Pediatric Eye Disease Investigator Group Amblyopia Treatment Review

In Reply.—Dr Lempert's recent letter describes similar issues to those he has raised in previous letters to the editor. We have responded to these issues in the past and will reiterate our responses. The Amblyopia Treatment Studies (ATS) are a series of randomized, clinical trials designed to answer questions about the optimal management of amblyopia.1–9 The studies are conducted by the Pediatric Eye Disease Investigator Group (PEDIG), a large group of pediatric ophthalmologists and optometrists based in both university and community settings.10,11 Dr Lempert contends that a significant weakness of the ATS is the inclusion of only a small number of subjects from each center and suggests that this reflects a selection bias. In fact, by involving a larger number of participating centers, we are able to achieve a sample size sufficient to make statistically valid observations more rapidly than could be accomplished if only a limited number of centers participated. In addition, including a large number of diverse centers increases generalizability of the results.We agree that a clinical trial can never completely reflect daily practice. The informed-consent process itself probably educates parents of amblyopic children more than the usual instructions provided during routine care, and this may affect treatment compliance. Nevertheless, we deliberately designed the ATS to be conducted in a “real-world” environment as much as possible, with the exception of randomization of treatment assignment and a standardized protocol for assessing visual acuity.Dr Lempert contends that an additional weakness of the ATS was the lack of an untreated control group. When we designed our early studies, PEDIG investigators concluded that they could not maintain clinical equipoise (a balance between potential benefit and potential harm between treatment groups) in trials that required maintaining the child in an assigned untreated group for 4 to 6 months. However, in our analysis of these early studies, we did not find a significantly different treatment effect in older children, compared with younger children, within our 3- to 7-year age range. These new data have allowed us to design a short-duration study incorporating an untreated control group. We are currently conducting that randomized trial, comparing visual acuity improvement over 5 weeks between an untreated group and a group assigned to 2 hours of daily patching.Dr Lempert suggests that the observed improvement in visual acuity could occur because of maturation or a learning effect. In our completed ATS, the average improvement of amblyopic eye acuity ranged from 2.4 to 4.8 lines6,9 over 4 to 6 months. This improvement far exceeded that expected from a learning effect. It is important to note that the visual acuity improvement in amblyopic eyes also far exceeded the improvement seen in the fellow sound eyes over the same time period.Dr Lempert raises the possibility that organic causes may explain many cases of amblyopia observed in clinical studies. Although we cannot exclude rare cases of organic visual loss within our studies, we note that many of the amblyopic eyes in our studies improved to within the normal range. Thus, the presence of an abnormality of the optic nerve does not negate the importance of successful amblyopia treatment. Additional longer-term studies are needed to define whether these eyes become truly normal and, if so, whether they remain normal. We are currently conducting examinations on patients who were enrolled in our study of atropine versus patching and have reached the age of 10 years. We also plan to reexamine these patients at 15 years old.Dr Lempert suggests that we include biometry and disk imaging in future ATS. Using such technology would limit the number of centers that could participate in the studies and also exclude from participation a large number of the younger children who can provide recognition acuity and therefore participate in a randomized treatment trial but who would be unable to cooperate for biometric studies or fundus photography. Such morphologic studies are warranted but do not fit into our study design of large simple trials.Finally, Dr Lempert suggests that we have accepted “occlusion as the unquestioned mainstay of treatment for unilateral poor vision.” This is not true. However, in the past, we noted that patching is the mainstay of amblyopia therapy in North America. PEDIG studies have already investigated use of a pharmacologic agent, topical atropine, in the treatment of amblyopia.3 Thus far, we have concluded that both atropine and patching are appropriate for initial treatment of moderate amblyopia. Future randomized, clinical trials are needed to investigate additional modalities of amblyopia treatment in current use, including optical penalization, blurring filters, and systemic drugs.

National survey of amblyopia treatment in Japan: comparison with amblyopia treatment study results of the pediatric eye disease investigator group.

Amblyopia comes from the Greek word meaning dull sight or blunt sight. Amblyopia occurs to abnormal visual experience early in life. It can be both unilateral (U/L) and/or bilateral (B/L). Amblyopia itself produces no change in the appearance of ocular structures, but it nearly always develops in association with some other condition that is evident on physical examination, and which is responsible for abnormal visual experience. It is one of the most common causes of visual impairment in childhood. Unless it is successfully treated in early childhood, amblyopia usually persists into adulthood. In 1997, the pediatric eye disease investigator group (PEDIG) was formed to conduct clinical research in eye disorders affecting children. The studies were conducted through simple protocols with limited data collection and implemented by both university and community based pediatric eye care practitioners as part of their routine practice in USA. Hence PEDIG has laid emphasis on studies of treatment modalities of amblyopia, the Amblyopia Treatment Studies (ATS). The recent general guidelines for occlusion therapy are based on ongoing ATS. New concepts of management on amblyopia are practiced now- a-days based on ATS. This article is an update on amblyopia and its management. Nepal Journal of Medical Sciences | Volume 02 | Number 01 | Jan-Jun 2013 | Page 66-72 DOI: http://dx.doi.org/10.3126/njms.v2i1.7656

