Pediatric Ophthalmology

PURPOSE: To report practice patterns of intravitreal injections of anti-VEGF for retinopathy of prematurity (ROP) and outcomes data with a focus on retreatments and complications. DESIGN: Multicenter, international, retrospective, consecutive series. SUBJECTS: Patients with ROP treated with anti-VEGF injections from 2007 to 2021. METHODS: Twenfty-three sites (16 United States [US] and 7 non-US) participated. Data collected included demographics, birth characteristics, examination findings, and methods of injections. Comparisons between US and non-US sites were made. MAIN OUTCOME MEASURES: Primary outcomes included number and types of retreatments as well as complications. Secondary outcomes included specifics of the injection protocols, including types of medication, doses, distance from limbus, use of antibiotics, and quadrants where injections were delivered. RESULTS: A total of 1677 eyes of 918 patients (43% female, 57% male) were included. Mean gestational age was 25.7 weeks (range, 21.2-41.5 weeks), and mean birth weight was 787 g (range, 300-2700 g). Overall, a 30-gauge needle was most commonly used (51%), and the quadrant injected was most frequently the inferior-temporal (51.3%). The distance from the limbus ranged from 0.75 to 2 mm, with 1 mm being the most common (65%). Bevacizumab was the most common anti-VEGF (71.4%), with a dose of 0.625 mg in 64% of cases. Overall, 604 (36%) eyes required retreatment. Of those, 79.8% were retreated with laser alone, 10.6% with anti-VEGF injection alone, and 9.6% with combined laser and injection. Complications after anti-VEGF injections occurred in 15 (0.9%) eyes, and no cases of endophthalmitis were reported. Patients in the United States had lower birth weights and gestational ages (665.6 g and 24.5 weeks, respectively) compared with non-US patients (912.7 g and 26.9 weeks, respectively) (P < 0.0001). Retreatment with reinjection and laser was significantly more common in the US compared with the non-US group (8.5% vs. 4.7% [P = 0.0016] and 55% vs. 7.2% [P < 0.001], respectively). There was no difference in the incidence of complications between the 2 geographic subgroups. CONCLUSIONS: Anti-VEGF injections for ROP were safe and well tolerated despite a variance in practice patterns. Infants with ROP receiving injections in the US tended to be younger and smaller, and they were treated earlier with more retreatments than non-US neonates with ROP.

PURPOSE: To characterize long-term strabismus outcomes in children in the Infant Aphakia Treatment Study (IATS). METHODS: This study was a secondary data analysis of long-term ocular alignment characteristics of children aged 10.5 years who had previously been enrolled in a randomized clinical trial evaluating aphakic management after unilateral cataract surgery between 1 and 6 months of age. RESULTS: In the IATS study, 96 of 109 children (88%) developed strabismus through age 10.5 years. Half of the 20 children who were orthophoric at distance through age 5 years maintained orthophoria at distance fixation at 10.5 years. Esotropia was the most common type of strabismus prior to age 5 years (56/109 [51%]), whereas exotropia (49/109 [45%]) was the most common type of strabismus at 10.5 years (esotropia, 21%; isolated hypertropia, 17%). Strabismus surgery had been performed on 52 children (48%), with 18 of these (35%) achieving microtropia <10Δ. Strabismus was equally prevalent in children randomized to contact lens care compared with those randomized to primary intraocular lens implantation (45/54 [83%] vs 45/55 [82%]; P = 0.8). Median visual acuity in the study eye was 0.56 logMAR (20/72) for children with orthotropia or microtropia <10Δ versus 1.30 logMAR (20/400) for strabismus ≥10Δ (P = 0.0003). CONCLUSIONS: Strabismus-in particular, exotropia-is common irrespective of aphakia management 10 years following infant monocular cataract surgery. The delayed emergence of exotropia with longer follow-up indicates a need for caution in managing early esotropia in these children. Children with better visual acuity at 10 years of age are more likely to have better ocular alignment.

