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What’s New and Important in Pediatric Ophthalmology and Strabismus in 2020

“All-Stars” Handout

AAPOS, Austin, Texas, USA

Friday, March 27, 2020

Presented by the

AAPOS Professional Education Committee

Darron A Bacal, MD- Chairperson Tina Rutar, MD- Vice Chairperson Chrysavgi Adamopoulou, MD Austin E Bach, DO Anat Bachar Zipori, MD Kara M Cavuoto, MD Madhuri Chilakapati MD Robert A Clark MD Marina A Eisenberg, MD Ilana B Friedman, MD Jennifer A Galvin, MD Elena M Gianfermi, MD Michael E Gray, MD Gena Heidary MD PhD Alexander J Khammar MD Sharon S Lehman MD Phoebe Dean Lenhart, MD Emily A McCourt, MD Leah Reznick MD Jasleen K Singh, MD Kimberly G Yen MD Wadih M Zein, MD Laryssa A. Huryn, MD

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TABLE OF CONTENTS

1. Amblyopia page 3 2. Vision Screening page 5 3. Refractive error page 6 4. Visual Impairment page 8 5. Neuro-Ophthalmology page 9 6. Nystagmus page 11 7. Prematurity page 12 8. ROP page 13 9. Strabismus page 17 10. Strabismus surgery page 20 11. Anterior Segment page 22 12. Cataract page 24 13. Cataract surgery page 25 14. Glaucoma page 26 15. Refractive surgery page 27 16. Genetics page 28 17. Trauma page 32 18. Retina page 33 19. Retinoblastoma / Intraocular tumors page 36 20. Orbit page 39 21. Oculoplastics page 41 22. Infections page 43 23. Pediatrics / Infantile Disease/ Syndromes page 44 24. Uveitis page 47 25. Practice management / Health care systems / Education page 48

Amblyopia 3

1. AMBLYOPIA

Differential Experience-Dependent Plasticity of Form and Motion Mechanisms in Anisometropic Amblyopia Chen SI, Chandna A, Nicholas S, Norcia AM. Invest Ophthalmol Vis Sci. 2019 Oct 1;60(13):4109-4119.

In this study anisometropic amblyopic and dominant eyes were compared to control eyes in regards to responses to form/position sensitive stimuli and motion-transient stimuli. Responses were measured using VEP recordings with electrodes over the occipital lobe. Prior to treatment of amblyopia, responses of the amblyopic eyes to form/position were noted to be smaller than those of the control eyes while those of the dominant eyes were larger. This shows the rewiring of the neurons to increase input coming from the non-amblyopic eye. Responses to motion in the dominant eye were noted to be similar to controls whereas responses from the amblyopic eye to motion were smaller than those of the control. After treatment of the amblyopia, all responses of treated and control eyes were similar. This important study clinically shows the rewiring of neurons both pre- and post-amblyopia treatment.

A Randomized Trial of Binocular Dig Rush Game Treatment for Amblyopia in Children Aged 7 to 12 Years Pediatric Eye Disease Investigator Group: Jonathan M Holmes, Ruth E Manny, Elizabeth L Lazer, Eileen E Birch, et al. Ophthalmology. March 2019;126(3): 456-466. The purpose was to compare visual acuity (VA) improvement in children aged 7 to 12 years with amblyopia treated with binocular iPad game (Dig Rush) plus spectacle correction vs spectacle correction alone. It is a multi-center randomized clinical trial with 138 participants with amblyopia from strabismus, anisometropia, or both. Participants were required to have at least 16 weeks of optical treatment in spectacles if needed or demonstrate no improvement in amblyopic-eye visual acuity (VA) for at least 8 weeks prior to enrollment. Participants were randomized to Dig Rush (1 hour per day 5 days per week) plus spectacle wear as needed or continued spectacle wear. The main outcome measure was change in amblyopic eye VA from baseline to 4 weeks. There was no greater improvement in the amblyopic eye VA in the Dig Rush plus spectacle group compared to spectacle only group. Although adherence with Dig Rush was suboptimal it was better than that reported in other studies making it unlikely that decreased adherence was the cause of the poor response. The authors note that previous studies have suggested that the failure to find any dose-response relationship between duration of play, or increment of contrast, and improvement in VA casts doubt on the efficacy of binocular treatments such as Dig Rush per se. Although there is no apparent benefit of Dig Rush treatment over a 4 to 8- week period for 7 to 12-year old children, there is evidence that is may be beneficial in younger children. This is being evaluated in an ongoing PEDIG trial enrolling children age 4 to 6 years. The effect of asymmetrical accommodation on anisometropic amblyopia treatment outcomes. Toor S, Horwood A, Riddell P. JAAPOS. 2019 Aug;23(4):203-5. Previous research has revealed that the majority of children with anisometric amblyopiah have asymmetrical accommodation. This is a preliminary study that seeks to determine whether the type of accommodation response was associated with a poor amblyopia treatment outcome in the same patients. In this study, the type of accommodation response of 26 children with anisometropic amblyopia was determined in a previous study. The final visual acuity in the amblyopic

Amblyopia 4

eye, after treatment, was compared between those with symmetrical, aniso-, and anti-accommodation. The authors found that the difference in final visual acuity between the three accommodation groups was significant (P = 0.023). Subjects with anisometropic amblyopia with anti-accommodation had the poorest final visual acuity (0.42 ± 0.25 logMAR) with a statistically significant difference compared with those who had aniso-accommodation (0.14 ± 0.08 logMAR; P = 0.023). However, the difference failed to reach significance compared to those with symmetrical accommodation (0.20 ± 0.12 logMAR; P = 0.234), probably due to the small sample size. The initial visual acuity in the amblyopic eye and the degree of anisometropia were also significantly positively correlated with final visual acuity (P < 0.001 for both). The authors found that, in this study cohort, the presence of anti-accommodation in anisometropic amblyopia, initial visual acuity in the amblyopic eye, and the degree of anisometropia were also associated with a poorer outcome. It is possible that all these factors are associated, but further research is required to determine causal relationships. The authors suggest that their findings might be able to be used to predict which children might have a worse treatment outcomes in anisometropic amblyopia.

Vision Screening 5

2. VISION SCREENING

Refractive Errors and Amblyopia Among Children Screened by the UCLA Preschool Vision Program in Los Angeles County. Margines JB, Huang, C, Young A, Mehravaran S, Yu F, Mondino BJ, Coleman AL. Am J Ophthalmol. 2020 Feb; 210: 78-85. This was a five year retrospective evaluation of a vision screening program at UCLA, called the UCLA Preschool Vision Program (UPVP). From 2012 to 2017, the visual acuity and undilated noncycloplegic refractive screening of 93, 097 children was performed. From the total number of children screened, 85.3% were between the ages of 3 to 5 years old. From the total number of children screened, 15.3% met the specific refractive criteria for a referral for a full cycloplegic examination. Data analysis only from the right eye was included in this manuscript. From this pediatric cohort, UPVP performed 6779 cycloplegic examinations. Results noted 4018 (61%) with hyperopia, 1336 (20%) with myopia, 6122 (93%) with astigmatism. Regarding the demographics of the cohort indicated that Latino children had higher rates of astigmatism and worse visual acuity when compared to all other races and ethnicities. The diagnosis of refractive amblyopia was noted in 780 children (1% of the screened population and 11.5% of the examined population) and 27% of these children had both eyes affected (ie bilateral refractive amblyopia). The authors of the UPVP retrospective 5-year evaluation report the largest published data sampling on pre-school children in the USA. This study has limitations in its retrospective nature; however, the common refractive errors in this pediatric cohort as well as the diverse demographics of the children provide a helpful perspective for the diagnosis and treatment of refractive amblyopia. Furthermore, the screening criteria used for UPVP is a helpful tool and model for other amblyopia programs at the metropolitan, state, and national level.

Refractive Error 6

3. REFRACTIVE ERROR

A Randomized Clinical Trial of Immediate Versus Delayed Glasses for Moderate Hyperopia in Children 3 to 5 Years of Age. Holmes JM, Kulp MT, Dean TW, Suh DW, Kraker RT, Wallace DK, Petersen DB, Cotter SA, Crouch ER, Lorenzana IJ, Ticho BH, Verderber LC, Weise KK; Pediatric Eye Disease Investigator Group. Am J Ophthalmol. 2019 Dec;208:145-159. This was a prospective randomized clinical trial from the Pediatric Eye Disease Investigator Group. This study was designed to compare visual acuity and binocular outcomes in children with moderate hyperopia and normal vision assigned to glasses vs. those assigned to observation. There were 119 children between 3 and 5 years old enrolled with hyperopia between 3 and 6 diopters spherical equivalent. The patients were randomly assigned to observation vs. glasses. “Failure” on follow up was defined by subnormal distance acuity or stereoacuity, manifest strabismus or strabismus surgery. 84 (71%) of children completed the primary outcome and there was failure in 5/41 assigned to glasses and 4/43 assigned to observation. There was no significant failure rate for either group. Overall failure for visual acuity or binocularity was not common. There was insufficient enrollment, however the authors suggest that the low failure rate could be indicative that immediate glasses is necessary in this age group. A small but statistically significant trend toward emmetropia existed within the observation group. The authors point out the biggest limitation of course was the slow recruitment and the closure of the study prior to the planned time. Additionally, there was a greater than expected lost to follow up rate. The most important take away from this study is that it appears to be reasonable to observe patients in this age group with moderate hyperopia. Association Between Type of Educational System and Prevalence and Severity of Myopia Among Male Adolescents in Israel Bez D, Megreli J, Bez M et al. JAMA Ophthalmology. August 2019;137(8):887-893. This was a nationwide, cross-sectional study in Israel of the prevalence of myopia in male teenagers who were studying in the ultra-Orthodox, Orthodox, and secular educational systems. The authors sought to analyze the association between studying in different educational systems and the prevalence and severity of myopia among Jewish male adolescents in Israel. In 2013, there were 22, 823 male candidates for military service in Israel aged 17 to 18 years attending the military draft board who underwent a medical examination and a visual acuity assessment. Among the 22, 823 participants, there was a higher proportion of teenagers in the ultra-Orthodox educational system with myopia (1871 of 2276 [82.2%]) compared with adolescents in the Orthodox educational system (1604 of 3189 [50.3%]) and those in the secular educational system (5155 of 17 358 [29.7%]). Compared with teens in the secular educational system, those in the Orthodox educational system were more likely to have myopia (P < .001), as were those in the ultra-Orthodox educational system (P < .001). The multivariable analysis for high myopia (refractive error of at least −6.0 diopters) was 4.6 (P < .001) for teens in the Orthodox educational system and 38.5 (P < .001) for teens in the ultra-Orthodox educational system compared with teens in the secular educational system. The authors of this study provide evidence of the independent association between educational systems and the prevalence and severity of myopia. In particular, male teenagers in the ultra-Orthodox educational system have higher odds of having myopia and high myopia. Furthermore, these authors suggest that study styles that involve intensive reading and other near-work activities warrant consideration of further prevention strategies.

Myopia growth Chart Based on a Population-Based Survey (KNHANES IV-V):a NOVEL prediction model of myopic progression in Childhood. Dae Hee Kim, Hyun Taek Lim. J of Ped Ophthal & Strabismus.2019;56(2):73-77

Refractive Error 7

The purpose of this study is to introduce a novel myopia growth chart based on a population-based survey for the prediction of myopic progression. The study included 7,695 Korean participants aged 5 to 20 years from a population-based health survey (Korean National Health and Nutrition Examination Survey IV–V). The authors collected spherical equivalent (SE) data converted from noncycloplegic refraction data. To create a myopia growth chart, data were arranged in the order of SE from hyperopia to myopia to acquire specific percentiles of the SE by age. Myopia progression rates were calculated between two specific ages in each percentile. The mean age of the participants was 11.8 years and the mean SE was −1.82 diopters (D). The SE of the 10th percentile was +0.72 D for participants aged 5 and −0.25 D for those aged 20 years, resulting in a total change in refraction of −0.97 D. In contrast, the SE of the 90th percentile was −0.75 D for participants aged 5 years and −6.73 D for those aged 20 years, showing myopia progression of −5.98 D. The myopia progression rate from 5 to 20 years of age was estimated as −0.06, −0.15, and −0.40 D/year in the 10th, 50th, and 90th percentile groups, respectively. The authors concluded that the myopia growth chart may be used to diagnose the severity or to estimate the progression of myopia. A patient in a higher percentile of myopia for his or her age may have myopia progressing at a faster rate and thus require close observation. This study has some limitations. The KNHANES provides cross-sectional data. The continuity of the change in the refractive error corresponding to a specific percentile cannot be guaranteed. A cohort study for the refractive change should confirm the current findings. Moreover, the refractive data from the KNHANES are collected using noncycloplegic autorefraction. As such, the refractive data suggested in this study could be more myopic than it really was. However, studies on myopia screening using the same autorefractor used in this study showed that the autorefractor had reliable performance for the screening of myopic patients, with a sensitivity and specificity of 88.6% and 86.1%, respectively. Considering that the general purpose of a growth chart is early screening for progressive developmental abnormalities, the myopia growth chart using noncycloplegic refraction might be acceptable for screening patients at a risk of high myopia. Further studies using cycloplegic refractive data may compensate for such limitations. Considering that the refractive data can vary depending on the country and the population in the Republic of Korea has a relatively low ethnic variation, the myopia growth chart presented in this study cannot be directly applied in other countries. However, many countries already have refractive data from previous population-based studies. Thus, a myopia growth chart for specific countries and races can easily be made using those data.

