Catherine E. Stewart

Refractive adaptation in amblyopia: quantification of effect and implications for practice

Aim: To describe the visual response to spectacle correction (“refractive adaptation”) for children with unilateral amblyopia as a function of age, type of amblyopia, and category of refractive error. Method: Measurement of corrected amblyopic and fellow eye logMAR visual acuity in newly diagnosed children. Measurements repeated at 6 weekly intervals for a total 18 weeks. Results: Data were collected from 65 children of mean (SD) age 5.1 (1.4) years with previously untreated amblyopia and significant refractive error. Amblyopia was associated with anisometropia in 18 (5.5 (1.4) years), strabismus in 16 (4.2 (0.98) years), and mixed in 31 (5.2 (1.5) years) of the study participants. Mean (SD) corrected visual acuity of amblyopic eyes improved significantly (p<0.001) from 0.67 (0.38) to 0.43 (0.37) logMAR: a mean improvement of 0.24 (0.18), range 0.0–0.6 log units. Change in logMAR visual acuity did not significantly differ as a function of amblyopia type (p = 0.29) (anisometropia 0.22 (0.13); mixed 0.18 (0.14); strabismic 0.30 (0.24)) or for age (p = 0.38) (“under 4 years” 0.23 (0.18); “4–6 years” 0.24 (0.20); “over 6 years” 0.16 (0.23)). Conclusion: Refractive adaptation is a distinct component of amblyopia treatment. To appropriately evaluate mainstream therapies such as occlusion and penalisation, the beneficial effects of refractive adaptation need to be fully differentiated. A consequence for clinical practice is that children may start occlusion with improved visual acuity, possibly enhancing compliance, and in some cases unnecessary patching will be avoided.

Objectively monitored patching regimens for treatment of amblyopia: randomised trial.

Objectives To compare visual outcome in response to two prescribed rates of occlusion (six hours a day and 12 hours a day). Design Unmasked randomised trial. Setting Research clinics in two London hospitals. Participants 97 children with a confirmed diagnosis of amblyopia associated with strabismus, anisometropia, or both. Interventions: 18 week period of wearing glasses (refractive adaptation) followed by occlusion prescribed (“patching”) for six or 12 hours a day. Main outcome measures Visual acuity measured by logMAR letter recognition; objectively monitored rate of occlusion (hours a day). Results The mean age of children at study entry was 5.6 (SD 1.5) years. Ninety were eligible for occlusion but 10 dropped out in this phase, leaving 80 children who were randomised to a prescribed dose rate of six (n=40) or 12 (n=40) hours a day. The mean change in visual acuity of the amblyopic eye was not significantly different (P=0.64) between the two groups (0.26 (95% confidence interval 0.21 to 0.31) log units in six hour group; 0.24 (0.19 to 0.29) log units in 12 hour group). The mean dose rates (hours a day) actually received, however, were also not significantly different (4.2 (3.7 to 4.7) in six hour group v 6.2 (5.1 to 7.3) in 12 hour group; P=0.06). The visual outcome was similar for those children who received three to six hours a day or more than six to 12 hours a day, but significantly better than that in children who received less than three hours a day. Children aged under 4 required significantly less occlusion than older children. Visual outcome was not influenced by type of amblyopia. Conclusions Substantial (six hours a day) and maximal (12 hours a day) prescribed occlusion results in similar visual outcome. On average, the occlusion dose received in the maximal group was only 50% more than in the substantial group and in both groups was much less than that prescribed. Younger children required the least occlusion. Trials registration Clinical Trials NCT00274664.

Defining and measuring treatment outcome in unilateral amblyopia

Aim: To offer a critique of current methods of defining amblyopia treatment outcome and to examine alternative approaches. Method: Literature appraisal and descriptive case presentations. Results: Currently, the outcome of amblyopia treatment is expressed as the number of acuity chart lines gained or, alternatively, achievement of an arbitrarily adopted level of visual acuity. As binocular vision is optimised with equal visual input from each eye the authors propose that the optimum outcome of amblyopia therapy is to achieve a visual acuity in the amblyopic eye equal to that of its fellow. In addition, improvement should be graded as the proportion of change in visual acuity with respect to the absolute potential for improvement (that is, that pertaining in the fellow eye at end of treatment). Conclusions: There are two methods of appropriately describing the outcome of amblyopia treatment: firstly, by the difference in final visual acuity of amblyopic and fellow eye (residual amblyopia); secondly, the proportion of the deficit corrected.

