International Classification of Retinopathy of Prematurity, Third Edition.

PURPOSE: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., anti-vascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. DESIGN: Review of evidence-based literature, along with expert consensus opinion. PARTICIPANTS: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. METHODS: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. MAIN OUTCOME MEASURES: Consensus statement. RESULTS: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. CONCLUSIONS: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.

Genetic Variants of the Beta-Adrenergic Receptor Pathways as Both Risk and Protective Factors for Retinopathy of Prematurity.

PURPOSE: There is strong evidence that genetic factors influence retinopathy of prematurity (ROP), a neovascular eye disease. It has been previously suggested that polymorphisms in the genes involved in ß-adrenergic receptor (ADRß) pathways could protect against ROP. Antagonists for the ADRß are actively tested in clinical trials for ROP treatment, but not without controversy and safety concerns. This study was designed to assess whether genetic variations in components of the ADRß signaling pathways associate with risk of developing ROP. DESIGN: An observational case-control targeted genetic analysis. METHODS: A study was carried out in premature participants with (n = 30) or without (n = 34) ROP and full-term controls (n = 20), who were divided into a discovery cohort and a validation cohort. ROP was defined using International Classification of Retinopathy of Prematurity criteria (ICROP). Targeted sequencing of 20 genes in the ADRß pathways was performed in the discovery cohort. Polymerase chain reaction (PCR)/restriction enzyme analysis for some of the discovered ROP-associated variants was performed for validation of the results using the validation cohort. RESULTS: The discovery cohort revealed 543 bi-allelic variants within 20 genes of the ADRß pathways. Ten single-nucleotide variants (SNVs) in 5 genes including protein kinase A regulatory subunit 1α (PRKAR1A), rap guanine exchange factor 3 (RAPGEF3), adenylyl cyclase 4 (ADCY4), ADCY7, and ADCY9 were associated with ROP (P < .05). The most significant SNV was found in PRKAR1A (P = .001). Multiple variants located in the 3'-untranslated region (3'UTR) of RAPGEF3 were also associated with ROP (P < .05). PCR/restriction enzyme analysis of the 3'UTR of RAPGEF3 methodologically validated these findings. CONCLUSION: SNVs in PRKAR1A may represent protective factors whereas SNVs in RAPGEF3 may represent risk factors for ROP. PRKAR1α has previously been implicated in retinal vascular development whereas the RAPGEF3 product has a role in the maintenance of vascular barrier function, 2 processes important in ROP. Multicenter validation of these newly discovered risk factors could lead to valuable tools for predicting and preventing the development of severe ROP.

Dopamine-resistant hypotension and severe retinopathy of prematurity.

OBJECTIVE: To examine the relationship between the cause or severity of hypotension and the development of severe ROP (sROP) (≥stage 3 or stage 2 with plus disease in zone I or II). STUDY DESIGN: Infants (<28 weeks' gestation, n = 242) were observed for hypotension and treated with a standardized hypotension-treatment protocol. Hypotension was classified as resulting from one of the following causes: (1) culture-positive infection and/or necrotizing enterocolitis; (2) patent ductus arteriosus ligation; or (3) "idiopathic" (no cause identified other than prematurity), and as being either dopamine responsive or dopamine resistant. Cortisol levels were measured for infants with dopamine-resistant hypotension. Eye examinations were performed until the retinopathy of prematurity resolved or the vasculature matured. Multivariable logistic regression analysis was performed to determine the relationship between the cause/severity of hypotension and sROP. RESULTS: Overall, 66% of infants developed hypotension (41% were dopamine responsive and 25% were dopamine resistant). sROP developed in 19% of infants. "Idiopathic" dopamine-resistant hypotension was the only cause significantly related to sROP. Of the infants with dopamine-resistant hypotension, 66% had low serum cortisol (≤10 µg/dL). Low cortisol, in the presence of dopamine-resistant hypotension, was significantly associated with sROP and accounted for the relationship between "idiopathic" hypotension and sROP. When low cortisol was included in statistical models, other known risk factors, such as immature gestation, were no longer significantly related to sROP. CONCLUSION: Low cortisol, in the presence of dopamine-resistant hypotension, has the greatest magnitude of association with sROP.

The impact of early exposure to general anesthesia on visual and neurocognitive development.