Visual Impairment 8

4.VISUAL IMPAIRMENT

Predisposing factors, ophthalmic manifestations, and radiographic findings in children with cerebral visual impairment. Suma Ganesh, MS, DNB; Rolli Khurana, MS; Sonia Sharma, M Optom; Soveeta Rath, DNB, FICO J Pediatr Ophthalmol Strabismus. 2019;56(5):313-318

This study describes the predisposing factors and ophthalmic manifestations of children presenting with cerebral visual impairment in a tertiary eye institute. A retrospective cross-sectional analysis of patients younger than 16 years with neuroradiological and clinical evidence of retrogeniculate visual pathway pathology was performed. Detailed histories, ophthalmic examinations, and MRI findings were compiled and analyzed. Of the 88 cases included in the study, the median age was 32 months (range: 1 to 180 months). Antenatal history and preterm delivery was positive in 25.0% and 37.5% of patients, respectively. A simple myopic astigmatism was the most common refractive error. Accommodative anomalies were noted in 6 children. In conclusion, this is a descriptive study in which the authors emphasized the importance of the etiological factors that cause cerebral visual impairment in the antenatal and perinatal period. During assessment of any child with visual impairment or neurodevelopmental delay, these factors should be looked for. The various ophthalmic manifestations could guide the multidisciplinary team treating the child with cerebral visual impairment to understand the various types of visual impairment that affect the neurodevelopment of the child and plan rehabilitation strategies accordingly. However, a larger sample size and a multicentric study in the future may be a better reflection of the same. Association of visual acuity with educational outcomes: a prospective cohort study. Jan C, Li SM, Kang MT, Liu L, Li H, Jin L, Qin X, Congdon N, Wang N. Br J Ophthalmol. 2019 Nov;103(11):1666-1671. The impact of vision abnormalities on educational outcomes is complex and previous studies have given conflicting information. This study was a prospective, longitudinal study on Chinese children in grade 7 in an effort to quantify the impact of visual acuity, refractive error, and glasses wear on subsequent academic performance. Cycloplegic autorefraction was obtained at baseline along with demographics and risk factors for myopia. Academic test scores were obtained from the local Bureau of Education. There were 2363 eligible children of which 73.1% (1728) had 7th grade test scores available. 1599 had 9th grade test scores. The following were significantly associated with higher 9th grade scores: younger age, male sex, less time outdoors, better baseline visual acuity, higher parental education and income, and parental myopia. Refractive error and spectacle wear were not associated. In multivariate analysis, baseline test score, presenting visual acuity, age, quality of life, parental education, and myopia were associate with better 9th grade scores. Overall the study suggests better visual acuity is associated with better academic outcomes in middle school students.

Neuro-Ophthalmology 9

5.NEURO-OPHTHALMOLOGY

Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder. Yamamura T, Kleiter I, Fujihara K, et al. N Engl J Med. 2019 Nov 28;381(22):2114-2124.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system and is associated with autoantibodies to anti-aquaporin-4 (AQP4-IgG) in approximately two thirds of patients. Interleukin-6 is involved in the pathogenesis of the disorder. Satralizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor. The efficacy of satralizumab added to immunosuppressant treatment in patients with NMOSD was studied in a phase 3, randomized, double-blind, placebo-controlled trial. Patients with NMOSD who were seropositive or seronegative for AQP4-IgG were randomized to receive either satralizumab or placebo, administered subcutaneously every two to four weeks, added to stable immunosuppressant treatment. The primary end point was the first protocol-defined relapse in a time-to-event analysis. Key secondary end points were the change from baseline to week 24 in a pain score and a functional assessment of chronic illness therapy fatigue score.

A total of 83 patients were enrolled, with 41 assigned to the satralizumab group and 42 to the placebo group. Mean age of patients was 41 and 43 years, respectively; the age range of patients was 12 to 74 years. The median treatment duration with satralizumab in the double-blind period was 107.4 weeks. Relapse occurred in 8 patients (20%) receiving satralizumab and in 18 (43%) receiving placebo (hazard ratio, 0.38; 95% confidence interval [CI], 0.16 to 0.88). Among 55 AQP4-IgG-seropositive patients, relapse occurred in 11% of those in the satralizumab group and in 43% of those in the placebo group (hazard ratio, 0.21; 95% CI, 0.06 to 0.75); among 28 AQP4-IgG-seronegative patients, relapse occurred in 36% and 43%, respectively (hazard ratio, 0.66; 95% CI, 0.20 to 2.24). There was no difference in pain and chronic illness therapy fatigue scores between groups.

In conclusion, among patients with NMOSD who are AQP4-IgG seropositive, satralizumab added to immunosuppressant treatment led to a lower risk of relapse than placebo. Pediatric ophthalmologists should be aware of this new medication for a potentially blinding disease. Eculizumab, a terminal complement inhibitor, has also been shown effective treatment for this disease in another 2019 NEJM publication.

Likelihood of Diagnosing Neuroblastoma in Isolated Horner Syndrome Ben Shabat, Avi; Ash, Shifra; Luckman, Judith; Toledano, Helen; Goldenberg-Cohen, Nitza Less Journal of Neuro-Ophthalmology. 39(3):308-312, September 2019. In this retrospective review, the authors characterized two cohorts of patients. First they evaluated the charts of 40 pediatric patients with Horner syndrome with respect to underlying etiology. The majority of patients had idiopathic Horner syndrome (58%). Second the authors reviewed the charts of 135 patients with neuroblastoma to investigate the frequency of these patients presenting with Horner syndrome. Of these, only one patient with neuroblastoma had signs of Horner syndrome. The authors conclude that Horner syndrome should not immediately raise the specter of neuroblastoma because this occurs less commonly. Nevertheless, they advocate for evaluation when Horner syndrome is present. Optic Nerve Sheath Diameter Ultrasound: Optic Nerve Growth Curve and Its Application to Detect Intracranial Hypertension in Children. Fontanel L, Pensiero S, Ronfani L, Rosolen V, Barbi E. Am J Ophthalmol. 2019 Dec;208:421-428.

Neuro-Ophthalmology 10

There were two goals of this prospective cross-sectional study; the first was to create a growth curve of optic nerve sheath diameter (ONSD) values in pediatric patients and the second was to identify cut off values of ONSD to help diagnose intracranial hypertension. The authors performed B scan ultrasonography on each eye of 215 subjects aged 0-18, 165 of these were healthy, 29 who had intracranial hypertension, and 21 with optic disc drusen. The authors found that the ONSD was not different in the normal children and those with optic disc drusen, but did vary from those with IIH. The authors defined normal growth curve in children and noted that there is rapid change in the first year of life followed by a growth curve until about the age of 10 when adult values are the same as the pediatric values. The authors found that their ranges could identify IIH with 100% sensitivity and 84-99% specificity. There were multiple limitations of this paper, one of the main ones being there were no patients with increased intracranial pressure under the age of 4. This paper proved to be controversial with multiple letters to the editor from other ophthalmologists. Optical coherence tomography is highly sensitive in detecting prior optic neuritis. Xu SC, Kardon RH, Leavitt JA, Flanagan EP, et al. Neurology. Feb 2019;92(6):e527-e535. In this retrospective study, the authors examined the use of OCT to detect episodes of prior optic neuritis in a cohort of 51 patients. The goal of the study was to evaluate whether OCT was an effective tool for detecting a prior episode of optic neuritis in patients with unilateral optic neuritis. By utilizing interocular differences as measured with OCT, the authors determined that an interocular difference of ≥9 µm for rNFL or ≥6 µm for GCIPL were reflective of prior optic neuritis. The reduction in GCIPL was a more sensitive measure (76% for GCIPL and 37% for RNFL) to reflect prior optic neuritis as compared to age matched controls. This study defines thresholds for interocular differences which may provide a quantitative way of detecting prior optic neuritis and establishes which measure of OCT is most effective in screening when the history is unknown.

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6 NYSTAGMUS Long-term Outcomes Following Surgery for Infantile Nystagmus Syndrome With Abnormal Head Positioning. Zheng Y, Law JJ, Holt DG, Morrison DG, Donahue SP. Am J Ophthalmol. 2020 Feb;210:3-7. This retrospective observational case series of 150 patients who had surgery for abnormal head position (AHP) associated with infantile nystagmus syndrome (INS) was performed at one academic institution. The goal of this study was to better understand the long term outcomes in these patients in terms of their head position, duction limitations, and strabismus. The authors defined success in head position as 10 degrees or less. Most (119) patients had surgery for horizontal head position, 31 for chin up/down position, and none in this series for torsional head positioning. Most patients had a 50-60% augmentation and 38 patients had a dose adjustment to account for strabismus. The authors found that at 10 years, there were no overcorrections and 7% of patients had an under correction. 9% of patients had surgery for over or under correction during that 10 year time period. There was also a 7% rate of induced strabismus after the surgery. While some patients had an initial duction limitation, at 10 years, no patients had any limitations the ductions. Overall there was a 21% reoperation rate. The authors concluded that their paper supports surgery as a long term solution for AHP in patients with INS. They pointed out the main limitations being the retrospective nature of the study as well as selection bias in the patients with return follow up may not represent entire cohort. The main take home message from this paper is that AHP can be treated long term by a Kestenbaum-Anderson procedure, though the risk of needing more eye muscle surgery for over or under correction or strabismus is about 20%. .

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7. PREMATURITY.

There are no all-star articles in this section.

ROP 13

8. RETINOPATHY OF PREMATURITY

Treatment of non-type 1 retinopathy of prematurity in the Postnatal Growth and Retinopathy of Prematurity (G-ROP) study. Liu T, Tomlinson LA, Ying GS, Yang MB, Binenbaum G; G-ROP Study Group J AAPOS. 2019 Dec;23(6):332 The authors used secondary analysis of data from the Postnatal Growth and Retinopathy of Prematurity (G-ROP) study to determine the prevalence and characteristics of eyes that were treated without reaching Type 1 ROP. Recommendations from the Early Treatment for Retinopathy of Prematurity (ETROP) guidelines and clinical judgement determine when treatment for ROP will occur. Of those treated, 12.5% did not meet the accepted criteria of Type 1 ROP. The most common reason for treatment of an eye without Type 1 disease was that the other eye has Type 1 disease was being treated. The literature demonstrates that there is high concordance between the eyes and it is correct to assume that the less involved eye will progress to need treatment. Treatment at the same time may avoid risks of sedation or intubation. The second most common reason was the presence of worrisome structural issues. Other reasons include logistical considerations. The remainder of the eye treated without achieving Type 1 disease were Stage 3, Zone II with pre-plus. Pre-plus is a characteristic that may be concerning for the possibility of progression although the literature does not show any improved outcome by treating Type 2 disease. Approximately 1 in 8 eyes in the G-ROP study were treated for ROP that did not meet accepted criteria of Type 1 disease. The authors suggest that understanding why clinicians may vary from accepted guidelines may help building future guidelines.

Short-term retinal detachment risk after treatment of type 1 retinopathy of prematurity with laser photocoagulation versus intravitreal bevacizumab. Barry GP, Tauber KA, Fisher M, Greenberg S, Zobal-Ratner J, Binenbaum G. J AAPOS. 2019 Oct;23(5):260.e1-4

Retinopathy of prematurity (ROP) is a potentially blinding condition. Because of the immature retinal vasculature, a fibro-proliferative retinopathy may develop and cause tractional retinal detachments, an important cause of severe visual impairment in infants with ROP. There are limited available data comparing structural outcomes in patients treated with intravitreal bevacizumab versus laser for ROP. Therefore, the authors conducted this retrospective study in order to compare the short-term risk of retinal detachment after treatment of type 1 retinopathy of prematurity treated with panretinal photocoagulation laser versus intravitreal bevacizumab. They included 222 eyes of 115 consecutive infants treated for type 1 ROP between 2010 and 2018. An a priori decision was made to divide infants into two groups, those treated before postmenstrual age (PMA) of 36 0/7 weeks and those treated at or after PMA of 36 0/7 weeks. The authors chose PMA at time of treatment as a marker for disease aggression, because it was objectively measured and easily reproducible. Despite previously described more refined measures of classifications. The primary outcome was presence of any retinal detachment (stage 4A, 4B, or 5) during the 8 weeks following treatment. In eyes treated before 36 0/7 weeks' PMA, retinal detachment occurred in 0 of 34 eyes treated initially with bevacizumab compared with 9 of 56 (16%) treated with laser (P 5 0.0112); in eyes treated at or after 36 0/7 weeks, in 0 of 2 eyes treated with bevacizumab and 1 of 130 eyes (0.8%) treated with laser. The authors conclude that the short-term risk of retinal detachment among infants requiring treatment for type 1 ROP prior to 36 0/7 weeks' PMA was lower in eyes treated with intravitreal bevacizumab than in eyes treated with laser, presumably due to the faster effect of bevacizumab in eyes that have more aggressive ROP. Generally, intravitreal bevacizumab works faster than laser, because bevacizumab directly binds to VEGF receptors, whereas laser works by destroying the source of VEGF production; therefore, there is a theoretical benefit to using bevacizumab in certain clinical situations, for example, where ROP is progressing rapidly.

