Retinopathy of Prematurity in the 21st Century and the Complex Impact of Supplemental Oxygen.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. Not only do the epidemiologic determinants and distributions of patients with ROP vary worldwide, but clinical differences have also been described. The Third Edition of the International Classification of ROP (ICROP3) acknowledges that aggressive ROP (AROP) can occur in larger preterm infants and involve areas of the more anterior retina, particularly in low-resource settings with unmonitored oxygen supplementation. As sub-specialty training programs are underway to address an epidemic of ROP in sub-Saharan Africa, recognizing characteristic retinal pathology in preterm infants exposed to unmonitored supplemental oxygen is important to proper diagnosis and treatment. This paper describes specific features associated with various ROP presentations: oxygen-induced retinopathy in animal models, traditional ROP seen in high-income countries with modern oxygen management, and ROP related to excessive oxygen supplementation in low- and middle-income countries: oxygen-associated ROP (OA-ROP).

Comparison in Retreatments between Bevacizumab and Ranibizumab Intravitreal Injections for Retinopathy of Prematurity: A Multicenter Study.

PURPOSE: To compare the types and dosages of anti-vascular endothelial growth factors (VEGFs) to ascertain whether specific dosages or types of injection were associated with retreatment in clinical practice in the United States. DESIGN: Multicenter, retrospective, consecutive series. PARTICIPANTS: Patients with retinopathy of prematurity (ROP) treated with anti-VEGF injections from 2007 to 2021. METHODS: Sixteen sites from the United States participated. Data collected included demographics, birth characteristics, examination findings, type and dose of anti-VEGF treatment, retreatment rates, and time to retreatment. Comparisons of retreatment rates between bevacizumab and ranibizumab intravitreal injections were made. MAIN OUTCOME MEASURES: Relative rate of retreatment between varying types of anti-VEGF therapy, including bevacizumab and ranibizumab, and the various dosages used for each. RESULTS: Data from 873 eyes of 661 patients (61% male and 39% female) were collected. After exclusion of 40 eyes treated with laser before anti-VEGF injection and 266 eyes re-treated with laser at or beyond 8 weeks after the initial anti-VEGF treatment, 567 eyes of 307 patients (63% male and 37% female) remained and were included in the primary analysis. There was no difference between the no retreatment and retreatment groups in terms of birthweight, gestational age, age at first injection, ROP stages, or number of involved clock hours. The retreatment group had a larger percentage of aggressive ROP (34% vs. 18%, P < 0.001) and greater percentage of zone 1 ROP (49 vs. 34%, P = 0.001) than the no retreatment group. Ranibizumab use was associated with a higher rate of retreatment than bevacizumab use (58% vs. 37%, P < 0.001), whereas the rate of retreatment was not associated with a specific dose of ranibizumab (R2 = 0.67, P = 0.32). Meanwhile, lower doses of bevacizumab were associated with higher rates of retreatment compared with the higher doses (R2 = 0.84, P = 0.01). There was a dose-specific trend with higher doses trending toward lower retreatments for bevacizumab. CONCLUSIONS: In a multicenter study of ROP patients initially treated with anti-VEGF therapy, ranibizumab and lower-dose bevacizumab use were associated with an increased rate of retreatment when compared with higher-dose bevacizumab. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Practice Patterns and Outcomes of Intravitreal Anti-VEGF Injection for Retinopathy of Prematurity: An International Multicenter Study.

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

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.

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.

Survey of Intravitreal Injection Techniques Among Retina Specialists in Mexico.

PURPOSE: To report technique preferences for intravitreal injections among retina specialists in Mexico. METHODS: Cross-sectional survey. Ophthalmologists with a two-year retina training, active members of the Mexican Retina Association, were contacted through email to answer a survey consisting of 37 items regarding their IVI application technique. RESULTS: A total of 133 retina specialists participated, with a response rate of 78%. Forty-five percent applied the intravitreal injections in an operating room designated for the procedure. Sixty-three percent reported never injecting both eyes on the same day. Ninety-six percent wore a face mask during the procedure and 91% wore gloves. Eighty-two percent used a lid speculum. Tetracaine drops were the anesthetic method employed by 97% of participants. All participants utilized povidone-iodine for antisepsis. Eighty percent measured the puncture site with a caliper. Superotemporal quadrant was the one chosen to place the injection by 63% of participants. Fifty-nine percent indicated post-injection antibiotic drops for several days. Post-injection counting fingers visual acuity was verified by 53% of the participants. Fifty-six percent of the participants placed an eye-patch after the procedure. CONCLUSION: There are different practices regarding the application of intravitreal injections among retina specialists in Mexico. Performing this type of survey periodically could show changes in preferences, as new evidence is incorporated into clinical practice.

