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).

Retinopathy of Prematurity: A Global Perspective and Recent Developments.

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.

Metallic intraocular foreign body as detected by magnetic resonance imaging without complications- A case report.

PURPOSE: To describe a case and present unique images of a metallic intraocular foreign body that was identified in a 12-year-old male patient who underwent routine magnetic resonance imaging (MRI) to assess neurodevelopmental delay. OBSERVATIONS: We present MRI and diagnostic imaging of a metallic intraocular foreign body in a young patient with no known history of trauma or reason for the existence of metal in the eye area. Computed tomography scan was performed to confirm the presence of the intraocular foreign body, followed by optical coherence tomography and electroretinogram to assess visual status. It was determined that no surgical intervention was currently required as no visual impairment or ocular toxicity was identified. The patient continues to be monitored. CONCLUSIONS AND IMPORTANCE: This case presentation highlights the novel imaging features of a metallic intraocular foreign body, unexpectedly detected with MRI.

Low-dose ranibizumab as primary treatment of posterior type I retinopathy of prematurity.

OBJECTIVE: The aim of this study was to evaluate the visual and structural outcomes of eyes that received ranibizumab as treatment for retinopathy of prematurity (ROP). METHODS: This was a retrospective case series of infants who received a 0.2 mg (0.02 mL) intravitreal injection of ranibizumab as the primary treatment for type 1 ROP. Outcome measures included regression or recurrence of ROP, complications of treatment, and assessment of visual acuity and refractive error. RESULTS: Forty-two eyes of 21 infants (13 male) were included. Mean gestational age and birth weight were 24.6 ± 1.3 weeks and 613 ± 91 g, respectively. Mean age at injection was 37.4 ± 2.2 weeks postmenstrual age, and mean follow-up period was 10.1 ± 7 months. Active neovascularization regressed rapidly, and anatomical outcomes were favourable in all eyes. Twelve eyes of 6 infants received supplemental laser photocoagulation at a mean post-menstrual age (PMA) of 72.0 ± 27.3 weeks when vascularization had not advanced beyond zone II. Visual acuity was measurable in 28 of 42 eyes. Mean visual acuity was 0.94 ± 0.36 logMAR. Mean spherical equivalent was +1.00. There were no ocular or systemic complications in these patients and no cicatricial complications were observed with no progression to stage 4 or 5 disease. CONCLUSIONS: A single intravitreal dose of 0.2 mg (0.02 mL) ranibizumab showed favourable anatomical and functional outcomes in eyes with type 1 ROP.

Computer-aided diagnosis of retinopathy in retinal fundus images of preterm infants via quantification of vascular tortuosity.

Retinopathy of prematurity (ROP), a disorder of the retina occurring in preterm infants, is the leading cause of preventable childhood blindness. An active phase of ROP that requires treatment is associated with the presence of plus disease, which is diagnosed clinically in a qualitative manner by visual assessment of the existence of a certain level of increase in the thickness and tortuosity of retinal vessels. The present study performs computer-aided diagnosis (CAD) of plus disease via quantitative measurement of tortuosity in retinal fundus images of preterm infants. Digital image processing techniques were developed for the detection of retinal vessels and measurement of their tortuosity. The total lengths of abnormally tortuous vessels in each quadrant and the entire image were then computed. A minimum-length diagnostic-decision-making criterion was developed to assess the diagnostic sensitivity and specificity of the values obtained. The area ([Formula: see text]) under the receiver operating characteristic curve was used to assess the overall diagnostic accuracy of the methods. Using a set of 19 retinal fundus images of preterm infants with plus disease and 91 without plus disease, the proposed methods provided an overall diagnostic accuracy of [Formula: see text]. Using the total length of all abnormally tortuous vessel segments in an image, our techniques are capable of CAD of plus disease with high accuracy without the need for manual selection of vessels to analyze. The proposed methods may be used in a clinical or teleophthalmological setting.

Timely implementation of a retinopathy of prematurity telemedicine system.

