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PURPOSE: The International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), acknowledged that plus-like retinopathy of prematurity (ROP) vascular changes occurs along a spectrum. Historically, clinician-experts demonstrate variable agreement for plus diagnosis. We developed a 9-photograph reference image set for grading plus-like changes and compared intergrader agreement of the set with standard grading with no plus, preplus, and plus disease. DESIGN: Retinal photographic grading and expert consensus opinion. PARTICIPANTS: The development set included 34 international ICROP3 committee members. The validation set included 30 ophthalmologists with ROP expertise (15 ICROP3 committee members and 15 non-ICROP3 members) METHODS: Nine ROP fundus images (P1 through P9) representing increasing degrees of zone I vascular tortuosity and dilation, based on the 34 ICROP3 committee members' gradings and consensus image reviews, were used to establish standard photographs for the plus (P) score. Study participants graded 150 fundus photographs 2 ways, separated by a 1-week washout period: (1) no plus, preplus, or plus disease and (2) choosing the closest P score image. MAIN OUTCOME MEASURES: Intergrader agreement measured by intraclass correlation coefficient. RESULTS: Intergrader agreement was higher using the P score (intraclass correlation coefficient, 0.75; 95% confidence interval, 0.71-0.79) than no plus, preplus, or plus disease (intraclass correlation coefficient, 0.67; 95% confidence interval, 0.62-0.72). Mean ± standard deviation P scores for images with mode gradings of no plus, preplus, and plus disease were 2.5 ± 0.7, 4.8 ± 0.8, and 7.4 ± 0.8, respectively. CONCLUSIONS: Intergrader agreement of plus-like vascular change in ROP using the P score is high. We now incorporate this 9-image reference set into ICROP3 for use in clinician daily practice alongside zone, stage, and plus assessment. P score is not yet meant to replace plus diagnosis for treatment decisions, but its use at our institutions has permitted better comparison between examinations for progression and regression, communication between examiners, and documentation of vascular change without fundus imaging. P score also could provide more detailed ROP classification for clinical trials, consistent with the spectrum of plus-like change that is now formally part of the International Classification of Retinopathy of Prematurity. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Purpose: The primary objective of this study was to develop and validate an AI algorithm as a screening tool for the detection of retinopathy of prematurity (ROP). Participants: Images were collected from infants enrolled in the KIDROP tele-ROP screening program. Methods: We developed a deep learning (DL) algorithm with 227,326 wide-field images from multiple camera systems obtained from the KIDROP tele-ROP screening program in India over an 11-year period. 37,477 temporal retina images were utilized with the dataset split into train (n = 25,982, 69.33%), validation (n = 4,006, 10.69%), and an independent test set (n = 7,489, 19.98%). The algorithm consists of a binary classifier that distinguishes between the presence of ROP (Stages 1-3) and the absence of ROP. The image labels were retrieved from the daily registers of the tele-ROP program. They consist of per-eye diagnoses provided by trained ROP graders based on all images captured during the screening session. Infants requiring treatment and a proportion of those not requiring urgent referral had an additional confirmatory diagnosis from an ROP specialist. Results: Of the 7,489 temporal images analyzed in the test set, 2,249 (30.0%) images showed the presence of ROP. The sensitivity and specificity to detect ROP was 91.46% (95% CI: 90.23%-92.59%) and 91.22% (95% CI: 90.42%-91.97%), respectively, while the positive predictive value (PPV) was 81.72% (95% CI: 80.37%-83.00%), negative predictive value (NPV) was 96.14% (95% CI: 95.60%-96.61%) and the AUROC was 0.970. Conclusion: The novel ROP screening algorithm demonstrated high sensitivity and specificity in detecting the presence of ROP. A prospective clinical validation in a real-world tele-ROP platform is under consideration. It has the potential to lower the number of screening sessions required to be conducted by a specialist for a high-risk preterm infant thus significantly improving workflow efficiency.
