A recent Pediatric Eye Disease Investigator Group article demonstrates that treatment of amblyopia with weekend atropine provides the same level of improvement as daily atropine.1Pediatric Eye Disease Investigator GroupA randomized trial of atropine regimens for treatment of moderate amblyopia in children.Ophthalmology. 2004; 111: 2076-2085Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar It was previously shown that atropine occlusion is equivalent to patching2Pediatric Eye Disease Investigator GroupA randomized trial of atropine vs. patching for treatment of moderate amblyopia in children.Arch Ophthalmol. 2002; 120: 268-278Crossref PubMed Scopus (427) Google Scholar and that 6 hours of patching is equivalent to 2 hours of daily patching.3Repka M.K. Beck R.W. Holmes J.M. et al.Pediatric Eye Disease Investigator GroupA randomized trial of patching regimens for treatment of moderate amblyopia in children.Arch Ophthalmol. 2003; 121: 603-611Crossref PubMed Scopus (340) Google Scholar It remains necessary to certify that the treatment protocols are more effective than a placebo. Although the authors “did not believe that [they] feasibly could include an untreated control group,”1Pediatric Eye Disease Investigator GroupA randomized trial of atropine regimens for treatment of moderate amblyopia in children.Ophthalmology. 2004; 111: 2076-2085Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar it would have been possible, for example, to add in a group treated only with a short-acting cycloplegic. “Clinical research must be designed and conducted with rigorous methodology to generate reliable and valid data. A placebo control must be required to optimize the chance of achieving a valid test or treatment efficacy.”4Miller F.G. Emanuel E.J. Rosenstein D.L. Straus S.E. Ethical issues concerning research in complementary and alternative medicine.JAMA. 2004; 291: 599-604Crossref PubMed Scopus (95) Google Scholar This concept was recently reaffirmed in the ophthalmic literature.5Beck R.W. Reporting the results of randomized clinical trials a priority of Archives of Ophthalmology.Arch Ophthalmol. 2004; 122: 1038-1039Crossref PubMed Scopus (1) Google Scholar Amblyopia studies should not be exempted from these basic requirements. It would be helpful for future studies of amblyopia treatment to comply with accepted standards of clinical research. Atropine Regimens for Amblyopia: Author replyOphthalmologyVol. 112Issue 8PreviewWe disagree with Dr Lempert’s comment with regard to our methodology. The randomized trials conducted by the Pediatric Eye Disease Investigator Group follow well-accepted clinical trial methodology. In a randomized clinical trial, a control group may be assigned standard care rather than a placebo. In this specific amblyopia treatment trial, the daily atropine group was the control group, which was compared with the weekend-only atropine group. Before initiation of a Pediatric Eye Disease Investigator Group study, every protocol is reviewed and approved by an independent National Eye Institute-appointed panel of experts that includes statisticians and clinical trialists. Full-Text PDF

BACKGROUND:To plan a future randomized clinical trial, we conducted a pilot study to determine whether children randomized to near or non-near activities would perform prescribed activities. A secondary aim was to obtain a preliminary estimate of the effect of near versus non-near activities on amblyopic eye visual acuity, when combined with 2 hours of daily patching.METHODS:Sixty-four children, 3 to less than 7 years of age, with anisometropic, strabismic, or combined amblyopia (20/40 to 20/400) were randomly assigned to receive either 2 hours of daily patching with near activities or 2 hours of daily patching without near activities. Parents completed daily calendars for 4 weeks recording the activities performed while patched and received a weekly telephone call in which they were asked to describe the activities performed during the previous 2 hours of patching. Visual acuity was assessed at 4 weeks.RESULTS:The children assigned to near visual activities performed more near activities than those assigned to non-near activities (by calendars, mean 1.6 +/- 0.5 hours versus 0.2 +/- 0.2 hours daily, P < 0.001; by telephone interviews, 1.6 +/- 0.4 hours versus 0.4 +/- 0.5 hours daily, P < 0.001). After 4 weeks of treatment, there was a suggestion of greater improvement in amblyopic eye visual acuity in those assigned to near visual activities (mean 2.6 lines versus 1.6 lines, P = 0.07). The treatment group difference in visual acuity was present for patients with severe amblyopia but not moderate amblyopia.CONCLUSIONS:Children patched and instructed to perform near activities for amblyopia spent more time performing those near activities than children who were instructed to perform non-near activities. Our results suggest that performing near activities while patched may be beneficial in treating amblyopia. Based on our data, a formal randomized amblyopia treatment trial of patching with and without near activities is both feasible and desirable.

