Financial Disclosures. Amblyopia: What the Studies Show. Acknowledgements. Development of PEDIG. PEDIG Protocols. Amblyopia Treatment Dogma Pre-ATS

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1 Amblyopia: What the Studies Show Zachary S. McCarty, OD Financial Disclosures Acknowledgements Development of PEDIG PEDIG is a network dedicated to conducting multi-center studies in strabismus, amblyopia, and other eye disorders that affect children. Formed in 1997, the network is funded by the National Eye Institute. There are currently over 100 participating institutional or community based sites with over 200 pediatric ophthalmologists and pediatric optometrists PEDIG Protocols Completed Current Strabismus 2 2 Amblyopia 19 2 Nasolacrimal Duct Obstruction 3 0 Hyperopia/Myopia 1 1 Convergence Insufficiency 1 1 Registries 0 1 PEDIG - ATS Methods Amblyopia Treatment Dogma Pre-ATS Mainstay of treatment = occlusion Rx spectacles and occlusion simultaneously Randomized trials and prospective observational studies Masked outcomes Patch full-time, especially if severe amblyopia Never patch less than 4 hours is better than atropine penalization Atropine only for moderate amblyopia Amblyopia cannot be treated beyond 6-9 years Rx near activities when patched

2 Amblyopia Definitions Refractive Correction Guidelines Based on 1% cyclopentolate refraction Moderate amblyopia = 20/40-20/80 Severe amblyopia = 20/100 or worse Full anisometropia, astigmatism, and myopia Hyperopia Fully correct (primarily for ET) Under-correct symmetrically* *no more than 1.50 DS for most PEDIG* studies Study Objectives ATS-5 Spectacle correction for anisometropic amblyopia To determine in previously untreated anisometropic amblyopic patients: the incidence of resolution of amblyopia with spectacle correction alone the time course of visual acuity improvement with spectacle correction alone Amount of Anisometropia (sph eq) N= to <1.00D 9% 1.00 to <2.00D 14% 2.00 to <3.00D 16% 3.00 to <4.00D 3 >4.00D 32% Mean (SD) : 3.21 (1.46) Amblyopic Eye Refractive Error (sph eq) N= D to <Plano 5% Plano to <+1.00 D 1% 1.00 to <+2.00 D 5% to <+3.00 D 4% to <+4.00 D 11% D *3 patients meeting cylinder criteria only are excluded Mean (SD): (2.07)

3 Time to Best-Measured Acuity, n(%) N=84 Baseline 9 (11%) 5 weeks 33 (39%) 10 weeks 28 (33%) 15 weeks 6 (7%) 20 weeks 6 (7%) >25 weeks 2 (2%) }91% in ~4 months Lines Improvement from Baseline to Best-Measured Acuity Overall (N=84): Mean lines 65 (77%) improved > 2 lines 50 (6) improved > 3 lines Baseline amblyopic eye acuity: 20/40 to 20/100 (N=66) 2.9 lines 20/125 to 20/250 (N=18) 2.8 lines ATS5 Resolution of Amblyopia (IOD 1 line) Acuity level n (%) Overall 23 (27%) 20/40-20/ (33%) 20/125-20/250 1 (6%) Conclusions Refractive correction with spectacles alone improves visual acuity in many cases and results in resolution in at least 1/3 of 3-<7 year old children with previously untreated anisometropic amblyopia Mean improvement is about 3 logmar lines Most cases of resolution occur with moderate amblyopia ATS5 ATS5 Conclusions The average 3-line improvement in visual acuity may lessen the burden of subsequent amblyopia therapy for amblyopic children, particularly for those with denser levels of amblyopia Potential Advantages of Amblyopia Treatment with Spectacles Alone Some children will not need occlusion If occlusion needed: Better visual acuity when start Possibly better compliance One new treatment at a time ATS5 ATS5

