study of adult strabismus...

SAS1 Protocol v1.1 7-15-15

1

2

STUDY OF ADULT STRABISMUS 3

(SAS1) 4

5

A Prospective Observational Study of Adult 6

Strabismus 7

8

SAS1a: A Prospective Observational Study of Adult Convergence Insufficiency (CI) 9

SAS1b: A Prospective Observational Study of Adult Divergence Insufficiency (DI) 10

SAS1c: A Prospective Observational Study of Adult Small-Angle Hypertropia (HT) 11

12

13

PROTOCOL 14

15

Version 1.1 16

July 15, 2015 17 18

19 20 21 22 23 24 25 26 27 28 29 30 31

32


33 34

CONTACT INFORMATION 35

36

37 COORDINATING CENTER 38

Raymond T. Kraker, M.S.P.H. (Director) 39 Jaeb Center for Health Research 40 15310 Amberly Drive, Suite 350 41

Tampa, FL 33647 42 Phone (888) 79PEDIG or (813) 975-8690 43

Fax (888) 69PEDIG or (813) 975-8761 44 Email: [email protected] 45

46 47

PROTOCOL CHAIR 48 Eric Crouch, M.D. 49

Virginia Pediatric Eye Center 50 880 Kempsville Road, Suite 2500 51

Norfolk, VA 23502 52 Phone (757) 461-0050 53

Fax (757) 461-4538 54 Email: [email protected] 55

56


TABLE OF CONTENTS 57 58 CHAPTER 1: BACKGROUND AND SUMMARY ....................................................................................................... 1-1 59

1.1 Background .............................................................................................................................................. 1-1 60 1.2 Rationale for the study ............................................................................................................................. 1-2 61 1.3 Considerations .......................................................................................................................................... 1-2 62 1.4 Study Objectives ...................................................................................................................................... 1-3 63 1.5 Synopsis of Study Design ........................................................................................................................ 1-3 64

1.5.1 Synopsis of Study Design for CI ......................................................................................................... 1-3 65 1.5.2 Study Flow Chart: CI ........................................................................................................................... 1-5 66 1.5.3 Synopsis of Study Design for DI ......................................................................................................... 1-6 67 1.5.4 Study Flow Chart: DI ........................................................................................................................... 1-8 68 1.5.5 Synopsis of Study Design for HT ........................................................................................................ 1-9 69 1.5.6 Study Flow Chart: HT........................................................................................................................ 1-11 70

CHAPTER 2: SUBJECT ENROLLMENT .................................................................................................................. 2-12 71 2.1 Eligibility Assessment and Informed Consent ....................................................................................... 2-12 72 2.2 Eligibility and Exclusion Criteria ........................................................................................................... 2-12 73

2.2.1 Eligibility Criteria for CI ................................................................................................................... 2-12 74 2.2.2 Eligibility Criteria for DI ................................................................................................................... 2-13 75 2.2.3 Eligibility Criteria for HT .................................................................................................................. 2-13 76

2.3 Historical Information ............................................................................................................................ 2-14 77 2.4 Procedures at the Enrollment Visit ......................................................................................................... 2-14 78

2.4.1 Enrollment Procedures for CI ............................................................................................................ 2-14 79 2.4.2 Enrollment Procedures for DI ............................................................................................................ 2-15 80 2.4.3 Enrollment Procedures for HT ........................................................................................................... 2-16 81

CHAPTER 3: TREATMENT AND FOLLOW-UP ....................................................................................................... 3-1 82 3.1 Treatment ................................................................................................................................................. 3-1 83 3.2 Visit Schedule .......................................................................................................................................... 3-1 84 3.3 Follow-up Visit Testing Procedures (10-week and 12-month visits) ....................................................... 3-1 85

3.3.1 Follow-up Visit Testing Procedures for CI .......................................................................................... 3-1 86 3.3.2 Follow-up Visit Testing Procedures for DI .......................................................................................... 3-2 87 3.3.3 Follow-up Visit Testing Procedures for HT ........................................................................................ 3-2 88

3.4 Non-study Visits ...................................................................................................................................... 3-2 89 3.5 Initiating a New Treatment ...................................................................................................................... 3-2 90

CHAPTER 4: MISCELLANEOUS CONSIDERATIONS ............................................................................................ 4-1 91 4.1 Contacts by the Jaeb Center for Health Research and Sites ..................................................................... 4-1 92 4.2 Subject Withdrawals ................................................................................................................................ 4-1 93 4.3 Management of Refractive Error .............................................................................................................. 4-1 94 4.4 Risks ......................................................................................................................................................... 4-1 95

4.4.1 Risks of Examination Procedures ........................................................................................................ 4-1 96 4.5 Reporting of Adverse Events ................................................................................................................... 4-1 97

4.5.1 Risk Assessment .................................................................................................................................. 4-1 98 4.6 Discontinuation of Study .......................................................................................................................... 4-1 99 4.7 Travel Reimbursement ............................................................................................................................. 4-1 100 4.8 Study Costs .............................................................................................................................................. 4-2 101 4.9 General Considerations ............................................................................................................................ 4-2 102

CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS .................................................... 5-1 103 5.1 Assessment of Investigator Interest / Recruitment Potential .................................................................... 5-1 104 5.2 Sample Size .............................................................................................................................................. 5-1 105 5.3 Primary Analysis – Symptom Success at One Year ................................................................................. 5-2 106 5.4 Secondary Analysis – Motor Success at One Year .................................................................................. 5-3 107 5.5 Additional Analyses ................................................................................................................................. 5-3 108

5.5.1 Secondary Outcomes at One Year ....................................................................................................... 5-3 109 5.5.2 Outcomes at 10 Weeks ........................................................................................................................ 5-3 110

CHAPTER 6: REFERENCES ......................................................................................................................................... 6-1 111 112

SAS1 Protocol v1.1 7-15-15 1-1

CHAPTER 1: BACKGROUND AND SUMMARY 113 114 This study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and is 115 funded through a cooperative agreement from the National Eye Institute. 116 117 1.1 Background 118

