Comparison of Visual Acuity Results Between ATS-HOTV and E-ETDRS Testing Methods in Children With Optic Pathway Gliomas.

Purpose: To determine if visual acuity (VA) outcomes are comparable using the amblyopia treatment study HOTV protocol (ATS-HOTV) and electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS) protocol in children with optic pathway gliomas (OPGs). Methods: Children enrolled in a prospective study of OPGs were eligible if they completed both the ATS-HOTV and E-ETDRS during the same visit. The contribution of age, testing order, having neurofibromatosis type 1, visual field loss, and circumpapillary retinal nerve fiber layer thickness to VA difference were assessed using generalized estimating equations to account for the intereye correlation. Results: Forty-eight children (median age, 10.3 years; range, 5.2-17.1 years; 49% female) met inclusion criteria and contributed 93 study eyes at their initial visit. Eleven patients (22 eyes) had more than one study visit, permitting longitudinal evaluation. ATS-HOTV measures of VA were higher than E-ETDRS at the initial (0.13 ± 0.36 vs. 0.23 ± 0.39 logarithm of the minimum angle of resolution [logMAR], P < 0.001) and all visits (0.13 ± 0.34 vs. 0.21 ± 0.36 logMAR, P < 0.001). VA remained significantly higher with ATS-HOTV regardless of test order, but the mean difference between tests was most profound when tested with ATS-HOTV first compared to E-ETDRS first (P < 0.001). Conclusions: VA results differ significantly between the ATS-HOTV and E-ETDRS testing methods in children with OPGs. Given the wide range of ages and testing ability of children, one VA testing method should be used throughout longitudinal OPG clinical trials. Translational Relevance: It is imperative that age-appropriate VA testing methods are standardized across all pediatric OPG clinical trials.

Changes in institutional oxygen saturation targets are associated with an increased rate of severe retinopathy of prematurity.

PURPOSE: To evaluate the effect of changes in institutional peripheral oxygen saturation (SpO2) targets, made in response to recent randomized trials, on risk of developing severe retinopathy of prematurity (ROP). METHODS: This study was a secondary analysis of data from 21 North American hospitals during the periods 2006-2012 and 2015-2017. Hospitals were categorized based on whether or not SpO2 targets were increased between the two study periods. Severe ROP (type 1, type 2, or zone III stage 3+) rates were compared within and between groups. Generalized mixed effect models with random intercepts were used to account for within-center clustering and to calculate odds ratios (aOR) adjusted by birth weight (BW) and gestational age (GA), using patient-level data. RESULTS: A total of 8,142 infants underwent ROP examinations at 21 hospitals during the two study periods: 5,716 in 2006-2012 (mean BW, 1109 ± 369 g; GA, 28.0 ± 2.6; 11.6% severe ROP); 2,426 in 2015-2017 (mean BW, 1086 ± 347 g; GA, 28.0 ± 2.8; 12.8% severe ROP). Fourteen hospitals increased SpO2 targets, and 7 hospitals did not. Hospitals that increased targets had a 3% increase in severe ROP (from 12% to 15%; aOR = 1.25; 95% CI, 1.01-1.55; P = 0.044); hospitals without SpO2 changes had a 2% decrease (from 11% to 9%; aOR = 0.72; 95% CI, 0.52-1.00; P = 0.049). The difference in change of severe ROP between groups of hospitals was significant (P = 0.005). CONCLUSIONS: Increases in institutional SpO2 targets in response to recent randomized trials were associated with increased severe ROP. Hospitals considering increasing their SpO2 targets should anticipate increases in rates of severe ROP and manage screening and treatment resources accordingly.

Implementation of telemedicine screening for retinopathy of prematurity in rural areas in Guatemala.