We disagree with Dr Lempert’s comment with regard to our methodology. The randomized trials conducted by the Pediatric Eye Disease Investigator Group follow well-accepted clinical trial methodology. In a randomized clinical trial, a control group may be assigned standard care rather than a placebo. In this specific amblyopia treatment trial, the daily atropine group was the control group, which was compared with the weekend-only atropine group. Before initiation of a Pediatric Eye Disease Investigator Group study, every protocol is reviewed and approved by an independent National Eye Institute-appointed panel of experts that includes statisticians and clinical trialists. In addition, Dr Lempert inaccurately cites the Archives of Ophthalmology editorial written by one of us (RWB).1Beck R.W. Reporting the results of randomized clinical trials a priority of Archives of Ophthalmology.Arch Ophthalmol. 2004; 122: 1038-1039Crossref PubMed Scopus (1) Google Scholar The importance of randomization in clinical trials is emphasized, but the editorial does not address the issue of placebo controls and when they are needed. Atropine Regimens for AmblyopiaOphthalmologyVol. 112Issue 8PreviewA recent Pediatric Eye Disease Investigator Group article demonstrates that treatment of amblyopia with weekend atropine provides the same level of improvement as daily atropine.1 It was previously shown that atropine occlusion is equivalent to patching2 and that 6 hours of patching is equivalent to 2 hours of daily patching.3 Full-Text PDF

OBJECTIVE:To compare patching and atropine sulfate as treatments for moderate amblyopia in children 18 months after completion of a 6-month randomized trial.METHODS:In a randomized, multicenter (47 sites) clinical trial, 419 children younger than 7 years with amblyopia (20/40 to 20/100 in the affected eye) were assigned to receive either patching or atropine eye drops for 6 months. Between 6 months and 2 years, treatment was at the discretion of the investigator. Main Outcome Measure Visual acuity in the amblyopic eye and sound eye after 2 years.RESULTS:At 2 years, visual acuity in the amblyopic eye improved from baseline a mean of 3.7 lines in the patching group and 3.6 lines in the atropine group. The difference in visual acuity between treatment groups was small: 0.01 logMAR (95% confidence interval, -0.02 to 0.04). In both treatment groups, the mean amblyopic eye acuity was approximately 20/32, 1.8 lines worse than the mean sound eye acuity, which was approximately 20/20.CONCLUSIONS:Atropine or patching for 6 months followed by best clinical care until 2 years produced similar improvement of moderate amblyopia in children between 3 and 7 years of age at enrollment. However, on average the amblyopic eye acuity was still approximately 2 lines worse than the sound eye.