Epidemiology and clinical characteristics: 119 New onset adult strabismus has been estimated to affect 54.1/100,000 in a recent population-120 based study in the USA.1 In this study, the most common types of new onset strabismus in 121 adults, after paralytic strabismus, were convergence insufficiency (8.4/100,000), small angle 122 hypertropia (7.5/100,000) and divergence insufficiency (6.0/100,000). For each of these 123 types the incidence increased with increasing age.1 124 125 Convergence insufficiency: 126 Convergence insufficiency (CI) is characterized by an exodeviation greater at near than at 127 distance and a remote near point of convergence and/or decreased positive fusional vergence.2 128 It is typically associated with symptoms such as diplopia, eyestrain, asthenopia, frontal 129 headaches or problems reading.2-4 Treatment consists of either exercises,3, 4prisms,3, 4 surgery,4-130 6 or botulinum toxin injection.7 131 132 There is a paucity of evidence for the effectiveness of treatment for CI in adults, with most 133 previous reports studying effects in children. A recent Cochrane review2 identified two 134 previous randomized clinical trials in adults. Teitelbaum et al8 randomly assigned 29 135 presbyopic patients with symptomatic CI to either progressive addition lenses with base-in 136 prism or progressive addition lenses with no prism. The authors concluded that base-in prism 137 glasses were effective in reducing the symptoms of CI, although interestingly, symptoms also 138 significantly improved with progressive addition lenses with no prism.8 Birnbaum et al9 139 randomly assigned 60 male adult patients to receive office-based vision therapy/orthoptics with 140 supplemental home therapy, home vision therapy alone, or no treatment. Office vision therapy 141 with supplemental home therapy was reported to be most effective with a success rate of 62%. 142 Despite the findings of these two randomized trials there remains much uncertainty as to which 143 treatments are most effective for a given adult patient with CI and what are realistic success 144 rates. 145 146 Divergence insufficiency: 147 Divergence insufficiency (DI) esotropia is a comitant esodeviation worse at distance fixation 148 than at near, typically associated with symptoms of diplopia at distance.10 Treatment most often 149 consists of either prism correction10-13 or strabismus surgery.14, 15 The established surgical 150 procedure for DI esotropia is lateral rectus resection.16-18 Nevertheless, in recent years bilateral 151 medial rectus recession has been advocated.14, 15, 19 There are few studies comparing treatments 152 for DI esotropia, and little data on treatment outcomes, especially over the long-term. One recent 153 study19 claimed medial rectus recession was equivalent to lateral rectus resection but it was 154 retrospective, not randomized, and had small sample size (n=24) and therefore of insufficient 155 power to make such a determination. 156 157 Hypertropia: 158 New onset small angle hypertropia (HT) in adults presents as a comitant hyperdeviation, 159 typically less than 10 prism diopters, in the absence of oblique muscle dysfunction. The patient 160


typically experiences symptoms of vertical diplopia. There are a range of possible causes for 161 such vertical misalignment including skew deviation, sagging eye syndrome,20 myotoxicity 162 following cataract surgery,21, 22 presumed micro-vascular event, or even central peripheral rivalry 163 (dragged fovea-diplopia syndrome).23-25 Treatment most often consists of prism correction of 164 diplopia or strabismus surgery, although partial occlusion may be used in cases of central 165 peripheral rivalry. Regarding surgical approaches for small angle HT, some surgeons perform 166 superior rectus recession, while others have advocated mini-tenotomy (snip) procedures.26 There 167 are, however, limited data on the effectiveness of these treatments for small angle HT and few 168 studies, if any, comparing treatment outcomes. 169 170 Prospective Observational Studies: 171 A prospective observational study monitors different forms of treatment applied to patients with 172 a certain condition. Individuals are enrolled in a prospective observational study on the basis of 173 either disease or exposure status. The care provider, not a protocol, decides how a patient gets 174 treated. Through direct data collection from care providers, the results of the ongoing disease 175 process and medical care can then be observed. 176 177 Prospective observational studies have the advantage of applying inclusion/exclusion criteria and 178 not dictating management. The large patient sample often enables better estimation of outcome 179 rates. Also, since data are collected within standard clinical practice, the results have high 180 external validity. Weaknesses of observational studies include difficulty in identifying and 181 controlling all sources of bias, and challenges with respect to data analyses. There may also be 182 variability in time intervals between visits and treatments, and the potential for confounding 183 makes treatment group comparisons difficult to interpret. Despite these weaknesses, future 184 randomized controlled trials may be developed based on preliminary estimates of treatment 185 effects that an observational study provides for the studied conditions. 186 187 1.2 Rationale for the study 188

Purpose of an adult CI-DI-HT strabismus prospective observational study: 189 A prospective adult strabismus observational study will provide data on the numbers, types and 190 clinical characteristics of adult patients with CI, DI or HT who are seen by PEDIG investigators 191 and are receiving certain types of treatments , and on the outcomes of those treatments over one 192 year. These data will be used to generate hypotheses for possible future PEDIG studies, 193 including randomized trials. Data collected will include angle of deviation, diplopia severity, 194 treatment type, and treatment outcome. 195 196 Public health importance: 197 There are limited prospective, standardized data available on adults with convergence 198 insufficiency, divergence insufficiency or small angle hypertropia, the commonest causes of non-199 paralytic adult strabismus. This study will inform regarding the numbers and types of adults 200 with these conditions seen by PEDIG investigators, enabling the generation of hypotheses for 201 potential PEDIG studies and estimation of their recruitment feasibility. 202 203 1.3 Considerations 204

It is recognized that estimates of treatment success may be biased by patient selection, but for 205 some conditions / treatments, these data will be the best available for planning future PEDIG 206 studies. 207 208


1.4 Study Objectives 209

To describe clinical characteristics, treatments, and one-year outcomes of adults with 210 convergence insufficiency, divergence insufficiency, or small angle hypertropia. Treatment 211 comparisons within the studied conditions will also be done to help develop future studies. 212 213 1.5 Synopsis of Study Design 214

1.5.1 Synopsis of Study Design for CI 215

Major Eligibility Criteria (see section 2.2.1 for full details) 216

• Adults ≥18 years of age (adult onset of CI not required) 217

• No strabismus surgery in the past 10 years 218

• CI Symptom Survey score ≥21 points 219

• Near exodeviation of ≥4∆ and at least 4∆ larger than at distance by PACT 220

• Distance exodeviation ≤15∆ by PACT 221

• Vertical deviation ≤2∆ at distance and near by PACT 222

• No constant exotropia at distance or near 223

• Reduced positive fusional vergence (PFV) at near (<20∆ or fails Sheard’s criterion that the 224 PFV measures less than twice the magnitude of the near phoria) 225

• Near point of convergence (NPC) of ≥6 cm break 226

• No paralytic strabismus, paretic strabismus, restrictive strabismus, monocular diplopia, 227 thyroid eye disease, myasthenia gravis, chronic progressive external ophthalmoplegia, or eye 228 movement abnormalities associated with known neurological disease. Patients with 229 Parkinson's disease can be enrolled if non-paretic deviation. 230

• Visual acuity 20/50 or better in both eyes by ETDRS or Snellen 231

• Ability to fuse with prism in space (see section 2.4.1) 232

• Investigator is initiating treatment with prism, orthoptic exercises, botulinum toxin injection 233 or surgery 234