PURPOSE: To examine the feasibility of a retinopathy of prematurity (ROP) telemedicine evaluation system of providing timely feedback to a neonatal intensive care unit (NICU) with at-risk premature infants. METHODS: This was a prospective observational study of premature infants with birth weights of <1251 g in five NICUs in the United States. Infants scheduled for clinically indicated ROP evaluations underwent indirect ophthalmoscopic examinations and digital imaging on the same day. Imaging was performed by nonphysician retinal imagers. Times required were determined from obtaining digital images of both eyes to submission via web-based system to a secure server for grading by trained readers at a central reading center to sending back grading results to the clinical center. RESULTS: A total of 1,642 image sets of eyes of 292 infants were obtained, from 823 imaging sessions. The mean turnaround time from submission of image sets of both eyes to return of the grading results to the clinical center was 10.1 ± 11.3 hours (standard deviation), with a median of 12.0 hours (1st quartile, 0.9 hours; 3rd quartile, 16 hours). Overall, 95.5% of gradings (95% CI, 93.9%-96.7%) were returned within 24 hours. Subgroup analyses found, for image sets submitted to the reading center before 2 p.m. Eastern Standard Time, median time to report was 1.7 hours (1st quartile, 0.7 hours; 3rd quartile, 15.5 hours) compared with those submitted after 2pm (median, 14.1 hours; 1st quartile, 11.2, hours; 3rd quartile, 16.3 hours). CONCLUSIONS: An ROP telemedicine approach can provide timely feedback to the NICU regarding the detection of potentially serious ROP and thus referral to an ophthalmologist for examination and consideration of treatment.

Computer-aided diagnosis of plus disease via measurement of vessel thickness in retinal fundus images of preterm infants.

Changes in the characteristics of retinal vessels such as width and tortuosity can be signs of the presence of several diseases such retinopathy of prematurity (ROP) and diabetic retinopathy. Plus disease is an indicator of ROP which requires treatment and is signified by an increase in posterior venular width. In this work, we present image processing techniques for the detection, segmentation, tracking, and measurement of the width of the major temporal arcade (MTA), which is the thickest venular branch in the retina. Several image processing techniques have been employed, including the use of Gabor filters to detect the MTA, morphological image processing to obtain its skeleton, Canny's method to detect and select MTA vessel-edge candidates, least-squares fitting to interpolate the MTA edges, and geometrical procedures to measure the width of the MTA. The results, obtained using 110 retinal fundus images of preterm infants, indicate a statistically highly significant difference in MTA width of normal cases as compared to cases with plus disease (p<0.01). The results provide good accuracy in computer-aided diagnosis (CAD) of plus disease with an area under the receiver operating characteristic curve of 0.76. The proposed methods may be used in CAD of plus disease and timely treatment of ROP in a clinical or teleophthalmological setting.

Computer-aided diagnosis of plus disease in retinal fundus images of preterm infants via measurement of vessel tortuosity.

An increase in retinal vessel tortuosity can be indicative of the presence of various diseases including retinopathy of prematurity (ROP). Accurate detection and measurement of such changes could help in computer-aided diagnosis of plus disease, which warrants treatment of ROP. We present image processing methods for detection and segmentation of retinal vessels, quantification of vessel tortuosity, and diagnostic-decision-making criteria that incorporate the clinical definition of plus-diagnosis. The obtained results using 110 retinal fundus images of preterm infants (91 without plus and 19 with plus) provide high sensitivity = 0.89 (17/19) and excellent specificity = 0.95 (86/91) in the diagnosis of plus disease.

Quantification of the changes in the openness of the major temporal arcade in retinal fundus images of preterm infants with plus disease.

PURPOSE: We tested the hypothesis that the openness of the major temporal arcade (MTA) changes in the presence of plus disease, by quantification via parabolic modeling of the MTA, as well as measurement of an arcade angle for comparative analysis. Such analysis could assist in the detection and treatment of progressive retinopathy of prematurity. METHODS: Digital image processing techniques were applied for the detection and modeling of the MTA via a graphical user interface (GUI) to quantify the openness of the MTA. An arcade angle measure, based on a previously proposed method, also was obtained via the GUI for comparative analysis. The statistical significance of the differences between the plus and no-plus cases for each parameter was analyzed using the P value. The area (Az) under the receiver operating characteristic curve was used to assess the diagnostic performance of each feature. RESULTS: The temporal arcade angle measure and the openness parameter of the parabolic model were used to perform discrimination of plus versus no-plus cases. Using a set of 19 cases with plus and 91 with no plus disease, Az=0.70 was obtained using the results of dual-parabolic modeling in screening for plus disease. The arcade angle measure provided comparable results with Az=0.73. CONCLUSIONS: Using our proposed image analysis techniques and software, this study demonstrates, for the first time to our knowledge, that the openness of the MTA decreases in the presence of plus disease.

Assessment of vessel tortuosity in retinal images of preterm infants.

Diagnosis of plus disease is crucial for timely treatment and management of retinopathy of prematurity. An indicator of the presence of plus disease is an increase in the tortuosity of blood vessels in the retina. In this work, we propose a new angle-variation-based measure for quantification of tortuosity in retinal fundus images of preterm infants. The methods include the use of Gabor filters to detect vessels as well as to obtain their orientation at each pixel. Morphological image processing methods are used to obtain a skeleton image of the vessels for measurement of tortuosity. Out of 11 vessel segments, marked by an expert ophthalmologist as showing high levels of tortuosity due to plus disease, all were correctly identified using the proposed methods.