4 ATS-13: Objective ATS-13 Spectacle correction for strabismic and combinedmechanism amblyopia To evaluate the effectiveness of refractive correction alone for the treatment of previously untreated strabismic or combined-mechanism amblyopia in children 3 to <7 years old Change in Visual Acuity Between Baseline & 18 Weeks: Overall Change in Visual Acuity Between Baseline & 18 Weeks Amblyopic eye VA improved a mean of 2.6 lines (95% CI = 2.3 to 3.0 lines) of children improved 2 lines 54% of children improved 3 lines Resolution of amblyopia in 32% (95% CI= 24% to 41%) Mean Change in Amblyopic VA (logmar lines) Lines Combined 3.2 Lines Strabismus % Improve 2 lines 69% 88% % Resolve* 28% 4 Adjusted P = from an ANCOVA *Amblyopic eye visual acuity within 1 line of fellow eye acuity Summary Change in Visual Acuity from Baseline to 18 weeks: Amblyopic eye VA improved in both causal groups, including strabismic-only subjects who remained heterotropic Most improvement seen by 18 weeks Treatment effect was greater for strabismic than combinedmechanism amblyopia Factors Associated with Improvement in VA: Strabismus group: worse baseline VA and better baseline stereoacuity associated with more improvement Combined group: better baseline stereoacuity associated with more improvement CP, 6 YO CYCLO RET: CT: ORTHO Case Example (Aniso) - Spectacle wear only OD: DS OS: X180 DATE VA OD VA OS 10/2013 sc 20/20 sc 20/50 5/2013 cc 20/20 cc 20/20 1/2014 cc 20/20 cc 20/20

5 LF, 5 YO CYCLO RET: CT: ORTHO Case Example (Aniso) - Spectacle wear only OD: X180 OS: X180 DATE VA OD VA OS Case Example (Combined) - Spectacle wear only WW, 4 YO CYCLO RET: CT: SC 35 RET CC ORTHO OD: X180 OS: DS DATE VA OD VA OS TREATMENT 6/2013 sc 20/150 sc 20/50 8/2013 sc 20/50 sc 20/25 12/2013 cc 20/25 cc 20/20 7/2013 not weaing specs FT cc 20/150 cc 20/80 11/2013 cc 20/60 cc 20/40 2/2014 cc 20/40 cc 20/30 Start patching 2 hours per day Cont. patching 2 hours per day ATS: Randomized Clinical Trials vs Atropine? How much? Treatment 1 Patients Randomized Treatment 2 Completed Outcome Exam Completed RCT s: Amblyopia Treatment Studies 3 to <7 years STUDY PRESCRIBED TREATMENTS ATS-1 ATS-2B ATS-2A ATS-4 6 hrs patching vs daily atropine 2 hrs patching vs 6 hrs patching* 6 hrs patching vs full-time patching Daily atropine vs weekend atropine DEPTH OF AMBLYOPIA Moderate Moderate Severe Moderate *1 hr of near activity while patched for both groups MEAN LINES INCREASE VA MEAN VA POST-TX 20/30 20/ /32 20/ /50 20/ / /32-2 Arch Ophthalmol 2002;120: & 2003;121:503-11; Ophthalmology 2003;110: & 2004;111: ATS-1 6 hours daily patching vs daily atropine

6 Objectives To compare patching and atropine as treatments for moderate amblyopia in children 3 to <7 years old ATS 1 - Amblyopic Eye Acuity at 6 Months PATCHING (N = 208) ATROPINE (N = 194) To develop estimates of the success rates of treatment To identify factors that may be associated with successful treatment Mean improvement from baseline Mean acuity at 6 months (Snellen approximation) 3.16 lines 2.84 lines 20/30 20/30-2 ATS1 ATS1 >20/30 or >3 line improvement from baseline 79% 74% Amblyopic Eye Visual Acuity Cumulative Distribution Amblyopic Eye at 6 Months ATS1 N=208 6-month Amblyopic Eye Visual Acuity Atropine N=194 >20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160 Amblyopic Eye Mean Acuity at Each Visit 20/20 20/25 20/30 20/40 20/50 20/60 20/80 20/60-20/40 20/50 + Atropine 20/30-20/30 20/ / wks 5 wks 16 wks 6 mos ATS1 34 ATS-2B 2 hour daily vs 6 hour daily patching Amblyopic Eye Acuity at 4 Months 2 Hours N=92 6 Hours N=89 Mean improvement from baseline 2.4 lines 2.4 lines Mean acuity at 4 months (Snellen approximation) 20/ /32-2 >20/32 or >3 line improvement from baseline 62% 62% ATS2B