• If initiating treatment with botulinum toxin or surgery, planned injection or surgery to be 235 within 60 days of enrollment. 236

• Treatment to be initiated has not been used within the past one year 237 238 Treatment 239 Treatment is per the investigator’s usual clinical practice. 240 241 Data will be collected for the following treatment modalities: 242

• Bilateral medial rectus muscle resection surgery 243

• Single medial rectus muscle resection surgery 244

• Recess lateral rectus muscle resection medial rectus muscle surgery 245

• Bilateral lateral rectus muscle recession surgery 246

• Single lateral rectus muscle recession surgery 247

• Botulinum toxin injection 248

• Prisms 249

• Orthoptic exercises, including computer-based therapy 250 251 Sample Size 252 50 subjects per non-surgical treatment modality (prism, orthoptic exercises) and up to 100 253 subjects undergoing surgery (maximum 50 per surgical modality) will be enrolled, for a total of 254


up to 200 subjects with CI. Recruitment will continue for 1 year, at which time the determination 255 will be made whether the recruitment period should be extended to allow for additional subjects 256 to be enrolled in treatment modality groups that have not reached their maximum. 257 258 Visit Schedule 259

• Baseline Visit 260

• 10 week ± 3 weeks following intervention 261

• 12-months ± 2 months following intervention 262 263 Visits will be timed from the date of surgery or botulinum toxin injection (if applicable); or if 264 prescribed prism or orthoptic exercises, visits will be timed from the day of enrollment. Subjects 265 can remain in the study up to an additional year and have up to two additional follow up visits if 266 their treatment modality is changed during the study. 267 268 Outcome 269 The primary outcome will be symptom success at the 10-week and 12-month visit, defined as 270 improvement of CI Symptom Survey (CISS) score of at least 9 points and an outcome score of 271 <21 points. For surgical treatment, a secondary, motor outcome will evaluate how often subjects 272 have become orthotropic at distance and near after treatment. 273

274


Baseline Exam

Confirm Eligibility as Defined in Section 2.2.1

Testing Procedures • CI Symptom Survey (CISS) • Diplopia Questionnaire • Adult Strabismus 20 (AS-20) Questionnaire • Distance visual acuity (ETDRS or Snellen) • Ocular Alignment (cover/uncover, SPCT, PACT) • Fusion with prism in space • Positive fusional vergence • Near point of convergence

1.5.2 Study Flow Chart: CI 275

276 277 278 279 280 281

Interim Outcome Exam: 10 weeks ± 3 weeks

(timed from initiation of treatment)

• CI Symptom Survey (CISS) • Diplopia Questionnaire • Adult Strabismus 20 (AS-20) Questionnaire • Distance visual acuity (ETDRS or Snellen: Same as at baseline) • Ocular Alignment (cover/uncover, SPCT, PACT) • Positive fusional vergence

• Near point of convergence

Outcome Exam: 12-Month ± 2 months exam


• CI Symptom Survey (CISS) • Diplopia Questionnaire • Adult Strabismus 20 (AS-20) Questionnaire • Distance visual acuity (ETDRS or Snellen: Same as at baseline) • Ocular Alignment (cover/uncover, SPCT, PACT) • Positive fusional vergence • Near point of convergence


1.5.3 Synopsis of Study Design for DI 282


• Adults ≥18 years of age 284

• Adult-onset DI (at ≥18 years of age) 285

• No prior strabismus surgery 286

• Symptoms of diplopia at distance with a frequency of sometimes or worse in primary 287 position 288

• Distance esodeviation of 2∆ to 30∆ and at least 50% larger than magnitude of deviation at 289 near by PACT 290

• No more than 5∆ difference between right and left gaze by PACT 291

• No more than 10∆ difference between primary position and either upgaze or downgaze by 292 PACT 293

• Any coexisting vertical deviation must be less than the distance esodeviation and ≤10∆ by 294 PACT 295

• No paralytic strabismus, paretic strabismus, restrictive strabismus, monocular diplopia, 296 thyroid eye disease, myasthenia gravis, chronic progressive external ophthalmoplegia, or eye 297 movement abnormalities associated with known neurological disease. Patients with 298 Parkinson's disease can be enrolled if non-paretic deviation 299



• Investigator is initiating treatment with prism, orthoptic exercises, botulinum toxin injection, 302 or surgery 303



• Bilateral lateral rectus muscle resection surgery 312

• Single lateral rectus muscle resection surgery 313

• Recess medial rectus muscle resection lateral rectus muscle surgery 314

• Bilateral medial rectus muscle recession surgery 315

• Single medial rectus muscle recession surgery 316


• Prisms 318

• Orthoptic exercises, including computer-based therapy 319 320 Sample Size 321 50 subjects per non-surgical treatment modality (prism, orthoptic exercises) and up to 150 322 subjects undergoing surgery (maximum 50 per surgical modality) will be enrolled, for a total of 323 up to 250 subjects with DI. Recruitment will continue for 1 year, at which time the 324 determination will be made whether the recruitment period should be extended to allow for 325 additional subjects to be enrolled in treatment modality groups that have not reached their 326 maximum. 327 328


Visit Schedule 329


• 10 week ± 3 weeks following intervention 331

• 12-months ± 2 months following intervention 332 333 Visits will be timed from the date of surgery or botulinum toxin (if applicable); or if prescribed 334 prism or orthoptic exercises, visits will be timed from the day of enrollment. Subjects can 335 remain in the study up to an additional year and have up to two additional follow up visits if their 336 treatment modality is changed during the study. 337 338 Outcomes 339 The primary outcome will be symptom success at the 10-week and 12-month visit, defined as 340 diplopia “rarely” or “never” in primary position at distance on the diplopia questionnaire. For 341 surgical treatment, a secondary, motor outcome will evaluate how often subjects have become 342 orthotropic at distance and near after treatment. 343

344


Baseline Exam


Testing Procedures • Diplopia Questionnaire • Adult Strabismus 20 (AS-20) Questionnaire • Distance visual acuity (ETDRS or Snellen) • Ocular Alignment (cover/uncover, SPCT, PACT) • Fusion with prism in space

• Negative fusional vergence

1.5.4 Study Flow Chart: DI 345

346 347


(timed from initiation of treatment) • Diplopia Questionnaire • Adult Strabismus 20 (AS-20) Questionnaire • Distance visual acuity (ETDRS or Snellen: Same as at baseline) • Ocular Alignment (cover/uncover, SPCT, PACT)




• Diplopia Questionnaire • Adult Strabismus 20 (AS-20) Questionnaire • Distance visual acuity (ETDRS or Snellen: Same as at baseline) • Ocular Alignment (cover/uncover, SPCT, PACT)