The current state of retinopathy of prematurity in India, Kenya, Mexico, Nigeria, Philippines, Romania, Thailand, and Venezuela.

Retinopathy of prematurity (ROP) is one of the leading causes of preventable blindness in children worldwide. Middle-income nations are currently experiencing epidemic levels of ROP, because greater access to neonatal intensive care units has improved survival rates of premature infants, but without sophisticated oxygen regulation. The epidemiology, screening infrastructure, treatment options, and challenges that these countries face are often tied to unique local socioeconomic, cultural, geopolitical, and medical factors. We present an overview and narratives of the current state of ROP in eight countries that are or soon will be experiencing ROP epidemics-India, Kenya, Mexico, Nigeria, Phillipines, Romania, Thailand, and Venezuela-with a view to fostering both an understanding of the differences in the ROP landscape in various settings and an interest in the further development of ROP screening and treatment services tailored to local requirements.

Detection of Candida Endophthalmitis in a Newborn Using Handheld Spectral-Domain Optical Coherence Tomography.

In a newborn with candidemia, two retinal lesions were seen without external inflammatory signs or reaction in the anterior chamber or vitreous. However, handheld spectral domain-optical coherence tomography (HH SD-OCT) images show that one of the retinal lesions had a "firework display" projecting to the vitreous that was not identified in indirect ophthalmoscopy. This finding suggested a Candida endophthalmitis. HH SD-OCT findings allowed us to make an accurate diagnosis and, therefore, modified the decision-making process in the treatment of the pathology.

Retinal vascular changes in preterm infants: heart and lung diseases and plus disease.

PURPOSE: To report the retinal vascular features of preterm infants with congenital heart disease (CHD), lung disease (pulmonary hypertension [PH] and bronchopulmonary dysplasia [BPD]), and ROP with plus disease to determine whether these disease entities are distinguishable on the basis of retinal vessel morphology. METHODS: The medical records of preterm infants with CHD, lung disease, and ROP with plus disease were reviewed retrospectively. Qualitative vascular findings were validated using computer-based software to analyze 25 representative images, each corresponding to one infant's eye. The images were organized into five groups, based on clinical information. Vessel diameter (d) and tortuosity index (TI) were measured. RESULTS: A total of 106 infants (mean gestational age, 30.5 ± 2.22 weeks) were initially included. Ophthalmologic evaluation of preterm infants with CHD and lung diseases showed vascular tortuosity without vasodilation at the posterior pole as well as in the periphery. Quantitative analysis showed that venular diameter was significantly increased in the plus disease group (P = 0.0022) compared to other groups. There was significantly less tortuosity in both arterioles and venules in BPD (P < 0.001, P = 0.0453) compared with plus group. CONCLUSIONS: The patterns of retinal vascular tortuosity observed in preterm infants may be unique to different systemic congestive conditions and could have therapeutic implications.

Assessment of a Tele-education System to Enhance Retinopathy of Prematurity Training by International Ophthalmologists-in-Training in Mexico.

PURPOSE: To evaluate a tele-education system developed to improve diagnostic competency in retinopathy of prematurity (ROP) by ophthalmologists-in-training in Mexico. DESIGN: Prospective, randomized cohort study. PARTICIPANTS: Fifty-eight ophthalmology residents and fellows from a training program in Mexico consented to participate. Twenty-nine of 58 trainees (50%) were randomized to the educational intervention (pretest, ROP tutorial, ROP educational chapters, and posttest), and 29 of 58 trainees (50%) were randomized to a control group (pretest and posttest only). METHODS: A secure web-based educational system was created using clinical cases (20 pretest, 20 posttest, and 25 training chapter-based) developed from a repository of over 2500 unique image sets of ROP. For each image set used, a reference standard ROP diagnosis was established by combining the clinical diagnosis by indirect ophthalmoscope examination and image-based diagnosis by multiple experts. Trainees were presented with image-based clinical cases of ROP during a pretest, posttest, and training chapters. MAIN OUTCOME MEASURES: The accuracy of ROP diagnosis (e.g., plus disease, zone, stage, category) was determined using sensitivity and specificity calculations from the pretest and posttest results of the educational intervention group versus control group. The unweighted kappa statistic was used to analyze the intragrader agreement for ROP diagnosis by the ophthalmologists-in-training during the pretest and posttest for both groups. RESULTS: Trainees completing the tele-education system had statistically significant improvements (P < 0.01) in the accuracy of ROP diagnosis for plus disease, zone, stage, category, and aggressive posterior ROP (AP-ROP). Compared with the control group, trainees who completed the ROP tele-education system performed better on the posttest for accurately diagnosing plus disease (67% vs. 48%; P = 0.04) and the presence of ROP (96% vs. 91%; P < 0.01). The specificity for diagnosing AP-ROP (94% vs. 78%; P < 0.01), type 2 ROP or worse (92% vs. 84%; P = 0.04), and ROP requiring treatment (89% vs. 79%; P < 0.01) was better for the trainees completing the tele-education system compared with the control group. Intragrader agreement improved for identification of plus disease, zone, stage, and category of ROP after completion of the educational intervention. CONCLUSIONS: A tele-education system for ROP education was effective in improving the diagnostic accuracy of ROP by ophthalmologists-in-training in Mexico. This system has the potential to increase competency in ROP diagnosis and management for ophthalmologists-in-training from middle-income nations.