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Secondary 12-Month Ocular Outcomes of a Phase 1 Dosing Study of Bevacizumab for Retinopathy of Prematurity. Crouch ER, Kraker RT, Wallace DK, Holmes JM, Repka MX, Collinge JE, Bremer DL, Gray ME, Smith HA, Steinkuller PG; for the Writing Committee for Pediatric Eye Disease Investigator Group. JAMA Ophthalmol. 2020; 138 (1): 14-20. The authors from PEDIG evaluated the 12-month ocular outcomes of 5 different doses (0.625mg, 0.25mg, 0.125mg, 0.063mg, 0.031mg) of Bevacizumab for type 1 Retinopathy of Prematurity (ROP). This prospective, masked cohort multicenter study was conducted from April 2016 to October 2017. The study eyes were treated with the four lower doses of Bevacizumab and the fellow eye was treated with one dosage level higher than the treated eye. Forty-six of the 61 infants (75%) had a 12-month follow up evaluation with 46 study eyes and 43 fellow eyes. Secondary outcomes included: amblyopia, alignment, nystagmus, and cycloplegic refraction. Results showed fewer than one quartile of the infants had abnormal cycloplegic refraction: 14% with myopia greater than -5.00 D spherical equivalent, 2% with hyperopia greater than +5.00 D spherical equivalent, 11% with anisometropia greater than 1.50 D spherical equivalent. Abnormalities in the cornea, lens and/or anterior segment was reported in fewer than 3% of infants. Abnormalities in the optic nerve and retina was reported with 11% of the infants with optic nerve atrophy and 1% with total retinal detachment. Abnormal sensorimotor findings included:15% with manifest nystagmus and 30% with strabismus. This PEDIG study reports that low-dose Bevacizumab treatment for type 1 ROP has ocular abnormalities such as high myopia, optic nerve atrophy, strabismus, nystagmus at similar reported rates in infants treated with higher doses of Bevacizumab at 12-month follow up. Limitations of this study include using 4 doses to compare to 1 higher level dose of Bevacizumab, rather than 1 specific dose compared with the fellow eye. Although this is a masked multicenter prospective study, only 46 of the 61 infants (75%) had a 12-month follow up evaluation. Future studies with a comparison of low dose Bevacizumab for ROP should evaluate 3 month and 6 month corrected age follow up in regards to the progression from treatment to 12 months corrected age. Individual Risk Prediction for Sight-Threatening Retinopathy of Prematurity Using Birth Characteristics Pivodic A, Hard AL, Lofquvist C, Smith LEH, Wu C, Brunder MC, Lagreze WA, Stahl A, Holmstrom G, Wikland KA, Johansson H, Nilsson S, Hellstrom A. JAMA Ophthalmol. 2020; 138 (1): 21-29. The authors wanted to create and validate an easy-to-use prediction model using only birth characteristics and to describe a continuous hazard function for ROP treatment. This was a retrospective cohort study from the Swedish National Patient Registry data of infants screened for ROP and born between January 1, 2007 and August 7, 2018. Analysis was performed with Poisson regression for time-varying data (postnatal age, gestational age (GA), gender, birth weight to develop an individualized predictive model for ROP treatment: called DIGIROP-Birth [Digital ROP]). Of note, the model had been validated internally and externally (in US and European cohorts) and compared with 4 published prediction models. Among 7609 infants (54.6% boys; mean GA 28.1 weeks; mean birth weight, 1119 g), 442 (5.8%) were treated for ROP, including 142 (40.1%) treated of 354 born at less than 24 gestational weeks. Irrespective of GA, the risk for receiving ROP treatment increased during post-natal weeks eight through twelve and decreased thereafter. Validations of DIGIROP-Birth for 24 to 30 weeks' GA showed high predictive ability for the model overall (for internal validation, 0.94 for temporal validation, 0.87 for US external validation, and 0.90 for European external validation) by calendar periods and by race/ethnicity. The sensitivity, specificity, PPV, and NPV were numerically at least as high as those obtained from CHOP-ROP (Children's Hospital of Philadelphia-ROP), OMA-ROP (Omaha-ROP), WINROP (weight, insulin-like growth factor 1, neonatal, ROP), and CO-ROP (Colorado-ROP), models requiring more complex postnatal data. In conclusion, the authors report that their study validated an individualized prediction model for infants born at 24 to 30 weeks' GA, enabling early risk prediction of ROP treatment based on birth characteristics data. In particular, the authors report that postnatal age rather than post-menstrual age was a better predictive variable for the temporal risk of ROP treatment. The authors performed complex data analyses and made appropriate comparisons to the previously published ROP

ROP 15

studies. While the statistical model is an accessible online for further application, further longitudinal neonatal data would be helpful to make a stronger case for using postnatal age rather than post-menstral age regarding the risk of ROP treatment. Validation of the Postnatal Growth and Retinopathy of Prematurity Screening Criteria Binenbaum G, Tomlinson LA, Campomanes AG, Bell EF, Donohue P, Morrison D, Quinn GE, Repka MX, Rogers D, Yang MB, Yu Y, Ying GS; for the Postnatal Growth and Retinopathy of Prematurity (G-ROP) Study Group. JAMA Ophthalmol. 2020; 138 (1): 31-37. The authors of the G-ROP study group wanted validate the ROP screening criteria and to explore if a reduction in the number of infants receiving ROP examination could be validated. Among the 3981 infants in the study (1878 girls and 2103 boys; median gestational age, 28 weeks; median birth weight, 1072 g; 1966 white; 942 black; 321 Latino; 120 Asian; 22 Native Hawaian or Pacific Islander; and 25 American Indian or Alaskan Native), the G-ROP criteria correctly predicted 219 of 219 cases of type 1 ROP (sensitivity, 100%; 95% CI, 98.3%-100%), while reducing the number of infants undergoing examinations by 35.6% (n = 1418). The authors report that 100% correct clinical criteria was achieved for type 1 ROP and in turn, more than one-third of the neonatal infants had a reduced number of ROP examinations. Further analysis also showed 100% correct clinical criteria: in a combined G-ROP-1 and G-ROP-2 cohort of 11,463 infants, the G-ROP criteria predicted 677 of 677 cases of type 1 ROP (sensitivity, 100%; 95% CI, 99.4%-100%), reducing the number of infants receiving examinations by 32.5% (n = 3730). This is compared to the non G-ROP criteria (birth weight <1501 g or gestational age ≤30 weeks 0 days) with a prediction of 674 of 677 type 1 ROP cases (sensitivity, 99.6%; 95% CI, 98.7%-99.8%). In conclusion, the authors of this G-ROP study group found that the G-ROP screening criteria were generalizable on validation and, if used clinically in the United States and Canada, could reduce the number of infants receiving ROP examinations. Furthermore, the large G-ROP cohorts provide evidence-based screening criteria that have higher sensitivity and higher specificity for type 1 ROP than currently recommended guidelines. It would be prudent for neonatologists and ophthalmologists who evaluate this neonates at risk for ROP consider the G-ROP findings and revise their NICU guidelines for ROP screening.

Factors in Premature Infants Associated With Low Risk of Developing Retinopathy of Prematurity Wade KC, Ying GS, Baumritter MS; et al. JAMA Ophthalmology. February 2019;137(2):160-166. This study evaluated characteristics of infants at low risk for development of retinopathy of prematurity (ROP) in North American neonatal intensive care units, especially whom post-discharge screening may be of limited value. In addition, the authors did a post hoc analysis of prospectively collected in-hospital ROP examination results among infants enrolled. In order to characterize the infants at low risk for ROP, the authors characterized infants without ROP and performed logistic regression on the subset of infants who were 27 to 33 weeks’ gestational age to determine characteristics associated with the absence of ROP during all in-hospital examinations. A total of 1257 infants born at 22 to 35 weeks’ gestation with birth weights less than 1251 g underwent 4,113 ROP examinations between 31 and 47 weeks’ post-menstrual age. Overall, 1,153 examinations (38%) showed no ROP, and 456 infants (36%) did not have ROP prior to study center discharge or study end point. Among infants without ROP during examinations at 32 and 33 weeks’ post-menstrual age, 16 (9.4%) and 14 (5.3%) subsequently underwent ROP treatment, respectively. At hospital discharge, there was no ROP in 59% of infants of 27 to 33 weeks’ gestational age, compared with 15% of those who were less than 27 weeks’ gestational age (P ≤ .001). With more than 85% follow-up among infants without ROP by 37 weeks’ post-menstrual age, none were treated for ROP. In a multivariate analysis of infants born at 27 to 33 weeks’ gestation, larger birth weight and higher gestational age were statistically significantly associated with absence of ROP. In summary, the findings suggest that, for infants of 27 weeks’ gestational age or greater and birth weights larger than

ROP 16

750 g, if no ROP has been detected by discharge at near-term post-menstrual age, then further ROP surveillance has limited value. Neurodevelopmental Outcomes of Preterm Infants with Retinopathy of Prematurity Treatment Girija Natarajan, Seetha Shankaran, Tracy Nolen, et. al Pediatrics. August 2019; 144(2): e20183537. This study aimed to determine whether there is a difference in adverse outcomes between bevacizumab therapy and surgery for retinopathy of prematurity in extremely pre-term infants. The study was a retrospective analysis of prospective data on preterm infants 22-26 +6/7 weeks gestational age. The primary outcomes were death and severe neurodevelopmental impairment (NDI) at 18-26 months’ corrected age (a composite score of Bayley Scales of Infant and Toddler Development Classification Scale greater than or equal to 2, and bilateral blindness or hearing). The study included 405 infants from multiple health centers. The results demonstrated that the bevacizumab group were a sicker cohort with lower median birth weight, longer durations of conventional ventilation, and longer supplemental oxygen. Rates of death or severe NDI did not differ between the groups. But, the bevacizumab group had a greater odds of death and developmental scores were significantly lower in the bevacizumab group. There may be significant selection bias given that the physicians chose which patients received injection versus laser and that the bevacizumab group was a sicker group of patients. This study was the first to observe that mortality through infancy was significantly higher in the bevacizumab group than the surgery group. Although not conclusive, these results do highlight the need for rigorous appraisal of the risks and benefits of bevacizumab in a large randomized trial with neurodevelopmental follow up.

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Strabismus 17

9. STRABISMUS Conservative management of intermittent exotropia to defer or avoid surgery. Kushner BJ. J AAPOS 2019 Oct;23:256.e1-6

Surgery for intermittent exotropia performed at a very young age has poorer sensory outcomes than surgery performed later; moreover, postoperative recurrence is common, regardless of age. Alternate occlusion decreases the size of the exotropia and improves control. The purpose of this retrospective study was to report the long-term effects of part-time alternate occlusion and overminus spectacles combined with prism on delaying or avoiding surgery in intermittent exotropia. The author included 279 consecutive patients from 1979 to 2010 who had poorly controlled intermittent exotropia and were treated with alternate occlusion, followed in some cases by overminus spectacles with base-in prism. All the patients had initial control poor enough to otherwise be considered candidates for surgery. After occlusion therapy, 219 (78%) improved their angle and control, and 62 (22%) converted to an exophoria. After 1 year, 9 cases deteriorated, and surgery was recommended. In 207 (74%), conservative treatment delayed surgery for at least 1 year. At 20 years, 42 of 279 patients were still being followed. Of these, 22 of 219 (7%) were known to have not undergone surgery, and 127 (45%) had undergone surgery; 130 (47%) were lost to follow-up. The results also indicate that this therapy regimen was more effective in younger patients. The author concludes that part-time alternate occlusion and overminus spectacles with prism can defer the need for surgery in a large percentage of patients with intermittent exotropia; for a small number it may be curative. Despite a recent PEDIG report on occlusion therapy in intermittent exotropia, this study demonstrates a beneficial effect of occlusion therapy in patients with fair/poor control with several decades of experience.

Three-Year Observation of Children 3 to 10 Years of Age with Untreated Intermittent Exotropia. Pediatric Eye Disease Investigator Group; Writing Committee, Mohney BG, Cotter SA, Chandler DL, Holmes JM, Wallace DK, Yamada T, Petersen DB, Kraker RT, Morse CL, Melia BM, Wu R. Ophthalmology. 2019 Sep;126(9):1249-1260. The purpose of this study is to describe the course of intermittent exotropia (IXT) in children followed up without treatment for three years. Participants consisted of 183 children ages 3 to 10 years with previously untreated IXT and 400 seconds of arc or better near stereoacuity. Participants were to receive no treatment unless deterioration criteria were met at follow-up visits occurring at 3 months, 6 months, or 6-month intervals thereafter for 3 years. Deterioration was defined as constant exotropia > 10 diopters at near and distance, decrease in near stereoacuity of > 2-octave, or prescribing treatment without meeting either of the two previous criteria. An important consideration for this study is that eligibility criteria required willingness of investigator and family to observe without treatment for 3 years. This criterion likely screened out children with poor or deteriorating control, so the study describes natural history of IXT in children with stable control at recruitment. The results indicate that probability of protocol-specified deterioration by 3 years was 15% (95% confidence interval, 10-22%) but that was likely an overestimate due to misclassification. Among 25 deteriorations, 2 met motor deterioration, 11 met stereoacuity deterioration, and 12 started treatment without meeting either criteria (7 for social concern, 1 for diplopia, 4 for other reasons). Among the 132 participants who completed the 3-year visit and had not been treated during the study, only 1 met motor or stereoacuity deterioration criteria at 3 years. Of the 4 participants completing the 3-year visit who previously met deterioration criteria but did not start treatment, none still met deterioration criteria at the 3-year visit. Among children 3 to10 years of age with IXT for whom surgery was not considered to be immediately necessary, stereoacuity deterioration or progression to constant exotropia over 3 years was uncommon and exotropia control, stereoacuity, and magnitude of deviation remained stable or improved slightly.

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Postconcussion: Receded Near Point of Convergence is not Diagnostic of Convergence Insufficiency. Raghuram A, Cotter SA, Gowrisankaran S, Kanji J, Howell DR, Meehan WP, Shah AS. Am J Ophthalmol. 2019 Oct;206:235-244. Near point of convergence (NPC) is one of 5 components of the vestibular / ocular motor screening tool used often in sports related concussion evaluations. However it is unknown if this is test actually suggests a diagnosis of convergence insufficiency. The goal of this study was to determine the frequency of recorded NPC in patients with chronic concussion symptoms and those with isolated NPC to understand the frequency of convergence insufficiency and other eye movement disorders in this setting. The authors performed a retrospective cross-sectional study on patients who had suffered a concussion who had normal acuity, chronic concussion symptoms, and had undergone a sensorimotor examination. The patients were recruited from a multidisciplinary concussion clinic at a large children’s hospital The frequency of a receded NPC and other oculomotor disorders was recorded. The authors found that of the 83 patients, 74 (89%) had a receded NPC. They looked further at these patients and found that 95% of this cohort had oculomotor disorders, 41% had disorders of accommodation only, 28% of the patients had convergence insufficiency (CI) and accommodative deficit, and 8% had CI only. Oculomotor disorder was the most common disorder and convergence insufficiency (+/- accommodative disorder) was the most common disorder of vergence, but only present in about a third of patients. The authors concluded that a receded near point is not synonymous of convergence insufficiency and point out that since treatment options for CI, accommodative insufficiency and other oculomotor disorders are different, that the patients get a thorough examination so that they can be prescribed a proper treatment. Prevalence of Sagging Eye Syndrome in Adults with Binocular Diplopia. Goseki T, Suh SY, Robbins L, Pineles SL, Velez FG, Demer JL. Am J Ophthalmol. 2020 Jan;209:55-61. This retrospective observational case series was designed to elucidate the prevalence of sagging eye syndrome (SES) in adults with diplopia. SES was defined about 10 years ago and is a horizontal and/or vertical strabismus due to orbital connective tissue degeneration and causes binocular diplopia in adult patients. The authors reviewed the medical records of adult patients with binocular diplopia at one institution over a 4-year period. Causes of diplopia were recorded as well as additional data for patients with SES including alignment, treatment, and outcomes. Of the 945 adult patients with diplopia, (mean age of 66), SES was the most common cause (31%). Patients with SES were more likely to be older and female. Thirty-five percent of patients had age related esotropia at distance and 65% of cases of SES had cyclovertical strabismus. Both age related esotropia and small angle cyclovertical muscle strabismus with or without vertical deviation were included in the definition of SES. Half of the patients with SES has strabismus surgery and the diplopia was resolved in all cases. The authors concluded that SES is an important and frequent cause of diplopia in the adult. The high prevalence of SES is an important contribution to the literature for the pediatric ophthalmologist. Brain abnormalities in infantile esotropia as predictor for consecutive exotropia. Calis F, Atilla H, Bingol Kiziltunc P, Alay C. Strabismus. 2019 Dec;27(4):199-204. Prior studies have shown an association between strabismus and central nervous system damage. It is thought that this is due to white matter lesions referred to as white matter damage of immaturity (WMDI). In the retrospective study, the authors compared the MRI findings in patients who underwent surgery for infantile esotropia with and without consecutive exotropia to determine predictors of surgical success. Twenty-eight patients from 2001-2014 were included, with 17 in group 1 (consecutive exotropia) and 11 in group 2 (good post-operative alignment). The mean follow up was 47 ± 33.54 (12–102) months. There was no statistically significant in the gender, prematurity, mean preoperative angle, cycloplegic refractive error, mean age at surgery or mean amount of surgery. However there were differences in the MRI findings as 17.6% of patients in group 1 had bilateral WMDI with a severity of

Strabismus 19

grade 3–4 whereas none of the patients in group 2 had WMDI. The authors concluded that WMDI may be a risk factor for consecutive deviation in patients with infantile esotropia.

