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.

Surgery for stage 5 retinopathy of prematurity.

PURPOSE OF REVIEW: Our understanding of the pathogenesis and surgical management of stage 5 retinopathy of prematurity has come a long way. Despite of new technologies in retinal surgical devices, the dissection of thick membranes is still a challenge. We use a capsulotomy 'plug on tip' 0.05 mm designed for capsular fimosis. This diathermy instrument is used to cut the lens capsule by low power waves transmitted from the tip of an active incising electrode and make incisions in the tissue. We tested this technique with 226 infants of which all 226 eyes retrolental membrane were removed. In 6-46 months follow-up, light perception or better visual function was achieved in 92%. RECENT FINDINGS: Despite of new technologies in retinal surgical devices, the dissection of thick membranes is still a challenge. Sometimes, we need to use tools that were made for another purpose and adapt it to our current techniques. SUMMARY: Achieving at least a vision of light perception in eyes that were considered untreatable is a good outcome as light perception maintains the circadian circle and helps in the brain development. VIDEO ABSTRACT: http://links.lww.com/COOP/A47.

PREOPERATIVE ANATOMICAL FEATURES ASSOCIATED WITH IMPROVED SURGICAL OUTCOMES FOR STAGE 5 RETINOPATHY OF PREMATURITY.

PURPOSE: To describe preoperative anatomical features of Stage 5 retinopathy of prematurity with results of surgery and patient-related and surgery-related factors affecting postoperative success. METHODS: Forty eyes of 33 infants who underwent vitrectomy with lensectomy or lens-sparing vitrectomy for Stage 5 retinopathy of prematurity were enrolled. Stage 5 cases were divided into different groups according to their preoperative anatomical features as follows: A: for eyes with ophthalmoscopically observable total retinal detachment; B: for eyes with total leucocoria associated with funnel retinal detachment; and C: for eyes with very shallow anterior chamber and corneal opacity. Only A and B eyes underwent surgery. The effect of the presence of vascular dilation and tortuosity, preoperative treatment status, surgically induced posterior hyaloid detachment, and sparing the lens on anatomical and functional results was evaluated. RESULTS: Thirty-five percentage of the eyes were in Group A and 65% were in Group B. The mean follow-up was 30.6 months (12-68). Anatomical success was 55.5% for Group A and 15.4% for Group B (P: 0.047), and functional success was 33.3% for Group A and 7.7% for Group B at the third year (P: 0.125). The presence of vascular dilation and tortuosity and postoperative vitreous hemorrhage were found to have negative effects; preoperative treatment and surgical induction of posterior hyaloid detachment were found to have positive effects on anatomical and functional results. CONCLUSION: Surgery for ophthalmoscopically observable retinopathy of prematurity-associated retinal detachment resulted in better anatomical and functional outcomes, and the results are even better in eyes with preoperative treatment, lens-sparing vitrectomy, and surgically induced posterior hyaloid detachment.

Treatment of retinopathy of prematurity (ROP) outside International Classification of ROP (ICROP) guidelines.

AIM: To evaluate the incidence and clinical indications for which eyes were treated for retinopathy of prematurity (ROP) outside the guidelines set by International Classification of ROP (ICROP). METHODS: Medical records of the patients treated at a single tertiary care ophthalmology hospital for ROP from January 2016 to December 2019 were retrospectively analysed to evaluate the indications for which they were treated. RESULTS: Out of 241 eyes, 33 eyes (13.7%) were treated outside the guidelines. The reasons for the treatment outside the guidelines were structural changes (n = 24, 72.7%), persistent stage 3 ROP that did not show any sign of regression for 6 weeks (n = 7, 21.2%) and active ROP with fellow eye being treated (n = 2, 6.1%). The recorded specific structural changes were tangential traction with temporal vessel straightening concerning for macular distortion and ectopia (n = 5, 15.2%), and stage 3 neovascularisation or ridge with anteroposterior traction with risk of progression to stage 4 disease (n = 19, 57.6%). Pre-plus disease was present in 11 eyes (33.3%).After the treatment, ROP stages regressed and retinal vessels grew either until the ora or at least into zone III in all the treated eyes. None of the eyes showed worsening of structural changes after treatment. The mean follow-up of the patients was 12.4 ± 11.7 months. CONCLUSION: Experts occasionally recommend treatment in eyes with disease milder than type 1 ROP. This study may help paediatric retinal practitioners in decision-making in borderline cases.