PURPOSE: To report findings of a telemedicine retinopathy of prematurity (ROP) screening program in six neonatal units in rural areas of Guatemala, using a portable, noncontact, 40° field digital fundus camera (Pictor Plus) operated by trained technicians. METHODS: National ROP Program Guidelines screening criteria were used: gestational age <36 weeks and/or birth weight (BW) <2000 g, or GA <36 weeks but BW ≥2000 g, with qualifying medical history. Retinal images were obtained by two technicians and graded by ophthalmologists experienced in ROP. Infants with signs of pre-plus or plus disease in one or both eyes were referred for clinical examination. Screening was stopped when retinal vessels in anterior zone II were normal on two successive evaluations or the infant had reached 45 week's postmenstrual age. RESULTS: A total of 418 of 1,890 eligible infants (22.1%) were screened. Mean GA was 33.9 ± 2.2 weeks (range, 27-36), and mean BW 1728.3 ± 379.3 g (range, 840-2830 g). Thirty-three infants (8.6%) developed plus or pre-plus disease, and 19 (58%) underwent ophthalmologic examination. Fifteen infants were confirmed with type 1 ROP, and 14 were treated. Mean GA of treated infants treated was 33.6 ± 3.0 weeks (range, 32-34.9), and mean BW was 1,646 ± 245.8 g (range, 1100-1774.1 g). CONCLUSIONS: Imaging with a noncontact fundus camera can facilitate detection of treatable ROP in countries with limited resources. Strengthening the health systems, including motivation and continued training of neonatal intensive care personnel is essential to improve and maintain program effectiveness. Reasons for, and interventions to address the low uptake of screening need to be explored to extend coverage of ROP screening to district hospitals in Guatemala.

Extending Hui-Walter framework to correlated outcomes with application to diagnosis tests of an eye disease among premature infants.

Diagnostic accuracy, a measure of diagnostic tests for correctly identifying patients with or without a target disease, plays an important role in evidence-based medicine. Diagnostic accuracy of a new test ideally should be evaluated by comparing to a gold standard; however, in many medical applications it may be invasive, costly, or even unethical to obtain a gold standard for particular diseases. When the accuracy of a new candidate test under evaluation is assessed by comparison to an imperfect reference test, bias is expected to occur and result in either overestimates or underestimates of its true accuracy. In addition, diagnostic test studies often involve repeated measurements of the same patient, such as the paired eyes or multiple teeth, and generally lead to correlated and clustered data. Using the conventional statistical methods to estimate diagnostic accuracy can be biased by ignoring the within-cluster correlations. Despite numerous statistical approaches have been proposed to tackle this problem, the methodology to deal with correlated and clustered data in the absence of a gold standard is limited. In this article, we propose a method based on the composite likelihood function to derive simple and intuitive closed-form solutions for estimates of diagnostic accuracy, in terms of sensitivity and specificity. Through simulation studies, we illustrate the relative advantages of the proposed method over the existing methods that simply treat an imperfect reference test as a gold standard in correlated and clustered data. Compared with the existing methods, the proposed method can reduce not only substantial bias, but also the computational burden. Moreover, to demonstrate the utility of this approach, we apply the proposed method to the study of National-Eye-Institute-funded Telemedicine Approaches to Evaluating of Acute-Phase Retinopathy of Prematurity (e-ROP), for estimating accuracies of both the ophthalmologist examination and the image evaluation.

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.

Neurodevelopmental outcome of preterm infants enrolled in myo-inositol randomized controlled trial.

OBJECTIVE: This study evaluates the 24-month follow-up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial. STUDY DESIGN: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score <85, moderate or severe cerebral palsy, blindness, or hearing loss that prevents communication despite amplification were assessed. RESULTS: Primary outcome was determined for 605/638 (95%). The mean gestational age was 25.8 ± 1.3 weeks and mean birthweight was 805 ± 192 g. Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p = 0.40). CONCLUSIONS: Treatment group did not affect the risk of death or survival with moderate/severe NDI. Despite early termination, this study represents the largest RCT of extremely preterm infants treated with myo-inositol with neurodevelopmental outcome data.

Early angiographic signs of retinopathy of prematurity requiring treatment.

BACKGROUND/OBJECTIVES: Fluorescein angiography (FA) has been a pivotal tool to study the pathophysiology of retinopathy of prematurity (ROP) in vivo. We examined the course of ROP using FA in order to assess the predictive value of angiographic features. SUBJECTS/METHODS: This is an observational retrospective cohort multi-center study of eyes screened for ROP with binocular indirect ophthalmoscope and with FA. All infants undergoing screening examination for ROP who had retinal vasculature limited to Zone I and posterior Zone II vascularization underwent FA between 31 and 34 weeks postmenstrual age. RetCam fundus imaging and video digital fluorescein angiography were performed in the neonatal intensive care units. Masked grading of the FA images was retrospectively conducted by two ROP expert ophthalmologists. Ten criteria that describe retinovascular and choroidal features on FA were used to assess their predictive value for development of treatment-requiring ROP. RESULTS: A total of 98 eyes of 56 patients were included for this study. FAs of eyes of premature infants show a wide range of features either at the junction between the vascular and avascular retina and posteriorly to that. Among the angiographic features evaluated, leakage, shunts and hyperfluorescent lesions at the junction between vascular and avascular zone were predictive of the development of treatment-requiring ROP (p < 0.05), but findings in the posterior vascularized retina were not. CONCLUSIONS: FA can add to our understanding of the evolution of vascular abnormalities in the course of ROP and can help predict which eyes will go on to treatment.