Strabismus Surgery 20

10. STRABISMUS SURGERY Diplopia after strabismus surgery for adults with nondiplopic childhood-onset strabismus. Wang JY, Leske DA, Hatt SR, Holmes JM; J AAPOS. 2019 Dec;23(6):313.e1-313. Although postoperative diplopia after strabismus surgery in nondiplopic adults is rare, it can influence patients and ophthalmologists in making decisions to proceed with surgery. The authors sought to describe the frequency and to report health-related quality-of-life (HRQOL) outcomes. Diplopia was assessed using a standardized diplopia questionnaire and HRQOL was assessed using the Adult Strabismus-20 (AS-20) questionnaire. The authors demonstrated constant postoperative diplopia in this population was low at 2% at 1 year. The data revealed that in the small number of cases where diplopia occurred, improved quality of life scores appeared to outweigh the new diplopia. Despite limitations of small sample size and incomplete data, the authors propose the information revealed can be useful in informed consent discussions with patients. Strabismus surgery infection prophylaxis and timing of first postoperative visit. Caroline N. DeBenedictis, MD; Shaden H. Yassin, MD; Kammi Gunton, MD; Leonard B. Nelson, MD; Benjamin E. Leiby, PhD; Sarah E. Hegarty, MPhil; Bruce Schnall, MD J Pediatr Ophthalmol Strabismus. 2019;56(6):354-359 Postoperative infection following strabismus surgery is a rare but potentially visually devastating disorder. Endophthalmitis, with an estimated incidence of 1:3,500 to 1:85,000, can result in a complete loss of vision in the affected eye. Periocular infection, either cellulitis or subconjunctival abscess, following strabismus surgery is more common with a reported incidence of 1:1,000 to 1:1,900. The uncommon occurrence of postoperative infections after strabismus surgery has made it difficult to study the most effective means of prophylaxis. This study was undertaken to characterize the practice patterns of pediatric ophthalmologists regarding their use of infection prophylaxis and timing of the first postoperative visit after strabismus surgery. A ten-question multiple-choice, close ended questionnaire was e-mailed to members of the American Association for Pediatric Ophthalmology and Strabismus listserv. Survey responses were summarized using frequencies and percentages. Univariable tests of association between prophylactic measures and surgeons reporting a prior episode of postoperative cellulitis or endophthalmitis were performed. Three hundred eighty pediatric ophthalmologists completed the survey. Most ophthalmologists instill 5% povidone-iodine solution during surgical preparation (88.4%), use topical antibiotics with or without steroids at the conclusion of surgery (90%), and prescribe oral or topical antibiotics postoperatively (85.5%). Eighty-five percent of strabismus surgeons routinely see patients for the first postoperative visit within the first week, although there is no consensus as to which day is preferred. Responders previously reporting experience with a postoperative infection were more likely to use intraoperative intravenous antibiotics (P = .002) and Tegaderm tape (3M, St. Paul, MN) or other adhesive drape to isolate the eyelids/eyelashes (P = .047). The authors of this study coclude that a common practice pattern appears to exist regarding the use of 5% povidone-iodine solution in surgical preparation, application of topical antibiotics at the end of surgery, and a postoperative regimen of topical antibiotics/steroids. There is no prevailing practice pattern regarding the timing of the first postoperative visit. Previous experience with postoperative cellulitis or endophthalmitis may lead to the adoption of more formidable infection prophylaxis measures such as intravenous antibiotics prior to surgery. Innovative techniques for the treatment of adult strabismus. Pineles SL, Chang MY, Holmes JM, Kekunnaya R, Özkan SB, Velez FG J AAPOS. 2019 Jun;23(3):132-139.

Strabismus Surgery 21

Surgical treatment of adult strabismus carries special challenges that may not be present when treating children. Diplopia associated with incomitant misalignments, small symptomatic deviations and torsional deviations cause complexity. The authors provide several innovative techniques for surgeons treating patients with adult strabismus. Posterior fixation sutures combined with an adjustable recession allows for more precise correction of a deviation in cases involving incomitant strabismus. Adult strabismus may involve vertical deviation requiring surgery involving more than one rectus muscle. It is important to consider sparing of ciliary circulation pf the muscle in order to prevent anterior segment ischemia. Selective surgery on the nasal or temporal aspects of eye muscles of the vertical muscles can improve alignment and lessen the risk. The use of Botox in cases of long standing paralytic strabismus cases can replace the need for traction sutures. Extra large deviations are often not sufficiently improved by simple recess/resect procedures. The authors describe an extraocular muscle transplantation technique for large angle strabismus cases. Correction of excyclotorsion with an anterior superior oblique tuck similar to procedure described by Hoeckele and colleagues may carry less risk for complications of induced vertical deviation and Brown syndrome. The authors offer several innovative techniques that may be used to help improve the alignment of challenging patients with adult strabismus. Ocular ductions after rectus muscle recession and resection in thyroid eye disease. Matlach J, Döllinger VKR, Eha J, Elflein HM, Weyer-Elberich V, Mildenberger P, Pitz S. Strabismus. 2019 Sep;27(3):143-148. Resection of rectus muscles for patients with thyroid eye disease (TED) was traditionally avoided as it was thought to increase restriction. In this retrospective chart review, the authors included 11 1 eyes of patients with TED from 1991-2015 who underwent a recess/resect procedure and compared them to patients with recession only. Both types of procedures improved ductions, but there was a statistically significant difference in abduction when comparing pre-op to 3 months post-op in patients undergoing a horizontal recess/resect procedure and vertical recession only. However the overall comparison of ductions did not reveal any statistically significant difference between the surgical groups. The study is limited by the subjective nature of duction evaluation, small sample size of the recession alone groups and the possibility that prior orbital decompression confounded the results. The authors conclude that recess/resect procedure do not limit ductions and improve ocular alignment. .

Anterior Segment 22

11. ANTERIOR SEGMENT

Accelerated corneal cross-linking in children with keratoconus: 5-year results and a comparison of two protocols Agca A, Tulu B, Yasa D, Yildiz BK, Sucu ME, Genc S, Fazil K, Yildirim Y. J Cataract Refract Surg. Post Acceptance: January 30, 2020. E-pub ahead of print.

This retrospective case-control study conducted in Turkey evaluated the long-term clinical results of two different accelerated corneal cross-linking (CXL) protocols in pediatric patients with keratoconus. Patients who were younger than 18 years were included. Group 1 received 4 min of illumination at 30 mW/cm2 and Group 2 received 5 minutes of illumination at 18 mW/cm2. Uncorrected (UDVA) and corrected distance visual acuity (CDVA), manifest refraction, corneal topographic parameters and corneal higher order aberrations (HOA) were evaluated at baseline and during 1-, 3-, and 5-year follow-up visits. 143 eyes from 86 patients were included in the study. There were 30 and 113 eyes in Groups 1 and 2, respectively. Mean follow-up time was 4.15±0.99 years. K mean and/or K max progressed ≥1D in 7 (23.3%) eyes in Group 1 and 19 (16.8%) eyes in Group 2 (p=0.411). K mean and/or K max decreased ≥2D in 2 (6.7%) eyes in Group 1 and 24 (21.2%) eyes in Group 2 (p=0.06). In Group 1, there were no statistically significant differences in topographic parameters during follow-up. In Group 2, there was a statistically significant reduction in total HOA and Coma during the 5-year visit when compared to the preoperative visit (p=0.005 and p=0.045, respectively). The authors conclude that accelerated CXL is beneficial in terms of halting the progression of keratoconus in pediatric patients throughout 5-years of follow-up exams. An increased irradiance with a reduced application time reduces the topographic effects of corneal crosslinking.

Why this is important: Use of accelerated CXL protocols, while not currently FDA-approved in the United States, may make the procedure more tolerable for children/ adolescents in an outpatient setting. However, few studies have compared outcomes between accelerated and standard CXL in pediatric patients. Further, no studies have followed accelerated CXL patients beyond 3 years. This study shows that the accelerated CXL procedure halts progression of KCN in the majority of pediatric patients for up to 5 years.

Glaucoma and Cornea Surgery Outcomes in Peters Anomaly Dolezal KA, Besirli CG, Mian SI, Sugar A, Moroi SE, Bohnsack BL. Am J Ophthalmol. 2019 Dec;208:367-375. Peters anomaly is associated with glaucoma in 50-70% of cases and there is a paucity of literature describing the management of glaucoma in this difficult disease. The authors of this paper performed a retrospective case series of 58 eyes of 37 patients over a 30 year period at one academic institution. Their goal was to describe the cornea and glaucoma outcomes in this special patient population. The authors looked at visual acuity, intraocular pressure (IOP), graft survival, and success of glaucoma surgery. They found that 23 of the 58 eyes had penetrating keratoplasty (PKP) with an average of 2 grafts per eye and a PKP survival at 1 year of 60% (which decreased to 34% at year 10). Thirty-four of the 58 eyes were diagnosed with glaucoma at a mean age of 2.8 years and 20 eyes required glaucoma surgery with an average of 3 surgeries per eye. Glaucoma drainage devices (GDD) were successful in 53% of cases, laser cycloablation successful in 67% of cases, trabeculotomy with mitomycin C was successful in 25% of cases and without mitomycin c had 0% success. The highest success was in patients with GDD and also cycloablation (80% of the successes). Eyes that had PKP did not have a higher rate of glaucoma. Visual acuities were not available in all patients, but the authors found 9 eyes of 8 patients with a vision of 20/200 or better - and 5 of these eyes did not undergo a PKP or glaucoma surgery while 3 of these eyes had one or more PKP. Only one of the eyes with vision 20/200 or better had

Anterior Segment 23

both PKP and glaucoma surgery. The authors concluded that PKP in eyes with Peters anomaly had poor long term success and that greater than 50% of the eyes with Peters have secondary glaucoma that requires multiple surgical procedures. This study has a lot of important data to better help counsel parents of patients with this difficult to treat disease despite its retrospective nature, lack of control group, and variable disease severity at presentation. Aggressive treatment of glaucoma with GDD and cycloablation demonstrated good control of glaucoma. Most importantly guiding parents to better understanding the poor visual outcomes in these cases despite excellent care is helpful to the pediatric ophthalmologist treating these difficult cases.

Cataract 24

12. CATARACT

Prevalence of Cerebrotendinous Xanthomatosis Among Patients Diagnosed With Acquired Juvenile-Onset Idiopathic Bilateral Cataracts. Freedman SF, Brennand C, Chiang J, DeBarber A, DelMonte MA, Duell PB, Fiorito J, Marshall R. JAMA Ophthalmol. 2019; 137 (11): 1312-1316. The authors evaluated the prevalence of cerebrotendinous xanthomatosis (CTX) in patients diagnosed with bilateral idiopathic cataracts from ages 2 to 21 years at 26 sites in the USA from November 2015 to June 2017. Of note, eligible study participants were identified through a retrospective medical record review. CTX is a rare autosomal recessive bile acid synthesis disorder caused by mutations in CYP27A1, the gene encoding sterol 27-hydroxylase, resulting in elevated levels of plasma cholestanol and urinary bile alcohols. Clinical symptoms and signs may include early-onset chronic diarrhea, juvenile-onset bilateral cataracts, cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration. Although initiation of treatment at a young age can prevent disease complications, diagnosis often occurs after the onset of permanent neurologic damage. Of 170 tested patients, 88 (51.8%) were male, with the median age at 10 (with range of 2 to 49) years. Three patients (1.8%) had biochemical and genetic confirmation of newly diagnosed CTX (plasma cholestanol level greater than 1.0 mg/dL, positive urine bile alcohol result, and disease-causative mutations in CYP27A1). The mean age at cataract diagnosis for patients with CTX was at 12 (with range of 8 to 16) years. The authors report that 1.8% of patients in the study were diagnosed as having CTX, which is 500-fold the currently estimated prevalence of CTX in the general population (3 to 5 per 100,000). These findings suggest that juvenile-onset idiopathic bilateral cataracts may be useful as a screening marker for CTX. Furthermore, ophthalmologist can play an important role to help with early identification of this diagnosis.

Cataract Surgery 25

13. CATARACT SURGERY

Intraocular Lens Implantation during Early Childhood: A Report by the American Academy of Ophthalmology Scott R. Lambert, Vinay K. Aakalu, Amy K. Hutchinson, Stacy L. Pineles, Jennifer A. Galvin, Gena Heidary, Gil Binenbaum, Deborah K. VanderVeen. Ophthalmology. Oct 2019;126:1454-1461. The controversy around intraocular lens (IOL) implantation in early childhood centers around the optimal age to consider primary IOL implantation after surgical aphakia. IOL implantation in children has significantly greater morbidity than occurs in older adults, including high rates of visual axis opacification and post-surgical unexpected refractive errors. This technical assessment reported the results of a literature review of studies reporting outcomes after cataract surgery in children ages 2 and under. Only 14 publications were deemed of sufficient quality for inclusion, but 8 were randomized control trials and 6 others were higher quality case-control and cohort studies, so the level of evidence was high. The results are similar to those reported for the individual randomized clinical trials – IOL implantation under age 6 months was associated with significant more visual axis opacifications and unexpected myopic shifts. Visual outcomes and glaucoma risk were statistically equivalent between IOL and contact lens/spectacle correction, but the IOL group had significantly greater corneal endothelial cell loss. The study concludes by stating that IOL implantation is not recommended before age 6 months and future research to improve surgical techniques to reduce visual axis opacification and more accurate predictions of postoperative refractive error are important steps to meet before IOL implantation in very young infants can become the standard of care.

