Disclosures. Case. The pupil is the aperture of the eye. Pupils 10/21/2014. Neuro ophthalmology update: Approaching pupils and eyelids clinically

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2 10/21/2014 Disclosures Neuro ophthalmology update: Approaching pupils and eyelids clinically Heather Moss, MD, PhD Wendy Stone, OD, FAAO Dr. Moss receives research funding from NIH and Illinois Society for the Prevention of Blindness UIC ophthalmology receives funding from Research to Prevent Blindness Dr. Stone has no disclosures Pupil and eyelids Primary eye care providers Case 56 year old, droopy lid x 1 week Can be an important clue to underlying neurological disease Often present to general eye clinic Often are overlooked Recognize pupil/lid abnormalities Use examination techniques to categorize them Further questioning: pain in back/shoulder, lower arm numbness The pupil is the aperture of the eye Pupils eye anatomy.html 1

3 10/21/2014 Antagonist muscles determine resting pupil size Pupil innervation & pharmacology Parasympathetic (constricts) Sympathetic (dilates) Receptor muscarinic adrenergic (α, β) Neurotransmitter acetylcholine nor epinephrine Agonist Antagonist pilocarpine scopolamine hydroxyamphetamine apraclonadine cocaine (indirect) 09_Pupil.JPG/ /15 09_Pupil.JPG Neurological pupil signs Anisocoria Anisocoria Light/near dissociation Afferent pupillary defect Determine which pupil is abnormal Compare both pupils in light vs dark environments Is anisocoria greater in dark or light? Video Example Light Greater anisocoria in light Large pupil is not constricting (as well) Right pupil is not constricting Right parasympathetic problem Dark 2

4 10/21/2014 Parasympathetic anatomy Causes of poor pupil constriction Dorsal midbrain syndrome Cranial nerve III palsy CN III to Lids EOMs PTN pretectal nucleus E W edinger westfal nucleus III cranial nerve III CG ciliary ganglion LGN lateral geniculate nucleus Tonic pupil Cholinergic toxicity Structural Distinguishing mydriasis: drop testing Sensitivity to pilocarpine Constricts to 0.125% Does not constrict to 1% Tonic pupil Third nerve palsy Partial pharm. dilation Pharmacological dilation Pupil muscle injury CN III to Lids EOMs Distinguishing Mydriasis: by the company it keeps Dorsal midbrain syndrome Light/near dissociation eye movement problems 2. Cranial nerve III palsy Ptosis, ocular misalignment 3. Tonic pupil Light/near dissociation 4. Cholinergic toxicity, structural History Neurological pupil signs Anisocoria Light/near dissociation Afferent pupillary defect Pupil near and light reflexes are different cerebral cortex Near reflex bypasses the pretectal nucleii Light/near dissociation when PTN damaged More pupillary fibers subserve the near reflex than the light reflex Light/near dissociation in cilliary ganglion lesion 3

5 10/21/2014 Light near dissociation from a dorsal midbrain lesion Light near dissociation from a ciliary ganglion lesion Anisocoria Is anisocoria greater in dark or light? Light Determine which pupil is abnormal Compare both pupils in light vs dark environments Dark Greater anisocoria in dark Small pupil is not dilating (as well) Left pupil is not dilating Left sympathetic problem Sympathetic anatomy Sympathetic injury = Horner s syndrome Cavernous sinus Lateral medullary stroke Carotid dissection sweating Lung apex tumor 4