Progression from preplus to plus disease in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study: incidence, timing, and predictors.

PURPOSE: To determine the incidence of and timing and predictors for progression from pre-plus to plus disease, based on evaluation of images. METHODS: Two trained readers independently evaluated posterior pole images of infants from 13 North American centers for pre-plus/plus disease, stage, and zone of retinopathy of prematurity (ROP). Discrepancies between readers were adjudicated. To be eligible for analysis, eyes had to have at least two imaging sessions, the earlier one with pre-plus disease. RESULTS: Of 681 eyes of 444 infants with pre-plus first detected at mean postmenstrual age (PMA) of 35.5 ± 2.1 weeks, 54 (7.9%) progressed to plus disease at a mean PMA of 37.6 ± 2.4 weeks with the mean interval for progression of 2.7 weeks (range, 0.4-8.9 weeks). Progression rate was higher for eyes with larger number of quadrants of pre-plus (44% for eyes with four quadrants vs 4% with one quadrant [P < 0.0001]), earlier PMA with pre-plus (18% for 32 weeks' PMA vs 3% for PMA of >37 weeks [P = 0.02]), higher ROP stage (12% for stage 3, 2.5% for no ROP [P < 0.0001]), lower ROP zone (24% for zone I, 6% for zone II or no ROP [P < 0.0001]) at the time of first pre-plus detection. CONCLUSIONS: Based on image evaluation, 8% of eyes progressed from pre-plus to plus disease at a mean interval of 3 weeks. Pre-plus in multiple quadrants, higher stages of ROP, and lower zones of ROP were associated with higher risk of progression. Image evaluation for pre-plus may help in the identification of high-risk eyes for developing plus disease.

Incidence of Retinopathy of Prematurity in Botswana: A Prospective Observational Study.

BACKGROUND: Retinopathy of prematurity (ROP) is a widely recognized cause of blindness after preterm birth. The incidence of ROP is rising especially in low- and middle-income countries (LMIC) because of improved neonatal care and increased survival of very premature neonates. To date, there is no data on incidence of ROP in Botswana. OBJECTIVE: The purpose of this study was to provide initial data and determine ROP-associated risk factors from a single neonatal care center on the incidence of ROP in Gaborone, Botswana. METHODS: A prospective observational study was conducted at Princess Marina Hospital (PMH) in Gaborone, Botswana. Premature neonates with birth weights (BW) of <1,801 g or gestational age (GA) of <34 weeks were enrolled in this study. Diagnostic examinations were conducted using an indirect ophthalmoscope with 28D lens. ROP findings were classified according to the most advanced stage of ROP reached using the International Classification of ROP (2005). Data were entered into STATA version 15 statistical software for analysis. RESULTS: There were 264 premature infants enrolled in the study. ROP screening was performed on 200 (75.8%). Of all 264 enrolled patients 133 (50.4%) were female. The mean GA was 30.3±2.6 (range 24-37) weeks and the mean BW was 1302.2±285.9 g (range 725-2035). Out of 200 who were screened, we identified 22 with ROP with a ROP incidence of 11%. The incidence of type 1 ROP (sight-threatening) was found to be 3.5%. This study identified a significant difference in possible ROP risk factors between those infants who develop ROP and those who do not, eg, BW (p<0.001), GA (p=0.024) and blood transfusion (p=0.001). CONCLUSION: This study demonstrates that ROP is a treatable cause of blindness in Botswana. Lack of a proper screening protocol, delay in diagnosis and management are plausible reasons for poor outcome in those who were diagnosed with type 1 ROP.

Symmetry of Disease in Retinopathy of Prematurity in the Postnatal Growth and Retinopathy of Prematurity (G-ROP) Study.