Glaucoma 26

14. GLAUCOMA

Longitudinal reproducibility of spectral domain optical coherence tomography in children with physiologic cupping and stable glaucoma. Xu L, Freedman SF, Silverstein E, Muir K, El-Dairi M. J AAPOS 2019 Oct;23:262.e1-6.

Primary congenital glaucoma (PCG) is difficult to manage, let alone assess. Reliable visual field information, which furnishes important information for managing many adult glaucoma patients, is often unavailable in children. Spectralis spectral domain optical coherence tomography (SD-OCT; Heidelberg-Engineering, Heidelberg, Germany) has previously shown good reproducibility for measurements of both peripapillary retinal nerve fiber layer (pRNFL) and macular thicknesses in adults with suspected glaucomatous discs. By contrast, in children, good reproducibility of OCT imaging has been shown only in children with normal eyes and with non-glaucomatous optic neuropathies. The authors conducted this retrospective study to determine whether Spectralis SD-OCT measurements are reproducible over time in children with physiologic cupping and stable glaucoma. Subjects were identified from a subset of participants in an earlier retrospective study conducted by the same authors and included children (<18 years of age) with physiologic cupping and stable primary congenital glaucoma (PCG) having had at least 2 SD-OCTs over a period between April 2010 and September 2015. Thicknesses of average peripapillary retinal nerve fiber layer (pRNFL) and six individual sectors and volumes of three segmented retinal layers and total retina were measured. Spectralis review software was used for segmentation. Intraclass correlation coefficients (ICC) and coefficient of variation (COV) were calculated. The ICC is a statistic that describes how strongly units in the same group resemble one another. According to Munro’s classification of reliability coefficients, 0.26-0.49 was classified as low correlation; 0.50-0.69, as moderate correlation; 0.70-0.89, as high correlation; and 0.90-1.00, as very high correlation. The COV is a measure of spread that describes the amount of variability relative to the mean. A total of 35 eyes of 35 children were included: 15 eyes had physiologic cupping; 20 eyes, PCG. Mean ages at initial SD-OCT were 11.2 ±3.3 years and 9.7 ± 3.3, respectively; mean intervals between first and last imaging were 2.2 ± 1.1 and 3.0 ± 1.4 years, respectively. ICCs across three visits for both groups for average and sectoral pRNFL thicknesses were 0.887-0.997 and for segmented retinal volumes were 0.806-0.993. ICCs for total retinal volume for physiologic cupping and PCG were 0.993 and 0.954, respectively. COVs for average pRNFL thickness were 0.9% and 1.7%, respectively. For all other measurements, COVs ranged from 0.3% to 5.4%. The authors conclude that the reproducibility of longitudinal SD-OCT measurements for average pRNFL thickness in children with stable glaucoma over about 2 years is comparable to short-term reproducibility (COV) in normal children (1.16%) and normal and glaucoma adults (1.62%-3.4%).

Refractive Surgery 27

15. REFRACTIVE SURGERY

Therea re no all-star articles in this section.

Genetics 28

16. GENETICS

Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials. Maguire AM, Russell S, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, Marshall KA, McCague S, Reichert H, Davis M, Simonelli F, Leroy BP, Wright JF, High KA, Bennett J. Ophthalmology. 2019 Sep;126(9):1273-1285. This is a report on the durability of voretigene neparvovec-rzyl (VN)adeno-associated viral vector-based gene therapy for RPE65 mutation-associated inherited retinal dystrophy (IRD), including results of a phase 1 follow-on study at year 4 and phase 3 study at year 2. The studies are an open-label phase 1 follow-on clinical trial and an open-label, randomized, controlled phase 3 clinical trial. Forty subjects received 1.5×10

11 vector genomes (vg) of VN per eye in at least 1 eye during the trials, including 11

phase 1 follow-on subjects and 29 phase 3 subjects (20 original intervention [OI] and 9 control/intervention[CI]).The end points common to the phase 1 and phase 3 studies included change in performance on the Multi-Luminance Mobility Test (MLMT) within the illuminance range evaluated, full-field light sensitivity threshold (FST) testing, and best-corrected visual acuity (BCVA). Safety end points included adverse event reporting, ophthalmic examination, physical examination, and laboratory testing. Mean (standard deviation) MLMT lux score change was 2.4 (1.3) at 4 years compared with 2.6 (1.6) at 1 year after administration in phase 1 follow-on subjects (n = 8), 1.9 (1.1) at 2 years, and 1.9 (1.0) at 1 year post-administration in OI subjects (n = 20), and 2.1 (1.6) at 1 year post-administration in CI subjects (n = 9). All 3 groups maintained an average improvement in FST, reflecting more than a 2 log10(cd.s/m2) improvement in light sensitivity at 1 year and subsequent available follow-up visits. The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no deleterious immune responses occurred. The data suggests that the effect of therapy, which is nearly maximal by 30 days after VN administration, is durable for 4 years, with observation ongoing. Clinical utility of genetic testing in 201 preschool children with inherited eye disorders. Lenassi E, Clayton-Smith J, Douzgou S, Ramsden SC, Ingram S, Hall G, Hardcastle CL, Fletcher TA, Taylor RL, Ellingford JM, Newman WD, Fenerty C, Sharma V, Lloyd IC, Biswas S, Ashworth JL, Black GC, Sergouniotis PI. Genet Med. 2019 Dec 18. A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. This study assesses the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). Two hundred one unrelated children (0-5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011-2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis,28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). Thus, genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients. Visual Impairment in Retinitis Pigmentosa. Vezinaw CM, Fishman GA, McAnany JJ. Retina. 2019 Sep 23.

Genetics 29

The authors of this paper sought to evaluate the genetic subtypes by age range of patients with RP who have vision of 20/200 or worse in the better seeing eye. All patients were examined by one physician. The charts of 1095 RP patients were reviewed and 215 were included in the study (excluding systemic diseases and unconfirmed genotypes). The authors found that 0.46% patients and no light perception in each eye and 80.4% had vision better than 20/200. In the cohort of patients who had vision of 20/200 or worse in one eye had no significant differences in the mode of inheritance. They ultimately found that 80% of the patients had better vision than 20/200 and thus not legally blind. This is helpful in counselling patients with a diagnosis of RP. Spectrum of Disease Severity and Phenotype in Choroideremia Carriers. Jauregui R, Park KS, Tanaka AJ, Cho A, Paavo M, Zernant J, Francis JH, Allikmets R, Sparrow JR, Tsang SH. American Journal of Ophthalmology. 2019 Nov 1;207:77-86. Choroideremia is an X-linked disorder characterized by degeneration of the retina, retinal pigment epithelium (RPE), and choroid owing to mutations in the CHM gene. Patients afflicted with the disease typically present with poor night vision followed by a gradual loss of peripheral vision that encroaches upon the macula, often culminating in legal blindness in the fourth or fifth decade. Twelve unrelated female patients with a clinical and genetic diagnosis of choroideremia carriers were included in this study. Disease severity among these phenotypes ranged from mild to severe, resembling the typical presentation of choroideremia in male patients. Mild disease presented with retinal pigment epithelium mottling, a patchy pattern of hypoautofluorescent speckles on SW-FAF, and intact retinal layers on spectral-domain OCT. Severe disease presented with widespread chorioretinal atrophy as shown by SW-FAF and spectral-domain OCT. Each of the identified genetic variants in CHM was predicted to be disease-causing according to in silico prediction software. Disease progression analysis of 4 patients with follow-up showed a decline in visual acuity for 2 patients, with progression observed on spectral-domain OCT in 1 of the patients. No significant disease progression on SW-FAF was observed for any of the patients. Symptomatic female subjects should be considered for current and upcoming gene replacement therapy clinical trials. GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies. Bouzia Z, Georgiou M, Hull S, Robson AG, Fujinami K, Rotsos T, Pontikos N, Arno G, Webster AR, Hardcastle AJ, Fiorentino A., Michaelides, M. American Journal of Ophthalmology. 2019 Nov 5. GUCY2D-associated Leber congenital amaurosis is a severe early-onset retinal dystrophy associated with very poor VA from birth. Twenty-one subjects with GUCY2D-LCA from a single referral center were included, with a mean follow-up ± standard deviation (SD) of 10 ± 11.85 years. Marked reduction in visual acuity (VA) and nystagmus was documented in all patients within the first 3 years of life. Fifty-seven percent (n = 12) exhibited photophobia and 38% (n = 8) had nyctalopia. VA was worse than hand motion in 71% of the patients (n = 15). Longitudinal assessment of VA showed stability in all patients, except 1 patient who experienced deterioration over a follow-up of 44 years. Hyperopia was reported in 13 of the 17 subjects (71%) with available refraction data. Eighteen subjects had either normal fundus appearance (n = 14) or a blond fundus (n = 3), while only 4 of the eldest subjects had mild retinal pigment epithelium (RPE) atrophy (mean, 49 years; range 40-54 years). OCT data were available for 11 subjects and 4 different grades of ellipsoid zone (EZ) integrity were identified: (1) continuous/intact EZ (n = 6), (2) focally disrupted EZ (n = 2), (3) focally disrupted with RPE changes (n = 2), and (4) diffuse EZ disruption with RPE changes (n = 1). All examined subjects had stable OCT findings over the long follow-up period. Full-field ERGs showed evidence of a severe cone-rod dystrophy in 5 of 6 patients and undetectable ERGs in 1 subject. Novel genotype-phenotype correlations are also reported. Despite the severely affected photoreceptor function, the relatively preserved photoreceptor structure based on EZ integrity until late in the disease in the majority of subjects suggests a wide therapeutic window for gene therapy trials.

Genetics 30

Changes in retinal sensitivity after gene therapy in choroideremia. Fischer MD, Ochakovski GA, Beier B, Seitz IP, Vaheb Y, Kortuem C, Reichel FF, Kuehlewein L, Kahle NA, Peters T, Girach A. Retina. 2020 Jan 1;40(1):160-8. Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). Six male patients (51–60 years) with CHM received AAV2-REP1, by a single 0.1-mL subretinal injection of 1011 genome particles during vitrectomy (THOR (NCT02671539), Phase 2, open-label, single-center, randomized study). Twelve-month data are reported. In study eyes, 4 patients experienced minor changes in best-corrected visual acuity (−4 to +1 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); one gained 17 letters and another lost 14 letters. Control eyes had changes of −2 to +4 letters. In 5/6 patients, improvements in mean (95% confidence intervals) retinal sensitivity (2.3 [4.0] dB), peak retinal sensitivity (2.8 [3.5] dB), and gaze fixation area (−36.1 [66.9] deg2) were recorded. Changes in anatomical endpoints were similar between study and control eyes. Adverse events were consistent with the surgical procedure. Gene therapy with AAV2-REP1 can maintain, and in some cases, improve, visual acuity in CHM. Longer term follow-up is required to establish whether these benefits are maintained. Efficacy of topical brinzolamide in children with retinal dystrophies. Scruggs BA, Chen CV, Pfeifer W, Wiley JS, Wang K, Drack AV. Ophthalmic genetics. 2019 Jul 4;40(4):350-8. Inherited retinal dystrophies are a leading cause of irreversible blindness in children. A retrospective chart review was performed to identify pediatric patients with inherited retinal dystrophies who received topical brinzolamide at a single university center between 2008 and 2015. Serial visual acuity and central macular thicknesses were compared to assess the efficacy of brinzolamide. Seven subjects were identified who met the inclusion criteria. Four had juvenile X-linked retinoschisis, two had retinitis pigmentosa, and one had Leber congenital amaurosis. All were prescribed brinzolamide thrice daily; however, one patient was completely non-compliant. Four of the six treated patients exhibited a mild decrease in central macular thickness in both eyes during the study with all six treated patients having significantly improved vision at the first endpoint, 33.2 ± 8.2 months after treatment initiation. For treated patients, average visual acuity (LogMAR) ± standard error of the mean improved from 0.5 ± 0.04 pre-treatment to 0.3 ± 0.1 at the second endpoint, 50.2 ± 7.3 months after treatment initiation. Mild anatomic improvement of macular cysts was seen in pediatric patients using brinzolamide. Visual acuity improvement occurred even without significant reduction in macular cysts. Further studies are needed to determine whether the beneficial effects of carbonic anhydrase inhibitors are sustained in children with inherited retinal degenerations. Retinal findings in pediatric patients with Usher syndrome Type 1 due to mutations in MYO7A gene. Subirà O, Català-Mora J, Díaz-Cascajosa J, Padrón-Pérez N, et al. Eye (Lond). 2019 Jul 18. This study describes retinal alterations detected by swept-source optical coherence tomography (SS-OCT) in pediatric patients with Usher syndrome type 1 (USH1) and compares these findings to previously published reports. Thirty-two eyes from 16 patients (11 males and 5 females) with a genetic diagnosis of USH1 because of MYO7A mutations underwent SS-OCT. Patients ranged in age from 4 to 17 years (mean, 11,13 ± 4,29). The subfoveal and macular area were analyzed with SS-OCT at 1050 nm using 12 radial scans of 12.0 mm. Structural abnormalities were evaluated and correlated with best-corrected visual acuity (BCVA). The most common qualitative retinal abnormality was external layer damage in macular area. Specific alterations included external limiting membrane loss/disruption (27 eyes; 84.4%), disruption of

Genetics 31

the Myoid zone (27 eyes; 84.4%); Ellipsoid zone disruption (28 eyes; 87.5%), and loss of the outer segments (29 eyes; 90.6%). The damage of the retinal pigment epithelium was divided according to the loss of the different layers: phagosome zone (30 eyes; 93.8%), melanosome zone (29 eyes; 90.6%) and mitochondria zone (0 eyes; 0%). The presence of cystoid macular edema (CME) was significantly correlated with alterations in photoreceptors. Disruption or absence of the myoid and ellipsoid zones of the photoreceptors were the only variables independently associated with decreased BCVA. The findings of this study suggest that the physiopathologic basis of early-stage Usher syndrome (USH) may be changes in the outer retinal layer, particularly the photoreceptors, which in turn may cause alterations-such as CME in the inner retinal layers. Accordingly, monitoring the condition of photoreceptors during follow-up may be advisable for the early detection of pathologic changes.