PURPOSE: The aim of this study was to evaluate the clinical and topographic features of posterior polymorphous corneal dystrophy (PPCD) in children aged 15 years or younger with a long-term follow-up. Retrospective case series. METHODS: A retrospective chart review of patients who were diagnosed with PPCD at Boston Children's Hospital from 1999 to 2020 was performed. Data collected included age at the time of diagnosis, slit lamp findings, cycloplegic refraction, best-corrected visual acuity, central corneal thickness, specular microscopy, and corneal topography findings whenever available. RESULTS: Twenty-seven eyes of 19 patients were included (11 unilateral and 8 bilateral cases). Ten patients were girls (52.6%). Left eye was affected in 14 eyes. The mean age at the time of diagnosis was 8.5 ± 3.3 years, with a mean follow-up of 5.3 years. In unilateral cases, there was a statistically significant difference in the endothelial cell density (P = 0.01), coefficient variation (P = 0.03), and hexagonality (P = 0.01) between the affected and the contralateral unaffected eyes. The mean best-corrected visual acuity at initial presentation was 0.8 ± 0.2 compared with 0.9 ± 0.08 in unaffected eyes (P = 0.04). The mean astigmatism was higher in the affected eye (+1.7 diopters) compared with (+1.00) the unaffected eye (P = 0.07). At initial presentation, 7 of 27 eyes had amblyopia, which resolved, either partially or completely, in 5 eyes after treatment. CONCLUSIONS: PPCD can present early in children with astigmatism and anisometropic amblyopia. A careful slit lamp examination for children presenting with anisoastigmatism is necessary to diagnose PPCD. Contrary to adults, presentation is often unilateral. Such patients should be followed up regularly with cycloplegic retinoscopy to prevent and treat refractive amblyopia if present.

Refraction predictions from intraocular lens (IOL) calculation formulae are inaccurate in children. We sought to quantify the relationship between age and prediction error using a model derived from the biometry measurements of children enrolled in the Infant Aphakia Treatment Study (IATS) when they were ≤7 months of age. We calculated theoretical predicted refractions in diopters (D) using axial length, average keratometry, and IOL powers at each measurement time point using the Holladay 1 formula. We compared the predicted refraction to the actual refraction and calculated the absolute prediction error (APE). We found that the median APE was 1.60 D (IQR, 0.73-3.11 D) at a mean age (corrected for estimated gestational age) of 0.20 ± 0.14 years and decreased to 1.11 D (IQR, 0.42-2.20 D) at 10.60 ± 0.27 years. We analyzed the association of age with APE using linear mixed-effects models adjusting for axial length, average keratometry, and IOL power and found that as age doubled, APE decreased by 0.25 D (95% CI, 0.09-0.40 D). The accuracy of IOL calculations increases with age, independent of biometry measurements and IOL power.

AIM: To describe survival and neonatal morbidities in infants born before 24 weeks of gestation during a 12-year period. METHODS: Data were retrieved from national registries and validated in medical files of infants born before 24 weeks of gestation 2007-2018 in Sweden. Temporal changes were evaluated. RESULTS: In 2007-2018, 282 live births were recorded at 22 weeks and 460 at 23 weeks of gestation. Survival to discharge from hospital of infants born alive at 22 and 23 weeks increased from 20% to 38% (p = 0.006) and from 45% to 67% (p < 0.001) respectively. Caesarean section increased from 12% to 22% (p = 0.038) for infants born at 22 weeks. Neonatal morbidity rates in infants alive at 40 weeks of postmenstrual age (n = 399) were unchanged except for an increase in necrotising enterocolitis from 0 to 33% (p = 0.017) in infants born at 22 weeks of gestation. Bronchopulmonary dysplasia was more common in boys than girls, 90% versus 82% (p = 0.044). The number of infants surviving to 40 weeks doubled over time. CONCLUSION: Increased survival of infants born before 24 weeks of gestation resulted in increasing numbers of very immature infants with severe neonatal morbidities likely to have a negative impact on long-term outcome.

BACKGROUND: Ocular abnormalities (OA) in pediatric patients with acute lymphoblastic leukemia (ALL) are common findings both at diagnosis and later in follow-up. The frequency, predictors, and prognostic impact of OA in the context of recent ALL protocols are not well characterized. PROCEDURE: Single-center retrospective analysis of the medical records of 224 patients with ALL enrolled on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. RESULTS: Overall, 217 (98%) patients had at least one ophthalmic exam. Retinal hemorrhages were the most frequent abnormalities at diagnosis (11%) and cataracts at later time points (13%). OA at diagnosis were associated with age ≥10 years and with the severity of anemia and thrombocytopenia; they were also univariately associated with lower 5-year event-free survival (EFS) (high risk [HR] = 3.09 [95% CI: 1.38-6.94]; p = .006), but not in a disease-free survival (DFS) model adjusted for end-induction minimal residual disease (p = .82). The cumulative incidence of cataract was 13.1% ± 2.8% at 43 months from diagnosis; its development was associated with high presenting white blood cell count (≥50,000/μl) (p = .010), male sex (p = .036), higher risk group (p = .025), and cranial radiation (p = .004). Cataract was associated with decreased visual acuity. CONCLUSIONS: OA at diagnosis, present in 12% of patients, were associated with older age, anemia, and thrombocytopenia and did not carry a significant prognostic impact. Cataracts were detected in over 10% of patients and were associated with decreased visual acuity, thus supporting routine screening after completion of therapy, especially for those treated with high-risk protocols.