Ranibizumab Injection as Primary Treatment in Patients with Retinopathy of Prematurity: Anatomic Outcomes and Influencing Factors.

PURPOSE: To investigate the anatomic outcomes and influencing factors of ranibizumab in the treatment of retinopathy of prematurity (ROP). DESIGN: Retrospective case series. PARTICIPANTS: A total of 283 eyes of 145 patients with type 1 ROP treated with intravitreal injection of ranibizumab (IVR) as primary treatment. METHODS: Retrospective review of infants who were diagnosed with type 1 ROP and accepted IVR (0.25 mg/0.025 ml) as primary treatment from January 2012 to August 2015. The anatomic outcomes and the influencing factors were analyzed. MAIN OUTCOME MEASURES: Anatomic outcomes of ROP eyes after IVR and the influencing factors. RESULTS: A total of 283 eyes of 145 patients were included in this study. There were a total of 266 eyes (94.0%) in the positive response group and 17 eyes (6.0%) in the negative/no response group after IVR. Within the positive response group, 139 eyes (48.6%) were in the regression without reactivation subgroup, and 127 eyes (44.9%) were in the regression with reactivation subgroup. A total of 152 eyes received additional laser or surgical treatment. At the last visit, 278 eyes (98.2%) had attached retinas, and 5 eyes (1.8%) had retinal detachment. A classification tree model showed that for patients with gestational age (GA) ≤29.5 weeks, the possibility of experiencing reactivation after IVR is higher than that of those with GA >29.5 weeks (61.6% vs. 29.6%). Moreover, for patients with GA ≤29.5 weeks, those diagnosed with zone II stage 2+ ROP have a lower possibility of experiencing reactivation than other patients (37.9% vs. 80%). CONCLUSIONS: Intravitreal injection of ranibizumab seemed to be effective in treating patients with ROP. After treatment, there were primarily 3 different outcomes. Our predictive tree model is helpful for ophthalmologists to evaluate the risk of reactivation.

Intraocular Hemorrhages and Retinopathy of Prematurity in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study.

PURPOSE: To describe the clinical characteristics of intraocular hemorrhages (IOHs) in infants in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study and to evaluate their potential use for prediction of disease severity. DESIGN: Secondary data analysis from a prospective study. PARTICIPANTS: Preterm infants with birth weight (BW) ≤1250 g. METHODS: Infants underwent serial digital retinal imaging in both eyes starting at 32 weeks' postmenstrual age. Nonphysician trained readers (TRs) evaluated all image sets from eyes that ever had IOHs documented on image evaluation or eye examination for the presence, location, type, area, and relation of the IOH to the junction between vascularized and avascular retina. Associations of IOH with demographic and neonatal factors, and with the presence and severity of retinopathy of prematurity (ROP) were investigated by univariate and multivariate analyses. Sensitivity and specificity of the telemedicine system for detecting referral-warranted ROP (RW-ROP) were calculated with and without incorporating hemorrhage into the standardized grading protocol. MAIN OUTCOME MEASURES: Retinal and vitreous hemorrhage. RESULTS: Among 1239 infants (mean [standard deviation] BW = 864 [212] g; gestational age [GA] = 27 [2.2] weeks) who underwent an average of 3.2 imaging sessions, 22% had an IOH in an eye on at least 1 of the e-ROP visits. Classification of IOH was preretinal (57%), blot (57%), dot (38%), flame-shaped (16%), and vitreous (8%); most IOHs were unilateral (70%). The IOH resolved in 35% of eyes by the next imaging session and in the majority (76%) of cases by 8 weeks after initial detection. Presence of IOH was inversely associated with BW and GA and significantly associated (P < 0.0001) with the presence and severity of ROP (BW and GA adjusted odds ratios [ORs] of 2.46 for any ROP, 2.88 for stage 3, and 3.19 for RW-ROP). Incorporating IOH into the grading protocol minimally altered the sensitivity of the system (94% vs. 95%). CONCLUSIONS: Approximately 1 in 5 preterm infants examined had IOHs, generally unilateral. The presence of hemorrhage was directly correlated with both presence and severity of ROP and inversely correlated with BW and GA, although including hemorrhage in the grading algorithm only minimally improved the sensitivity of the telemedicine system to detect RW-ROP.

