, defined as completing 1 year of follow-up or experiencing a decrease in visual acuity of 10 letters or more during the follow-up period. The 3-month visit was completed by 69 patients (86%) and the 6-month visit by 71 patients (89%).
CHANGE IN AMBLYOPIC EYE VISUAL ACUITY DURING THE FOLLOW-UP PERIOD
For 67 patients completing the study, the mean ± SD change in amblyopic eye visual acuity since treatment discontinuation was 0.0 ± 4.1 letters at 3 months, –1.0 ± 3.9 letters at 6 months, and –1.3 ± 5.1 letters at 1 year. One-year visual acuity was within 4 letters (<1 line) of the visual acuity at the time of treatment discontinuation for 46 patients (69%) (Table 2 and Figure, A). Two patients (3%) had an increase in visual acuity of 10 letters or more, and 6 patients (9%) had an increase of 5 to 9 letters. Five patients (7%) had a visual acuity decrease of 10 letters or more (eTable), and 8 patients (12%) had a decrease of 5 to 9 letters. The cumulative probability of a worsening of 10 letters or more during the 1-year follow-up period was 7% (95% confidence interval, 3%-17%) overall, 4% among 47 patients aged 7 to 9 years, and 15% among 20 patients aged 10 to 12 years at the time of entry into the randomized trial (Table 2).
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Table 2. Change in Visual Acuity While Receiving Treatment and After Treatment Discontinuation According to Age Group*
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Figure. The plots include 67 patients who completed the observation phase, defined as completing 1 year of follow-up or experiencing a decrease in visual acuity of 10 letters or more during the follow-up period. For the one patient who experienced a decrease in visual acuity of 10 letters or more prior to the 1-year visit, the 1-year acuity is the acuity at the time of the decrease. A letter score of 85 corresponds to 20/20, with 5 letters representing 1 line. Lower letter scores indicate worse visual acuity. A, Visual acuity at treatment discontinuation vs visual acuity at 1 year after treatment discontinuation. B, Visual acuity before treatment vs visual acuity at 1 year after treatment discontinuation.
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eTable. Brief Data Listing for Patients Experiencing 10 Letters or More Worsening During 1 Year Following Treatment Discontinuation*
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Among 61 patients who improved 10 to 19 letters while receiving treatment, the following 4 patients (cumulative probability, 8%) experienced a decrease of 10 letters or more after discontinuation of treatment: a 7.8-year-old patient whose visual acuity decreased from 20/25 to 20/50 at 6 months, a 7.8-year-old patient whose visual acuity decreased from 20/25 to 20/40 at 1 year, an 11.2-year-old patient whose visual acuity decreased from 20/20 to 20/40 at 1 year, and an 11.3-year-old patient whose visual acuity decreased from 20/40 to 20/63 at 1 year (eTable). Among 19 patients who improved 20 letters or more while receiving treatment, 1 patient (cumulative probability, 6%) experienced a decrease of 10 letters or more after discontinuation of treatment; the visual acuity of this 12.9-year-old patient decreased from 20/40 to 20/63 at the 1-year visit. The online table (eTable) gives the baseline characteristics of 5 patients who experienced a worsening of 10 letters or more and the course of their visual acuity after stopping treatment.
In most patients (82%), the 1-year amblyopic eye visual acuity remained 10 letters or more better than the pretreatment visual acuity, and no patient had a 1-year visual acuity that was worse than the pretreatment visual acuity (Figure, B). The mean ± SD 1-year visual acuity was 16 ± 9 letters (3.2 ± 1.8 lines) better than the pretreatment visual acuity, with a 1-year improvement in visual acuity of 30 letters or more in 3 patients (4%), 20 to 29 letters in 16 patients (24%), 10 to 19 letters in 36 patients (54%), 5 to 9 letters in 9 patients (13%), and 0 to 4 letters in 3 patients (4%). Comparing the 1-year visual acuity with the improvement in visual acuity gained while receiving treatment, the percentage of visual acuity improvement retained for each patient ranged from 13% to 100%, with a median of 91%. Twenty-nine patients (43%) maintained 100% of their visual acuity improvement.
CHARACTERISTICS OF PATIENTS NOT COMPLETING THE STUDY
Among 13 patients not completing the study, 5 had no protocol follow-up visits, 3 dropped out after the 3-month visit, and 5 dropped out after the 6-month visit. The mean age of the patients not completing the study was 9.6 years, compared with 9.2 years for the patients who completed the study; 69% of the patients not completing the study were female, compared with 37% of the patients who completed the study. The mean amblyopic eye visual acuity at the time of treatment discontinuation was 8 letters (1.6 lines) worse in the patients who did not complete the study than in the patients who completed the study (P =.03).