7 Amblyopic Eye at 4 Months 2-Hours N=92 Amblyopic Eye Visual Acuity Cumulative Distribution 6-Hours N=89 ATS-2A 6 hour daily patching vs fulltime daily patching >20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160 ATS2B 4-month Amblyopic Eye Visual Acuity Amblyopic Eye Acuity at 4 Months Amblyopic Eye at 4 Months 6-Hours N=73 6 Hours N=73 Full-time N=84 Mean improvement from baseline 4.8 lines 4.7 lines Mean acuity at 4 months (Snellen approximation) 20/50 20/50-2 Amblyopic Eye Visual Acuity Cumulative Distribution Full-time N=84 >20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160 >20/200 ATS2A ATS2A 4-month Amblyopic Eye Visual Acuity Dosage vs atropine 6 hrs of patching is faster than daily atropine Choice for child/family Prescribed 2 vs 6 hrs; 6 hrs vs full-time On average the same; one not better than the other Lesser amount prescribed = greater compliance? prescribed done RCT of Occlusion Dose Monitors 52 8 yr-olds with strabismic or combined amblyopia Optimal spectacles and randomized to: No patching Rx 3 hrs of patching Rx 6 hrs of patching 12 wk outcome: compliance Mean patching time: Rx 3 hrs = 1.75 hrs *PEDIG. Arch Ophthalmol ; Rx 6 hrs = 2.5 hrs Awan et al. Invest Ophthalmol Vis Sci 2005

8 Treatment for 3 to <7 yrs Consider glasses only first Moderate amblyopia - start with 2 hrs/day Severe amblyopia - start with 6 hrs/day* If inadequate response: increase patching intensity (ATS 15) OR prescribe atropine *ATS-6: 2 hrs for some with severe amblyopia = effective TS, 5 YO CYCLO RET: RX D: CT: ORTHO Case Example - Moderate Amblyopia OD: X180 OS: X180 OD: X180 OS: X180 DATE VA OD VA OS TREATMENT 5/2013 sc 20/20 sc 20/80 Specs Only 9/2013 cc 20/25 cc 20/50 1/2014 cc 20/25 cc 20/25 Start 2 hrs per day Cont 2 hrs per day WE, 5 YO CYCLO RET: RX D: CT: ORTHO Case Example - Moderate Amblyopia OD: X180 OS: X180 OD: X180 OS: X180 DATE VA OD VA OS TREATMENT 3/2013 sc 20/25 sc 20/60 6/2013 cc 20/20 cc 20/50 9/2013 cc 20/20 cc 20/25 New specs AND Cont 2 hrs per day Cont 2 hrs per day Cont 2 hrs per day DW, 7 YO CYCLO RET: RX D: CT: ORTHO Case Example - Severe Amblyopia OD: X180 OS: DS OD: X180 OS: DS DATE VA OD VA OS TREATMENT 8/2013 sc 20/25 sc 20/150 11/2013 cc 20/20 cc 20/30 Specs AND 2 hrs per day Cont 2 hrs per day Case Example - Severe Amblyopia KP, 3 YO 10/ /2013 CYCLO RET: OD: DS X180 OS: X X180 RX D: CT: SC 25 LET CC ORTHO FULL DATE VA OD VA OS TREATMENT 10/2012 sc 20/30 sc 20/300 Specs Only 12/2012 cc 20/25 cc 20/200 Start 4 hrs per day 2/2013 cc 20/25 cc 20/40 Cont 4 hrs per day 4/2013 cc 20/25 cc 20/30 Cont 4 hrs per day 10/2013 cc 20/20 cc 20/50 1/2014 cc 20/20 cc 20/30 Update Specs AND taper 2 hrs per day SP, 7 YO CYCLO RET: RX D: CT: ORTHO Case Example - Severe Amblyopia OD: X180 OS: X180 OD: X180 OS: X180 DATE VA OD VA OS TREATMENT 8/2012 sc 20/25 sc 20/200 11/2012 cc 20/20 cc 20/60 3/2013 cc 20/20 cc 20/40 7/2013 cc 20/20 cc 20/30 Specs AND start 4 hrs per Cont day 4 hrs per day Cont 4 hrs per day Cont 4 hrs per day