The relationship of the subtypes of preterm birth with retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity is an adverse outcome of preterm birth and is a leading cause of childhood blindness. The relationship between the subtypes of preterm birth with retinopathy of prematurity is understudied. OBJECTIVE: To investigate whether there is a difference in the incidence of type 1 or type 2 retinopathy of prematurity in infants with preterm birth resulting from spontaneous preterm labor, a medical indication of preterm birth, or preterm premature rupture of the membranes. STUDY DESIGN: A retrospective cohort study was conducted of 827 infants screened for retinopathy of prematurity who were delivered at a single tertiary care center in Colorado. All infants fulfilled the American Academy of Pediatrics 2013 screening criteria for retinopathy of prematurity defined as "infants with a birth weight of ≤1500 g or gestational age of 30 weeks or less (as defined by the attending neonatologist) and selected infants with a birth weight between 1500 and 2000 g or gestational age of >30 weeks with an unstable clinical course, including those requiring cardiorespiratory support and who are believed by their attending pediatrician or neonatologist to be at high risk for retinopathy of prematurity." Two independent reviewers masked to retinopathy of prematurity outcomes determined whether preterm birth resulted from spontaneous preterm labor, medical indication of preterm birth, or preterm premature rupture of the membranes. Discrepancies were resolved by a third reviewer. Data were analyzed with univariate and multivariable logistic regression. RESULTS: In our cohort, the frequency of preterm birth resulting from spontaneous preterm labor, medical indication of preterm birth, or preterm premature rupture of the membranes was 34%, 40%, and 26%, respectively. The mean gestational age (weeks, days) ± SD (range) in the cohort and across the preterm birth subtypes was as follows: entire cohort, 28 weeks, 6 days ± 2 weeks, 3 days (23 weeks, 3 days - 36 weeks, 4 days); spontaneous preterm labor, 28 weeks 1 day ± 2 weeks, 3 days (23 weeks, 3 days - 33 weeks, 4 days); medical indication of preterm birth, 29 weeks, 1 day ± 2 weeks, 2 days (24-36 weeks, 4 days); preterm premature rupture of the membranes, 28 weeks, 4 days ± 2 weeks, 1 day (24-33 weeks, 1 day). Among infants with type 1, type 2, or no retinopathy of prematurity, the incidence of type 1 or type 2 retinopathy of prematurity in births from spontaneous preterm labor, medical indication of preterm birth, and preterm premature rupture of the membranes was 37 of 218 (17%), 27 of 272 (10%), and 10 of 164 (6%), respectively. Adjusted for gestational age, birth weight, and multiparity and compared with the preterm premature rupture of the membranes group, the odds ratios of spontaneous preterm labor and medical indication of preterm birth for type 1 or type 2 retinopathy of prematurity were 6.1 (95% confidence interval, 1.8 to 20, P = .003) and 5.5 (95% confidence interval, 1.4 to 21, P = .01), respectively. Among neonates born after preterm premature rupture of the membranes, the probability of developing type 1 or type 2 retinopathy of prematurity was greatest in infants with rupture of membrane duration of up to 24 hours. After 24 hours, the probability of developing type 1 or type 2 retinopathy of prematurity declined. The odds of developing type 1 or type 2 retinopathy of prematurity was 9.0 (95% confidence interval 2.3 to 34, P = .002) in infants who had preterm premature rupture of the membranes ≤ 24 hours compared with infants who had preterm premature rupture of the membranes > 24 hours. CONCLUSION: Type 1 or type 2 retinopathy of prematurity are adverse ocular outcomes linked with not only lower gestational age and birth weight at delivery but also with events in the intrauterine environment that trigger a preterm birth. The reduced incidence of type 1 or type 2 retinopathy of prematurity in the preterm premature rupture of the membranes group compared with other causes of preterm birth may be related to the perinatal therapies associated with preterm premature rupture of the membranes (such as corticosteroids, antibiotics, maternal-fetal surveillance), which may have an inhibitory effect on the development of retinopathy of prematurity. We suggest that the physiologic events that predispose infants to type 1 or type 2 retinopathy of prematurity begin before delivery.

Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disorder unique to premature infants. As premature births increase in many areas of the world, ROP has become a leading cause of childhood blindness. A better understanding of the pathogenesis of ROP, adherence to strict screening guidelines, and evolution of treatment options have reduced the number of sight-threatening complications from ROP.

Diagnostic Discrepancies in Retinopathy of Prematurity Classification.

PURPOSE: To identify the most common areas for discrepancy in retinopathy of prematurity (ROP) classification between experts. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 281 infants were identified as part of a multicenter, prospective, ROP cohort study from 7 participating centers. Each site had participating ophthalmologists who provided the clinical classification after routine examination using binocular indirect ophthalmoscopy (BIO) and obtained wide-angle retinal images, which were independently classified by 2 study experts. METHODS: Wide-angle retinal images (RetCam; Clarity Medical Systems, Pleasanton, CA) were obtained from study subjects, and 2 experts evaluated each image using a secure web-based module. Image-based classifications for zone, stage, plus disease, and overall disease category (no ROP, mild ROP, type II or pre-plus, and type I) were compared between the 2 experts and with the clinical classification obtained by BIO. MAIN OUTCOME MEASURES: Inter-expert image-based agreement and image-based versus ophthalmoscopic diagnostic agreement using absolute agreement and weighted kappa statistic. RESULTS: A total of 1553 study eye examinations from 281 infants were included in the study. Experts disagreed on the stage classification in 620 of 1553 comparisons (40%), plus disease classification (including pre-plus) in 287 of 1553 comparisons (18%), zone in 117 of 1553 comparisons (8%), and overall ROP category in 618 of 1553 comparisons (40%). However, agreement for presence versus absence of type 1 disease was >95%. There were no differences between image-based and clinical classification except for zone III disease. CONCLUSIONS: The most common area of discrepancy in ROP classification is stage, although inter-expert agreement for clinically significant disease, such as presence versus absence of type 1 and type 2 disease, is high. There were no differences between image-based grading and clinical examination in the ability to detect clinically significant disease. This study provides additional evidence that image-based classification of ROP reliably detects clinically significant levels of ROP with high accuracy compared with the clinical examination.

Plus Disease in Retinopathy of Prematurity: A Continuous Spectrum of Vascular Abnormality as a Basis of Diagnostic Variability.

PURPOSE: To identify patterns of interexpert discrepancy in plus disease diagnosis in retinopathy of prematurity (ROP). DESIGN: We developed 2 datasets of clinical images as part of the Imaging and Informatics in ROP study and determined a consensus reference standard diagnosis (RSD) for each image based on 3 independent image graders and the clinical examination results. We recruited 8 expert ROP clinicians to classify these images and compared the distribution of classifications between experts and the RSD. PARTICIPANTS: Eight participating experts with more than 10 years of clinical ROP experience and more than 5 peer-reviewed ROP publications who analyzed images obtained during routine ROP screening in neonatal intensive care units. METHODS: Expert classification of images of plus disease in ROP. MAIN OUTCOME MEASURES: Interexpert agreement (weighted κ statistic) and agreement and bias on ordinal classification between experts (analysis of variance [ANOVA]) and the RSD (percent agreement). RESULTS: There was variable interexpert agreement on diagnostic classifications between the 8 experts and the RSD (weighted κ, 0-0.75; mean, 0.30). The RSD agreement ranged from 80% to 94% for the dataset of 100 images and from 29% to 79% for the dataset of 34 images. However, when images were ranked in order of disease severity (by average expert classification), the pattern of expert classification revealed a consistent systematic bias for each expert consistent with unique cut points for the diagnosis of plus disease and preplus disease. The 2-way ANOVA model suggested a highly significant effect of both image and user on the average score (dataset A: P < 0.05 and adjusted R2 = 0.82; and dataset B: P < 0.05 and adjusted R2 = 0.6615). CONCLUSIONS: There is wide variability in the classification of plus disease by ROP experts, which occurs because experts have different cut points for the amounts of vascular abnormality required for presence of plus and preplus disease. This has important implications for research, teaching, and patient care for ROP and suggests that a continuous ROP plus disease severity score may reflect more accurately the behavior of expert ROP clinicians and may better standardize classification in the future.