OBJECTIVE To evaluate the effectiveness of treatment of amblyopia in children aged 7 to 17 years. METHODS At 49 clinical sites, 507 patients with amblyopic eye visual acuity ranging from 20/40 to 20/400 were provided with optimal optical correction and then randomized to a treatment group (2-6 hours per day of prescribed patching combined with near visual activities for all patients plus atropine sulfate for children aged 7 to 12 years) or an optical correction group (optical correction alone). Patients whose amblyopic eye acuity improved 10 or more letters (> or =2 lines) by 24 weeks were considered responders. RESULTS In the 7- to 12-year-olds (n = 404), 53% of the treatment group were responders compared with 25% of the optical correction group (P<.001). In the 13- to 17-year-olds (n = 103), the responder rates were 25% and 23%, respectively, overall (adjusted P = .22) but 47% and 20%, respectively, among patients not previously treated with patching and/or atropine for amblyopia (adjusted P = .03). Most patients, including responders, were left with a residual visual acuity deficit. CONCLUSIONS Amblyopia improves with optical correction alone in about one fourth of patients aged 7 to 17 years, although most patients who are initially treated with optical correction alone will require additional treatment for amblyopia. For patients aged 7 to 12 years, prescribing 2 to 6 hours per day of patching with near visual activities and atropine can improve visual acuity even if the amblyopia has been previously treated. For patients 13 to 17 years, prescribing patching 2 to 6 hours per day with near visual activities may improve visual acuity when amblyopia has not been previously treated but appears to be of little benefit if amblyopia was previously treated with patching. We do not yet know whether visual acuity improvement will be sustained once treatment is discontinued; therefore, conclusions regarding the long-term benefit of treatment and the development of treatment recommendations for amblyopia in children 7 years and older await the results of a follow-up study we are conducting on the patients who responded to treatment.

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Clinical trials have served as the foundation of much of the knowledge we have gained in the last 50 years with regard to the efficacy of treatments of various medical conditions. In very few conditions is the natural history of the disease so well defined, and the outcome of intervention so evident, that the benefits and adverse effects of a treatment can be determined without a prospective, controlled trial. Sometimes trial results confirm clinical impressions, and sometimes they do not. Drs von Noorden and Campos indicate that in their experience full-time patching produces better results than part-time patching in treating severe amblyopia. However, they provide no data to support this conclusion, and we are not aware of a prospective study that supports this claim. They indicate that, for most clinicians, full-time patching has been the standard of care for severe amblyopia. Nevertheless, whether to prescribe full-time or part-time patching for severe amblyopia is a controversy recently reported in the literature1Tan J.H Thompson J.R Gottlob I Differences in management of amblyopia between European countries.Br J Ophthalmol. 2003; 87: 291-296Crossref PubMed Scopus (25) Google Scholar and confirmed by a survey of our investigator group in 1998. Drs von Noorden and Campos state that “children who wear their patch only part of the prescribed time do not respond as well to treatment,” citing studies that report the response to patching, as a function of compliance, and measured by an occlusion dose monitor.2Loudon S.E Polling J.R Simonsz H.J A preliminary report about the relation between visual acuity increase and compliance in patching therapy for amblyopia.Strabismus. 2002; 10: 79-82Crossref PubMed Scopus (49) Google Scholar, 3Loudon S.E Polling J.R Simonsz H.J Electronically measured compliance with occlusion therapy for amblyopia is related to visual acuity increase.Graefes Arch Clin Exp Ophthalmol. 2003; 241: 176-180Crossref PubMed Scopus (71) Google Scholar In these studies, 14 children were prescribed a wide range of part-time occlusion regimens (from 15 minutes a day to 3 complete days per week) for a wide range of amblyopia severity (0.78 [20/25]–0.03 [20/667]). We question whether these data are useful in addressing the issue of part-time versus full time patching in severe amblyopia. In addition, any analysis of clinical trial data limited to compliant patients has considerable potential for bias and production of erroneous conclusions, particularly in a condition such as amblyopia, in which the response to treatment may influence subsequent compliance. There are examples in the literature of erroneous conclusions drawn from selected compliant populations.4Chene G Morlat P Leport C et al.Intention-to-treat vs. on-treatment analyses of clinical trial data experience from a study of pyrimethamine in the primary prophylaxis of toxoplasmosis in HIV-infected patients.Control Clin Trials. 