Every year millions of children are exposed to general anesthesia while undergoing surgical and diagnostic procedures. In the field of ophthalmology, 44,000 children are exposed to general anesthesia annually for strabismus surgery alone. While it is clear that general anesthesia is necessary for sedation and pain minimization during surgical procedures, the possibility of neurotoxic impairments from its exposure is of concern. In animals there is strong evidence linking early anesthesia exposure to abnormal neural development. but in humans the effects of anesthesia are debated. In humans many aspects of vision develop within the first year of life, making the visual system vulnerable to early adverse experiences and potentially vulnerable to early exposure to general anesthesia. We attempt to address whether the visual system is affected by early postnatal exposure to general anesthesia. We first summarize key mechanisms that could account for the neurotoxic effects of general anesthesia on the developing brain and review existing literature on the effects of early anesthesia exposure on the visual system in both animals and humans and on neurocognitive development in humans. Finally, we conclude by proposing future directions for research that could address unanswered questions regarding the impact of general anesthesia on visual development.

Ocular and developmental outcomes of a dosing study of bevacizumab for retinopathy of prematurity.

PURPOSE: To report 2-year ocular and developmental outcomes for infants receiving low doses of intravitreal bevacizumab for type 1 retinopathy of prematurity (ROP). METHODS: A total of 120 premature infants (mean birthweight, 687 g; mean gestational age, 24.8 weeks) with type 1 ROP were enrolled in a multicenter, phase 1 dose de-escalation study. One eye per infant received 0.25 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg of intravitreal bevacizumab; fellow eyes when treated received one dosage level higher. At 2 years, 70 of 120 children (58%) underwent ocular examinations; 51 (43%) were assessed using the Bayley Scale of Infant and Toddler Development. RESULTS: Correlation coefficients for the association of total dosage of bevacizumab with Bayley subscales were -0.20 for cognitive (95% CI, -0.45 to 0.08), -0.15 for motor (95% CI, -0.41 to 0.14), and -0.19 for language (95% CI, -0.44 to 0.10). Fourteen children (21%) had myopia greater than -5.00 D in one or both eyes, 7 (10%) had optic nerve atrophy and/or cupping, 20 (29%) had strabismus, 8 (11%) had manifest nystagmus, and 9 (13%) had amblyopia. CONCLUSIONS: In this study cohort, there was no statistically significant correlation between dosage of bevacizumab and Bayley scores at 2 years. However, the sample size was small and the retention rate relatively low, limiting our conclusions. Rates of high myopia and ocular abnormalities do not differ from those reported after larger bevacizumab doses.

Ocular neovascularization following hypoxic ischemic encephalopathy.

We present the findings of 2 children with neonatal hypoxic ischemic encephalopathy (HIE), who demonstrated ocular neovascularization at birth. While the cerebral effects of HIE have been well described, ocular effects have not. Our cases, combined with recent published laboratory research, demonstrate that significant ocular effects may accompany HIE.

Astigmatism progression in the early treatment for retinopathy of prematurity study to 6 years of age.

PURPOSE: To examine the prevalence of astigmatism (≥ 1.00 diopter [D]) and high astigmatism (≥ 2.00 D) from 6 months after term due date to 6 years of age in preterm children with birth weight of less than 1251 g in whom high-risk prethreshold retinopathy of prematurity (ROP) developed and who participated in the Early Treatment for ROP study. DESIGN: Observational cohort study. PARTICIPANTS: Four hundred one infants in whom high-risk prethreshold ROP developed in 1 or both eyes and were randomized to early treatment (ET) versus conventional management (CM). Refractive error was measured by cycloplegic retinoscopy. Eyes were excluded if they underwent additional retinal, glaucoma, or cataract surgery. INTERVENTION: Eyes were randomized to receive laser photocoagulation at high-risk prethreshold ROP or to receive treatment only if threshold ROP developed. MAIN OUTCOME MEASURES: Astigmatism and high astigmatism at each study visit. RESULTS: For both ET and CM eyes, there was a consistent increase in prevalence of astigmatism over time, increasing from 42% at 4 years to 52% by 6 years for the group of ET eyes and from 47% to 54%, respectively, in the CM eyes. There was no statistically significant difference between the slopes (rate of change per month) of the ET and CM eyes for both astigmatism and high astigmatism (P = 0.75). CONCLUSIONS: By 6 years of age, astigmatism of 1.00 D or more developed in more than 50% of eyes with high-risk prethreshold ROP, and nearly 25% of such eyes had high astigmatism (≥ 2.00 D). Presence of astigmatism was not influenced by timing of treatment, zone of acute-phase ROP, or presence of plus disease. However, there was a trend toward higher prevalence of astigmatism and high astigmatism in eyes with ROP residua. Most astigmatism was with-the-rule (75°-105°). More eyes with type 2 than type 1 ROP had astigmatism by 6 years. These findings reinforce the need for follow-up eye examinations through early grade school years in infants with high-risk prethreshold ROP. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Retinopathy of prematurity in infants weighing less than 500 grams at birth enrolled in the early treatment for retinopathy of prematurity study.