1.5.5 Synopsis of Study Design for HT 348



• Adult-onset HT (at ≥18 years of age) 351


• Symptoms of diplopia at distance or near with a frequency of sometimes or worse in primary 353 position at distance or reading position 354

• Vertical deviation ≥1∆ to ≤10∆ at distance and near by prism and alternate cover test (PACT) 355

• No more than 4∆ difference from the primary in any gaze position by PACT 356

• Any coexisting esodeviation must be less than the vertical deviation by PACT 357

• Any coexisting exodeviation ≤10∆ by PACT 358

• No convergence insufficiency as defined in section 2.2.1 359

• No paralytic strabismus, paretic strabismus, restrictive strabismus, monocular diplopia, 360 thyroid eye disease, myasthenia gravis, chronic progressive external ophthalmoplegia, or eye 361 movement abnormalities associated with known neurological disease. Patients with 362 Parkinson's disease can be enrolled if non-paretic deviation 363






• Vertical rectus muscle recession surgery 376

• Vertical rectus muscle mini-tenotomy (snip) surgery 377


• Prisms 379

• Orthoptic exercises, including computer-based therapy 380 381 Sample Size 382 50 subjects per non-surgical treatment modality (prism, orthoptic exercises) and up to 100 383 subjects undergoing surgery (maximum 50 per surgical modality) will be enrolled, for a total of 384 up to 200 subjects with HT. Recruitment will continue for 1 year, at which time the 385 determination will be made whether the recruitment period should be extended to allow for 386 additional subjects to be enrolled in treatment modality groups that have not reached their 387 maximum. 388 389 Visit Schedule 390


• 10-week ± 3 weeks following intervention 392

• 12-months ± 2 months following intervention 393 394

SAS1 Protocol v1.1 7-15-15 1-10

Visits will be timed from the date of surgery or botulinum toxin injection (if applicable); or if 395 prescribed prism or orthoptic exercises, visits will be timed from the day of enrollment. Subjects 396 can remain in the study up to an additional year and have up to two additional follow up visits if 397 their treatment modality is changed during the study. 398 399 Outcomes 400 The primary outcome will be symptom success at the 10-week and 12-month visit, defined as 401 diplopia “rarely” or “never” both in primary position at distance and in reading position on the 402 diplopia questionnaire. For surgical treatment, a secondary, motor outcome will evaluate how 403 often subjects have become orthotropic at distance and near after treatment. 404 405

406

SAS1 Protocol v1.1 7-15-15 1-11

Baseline Exam


Testing Procedures • Diplopia Questionnaire • Adult Strabismus 20 (AS-20) Questionnaire • Distance visual acuity (ETDRS or Snellen) • Ocular Alignment (cover/uncover, SPCT, PACT) • Fusion with prism in space • Vertical fusional amplitudes

• Double Maddox Rod Testing

1.5.6 Study Flow Chart: HT 407

408 409 410 411 412 413


(timed from initiation of treatment) • Diplopia Questionnaire • Adult Strabismus 20 (AS-20) Questionnaire • Distance visual acuity (ETDRS or Snellen: Same as at baseline) • Ocular Alignment (cover/uncover, SPCT, PACT) • Vertical fusional amplitudes • Double Maddox Rod Testing



• Diplopia Questionnaire • Adult Strabismus 20 (AS-20) Questionnaire • Distance visual acuity (ETDRS or Snellen: Same as at baseline) • Ocular Alignment (cover/uncover, SPCT, PACT) • Vertical fusional amplitudes • Double Maddox Rod Testing

SAS1 Protocol v1.1 7-15-15 2-12

CHAPTER 2: SUBJECT ENROLLMENT 414 415 2.1 Eligibility Assessment and Informed Consent 416

A maximum of 650 subjects will be enrolled in the study. A maximum of 50 subjects per 417 treatment modality (prism, orthoptic exercises, surgery of a specific type) per condition (CI, DI, 418 HT) will be enrolled, with up to 100 CI subjects treated with surgery, up to 150 DI subjects 419 treated with surgery, and up to 100 HT subjects treated with surgery. Recruitment will continue 420 for 1 year, at which time the determination will be made whether the recruitment period should 421 be extended to allow for additional subjects to be enrolled in treatment modality groups that have 422 not reached their maximum. 423 424 A subject is considered for the study after undergoing a routine eye examination (by a study 425 investigator as part of standard of care), or a referral, that identifies CI, DI, or HT that appears to 426 meet the eligibility criteria. The study will be discussed with the subject. Subjects who express 427 an interest in the study will be given a copy of the informed consent form to read. Written 428 informed consent must be obtained from the subject prior to performing any study-specific 429 procedures that are not part of the subject’s routine care. 430 431 432 2.2 Eligibility and Exclusion Criteria 433

2.2.1 Eligibility Criteria for CI 434

The following criteria must be met for the subject to be enrolled into the study: 435

• Adults ≥18 years of age (adult onset of CI not required) 436

• No strabismus surgery within the past 10 years 437

• CI Symptom Survey score ≥21 points 438

• Near exodeviation of ≥4∆ and at least 4∆ larger than at distance by PACT 439

• Distance exodeviation ≤15∆ by PACT 440

• Vertical deviation ≤2∆ at distance and near by PACT 441

• No constant exotropia at distance or near 442

• Reduced positive fusional vergence (PFV) at near (<20∆ or fails Sheard’s criterion that the 443 PFV measures less than twice the magnitude of the near phoria) 444

• Near point of convergence (NPC) of ≥6 cm break 445


• No paralytic strabismus (e.g., 3rd, 4th, or 6th cranial nerve palsies, skew deviation, Duane 447 syndrome) 448

• No restrictive strabismus (e.g., blowout fracture, thyroid eye disease, post scleral buckle, 449 Brown syndrome) 450

• No monocular diplopia 451

• No paretic strabismus, thyroid eye disease, myasthenia gravis, chronic progressive external 452 ophthalmoplegia, or eye movement abnormalities associated with known neurological 453 disease. Patients with Parkinson's disease can be enrolled if non-paretic deviation. 454

• No inferior or superior oblique overaction defined as 2+ or greater 455


• Ability to understand and complete a survey 457


SAS1 Protocol v1.1 7-15-15 2-13

• If initiating treatment with botulinum toxin or surgery, planned injection or surgery to be 460 within 60 days of enrollment 461

• Single treatment modality is planned (e.g., no combined prism and orthoptic exercises) 462

• Treatment to be initiated has not been used within the past one year 463 464

2.2.2 Eligibility Criteria for DI 465



• Adult-onset DI (at ≥18 years of age) 468


• Symptoms of diplopia at distance with a frequency of sometimes or worse in primary 470 position (in current glasses if wearing glasses) 471