1998; 19: 233-248Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 5The Coronary Drug Project Research GroupInfluence of adherence to treatment and response of cholesterol on mortality in the Coronary Drug Project.N Engl J Med. 1980; 303: 1038-1041Crossref PubMed Scopus (663) Google Scholar Drs von Noorden and Campos contend that a treatment group difference might have become apparent with longer follow up. In designing the trial, the 4-month follow-up period represented the maximum length of time we believed that the fixed treatment regimens (6 hours/day or full-time patching) could be prescribed before a change in the treatment might be necessary for patients who had not responded well to the randomized treatment assignment. It is conceivable that treating for longer might show greater benefit with full-time than part-time patching, although there is no suggestion of even a trend in our data favoring a delayed benefit for full-time patching comparing our results at 5 weeks with our results at 4 months. As noted by Drs von Noorden and Campos, we state that our study compared prescribed patching regimens and not the actual number of hours of occlusion that were achieved. We commented in the “Discussion” that it is possible that the results reflect, at least in part, suboptimal compliance in the full-time patching group. However, we designed this trial to assess the effectiveness of the prescribed patching regimens rather than their efficacy. Efficacy refers to whether a treatment has benefit under highly controlled conditions, whereas effectiveness refers to whether a treatment has benefit as used in the real world. A greater number of hours of actual patching could have greater efficacy than fewer hours, but if this intensity of patching can only be achieved in a minority of cases, it would not be a very effective treatment. Our compliance data suggest that most patients are not able to achieve full-time patching, so although it is of scientific interest as to whether full-time occlusion can produce a better outcome than part-time occlusion, this may have limited clinical utility. We have not yet studied the potential benefit of full-time patching in patients who have had an incomplete response to part-time patching, but our data suggest it is entirely reasonable to prescribe an initial course of part-time occlusion for severe amblyopia. In response to Dr Greenberg's comments, the inclusion of multiple community-based sites, rather than limiting a trial to tertiary referral centers, has the advantage of enhancing generalizability of the results. The type of patient enrolled in this study, with severe anisometropic or strabismic amblyopia and no patching during the preceding 6 months, was seen much more commonly at our community-based sites than at our institution-based sites. Including multiple community-based centers in the trial design is not unorthodox, but is a priority for future clinical trials funded by the National Institutes of Health, according to its director.6Re-engineering the clinical research enterprise. Available at: http://www.nihroadmap.nih.gov/clinicalresearch/index.asp. Accessed January 13, 2004Google Scholar As a rule, it is highly inaccurate to extrapolate from an individual's recollection of his or her own practice to the number of patients that can be recruited for a randomized clinical trial with strict inclusion criteria such as severe anisometropic or strabismic amblyopia and no patching during the preceding 6 months. Clinical trialists often use 50% or even 10% of the number cited by individual investigators before a study when considering feasibility of recruitment. As noted above, a substantial proportion of pediatric eye care providers prescribed part-time patching for severe amblyopia before the initiation of our study. Many eye care providers request that the child perform some activities at near requiring visual attention for some of the time the patch is worn. Because, as noted by Dr Greenberg, it is not known whether performing near activities influences the response to occlusion therapy, this was included in the protocol in both groups to standardize that aspect of the treatment regimens. We will be conducting a future trial to determine whether near activities are beneficial during patching. Dr Greenberg provides a single case report to refute our findings. Of interest, in the occlusion dose monitor studies cited earlier,2Loudon S.E Polling J.R Simonsz H.J A preliminary report about the relation between visual acuity increase and compliance in patching therapy for amblyopia.Strabismus. 