PURPOSE: To describe patient characteristics, classification, and onset of prethreshold retinopathy of prematurity (ROP), and ocular findings at 6 months corrected age in infants with birth weights <500 g who were enrolled in the Early Treatment for Retinopathy of Prematurity (ETROP) Study. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Sixty-three infants with birth weights <500 g who developed ROP and were enrolled in the ETROP Study. METHODS: Infants <1251 g at birth were logged at 26 study centers from October 1, 2000, to September 30, 2002, and underwent examinations for ROP. Infants who developed ROP and whose parents/legal guardians consented were enrolled in the ETROP Study. Infants who developed high-risk prethreshold ROP were randomized; 1 eye was treated early with peripheral retinal ablation and the other eye was managed conventionally, or, in asymmetric cases, the high-risk eye was randomized to early peripheral retinal ablation or conventional management. All eyes reaching prethreshold ROP were examined when infants reached 6 months corrected age. MAIN OUTCOME MEASURES: Retinopathy of prematurity incidence, characteristics, and ocular findings among participants. RESULTS: Thirty-four infants reached prethreshold or worse severity in 1 or both eyes. Retinopathy of prematurity was located in zone I in 43.3% of all prethreshold eyes, and plus disease was present in 46.7%. Median postmenstrual age for diagnosis of all prethreshold ROP was 36.1 weeks, but earlier (35.1 weeks) for eyes that developed high-risk prethreshold ROP. In the 27 surviving infants with prethreshold ROP, ophthalmic examination at 6 months corrected age showed a normal posterior pole in 22 (81.5%), a favorable structural outcome with posterior pole abnormalities in 4 (14.8%), and an unfavorable structural outcome (stage 4B) in 1 (3.7%). One infant developed amblyopia, 4 infants developed nystagmus, 4 infants developed strabismus, and 8 infants developed myopia >-5.00 diopters. CONCLUSIONS: This is the first report on characteristics of prethreshold ROP in infants with birth weights <500 g. These infants are at high risk for developing prethreshold ROP, although many initially achieve a favorable structural outcome. They are at risk of developing strabismus, nystagmus, high myopia, and abnormal retinal structure and should therefore receive continued long-term follow-up. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Tissue-limited mosaicism for monosomy 13.

Karyotypic discordance between different tissues in an individual is uncommon. We report on a patient with multiple congenital anomalies and mosaicism for monosomy 13 limited to fibroblasts. Findings include microcephaly, agenesis of the corpus callosum, bilateral posterior colobomas, cataract and optic nerve dysplasia, patent foramen ovale, renal hypoplasia, hypospadias and unilateral inguinal hernia, unilateral hypoplasia of the lower limb, sparse and patchy hair, subtle pigmentary mosaicism, and global developmental delay. The lymphocyte karyotype was normal, whereas the fibroblast karyotype showed mosaicism for a del(13)(q11→ter). Review of the literature identified three previous reports of similar patients with multiple congenital anomalies, normal lymphocyte karyotype, and subsequent, diagnostic fibroblast karyotyping. Comparison of the previously reported patients with the patient reported here defines a common phenotype for tissue-limited mosaicism for monosomy 13 consisting of prenatal-onset growth deficiency; microcephaly; facial abnormalities including prominent nasal bridge, hypertelorism, ptosis, epicanthal folds, microphthalmia, coloboma, retinoblastoma, prominent maxilla, micrognathia, and low-set ears; limb abnormalities including small to absent thumbs, clinodactyly of fifth finger, fused metacarpal bones 4 and 5, talipes equinovarus, and short first toe; cardiac defect; renal anomalies; and genitalia abnormalities including hypospadias and cryptorchidism. In conclusion, this case further emphasizes that fibroblast karyotyping should be employed when the diagnosis remains unclear, especially in the presence of pigmentary mosaicism or segmental hypoplasia.