Three patients who dropped out following the 3-month visit had changes in visual acuity from the time of treatment discontinuation to the 3-month visit of –5, –4, and –2 letters, and 5 patients who dropped out following the 6-month visit had changes in visual acuity from the time of treatment discontinuation to the 6-month visit of –9, –5, –5, –4, and 3 letters. Using the data of the patients who completed the study to impute the 1-year risk of worsening 10 letters or more for the patients who did not complete the study provided an estimate that 7% of 13 noncompleters would have had a worsening of 10 letters or more in visual acuity if follow-up had been complete.
COMMENT
In this prospective study of 80 children aged 7 to 12 years with amblyopia, visual acuity improvement of 10 letters or more (2 lines) that occurred with patching and atropine treatment was generally sustained during 1 year of observation after treatment other than refractive correction was discontinued. The 1-year probability of a worsening in visual acuity of 10 letters or more (2 lines) was 7%. This low risk cannot be compared with the risk reported in previous studies5-11 because those studies involved children of different ages or were retrospective investigations with heterogeneous patient populations, small sample sizes, high dropout rates, variable lengths of follow-up, and unspecified or varying criteria for successful treatment and for significant loss of visual acuity after discontinuation of treatment.
A possible explanation for the notably low incidence of visual acuity worsening after treatment discontinuation relates to the role of spectacle correction in our study. Concurrent with the initiation of patching and atropine treatments at the time of enrollment in the randomized trial, 51% of patients were prescribed spectacles, and an additional 34% required a prescription change in their spectacles. We assume that in many of these patients a portion of the improvement that occurred while receiving treatment was due to spectacle wear and not solely due to the effect of patching and atropine. In the randomized trial, control group patients aged 7 to 12 years received spectacle correction alone, and their visual acuity improved a mean of 7 letters.12 At the time of discontinuation of patching and atropine treatment, spectacle wear was continued. Because improvement as a result of spectacle wear would not be expected to be lost when spectacle wear was continued, some patients might not have been capable of losing 10 letters or more in visual acuity when patching and atropine was discontinued. If this was an explanation for the low incidence of worsening, we might expect to have found that worsening by 10 letters or more occurred in the study principally in patients who had improved by substantially more than 10 letters while receiving treatment, but this was not found to be the case, as the risk of worsening 10 letters or more was 8% among patients who improved by 10 to 19 letters while receiving treatment and 6% among those who improved by 20 letters or more.
Although we had planned to assess whether the risk of visual acuity worsening after discontinuation of treatment was related to factors such as age at treatment initiation, pretreatment visual acuity, and amount of improvement while receiving treatment, the few patients who experienced a worsening of 10 letters or more (5 of 80 patients) precluded such analyses. Given this small number of observed events, the statistical power would be low for detecting associations if they truly existed.
The study completion percentage of 84% is somewhat lower than we had predicted but is not unexpected given that we anticipated more retention issues with the older population (7-12 years) in the present study than with the younger populations (<7 years) in other amblyopia studies by our Pediatric Eye Disease Investigator Group. However, using the follow-up visual acuity data of the patients who completed the study to estimate the 1-year visual acuity of those who did not complete the study suggests that the losses to follow-up did not appreciably bias the results.
In conclusion, we determined that the risk of substantial worsening in visual acuity (10 letters) is low after cessation of amblyopia treatment other than spectacle wear in children aged 7 to 12 years. Our data are encouraging and demonstrate that, when older children continue to wear their refractive correction after cessation of patching and atropine treatment, visual acuity improvement is generally sustained. These data are important because the results address one of the major arguments against the treatment of amblyopia in older children, namely, that effective treatment of amblyopia in older children would be of little value if the improvement in visual acuity could not be sustained once treatment has been discontinued. Data from this study combined with our previously published results12 support the treatment of amblyopia in children aged 7 to 12 years.
AUTHOR INFORMATION
Correspondence: Richard W. Hertle, MD, Jaeb Center for Health Research, 15310 Amberly Dr, Suite 350, Tampa, FL 33647 (pedig{at}jaeb.org).
Submitted for Publication: June 14, 2006; final revision received September 29, 2006; accepted November 17, 2006.
Financial Disclosure: None reported.
Funding/Support: This study was supported by cooperative agreement EY11751 from the National Eye Institute.
Additional Information: The online-only eTable is available.
*Writing Committee: The following members of the Pediatric Eye Disease Investigator Group take authorship responsibility for this study: Lead authors: Richard W. Hertle, MD; Mitchell M. Scheiman, OD; Roy W. Beck, MD, PhD; and Danielle L. Chandler, MSPH. Additional writing committee members (alphabetically): Darron A. Bacal, MD; Eileen Birch, PhD; Raymond H. Chu, OD; Jonathan M. Holmes, BM, BCh; Deborah L. Klimek, MD; Katherine A. Lee, MD, PhD; Michael X. Repka, MD; and David R. Weakley, Jr, MD.
Group Information: A list of the Pediatric Eye Disease Investigator Group members was published in Archives of Ophthalmology. 2005;123:445.
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SECTION EDITOR: ROY W. BECK, MD, PhD
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