1. Effect of Age on Response to Amblyopia Treatment in Children Holmes JM, Lazar EL, Melia BM, et al; Pediatric Eye Disease Investigator Group. Effect of age on response to amblyopia treatment in children [published online July 11, 2011]. Arch Ophthalmol. doi:10.1001/archophthalmol.2011.179. Copyright restrictions may apply

2. Introduction Evidence that amblyopia treatment is effective in some older children raises the longstanding question of whether or not there is a relationship between age and magnitude of amblyopia treatment response. Are older children less responsive to amblyopia treatment? Recently completed amblyopia treatment studies provide an opportunity to perform a meta-analysis to address this question. Copyright restrictions may apply

3. Methods Study Design –Meta-analysis of individual subject data from 4 randomized multicenter clinical trials of treatment for amblyopia with similar inclusion criteria and duration conducted by the Pediatric Eye Disease Investigator Group. Study Participants –996 children from 3 to less than 13 years of age with unilateral amblyopia (amblyopic eye visual acuities ranging from 20/40-20/400) caused by strabismus, anisometropia, or both. Copyright restrictions may apply

4. Methods Data Analysis – A multivariate linear regression analysis evaluated the relationship between age group (3 to <5 years, 5 to <7 years, and 7 to <13 years) and amblyopic eye visual acuity improvement, adjusting for the following: Baseline amblyopic eye visual acuity. Amblyopic eye spherical equivalent. Type of amblyopia. Prior amblyopia treatment and protocol. Copyright restrictions may apply

5. Results Children aged 7 to less than 13 years were less responsive to treatment than younger children for both moderate amblyopia (visual acuity 20/40-20/100) and severe amblyopia (20/125-20/400). Despite a reduced mean treatment response in children 7 to less than 13 years of age, some children show a marked improvement with treatment. There was no difference in treatment response within the age range of 3 to less than 7 years for moderate or severe amblyopia, although there was a suggestion of a steeper decline in response with age for children with severe amblyopia at baseline. Copyright restrictions may apply

6. Results Copyright restrictions may apply Relationship between age and amblyopic eye visual acuity improvement by treatment type in children 3 to less than 13 years of age with moderate amblyopia (A) or severe amblyopia (B).

7. Copyright restrictions may apply Results Forest plots of adjusted mean amblyopic visual acuity improvement by age group for children with moderate amblyopia (A) and children with severe amblyopia (B). The black dots indicate the adjusted mean for each age group for each protocol, and the horizontal lines indicate the 95% confidence interval for each mean.

8. Comment There are at least 2 possible reasons for reduced response to amblyopia treatment in older children (aged 7 to <13 years). –Declining plasticity of the central nervous system. –Poorer compliance with treatment. Despite the reduced treatment response in older children (aged 7 to <13 years), some individual children responded dramatically. –A wide range of individual responsiveness to low-intensity patching has been confirmed by other investigators using occlusion dose monitors. Copyright restrictions may apply

9. Comment The roles of decreased compliance vs decreased plasticity could be studied further using occlusion dose monitors. Decreased plasticity in older children might be addressed using pharmacological adjuvants such as levodopa—currently the focus of an ongoing Pediatric Eye Disease Investigator Group randomized clinical trial. Screening of children for amblyopia should be performed before the age of 7 years owing to a decreased mean response to treatment at older ages. Copyright restrictions may apply

10. Comment Limitations –Small number of protocols with limited overlap in age groups. –Arbitrary use of age categories to describe the nonlinear age effect. –No data beyond 17 to 24 weeks of treatment or on the duration of prior treatment. –Cannot generalize to causes other than anisometropia and/or strabismus. Copyright restrictions may apply

11. Contact Information If you have questions, please contact the corresponding author: –Jonathan M. Holmes, BM, BCh, Jaeb Center for Health Research, 15310 Amberly Dr, Ste 350, Tampa, FL 33647 (pedig@jaeb.org). Funding/Support This study was supported by the National Institutes of Health (grants EY011751 and EY018810) and by Research to Prevent Blindness, New York (Dr Holmes, as Olga Keith Weiss Scholar, and an unrestricted grant to the Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota). Copyright restrictions may apply