• Distance esodeviation of 2∆ to 30∆ and at least 50% larger than at near by PACT 472

• No more than 5∆ difference between right and left gaze by PACT 473

• No more than 10∆ difference between the primary position at distance and either upgaze or 474 downgaze ≤10∆ by PACT 475

• Any coexisting vertical deviation must be less than distance esodeviation and ≤10∆ by PACT 476





• No paretic strabismus, thyroid eye disease, myasthenia gravis, chronic progressive external 483 ophthalmoplegia, or eye movement abnormalities associated with known neurological 484 disease. Patients with Parkinson's disease can be enrolled if non-paretic deviation 485






• Single treatment modality planned (e.g., no combined prism and orthoptic exercises) 493


2.2.3 Eligibility Criteria for HT 496



• Adult-onset HT (at ≥18 years of age) 499


• Symptoms of diplopia at distance or near with a frequency of sometimes or worse in primary 501 or reading position (in current glasses if wearing glasses) 502

• Vertical deviation ≥1∆ to ≤10∆ at distance and near by PACT 503

• No more than 4∆ difference from the primary in any gaze position by PACT 504

• Any coexisting esodeviation must be less than the vertical deviation 505

SAS1 Protocol v1.1 7-15-15 2-14

• Any coexisting exodeviation ≤10∆ by PACT 506

• No convergence insufficiency as defined in section 2.2.1 507





• No paretic strabismus, thyroid eye disease, myasthenia gravis, chronic progressive external 514 ophthalmoplegia, or eye movement abnormalities associated with known neurological 515 disease. Patients with Parkinson's disease can be enrolled if non-paretic deviation. 516






• Single treatment modality planned (e.g., no combined prism and orthoptic exercises) 524


2.3 Historical Information 527

Historical information collected at enrollment will include the following: 528

• Presence of co-existing neurological conditions (e.g., Parkinson’s, Progressive supranuclear 529 palsy, basal ganglia disease, stroke, or intracranial tumor) and any treatment 530

• Presence of epiretinal membrane, age-related macular degeneration (dry or neovascular), or 531 macular pathology (if known) 532

• Heart disease 533

• Diabetes 534

• Autoimmune disease (other than myasthenia gravis and thyroid eye disease) 535

• Previous treatment for strabismus (surgical and/or non-surgical) 536

• Other major medical problems (e.g., significant head trauma) 537 538 2.4 Procedures at the Enrollment Visit 539

All examination procedures must be tested before initiating planned treatment and within 7 days 540 of enrollment. All examination procedures at enrollment are performed in the subject’s current 541 correction, if required, and without cycloplegia. Any subjects wearing pre-study prism 542 correction will be measured in trial frames without prism (unless otherwise noted below). If new 543 correction is prescribed on the day of testing, or if the subject forgot to bring his/her spectacles, 544 then testing should be done in trial frames. Full details for each procedure are listed in the 545 Procedures Manual. Questionnaires and the symptom survey (if applicable) should be 546 administered to the subject prior to other examination procedures. 547 548 2.4.1 Enrollment Procedures for CI 549

550 1. Convergence Insufficiency Symptom Survey (CISS) 551

SAS1 Protocol v1.1 7-15-15 2-15

552 2. Diplopia Questionnaire (DQ) 553

554 3. Adult Strabismus 20 (AS-20) Questionnaire 555

556 4. Distance Visual Acuity 557

� Monocular distance visual acuity testing will be performed in each eye using 558 ETDRS or Snellen optotypes. 559

� If wearing ground-in prism correction, testing will be done wearing current 560 correction with prism; if wearing Fresnel prism, testing will be done in trial 561 frames without prism correction. 562

563 The following must be tested by an examiner who is a pediatric ophthalmologist, 564 pediatric optometrist, or certified orthoptist. 565 566 5. Ocular Alignment Testing 567

� Ocular alignment will be assessed by the cover/uncover test and by simultaneous 568 prism and cover test (SPCT) in primary gaze position at distance (6 meters) and at 569 near (1/3 meter). 570

� Prism and alternate cover test (PACT) will be tested at distance (6 meters) and 571 near (1/3 meter) in primary position. 572 573

6. Fusion with Prism in Space 574 � Ability to fuse with prism in space will be determined by asking the subject to 575

view a 20/50 single optotype at 6 meters while neutralizing the deviation with free 576 prisms. Subjects should be asked if they can make the image single. Subjects 577 who are unable to make the image single are ineligible. 578 579

7. Positive Fusional Vergence (PFV) 580 � PFV will be measured with a horizontal prism bar and a hand-held fixation target 581

(20/50 single optotype) at 40 cm. Blur, break, and recovery points will be 582 recorded. If no blur point is detected, the PFV score will be the break point 583 measurement. 584

585 8. Near Point of Convergence (NPC) 586

� Break and recovery values will be measured. 587 588 2.4.2 Enrollment Procedures for DI 589

590 1. Diplopia Questionnaire 591




SAS1 Protocol v1.1 7-15-15 2-16




� Prism and alternate cover test (PACT) will be tested at distance (6 meters) and 609 near (1/3 meter) in primary position. 610

611 5. Fusion with Prism in Space 612

� Ability to fuse with prism will be determined by asking the subject to view a 613 20/50 single optotype at 6 meters, and using prism(s), determine if any 614 combination allows the subject to have single vision. Subjects who are unable to 615 make the image single are ineligible. 616 617

6. Negative Fusional Vergence (NFV) 618 � NFV will be measured with a horizontal prism bar while the subject is viewing an 619

accommodative target (20/50 single optotype) at 6 meters. Blur, break, and 620 recovery points will be recorded. If no blur point is measured, the NFV score will 621 be the break point measurement. 622

623 2.4.3 Enrollment Procedures for HT 624

625 1. Diplopia Questionnaire 626







� Prism and alternate cover test (PACT) will be tested at distance (6 meters) and 644 near (1/3 meter) in primary position. 645

SAS1 Protocol v1.1 7-15-15 2-17

646 5. Fusion with Prism in Space 647

� Ability to fuse with prism will be determined by asking the subject to view a 648 20/50 single optotype at 6 meters, and using prism(s), determine if any 649 combination allows the subject to have single vision. Subjects who are unable to 650 make the image single are ineligible. 651

652 6. Vertical Fusional Amplitudes 653

� Vertical fusional amplitudes will be measured with a vertical prism bar while the 654 subject is viewing an accommodative target (20/50 single optotype) at 6 meters. 655 Break and recovery points will be recorded. Measurements will be taken in both 656 vertical directions to measure the range of vertical fusion. 657

� Vertical deviation should be corrected at least with sufficient prism to give the 658 subject single vision either in current correction (if pre-study prism) or with prism 659 correction in trial frames. 660

