Pediatric Ophthalmology

Falcone MM, Hunter DG, Gaier ED. Emerging therapies for amblyopia. Semin Ophthalmol 2021;36(4):282-288.Abstract
Traditional therapies to treat amblyopia, such as optical correction or occlusion/penalization of the non-amblyopic eye, are efficacious but are not without limitations such as poor adherence and decreased success with increasing age. Recently, there has been an interest in new amblyopia therapies, some using binocular techniques, through a variety of platforms including video games, movies, and virtual reality. Overall, available efficacy results for these treatments are highly variable.
Elhusseiny AM, MacKinnon S, Zurakowski D, Huynh E, Dagi LR. Long-term ophthalmic outcomes in 120 children with unilateral coronal synostosis: a 20-year retrospective analysis. J AAPOS 2021;Abstract
BACKGROUND: Prior studies comparing ophthalmic outcomes after treating unicoronal synostosis (UCS) by early endoscopic strip craniectomy (ESC) versus later fronto-orbital advancement (FOA) are modest in sample size, or lack consistent age adjustment. We report long-term, age-adjusted ophthalmic outcomes for a large cohort after nonrandomized treatment by one of these two options. METHODS: The following data was retrieved from a retrospective review of the medical records of patients with treated UCS born since 2000: cycloplegic refractions, sensorimotor examinations, and strabismus procedures before craniofacial repair and postoperatively at approximately 18 and 60 months of age. V-pattern strabismus was graded as mild (absent or + 1/-1 oblique dysfunction) versus moderate-to-severe (≥+2/-2 oblique dysfunction or left to right vertical alignment change of ≥20Δ or ocular torticollis >15°). RESULTS: A total of 120 infants were included: 60 treated by FOA and 60 by ESC. By the late examination, aniso-astigmatism was present in 71.8% of FOA-treated patients and 46% of ESC-treated patients (P < 0.0001). By late examination, the age-adjusted odds ratio of moderate-to-severe V-pattern strabismus after treatment by FOA versus ESC was 2.65 (95% CI, 1.37-6.28; P = 0.02); strabismus surgery was performed in 26 infants treated by FOA compared with 13 treated by ESC (OR = 2.8; P = 0.02). Amblyopia developed in 60% of FOA-treated patients compared with 35% of those treated by ESC (OR 3.0; 95% CI, 1.3-6.7; P = 0.02). CONCLUSIONS: Our age-adjusted ophthalmic results confirm better long-term outcomes after treatment of USC by endoscopic strip craniectomy. Recognition and referral of affected infants by the earliest months of life facilitates the opportunity for endoscopic repair.
Rosenblatt TR, Ji MH, Vail D, Ludwig CA, Al-Moujahed A, Pasricha MV, Callaway NF, Kumm J, Moshfeghi DM. Key factors in a rigorous longitudinal image-based assessment of retinopathy of prematurity. Sci Rep 2021;11(1):5369.Abstract
To describe a database of longitudinally graded telemedicine retinal images to be used as a comparator for future studies assessing grader recall bias and ability to detect typical progression (e.g. International Classification of Retinopathy of Prematurity (ICROP) stages) as well as incremental changes in retinopathy of prematurity (ROP). Cohort comprised of retinal images from 84 eyes of 42 patients who were sequentially screened for ROP over 6 consecutive weeks in a telemedicine program and then followed to vascular maturation or treatment, and then disease stabilization. De-identified retinal images across the 6 weekly exams (2520 total images) were graded by an ROP expert based on whether ROP had improved, worsened, or stayed the same compared to the prior week's images, corresponding to an overall clinical "gestalt" score. Subsequently, we examined which parameters might have influenced the examiner's ability to detect longitudinal change; images were graded by the same ROP expert by image view (central, inferior, nasal, superior, temporal) and by retinal components (vascular tortuosity, vascular dilation, stage, hemorrhage, vessel growth), again determining if each particular retinal component or ROP in each image view had improved, worsened, or stayed the same compared to the prior week's images. Agreement between gestalt scores and view, component, and component by view scores was assessed using percent agreement, absolute agreement, and Cohen's weighted kappa statistic to determine if any of the hypothesized image features correlated with the ability to predict ROP disease trajectory in patients. The central view showed substantial agreement with gestalt scores (κ = 0.63), with moderate agreement in the remaining views. Of retinal components, vascular tortuosity showed the most overall agreement with gestalt (κ = 0.42-0.61), with only slight to fair agreement for all other components. This is a well-defined ROP database graded by one expert in a real-world setting in a masked fashion that correlated with the actual (remote in time) exams and known outcomes. This provides a foundation for subsequent study of telemedicine's ability to longitudinally assess ROP disease trajectory, as well as for potential artificial intelligence approaches to retinal image grading, in order to expand patient access to timely, accurate ROP screening.