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Purpose: To measure the levels of inflammatory factors in tear fluid of pre-term infants with and without retinopathy of prematurity (ROP). Methods: The cross-sectional pilot study included 29 pre-term infants undergoing routine ROP screening. Pre-term infants were grouped as those without ROP (no ROP; n = 14) and with ROP (ROP; n = 15). Sterile Schirmer's strips were used to collect the tear fluid from pre-term infants. Inflammatory factors such as interleukin (IL)-6, IL-8, MCP1 (Monocyte Chemoattractant Protein 1; CCL2), RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted; CCL5), and soluble L-selectin (sL-selectin) were measured by cytometric bead array using a flow cytometer. Results: Birth weight (BW) and gestation age (GA) were significantly (P < 0.05) lower in pre-term infants with ROP compared with those without ROP. Higher levels of RANTES (P < 0.05) and IL-8 (P = 0.09) were observed in the tear fluid of pre-term infants with ROP compared with those without ROP. Lower levels of tear fluid IL-6 (P = 0.14) and sL-selectin (P = 0.18) were measured in pre-term infants with ROP compared with those without ROP. IL-8 and RANTES were significantly (P < 0.05) higher in the tear fluid of pre-term infants with stage 3 ROP compared with those without ROP. Tear fluid RANTES level was observed to be inversely associated with GA and BW of pre-term infants with ROP and not in those without ROP. Furthermore, the area under the curve and odds ratio analysis demonstrated the relevance of RANTES/BW (AUC = 0.798; OR-7.2) and RANTES/MCP1 (AUC = 0.824; OR-6.8) ratios in ROP. Conclusions: Distinct changes were observed in the levels of tear inflammatory factors in ROP infants. The status of RANTES in ROP suggests its possible role in pathobiology and warrants further mechanistic studies to harness it in ROP screening and management.
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Retinopatia da Prematuridade , Recém-Nascido , Lactente , Humanos , Retinopatia da Prematuridade/diagnóstico , Estudos Transversais , Interleucina-8 , Projetos Piloto , Idade Gestacional , Fatores de Risco , Recém-Nascido Prematuro , Peso ao Nascer , Selectinas , Estudos RetrospectivosRESUMO
Deregulation of vascular endothelial growth factor (VEGF) levels leads to retinopathy of prematurity (ROP). Vitamin D (VIT-D) is known to regulate VEGF in an oxygen dependent manner. The purpose of this study was to correlate tear levels of VEGF and VIT-D with different ROP stages in preterm infants. In this prospective cross-sectional study, we enrolled 104 pre-term infants. They were grouped into: Group-1 (Classical ROP) and Group-2 (Aggressive ROP), which were further subdivided into Group-1A (progressing), Group-1B (regressing), Group-2A (pre-treatment), and Group-2B (post-treatment). Tear VEGF and VIT-D levels and their association with different ROP stages were assessed. Stage 1 and stage 2 had higher whereas stage 3 had lower VEGF levels in Group-1B compared to Group-1A. Stage 1 and stage 3 showed higher levels of VIT-D with no difference in stage 2 in Group-1B compared to Group-1A., Group-2B showed higher VEGF and lower VIT-D levels compared to Group-2A. Presence of a positive correlation at an early stage (stage 1) of ROP and a negative correlation at a more advanced stage (stage 3) of ROP with VIT-D and VEGF implies stage-specific distinct signaling crosstalk. These findings suggest that VIT-D supplementation may have the potential to modify the course and outcome of ROP.
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Recém-Nascido Prematuro , Retinopatia da Prematuridade , Lactente , Humanos , Recém-Nascido , Fator A de Crescimento do Endotélio Vascular , Vitamina D , Estudos Prospectivos , Retinopatia da Prematuridade/metabolismo , Estudos Transversais , Idade GestacionalRESUMO
PURPOSE: Control of blindness due to retinopathy of prematurity (ROP) requires timely screening and treatment within 48-72 h. Anticipating that the coronavirus disease 2019 (COVID-19) pandemic would disrupt ROP services, we devised strategies ''on-the''-go"" to ameliorate this possiblity. We describe the successful outcomes of this approach in preventing infant blindness during the pandemic. METHODS: Data on the number of preemies recruited, screened and treated in the Karnataka Internet-assisted Diagnosis of Retinopathy of Prematurity (KIDROP) program were collected in a retrospective (2019, interval 1) - prospective (2020, interval 2) manner. We summarize 10 key strategies that were developed as we faced logistic, operational and implementation challenges. These included pragmatic methods of enhancing enrolment, transporting for screening and ensuring timely treatment in the outreach. RESULTS: The total number of ROP screening sessions was 20,598 (7,197 new) and 14,371 (5,773 new) during interval 1 and 2 respectively. Of these, 166 (2.3%) and 157 (2.7%) infants required treatment during interval 1 and 2 respectively. All infants needing treatment during the COVID period, were treated on time which was possible due to successful implementation of the 'on-the-go' strategies throughout the state of Karnataka. The fiscal equivalent of the blindness prevented during this period is USD 15.6 million. CONCLUSION: The greater decline in the number of ROP screening episodes in neonatal units in government hospitals was because several were converted to 'COVID only" hospitals. KIDROP's multi-zonal, decentralized strategy, which uses non-physician-based imaging in a telemedicine network, ensured that essential ROP services continued even during the lockdown.