CD10+ Cells and IgM in Pathogen Response in Lumpfish (Cyclopterus lumpus) Eye Tissues.

Lumpfish (Cyclopterus lumpus), a North Atlantic "cleaner" fish, is utilized to biocontrol salmon louse (Lepeophtheirus salmonis) in Atlantic salmon (Salmo salar) farms. Lumpfish require excellent vision to scan for and eat louse on salmon skin. The lumpfish eye immune response to infectious diseases has not been explored. We examined the ocular response to a natural parasite infection in wild lumpfish and to an experimental bacterial infection in cultured lumpfish. Cysts associated with natural myxozoan infection in the ocular scleral cartilage of wild adult lumpfish harbored cells expressing cluster of differentiation 10 (CD10) and immunoglobulin M (IgM). Experimental Vibrio anguillarum infection, which led to exophthalmos and disorganization of the retinal tissues was associated with disruption of normal CD10 expression, CD10+ cellular infiltration and IgM expression. We further describe the lumpfish CD10 orthologue and characterize the lumpfish scleral skeleton in the context of myxozoan scleral cysts. We propose that lumpfish develop an intraocular response to pathogens, exemplified herein by myxozoan and V. anguillarum infection involving novel CD10+ cells and IgM+ cells to contain and mitigate damage to eye structures. This work is the first demonstration of CD10 and IgM expressing cells in a novel ocular immune system component in response to disease in a teleost.

Short-term Outcomes After Very Low-Dose Intravitreous Bevacizumab for Retinopathy of Prematurity.

Importance: Intravitreous bevacizumab (0.25 mg to 0.625 mg) is commonly used to treat type 1 retinopathy of prematurity (ROP), but there are concerns about systemic toxicity, particularly the risk of neurodevelopmental delay. A much lower dose may be effective for ROP while reducing systemic risk. Previously, after testing doses of 0.25 mg to 0.031 mg, doses as low as 0.031 mg were found to be effective in small cohorts of infants. Objective: To find the lowest dose of intravitreous bevacizumab effective for severe ROP. Design, Setting, and Participants: Between April 2017 and May 2019, 59 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, dose de-escalation study. In cohorts of 10 to 14 infants, 1 eye per infant received 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg of intravitreous bevacizumab. Diluted bevacizumab was prepared by individual research pharmacies and delivered using 300-µL syringes with 5/16-inch, 30-guage fixed needles. Analysis began July 2019. Interventions: Bevacizumab intravitreous injections at 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. Main Outcomes and Measures: Success was defined as improvement by 4 days postinjection and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks. Results: Fifty-five of 59 enrolled infants had 4-week outcomes completed; the mean (SD) birth weight was 664 (258) g, and the mean (SD) gestational age was 24.8 (1.6) weeks. A successful 4-week outcome was achieved for 13 of 13 eyes (100%) receiving 0.016 mg, 9 of 9 eyes (100%) receiving 0.008 mg, 9 of 10 eyes (90%) receiving 0.004 mg, but only 17 of 23 eyes (74%) receiving 0.002 mg. Conclusions and Relevance: These data suggest that 0.004 mg may be the lowest dose of bevacizumab effective for ROP. Further investigation is warranted to confirm effectiveness of very low-dose intravitreous bevacizumab and its effect on plasma vascular endothelial growth factor levels and peripheral retinal vascularization.

Astigmatism in the Early Treatment for Retinopathy Of Prematurity Study: findings to 3 years of age.