Trauma 32

17. TRAUMA

Long-term visual outcomes following abusive head trauma with retinal hemorrhage. Weldy E, Shimoda A, Patnaik J, Jung J, Singh J J AAPOS. 2019 Dec;23(6):329.e1-329. There is limited research detailing the prevalence of specific ocular findings and long term outcomes of children with AHT. The authors used a retrospective review identifying medical records of patients with diagnosis of retinal hemorrhages and abusive head trauma in order to formally evaluate visual outcomes in this population seen at a single tertiary care facility. Data was extracted for patients with at least one month interval since initial visit. Visual impairment in at least one eye was found in 46 % of the children in the study. Ocular abnormalities included strabismus (43%), amblyopia (40%), cortical visual impairment (19%), and optic disc pallor (13%). The incidence of these ocular co-morbidities is higher than in the general population. Cortical visual impairment was found in 1 in 5 children in this group and was similar to other published literature. Limitations of this study include retrospective nature and poor follow up. This study is important for pediatric ophthalmologists because it highlights the need for ophthalmologic follow up in children with AHT and retinal hemorrhages. Patterns of Pediatric Firearm-Related Ocular Trauma in the United States. Weiss R, He C, Gise R, Parsikia A, Mbekeani JN. JAMA Ophthalmol. 2019; 137 (12): 1363-1370. The authors present a large retrospective analysis from the National Trauma Data Bank, the largest national registry of hospitalized trauma cases in the USA. Analysis included the firearm-related ocular injuries (n = 1972) of pediatric patients (defined as younger than 21 years) hospitalized between January 1, 2008, and December 31, 2014. A total of 8715 firearm-related ocular injuries were identified. Of these ocular injuries, 1972 (22.6%) occurred in pediatric patients, most of whom were male (1678 [85.1%]) and adolescents (1037 [52.6%]), with a mean age of 15.2 years. The most common types of firearm-related ocular injuries were open wound of the eyeball (820 [41.6%]) and ocular adnexa (502 [25.5%]), orbital injuries or fractures (591 [30.0%]), and contusion of the eye or adnexa (417 [21.1%]). The authors reported that analyses showed that chidren from ages 0 to 3 years had a greater odds of unintentional injuries (P < .001) and injuries occurring at home (P < .001), and those teenagers/young adults from ages 19 to 21 years had greater odds of assault injuries (P < .001) and injuries occurring on the street (P < .001). Demographic analyses showed that black patients had the greatest odds of having injuries with assault intention (P < .001) while white patients had the greatest likelihood for self-inflicted injury (P < .001). Traumatic brain injury resulted mostly from self-inflicted trauma (P < .001), as did visual pathway injuries (P < .001). The authors conclude that pediatric firearm-related ocular injuries from 2008 through 2014 were predominantly sight-threatening and associated with traumatic brain injury. Future studies and further data analyses would be helpful to include more possible risk factors, including gender, age, race/ethnicity, and injury intention. Studying the relationships between demographics and ocular injuries can have its limitations but at the same time, can be helpful to the families and communities to develop strategies to prevent pediatric firearm-related ocular injuries.

Retina 33

18. RETINA

Phenotypic Spectrum of the Foveal Configuration and Foveal Avascular Zone in Patients With Alport Syndrome. Hess K, Pfau M, Wintergerst MWM, Loeffler KU, Holz FG, Herrmann P. Invest Ophthalmol Vis Sci. 2020 Feb 7;61(2):5. This study investigates characteristics of the foveal pit and the foveal avascular zone (FAZ) in patients with Alport syndrome (AS), a rare monogenetic disease due to mutations in genes encoding for collagen type IV. Twenty-eight eyes of nine patients with AS, and five autosomal-recessive carriers and 15 eyes from 15 age-similar healthy control subjects were examined using optical coherence tomography (OCT) and OCT-angiography (OCT-A). Foveal configuration and FAZ measures including the FAZ area, circularity, and vessel density in the central 1° and 3° were correlated. Foveal hypoplasia was found in 10 eyes from seven patients with either genotype. In contrast, a staircase foveopathy was found in seven eyes of four X-linked AS patients. The average FAZ area did not differ significantly between AS patients and control subjects (mean ± SD 0.24 ± 0.24 mm2 vs. 0.21 ± 0.09 mm2; P = 0.64). Five eyes showed absence or severe anomalies of the FAZ with crossing macular capillaries that was linked to the degree of foveal hypoplasia on OCT images leading to a significant inverse correlation of FAZ area and foveal thickness (r = -0.88; P < 0.001). In contrary, female patients with X-linked mutations exhibited a significantly greater FAZ area (0.48 ± 0.30 mm2 vs. 0.21 ± 0.09 mm2; P = 0.007), in line with OCT findings of a staircase foveopathy. The foveal phenotypic spectrum in AS ranges from foveal hypoplasia and absence of a FAZ to staircase foveopathy with an enlarged FAZ. Because the development of the FAZ and foveal pit are closely related, these findings suggest an important role for collagen type IV in foveal development and maturation. Ocular Adverse Events Associated with MEK Inhibitors. Méndez-Martínez S, Calvo P, Ruiz-Moreno O, Pardiñas Barón N, Leciñena Bueno J, Gil Ruiz MDR, Pablo L. Retina. 2019 Aug;39(8):1435-1450. This is a review article on the ocular adverse events (OAE) associated with MEK inhibitors. MEK inhibitors have been used to treat various types of cancer, which we have seen this use in pediatric patients, such as the treatment of optic gliomas. This review article covers 127 papers on the OAE in this medication. Most OAE include retinal vein occlusion and MEKAR (MEK associated retinopathy). It is reported that up to 90% of patients will develop MEKAR which. Include blurry vision, transient visual disturbances, flashes, and subretinal fluid that resembles CSCR. This is bilateral, multifocal and symmetrical. Other OAE include conjunctivitis, episcleritis, periorbital edema, epiphora, and dry eye. This review article establishes a grading system and algorithm for management of these OAE.

Pediatric Retinal Detachment in an Asian Population with High Prevalence of Myopia: Clinical Characteristics, Surgical Outcomes, and Prognostic Factors. Tsai ASH, Wong CW, Lim L, Yeo I, Wong D, Wong E, Ang CL, Ong SG, Lee SY, Tan G. Retina. 2019 Sep;39(9):1751-1760. The purpose of this study is to review the clinical characteristics, anatomical and surgical outcomes of pediatric retina detachments in an Asian population with high myopia over a 20 year period. This was a retrospective chart review from a single center at Singapore National Eye Center. This cohort included 171 eyes of 152 patients. There was at least a 6 mo follow up. The mean spherical equivalent was -6.75 D. The median BCVA was 20/400 with only 30 eyes seeing better than 20/40. Most of these patients who had a RD were high myopes, and the rest were post trauma and post intraocular surgery eyes. 83% of the eyes had one retina surgery repair, and a majority of these patients were primary SB. Anatomic success after one surgery was achieved in 60.7% of the eyes. 18 cases were surgical failures due to

Retina 34

PVR. Older patients had better odds of success. A longer duration of symptoms or presence of a cataract at presentation resulted in lower odds of success. The overall success was about 86.7 %. This study does highlight some important issues in counselling families when a child has a retinal detachment. Ultra-wide field fundus autofluorescence for the detection of inherited retinal disease in difficult to examine patients. Darakhshanda Khurram Butt, FRCS Ophth (Glasgow); Avinash Gurbaxani, FRCS (Ed) (Ophth); Igor Kozak, MD, PhD, MAS J Pediatr Ophthalmol Strabismus. 2019;56(6):383-387. This study assessed the ease and utility of UWFFAF in detecting difficult-to-examine children in clinic with suspected inherited retinal disease. The main outcome measure was to assess the sensitivity of UWF-FAF, UWF-CF photography, and clinical examination in diagnosing the disease. The authors hypothesized that UWF-FAF has higher sensitivity to detect disease than color fundus photography or clinical examination.C hildren with suspected inherited retinal disease were examined clinically and then underwent UWF imaging (color fundus imaging and fundus autofluorescence) using the Optos Tx-200 imaging system (Optos, Dunfermline, United Kingdom). Patient ages ranged from 1 to 13 years (mean: 5.6 years). The study included 112 eyes of 59 patients. Image acquisition was successful even in small children. UWF-FAF was the most sensitive in detecting the disease (94.9%), followed by UWF-CF (67.7%) and clinical examination (49.1%). The authors concluded that UWF-FAF imaging is superior to fundus photography and clinical examination in detecting pathology in children with suspected inherited retinal diseases. It is a feasible and perhaps clinically essential tool to be used for this condition. This is the first study that focuses on comparisons of clinical examination and UWF-FAF retinal imaging in a pediatric population whose clinical conditions present a challenge for examiners. The study has limitations such as its retrospective nature. Also, intraobserver readings were not used and the optic nerve hasn’t been analyzed. Rhegmatogenous Retinal Detachment in Children: Clinical Factors Predictive of Successful Surgical Repair. Smith JM, Ward LT, Townsend JH, Yan J, Hendrick AM, Cribbs BE, Yeh S, Jain N, Hubbard GB 3rd. Ophthalmology. 2019 Sep;126(9):1263-1270 This retrospective interventional case series sought to describe presenting clinical features that are associated with successful repair of pediatric rhegmatogenous retinal detachment (RRD). Participants included 212 eyes of 191 patients 0-18 years of age undergoing repair of RRD between 2001-2015 with minimum follow-up of 3 months. Patients were divided into 3 age groups (0-6 years, 7-12 years, and 13-18 years) and comparisons were made using bivariate and multivariate estimating equation models. The main outcome measure was complete reattachment of the retina at follow-up. Mean follow-up was 36.3 months. Of 212 eyes, 166 (78%) achieved total reattachment at final follow-up. In the two younger cohorts Stickler syndrome was more likely (OR, 0.45; 95% CI 0.22-0.91) whereas in the oldest cohort blunt trauma was more likely (OR, 2.3; 95% CI, 1.2-4.4). Subtotal RD was more likely to be repaired successfully (OR, 0.3; 95% CI 0.12-0.78) than total RD (OR, 3.6; 95% CI, 1.5-8.4; P= 0.0100). Eyes with previous vitreoretinal surgery were less likely to undergo successful repair (OR, 0.30; 95% CI, 0.12-0.78; P=0.0258). There was higher success with primary scleral buckle (SB 63%) and combined SB plus pars plana vitrectomy (PPV 68%) compared with PPV alone (51%). The macula was more often detached in younger patients and they have lower rate of self-reported symptoms highlighting need for regular dilated exams particularly with higher risk factors for RRD such as high myopia or ROP. Among patients with successful reattachment, there were lower levels of vision in the youngest cohort possibly due to amblyopia secondary to detachment subsequent sequalae including cataract, strabismus, and refractive error. However, the authors point out that vision outcomes should be interpreted with caution as vision can be difficult to measure in children. Overall, successful anatomic repair of pediatric RRD is possible in most pediatric patients.

Retina 35

Prevalence and Onset of Pediatric Sickle Cell Retinopathy Jonathan Li, Lloyd Bender, James Shaffer, Daniel Cohen, et al Ophthalmology. July 2019;126(7): 1000-1006. This retrospective cohort study sought to determine the prevalence, age of onset, and risk factors associated with sickle cell retinopathy (SCR) to inform development screening guidelines for asymptomatic children. Risk factors evaluated included markers of sickle cell hemoglobinopathy (SCH) severity (number of emergency room or hospital admissions for crises, number of transfusions, hydroxyurea therapy, and transcranial Doppler-confirm cerebral vasculopathy), genotype, gender, and race. Of 398 children (mean age, 9.6+ +/- 4.6 years; age 0–18 years), 208 (52%) showed sickle cell homozygote (SS) genotype, 113 (28%) showed sickle cell hemoglobin C (SC) genotype, and 77 (19%) showed trait genotype. Forty-eight children (12.1%) demonstrated SCR, 44 of 398 children (11.1%; 95% confidence interval, 8.3%-14.5%) demonstrated NPR, and 9 of 398 children (2.3%; 95% confidence interval, 1.2%-4.2%) demonstrated PR. Prevalence was higher for SC than SS genotype for NPR (21% vs 9%) and PR (5% vs 1%); onset for SC genotype was earlier than that for SS genotype for NPR (youngest diagnosis 4.8 vs 6.1 years) and PR (12.2 vs 15.4 years). No other risk factors were associated significantly with SCR. This is the largest study of children with SCH to date in North America even if children with sickle cell trait are excluded from the cohort. The study period is also the most recent permitting and analysis of new potential risk factors that have emerged as standard of care for children with SCH and have not been analyzed previously. The authors identify potential referral bias relating to referral of sicker children which makes their recommendations more conservative in terms of not missing any treatable SCR. They suggest screening to identify PR in children without ophthalmologic symptoms begin by nine years of age for children with SC disease and by 13 years of age for children with SS disease. Clinical markers SCH severity evaluated in the study do not seem to have value in determining screening guidelines.

Retinoblastoma / Intraocular tumors 36

19. RETINOBLASTOMA / INTRAOCULAR TUMORS

Ophthalmic Vascular Events After Intra-Arterial Chemotherapy for Retinoblastoma: Real-World Comparison Between Primary and Secondary Treatments. Ancona-Lezama D, Dalvin LA, Lucio-Alvarez JA, Jabbour P, Shields CL. Retina. 2019 Dec;39(12):2264-2272. The use of intraarterial chemotherapy (IAC) for Rb has been increasing use in attempts to salvage the globe. The goal of this paper is to report the ophthalmic vascular events after IAC as first line or secondary line of treatment over a 10 year period. This was a retrospective chart review of patients with unilateral and bilateral Rb seen by the oncology service at Wills Eye hospital. 203 eyes of 196 patients met the inclusion criteria. These patients received 682 IAC infusions. Patients were dividied into 2 groups: primary and secondary IAC. Adverse vascular events were similar in the two groups and included retinal vasculature attenuation, peripheral retinal pruning, BRAO, CRAO, macular ischemia, VH, subretinal hemorrhage, RPE atrophy, choroidal atrophy, disc pallor, and ophthalmic artery occlusions. These vascular events occurred in a small number of infusions (about 5% per infusion). This articles does evaluate the vascular events that can occur but does help differentiate between primary IAC and secondary IAC and no differences.