6 10/21/2014 The logic behind drop testing for Horner s syndrome Distinguishing meiosis: Drop testing Normal sympathetic tone third order neuron Iris dilator 1. less release Low sympathetic tone 2. Receptor up regulation Cocaine Hydroxyamphetamine Apraclonidine (Iopidine) pharmacology physiology Clinical effect Timing of finding Inhibits presynaptic reuptake Stimulates presynaptic release Stimulates muscle receptors Potentiates sympathetic activity Potentiates third order neuron activity Proportional to receptor density Potentiates anisocoria Potentiates anisocoria if 3 rd order neuron injured Reverses anisocoria immediately delayed delayed Highlights Cocaine dilation effect correlates with sympathetic function (immediate) Apraclonidine dilation effect is inverse with sympathetic function (delayed) Hydroxyamphetamine dilation effect correlates with 3 rd order neuron function (delayed) Positive cocaine test before After A positive cocaine test results in greater anisocoria Hydroxyamphetamine test (intact third order neuron) before Case 56 year old, droopy lid x 1 week After Results in less anisocoria Further questioning: pain in back/shoulder, lower arm numbness 5

7 10/21/2014 Positive apraclonidinetest Distinguishing Horner s syndrome: by the company it keeps 1 st order (brain) Neurological symptoms 2 nd order (lung) 3 rd order (carotid) No anhydrosis 3 rd order (cavernous sinus) 3,4,6, V1, V2 palsies All miosis is not Horner s syndrome Causes of miosis: Old tonic pupil Pharmacologic Iritis Neurological pupil signs Anisocoria Light/near dissociation Afferent pupillary defect Anisocoria Is anisocoria greater in light or dark? Light Determine which pupil is abnormal Compare both pupils in light vs dark environments Dark Neither both pupils constrict and dilate appropriately physiologic anisocoria 6

8 10/21/2014 Neurological pupil signs Anisocoria Light/near dissociation Afferent pupillary defect Afferent pupil function: Pupillary light reflex ON optic nerve CHI chiasm OT optic tract LGN lateral geniculate nucleus PTN pretectal nucleus E W edinger westfal nucleus III cranial nerve III CG ciliary ganglion Rules of the light reflex Providing the efferent pupillary pathways are intact: Left relative APD from left optic nerve injury The size of both pupils Is always equal Reflects the total amount of signal reaching the brainstem nuclei rapd reflects reduced light transmission by the affected eye Video Example rapd is not normal Typically reflects optic nerve disease Can be seen with severe retinal/corneal disease If no cause apparent need to consider orbital/intracranial optic nerve or tract disease 7

9 10/21/2014 Putting it together Lids Pupil Other Case Progressive ptosis and ophthalmoplegia x 12yrs III ptosis Dilated (constricts poorly) EOM limitations VII Orbicularis weakness, wide PF Unaffected Lower facial weakness Sympathetic Upper & lower lid ptosis Constricted (dilates poorly) +/ anhydrosis Myopathic NMJ Ptosis, orbicularis weakness Unaffected MG Affected botulism Other muscle weakness Dorsal midbrain retraction Light near dissociation Upgaze limitation Eyelids can be too high or too low Eyelids R. Retraction OR L. Ptosis? III VII sympathetic Eye lid control Upper lid nerves VII (closes) III (opens) Sympathetic (opens) levator Nerve causes of ptosis tarsal Third nerve palsy (parasympathetic) sympathetic Lower lid nerves VII (closes) Sympathetic (opens) tarsal Horner s (sympathetic) VII Dorsal Midbrain control overview Balcer LJ, et al. Am J Ophthalmol 1996;122:437. 8

10 10/21/2014 Nerve causes of retraction Dyskinesis/Synkinesis: a finding of chronic nerve injury Following injury, axons can re wire incorrectly Facial (VII) nerve palsy Dorsal midbrain injury Manifests as inappropriate lid or pupil action with attempted action CN III aberrant regeneration Another example of dyskinesis/synkinesis Muscle disease can cause lid abnormalities 9

11 10/21/2014 Eye lid muscles Ptosis from myopathy Chronic Progressive External Ophthalmoplegia Upper lid muscles Orbicularis oculii Levator palpebrae Superior tarsal Lower lid muscles Orbicularis oculii Inferior tarsal overview Case Progressive ptosis and ophthalmoplegia x 12yrs Ptosis from neuro muscular junction disease (myasthenia) Distinguishing ptosis Ice pack test for myasthenia Muscle disease Myasthenia Gravis Decreased acetylcholinesterase activity Comparable to Tensilon Apply over closed lid x 1 2 minutes Works best on ptosis (not motility) Slowly progressive Diffuse & symmetric Variable History testing Can be focal 10