Design of the Monitored Occlusion Treatment of Amblyopia Study (MOTAS)

Background/aims: The effectiveness of occlusion therapy for the treatment of amblyopia is a research priority. The authors describe the design of the Monitored Occlusion Treatment for Amblyopia Study (MOTAS) and its methodology. MOTAS will determine the dose-response relation for occlusion therapy as a function of age and category of amblyopia. Methods: Subjects progress through up to three study phases: (1) Assessment and baseline phase: On confirmation of eligibility, and after parental consent, baseline visual functions are determined, and spectacles prescribed as necessary; (2) Refractive adaptation phase: Subjects wear spectacles full time and return to clinic at 6 weekly intervals until 18 weeks, by which time all improvement due to refractive correction is complete; (3) Occlusion phase: All subjects are prescribed 6 hours of occlusion per day. Daily occlusion is objectively monitored using an occlusion dose monitor (ODM). Outcome variables: visual acuity (logMAR charts), log contrast sensitivity (Pelli-Robson chart), and stereoacuity (Frisby) are assessed at 2 weekly intervals until gains in visual acuity cease to be statistically verifiable. Conclusion: Four methodological issues have been addressed; firstly, baseline stability of visual function; secondly, differentiation of refractive adaptation from occlusion; thirdly, objective measurement of occlusion dose and concordance; fourthly, use of validated outcome measures.

Compliance With Occlusion Therapy for Childhood Amblyopia

PURPOSE Explore compliance with occlusion treatment of amblyopia in the Monitored and Randomized Occlusion Treatment of Amblyopia Studies (MOTAS and ROTAS), using objective monitoring. METHODS Both studies had a three-phase protocol: initial assessment, refractive adaptation, and occlusion. In the occlusion phase, participants were instructed to dose for 6 hours/day (MOTAS) or randomized to 6 or 12 hour/day (ROTAS). Dose was monitored continuously using an occlusion dose monitor (ODM). RESULTS One hundred and fifty-two patients (71 male, 81 female; 122 Caucasian, 30 non-Caucasian) of mean ± SD age 68 ± 18 months participated. Amblyopia was defined as an interocular acuity difference of at least 0.1 logMAR and was associated with anisometropia in 50, strabismus in 44, and both (mixed) in 58. Median duration of occlusion was 99 days (interquartile range 72 days). Mean compliance was 44%, mean proportion of days with no patch worn was 42%. Compliance was lower (39%) on weekends compared with weekdays (46%, P = 0.04), as was the likelihood of dosing at all (52% vs. 60%, P = 0.028). Compliance was lower when attendance was less frequent (P < 0.001) and with prolonged treatment duration (P < 0.001). Age, sex, amblyopia type, and severity were not associated with compliance. Mixture modeling suggested three subpopulations of patch day doses: less than 30 minutes; doses that achieve 30% to 80% compliance; and doses that achieve around 100% compliance. CONCLUSIONS This study shows that compliance with patching treatment averages less than 50% and is influenced by several factors. A greater understanding of these influences should improve treatment outcome. (ClinicalTrials.gov number, NCT00274664).

Amblyopia therapy: an update.

We review the findings of trials of mainstay amblyopia treatment conducted within the last 5 years. These have confirmed that an initial period of full-time refractive correction is beneficial in all types of amblyopia. Adopting this practice may allow up to 30% of children to avoid any further treatment. Studies that have investigated the role of atropine occlusion as a first-line treatment for amblyopia have shown “weekend atropine” to be as effective as patching for children with both moderate and severe amblyopia. Where patching is prescribed, 2−4 hours/day of occlusion appears sufficient to provide an optimum outcome for the majority of children, although those over 6 years tend to require a larger dose to achieve best outcome, their amblyopia being more resistant to treatment. Educational interventions such as cartoons and written and video explanations of treatment aimed at improving compliance appear to raise it to a therapeutic level in those who may otherwise have poor compliance or drop out from treatment. Formal, evidence-based practice guidelines for the management of amblyopia have emerged although their adoption by practitioners, at least in the United Kingdom, has been questioned.

The optical treatment of amblyopia.

The role of refractive correction has been underestimated as a distinct component of amblyopia therapy. Until relatively recently, the extent to which it could ameliorate the amblyopic acuity deficit remained unquantified and the time course of its effect unknown. Improvement of vision after refractive correction appears to occur in all the major types of amblyopia, including, somewhat surprisingly, in the presence of strabismus. Although the neurophysiological basis of the remediative effect of such “optical treatment” is unknown, some insight is now available from animal models and psychophysical investigations in humans. An appreciation of the role that refractive correction can play in the overall management of amblyopia has led to the formulation of new treatment guidelines, whereby a defined period of spectacle or contact lens wear always precedes traditional therapies, such as occlusion or penalization.

Intermediate spatial frequency letter contrast sensitivity: its relation to visual resolution before and during amblyopia treatment.

We examined the loss of letter contrast sensitivity (LCS) measured using the Pelli‐Robson chart, and the extent to which any such loss was modulated by spectacle wear and occlusion therapy in children participating in an amblyopia treatment trial. Their initial mean interocular difference in logMAR acuity was approximately three times that of their LCS (0.45 vs 0.14 log units). Log LCS was weakly though significantly correlated with logMAR visual acuity (VA) for all VAs better than 0.90 (r = −0.19, 95% CI: −0.28 to −0.10) whereas for all VAs of 0.90 or poorer, log LCS was markedly and significantly correlated with VA (r = −0.72, 95% CI: −0.83 to −0.53). LCS in those children with a ≥0.1 log unit interocular difference on this test improved commensurately with VA during treatment. We conjecture that the spatial visual loss in all but the most severe amblyopes occurs in an area of resolution and contrast space that lies beyond that sampled by the Pelli‐Robson chart.