Vascular changes on fluorescein angiography of premature infants with low risk of retinopathy of prematurity after high oxygen exposure.

PURPOSE: To describe a wide array of peripheral vascular changes using fluorescein angiography in preterm neonates, without high risk characteristics for developing retinopathy of prematurity, that were exposed to high oxygen concentration. METHODS: Retrospective, two center, case series. Newborns at two different hospitals with ≥1500 g or gestational age of ≥32 weeks, fluorescein angiography performed, and with high oxygen exposure without adequate control were included. RESULTS: 294 infants diagnosed with ROP were analyzed. Only 28 eyes from 14 patients with peripheral vascular abnormalities in older and heavier babies were included. Two distinct type of peripheral vascular changes were observed: group 1 or non-proliferative: areas of capillary non-perfusion along with widespread arteriovenous shunting between adjacent primary vessels, tortuosity of primary vessels, abnormal budding of tertiary vessels and capillaries, abnormal capillary tufts and absence of foveal avascular zone; group 2 or proliferative: all of the characteristics of group 1 plus leakage of dye from the boundary between perfused and non-perfused retina and/or optic disc. CONCLUSION: Peripheral vascular abnormalities different from retinopathy of prematurity are observed in older than 32 weeks of gestational age, and heavier than 1500 g babies. This makes the authors classify these patients as having a disease caused solely by oxygen dysregulation at the neonatal intensive care unit similarly to the oxygen induced retinopathy in experimental studies.

[Neurodevelopment in patients with retinopathy of prematurity treated with intravitreal bevacizumab. Case series]. / Neurodesarrollo en pacientes con retinopatía del prematuro tratados con bevacizumab intravítreo. Serie de casos.

BACKGROUND: Retinopathy of prematurity (ROP) is an eye disease caused by an alteration in retinal vasculogenesis that may lead to partial or complete vision loss with a harmful impact in terms of neurodevelopment. The purpose of the present study was to determine the neurodevelopment in patients with type i retinopathy of prematurity treated with intravitreal bevacizumab. MATERIAL AND METHODS: Case series. The inclusion criteria were: patients with type I ROP treated with a dose of 0.625mg/0.025ml of intravitreal bevacizumab. Demographic data and comorbidities were documented. Neurodevelopment was evaluated with the screening test of the Bayley Scale of Infant Development (BSID) in all patients between 11 and 28 weeks of age. RESULTS: Seven patients were included in the study. Four patients showed normal neurodevelopment according to the overall scores of the BSID scale. The distribution of high risk for neurodevelopmental delay in the different areas evaluated were as follows: 3 patients presented it in the cognitive area, one in the receptive communication area, one in the expressive area, one in the fine motor skills and 3 patients in the gross motor skills area. CONCLUSIONS: In these case series, the majority of patients treated with intravitreal bevacizumab for ROP showed normal neurodevelopment scores.

The Economic Model of Retinopathy of Prematurity (EcROP) Screening and Treatment: Mexico and the United States.