9 What if patching isn t an option? Sweaty kid? Reaction to patch adhesive? Atropine Treatment Lessons learned? RCT s: Amblyopia Treatment Studies 3 to <7 years STUDY PRESCRIBED TREATMENTS ATS-1 ATS-2B ATS-2A ATS-4 6 hrs patching vs daily atropine 2 hrs patching vs 6 hrs patching* 6 hrs patching vs full-time patching Daily atropine vs weekend atropine DEPTH OF AMBLYOPIA Moderate Moderate Severe Moderate *1 hr of near activity while patched for both groups MEAN LINES INCREASE VA MEAN VA POST-TX 20/30 20/ /32 20/ /50 20/ / /32-2 Arch Ophthalmol 2002;120: & 2003;121:503-11; Ophthalmology 2003;110: & 2004;111: ATS-4 Daily atropine vs weekend atropine Study Objectives Amblyopic Eye at 4 Months To compare daily versus weekend atropine (twodays) for moderate amblyopia (20/40 to 20/80) in children 3 to <7 years old Weekend atropine N=83 Daily atropine N=77 To determine the maximum amount of improvement that could be achieved with these atropine schedules. Mean improvement from baseline 2.3 lines 2.3 lines Mean acuity at 4 months (Snellen approximation) 20/ /32-1 >20/32 or >3 line improvement from baseline 66% 66%

10 Amblyopic Eye at 4 Months Amblyopic Eye Visual Acuity Cumulative Distribution Acuity at Study Completion Daily Atropine N=77 20/25 or better OR equal to sound eye Daily - 39 (47%) Weekend - 45 (53%) Weekend Atropine Mean Amblyopic eye acuity N=83 Daily 0.23 logmar (20/32-3) 2.3 lines of improvement >20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 Weekend 0.21 log MAR (20/32-1) >20/100 >20/125 >20/160 4-month Amblyopic Eye Visual Acuity 2.5 lines of improvement 55 Atropine Side Effects Atropine Treatment for 3 to <7 yrs Dosage Cost Side effects? Systemic reactions Treatment similar to 2- and 6-hrs of prescribed patching First-line treatment and consider for patching failures PEDIG. Ophthalmology 2004;111: ; Arch Ophthalmol. 2009;127:22-30; Arch Ophthalmol. 2008;126: Bowel and bladder lose their tone Heart runs alone Study Objective ATS-8 Add plano lens to sound eye? To compare the effectiveness and safety of weekend atropine augmented with a plano lens for the sound eye versus weekend atropine alone for moderate amblyopia (20/40 to 20/100) in children 3 to <7 years old

11 Add plano lens to sound eye? As initial treatment, added plano lens for sound eye does not augment treatment effect significantly (mean lines increase VA) Amblyopic eye 20/25 atropine only = 29% Atropine with Plano lens = 4 Amblyopic Eye at 18 Weeks Atropine Only Group N=84 Atropine + Plano Group N=88 Mean acuity at baseline 20/ /63 Mean acuity at 18 wks 20/ /32-1 Prop improving 3+ lines from baseline 57% Mean improvement from baseline 2.4 lines 2.8 lines What about ATS 16? (Effect of adding Plano lens for residual amblyopia) Arch Ophthalmol. 2009;127(1):22-30 Mean Difference 95% CI 0.3 lines (-0.2, 0.8) Amblyopic Eye at 18 Weeks Atropine Penalization: Clinical Pearls 4 29% Test VA through full plus No atropine for 2 weeks before diagnose reverse amblyopia 63 Study Design Enrollment Recurrence? 156 children Study period off treatment 5w 13w 26w 52w Previous Rx Treatment STOPPED