5 Years on

The title of this editorial makes reference to that previously published here in 20061 that introduced a series of amblyopia-related articles based on author presentations to an invited group of participants assembled under the auspices of the London-based Novartis Foundation. Now, in 2011, we are grateful once again to be given the opportunity to introduce a further series of articles arising out of contributions to the 1st City University Symposium* that recently reviewed progress in selected sub-fields of amblyopia research. Casting our eyes over the subject matter and content of those articles published in 2006 and making comparison with those published in this issue allows us to gauge the depth and direction of progress that has occurred over the past 5 years. Two topics common to both the present and 2006 reviews are, not unsurprisingly, the neuroscientific underpinnings of amblyopia arising out of animal studies, and the treatment of children. In the former case, Sengpiel here provides an overview of how experimental models of amblyopia have contributed to our understanding of the human condition focusing specifically on strategies that may prevent or reverse the effects of monocular deprivation. It is our experience that those working with animals often, and not without good reason, avoid extrapolating techniques and findings from the laboratory to human amblyopia specifically with regard to treatment. However, Sengpiel rightfully draws attention to how animal models of monocular deprivation can inform the practice of occlusion therapy with amblyopic children. Where the treatment of human amblyopia is concerned, Stewart, Moseley, and Fielder focus their review on the abundance of clinical treatment trials conducted since 2006 (certainly exceeding the total number ever previously published) that have great potential to advance clinical practice. Progress highlighted includes the now firmly established benefits of refractive correction (optical treatment/ refractive adaptation) as a therapy in its own right for all major subtypes of amblyopia and that atropine penalization appears to produce similar outcomes to the still more widely practiced occlusion therapy for those with moderate or severe amblyopia. Yet these authors observe that while trial outcomes have translated into practice guidelines, practitioner uptake and implementation of such knowledge is not universal. A subtopic not touched upon in the preceding 2006 review of treatment2 was the role of education and family support in improving compliance with occlusion therapy, and given that we now more fully understand the relationship between visual outcomes and prescribed occlusion dose, this would seem an important advance. Although by 2006, the potential of therapies other than mainstream penalization and occlusion had been demonstrated in the (psychophysics) laboratory,3 their implementation into routine clinical practice still appeared some way off. In 2011, Astle, McGraw, and Webb describe promising advances in what they term learning-based interventions among adult amblyopic observers (in whom it is now accepted retain sufficient neural plasticity that it may be manipulated). The effectiveness of this approach now appears to be on the cusp of emerging from the laboratory to await evaluation by randomized, controlled trial. In a similar manner by which traditional views of neural plasticity are being overturned by findings such as those of Astle and colleagues, Hess, Mansouri, and Thompson describe an entirely new treatment modality underpinned by the notion that active suppression lies at the heart of the amblyopic deficit while cellular function remains intact. They further conjecture that contrary to the traditional view, which focuses on treatment of the monocular Strabismus, 19(3), 85–86, 2011

Treatment of Amblyopia Using Personalized Dosing Strategies: Statistical Modelling and Clinical Implementation

ABSTRACT Purpose: To generate a statistical model for personalizing a patient’s occlusion therapy regimen. Methods: Statistical modelling was undertaken on a combined data set of the Monitored Occlusion Treatment of Amblyopia Study (MOTAS) and the Randomized Occlusion Treatment of Amblyopia Study (ROTAS). This exercise permits the calculation of future patients’ total effective dose (TED)—that predicted to achieve their best attainable visual acuity. Daily patching regimens (hours/day) can be calculated from the TED. Results: Occlusion data for 149 study participants with amblyopia (anisometropic in 50, strabismic in 43, and mixed in 56) were analyzed. Median time to best observed visual acuity was 63 days (25% and 75% quartiles; 28 and 91 days). Median visual acuity in the amblyopic eye at start of occlusion was 0.40 logMAR (quartiles 0.22 and 0.68 logMAR) and at end of occlusion was 0.12 (quartiles 0.025 and 0.32 logMAR). Median lower and upper estimates of TED were 120 hours (quartiles 34 and 242 hours), and 176 hours (quartiles 84 and 316 hours). The data suggest a piecewise linear relationship (P = 0.008) between patching dose-rate (hours/day) and TED with a single breakpoint estimated at 2.16 (standard error 0.51) hours/day, suggesting doses below 2.16 hours/day are less effective. Conclusion: We introduce the concept of TED of occlusion. Predictors for TED are visual acuity deficit, amblyopia type, and age at start of occlusion therapy. Dose-rates prescribed within the model range from 2.5 to 12 hours/day and can be revised dynamically throughout treatment in response to recorded patient compliance: a personalized dosing strategy.