PURPOSE: To examine the prevalence of astigmatism (> or =1.00 diopter [D]) and high astigmatism (> or =2.00 D) at 6 and 9 months corrected age and 2 and 3 years postnatal age, in preterm children with birth weight of less than 1251 g in whom high-risk prethreshold retinopathy of prematurity (ROP) developed and who participated in the Early Treatment for Retinopathy of Prematurity (ETROP) Study. DESIGN: Randomized, controlled clinical trial. PARTICIPANTS: Four hundred one infants in whom prethreshold ROP developed in one or both eyes and who were randomized after they were determined to have a high risk (> or =15%) of poor structural outcome without treatment using the Risk Management of Retinopathy of Prematurity (RM-ROP2) program. Refractive error was measured by cycloplegic retinoscopy. Eyes with additional retinal, glaucoma, or cataract surgery were excluded. INTERVENTION: Eyes were randomized to receive laser photocoagulation at high-risk prethreshold ROP (early treated [ET]) or to be conventionally managed (CM), receiving treatment only if threshold ROP developed. MAIN OUTCOME MEASURES: Astigmatism and high astigmatism at each visit. Astigmatism was classified as with-the-rule (WTR; 75 degrees -105 degrees ), against-the-rule (ATR; 0 degrees -15 degrees and 165 degrees -180 degrees ), or oblique (OBL; 16 degrees -74 degrees and 106 degrees -164 degrees ). RESULTS: The prevalence of astigmatism in ET and CM eyes was similar at each test age. For both groups, there was an increase in prevalence of astigmatism from approximately 32% at 6 months to approximately 42% by 3 years, mostly occurring between 6 and 9 months. Among eyes that could be refracted, astigmatism was not influenced by zone of acute-phase ROP, presence of plus disease, or retinal residua of ROP. Eyes with astigmatism and high astigmatism most often had WTR astigmatism. CONCLUSIONS: By age 3 years, nearly 43% of eyes treated at high-risk prethreshold ROP developed astigmatism of > or =1.00 D and nearly 20% had astigmatism of > or =2.00 D. Presence of astigmatism was not influenced by timing of treatment of acute-phase ROP or by characteristics of acute-phase or cicatricial ROP. These findings reinforce the need for follow-up eye examinations in infants with high-risk prethreshold ROP. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Cortical visual impairment: new directions.

Cortical visual impairment is the leading cause of bilateral low vision in children in the U.S., yet very little research is being performed to find new diagnostic measures and treatments. Dr. Velma Dobson pioneering work on visual assessments of developmentally delayed children stands out as highly significant in this field. Future research will assess new diagnostic measures, including advanced imaging techniques. In addition, research will evaluate methods to prevent, treat, and rehabilitate infants and children afflicted with this condition.

Progression of myopia and high myopia in the early treatment for retinopathy of prematurity study: findings to 3 years of age.

PURPOSE: Examine the prevalence of myopia and high myopia, at 6 and 9 months postterm and 2 and 3 years postnatal in preterm children with birth weights < 1251 g who developed high-risk prethreshold retinopathy of prematurity (ROP) in the neonatal period and participated in the Early Treatment for ROP Study. DESIGN: Randomized controlled clinical trial. PARTICIPANTS: Four hundred one infants who developed prethreshold ROP and were determined to have a significant risk (>/=15%) of poor structural outcomes without treatment. Children underwent cycloplegic retinoscopy at examinations between 6 months postterm and 3 years' postnatal age. INTERVENTION: Eyes were randomized to receive treatment at high-risk prethreshold ROP (early treated [ET]) or conventional management (CM), with treatment only if threshold ROP developed. MAIN OUTCOME MEASURES: Myopia (spherical equivalent >/= 0.25 diopters [D]) or high myopia (>/=5.00 D) at each visit. RESULTS: Prevalences of myopia were similar in treated eyes in the ET and CM groups, increasing from approximately 58% to 68% between 6 and 9 months, with little change thereafter. Both ET and CM eyes showed an increasing prevalence of high myopia, approximately 19% at 6 months and increasing 4% to 8% at successive examinations. Zone of ROP and presence or absence of plus disease had little effect on prevalence of myopia or high myopia between ages 6 months and 3 years. However, eyes with ROP residua (straightened temporal vessels or macular heterotopia) showed a higher prevalence of myopia and high myopia than eyes without residua. CONCLUSIONS: Approximately 70% of high-risk prethreshold ROP eyes were myopic in early childhood, and the proportion with high myopia increased steadily between ages 6 months and 3 years. Timing of treatment of high-risk prethreshold ROP did not influence refractive error development. There was little difference in prevalence of myopia or high myopia between eyes with zone I and eyes with zone II ROP, nor between eyes with plus disease and eyes with no plus disease. However, prevalence of myopia and high myopia was higher in eyes with retinal residua of ROP than in eyes with normal-appearing posterior poles, highlighting the importance of follow-up eye examinations of infants who had prethreshold ROP.