PURPOSE: To describe an economic (Ec) model for estimating the impact of screening and treatment for retinopathy of prematurity (ROP). DESIGN: EcROP is a cost-effectiveness, cost-utility, and cost-benefit analysis. METHODS: We surveyed caregivers of 52 children at schools for the blind or pediatric eye clinics in Atlanta, Georgia and 43 in Mexico City. A decision analytic model with sensitivity analysis determined the incremental cost-effectiveness (primary outcome) and incremental monetary benefit (secondary outcome) of an ideal (100% screening) national ROP program as compared to estimates of current practice. Direct costs included screening and treatment expenditures. Indirect costs estimated lost productivity of caretaker(s) and blind individuals as determined by face-to-face surveys. Utility and effectiveness were measured in quality-adjusted life years and benefit in US dollars. EcROP includes a sensitivity analysis to assesses the incremental cost-effectiveness and societal impact of ROP screening and treatment within a country or economic region. Estimates are based on evidence-based clinical data and region-specific economic data acquired from direct field survey. RESULTS: In both Mexico and the United States, an ideal national ROP screening and treatment program was highly cost-saving. The incremental net benefit of an ideal ROP program over current practice is $5556 per child ($206 574 333 annually) and $3628 per child ($205 906 959 annually) in Mexico and the United States, respectively. CONCLUSION: EcROP demonstrates that ROP screening and treatment is highly beneficial for quality of life, cost saving, and cost-effectiveness in the United States and Mexico. EcROP can be applied to any country or region to provide data for informed allocation of limited health care resources.

Expert Diagnosis of Plus Disease in Retinopathy of Prematurity From Computer-Based Image Analysis.

IMPORTANCE: Published definitions of plus disease in retinopathy of prematurity (ROP) reference arterial tortuosity and venous dilation within the posterior pole based on a standard published photograph. One possible explanation for limited interexpert reliability for a diagnosis of plus disease is that experts deviate from the published definitions. OBJECTIVE: To identify vascular features used by experts for diagnosis of plus disease through quantitative image analysis. DESIGN, SETTING, AND PARTICIPANTS: A computer-based image analysis system (Imaging and Informatics in ROP [i-ROP]) was developed using a set of 77 digital fundus images, and the system was designed to classify images compared with a reference standard diagnosis (RSD). System performance was analyzed as a function of the field of view (circular crops with a radius of 1-6 disc diameters) and vessel subtype (arteries only, veins only, or all vessels). Routine ROP screening was conducted from June 29, 2011, to October 14, 2014, in neonatal intensive care units at 8 academic institutions, with a subset of 73 images independently classified by 11 ROP experts for validation. The RSD was compared with the majority diagnosis of experts. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the percentage of accuracy of the i-ROP system classification of plus disease, with the RSD as a function of the field of view and vessel type. Secondary outcome measures included the accuracy of the 11 experts compared with the RSD. RESULTS: Accuracy of plus disease diagnosis by the i-ROP computer-based system was highest (95%; 95% CI, 94%-95%) when it incorporated vascular tortuosity from both arteries and veins and with the widest field of view (6-disc diameter radius). Accuracy was 90% or less when using only arterial tortuosity and 85% or less using a 2- to 3-disc diameter view similar to the standard published photograph. Diagnostic accuracy of the i-ROP system (95%) was comparable to that of 11 expert physicians (mean 87%, range 79%-99%). CONCLUSIONS AND RELEVANCE: Experts in ROP appear to consider findings from beyond the posterior retina when diagnosing plus disease and consider tortuosity of both arteries and veins, in contrast with published definitions. It is feasible for a computer-based image analysis system to perform comparably with ROP experts, using manually segmented images.

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.

Color fundus photography versus fluorescein angiography in identification of the macular center and zone in retinopathy of prematurity.

PURPOSE: To examine the usefulness of fluorescein angiography (FA) in identifying the macular center and diagnosis of zone in patients with retinopathy of prematurity (ROP). DESIGN: Validity and reliability analysis of diagnostic tools. METHODS: Thirty-two sets (16 color fundus photographs and 16 color fundus photographs paired with the corresponding FA images) of wide-angle retinal images obtained from 16 eyes of 8 infants with ROP were compiled on a secure web site. Nine ROP experts (3 pediatric ophthalmologists and 6 vitreoretinal surgeons) participated in the study. For each image set, experts identified the macular center and provided a diagnosis of zone. MAIN OUTCOME MEASURES: (1) Sensitivity and specificity of zone diagnosis and (2) computer-facilitated diagnosis of zone, based on precise measurement of the macular center, optic disc center, and peripheral ROP. RESULTS: Computer-facilitated diagnosis of zone agreed with the expert's diagnosis of zone in 28 (62%) of 45 cases using color fundus photographs and in 31 (69%) of 45 cases using FA images. Mean (95% confidence interval) sensitivity for detection of zone I by experts compared with a consensus reference standard diagnosis when interpreting the color fundus images alone versus interpreting the color fundus photographs and FA images was 47% (range, 35.3% to 59.3%) and 61.1% (range, 48.9% to 72.4%), respectively (t(9) ≥ (2.063); P = .073). CONCLUSIONS: There is a marginally significant difference in zone diagnosis when using color fundus photographs compared with using color fundus photographs and the corresponding FA images. There is inconsistency between traditional zone diagnosis (based on ophthalmoscopic examination and image review) compared with a computer-facilitated diagnosis of zone.