Plus Disease in Retinopathy of Prematurity: Improving Diagnosis by Ranking Disease Severity and Using Quantitative Image Analysis.

PURPOSE: To determine expert agreement on relative retinopathy of prematurity (ROP) disease severity and whether computer-based image analysis can model relative disease severity, and to propose consideration of a more continuous severity score for ROP. DESIGN: We developed 2 databases of clinical images of varying disease severity (100 images and 34 images) as part of the Imaging and Informatics in ROP (i-ROP) cohort study and recruited expert physician, nonexpert physician, and nonphysician graders to classify and perform pairwise comparisons on both databases. PARTICIPANTS: Six participating expert ROP clinician-scientists, each with a minimum of 10 years of clinical ROP experience and 5 ROP publications, and 5 image graders (3 physicians and 2 nonphysician graders) who analyzed images that were obtained during routine ROP screening in neonatal intensive care units. METHODS: Images in both databases were ranked by average disease classification (classification ranking), by pairwise comparison using the Elo rating method (comparison ranking), and by correlation with the i-ROP computer-based image analysis system. MAIN OUTCOME MEASURES: Interexpert agreement (weighted κ statistic) compared with the correlation coefficient (CC) between experts on pairwise comparisons and correlation between expert rankings and computer-based image analysis modeling. RESULTS: There was variable interexpert agreement on diagnostic classification of disease (plus, preplus, or normal) among the 6 experts (mean weighted κ, 0.27; range, 0.06-0.63), but good correlation between experts on comparison ranking of disease severity (mean CC, 0.84; range, 0.74-0.93) on the set of 34 images. Comparison ranking provided a severity ranking that was in good agreement with ranking obtained by classification ranking (CC, 0.92). Comparison ranking on the larger dataset by both expert and nonexpert graders demonstrated good correlation (mean CC, 0.97; range, 0.95-0.98). The i-ROP system was able to model this continuous severity with good correlation (CC, 0.86). CONCLUSIONS: Experts diagnose plus disease on a continuum, with poor absolute agreement on classification but good relative agreement on disease severity. These results suggest that the use of pairwise rankings and a continuous severity score, such as that provided by the i-ROP system, may improve agreement on disease severity in the future.

Antivascular endothelial growth factor in the treatment of retinopathy of prematurity.

PURPOSE OF REVIEW: To review the most recent literature regarding the clinical experience of antivascular endothelial growth factor (anti-VEGF) therapies in the treatment of retinopathy of prematurity (ROP). RECENT FINDINGS: Anti-VEGF agents in stage 3+ and aggressive posterior ROP have been shown to induce rapid ROP regression. However, significant reoccurrence rates can require repeat injections and thus longer term and more frequent follow-up. Initial studies reflect conflicting evidence regarding significant systemic side effects of these treatments, and outcomes in these patients past the first few years of life are yet to be definitively determined. SUMMARY: Although anti-VEGF therapies show promise in the treatment of ROP, frequent reoccurrences and lack of thorough data about long-term side effects of pharmacologic intervention necessitate further research before anti-VEGF agents become the mainstay of ROP management.

CHOROIDAL THICKNESS IN INFANTS WITH RETINOPATHY OF PREMATURITY.