12 10/21/2014 Pre Hold for 2 minutes Positive Ice Pack Test Post Muscle cause of eyelid retraction: thyroid eye disease Pre Post Approaching Pupil and Lid Problems Putting it together Recognize Anisocoria Light/near dissociation R APD Ptosis Lid Retraction Categorize Provocative testing Eye drops Ice pack test Examine for accompanying features Lids Pupil Other III ptosis Dilated (constricts poorly) VII Sympathetic Myopathic NMJ Orbicularis weakness, wide PF Upper & lower lid ptosis Ptosis, orbicularis weakness Unaffected Constricted (dilates poorly) Unaffected MG Affected botulism EOM limitations Lower facial weakness +/ anhydrosis Other muscle weakness Dorsal midbrain retraction Light near dissociation Upgaze limitation 11

13 10/21/2014 Putting it together Lids Pupil Other III ptosis Dilated (constricts poorly) EOM limitations VII Orbicularis weakness, wide PF Unaffected Lower facial weakness Sympathetic Upper & lower lid ptosis Constricted (dilates poorly) +/ anhydrosis Myopathic NMJ Ptosis, orbicularis weakness Unaffected MG Affected botulism Other muscle weakness Dorsal midbrain retraction Light near dissociation Upgaze limitation 12

14 Development of PEDIG Update on Research from Pediatric Eye Disease Investigator Group (PEDIG) Yi Pang, OD, Ph.D. Iris Kassem, MD, Ph.D. PEDIG is a network dedicated to conducting multicenter studies in strabismus, amblyopia, and other eye disorders that affect children. Formed in 1997, the network is funded by the National Eye Institute. More than 100 publications 1 2 Outlines Congenital esotropia observational study (CEOS) Amblyopia treatment studies conducted by PEDIG Treatment of nasolacrimal duct obstruction studies Overview of currently active PEDIG studies Congenital Esotropia Observational Study (CEOS) 3 CEOS Protocol Follow without surgery Primary outcome: weeks of age Continued follow up until time of surgery or 12 mos of age Esotropia at Outcome (N = 170) 46 Resolved 124 Persistent ET 31% 25% 14% 14% 9% 2% 5% Size of Esotropia (pd) 1

15 CEOS Lesson Learned Younger age and intermittency/variability of ET at enrollment associated with increased probability of resolution Probability of resolution low with constant ET >40 pd on two consecutive exams Am J Ophthalmol 2002;133(1): Am J Ophthalmol 2002;133(1):102-8 CEOS Lesson Learned Spontaneous resolution of esotropia developing in infancy does occur Spontaneous resolution rarely occurs when an infant has a constant ET >40 pd that is stable or increased in size on a 2nd exam in the absence of hyperopia >+3.00 D Am J Ophthalmol 2002;133(1): Am J Ophthalmol 2002;133(1):102-8 ATS 1-9 Lesson Learned Amblyopia in 3 to <7 Year Olds Amblyopia Treatment Study (ATS 1 to ATS 18) Moderate Amblyopia Both atropine and patching are effective treatments Prescribing 2 hours or 6 hours of daily patching produces similar improvement Prescribing daily or weekend-only atropine produces similar improvement Severe Amblyopia Prescribing 6 hours or full-time daily patching produces similar improvement 10 ATS 1-9 Lesson Learned Amblyopia in 7 to <18 Year Olds Amblyopia improves with optical correction alone in about 1/4 of patients; though most will require additional treatment For 7 to <13 year olds, prescribing patching 2 to 6 hours/day with near activities and atropine can improve visual acuity even if the amblyopia has been previously treated. For 13 to <18 year olds, prescribing patching 2 to 6 hours/day with near 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. Complete resolution of amblyopia is unusual even when there is a response to treatment 11 What Else Do We Know about Amblyopia? Recent Amblyopia Treatment Studies (ATS 10, ATS 13, ATS 15, ATS 16) 2