Scelfo C, Mantagos IS. Neurotrophic Keratopathy in Pediatric Patients. Semin Ophthalmol 2021;36(4):289-295.Abstract
Purpose: This review provides an overview of the causes and treatment of neurotrophic keratopathy in the pediatric population.Methods: A thorough review of the current literature discussing neurotrophic keratopathy was conducted then summarized.Results:Fourty-nine papers were reviewed. Congenital and acquired causes of neurotrophic keratopathy exist in the pediatric population. Both medical and surgical approaches to treatment have been trialed, albeit to a limited extent, in pediatric patients. Conservative treatment includes topical lubrication and antibiotics to prevent concurrent infectious ulcer formation. Various neurotrophic factors have been trialed in the form of serum drops to restore corneal sensation when conservative measures fail. Surgically, different corneal neurotization techniques have been developed whereby a donor nerve is routed to the anesthetized cornea to restore innervation and sensation. Conclusions: Advances in the treatment of neurotrophic keratopathy have made corneal reinnervation and restoration of vision more easily attainable in pediatric patients.
Zhang YJ, Jimenez L, Azova S, Kremen J, Chan Y-M, Elhusseiny AM, Saeed H, Goldsmith J, Al-Ibraheemi A, O'Connell AE, Kovbasnjuk O, Rodan L, Agrawal PB, Thiagarajah JR. Novel variants in the stem cell niche factor WNT2B define the disease phenotype as a congenital enteropathy with ocular dysgenesis. Eur J Hum Genet 2021;29(6):998-1007.Abstract
WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein's putative involvement in multiple developmental and stem cell maintenance pathways.
Ehrenberg M, Bagdonite-Bejarano L, Fulton AB, Orenstein N, Yahalom C. Genetic causes of nystagmus, foveal hypoplasia and subnormal visual acuity- other than albinism. Ophthalmic Genet 2021;42(3):243-251.Abstract
Background: To describe genetic molecular findings in individuals with congenital nystagmus, foveal hypoplasia, and subnormal vision, with normal ocular pigmentation (absence of diffuse transillumination or transparent retinal pigment typical for albinism).Methods: This is a retrospective, multicenter study of ophthalmic, systemic, and genetic features, as collected from medical records of patients diagnosed with infantile nystagmus and foveal hypoplasia. Ophthalmic findings include best-corrected visual acuity (BCVA), biomicroscopic examination, cycloplegic refraction, retinal examination, macular optical coherence tomography, and electroretinography. Genetic information was retrieved from the participating genetic clinics and included ethnicity and molecular diagnosis.Results: Thirty-one individuals met the inclusion criteria and had a secure molecular diagnosis. Mutations in two genes predominated, constituting 77.4% of all the represented genes: SLC38A8 (45.1%) and PAX6 (32.3%). Seventy-eight percent of the subjects who had a measurable BCVA had moderate and severe visual impairment (range 20/80 to 20/270). Most patients with a mutation in SLC38A8 had mild to moderate astigmatism, while most patients with PAX6 mutation had moderate and severe myopia. Patients in the PAX6 group had variable degrees of anterior segment manifestations.Conclusion: In our cohort, the main causative genes for congenital nystagmus and foveal hypoplasia in normally pigmented eyes were SLC38A8 and PAX6. A mild phenotype in PAX6 mutations may be an under-diagnosed cause of nystagmus and foveal hypoplasia. Reaching an accurate genetic diagnosis is essential for both the patients and their family members. This enables predicting disease prognosis, tailoring correct follow-up, and providing genetic counseling and family planning to affected families.