The challenge of screening for retinopathy of prematurity.

Screening for retinopathy of prematurity (ROP) and the optimum treatment of sight-threatening disease requires detailed understanding of the infants at risk and timely identification. Despite a plethora of guidelines, not all populations and situations are adequately covered, so that what should be preventable visual disability still occurs. This article considers the design of screening guidelines and the possibility of a global guideline, although in certain parts of the world manpower for ROP screening is not available. Algorithms linked to the increase in weight of preterm infants over time may refine the number of babies needing to undergo treatment.

Computer-aided diagnosis of proliferative diabetic retinopathy via modeling of the major temporal arcade in retinal fundus images.

Monitoring the openness of the major temporal arcade (MTA) and how it changes over time could facilitate diagnosis and treatment of proliferative diabetic retinopathy (PDR). We present methods for user-guided semiautomated modeling and measurement of the openness of the MTA based on Gabor filters for the detection of retinal vessels, morphological image processing, and a form of the generalized Hough transform for the detection of parabolas. The methods, implemented via a graphical user interface, were tested with retinal fundus images of 11 normal individuals and 11 patients with PDR in the present pilot study on potential clinical application. A method of arcade angle measurement was used for comparative analysis. The results using the openness parameters of single- and dual-parabolic models as well as the arcade angle measurements indicate areas under the receiver operating characteristics of A z = 0.87, 0.82, and 0.80, respectively. The proposed methods are expected to facilitate quantitative analysis of the architecture of the MTA, as well as assist in detection and diagnosis of PDR.

Are we there yet? Bevacizumab therapy for retinopathy of prematurity.

The publication of the BEAT-ROP study of bevacizumab (Avastin) treatment for Zone I and II retinopathy of prematurity (ROP) has raised hopes that there might now be a simpler, cheaper and more effective treatment than laser therapy, the current standard of care. However, we would urge caution at this point in time. We review the scientific background to the use of intravitreal anti-vascular endothelial growth factor for ROP, highlight a number of design issues in the BEAT-ROP study and problems with interpretation of the results. For example, no visual outcomes were reported and the study was underpowered to assess longer term safety. Intravitreal bevacizumab leaks into the systemic circulation in animals and adult humans and there are real concerns of potential harm to the developing preterm infant because vascular growth factors play a critical role in organogenesis. We conclude that bevacizumab should be reserved for exceptional circumstances and compassionate use pending further studies. Laser remains the proven effective therapy for first line treatment of all forms of ROP with little systemic morbidity. Neonatology and ophthalmology have an impressive record of conducting collaborative multicentre studies and we urgently need further rigorously designed, adequately powered randomised trials of anti-VEGF agents that evaluate visual outcomes as well as short and long term ocular and systemic safety.

Digital image analysis in retinopathy of prematurity: a comparison of vessel selection methods.

PURPOSE: To evaluate vessel selection methods to distinguish between eyes with and without retinopathy of prematurity (ROP) and between different stages of ROP when quantifying the associated vessel changes in width and tortuosity semiautomatically from digital retinal images. METHODS: Color digital images from 75 infants screened for ROP were cropped to a standardized diameter of 240 pixels and evaluated by semiautomated vessel analysis software, Computer-Aided Image Analysis of the Retina (CAIAR), to measure retinal vessel width and tortuosity. Two methods of vessel selection were used: (1) clinical observer selecting the most prominent arteriole or venule in each retinal quadrant (4-vessel analysis) and then separately the 4 most prominent arterioles and venules from each quadrant (8-vessel analysis); (2) CAIAR selecting, regardless of retinal quadrant, the 4 widest or most tortuous arterioles or venules. Selected vessels were measured by CAIAR for tortuosity and width. RESULTS: When comparing ROP stages, whether observer or CAIAR selected and whether 4 or 8 vessels were analyzed, we found that arteriolar tortuosity was significantly greater with advancing ROP stage for stage 0 versus stage 2; stage 0 or 1 versus stage 3; stages 1+2 combined versus stage 3; and stage 0 versus 1+2+3 combined (P < 0.01). Venular tortuosity was significantly greater with advancing ROP stage for stage 0 versus stage 3 and stage 0 versus stages 1 and 2+3 combined (P < 0.01). Width parameters did not help us to distinguish between stages. CONCLUSIONS: Distinguishing between arterioles and venules is not necessary to differentiate stage 0 ROP from stage 2 or 3 ROP when one is using CAIAR. Tortuosity shows more promise than width at providing a reliable vessel parameter for distinguishing between eyes without and with ROP.

Computer-aided diagnosis of proliferative diabetic retinopathy.