12 Study Design Enrollment 156 children Study period off treatment Previous strabismic/aniso At least 3 mo 5w 13w 26w 52w At least 2h/d or 1gtt/w Initial Amblyopic Eye Acuity Previous Rx Enrollment Amblyopic Eye Acuity At least 3 logmar improvement Monitored for recurrence 2 logmar decrease in VA Confirmed by 2 nd VA test Pts Timing of the 35 recurrences % of recurrence occurred within 6 months of stopping 14 (4) patching 10 (29%) 5 (14%) Weeks 6 (17%) Recurrence Risk among patching groups Low Intensity Non-weaned 2h 2h Moderate Intensity Weaned 6/8h 2h Moderate Intensity Non-weaned 6/8h 6/8h Recurrence 14% 14% 42% ( ) 4.4 ( ) Odds ratio Adjusted for age, VA, tropia, stereo, duration No change in odds ratio Conclusions of Amblyopia Recurrence Study ¼ of successfully amblyopic children experience a recurrence over 1 year of follow-up Recurrence risk is similar for stopping patching and atropine Most recurrences occur within 3 months early follow-up is critical but long term follow-up is also important If 6 or more hours of patching stopped recurrence risk is lower if patching is reduced to 2 hours per day before cessation suggests weaning is beneficial Amblyopic Eye Acuity at 2 Years Mean improvement from baseline Mean acuity at 2 years (Snellen approximation) PATCHING N = 188 ATROPINE N = lines 3.6 lines 20/ /32 +2 Amblyopic Eye Visual Acuity Cumulative Distribution Amblyopic Eye at 2 Years N=188 Atropine N=175 >20/32 or >3 line improvement from baseline ATS1 86% 83% ATS1 >20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160 2-year Amblyopic Eye Visual Acuity

13 Currently prospectively analyzing ATS 1 patients at 10 year anniversary of completing study What about children older than 7? What have we learned about amblyopia treatment? Objectives ATS-3 Amblyopia treatment in children 7-13 years old To determine the response rate to amblyopia treatment in children from 7 to <18 years To determine the frequency of recidivism of successfullytreated amblyopia in children 7 to <18 years Randomized, controlled multi-center clinical trial Sample size: >360 children (>90 in each of 4 age groups) Treatment groups: Control Group: Optical correction only Active Group: Study Design Optical correction plus near activities Atropine (patients <13 yrs only) PEDIG. Archives of Ophthalmology 2005;123: Maximum Improvement in Amblyopic Eye Acuity Patients with Baseline Acuity 20/40 to 20/80 45% 28% 29% 21% 3 27% 36% 1 31% 48% 15% 18% 14% 11% 1 19% 8% 23% 11% 14% 14% 17% 24% 35% 26% 38% 53% 42% 7 to <9 9 to <11 11 to <13 13 to <18 7 to <9 9 to <11 11 to <13 13 to <18 N=53 N=56 N=28 N=29 N=58 N=49 N=26 N=28 Treatment Group Optical Correction Group >=15 10 to <15 5 to <10 <5 letters

14 Maximum Improvement in Amblyopic Eye Acuity Patients with Baseline Acuity 20/100 to 20/400 64% 14% 14% 7% 29% 29% 24% 18% 73% 18% 9% 14% 33% 33% 19% 29% 5% 33% 33% 27% 27% 19% 27% 2 27% 27% 27% 21% 11% 21% 47% 7 to <9 9 to <11 11 to <1313 to <18 7 to <9 9 to <11 11 to <1313 to <18 N=28 N=17 N=11 N=21 N=21 N=26 N=15 N=19 Treatment Group Optical Correction Group >=15 10 to <15 5 to <10 <5 letters Percentage of patients labeled as responders Study Summary Treatment Group Optical Correction Only 7 to <9 9 to <11 11 to <13 13 to <18 Age at Randomization Conclusions Amblyopic eye vision improves with optical correction alone in about ¼ of 7 to <18 year olds. In 7 to < 13 year olds, additional improvement is seen with patching/atropine regardless of whether amblyopia was previously treated. In 13 to <18 year olds, additional improvement may occur with patching if amblyopia was not previously treated, but may not occur if previously treated. What about patching vs atropine in children ages 7 to < 13? Most amblyopic eyes have remaining visual deficit. Persistence of effect after treatment cessation is currently being evaluated. Study Objective ATS-9 vs atropine in children ages 7 to < 13 To compare the effectiveness of weekend atropine plus near activities and daily patching plus near activities for moderate amblyopia (20/40 to 20/100) in 7 to <13 years olds. To determine the maximum improvement with each treatment