PURPOSE: To evaluate choroidal thickness in premature infants and its relationship with stage of retinopathy of prematurity (ROP) using spectral domain optical coherence tomography (SD-OCT). METHODS: Spectral domain optical coherence tomography imaging for measuring subfoveal choroidal thickness was performed for 80 premature infants. Subfoveal choroidal thickness was defined as the distance from the hyperreflective line of the outermost retinal pigment epithelium (RPE) to the innermost hyperreflective line of the choroidoscleral junction. Each measurement was performed at the central fovea (CF) and 0.75 mm to 1.5 mm nasal (N1 and N2) and temporal (T1 and T2) to the fovea. Subfoveal choroidal thickness and grading of cystoid macular edema (CME) were analyzed statistically. RESULTS: Choroidal thickness of CF was found to be significantly greater than nasal (N1 and N2) and temporal (T1 and T2) choroidal thickness (P < 0.05). There was no significant relationship between stage of ROP and nasal (N1 and N2) choroidal thickness (P = 0.057, P = 0.282, respectively). However, CF and temporal (T1 and T2) choroidal thickness was found to be significantly lower at a higher stage of ROP (P = 0.005, P = 0.01 and P = 0.001). No significant relationship was found between subfoveal choroidal thickness and the grades of cystoid macular edema (P > 0.05). The choroidal thickness of CF was found to be correlated with birth weight (r = 0.267, P = 0.017) but not birth week (r = 0.140, P = 0.217). Maximum stage of ROP was found to be negatively correlated with choroidal thickness, at N1, T1, and T2 (r < -0.250, P < 0.02). CONCLUSION: The subfoveal choroid in premature infants can be effectively evaluated using a portable SD-OCT device. Choroidal thickness gets thinner with the severity of ROP and the decrease is more prominent at the central and temporal location. Cystoid macular edema is not correlated with choroidal thickness in premature infants.

New insights in diagnosis and treatment for Retinopathy of Prematurity.

The purpose of this study was to review current perspectives on diagnosis and treatment of Retinopathy of Prematurity (ROP). We performed a systematic review of how much has been produced in research published online and on print regarding ROP in different settings around the world. Early Treatment for ROP (ETROP) classification is the currently accepted classification of ROP. Fluorescein angiography and spectral domain optical coherence tomography (SD-OCT) may eventually lead to changes in the definition of ROP, and as a consequence, they will serve as a guide for treatment. Intravitreal anti-VEGF therapy has proven to be more effective in terms of lowering recurrence, allowing growth of the peripheral retina, and diminishing the incidence of retinal detachment when proliferative ROP is diagnosed. Whether anti-VEGF plus laser are better than any of these therapies separately remains a subject of discussion. Telemedicine is evolving everyday to allow access to remote areas that do not count with a retina specialist for treatment. A management algorithm is proposed according to our reference center experience. ROP is an evolving subject, with a vulnerable population of study that, once treated with good results, leads to a reduction in visual disability and in consequence, in a lifetime improvement.

Pathophysiology and mechanisms of severe retinopathy of prematurity.

Retinopathy of prematurity (ROP) affects only premature infants, but as premature births increase in many areas of the world, ROP has become a leading cause of childhood blindness. Blindness can occur from aberrant developmental angiogenesis that leads to fibrovascular retinal detachment. To treat severe ROP, it is important to study normal developmental angiogenesis and the stresses that activate pathologic signaling events and aberrant angiogenesis in ROP. Vascular endothelial growth factor (VEGF) signaling is important in both physiologic and pathologic developmental angiogenesis. Based on studies in animal models of oxygen-induced retinopathy (OIR), exogenous factors such as oxygen levels, oxidative stress, inflammation, and nutritional capacity have been linked to severe ROP through dysregulated signaling pathways involving hypoxia-inducible factors and angiogenic factors like VEGF, oxidative species, and neuroprotective growth factors to cause phases of ROP. This translational science review focuses on studies performed in animal models of OIR representative of human ROP and highlights several areas: mechanisms for aberrant growth of blood vessels into the vitreous rather than into the retina through over-activation of VEGF receptor 2 signaling, the importance of targeting different cells in the retina to inhibit aberrant angiogenesis and promote physiologic retinal vascular development, toxicity from broad and targeted inhibition of VEGF bioactivity, and the role of VEGF in neuroprotection in retinal development. Several future translational treatments are discussed, including considerations for targeted inhibition of VEGF signaling instead of broad intravitreal anti-VEGF treatment.

Influence of Fluorescein Angiography on the Diagnosis and Management of Retinopathy of Prematurity.