Secondary Prevention of Retinoblastoma Revisited: Laser Photocoagulation of Invisible New Retinoblastoma. Soliman SE, VandenHoven C, MacKeen LD, Gallie BL. Ophthalmology. 2020 Jan;127(1):122-127. Invisible retinoblastoma tumors are now detected with screening for retinal tumors in at-risk neonates (those inheriting RB1 pathogenic alleles from affected parents) using handheld OCT. Laser photocoagulation is challenging, requiring exact localization of a tumor invisible to indirect ophthalmoscopy and standard imaging. This retrospective, noncomparative, single-institutional, observational case series utilizes a protocol involving OCT-guided localization and photocoagulation of these invisible tumors with 1-year follow-up. Participants included children with any clinically invisible retinoblastoma tumor that was detected on OCT posterior pole screening. More specifically invisible tumors consisted of round homogeneous within the inner nuclear layer. Software calipers placed beside anatomic retinal landmarks (branched/curved vessels, fovea, or optic disc) mapped the tumor location and extent. A single laser (532 nm) burn flagged the location, and OCT evaluated the tumor-laser burn relationship; laser treatment was then continued in the correct location. Post-laser OCT ensured complete treatment. The main outcome measures were accuracy (frequency of geographic miss and skip areas), effectiveness (recurrence rate), and burden (scar size and characteristics at final follow-up) of laser treatment.

Eleven new invisible posterior pole tumors in 7 eyes of 5 children were treated by this technique. Localization and tumor-laser burn relationships were accurate in 11 of 11 tumors (100%, 95% confidence interval [CI], 49.9-100), and all showed swelling and hyper-reflectiveness of the tumor in post-laser OCT. Two photocoagulation sessions (2 weeks apart) were sufficient to successfully manage 9 of 11 tumors (82%, 95% CI, 37.4-100) with resulting permanent flat scars. One tumor (9%, 95% CI, 0.2-50.6) developed OCT-detected subclinical recurrences within 3 months, treated by 1 laser session. No treatment scar showed gliosis, foveal involvement, or retinal traction at 1-year follow-up. Scar expansion occurred in 1 tumor (9%, 95% CI, 0.2-50.6), and all scars (100%, 95% CI, 49.9-100) showed pigmentary changes. In summary, OCT-guided localization and photocoagulation technique is valuable in achieving precision results in managing invisible new retinoblastoma tumors. This technique shows a potential to improve outcomes of secondary prevention screening for retinoblastoma.

Retinoblastoma / Intraocular tumors 37

Racial, Ethnic, and Socioeconomic Disparities in Retinoblastoma Enucleation: A Population-Based Study, SEER 18 2000-2014. Rajeshuni N, Whittemore AS, Ludwig CA, Mruthyunjaya P, Moshfeghi DM. Am J Ophthalmol. 2019 Nov;207:215-223. The purpose of this study was to determine the effect of race, ethnicity, socioeconomic status on enucleation in cases of retinoblastoma (Rb). This study augmented a previous study on the same population that showed the increase rate of enucleation in low SES, non white patients, but the goal of this study was to use a multivariate model to look at the combined effects of the SES and tumor characteristics. A retrospective cohort analysis was performed using patients under 18 years old from 18 registries who were diagnosed with Rb between 2000 and 2014. The primary outcome included enucleation odds ratio. The authors did not find any relationship between race, ethnicity and SES and stage at diagnosis. Seventy one percent of the patients had enucleation, and the factors associated with enucleation included Asian race, black race, Hispanic ethnicity, low socioeconomic status, older age at diagnosis, unilateral disease, advanced stage. Over time the enucleation rates decreased over all groups. The authors concluded that more investigation needs to be done to better understand the cause of these discrepancies. They suggest that there are systematic disparities and the treatment differences cannot be attributed to poor follow up or late diagnosis. This could be due to physicians treating these patients differently and/ or decreased access to globe sparing treatments. The authors pointed out the main limitations of this paper including the preexisting data set, retrospective nature, and that these registries don't cover every patient in the United States (though about 75%). Overall this paper is important to the pediatric ophthalmologist in that it demonstrates that our system results in different treatments among patients in different SES. Vision and visual potential for perifoveal retinoblastoma after optical coherence tomographic-guided sequential laser photocoagulation Soliman S, VandenHoven C, Mackeen L, Gallie B. Br J Ophthalmol. June 2019;103:753-760. The authors of this study hypothesized that avoiding direct laser treatment to the foveal edge of perifoval RB tumors might enhance visual potential while still adequately achieving tumor control. Therefore they performed this retrospective interventional case series of children with perifoveal RB treated with laser after chemotherapy monitored at each session by optical coherence tomography (OCT). 22 eyes (20 patients) were analyzed, including 14 juxtafoveal (fovea <3000 µm from tumor edge) and 8 foveolar (tumor underlying fovea) tumors. After tumor chemoreduction, laser was performed under general anesthesia with OCT guidance. The OCT was used to identify and document the fovea to design the foveal sparing laser crescent. In later sessions OCT was also used to dermine residual tumor areas and height. Post-laser OCT ensured accuracy of laser treatments. With juxtafoveal tumors, foveal pit preservation was observed in 13/14 eyes (with >= 500 µm of perifoveal retina tumor free). In 1 eye the fovea was flattened by an epiretinal membrane. 12 eyes had normal central fovealor thickness. Foveolar tumors had worse anatomical outcomes: 5/8 had tumor recurrences and none had restored foveal pit or perifoveal retina. Acceptable (>= 1.0 logMAR or good (>= 0.5 logMAR) visual acuity was found in 12/14 and 8/14 eyes with juxtafoveal tumors, and 5/6 and 0/6 eyes with foveolar tumors respectively. This study did not include data on children who underwent amblyopia therapy. The authors summarize that visual potential and anatomical results were better in juxtafoveal RB compared to foveolar RB in children treated with foveal-sparing laser photocoagulation guided by OCT. The predictive value of magnetic resonance imaging of retinoblastoma for the likelihood of high-risk pathologic features Hiasat J, Saleh A, Al-Hussaini M, Al Nawaiseh I, et al. EJO, March 2019, 29(2) 262–268

Retinoblastoma / Intraocular tumors 38

The goal was to evaluate the predictive value of magnetic resonance imaging in retinoblastoma for the likelihood of high risk pathologic features. A retrospective study of 64 eyes enucleated from 60 retinoblastoma patients. Contrast-enhanced magnetic resonance imaging was performed before enucleation. Main outcome measures included demographics, laterality, accuracy, sensitivity, and specificity of magnetic resonance imaging in detecting high-risk pathologic features. Optic nerve invasion and choroidal invasion were seen microscopically in 34 (53%) and 28 (44%) eyes, respectively, while they were detected in magnetic resonance imaging in 22 (34%) and 15 (23%) eyes, respectively. The accuracy of magnetic resonance imaging in detecting prelaminar invasion was 77% (sensitivity 89%, specificity 98%), 56% for laminar invasion (sensitivity 27%, specificity 94%), 84% for postlaminar invasion (sensitivity 42%, specificity 98%), and 100% for optic cut edge invasion (sensitivity100%, specificity 100%). The accuracy of magnetic resonance imaging in detecting focal choroidal invasion was 48% (sensitivity 33%, specificity 97%), and 84% for massive choroidal invasion (sensitivity 53%, specificity 98%), and the accuracy in detecting extrascleral extension was 96% (sensitivity 67%, specificity 98%). Magnetic resonance imaging should not be the only method to stratify patients at high risk from those who are not, even though it can predict with high accuracy extensive postlaminar optic nerve invasion, massive choroidal invasion, and extrascleral tumor extension.

Orbit 39

20. ORBIT

Teprotumumab for the Treatment of Active Thyroid Eye Disease. Douglas RS, Kahaly GJ, Patel A, et al. N Engl J Med. 2020 Jan 23;382(4):341-352. This study evaluated the IGF-IR inhibitor teprotumumab against placebo in patients with active thyroid eye disease. A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group in this randomized, double-masked multicenter trial. Infusions of teprotumumab or placebo were given once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. There were multiple prespecified secondary outcomes, including a diplopia response (a reduction in diplopia of ≥1 grade). A four point diplopia scale was used: 0 = patient reports no diplopia, 1 = diplopia in primary position when tired or when first awakening, 2 = diplopia at extremes of gaze, or 3 = constant diplopia in primary or reading position. The percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001). All secondary outcomes were significantly better with teprotumumab than with placebo, including diplopia response (68% [19 of 28] vs. 29% [8 of 28], P=0.001). The positive diplopia response was seen by 12 weeks in all 28 teprotumumab treated patients with diplopia at baseline. Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging both before and after treatment. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation. The study was funded by Horizon Therapeutics, the manufacturer of teprotumumab.

Strabismologists now have a new treatment to offer patients with active thyroid eye disease who are experiencing diplopia beyond prisms and monocular occlusion.

Long-term Methimazole Therapy in Juvenile Graves’ Disease: A Randomized Trial Fereidoun Azizi, Miralireza Takyar, Elham Madreseh, and Atieh Amouzegar Pediatrics May 2019; 143 (5) e:20183034 Hyperthyroidism is not a common disease in children and adolescence. For a majority of these patients, it is caused by a toxic goiter. The three standard treatment modalities have been suboptimal because of significant side effects and a high relapse rate. There have been a few studies that report long-term therapy of antithyroid drugs as effective and safe in curing hyperthyroidism. The study aimed to compare short and long term usage of methimazole treatment in juvenile Graves’ as well as variables associated with remission of hyperthyroidism. In a randomized, parallel group trial, 66 consecutive patients with untreated Graves’ were enrolled. After a medial of 22 months of methimazole treatment, the group was randomized to either receive low-dose methimazole treatment or to discontinue the treatment. The long-term group completed 96-120 months of methimazole treatment. At baseline, the short and long term treatment groups had similar profiles (age, sex, goiter degree, ophthalmopathy. fT4, T3, and thyrotopin levels). After 48 months, 16 patients in the short-term group (67%) and 3 patients in the long-term group (12.5%) relapsed (p< 0.001). Side effects only occurred in the first stage of methimazole treatment when all patients were being treatment and these were cutaneous reactions (3 patients). No serious complications occurred in the long-term group on low-dose treatment. In this study, the researchers demonstrate that long-term low-dose methimazole treatment is both effective and safe in treating the hyperthyroidism and preventing relapse. The other benefit of using methimazole is that the other choices of therapy (surgical resection and radioiodine) can lead to other medical issues and life-long hypothyroidism. The limitations of the study include small number of patients, the subjects were only of west Asian descent potentially limiting its applicability to other populations, and that the study was not double-blinded possibly creating selection bias. In summary, this study suggests that long-term

Orbit 40

methimazole is safe and effective treatment for juvenile Graves’ hyperthyroidism with higher recovery rates than the short term treatment.

Medical and sclerosing agents in the treatment of orbital lymphatic malformations: what's new?

Lam SC, Yuen HKL.

Curr Opin Ophthalmol. 2019 Sep;30(5):380-385

Orbital lymphatic malformations can cause visual loss from compressive optic neuropathy, amblyopia, or strabismus. In addition, proptosis and motility disturbance can cause cosmetic disfigurement. First line management in the past was mainly observation for asymptomatic lesions and surgical debulking. Surgery however is fraught with issues such as bleeding, proximity to vital structures and high recurrence. Sclerotherapy is less invasive with faster recovery time than surgery. Drawbacks include discomfort on injection, edema, and compartment syndrome. It also usually takes 4-6 weeks for fibrosis to occur so it is not useful for acute cases. A review paper comparing sclerotherapy and surgery found no significant difference in outcome. All agents are effective with excellent overall responses between 71-100%. Choice of agent should be guided by side-effect profile and availability. STS decreases proptosis by 75% after 1-3 sessions, is relatively painless and effective at low concentrations. Side effects are dose and strength dependent with significant swelling and the need for proper hydration to avoid hemoglobinuria. OK-342 (Picibanil) causes regression in 96% of patients with no pain on injection, however can cause inflammation, and low grade fever. It may take 6 weeks or more to take effect which is longer than other agents. Ethanol (absolute alcohol) is the most potent agent and is cheap and easily accessible but there is a high incidence of side effects such as skin necrosis and systemic toxicity. Doxycycline has a high success rate with only 1 treatment and is cheap and easily available with the lowest rate of complications. Side effects include pain on injection and teeth staining in children. Bleomycin A2 can be injected intralesionally or interstitially with good results and incites less inflammatory reaction. Complications include flu-like symptoms, hair loss and hyperpigmentation of skin. Patients must also avoid live vaccines for 3 months. Bleomycin A5 is as effective as bleomycin A2 but has fewer complications and is more cost effective. Medical treatments are available with varying success rates. Sirolimus blocks VEGF signalling and induces partial to complete remission in more than half the patients with acceptable side effects and may be used topically. There is no consensus on dosage or duration of treatment. Side effects include anemia, elevated triglycerides and immunosuppression. Sildenafil caused symptomatic improvement in patients within 12 weeks and is more effective in macrocystic or mixed lymphatic malformations. Side effects include mild diarrhea. Bevacizumab has been used in combination with bleomycin with favorable responses. Recently, PIK3CA mutations have been identified in lymphatic malformations and some targeted therapies are being developed. The authors offer a comprehensive evaluation of sclerosing and medical agents available for use in lymphatic orbital malformations along with their efficacy and side effect profile.