PURPOSE: To evaluate the efficacy and safety of cenegermin 0.002% ophthalmic drops in the management of pediatric neurotrophic keratopathy (NK). METHODS: Retrospective chart review of children under the age of 18 years diagnosed with NK at Boston Children's Hospital/Massachusetts Eye and Ear Infirmary and treated with topical cenegermin 0.002% ophthalmic solution between June 2018 and June 2021 was performed. Data collection included etiology of NK, age at time of initiation of topical cenegermin, laterality, ethnicity, gender, history of previous ocular therapy, pre- and post-therapy best corrected visual acuity, pre- and post-therapy cornea examination, any adverse events from topical cenegermin, associated ocular conditions, and history of ocular surgeries. RESULTS: The current study includes four eyes of four pediatric patients with a mean age of 4.5 ± 2.0 years at the time of initiation of topical cenegermin therapy. The mean time from NK diagnosis until start of topical cenegermin drops was 5.2 ± 4.3 months and mean follow-up time was 15 ± 9.6 months. In all four patients, marked improvement in epitheliopathy was demonstrated after completion of therapy. Best corrected visual acuity was measurable in 3 eyes of 3 patients, and it improved from a mean of 0.07 ± 0.01 to a mean of 0.29 ± 0.26 (P = 0.3). No adverse events related to cenegermin therapy were noted. CONCLUSION: Topical cenegermin was effective in improving corneal healing for pediatric NK.

Importance: Intravitreal bevacizumab effectively treats severe retinopathy of prematurity (ROP), but it enters the bloodstream and may reduce serum vascular endothelial growth factor (VEGF), potentially causing detrimental effects on developing organs in the premature infant. Objective: To evaluate the association of intravitreal bevacizumab with plasma bevacizumab and VEGF concentrations at 2 and 4 weeks after predefined, de-escalating doses of intravitreal bevacizumab were administered to infants with severe ROP. Design, Setting, and Participants: This phase 1 dose de-escalation case series study was conducted at 10 US hospitals of ophthalmology institutions from May 21, 2015, to May 7, 2019. Blood samples were collected 2 and 4 weeks after intravitreal bevacizumab injection. Participants included 83 premature infants with type 1 ROP in 1 or both eyes and no previous ROP treatment. Data were analyzed from April 2017 to August 2021. Interventions: Study eyes received a single bevacizumab injection of 0.250 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. When the fellow eye required treatment, one dose higher was administered. Total dose administered at baseline was defined as the sum of doses given to each eye within 3 days of initial study-eye injection. Main Outcomes and Measures: Plasma bevacizumab concentration at 2 and 4 weeks after injection and the percentage change in plasma VEGF concentrations from pretreatment levels. Results: A total of 83 infants (mean [SD] age, 25 [2] weeks; 48 boys [58%]) were included in this study. Higher doses of bevacizumab administered at baseline were associated with higher plasma bevacizumab concentrations at 2 weeks (ρ, 0.53; 95% CI, 0.31-0.70) and 4 weeks (ρ, 0.44; 95% CI, 0.18-0.64). Plasma VEGF concentrations decreased by 50% or more from pretreatment levels in 40 of 66 infants (61%) at 2 weeks and 31 of 61 infants (51%) at 4 weeks, but no association was observed between the total dose of bevacizumab administered at baseline and percentage change in plasma VEGF concentrations 2 weeks (ρ, -0.04; 95% CI, -0.28 to 0.20) or 4 weeks (ρ, -0.17; 95% CI, -0.41 to 0.08) after injection. Conclusions and Relevance: Results of this phase 1 dose de-escalation case series study revealed that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF levels for most infants at 2 and 4 weeks after intravitreal administration; however, no association was observed between total bevacizumab dose administered and reductions in plasma VEGF levels from preinjection to 2 weeks or 4 weeks. Additional studies are needed to evaluate the long-term effects of low-dose bevacizumab on neurodevelopment and retinal structure.