Retinal fluorescein angiographic changes following intravitreal anti-VEGF therapy.

PURPOSE: To describe the retinal vascular morphology in eyes injected with intravitreal bevacizumab for treatment-requiring retinopathy of prematurity (ROP). METHODS: In this prospective, nonrandomized case series, fundus photographs and fluorescein angiography in patients diagnosed with stage 3 threshold or prethreshold ROP, were obtained immediately before and 1 month after injection of 0.03 cc (0.75 mg) of intravitreal bevacizumab using wide-field digital pediatric imaging system. RESULTS: A total of 47 eyes of 26 patients were included. Before treatment, fluorescein angiography showed vascular abnormalities, including capillary nonperfusion throughout and shunting in the vascularized retina, demarcation line, limited vessel development, new vessels leakage, avascular periphery and absence of foveal avascular zone. After intravitreal bevacizumab, fluorescein angiography showed involution of the neovascularization, flattening of the demarcation line and subsequent growth of vessels to the capillary-free zones. During the following weeks large areas devoid of microvessels were seen as well as vascular remodeling with uneven spacing of the retinal capillaries and vascular loops in the areas that were previously devoid of vessels. In some patients, retinal vessels in the far periphery never developed: patients with these findings did not subsequently develop pathological neovascularization. CONCLUSIONS: In this study cohort, patients showed improvement of their abnormal vascular findings after intravitreal bevacizumab, however even when the vascular pattern remained abnormal, there was creation of small vessels, establishment of directional flow, maturation of retinal vessels, and adjustment of vascular density.

Development and Evaluation of Reference Standards for Image-based Telemedicine Diagnosis and Clinical Research Studies in Ophthalmology.

Information systems managing image-based data for telemedicine or clinical research applications require a reference standard representing the correct diagnosis. Accurate reference standards are difficult to establish because of imperfect agreement among physicians, and discrepancies between clinical vs. image-based diagnosis. This study is designed to describe the development and evaluation of reference standards for image-based diagnosis, which combine diagnostic impressions of multiple image readers with the actual clinical diagnoses. We show that agreement between image reading and clinical examinations was imperfect (689 [32%] discrepancies in 2148 image readings), as was inter-reader agreement (kappa 0.490-0.652). This was improved by establishing an image-based reference standard defined as the majority diagnosis given by three readers (13% discrepancies with image readers). It was further improved by establishing an overall reference standard that incorporated the clinical diagnosis (10% discrepancies with image readers). These principles of establishing reference standards may be applied to improve robustness of real-world systems supporting image-based diagnosis.

Short-term effects of intravitreal bevacizumab for subfoveal choroidal neovascularization in pathologic myopia.

PURPOSE: To determine short-term effects of intravitreal bevacizumab for subfoveal choroidal neovascularization (CNV) in pathologic myopia. METHODS: In this prospective interventional case series, patients were treated with 2.5 mg of intravitreal bevacizumab and followed for 3 months. Best-corrected visual acuity (BCVA), optical coherence tomography (OCT), and fluorescein angiography (FA) were recorded. Indications for retreatment were active leaking CNV shown by FA and presence of subretinal fluid by OCT in combination with visual disturbances. RESULTS: Fourteen patients were included, with a mean age of 53.86 +/- 16.26 years (range 29-85). Mean spherical equivalent was -13.87 +/- 3.68 diopters (-7.25 to -20.50). Minimum follow-up was 3 months. There were no adverse events. The mean initial visual acuity was 20/200 improving to 20/100 at 2 weeks, 20/80 at 4 weeks, and 20/60 at 8 and 12 weeks (P=0.007; P=0.001; P=0.005; P=0.001, respectively). Initial foveal thickness improved from 385.43 microm +/- 125.83 microm to 257.64 +/- 76.6 microm and 194.54 +/- 54.35 microm after the first and third month, respectively (P=0.001). CONCLUSIONS: Initial treatment results of patients with CNV due to pathologic myopia did not reveal any short-term safety concerns. Intravitreal bevacizumab resulted in a significant decrease in foveal thickness and improvement in visual acuity. These favorable initial results support further larger and long-term studies.