15 Amblyopic Eye at 17 Weeks Atropine Group N=89 Group N=84 Mean acuity at baseline 20/ /63 +2 Mean acuity at 17 wks 20/ /40 +1 Mean improvement from baseline Mean Difference* 95% CI 1.5 lines 1.7 lines 0.2 lines (-0.2 to 0.6) * Controlling for baseline acuity. Atropine interval shown Amblyopic Eye Visual Acuity Cumulative Distribution Amblyopic Eye at 17 Weeks Atropine N=89 Amblyopic Eye Visual Acuity at Four-month Outcome Exam N=84 >20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160 >20/200 Amblyopic Eye at Maximal Acuity Atropine Group Group N=95 N=98 Mean acuity at baseline 20/ /63 +2 Mean acuity at maximal 20/ /32-2 Mean improvement from baseline Mean Difference 2.2 lines 2.2 lines 0.0 lines What about children with bilateral amblyopia? 95% CI (-0.3 to 0.4) * Controlling for baseline acuity. Atropine interval shown 16 Study Aims ATS-7 Treating children with bilateral amblyopia To determine the amount and time course of binocular visual acuity improvement during treatment of bilateral refractive amblyopia in children age 3 to <10 years old PEDIG. Am J Ophthalmol 2007; 114:487-96

16 Mean Binocular Visual Acuity Improvement After 1 year Improvement at One Year Stratified by Baseline Acuity Baseline Binocular VA Lines Improvement 3.9 lines (95% CI = 3.5 to 4.2) 20/40 to 20/80 (N=84) 3.4 lines (3.2 to 3.7) 20/100 to 20/320 (N=16) 6.3 lines (5.1 to 7.5) Cumulative Probability of Binocular Acuity > 20/25 Weeks Cumulative Probability 5 21% 13 46% 26 59% 52 74% What if amblyopia stops improving with patching alone? Study Objective ATS-15 Increasing patching after stability / no improvement To determine if prescribing an increased patching dosage improves amblyopic eye visual acuity in children age 3 to < 8 with apparently stable residual amblyopia from anisometropia and/or strabismus following initial prescribed treatment of 2 hours daily patching and spectacles if needed

17 Amblyopic Eye Visual Acuity Amblyopic Eye Visual Acuity Improvement Visit 2-Hour 6-Hour Percentage of Subjects 18% 4 39% 51% 10-Week Outcome Best Post-Randomization Proportion with 2 logmar line improvement since baseline ES, 4 YO CYCLO RET: Case Example - Increased OD: X180 OS: DS RX D: FULL CT: SC 30 RET CC ORTHO DATE VA OD VA OS TREATMENT 2/2013 sc 20/200 sc 20/60 Specs Only 5/2013 cc 20/150 cc 20/25 Start 2 hrs per day 8/2013 cc 20/150 cc 20/20 Cont 2 hrs per day 10/2013 cc 20/70 cc 20/30 Cont 2 hrs per day 12/2013 cc 20/80 cc 20/20 Increase to 4 hrs per day 2/2014 cc 20/50 cc 20/20 Cont 4 hrs per day Dogma vs Evidence-based treatment Amblyopia Treatment Dogma Pre-ATS Mainstay of treatment = occlusion Rx spectacles and occlusion simultaneously Patch full-time, especially if severe amblyopia Never patch less than 4 hours is better than atropine penalization Atropine only for moderate amblyopia Amblyopia cannot be treated beyond 6-9 years Rx near activities when patched Evidence-Based, Step-Wise Management Strategy for Amblyopia Moderate amblyopia due to anisometropia and/or strabismus Spectacle correction, and follow every 6-10 weeks until no further improvement If amblyopia persists, initiate additional amblyopia treatment (2 hours daily patching or weekend atropine), and follow every 6-10 weeks until no further improvement If amblyopia persists, consider increasing patching dosage from 2 to 6 daily hours* and follow every 6-10 weeks until no further improvement When maximum acuity achieved, taper or stop treatment and monitor for amblyopia recurrence *Alternative approaches include changing treatment modality to atropine or Bangerter filter have yet to be studied.