Monitoring the openness of the major temporal arcade (MTA) and how it changes over time could facilitate improved diagnosis and timely treatment of proliferative diabetic retinopathy (PDR). We present methods for user-guided modeling and measurement of the openness of the MTA based on a form of the generalized Hough transform for the detection of parabolas, and to compare it with a method of arcade angle measurement. The methods, implemented via a graphical user interface, were tested with retinal fundus images of 10 normal individuals and 15 patients with PDR. The results using the openness parameters of single- and dual-parabolic models as well as the arcade angle measurements indicate areas under the receiver operating characteristics of A(z)= 0.94, 0.87, and 0.84, respectively. The proposed methods should facilitate improved quantitative analysis of the architecture of the MTA, as well as assist in detection, diagnosis, and improved treatment of PDR.

Detection of the optic nerve head in fundus images of the retina with Gabor filters and phase portrait analysis.

We propose a method using Gabor filters and phase portraits to automatically locate the optic nerve head (ONH) in fundus images of the retina. Because the center of the ONH is at or near the focal point of convergence of the retinal vessels, the method includes detection of the vessels using Gabor filters, detection of peaks in the node map obtained via phase portrait analysis, and an intensity-based condition. The method was tested on 40 images from the Digital Retinal Images for Vessel Extraction (DRIVE) database and 81 images from the Structured Analysis of the Retina (STARE) database. An ophthalmologist independently marked the center of the ONH for evaluation of the results. The evaluation of the results includes free-response receiver operating characteristics (FROC) and a measure of distance between the manually marked and detected centers. With the DRIVE database, the centers of the ONH were detected with an average distance of 0.36 mm (18 pixels) to the corresponding centers marked by the ophthalmologist. FROC analysis indicated a sensitivity of 100% at 2.7 false positives per image. With the STARE database, FROC analysis indicated a sensitivity of 88.9% at 4.6 false positives per image.

Detection of the optic nerve head in fundus images of the retina using the Hough transform for circles.

Detection of the optic nerve head (ONH) is a key preprocessing component in algorithms for the automatic extraction of the anatomical structures of the retina. We propose a method to automatically locate the ONH in fundus images of the retina. The method includes edge detection using the Sobel operators and detection of circles using the Hough transform. The Hough transform assists in the detection of the center and radius of a circle that approximates the margin of the ONH. Forty images of the retina from the Digital Retinal Images for Vessel Extraction (DRIVE) dataset were used to test the performance of the proposed method. The center and boundary of the ONH were independently marked by an ophthalmologist for evaluation. Free-response receiver operating characteristics (FROC) analysis as well as measures of distance and overlap were used to evaluate the performance of the proposed method. The centers of the ONH were detected with an average distance of 0.36 mm to the corresponding centers marked by the ophthalmologist; the detected circles had an average overlap of 0.73 with the boundaries of the ONH drawn by the ophthalmologist. FROC analysis indicated a sensitivity of detection of 92.5% at 8.9 false-positives per image. With an intensity-based criterion for the selection of the circle and a limit of 40 pixels (0.8 mm) on the distance between the center of the detected circle and the manually identified center of the ONH, a successful detection rate of 90% was obtained with the DRIVE dataset.

Computerized analysis of retinal vessel width and tortuosity in premature infants.

PURPOSE: To determine, with novel software, the feasibility of measuring the tortuosity and width of retinal veins and arteries from digital retinal images of infants at risk of retinopathy of prematurity (ROP). METHODS: The Computer-Aided Image Analysis of the Retina (CAIAR) program was developed to enable semiautomatic detection of retinal vasculature and measurement of vessel tortuosity and width from digital images. CAIAR was tested for accuracy and reproducibility of tortuosity and width measurements by using computer-generated vessel-like lines of known frequency, amplitude, and width. CAIAR was then tested by using clinical digital retinal images for correlation of vessel tortuosity and width readings compared with expert ophthalmologist grading. RESULTS: When applied to 16 computer-generated sinusoidal vessels, the tortuosity measured by CAIAR correlated very well with the known values. Width measures also increased as expected. When the CAIAR readings were compared with five expert ophthalmologists' grading of 75 vessels on 10 retinal images, moderate correlation was found in 10 of the 14 tortuosity output calculations (Spearman rho = 0.618-0.673). Width was less well correlated (rho = 0.415). CONCLUSIONS: The measures of tortuosity and width in CAIAR were validated using sequential model vessel analysis. On comparison of CAIAR output with assessments made by expert ophthalmologists, CAIAR correlates moderately with tortuosity grades, but less well with width grades. CAIAR offers the opportunity to develop an automated image analysis system for detecting the vascular changes at the posterior pole, which are becoming increasingly important in diagnosing treatable ROP.