16 ATS 10: Bangerter filter treatment Bangerter Filter V.S ATS 10 Lesson Learned Lower treatment burden with Bangerter filters compared to patching. Bangerter filter treatment is a reasonable option to consider when initiating treatment of moderate amblyopia. ATS-13: Spectacles for Strabismic Amblyopia Ophthalmology May;117(5): Change in Visual Acuity Between Baseline & 18 Weeks % Improve 2 lines 69% 88% % Resolve* 28% 40% Adjusted 17 P = from an ANCOVA *Amblyopic eye visual acuity within 1 line of fellow eye acuity ATS 13 Lesson Learned Optical treatment alone of strabismic and combined-mechanism amblyopia results in clinically meaningful improvement in amblyopic eye VA for most 3 to <7 year olds Amblyopia resolves in at least 25% without the need for additional treatment Ophthalmology 2011;119(1):

17 Residual Amblyopia Younger Kids When stable does increasing the treatment improve the outcome? ATS15 - at 2 hours per day, does increased patching help? ATS16 does adding plano to twice weekly atropine help? ATS15 - Amblyopic Eye Visual Acuity Improvement Proportion with 2 logmar line improvement since baseline ATS15 Lessons Learned When amblyopic eye stops improving with 2hrs daily patching, increasing dosage to 6hrs results in more improvement after 10wks compared with continuing 2 hours daily ATS16 Manuscript submitted to JAAPOS When stable does increasing the treatment improve the outcome? Adding plano to twice weekly atropine Ophthalmology 2013;120:

18 10/22/ Nasolacrimal Duct Obstruction 5% of full-term newborns, 1/3 bilateral + Nasolacrimal Duct PEDIG Studies Clinically evident at 3 4 weeks of age Lacrimation does not function normally until 6 weeks Membranous blockage of the Valve of Hasner 90% resolve in the first year of life Dye disappearance test confirms diagnosis Fluorescein solution to the tear film Note significant retention after 5 10 minutes No dye in the nose or pharynx after minutes American Academy of Ophthalmology + NLDO Treatment + PEDIG Studies Observation with lacrimal sac massage Surgery No spontaneous resolution Dacryocystitis acutely inflamed lacrimal sac with cellulitis of the overlying skin Surgery after infection is resolved Surgical Options: Probing and Irrigation Silicone tube intubation Balloon catheter dilation Medial infracture of the inferior turbinate Dacryocystorhinostimy 3 studies were completed for nasolacrimal duct obstruction NLD1: A Prospective Study of Primary Surgical Treatment of Nasolacrimal Duct Obstruction in Children Less Than Four Years Old NLD2: A Prospective Study of Surgical Procedures for Persistent Nasolacrimal Duct Obstruction in Children Less Than Four Years Old NLD3: A Randomized Trial Comparing Immediate Probing in an Office Setting with Deferred Probing in a Facility for Initial Surgical Treatment of Unilateral Nasolacrimal Duct Obstruction in Children 6 to <10 Months Old Unilateral NLDO assiciated with amblyogenic anisometropic refractive error (20%) + Nasolacrimal Duct Study 1 (NLD1) + Nasolacrimal Duct Study 1 (NLD1) A Prospective Study of Primary Surgical Treatment of Nasolacrimal Duct Obstruction in Children Less Than Four Years Old Objectives To report the success proportions of simple probing within different age groups of patients under 4 years of age To report the success proportions of balloon catheter dilation and nasolacrimal intubation procedures in patients under 4 years of age 1