661 7. Double Maddox Rod Testing 662

� Ocular cyclotorsion will be assessed by double Maddox rod in primary gaze 663 position at near (1/3 meters). 664

665


CHAPTER 3: TREATMENT AND FOLLOW-UP 666 667 3.1 Treatment 668

Treatment is at investigator discretion and may be changed or discontinued at any time during 669 the study. The type of treatment and other treatment details (e.g., magnitude of prism, amount of 670 orthoptic exercises) will be recorded at the time of enrollment when the treatment is prescribed. 671 For surgical subjects, the type and amount of surgery will be recorded. If an adjustable 672 technique is used, the final location of the muscle and alignment after adjustment will be 673 recorded. For those treated with botulinum toxin injection, the muscle(s) injected and dose will 674 be recorded. The timing of surgical intervention after enrollment is at investigator discretion; 675 however, the enrollment assessments must be redone if surgery is not done within 60 days. 676

677 Changing treatment within a modality (e.g., frequency, strength, intensity) has no impact on the 678 subject’s visit schedule. Switching to a different treatment or adding a second treatment to the 679 initial treatment has implications for the subject’s visit schedule (see section 3.5). 680

681 3.2 Visit Schedule 682

Subjects enrolled will have visits at the following times: 683

• 10 weeks ± 3 weeks following intervention 684

• 12 months ± 2 months following intervention 685 686 Visits will be timed from the date of surgery or botulinum toxin injection (if applicable); or if 687 prescribed prism or orthoptic exercises, will be timed from the day of enrollment. If a new 688 treatment is initiated, the visit schedule may restart or the subject’s study participation may end, 689 according to the details in section 3.5. 690 691 3.3 Follow-up Visit Testing Procedures (10-week and 12-month visits) 692

At each visit, data on treatments received, any change in the amount/intensity of treatment, or 693 any major change in eye condition since the last visit will be collected. In addition, the 694 following will be performed / completed as done at the enrollment exam in the subject’s current 695 correction, if required, and without cycloplegia. Any subjects wearing prism correction will be 696 measured in trial frames without prism (unless otherwise noted below). If new correction is 697 prescribed on the day of testing, or if the subject forgot to bring his/her spectacles, then testing 698 should be done in trial frames. 699 700 3.3.1 Follow-up Visit Testing Procedures for CI 701

See section 2.4.1 for details. 702 1. CISS 703 2. Diplopia Questionnaire 704 3. AS-20 Questionnaire 705 4. Distance Visual Acuity 706

• If wearing ground-in prism correction, testing will be done wearing current correction 707 with prism; if wearing Fresnel prism, testing will be done in trial frames without 708 prism correction. 709

5. Ocular Alignment Testing 710 6. Positive Fusional Vergence 711 7. Near Point of Convergence 712


713 3.3.2 Follow-up Visit Testing Procedures for DI 714

See section 2.4.2 for details. 715 1. Diplopia Questionnaire 716 2. AS-20 Questionnaire 717 3. Distance Visual Acuity 718


4. Ocular Alignment Testing 722 5. Negative Fusional Vergence 723

724 3.3.3 Follow-up Visit Testing Procedures for HT 725

See section 2.4.3 for details. 726 1. Diplopia Questionnaire 727 2. AS-20 Questionnaire 728 3. Distance Visual Acuity 729


4. Ocular Alignment Testing 733 5. Vertical Fusional Amplitudes 734

• Vertical deviation should be corrected at least with sufficient prism to give the subject 735 single vision either in current correction (if pre-study prism) or with prism correction 736 in trial frames. 737

6. Double Maddox Rod Testing 738 739 3.4 Non-study Visits 740

Additional non-study visits and treatment are at investigator discretion. Investigators must 741 follow the procedures for initiating a new treatment during the study as outlined in section 3.5. 742 743 3.5 Initiating a New Treatment 744

If any new treatment is initiated during the study an early outcome exam as outlined in section 745 3.3 will be completed. Study participation will end if the new treatment is prism or exercises, 746 unless initially enrolled in the surgery or botox injection group. If the new treatment is a new 747 surgical modality or botox injection (not a re-operation or re-injection in the study), the 748 examination will serve both as the outcome exam for the initial treatment and the baseline exam 749 for the newly initiated surgery or botox injection, if the subject still meets eligibility criteria. The 750 subject will then be followed for an additional 12-months in the study in the new treatment, as if 751 they had been newly enrolled. 752 753 In the event that the study category for the newly initiated surgical modality is no longer 754 recruiting subjects, the subject will complete an early outcome exam at the time the new surgery 755 or botox injection is prescribed and study participation will end for this subject. 756 757 Subjects who have had surgery or botox injection as their initial treatment (or as a new treatment 758 during the study) will continue to be followed until the 12-month outcome exam whether or not 759


an additional treatment is initiated. The exception is if a re-operation or re-injection is planned 760 prior to the 12-month outcome. In this case, an early outcome exam will be completed at the 761 time surgery is prescribed. Study participation will end following the outcome examination. 762 763 Subjects who have completed the study and are returning for additional treatment following an 764 unspecified period of time beyond the outcome exam may be enrolled a second time provided 765 they meet eligibility criteria and the study category for the newly initiated treatment is still 766 recruiting subjects. Subjects enrolling as a study subject a second time must repeat the consent 767 process. 768 769


CHAPTER 4: MISCELLANEOUS CONSIDERATIONS 770 771 4.1 Contacts by the Jaeb Center for Health Research and Sites 772

The Jaeb Center serves as the PEDIG Coordinating Center. The Jaeb Center will be provided 773 with the subject’s contact information. The Jaeb Center will contact each subject one month 774 before any 12-month visit (including a second 12-month visit which could be required if the 775 patient changed treatments during the study). Permission for such contacts will be included in 776 the Informed Consent Form. The principal purpose of the contacts will be to help coordinate 777 scheduling of the 12-month outcome examination. 778 779 4.2 Subject Withdrawals 780

Subjects may withdraw from the study at any time. This is expected to be a very infrequent 781 occurrence in view of the study design’s similarity to routine clinical practice. If the subject 782 indicates they want to withdraw from the study, the investigator personally should attempt to 783 speak with them to determine the reason. If their interest is in transferring their care to another 784 eye care provider, every effort should be made to comply with this and at the same time try to 785 keep the participant in the study under the new provider’s care. 786 787 4.3 Management of Refractive Error 788

Management of refractive error is at the discretion of the investigator. 789 790 4.4 Risks 791

There are no risks in this study that would not be part of usual care. 792 793 4.4.1 Risks of Examination Procedures 794

The procedures in this study are part of daily eye care practice in the United States and pose no 795 known risks. 796 797 4.5 Reporting of Adverse Events 798