2002; 10: 79-82Crossref PubMed Scopus (49) Google Scholar, 3Loudon S.E Polling J.R Simonsz H.J Electronically measured compliance with occlusion therapy for amblyopia is related to visual acuity increase.Graefes Arch Clin Exp Ophthalmol. 2003; 241: 176-180Crossref PubMed Scopus (71) Google Scholar there was one patient with severe strabismic amblyopia and an initial visual acuity (VA) of 20/200 who improved to 20/25 with only 1 hour of patching per day. We do not believe that a conclusion should be drawn from the latter case, that little patching improves severe amblyopia, any more than a conclusion should be drawn from Dr Greenberg's case that full-time patching is needed to treat successfully every case of severe amblyopia. Disparate results in case reports and case series point to the critical importance of prospective, randomized trials for providing meaningful, clinically relevant information for establishing treatment guidelines. Randomization reduces the potential selection bias to which Dr Greenberg refers. Complete masking of all outcome measurements is rarely obtainable in clinical trials, and >90% masking would be considered excellent. In our study, the VA outcome was measured using a highly automated, computerized, VA testing protocol, where there was little opportunity for even a biased nonmasked tester to influence the results.7Holmes J.M Beck R.W Repka M.X et al.The Amblyopia Treatment Study visual acuity testing protocol.Arch Ophthalmol. 2001; 119: 1345-1353Crossref PubMed Scopus (257) Google Scholar, 8Moke P.S Turpin A.H Beck R.W et al.Computerized method of visual acuity testing; adaptation of the Amblyopia Treatment Study visual acuity testing protocol.Am J Ophthalmol. 2001; 132: 903-909Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar We believe that our trial of 175 patients provides the best evidence available to date on the response of severe amblyopia to different prescribed patching regimens. We contend that our study was conducted with a high degree of rigor and that the validity of the results are comparable to that of any other trial funded by the National Eye Institute, including the 2 trials Dr Greenberg mentions. Perhaps Dr Greenberg will be reassured in knowing that an independent data and safety monitoring committee (Drs Barlow, Buckley, Davis, Dobson, Keltner, Osman, Palmer, and Phelps—see article for listing of full names and affiliations) appointed by the National Eye Institute approved the protocol before its initiation, monitored the data during the conduct of the trial, reviewed the results at the end of the trial, and approved the manuscript before its submission to Ophthalmology. The Pediatric Eye Disease Investigator Group, which conducted this trial, remains open to new investigators. We would welcome the involvement of Dr Greenberg and others with busy pediatric eye care practices. For information on becoming an investigator in the Pediatric Eye Disease Investigator Group, please contact the Pediatric Eye Disease Investigator Group Coordinating Center at [email protected].

BACKGROUND:Although amblyopia can be successfully treated with patching or atropine, there have been few prospective studies of amblyopia recurrence once treatment is discontinued.METHODS:We enrolled 156 children with successfully treated anisometropic or strabismic amblyopia (145 completed follow-up), who were younger than 8 years of age and who received continuous amblyopia treatment for the previous 3 months (prescribed at least 2 hours of daily patching or prescribed at least one drop of atropine per week) and who had improved at least 3 logMAR levels during the period of continuous treatment. Patients were followed off treatment for 52 weeks to assess recurrence of amblyopia, defined as a 2 or more logMAR level reduction of visual acuity from enrollment, confirmed by a second examination. Recurrence was also considered to have occurred if treatment was restarted because of a nonreplicated 2 or more logMAR level reduction of visual acuity.RESULTS:Recurrence occurred in 35 (24%) of 145 cases (95% confidence interval 17% to 32%) and was similar in patients who stopped patching (25%) and in patients who stopped atropine (21%). In patients treated with moderately intense patching (6 to 8 hours per day), recurrence was more common (11 of 26; 42%) when treatment was not reduced prior to cessation than when treatment was reduced to 2 hours per day prior to cessation (3 of 22; 14%, odds ratio 4.4, 95% confidence interval 1.0 to 18.7).CONCLUSIONS:Approximately one fourth of successfully treated amblyopic children experience a recurrence within the first year off treatment. For patients treated with 6 or more hours of daily patching, our data suggest that the risk of recurrence is greater when patching is stopped abruptly rather than when it is reduced to 2 hours per day prior to cessation. A randomized clinical trial of no weaning versus weaning in successfully-treated amblyopia is warranted to confirm these observational findings.