19 10/22/ NLD1 Study Population + NLD1 Subject Characteristics 953* total patients (1288 eyes) were enrolled by 70 investigators at 45 sites. Simple probing 718 pts (955 eyes) Balloon dilation 102 pts (151 eyes) Intubation 139 pts (182 eyes) *6 patients had a different procedure performed on each eye. ***Surgery type at investigator discretion, not randomized.*** For intubation patients, tubes were to be removed between 2 and 5 months after surgery and follow-up from time of removal. Age at surgery Simple Probing (N=718) Balloon (N=102) Intubation (N =139) Mean age (months) <12 months 337 (47%) 0 (0%) 24 (17%) 12- <24 months 338 (47%) 65 (64%) 86 (62%) 24 - <36 months 35 (5%) 25 (25%) 18 (13%) 36 - <48 months 8 (1%) 12 (12%) 11(8%) + NLD1 Subject Characteristics + NLD1 Baseline Characteristics Simple Probing (N=718) Balloon (N=102) Intubation (N =139) Female 50% 52% 49% White 81% 69% 73% Onset in first month of life* 84% 79% 68% Bilateral NLDO 33% 48% 31% *As opposed to onset between 1 and <6 months of life. Simple Probing (N=955) Balloon (N=151) Intubation (N =182) Epiphora 80% 64% 85% Mucous discharge 68 % 50% 64% Increased tear film 96% 93% 95% DDT abnormal* 83% 82% 88% *DDT = Dye Disappearance Test + NLD1 Follow Up Visits 1-month Interim Visit From surgery for simple probing and balloon procedures From tube removal for intubation procedures 6-Month Primary Outcome Visit Six months from surgery for all procedures Treatment success = absence of all three clinical signs of NLDO (epiphora, mucous discharge, and increased tear film) at 6 months Assessment of clinical signs performed by a certified examiner other than the surgeon Eyes re-operated before the 6-month visit were counted as treatment failures + Success of Simple Probing According to Age Percent Successful % 79% 79% 6 to <12 12 to <24 24 to <36 36 to <48 Months of age at surgery 56% N=11 in the oldest age group. 2

20 10/22/ Success of Balloon Dilation and Intubation Procedures Balloon (N=88 ) 82% (95% CI: 74%-88%) Success Intubation (N=150 ) 91% (95% CI: 86%-95%) 13 + NLD1 Conclusions In children 6-<36 months old, simple probing is a successful primary treatment of NLDO in about 75% of cases, with no decline in treatment success with increasing age. The study enrolled too few children ages 36 to 48 months to allow a conclusion regarding the probability of treatment success of simple probing n this age group. In children 12-<48 months old, balloon dilation is a successful primary treatment of NLDO in about 80% of cases. In children 6-<45 months old, intubation is a successful primary treatment of NLDO in about 90% of cases. + Nasolacrimal Duct Study 2 (NLD2) + NLD2 Objectives A Prospective Study of Surgical Procedures for Persistent Nasolacrimal Duct Obstruction in Children Less Than Four Years Old To compare the proportion of eyes with treatment success between balloon catheter dilation and nasolacrimal intubation To obtain point estimates on the proportion of eyes with treatment success for each surgery type + Randomized Trial Converted to Observational Study + Eligibility Criteria Study initiated as a randomized trial Patients randomized to balloon catheter dilation or nasolacrimal intubation Poor recruitment (8 patients randomized) Age 6 to < 48 months Onset of NLDO symptoms and/or signs prior to 6 months of age Study converted to an observational study Choice of procedure at investigator discretion (balloon, intubation, or repeat probing) Presence of epiphora, increased tear film, and/or mucopurulent discharge Previous single failed simple probing procedure for nasolacrimal duct obstruction 3