Oculoplastics 41

21. OCULOPLASTICS

Orbital Septum Fibrosis in Congenital Ptosis Correlates With Eyelid Function: A Clinicopathologic Study Heisel C, Heider A, Stewart K, et al Ophthalmic Plast Reconstr Surg Sept/Oct 2019;35:469–473 Congenital ptosis can threaten visual function and is usually treated with surgical correction. This study tests the hypothesis that congenital ptosis involves not only the levator muscle but also the orbital septum, which may tether the eyelid in the primary position. A retrospective chart review was performed on 30 patients (41 eyelids) with congenital ptosis who underwent surgical correction that included partial septum excision. Histologic analysis was performed by a masked pediatric pathologist, with grading of septal tissue disorganization and fibrosis based on standard histologic criteria. An independent comparison of histologic grading with clinical ptosis measures was then performed. Fifteen eyelids demonstrated significant septal fibrosis, 19 were mild, and 7 were not fibrotic. Thirty-six eyelids demonstrated histologic disorganization. Mildly fibrotic eyelids were found to have reduced preoperative levator function than those that were not fibrotic (2.84 ± 1.92 vs. 9.57 ± 4.76 mm; p <0.0001). Samples that demonstrated significant fibrosis were also found to have reduced preoperative levator function (4.67 ± 2.12 vs. 9.57 ± 4.76 mm; p = 0.0007). Histologically disorganized samples were also found to have a lower preoperative levator function (9.50 ± 6.04 vs. 3.99 ± 2.49; p = 0.0052). Orbital septae in patients with congenital ptosis demonstrate histologic disorganization and fibrosis. When decreased levator function is observed clinically, septal fibrosis and/or disorganization is likely present. These observations suggest that debulking the fibrotic septum during congenital ptosis surgery may improve outcomes by releasing the eyelid from its congenitally tethered position, improving eyelid elasticity. A Modified Levator Resection to Improve Postoperative Lagophthalmos and Eyelid Lag Yasser H. Al-Faky, Mohamed A. Abu El-Eneen, Khaled M. Selim, and Hassan A. Ali Ophthalmic Plast Reconstr Surg Nov/Dec 2020;36:38–44 This was a retrospective case-control study that looked to assess the effect of releasing the central attachment between the Whitnall’s ligament (WL) and the levator palpebrae superioris muscle on the postoperative levator function (LF), eyelid lag, and degree of lagophthalmos. The study included patients with moderate and severe simple congenital ptosis who underwent skin approach levator aponeurosis resection (LR) as a primary procedure with a minimum of 6-month follow up. Patients were divided into 2 groups; the first group underwent LR without WL release (control group) while the second group underwent LR with WL release. Preoperative demographics and clinical data were reviewed. Postoperative LF, eyelid lag, and degree of lagophthalmos as well as surgical outcomes were compared and analyzed in both groups. There were a total of 81 patients (88 eyelids) included in this study. 50 were males (61.7%) and the mean age was ±SD 12.0±9.5 years. The first group included 43 eyelids while the second had 45 eyelids. There was no statistical difference in demographics and preoperative data between both groups. The postoperative LF was higher in the second group (10.7±2.1mm) with less consecutive eyelid lag compared with the control group (7.8±1.9mm) (p < 0.001). The control group had acquired more postoperative lagophthalmos compared with the second group (p < 0.001). Complete surgical success was achieved in 82.2% in the second group compared with 60.5% in the control group (p = 0.024). The authors felt that releasing the central attachment between WL and levator palpebrae superioris muscle has achieved an improvement in LF with minimal postoperative eyelid lag, lagophthalmos, and corneal complications.

Conservative management of congenital dacryocystocele: resolution and complications Lee M, Park J, Kim N, Choung H, et al. Can J Ophthalmol. August 2019;54(4):421-425

Oculoplastics 42

Incidence of congenital dacryocystocele varies from 0.02% to 0.1% of newborns. The best treatment approach is controversial. Some people recommend early surgical intervention to reduce risks of infection and avoid further complex surgery. Others recommend monitoring due to high rates of spontaneous resolution. The authors of this study looked at a population of Asian children to evaluate the outcomes of conservative management for congenital dacryocystocele. 30 dacryocystoceles (28 infants) were retrospectively reviewed. Conservative treatment included digital massage four times daily and antibiotic eye drops if needed. 27 cases did not develop infection. Of these, 20/27 (74%) resolved spontaneously after conservative treatment. The mean duration of this treatment was 27.5 days. In 5 cases probing was needed due to persistent dacryocystoceles after 1 month of massage. 5 total cases developed infection including 3 at presentation. 2 cases became infected during the period of conservative management. These all received systemic antibiotic treatment, and 3 cases required external incision and drainage. All of these resolved without needing additional procedures. The authors conclude that uninfected cases of congenital dacryocystocele could be managed conservatively in a majority of cases. Vigilance is still needed to detect infection, but after infection is controlled conservative management is still an option.

Infections 43

22. INFECTIONS

Cortical Visual Impairment in Congenital Cytomegalovirus Infection. Haoxing Douglas Jin, MD; Gail J.Demmler-Harrison, MD; Jerry Miller, MS, PhD; Jane C.Edmond, MD et al. J of Ped Ophth & Strabismus.2019; 56(3): 194-202 The purpose of this study is to describe the presentation, evolution and long-term outcome of cortical visual impairment (CVI) in patients with symptomatic congenital cytomegalovirus (CMV) infection, and to identify risk factors for the development of CVI in patients with symptomatic congenital CMV. In this retrospective subanalysis of a long-term prospective cohort study eleven of seventy-seven (14.3%) patients had symptomatic CMV, zero of a hundred nine had asymptomatic CMV and fifty-one control patients had CVI. Overall, patients with symptomatic CMV had worse vision than patients with asymptomatic CMV, who in turn had worse vision than control patients. Microcephaly, intracranial calcification, dilatation of ventricles, encephalomalacia, seizure at birth, optic atrophy, chorioretinitis/retinal scars, strabismus, and neonatal onset of sensorineural hearing loss were risk factors associated with CVI. The study concluded that CVI may result from symptomatic congenital CMV infection. CVI may be suspected when one or more classic CMV symptoms present at birth. Microcephaly, intracranial calcification, dilatation of ventricles, encephalomalacia, seizure at birth, optic atrophy, chorioretinitis/retinal scars, strabismus, and neonatal onset of sensorineural hearing loss are risk factors for CVI. The relationship of CVI and its risk factors in patients with CMV suggests the potential to predict the development of CVI through predictive modeling in future research. Early screening of CVI in children born with symptomatic congenital CMV can facilitate educational, social, and developmental interventions.

Pediatrics / Syndromes / Systemic disease 44

23. PEDIATRICS / SYNDROMES / SYSTEMIC DISEASE

Ophthalmologic disorders and risk factors in children with autism spectrum disorder. Chang MY, Gandhi N, O'Hara M J AAPOS. 2019 Dec;23(6):337. Current literature suggests that children with autism spectrum disorder (ASD) have an increased rate of ophthalmologic disorders including refractive errors, strabismus, and amblyopia. The authors use a retrospective review of children with ASD who underwent ophthalmologic exam at a single institution over a 10-year period. The authors found an ophthalmologic diagnosis in 71% of children with ASD which exceeds previous studies. The presence of referral bias at this institution may have influenced this result. The presence of strabismus (32%), amblyopia (19%), and refractive errors (42%) in children with ASD exceeds the prevalence found in accepted databases for the general pediatric population. Optic neuropathy was found in 4% of children with ASD in this study. The optic atrophy was secondary to hydrocephalus or optic disc abnormalities including optic nerve hypoplasia (ONH). Previous studies have shown an association of ASD and ONH. This study revealed cerebral palsy was associated with the greatest risk of an ophthalmologic diagnosis in children with ASD. Children with ASD can have difficulty cooperating for vision screening. The authors emphasize that children with ASD who cannot cooperate for screening should be referred for complete eye examination. Anesthesia for pediatric ophthalmologic surgery. Waldschmidt B, Gordon N J AAPOS. 2019 Jun;23(3):127-131. The necessity of general anesthesia for almost all pediatric ophthalmology procedures requires pediatric ophthalmologists to have familiarity with recent recommendations in order to ensure patient safety. The authors review a wide range of issues covering risk factors for special populations to the 2016 warnings from the FDA concerning anesthesia neurotoxicity in children. Preoperative fasting guidelines must protect the child having anesthesia without causing risk from factors like hypoglycemia and dehydration. The use of the 8-6-4-2 rule or a variation of it is now commonly used at most institutions. Pediatric patients have a high rate of upper respiratory infections and it is not unusual for them to present for surgery with a history of recent infection or a current active URI which can increase the risk of complications. There is no consensus as to the correct timing for proceeding with a procedure although there are known risk factors that may suggest a longer interval may be safer: fever, productive cough, nontransparent rhinorrhea, change in baseline function, younger age, reactive airway disease, airway anomalies, and secondhand smoke. Preoperative anxiety is common and can be managed with multiple methods: education, use of child life specialists, distraction techniques as well and preoperative medications. Although some short procedures can be performed without an IV, there are risk factors, such as medical complexity or prolonged surgery time that warrant IV placement. The oculocardiac reflex causing bradycardia should be anticipated, prevented, and managed. Suggestions for managing postoperative emergence delirium are reviewed including adequate pain control. Acetaminophen and NSAID’s, as well as local anesthetics enable avoidance of the use of opioids. The use of dexamethasone and ondansetron is useful in avoiding postoperative nausea. Most human studies suggest have been reassuring about the effect of general anesthesia on the neurodevelopment of children. The authors emphasize that a teamwork approach of a pediatric anesthesiologist and pediatric ophthalmologist can provide safe and efficient care for patients. This article provides an excellent review of current recommendations for anesthesia for pediatric ophthalmology surgery. It is necessary read.

Pediatrics / Syndromes / Systemic disease 45

Visual and oculomotor outcomes in children with prenatal opioid exposure.

Lambert JE, Peeler CE.

Curr Opin Ophthalmol. 2019 Nov;30(6):449-453

Neonatal abstinence syndrome (NAS) is a consequence of opioid withdrawal in the early days of life, marked by irritability, hypertonia, feeding intolerance, and respiratory distress. They are treated with tapering doses of morphine. Opioids cause significantly higher rates of apoptosis which increases based on the duration and concentration of morphine exposure. Endogenous opioid receptors play a crucial role in oligodendrocyte development and myelination of CNS. Exposure to perinatal buprenorphine decreases expression of nerve growth factor and acetylcholine receptors which are findings associated with long term cognitive and behavioral deficits. Delayed white matter maturation is noted in opioid-exposed infants and when followed, older children are found to have smaller basal ganglia, caudate, thalamus, and cerebellar white matter volumes compared to controls. Decreases in these areas are linked to ADHD which is noted at a higher rate in exposed children. VEP latencies were longer in drug exposed groups suggesting delayed signal transmission. This bore out in those exposed to methadone as well but was not observed in buprenorphine exposed infants. In the methadone cohort this VEP latency disappeared at 36 months of age. There are studies suggesting that there is ‘catch-up’ maturation in these patients. With respect to oculomotor outcomes there are consistent reports of horizontal nystagmus with various forms of strabismus occuring as well. The authors discuss the effect that opioids have on white matter development, also noting that exposed infants have delayed maturation of afferent visual pathways but there is some ‘catch-up’ development in later childhood. Strabismus and nystagmus are more common and persist into childhood. Ocular manifestations of Sturge-Weber syndrome.

Silverstein M, Salvin J.

Curr Opin Ophthalmol. 2019 Sep;30(5):301-305

Sturge-Weber syndrome (SWS) has various manifestations including port-wine birthmark (PWB). While previously thought to follow the pattern of the trigeminal nerve, current literature clarifies that it follows the embryonic craniofacial pattern. About ½ of patients with SWS have communication disorders and ¼ have autism and sleep disorders. There is also a correlation with endocrine disorders including GH deficiency and central hypothyroidism. SWS is a sporadic mutation of GNAQ and can be variable. Some cases may even have absence of facial angiomas but exhibit the classic neuroimaging findings of parieto-occipital atrophy with heavy gyriform calcifications and angiomatous malformations in the parieto-occipital area. With respect to the ophthalmologist, glaucoma (30-70 %) and choroidal hemangioma (20-70%) of patients are most concerning. The proposed pathogenic mechanism for glaucoma is malformations of the AC angle (plays a greater role in early-onset glaucoma) and increased episcleral venous pressure from the vasculature of the PWB (later onset glaucoma). Patients should be examined at least annually with measurement of corneal diameter, axial length, OCT and HVF when possible. Small case series have shown topical medications to be successful. Aqueous suppressants are preferred in patients with congenital forms and latanoprost seems to work best in later-onset glaucoma. Goniotomy and trabeculotomy are the preferred initial surgeries due to low risk of adverse events but there is a high single procedure failure rate. Trabeculectomy with Ologen implant (collagen implant to decrease subconj scarring and bleb related complications) when compared with MMC was equally effective without complications such as thin blebs and shallow AC. Trabeculotomy-trabeculectomy works well creating two outflow tracts, with high success. Ahmed valve significantly reduces the need for medication but does have significant complications. Ex-Press shunt with MMC had better controlled IOP with fewer reoperations than trab with MMC. Cryocoagulation is a good alternative treatment. Choroidal hemangioma can be diffuse (DCH) or circumscribed (CCH). Vision loss from DCH occurs due to refractive error, foveal distortion and exudative RD. External beam radiotherapy, stereotactic radiotherapy, proton beam radiotherapy and plaque brachytherapy have been successful however the most up to date literature endorses PDT with verteporfin. This procedure may lead to initial worsening of VA and exudative detachment at 1 week but start to have improvement by 1 month. CCH can be asymptomatic but can cause problems if there is degeneration over the fovea, RD at the fovea, CME

Pediatrics / Syndromes / Systemic disease 46

leading to retinoschisis, neovascular glaucoma and total RD. Laser photocoagulation, transpupillary thermotherapy, ruthenium plaque therapy, external or proton beam radiation, and PDT can all be used. The aim of all therapy is to shrink the tumor near the macula and allow for resolution of subretinal fluid. The authors have reviewed the most common ophthalmologic concerns in patients with SWS and discuss the possible evaluation and management options available to both. Of interest is the use of PDT in patients with CCH and DCH as well as some novel surgical approaches to the glaucoma associated with this disorder.

Uveitis 47

24. UVEITIS

There are no all-star articles in this section.

Practice management / Health care systems / Education 48

25. PRACTICE MANAGEMENT/ HEALTH CARE SYSTEMS / EDUCATION

There are no all-star articles in this section.