No treatments are being prescribed that are not part of usual care. Investigators will abide by 799 local IRB reporting requirements. 800 801 4.5.1 Risk Assessment 802

It is the investigators’ opinion that the protocol’s level of risk is research not involving greater 803 than minimal risk. 804 805 4.6 Discontinuation of Study 806

The study may be discontinued by the Steering Committee (with approval of the Data and Safety 807 Monitoring Committee) prior to the preplanned completion of enrollment and follow-up for all 808 subjects. 809 810 4.7 Travel Reimbursement 811

Subjects will be compensated $25 for each 10-week visit and $50 for each 12-month visit (by 812 money-card) up to a maximum of $150. If there are extenuating circumstances, and the subject 813


is unable to complete study visits without additional funds for travel costs, additional funds may 814 be provided. 815 816 4.8 Study Costs 817

The study will pay for visits specific to the research study, but will not pay for usual care visits 818 that would occur whether or not the subject was in the study. The cost of usual care visits will be 819 the responsibility of the participant or his/her insurance company. 820 821 Any costs associated with treatment will not be paid for by the study and will be the 822 responsibility of the participant or his/her insurance company. 823 824 4.9 General Considerations 825

The study is being conducted in compliance with the policies described in the network policies 826 document, with the ethical principles that have their origin in the Declaration of Helsinki, with 827 the protocol described herein, and with the standards of Good Clinical Practice. 828 829 Data will be directly collected in electronic case report forms, which will be considered the 830 source data. 831 832 There is no restriction on the number of participants to be enrolled by a site. A risk-based 833 monitoring approach will be followed, consistent with the FDA “Guidance for Industry 834 Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 2013). 835


CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS 836 837 5.1 Assessment of Investigator Interest / Recruitment Potential 838

At the February 2014 PEDIG Study Group meeting, 18 (44%) of 41 ophthalmologist 839 investigators and 26 (65%) of 40 optometrists investigators indicated they would be willing to 840 participate in this study. In addition, 8 (20%) of 41 ophthalmologists and 8 (20%) of 40 841 optometrists rated this protocol in the top 5 of 18 protocol ideas reviewed with the group. The 842 study ranked 13th among the 18 protocol ideas reviewed with the group for the 81 investigators 843 overall. 844 845 Table 1 shows a summary of the results from a February 2015 email survey of PEDIG 846 investigators. For each condition (CI, DI, and HT), investigators were asked whether they 847 treated patients with the condition and how many they treated with various treatment modalities 848 over the course of one year. 849 850 Table 1: Assessment of Recruitment Potential 851

Condition

Number of Patients Treated in One Year In PEDIG Network*

Prism Orthoptic Exercises Surgery

CI 229 192 23**

DI 119 20 85***

HT 194 10 39**** * Cases treated with more than one type of treatment are counted for each type of treatment. 852 ** Bilateral medial rectus resection (N=11), other (N=12) 853 *** Bilateral medial rectus recession (N=51), bilateral lateral rectus resection (N=13), other (N=21) 854 ****Vertical rectus recession (N=37), other (N=2) 855 856 5.2 Sample Size 857

The maximum total sample size of 650 is based on a convenience sample of a maximum of 50 858 subjects per treatment modality (prism, orthoptic exercises, surgery of a specific type) per 859 condition (CI, DI, HT), with up to 100 subjects treated with surgery for CI and for HT, and up to 860 150 subjects treated with surgery for DI (Table 2). 861 862 Table 2: Maximum Sample Size for Each Condition/ Treatment Modality 863

Condition

Maximum Sample Size

Prism Orthoptic Exercises Surgery

CI 50 50 100*

DI 50 50 150*

HT 50 50 100* *Within this limit for the total number of surgeries for a given condition, no more than 50 surgeries of a specific 864 type (e.g. bilateral medial rectus recessions, bilateral lateral rectus resection, botulinum toxin injection, etc.) may be 865 enrolled. 866 867 Based on the assessment of recruitment potential (section 5.1), about half of the 868 modality/condition groups would be expected to be filled to 50 subjects within one year (see 869 Table 1). The remaining modality/condition groups might have a smaller-than-desired sample 870 size for analysis or might require recruitment for more than one year. 871 872

873


Table 3 shows the expected half-widths for the 95% confidence interval for the success 874 proportion estimate for each modality/condition group. 875 876 Table 3: Expected ½-Width of 95% Confidence Interval as a Function of Sample Size and 877 Success Proportion* 878

One-Year

Success Proportion

Sample Size

10

20

30

40

50

1% 6% 4% 4% 3% 3%

3% 11% 8% 6% 5% 5%

5% 14% 10% 8% 7% 6%

10% 19% 13% 11% 9% 8%

15% 22% 16% 13% 11% 10%

20% 25% 18% 14% 12% 11%

25% 27% 19% 16% 13% 12%

30% 28% 20% 16% 14% 13%

40% 30% 22% 18% 15% 14%

50% 31% 22% 18% 15% 14% *Note: The grey boxes indicate that validity of confidence interval widths is questionable because the normal 879 approximation might not be valid given these low probability of success and/or small sample sizes. 880 881 After accounting for up to 5% loss to follow-up, a sample size of 50 patients per treatment 882 modality (prism, orthoptic exercises, surgery of a specific type) per condition would contribute 883 about 47 subjects to the point estimate for a dichotomous success/failure outcome at one year. 884 With 47 subjects, the maximum width of the resulting confidence intervals on each point 885 estimate would be ±14%. 886 887 5.3 Primary Analysis – Symptom Success at One Year 888

For each of the modality/condition groups, the primary analysis will be an estimation of the 889 proportion of patients of patients with treatment success based on improvement of symptoms at 890 10 weeks post intervention and at one year, with 95% confidence intervals. 891 892 Table 4 shows the criteria for symptom success for each condition, which will be used to assess 893 all treatment modalities. 894 895 Table 4: One-Year Symptom Success Criteria for Each Condition 896

Condition One-Year Symptom Success Criteria

CI improvement of CI Symptom Survey (CISS) score of at least 9 points AND a score of <21 points

DI diplopia no more than rarely in the past week in the primary position (question #1.1 on the Diplopia questionnaire)

HT diplopia no more than rarely in the past week both in the primary position and for reading (questions #1.1 and #1.2 on the Diplopia questionnaire)

897 For patients who initiate a new treatment before completing one year of follow-up, the symptom 898 success/failure status from the visit at which treatment was changed (i.e., the 10-week interim 899 visit or an early outcome visit) will be brought forward as their one-year outcome. 900 901