21 10/22/ Study Population + Follow Up Visits 177* total patients (222 eyes) were enrolled by 53 investigators at 39 sites. Balloon Intubation 73 pts (95 eyes) 90 pts (104 eyes) Repeat probing 20 pts (23 eyes) *6 patients had a different type of procedure performed on each eye. For intubation patients, tubes were to be removed between 2 and 5 months after surgery. 1-month Interim Visit From surgery for balloon and repeat probing procedures From tube removal for intubation procedures 6-Month Primary Outcome Visit Six months from surgery for all procedures About 25% of patients had been in NLD1. + Age at Surgery* 21 + Treatment Success at 6 Months Age at surgery, in months Mean Range Balloon (N=73) to 41 Intubation (N=90) to 47 Repeat Probing (N=20) to 34 Percent Successful % (65%-85%) 84% (74%-91%) 56% (33%-76%) *Age at surgery refers to age at NLD2 study surgery. 0 Balloon (N=84) Intubation (N=88) Probing (N=21) NLD2 Results Risk ratio for intubation vs. balloon = 1.08 (95%CI = 0.91 to 1.27) + Tube Retention Time Vs. Success + Tube Type and Success Proportion of eyes with treatment success: Proportion of eyes with treatment success: 90% in the 59 eyes which had tubes retained >2 months 70% in the 29 eyes which had tubes retained <2 months Risk ratio for >2 months vs. <2 months = 1.27 (99% CI = 0.91 to 1.79) 79% in the 40 eyes with monocanalicular 87% in the 48 eyes with bicanalicular Risk ratio for bicanalicular versus monocanalicular = 1.07 (99% CI = 0.82 to 1.39) 4

22 10/22/ Conclusions + Nasolacrimal Duct Study 3 (NLD3) Balloon dilation and nasolacrimal intubation were successful in a similar proportion of patients with persistent NLDO after a single probing (77% and 84% respectively) Among intubations, neither tube retention time or tube type was statistically associated with success A Randomized Trial Comparing Immediate Probing in an Office Setting with Deferred Probing in a Facility for Initial Surgical Treatment of Unilateral Nasolacrimal Duct Obstruction in Children 6 to <10 Months Old The 56% success rate for repeat probing should be interpreted with caution because of the small sample size (21 eyes). + Objectives + Major Eligibility Criteria To evaluate the cost-effectiveness of a treatment strategy of office probing performed as soon as possible compared with a treatment strategy of a 6-month period of observation followed by probing in a surgical facility if needed To determine the proportion of subjects in the observation/deferred treatment group who resolve in 6 months without surgery Age 6 to < 10 months NLDO onset before 6 months of age Presence of one or more clinical signs of NLDO (epiphora, increased tear film, and/or mucopurulent discharge) in one eye No previous nasolacrimal duct surgery + Treatment Groups + Followup Randomization to one of following treatment strategies: Immediate Office Probing Approach Probing performed in office with topical anesthesia and infant restraint within two weeks of randomization 26-Week Visit (timed from randomization) Assessment of clinical signs For deferred group, if one or more signs of NLDO persist, surgery performed within 4 weeks. Observation / Deferred Facility Probing Approach 6 months of observation and nonsurgical treatment Lacrimal massage 2x daily when discharge present Antibiotic eyedrops 4x daily when discharge purulent If NLDO not resolved within 6 months, probing performed under general anesthesia in surgical facility Primary Outcome Visit at 18 Months of Age MASKED assessment of clinical signs ***During study, reoperation is at investigator discretion in both treatment groups between 6 weeks after initial surgery and one month before 18 months of age visit.*** 5