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Retinopathy of prematurity (ROP) is a vasoproliferative disease of the preterm retina that has the potential to cause vision impairment and blindness. Timely screening and treatment are hence critical for infants at risk for ROP. Screening for ROP is challenging in India owing to the limited resources, a vast at-risk population and lack of awareness among paediatricians and the public. Addressing ROP in India requires a comprehensive approach involving multiple sectors, considering the magnitude of the problem and the expected increase in need for ROP services due to the increased survival of preterm infants following improvements in neonatal care. The success of the Global Polio Eradication Initiative (GPEI) offers valuable lessons for improving ROP services in developing nations by applying its strategies. An approach for primary and secondary prevention of ROP is proposed, and the current challenges and a neonatal-led care model for ROP are discussed.
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Background: Retinopathy of prematurity (ROP) and abnormal brain development share similar risk factors and mechanisms. There has been contrasting evidence on the association of ROP with adverse neurodevelopmental outcomes. Objective: We analysed the association between ROP at levels of severity and treatment with all neurodevelopmental outcomes until adolescence. Data source: We followed PRISMA guidelines and searched Medline and Embase between 1 August 1990 and 31 March 2022. Study selection and participants: Randomised or quasi-randomised clinical trials and observational studies on preterm infants (<37 weeks) with ROP [type 1 or severe ROP, type 2 or milder ROP, laser or anti-vascular endothelial growth factor (VEGF) treated] were included. Data extraction and synthesis: We included studies on ROP and any neurocognitive or neuropsychiatric outcomes. Outcomes: The primary outcomes were as follows: cognitive composite scores evaluated between the ages of 18 and 48 months by the Bayley Scales of Infant and Toddler Development (BSID) or equivalent; neurodevelopmental impairment (NDI; moderate to severe NDI or severe NDI), cerebral palsy, cognitive impairment; and neuropsychiatric or behavioural problems. The secondary outcomes were as follows: motor and language composite scores evaluated between the ages of 18 and 48 months by BSID or equivalent; motor/language impairment; and moderate/severe NDI as defined by the authors. Results: In preterm infants, "any ROP" was associated with an increased risk of cognitive impairment or intellectual disability [n = 83,506; odds ratio (OR): 2.56; 95% CI: 1.40-4.69; p = 0.002], cerebral palsy (n = 3,706; OR: 2.26; 95% CI: 1.72-2.96; p < 0.001), behavioural problems (n = 81,439; OR: 2.45; 95% CI: 1.03-5.83; p = 0.04), or NDI as defined by authors (n = 1,930; OR: 3.83; 95% CI: 1.61-9.12; p = 0.002). Type 1 or severe ROP increased the risk of cerebral palsy (OR: 2.19; 95% CI: 1.23-3.88; p = 0.07), cognitive impairment or intellectual disability (n = 5,167; OR: 3.56; 95% CI: 2.6-4.86; p < 0.001), and behavioural problems (n = 5,500; OR: 2.76; 95% CI: 2.11-3.60; p < 0.001) more than type 2 ROP at 18-24 months. Infants treated with anti-VEGF had higher odds of moderate cognitive impairment than the laser surgery group if adjusted data (gestational age, sex severe intraventricular haemorrhage, bronchopulmonary dysplasia, sepsis, surgical necrotising enterocolitis, and maternal education) were analysed [adjusted OR (aOR): 1.93; 95% CI: 1.23-3.03; p = 0.04], but not for cerebral palsy (aOR: 1.29; 95% CI: 0.65-2.56; p = 0.45). All outcomes were adjudged with a "very low" certainty of evidence. Conclusion and relevance: Infants with "any ROP" had higher risks of cognitive impairment or intellectual disability, cerebral palsy, and behavioural problems. Anti-VEGF treatment increased the risk of moderate cognitive impairment. These results support the association of ROP and anti-VEGF treatment with adverse neurodevelopmental outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022326009.