PURPOSE: To determine the symmetry of retinopathy of prematurity (ROP) between fellow eyes in a broad-risk cohort. METHODS: A retrospective cohort study, the Postnatal Growth and ROP (G-ROP) Study, of 7483 infants undergoing ROP examinations conducted at 29 hospitals in the United States and Canada from 2006 to 2012. The main outcomes were the symmetry for the highest stage and the most severe type (1, 2, not 1 or 2, no ROP) of ROP and disease course of the fellow eye when only one eye developed type 1. RESULTS: 93% of infants had eyes symmetric for the highest stage and 94% for type. Among 459 infants who developed type 1, 379 (82.6%) did so in both eyes simultaneously and were treated bilaterally; 44 (10%) were treated for type 1 in one eye and type 2 in the fellow eye; and 36 (8%) were treated unilaterally initially, of which 6 fellow eyes developed type 1 and were treated (4 within 2 weeks, all within 4 weeks); 5 developed type 2 and regressed; and 25 developed ROP less than type 1 or 2, which was treated in 13 cases and regressed spontaneously in 12 cases. CONCLUSIONS: ROP was highly symmetric between eyes with respect to the presence and severity of disease in a large, broad-risk cohort representative of infants undergoing ROP screening. When type 1 develops in one eye and type 2 in the fellow eye, the risk of progression to type 1 in the fellow eye appears very low if it has not occurred within 4 weeks.

Functional and Morphologic Findings at Four Years After Intravitreal Bevacizumab or Laser for Type 1 ROP.

BACKGROUND AND OBJECTIVE: To compare morphologic and functional status at age 4 years for patients treated in one eye with laser photocoagulation and the other eye with intravitreal bevacizumab (IVB) injection for Type 1 retinopathy of prematurity (ROP). PATIENTS AND METHODS: In this single-center, randomized, controlled trial, best-corrected visual acuity (BCVA) in logMAR was obtained along with spherical equivalent refraction (SER), fluorescein angiography (FA), optical coherent tomography (OCT), and OCT angiography (OCTA). RESULTS: Eighteen babies (36 eyes) were selected for this study. BCVA and SER were similar in the two groups, but six patients had anisometropia of 4 diopters or more. IVB-treated eyes tended to have thinner foveal thickness than laser-treated eyes (mean difference: -5.33 pixels; 95% confidence interval, -9.62 to -1.05). CONCLUSION: Although the differences found here are minimal between the IVB-treated and laser-treated groups, further long-term evaluation of not only FA, but also OCT and OCTA, are needed in larger studies. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:180-186.].

Validation of the Postnatal Growth and Retinopathy of Prematurity Screening Criteria.

Importance: The first Postnatal Growth and Retinopathy of Prematurity Study (G-ROP-1) developed new screening criteria with 100% sensitivity for type 1 retinopathy of prematurity (ROP) and 30% reduction of infants requiring examinations in a retrospective development cohort of 7483 infants from 29 North American hospitals in 2006-2012. Infants meeting 1 or more of the following criteria undergo examinations: gestational age less than 28 weeks or birth weight less than 1051 g; weight gain less than 120 g during age 10 to 19 days, weight gain less than 180 g during age 20 to 29 days, or weight gain less than 170 g during age 30 to 39 days; or hydrocephalus. Objective: To evaluate the generalizability of the G-ROP screening criteria in a new cohort of at-risk infants. Design, Setting, and Participants: This prospective validation cohort study (G-ROP-2) was conducted at 41 hospitals in the United States and Canada (25 G-ROP-1 hospitals and 16 new hospitals) from September 8, 2015, to June 13, 2017, among 3981 premature infants at risk for ROP and with known ROP outcomes. Main Outcomes and Measures: Sensitivity for Early Treatment for Retinopathy of Prematurity Study type 1 ROP and potential reduction in infants receiving examinations. Results: Among the 3981 infants in the study (1878 girls and 2103 boys; median gestational age, 28 weeks [range, 22-35 weeks]; median birth weight, 1072 g [range, 350-4080 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). 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), while current criteria (birth weight <1501 g or gestational age ≤30 weeks 0 days) predicted 674 of 677 type 1 cases (sensitivity, 99.6%; 95% CI, 98.7%-99.8%). Conclusions and Relevance: This study 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 examinations. The large G-ROP cohorts provide evidence-based screening criteria that have higher sensitivity and higher specificity (fewer infants receiving examinations) for type 1 ROP than currently recommended guidelines.

The role of retinal photography and telemedicine in ROP screening.

Until advances in retinal imaging over recent decades, detection of retinopathy of prematurity requiring treatment depended largely on indirect ophthalmoscopy by ophthalmologists with experience in examination of low birth weight, often fragile infants. Recent studies have added to our understanding of the pros and cons of using this technology to provide timely care for the increasing number of infants at risk for ROP blindness worldwide.