23 10/22/ Outcomes Evaluated + Baseline Age Total costs of treatment between randomization and 18 months of age Costs of initial visit, surgeries (initial and reoperations), and medications Estimates costs based on 2011 Medicare fee schedule Clinical outcome at 18 months of age Success = no clinical signs of NLDO present on masked exam Months of symptoms between randomization and 18 months of age Immediate Subjects N=82 Deferred Subjects N=81 Age at Enrollment 6 to <7 mos 30% 33% 7 to <8 mos 34% 25% 8 to <9 mos 18% 16% 9 to <10 mos 17% 26% Mean, mos Immediate = immediate office probing treatment approach Deferred= observation/deferred facility probing treatment approach + Baseline Demographic Data + Baseline Clinical Signs Data Immediate Subjects N=82 Deferred Subjects N=81 Female gender 39% 52% Race White 83% 81% Hispanic 12% 9% Other 5% 8% Immediate = immediate office probing treatment approach Deferred= observation/deferred facility probing treatment approach Immediate Subjects N=81 Deferred Subjects N=82 Clinical sign present? Epiphora 86% 77% Increased tear film 100% 96% Mucous discharge 78% 73% Immediate = immediate office probing treatment approach Deferred = observation/deferred facility probing treatment approach + Six-Month Resolution Without Surgery in Observation / Deferred Facility Probing Group Subjects (N=67) % (95% CI) Resolved 66% (54% to 77%) + Cost-effectiveness at Age 18 Mos Outcome at 18 Months of Age Immediate Office Probing Group (N=75) Observation / Deferred Facility Probing Group (N=71) Difference (95% CI) Success 92% 82% 10% (-1% to 21%) Average months of symptoms* (-2.1 to -4.3) Average cost $562 $701 -$139 (-$377 to $94) *Average months of symptoms between randomization and age 18 months. Difference = immediate group vs. observation / deferred group CI = confidence interval 6

24 10/22/ Impact of Site of Service for Deferred Facility Probings Site of Service for Deferred Average Total Cost of Observation / Deferred Conclusion Facility Probings Probing* All in ambulatory surgery center $584 Difference = All in hospital outpatient department $775 $191 *Assumes observed 66% rate of resolution without surgery in observation/deferred probing group. + Conclusions The majority of deferred group subjects had their NLDO resolve within 6 months without surgery. Immediate office probing approach is likely more cost-effective than observation/deferred probing approach for treating unilateral NLDO Immediate office probing approach had slightly higher likelihood of success (although not quite statistically significant), fewer months of symptoms, and may be slightly less expensive. Conclusion similar across wide range of values for rate of 6-month resolution without surgery. Regardless of site of service for deferred probings, observation/deferred facility probing approach may cost slightly more than immediate office probing approach. + Nasolacrimal Duct Studies 1 and 3 Office Probing for Treatment of Nasolacrimal Duct Obstruction in Infants Conclusions: 75% success overall (95% CI, 70-80%) Probing less successful in bilaterals 63 vs 80% RR is 0.78 (95% CI ) + Current and Future PEDIG Studies Probing less successful if 2-3 clinical signs versus 1 71 vs 83% RR is 0.88 (95% CI ) + Studies In Follow-up Convergence Insufficiency Treatment Study (CITS) Hyperopia Treatment Study (HTS1) Intermittent Exotropia Study 1 (IXT1) Intermittent Exotropia Study 2 (IXT2) + Convergence Insufficiency Treatment Study Effectiveness of Home-Based Therapy for Symptomatic Convergence Insufficiency Objectives: To determine the effectiveness of active home-based computer vergence/accommodative therapy versus placebo home-based computer vergence/accommodative therapy for the treatment of symptomatic CI in children ages 9 to < 18 years. To compare computer-based therapy to home-based near target push-ups for the treatment of symptomatic CI in children ages 9 to < 18 years. 7