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The rise in preterm births and higher survival rates of premature infants have led to a global increase in retinopathy of prematurity (ROP), a vasoproliferative retinal disorder common in premature infants. ROP is one of the leading causes of childhood blindness. Clinical manifestation of ROP ranges from mild abnormal retinal neovascularization to bilateral retinal detachment and vision loss. The incidence of ROP is higher in middle income countries, including India, which has the highest number of global preterm births. Low birth weight and low gestational age are the primary risk factors for ROP; however, anemia, cardiac defects, blood transfusion, apnea, sepsis, respiratory distress syndrome, high exposure to oxygen and poor postnatal weight gain may also contribute to its development. India has stringent ROP screening guidelines revised in 2018, and screening of infants with either birth weight <2000 grams or gestational age <34 weeks is mandated. With an improved understanding of the pathogenesis of ROP in the past decades and advances in clinical research, treatment for ROP has evolved from cryotherapy to laser retinal ablation. Most recently, anti-vascular endothelial growth factor (anti-VEGF) drugs have emerged as a favorable treatment option for zone-I and II ROP. This article reviews the current approaches for ROP treatment in India with a particular focus on anti-VEGF drugs. The article also integrates the understanding of safety and risk-benefit evaluation of the current approaches in ROP management. The review concluded that there is a need to increase the ROP screening not only for preterm and low birth weight but also for optimal gestational age infants with healthy birth weight. Anti-VEGF therapies have shown improved efficacy, although studies are required to establish the long-term safety.
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PURPOSE: Recent advances in sequencing technologies have enabled radical and rapid progress in the genetic diagnosis of inherited retinal disorders (IRDs). Although the list of gene variations continues to grow, it lacks the genetic etiology of ethnic groups like South Asians. Differences in racial backgrounds and consanguinity add to genetic heterogeneity and phenotypic overlaps. METHODS: This retrospective study includes documented data from the Gen-Eye clinic from years 2014 to 2019. Medical records and pedigrees of 591 IRD patients of Indian origin and genetic reports of 117 probands were reviewed. Genotype-phenotype correlations were performed to classify as correlating, non-correlating and unsolved cases. RESULTS: Among the 591 patients, we observed a higher prevalence of clinically diagnosed retinitis pigmentosa (38.9%) followed by unspecified diagnoses (28.5%). Consanguinity was reported to be high (55.6%) in this cohort. Among the variants identified in 117 probands, 36.4% of variants were pathogenic, 19.2% were likely pathogenic, and 44.4% were of uncertain significance. Among the pathogenic and likely pathogenic variants, autosomal recessive inheritance showed higher prevalence. About 35% (41/117) of cases showed genotype-phenotype correlation. Within the correlating cases, retinitis pigmentosa and Stargardt disease were predominant. Novel variants identified in RP, Stargardt, and LCA are reported here. CONCLUSION: This first-of-a-kind report on an Indian cohort contributes to existing knowledge and expansion of variant databases, presenting relevant and plausible novel variants. Phenotypic overlap and variability lead to a differential diagnosis and hence a clear genotype-phenotype correlation helps in precise clinical confirmation. The study also emphasizes the importance of genetic counselling and testing for personalized vision care in a tertiary eye hospital.
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Doenças Retinianas , Retinose Pigmentar , Humanos , Aconselhamento Genético , Estudos Retrospectivos , Genótipo , Mutação , Testes Genéticos , Doenças Retinianas/diagnóstico , Doenças Retinianas/epidemiologia , Doenças Retinianas/genética , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/epidemiologia , Retinose Pigmentar/genética , Linhagem , Estudos de Associação Genética , FenótipoRESUMO
PURPOSE: Inter-clinician variation could cause uncertainty in disease management. This is reported to be high in Retinopathy of Prematurity (ROP), a potentially blinding retinal disease affecting premature infants. Machine learning has the potential to quantify the differences in decision-making between ROP specialists and trainees and may improve the accuracy of diagnosis. METHODS: An anonymized survey of ROP images was administered to the expert(s) and the trainee(s) using a study-designed user interface. The results were analyzed for repeatability as well as to identify the level of agreement in the classification. "Ground truth" was prepared for each individual and a unique classifier was built for each individual using the same. The classifier allowed the identification of the most important features used by each individual. RESULTS: Correlation and disagreement between the expert and the trainees were visualized using the Dipstick™ diagram. Intra-clinician repeatability and reclassification statistics were assessed for all. The repeatability was 88.4% and 86.2% for two trainees and 92.1% for the expert, respectively. Commonly used features differed for the expert and the trainees and accounted for the variability. CONCLUSION: This novel, automated algorithm quantifies the differences using machine learning techniques. This will help audit the training process by objectively measuring differences between experts and trainees. TRANSLATIONAL RELEVANCE: Training for image-based ROP diagnosis can be more objectively performed using this novel, machine learning-based automated image analyzer and classifier.