PURPOSE: To examine the influence of fluorescein angiography (FA) on the diagnosis and management of retinopathy of prematurity (ROP). DESIGN: Prospective cohort study. PARTICIPANTS: Nine recognized ROP experts (3 pediatric ophthalmologists and 6 retina specialists) interpreted 32 sets (16 color fundus photographs and 16 color fundus photographs paired with the corresponding FA images) of wide-angle retinal images from infants with ROP. METHODS: All experts independently reviewed the 32 image sets on a secure website and provided a diagnosis and management plan for the case presented, first based on color fundus photographs alone, and then based on color fundus photographs and corresponding FA images. MAIN OUTCOME MEASURES: Sensitivity and specificity of the ROP diagnosis (zone, stage, plus disease, and category, i.e., no ROP, mild ROP, type 2 ROP, and ROP requiring treatment) were calculated using a consensus reference standard diagnosis, determined from the diagnosis of the color fundus photographs by 3 experienced readers in combination with the clinical diagnosis based on ophthalmoscopic examination. The κ statistic was used to analyze the average intergrader agreement among experts for the diagnosis of zone, stage, plus disease, and category. RESULTS: Addition of FA to color fundus photography resulted in a significant improvement in sensitivity for diagnosis of stage 3 or worse disease (39.8% vs. 74.1%; P = 0.008), type 2 or worse ROP (69.4% vs. 86.8%; P = 0.013), and pre-plus or worse disease (50.5 vs. 62.6%; P = 0.031). There was a nonsignificant trend toward improved sensitivity for diagnosis of ROP requiring treatment (22.2% vs. 40.3%; P = 0.063). Using the κ statistic, addition of FA to color fundus photography significantly improved intergrader agreement for diagnosis of ROP requiring treatment. Addition of FA to color fundus photography did not affect intergrader agreement significantly for the diagnosis of stage, zone, or plus disease. CONCLUSIONS: Compared with color fundus photography alone, FA may improve the sensitivity of diagnosis of ROP by experts, particularly for stage 3 disease. In addition, intergrader agreement for diagnosis of ROP requiring treatment may improve with FA interpretation.

Long-term outcomes on lens clarity after lens-sparing vitrectomy for retinopathy of prematurity.

OBJECTIVE: To describe the long-term effect of lens-sparing vitrectomy surgery for advanced retinopathy of prematurity (ROP) on lens clarity. DESIGN: Retrospective case series at a single tertiary referral pediatric vitreoretinal practice. PARTICIPANTS: Four hundred ninety-six eyes from 351 patients were included. METHODS: A retrospective chart review was conducted of patients with diagnosis of ROP stage 4A, 4B, and 5 who underwent lens-sparing vitrectomy (LSV) between 1992 and 2013. Data were collected from patient charts, including gender, date of birth, gestational age at birth, birthweight, stage of ROP at presentation, initial treatment (laser or cryotherapy), date of LSV, date of lensectomy (if performed), lens status at time of lensectomy, date of last visit, lens status at last visit, subsequent retinal surgeries, and retinal attachment status at last visit. Patients were excluded if any surgery had been performed at an outside institution before referral, or if a scleral buckle had been placed. Eyes with a concurrent anatomic abnormality, such as coloboma or microcornea, or a known family history of familial exudative vitreoretinopathy (FEVR), were also excluded. MAIN OUTCOME MEASURES: Retinal reattachment after LSV, lensectomy after LSV, lens opacity at the time of lensectomy, and lens clarity at last follow-up. RESULTS: Four hundred ninety-six eyes from 351 patients met inclusion criteria for this study. The reattachment rate after a single LSV surgery was 82.1% for stage 4A, 69.5% for stage 4B, and 42.6% for stage 5. Subsequent retinal surgeries were required in 19.8% of eyes, with 88.7% of them including a lensectomy. Among eyes requiring lensectomy, 75% occurred within the first year after LSV surgery. Lens opacities were present in 26.6% of eyes at the time of lensectomy. Of all eyes in this series, 5.9% required lensectomy because of lens opacity. CONCLUSIONS: This study demonstrates that lens clarity is observed in most eyes after LSV surgery for advanced ROP for the patient's childhood. Within the first decade of life, if necessary, lensectomy after LSV occurred mostly within 1 year following LSV.