Hellgren G, Lundgren P, Pivodic A, Löfqvist C, Nilsson AK, Ley D, Sävman K, Smith LE, Hellström A. Decreased Platelet Counts and Serum Levels of VEGF-A, PDGF-BB, and BDNF in Extremely Preterm Infants Developing Severe ROP. Neonatology 2021;:1-10.Abstract
INTRODUCTION: Thrombocytopenia has been identified as an independent risk factor for retinopathy of prematurity (ROP), although underlying mechanisms are unknown. In this study, the association of platelet count and serum platelet-derived factors with ROP was investigated. METHODS: Data for 78 infants born at gestational age (GA) <28 weeks were included. Infants were classified as having no/mild ROP or severe ROP. Serum levels of vascular endothelial growth factor A, platelet-derived growth factor BB, and brain-derived neurotrophic factor were measured in serum samples collected from birth until postmenstrual age (PMA) 40 weeks. Platelet counts were obtained from samples taken for clinical indication. RESULTS: Postnatal platelet counts and serum concentrations of the 3 growth factors followed the same postnatal pattern, with lower levels in infants developing severe ROP at PMA 32 and 36 weeks (p < 0.05-0.001). With adjustment for GA, low platelet counts and low serum concentrations of all 3 factors at PMA 32 weeks were significantly associated with severe ROP. Serum concentrations of all 3 factors also strongly correlated with platelet count (p < 0.001). CONCLUSION: In this article, we show that ROP, platelet counts, and specific pro-angiogenic factors correlate. These data suggest that platelet-released factors might be involved in the regulation of retinal and systemic angiogenesis after extremely preterm birth. Further investigations are needed.
Hellström A, Nilsson AK, Wackernagel D, Pivodic A, Vanpee M, Sjöbom U, Hellgren G, Hallberg B, Domellöf M, Klevebro S, Hellström W, Andersson M, Lund A-M, Löfqvist C, Elfvin A, Sävman K, Hansen-Pupp I, Hård A-L, Smith LEH, Ley D. Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial. JAMA Pediatr 2021;175(4):359-367.Abstract
Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.
Jamerson EC, Solyman O, Yacoub MS, Abushanab MMI, Elhusseiny AM. Angle Surgery in Pediatric Glaucoma Following Cataract Surgery. Vision (Basel) 2021;5(1)Abstract
Glaucoma is a common and sight-threatening complication of pediatric cataract surgery Reported incidence varies due to variability in study designs and length of follow-up. Consistent and replicable risk factors for developing glaucoma following cataract surgery (GFCS) are early age at the time of surgery, microcornea, and additional surgical interventions. The exact mechanism for GFCS has yet to be completely elucidated. While medical therapy is the first line for treatment of GFCS, many eyes require surgical intervention, with various surgical modalities each posing a unique host of risks and benefits. Angle surgical techniques include goniotomy and trabeculotomy, with trabeculotomy demonstrating increased success over goniotomy as an initial procedure in pediatric eyes with GFCS given the success demonstrated throughout the literature in reducing IOP and number of IOP-lowering medications required post-operatively. The advent of microcatheter facilitated circumferential trabeculotomies lead to increased success compared to traditional <180° rigid probe trabeculotomy in GFCS. The advent of two-site rigid-probe trabeculotomy indicated that similar results could be attained without the use of the more expensive microcatheter system. Further studies of larger scale, with increased follow-up, and utilizing randomization would be beneficial in determining optimum surgical management of pediatric GFCS.