Amblyopia Treatment

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. 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 … 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

This Issue At A Glance

Clinical Translation of Recommendations from Randomized Clinical Trials on Patching Regimen for Amblyopia

Atropine Regimens for Amblyopia: Author reply

The Pediatric Eye Disease Investigator Group (PEDIG) is a network of university-based and community-based pediatric eye care practitioners that is conducting multiple clinical research studies. The group has conducted the Congenital Esotropia Observational Study, which assessed the early course of esotropia in infants, and the Amblyopia Treatment Studies, a series of randomized trials, the first of which compared atropine and patching for treatment of moderate amblyopia in children 3 to <7 years old. Herein, the results of these studies are summarized, and the current and future studies of the group are described.

13. RepkaMX,Wallace DK, Beck RW, et al; Pediatric Eye Disease Investigator Group. Two-year follow-up of a 6-month randomized trial of atropine vs patching for treatment of moderate amblyopia in children. Arch Ophthalmol. 2005;123(2):149-157. 14. RepkaMX, Kraker RT, Beck RW, et al; Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for treatment of moderate amblyopia: follow-up at age 10 years. Arch Ophthalmol. 2008;126(8):1039-1044.

Author reply

To determine whether there has been a change in treatment practice patterns of patients with amblyopia between the late 1990s and 2004. A questionnaire survey was mailed to 1,200 AAPOS members listed in the 2004 AAPOS directory. Seven scenarios were presented that described patients with amblyopia and the clinician was asked to choose from six treatment options. Respondents were asked to indicate their preferred initial treatment in 1998 (or during their initial year of practice if later than 1998) and in 2004. The scenarios were not necessarily those of patients who would meet the eligibility criteria for the Amblyopia Treatment Studies because they also included scenarios to assess the impact of amblyopia treatments in general. Three hundred eighty-nine surveys (33.1%) were returned. In four of the seven scenarios, comments suggested that a change in practice was attributable to recent publications of Pediatric Eye Disease Investigator Group trials. In all seven scenarios, atropine would have been offered in 2004 as an alternative to patching in 1998, and in five of the seven scenarios the combination of simultaneous atropine and patching would have been prescribed. In six of the seven scenarios, some type of nonspecific near work would now be prescribed as an adjunct treatment. A change in practice patterns was observed for some, but not all, scenarios. In many scenarios, this change was directly attributed to the recent Pediatric Eye Disease Investigator Group trials.

Amblyopia?

To analyze the top 100 most cited papers related to amblyopia. A bibliographic search in the Institute for Scientific Information Web of Knowledge across 55years was performed. Eighty-nine of the 100 papers were published in first-quartile journals. Half (50) of the senior authors were from the USA. Most papers dealt with clinical science (72) and included original research (84). Forty-two of the articles related to all three types of amblyopia (refractive, strabismic and deprivation). Thirty-four related to both strabismic and refractive amblyopia. Around two-thirds of the papers dealt with treatment (34) and pathophysiology (30). Almost a quarter (23%) of the papers were multicenter studies. Nearly half (48) of the papers were published between 2000 and 2010. The Pediatric Eye Disease Investigator Group (PEDIG) published the highest number of studies (11), which dealt more with treatment (p = 0.01) and had higher average number of citations per years (p = 0.05). A larger number of articles on the treatment of amblyopia are newer (p = 0.01). There was no correlation between the time of their publication and the number of citations (p = 0.68, r = 0.042). Half of the papers were published between 2000 and 2010 and were spearheaded by PEDIG. Most papers dealt with treatment and pathophysiology. This study provides an important historical perspective, emphasizing the need for additional research to better understand this preventable and curable childhood vision impairment.

Retrospective studies without control groups are sometimes useful for suggesting treatment effects and generating hypotheses, but they suffer from bias and confounding. In response to the need for better evidence for treatment, the Pediatric Eye Disease Investigator Group (PEDIG) has conducted several randomized amblyopia treatment trials over the past several years. Results have shown that spectacles alone are a powerful treatment for amblyopia; patching is superior to spectacles alone; initiating fewer hours of prescribed patching seems to be as effective as traditional treatment; patching is effective in older children, particularly if they have not previously been treated; atropine is as effective as patching after six months; and weekend atropine is equally effective as daily atropine. All studies have limitations, but randomized clinical trials limit bias and confounding and thus provide the highest level of evidence of treatment effect.