Vision development over an extended follow-up period in babies after successful vitrectomy for stage 4b retinopathy of prematurity.

PURPOSE/BACKGROUND: To demonstrate improvement in the vision of babies after successful vitrectomy for stage 4b retinopathy of prematurity (ROP) over an extended period of time. METHODS: This was an observational prospective case series. Eight babies who had undergone successful vitrectomy in either their only seeing eye (or both eyes) with stage 4b ROP were followed up post-operatively for a period of 80 weeks or more. Vision with Teller acuity chart, refraction, binocular indirect ophthalmoscopy, and documentation with RetCam was done at each visit. Vision of the (only/better) seeing operated eye with corrective glasses was graded for the purpose of statistical evaluation. Paired t test was performed to compare the vision prior to 30 weeks and at or after 80 weeks. RESULTS: Statistically significant improvement in vision was noted at or after 80 weeks as compared to the vision recorded before 30 weeks (p = 0.0062). CONCLUSIONS: Unlike in adult intraocular surgeries where stable visual acuity is reached well before 30 weeks, continuing improvement at 80 weeks and beyond is noted. Gradual restoration of the retinal architecture and plasticity of the infant's developing brain are thought to be responsible.

Intravitreal bevacizumab monotherapy for type-1 prethreshold, threshold, and aggressive posterior retinopathy of prematurity - 27 month follow-up results from Turkey.

PURPOSE: To study the efficacy of intravitreal bevacizumab (IVB) injection as a single treatment for retinopathy of prematurity (ROP). METHODS: This was a prospective interventional case series study performed in a clinical practice setting; a total of 122 patients including prethreshold (type 1) (n = 79, 152 eyes, six unilateral), threshold (n = 12, 24 eyes), and aggressive posterior (APROP) (n = 31, 62 eyes); cases were included without any randomization or masking. A total of 253 IVB injections, 238 in the first session, 11 in the second session, and four in the third session were performed, and followed up for a mean of 89.155 ± 4.277 (range 82 to 105) weeks of postmenstrual age (PMA). Regression of ROP, maturation of the retina, and associated complications were evaluated. RESULTS: Total regression was achieved in 227/238 eyes (95.4 %) after the first dose injection. The remaining 11 received a second injection, after which an additional seven (234/238; 98.2 %) regressed; after the third injection, the remaining 4 (238/238; 100 %) regressed. Complete retinal vascular maturation was achieved without any significant complications in all of the cases. CONCLUSIONS: IVB injection as monotherapy seems to be a very effective treatment modality for ROP. Based on timely intervention, IVB as a single treatment modality can salvage almost all ROP cases before stage 4.

Natural history of retinopathy of prematurity: two-year outcomes of a prospective study.

PURPOSE: To investigate the 2-year outcomes of the natural history of retinopathy of prematurity (ROP) in Taiwan. METHODS: A prospective study was conducted at two tertiary medical centers. Premature infants were screened and examined for ROP. The postmenstrual ages of developing each stage of ROP and the associated risk factors were recorded. RESULTS: A total of 698 infants were included. The incidences of ROP and treatment-requiring ROP in all patients with ROP were 29.7% and 37.2%. When only including patients with birth weight of 1,250 g or less, the incidences were 62.2% and 39.1%, respectively. In patients with ROP with birth weight over 1,250 g, 25% of them developed treatment-requiring ROP. The median postmenstrual ages for the development of Stage 1, Stage 2, and Type 1 ROP were 33.0, 34.0, and 34.7 weeks, respectively. Gestational age at birth and birth weight were the most important factors associated with treatment-requiring ROP (hazard ratios of 0.3 and 0.6). CONCLUSION: Our hospital-based study reveals an earlier postmenstrual age of developing ROP in this Asian population than in the Early Treatment for ROP study. Infants with birth weight over 1,250 g could still develop treatment-requiring ROP. Suboptimal oxygen control, different genetic dispositions among different races, inconsistencies in ROP diagnosis, and earlier screening might account for such a phenomenon.