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Retinopatia da Prematuridade , Recém-Nascido , Lactente , Humanos , Retinopatia da Prematuridade/diagnóstico , Recém-Nascido Prematuro , Aprendizado de Máquina , Fotografação , Variações Dependentes do Observador , Reprodutibilidade dos TestesRESUMO
Retinopathy of prematurity (ROP) is a significant cause of potentially preventable blindness in preterm infants worldwide. It is a disease caused by abnormal retinal vascularization that, if not detected and treated in a timely manner, can lead to retinal detachment and severe long term vision impairment. Neonatologists and pediatricians have an important role in the prevention, detection, and management of ROP. Geographic differences in the epidemiology of ROP have been seen globally over the last several decades because of regional differences in neonatal care. Our understanding of the pathophysiology, risk factors, prevention, screening, diagnosis, and treatment of ROP have also evolved over the years. New technological advances are now allowing for the incorporation of telemedicine and artificial intelligence in the management of ROP. In this comprehensive update, we provide a comprehensive review of pathophysiology, classification, diagnosis, global screening, and treatment of ROP. Key historical milestones as well as touching upon the very recent updates to the ROP classification system and technological advances in the field of artificial intelligence and ROP will also be discussed.
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Doenças do Prematuro , Retinopatia da Prematuridade , Inteligência Artificial , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Triagem Neonatal , Retinopatia da Prematuridade/diagnóstico , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/terapiaRESUMO
Retinopathy of prematurity (ROP) is the leading cause of preventable infant blindness in the world and predominantly affects babies who are born low birth weight and premature. India has the largest number of surviving preterm births born annually. ROP blindness can be largely prevented if there is a robust screening program which detects treatment requiring disease in time. ROP treatment must be provided within 48 h of reaching this threshold of treatment making it a relative emergency. During the severe acute respiratory syndrome-coronavirus disease 2019 pandemic in 2020 ROP screening was disrupted throughout the world due to lockdowns and restriction of movement of these infants, their families, specialists and healthcare workers. The Indian ROP Society issued guidelines for ROP screening and treatment in March 2020, which was aimed at preserving the chain-of-care despite the potential limitations and hazards during the (ongoing) pandemic. This preferred practice guideline is summarized in this manuscript.
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ABSTRACT: Retinopathy of prematurity (ROP) is the leading cause of preventable infant blindness in the world. India leads all nations with the highest number of premature infants born each year. Asia has the highest estimated incidence, where visual loss from ROP is over twice as high per million live births compared to established market economies. The problems of ROP management in these countries are compounded by a large cohort of babies who require screening, relatively few ROP specialists, and more recently medico-legal challenges. The authors share the Indian jurisprudence literature from the past decade relating to ROP, summarizing key clinical lessons learned from these legal judgments. The authors endeavor to enlist good clinical practices for various key steps involved in ROP care to help mitigate future litigations as well as protect the clinical interest of the infants who require ROP screening and treatment.
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Retinopatia da Prematuridade , Cegueira/epidemiologia , Cegueira/etiologia , Cegueira/prevenção & controle , Idade Gestacional , Humanos , Incidência , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Triagem Neonatal , Retinopatia da Prematuridade/diagnóstico , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/terapiaAssuntos
Retinopatia da Prematuridade , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Idade Gestacional , Humanos , Recém-Nascido , Injeções Intravítreas , Fotocoagulação a Laser , Lasers , Ranibizumab/uso terapêutico , Retinopatia da Prematuridade/diagnóstico , Retinopatia da Prematuridade/tratamento farmacológico , Retinopatia da Prematuridade/cirurgiaRESUMO
Purpose: To report the results of the survey for the role of anti-VEGF in the management of retinopathy of prematurity (ROP) among the members of Indian ROP (iROP) society. Methods: A questionnaire was designed in English using Google forms and its link was circulated to the members of the iROP society on their mobile numbers. The survey included questions pertaining to demographics, anti-VEGF agents, injection technique, post-injection follow-up, and documentation pertaining to their ROP practice. Anonymous responses were obtained and analyzed for individual questions. Results: 226 members of the society were contacted and 157 responded (69.4%) to the survey. 137 (87.2%) respondents used anti-VEGF in the management of ROP. Aggressive posterior ROP (APROP) was the most common indication (78, 52.7%). The procedure was carried out in the main operation room (102, 70.3%) simultaneously for both the eyes (97; 68%) under topical anesthesia (134; 86.4%) by most of the respondents. One-hundred thirteen (77.9%) respondents used half of the adult dose, irrespective of the agent used; however, more than half of them preferred bevacizumab (85, 54%). 53 (36.3%) respondents followed up infants as per disease severity rather than a fixed schedule while only 33 (23%) performed photo documentation. 151 (96.2%) respondents felt the need for guidelines regarding the usage of anti-VEGF in ROP. Conclusion: There is an increase in the trend towards the use of anti-VEGF in the management of severe ROP, particularly APROP. However, there are considerable variations among the ROP practitioners regarding the agent, dosage, follow-up schedule, and documentation, suggesting the need for uniform guidelines.