Rubin’s multiple imputation21 will be used to impute outcome for patients who have not changed 902 treatments but who are who are lost to follow-up or withdraw from the study prior to one-year 903 exam. 904 905 5.4 Secondary Analysis – Motor Success at One Year 906

For each surgery type within a condition, a secondary objective will be to calculate the 907 proportion of patients with motor success at one year and a 95% confidence interval. Motor 908 success will be defined as orthotropia by cover/uncover at distance and near fixation in primary 909 position at one year. Similar to the primary analysis of symptom success, for patients who 910 change treatments before completing one year of follow-up, the motor success/failure status from 911 the visit at which treatment was changed (i.e., the 10-week interim visit or an early outcome 912 visit) will be brought forward as the one-year outcome. In addition, Rubin’s multiple 913 imputation21 will be used to impute outcome for patients who have not changed treatments but 914 who are who are lost to follow-up or withdraw from the study prior to one-year exam. 915 916 5.5 Additional Analyses 917

5.5.1 Secondary Outcomes at One Year 918

Secondary outcomes at one year will be evaluated within each modality/condition. Secondary 919 outcomes to be assessed include motor alignment, near point of convergence (CI only), positive 920 fusional vergence (CI only), negative fusional vergence (DI only), vertical fusional vergence (HT 921 only), and the Adult Strabismus 20 (AS-20) questionnaire. In addition, mean CI Symptom 922 Survey (CISS) score will be evaluated for CI, and the AS-20 and Diplopia Questionnaire will be 923 evaluated as a continuous outcomes for all three conditions. 924 925 5.5.2 Outcomes at 10 Weeks 926

Outcomes at the 10-week interim visit will be evaluated similarly to the primary and secondary 927 analyses defined for one-year time points (sections 5.3, 5.4 and 5.5.1). 928 929 930


CHAPTER 6: REFERENCES 931 932 1. Martinez-Thompson JM, Diehl NN, Holmes JM, Mohney BG. Incidence, types, and lifetime 933

risk of adult-onset strabismus. Ophthalmology 2014;121:877-882. 934 2. Scheiman M, Gwiazda J, Li T. Non-surgical interventions for convergence insufficiency. 935

Cochrane Database of Systematic Reviews 2011;16:CD006768. 936 3. Lavrich JB. Convergence insufficiency and its current treatment. Current Opinion in 937

Ophthalmology 2010;21:356-360. 938 4. Cooper J, Jamal N. Convergence insufficiency-a major review. Optometry 2012;83:137-158. 939 5. von Noorden GK. Resection of both medial rectus muscles in organic convergence 940

insufficiency. American Journal of Ophthalmology 1976;81:223-226. 941 6. Choi DG, Rosenbaum AL. Medial rectus resection(s) with adjustable suture for intermittent 942

exotropia of the convergence insufficiency type. Journal of AAPOS: American Association 943 for Pediatric Ophthalmology & Strabismus 2001;5:13-17. 944

7. Saunte JP, Holmes JM. Sustained improvement of reading symptoms following botulinum 945 toxin A injection for convergence insufficiency. Strabismus 2014;22:95-99. 946

8. Teitelbaum B, Pang Y, Krall J. Effectiveness of base in prism for presbyopes with 947 convergence insufficiency. Optometry and Vision Science 2009;86:153-156. 948

9. Birnbaum MH, Soden R, Cohen AH. Efficacy of vision therapy for convergence 949 insufficiency in an adult male population. Journal of the American Optometric Association 950 1999;70:225-232. 951

10. Scheiman M, Gallaway M, Ciner E. Divergence insufficiency: characteristics, diagnosis, and 952 treatment. American Journal of Optometry & Physiological Optics 1986;63:425-431. 953

11. Tamhankar MA, Ying GS, Volpe NJ. Effectiveness of prisms in the management of diplopia 954 in patients due to diverse etiologies. Journal of Pediatric Ophthalmology and Strabismus 955 2012;49:222-228. 956

12. Prangen Ade H, Koch FL. Divergence Insufficiency: A Clinical Study. Transactions of the 957 American Ophthalmological Society 1937;35:136-148. 958

13. Godts D, Mathysen DG. Distance esotropia in the elderly. British Journal of Ophthalmology 959 2013;97:1415-1419. 960

14. Thomas AH. Divergence insufficiency. Journal of AAPOS: American Association for 961 Pediatric Ophthalmology & Strabismus 2000;4:359-361. 962

15. Bothun ED, Archer SM. Bilateral medial rectus muscle recession for divergence 963 insufficiency pattern esotropia. Journal of AAPOS: American Association for Pediatric 964 Ophthalmology & Strabismus 2005;9:3-6. 965

16. Wiggins RE, Jr., Baumgartner S. Diagnosis and management of divergence weakness in 966 adults. Ophthalmology 1999;106:1353-1356. 967

17. Simpson GV. Primary divergence insufficiency. Transactions of the American 968 Ophthalmological Society 1973;71:152-161; discussions 161-152. 969

18. Stager DR, Sr., Black T, Felius J. Unilateral lateral rectus resection for horizontal diplopia in 970 adults with divergence insufficiency. Graefes Archive for Clinical and Experimental 971 Ophthalmology 2013;251:1641-1644. 972

19. Chaudhuri Z, Demer JL. Medial rectus recession is as effective as lateral rectus resection in 973 divergence paralysis esotropia. Archives of Ophthalmology 2012;130:1280-1284. 974

20. Chaudhuri Z, Demer JL. Sagging eye syndrome: connective tissue involution as a cause of 975 horizontal and vertical strabismus in older patients. JAMA Ophthalmology 2013;131:619-976 625. 977

21. Rainin EA, Carlson BM. Postoperative diplopia and ptosis. A clinical hypothesis based on 978 the myotoxicity of local anesthetics. Archives of Ophthalmology 1985;103:1337-1339. 979


22. Johnson DA. Persistent vertical binocular diplopia after cataract surgery. American Journal 980 of Ophthalmology 2001;132:831-835. 981

23. Burgess D, Roper-Hall G, Burde RM. Binocular diplopia associated with subretinal 982 neovascular membranes. Archives of Ophthalmology 1980;98:311-317. 983

24. Brazis PW, Lee AG, Bolling JP. Binocular vertical diplopia due to subretinal neovascular 984 membrane. Strabismus 1998;6:127-131. 985

25. De Pool ME, Campbell JP, Broome SO, Guyton DL. The dragged-fovea diplopia syndrome: 986 clinical characteristics, diagnosis, and treatment. Ophthalmology 2005;112:1455-1462. 987

26. Wright KW. Mini-tenotomy procedure to correct diplopia associated with small-angle 988 strabismus. Transactions of the American Ophthalmological Society 2009;107:97-102. 989

990

study of adult strabismus...

Documents