Ambrosio L, Hansen RM, Moskowitz A, Oza A, Barrett D, Manganella J, Medina G, Kawai K, Fulton AB, Kenna M. Dark-adapted threshold and electroretinogram for diagnosis of Usher syndrome. Doc Ophthalmol 2021;143(1):39-51.Abstract
PURPOSE: To determine the utility of ophthalmology evaluation, dark-adapted threshold, and full-field electroretinogram for early detection of Usher syndrome in young patients with bilateral sensorineural hearing loss. METHODS: We identified 39 patients with secure genetic diagnoses of Usher Syndrome. Visual acuity, spherical equivalent, fundus appearance, dark-adapted threshold, and full-field electroretinogram results were summarized and compared to those in a group of healthy controls with normal hearing. In those Usher patients with repeated measures, regression analysis was done to evaluate for change in visual acuity and dark-adapted threshold with age. Spherical equivalent and full-field electroretinogram responses from dark- and light-adapted eyes were evaluated as a function of age. RESULTS: The majority of initial visual acuity and spherical equivalent results were within normal limits for age. Visual acuity and dark-adapted threshold worsened significantly with age in Usher type 1 but not in Usher type 2. At initial test, full-field electroretinogram responses from dark- and light-adapted eyes were abnormal in 53% of patients. Remarkably, nearly half of our patients (17% of Usher type 1 and 30% of Usher type 2) would have been missed by tests of retinal function alone if evaluated before age 10. CONCLUSIONS: Although there is an association of abnormal dark-adapted threshold and full-field electroretinogram at young ages in Usher patients, it appears that a small but important proportion of patients would not be detected by tests of retinal function alone. Thus, genetic testing is needed to secure a diagnosis of Usher syndrome.
Hong EH, Shin YU, Bae GH, Choi Y, Ahn SJ, Sobrin L, Hong R, Kim I, Cho H. Nationwide incidence and treatment pattern of retinopathy of prematurity in South Korea using the 2007-2018 national health insurance claims data. Sci Rep 2021;11(1):1451.Abstract
The aim of this study is to investigate the nationwide incidence and treatment pattern of retinopathy of prematurity (ROP) in South Korea. Using the population-based National Health Insurance database (2007-2018), the nationwide incidence of ROP among premature infants with a gestational age (GA) < 37 weeks (GA < 28 weeks, GA28; 28 weeks ≤ GA < 37 weeks; GA28-37) and the percentage of ROP infants who underwent treatment [surgery (vitrectomy, encircling/buckling); retinal ablation (laser photocoagulation, cryotherapy)] were evaluated. We identified 141,964 premature infants, 42,300 of whom had ROP, with a nationwide incidence of 29.8%. The incidence of ROP in GA28 group was 4.3 times higher than in GA28-37 group (63.6% [2240/3522] vs 28.9% [40,060/138,442], p < 0.001). As for the 12-year trends, the incidence of ROP decreased from 39.5% (3308/8366) in 2007 to 23.5% (2943/12,539) in 2018. 3.0% of ROP infants underwent treatment (25.0% in GA28; 1.7% in GA28-37); 0.2% (84/42,300) and 2.9% (1214/42,300) underwent surgery and retinal ablation, respectively. The overall percentage of ROP infants who underwent treatment has decreased from 4.7% in 2007 to 1.8% in 2018. This first Korean nationwide epidemiological study of ROP revealed a decreased incidence of ROP and a decreased percentage of ROP infants undergoing conventional treatment during a 12-year period.
Hu Z, Cao J, Choi EY, Li Y. Progressive retinal vessel malformation in a premature infant with Sturge-Weber syndrome: a case report and a literature review of ocular manifestations in Sturge-Weber syndrome. BMC Ophthalmol 2021;21(1):56.Abstract
BACKGROUND: Sturge-Weber syndrome is a disorder marked by a distinctive facial capillary malformation, neurological abnormalities, and ocular abnormalities such as glaucoma and choroidal hemangioma. CASE PRESENTATION: We report a case of progressively formed retinal vessel malformation in a premature male infant with Sturge-Weber syndrome and retinopathy of prematurity, after treatment with intravitreal anti-vascular endothelial growth factor (VEGF). The baby was born at 30 weeks gestation with a nevus flammeus involving his left eyelids and maxillary area. On postmenstrual age week 39, he received intravitreal anti-VEGF. Diffuse choroidal hemangioma became evident at 40 weeks, with the classic "tomato catsup fundus" appearance. These clinical findings characterized Sturge-weber syndrome. He presented with posterior retinal vessel tortuosity and vein-to-vein anastomoses at 44 weeks. CONCLUSION: This is a rare case of documented progression of retinal vessel malformations in a patient with Sturge-Weber syndrome and retinopathy of prematurity.

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