25 10/22/ Hyperopia Treatment Study A Randomized Trial of Glasses versus Observation for Moderate Hyperopia in Young Children Objective: To compare visual acuity outcomes and development of strabismus after a 3-year follow-up period in children 12 to <60 months old with moderate hyperopia who are randomized to: Prescribed glasses immediately or Observed and prescribed glasses only if pre-specified deterioration criteria are confirmed + Intermittent Exotropia Study 1 A Randomized Trial of Bilateral Lateral Rectus Recession versus Unilateral Lateral Rectus Recession with Medial Rectus Resection for Intermittent Exotropia Objective: To evaluate the effectiveness of bilateral lateral rectus muscle recession versus unilateral lateral rectus recession with medial rectus resection procedures for the treatment of basic type and pseudo divergence excess type intermittent exotropia. + Intermittent Exotropia Study 2 A Randomized Clinical Trial of Observation versus Occlusion Therapy for Intermittent Exotropia Objectives: To determine the effectiveness of occlusion for the treatment of IXT among patients aged 3 to <11 years To determine the natural history of IXT among patients aged 3 to <11 years + Esotropia Study 2 Data Collection for Esotropia Treated with Botulinum Toxin-A Injection Objectives: To determine how often PEDIG investigators are using BTX-A injection for treatment of esotropia. To describe what types of esotropia patients are being treated with BTX-A injection, information which will be used to refine the eligibility criteria for a potential future randomized trial. + Studies Currently Recruiting Subjects Amblyopia Treatment Study 18 (ATS18) Pediatric Cataract Surgery Outcomes Registry (C02) Intermittent Exotropia Study 3 (IXT3) + Amblyopia Treatment Study 18 A Randomized Trial of Binocular Treatment Versus Patching in 5 to <17 year olds Objectives: To compare the effectiveness of 1 hour/day of binocular game play 7 days per week (minimum of 4 days per week) with 2 hours/day of patching 7 days per week, in children 5 to <13 years of age (younger cohort), as a non-inferiority study. To compare the effectiveness of 1 hour/day of binocular game play 7 days per week (minimum of 4 days per week) with 2 hours/day of patching 7 days per week, in children 13 to <17 years of age (older cohort), as a superiority study. 8

26 10/22/ Major Eligibility Criteria Age 5 to <17 years Amblyopia associated with anisometropia, strabismus ( 10 at near), or both Visual Acuity Amblyopic eye 20/40 to 20/200 inclusive Fellow eye 20/25 or better Interocular difference 3 lines Wearing appropriate spectacle correction for 16 weeks and stable VA for 4 weeks No myopia greater than -6.00D spherical equivalent in either eye Ability to perform certain game-based activities + Amblyopia Treatment Study 18 Study Design Children 5 - <17 yo with Aniso/Strab/Combined Amblyopia Binocular tablet game 1 h/day Patching 2h/day Assessment of VA, stereo at 4, 8, 12 weeks Final masked exam at 16 weeks + Pediatric Cataract Surgery Outcomes Registry Objectives: To enroll individuals between birth and 13 years of age who have undergone cataract surgery in at least one eye into the data repository and follow for at least 5 years. Provide visual acuity outcomes data and define the occurrence and epidemiology of secondary complications by means of rigorous prospective data collection. + Major Eligibility Criteria Children who have had cataract surgery(ies) within 45 days for one or both eyes will be eligible for the registry if they meet the following criteria: Birth to 13 years of age at time of first surgery by investigator or elsewhere Subjects with traumatic cataracts are eligible Subjects with ocular comorbidities such as a persistent hyperplastic primary vitreous (PHPV, a.k.a. persistent fetal vasculature), retinopathy of prematurity, or Peter s anomaly are eligible. + Intermittent Exotropia Study 3 A Pilot Randomized Clinical Trial of Overminus Spectacle Therapy for Intermittent Exotropia Objective: In children with intermittent exotropia, age 3 - <7 years old, does overminus spectacle therapy result in better control of the deviation? + Major Eligibility Criteria Age 3 to < 7 years Intermittent exotropia (manifest deviation) meeting all of the following criteria: Intermittent exotropia or constant exotropia at distance Intermittent exotropia, exophoria, or orthophoria at near Exodeviation >15 at distance measured by PACT Near deviation does not exceed distance by >10 on PACT No prior strabismus, intraocular, or refractive surgery No previous substantial overminus treatment (overminused by 1.00D SE or more). SE in both eyes between -6.00D and +1.00D inclusive Distance visual 20/40 or better in both eyes No interocular difference of distance visual acuity more than 2 lines 9

27 10/22/ Intermittent Exotropia Study 3 Study Design Children 3 - <7 yo with Intermittent Exotropia Overminus Spectacles (-2.50 over Cr) Non-overminus 8 week masked assessment of IXT control 10

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