PURPOSE: To assess the test-retest reliability of the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity algorithm using the computerized Electronic Visual Acuity (EVA) tester in children 7 to < 13 years old.DESIGN: Test-retest reliability study.METHODS: This multicenter study involved 245 subjects at four clinical sites. As the main outcome measure, visual acuity was measured twice using the E-ETDRS testing protocol on the EVA system, which uses a programmed handheld device to communicate with a personal computer and a 17,inch monitor at a 3-m test distance.RESULTS: Test-retest reliability was high (r = .94 for right eyes and 0.96 for left eyes) and for both right and left eyes, 89% of retest scores were within 0.1 logarithm of the minimal angle of resolution (logMAR) (five let, ters) of the initial test score and 99% of retests were within 0.2 logMAR (10 letters). Reliability was high across the age range of 7 to <13 years. Based on 95% confidence level estimates, a change in visual acuity of 0.2 logMAR (10 letters) from a previous acuity measure is unlikely to result from measurement variability.CONCLUSIONS: The E-ETDRS protocol using the EVA has high test-retest reliability in children 7 to < 13 years of age. Potential advantages include better standardization across multiple sites, the ability to directly capture data electronically with an automatic acuity score calculation, the reduction of potential bias by limiting the tester's role, and the requirement of only a single testing distance for measurements from 20/800 to 20/12. This computerized testing method should be considered when visual acuity is used as an outcome measure in eye research involving children 7 to < 13 years old. (C) 2003 by Elsevier Inc. All rights reserved.

Objective: To describe the demographic and clinical characteristics of a cohort of children with moderate amblyopia participating in the Amblyopia Treatment Study 1, a randomized trial comparing atropine and patching.Methods: The children enrolled were younger than 7 years and had strabismic, anisometropic, or combined strabismic and anisometropic amblyopia. Visual acuity, measured with a standardized testing protocol using single-surround HOTV optotypes, was 20/40 to 20/100 in the amblyopic eye, with an intereye acuity difference of 3 or more logMAR lines. There were 419 children enrolled, 409 of whom met these criteria and were included in the analyses.Results: The mean age of the 409 children was 5.3 years. The cause of the amblyopia was strabismus in 38%, anisometropia in 37%, and both strabismus and anisometropia in 24%. The mean visual acuity of the amblyopic eyes (approximately 20/60) was similar among the strabismic, anisometropic, and combined groups (P = .24), but visual acuity of the sound eyes was worse in the strabismic group compared with the anisometropic group (P < .001). For the patients randomized into the patching group, 43% were initially treated for 6 hours per day, whereas 17% underwent full-time patching. Patients with poorer visual acuity in the amblyopic eye were prescribed more hours of patching than patients with better acuity (P = .003).Conclusions: In the Amblyopia Treatment Study 1, there were nearly equal proportions of patients with strabismic and anisometropic amblyopia. A similar level of visual impairment was found irrespective of the cause of amblyopia. There was considerable variation in treatment practices with regard to the number of hours of initial patching prescribed.

The four prism diopter base-out (4 delta BO) test is often recommended for use as an objective assessment of binocular visual function in patients with suspected microstrabismus or central suppression; however, many aspects of the test are unknown. In this series of investigations we evaluated: (1) inter-observer agreement between 2 examiners, using 15 subjects; (2) types of eye movements made and prevalence of the various response types demonstrated in 212 children and 116 adults with normal binocular vision, and 10 children and 4 adults with abnormal binocular vision; and (3) repeatability of test results for 22 subjects evaluated on two separate occasions. In addition, using an SRI Eye-tracker, we documented the eye movements made while testing 2 subjects with small angle strabismus and 4 subjects with normal binocular vision. We found the following results: (1) inter-observer agreement is high; (2) both children and adults exhibit many atypical responses, whether or not they have normal binocular vision; (3) diplopia awareness does not differentiate between subjects with normal and abnormal binocular vision; and (4) 4 delta BO test results are not repeatable. Due to frequent atypical and variable responses in subjects with or without normal binocular vision, we suggest the examiner use caution when making a diagnosis based solely on the 4 delta BO test.