PURPOSE: To describe the etiology, clinical features, and outcomes for a large contemporary cohort of children presenting with glaucoma at a tertiary referral center. METHODS: The medical records of patients presenting to Boston Children's Hospital from January 2014 to July 2019 with a diagnosis of childhood glaucoma were retrospectively reviewed. Data regarding etiology, treatment, and visual and anatomic outcomes were collected; visual acuity outcomes were analyzed by laterality and diagnosis categories, using the Childhood Glaucoma Research Network (CGRN) classifications. RESULTS: A total of 373 eyes of 246 patients (51% males) diagnosed with glaucoma before 18 years of age were identified. Mean follow-up was 7.04 ± 5.61 years; 137 cases were bilateral. The mean age at diagnosis was 4.55 ± 5.20 years. The most common diagnoses were glaucoma following cataract surgery (GFCS, 36.5%) and primary congenital glaucoma (PCG, 29.0%). Overall, 164 eyes (44.0%) underwent at least one glaucoma surgery. Intraocular pressure (IOP) was ≤21 mm Hg with or without glaucoma medications in 300 eyes (80.4%) at the last follow-up visit. Poor final best-corrected visual acuity (≤20/200) was found in 110 eyes; patients with poor final visual acuity tended to have poor visual acuity at presentation. The most common reason for poor vision was amblyopia. Uncontrolled IOP was an uncommon cause for vision loss. CONCLUSIONS: Childhood glaucoma can be challenging to manage, but poor vision usually results from amblyopia or presence of other ocular abnormalities or syndromes rather than glaucomatous optic neuropathy.

AIM: This study investigated childhood diagnoses in children born extremely preterm before 24 weeks of gestation. METHODS: Diagnoses of neurodevelopmental disorders and selected somatic diagnoses were retrospectively retrieved from national Swedish registries for children born before 24 weeks from 2007 to 2018. Their individual medical files were also examined. RESULTS: We studied 383 children born at a median of 23.3 (range 21.9-23.9) weeks, with a median birthweight of 565 (range 340-874) grams. Three-quarters (75%) had neurodevelopmental disorders, including speech disorders (52%), intellectual disabilities (40%), attention deficit hyperactivity disorder (30%), autism spectrum disorders (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%) and hearing impairment (5%). More boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%, p < 0.01) and visual impairment (25% vs. 14%, p < 0.01). Just over half of the cohort (55%) received habilitation care. The majority (88%) had somatic diagnoses, including asthma (63%) and failure to thrive/short stature (39%). CONCLUSION: Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long-term support needs at an early stage.

PURPOSE: To evaluate whether pediatric eyes that deviate from age-adjusted normative biometry parameters predict variation in myopic shift after cataract surgery. METHODS: This is a single institution longitudinal cohort study combining prospectively collected biometry data from normal eyes of children <10 years old with biometry data from eyes undergoing cataract surgery. Refractive data from patients with a minimum of 5 visits over ≥5 years of follow-up were used to calculate myopic shift and rate of refractive growth. Cataractous eyes that deviated from the middle quartiles of the age-adjusted normative values for axial length and keratometry were studied for variation in myopic shift and rate of refractive growth to 5 years and last follow-up visit. Multivariable analysis was performed to determine the association between myopic shift and rate of refractive growth and factors of age, sex, laterality, keratometry, axial length, intraocular lens power, and follow-up length. RESULTS: Normative values were derived from 100 eyes; there were 162 eyes in the cataract group with a median follow-up of 9.6 years (interquartile range: 7.3-12.2 years). The mean myopic shift ranged from 5.5 D (interquartile range: 6.3-3.5 D) for 0- to 2-year-olds to 1.0 D (interquartile range: 1.5-0.6 D) for 8- to 10-year-olds. Multivariable analysis showed that more myopic shift was associated with younger age (P < .001), lower keratometry (P = .01), and male gender (P = .027); greater rate of refractive growth was only associated with lower keratometry measures (P = .001). CONCLUSIONS: Age-based tables for intraocular lens power selection are useful, and modest adjustments can be considered for eyes with lower keratometry values than expected for age.