Circulating MicroRNAs as Biomarker for Vessel-Associated Retinal Diseases.

INTRODUCTION: Vessel-associated retinal diseases are a major cause of blindness and severe visual impairment. The identification of appropriate biomarkers is of great importance to better anticipate disease progression and establish more targeted treatment options. MicroRNAs (miRNAs) are short, single-stranded, noncoding ribonucleic acids that are involved in the posttranscriptional regulation of gene expression through hybridization with messenger RNA. The expression of certain miRNAs can be different in patients with pathological processes and can be used for the detection and differentiation of various diseases. In this study, we investigate to what extent previously in vitro identified miRNAs are present as cell-free circulating miRNAs in the serum and vitreous of human patients with and without vessel-associated retinal diseases. METHODS: Relative quantification by quantitative real-time polymerase chain reaction was used to analyze miRNA expression in patients with vessel-associated retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusion compared with control patients. RESULTS: In serum samples, miR-29a-3p and miR-192-5p showed increased expression in patients with neovascular AMD relative to control patients. Similarly, miR-335-5p, miR-192-5p, and miR-194-5p showed increased expression in serum from patients with proliferative DR. In vitreous samples, miR-100-5p was decreased in patients with proliferative DR. Differentially expressed miRNAs showed good diagnostic accuracy in receiver operating characteristic (ROC) and area under the ROC curve analysis. CONCLUSION: The miRNAs investigated in this study may have the potential to serve as biomarkers for vessel-associated retinal diseases. Combining multiple miRNAs may enhance the predictive power of the analysis.

[Ophthalmological Screening in Children and Adults with Intellectual Disability]. / Augenärztliches Screening für Menschen mit geistiger und Mehrfachbehinderung.

INTRODUCTION: Special Olympics Germany is the German association of the largest global movement to provide year-round sports training and athletic competition in a variety of Olympic-type sports for children and adults with intellectual and multiple disabilities. We offered all participants ophthalmological screening during the event in Offenburg, Baden-Württemberg, in 2017 as part of the health programme "Open Eyes - Better Vision". METHODS: A team of optometrists took medical histories, examined refraction status, visual acuity, colour vision and orthoptic status. Four experienced physicians in training and specialists from the Eye Centre, University of Freiburg, performed slit-lamp examinations, funduscopy and eye pressure measurements. Dilated funduscopy and OCT were also performed, as necessary. RESULTS: In total, we screened 166 persons (48% female = 80; 52% male = 86). The cover test was abnormal in about 45% (distant) and 47% (near) of patients, respectively. Six and 11% of patients, respectively, complained of double vision (9/156; 17/156; distant and near). Reduced colour vision with nine of nine tables (Colour Vision Testing Made Easy by Waggoner) was recorded in 8% of patients (11/143). We saw fundus abnormalities in 13% of patients (16/125). 41% of patients (48/118) needed a prescription of new glasses. 29% of patients (45/157) were hypersensitive to light. 10% of patients (16/160) had never been examined by an ophthalmologist. In 4% of patients (7/166) we recommended urgent consultation of an ophthalmologist (e.g. in case of corneal hydrops or elevated intraocular pressure). We discussed possible treatment (mainly dry eye) in 40% (66/166). DISCUSSION: People with intellectual disabilities do not necessarily and directly complain about new vision problems or general problems with the eyes. In addition, there may be limited access to ophthalmological care compared to people without mental disabilities. Due to the four percent of diagnoses requiring treatment and 53% of participants who do not have current refraction compensation, ophthalmological monitoring of the Special Olympics eye program "Opening Eyes - Better Vision" seems to be an efficient mean for improving healthcare in this vulnerable group.

Treated Cases of Retinopathy of Prematurity in Germany: 10-Year Data from the Retina.net Retinopathy of Prematurity Registry.

PURPOSE: To analyze changes in demographic parameters and retreatment patterns over a 10-year period in a clinical routine setting of infants with retinopathy of prematurity (ROP) requiring treatment documented in the German Retina.net ROP registry. DESIGN: Multicenter, noninterventional, observational registry study recruiting patients treated for ROP. SUBJECTS: A total of 692 eyes of 353 infants treated for ROP were documented in the Retina.net ROP registry over a 10-year period between 2011 and 2020. These cases cover about 15% of all infants treated for ROP in Germany. METHODS: The Retina.net ROP registry was established in 2012 to jointly collect information on infants treated for ROP. The database collects information on demographic parameters (gestational age [GA], birth weight, neonatal comorbidities) as well as treatment parameters (type of treatment, weight and age at treatment, and stage of ROP). A total of 19 centers contributed to the analysis. This is the 10-year analysis of data from 2011 to 2020, in which we focus on changes over time regarding the respective parameters. MAIN OUTCOME MEASURES: Changes over time in demographic parameters and treatment patterns for ROP in Germany. RESULTS: The overall incidence of treatment requiring ROP was 3.5% of all infants screened for ROP at participating centers. Gestational age, weight at birth, and weight at treatment remained stable over the 10-year period, whereas postmenstrual and postnatal age at treatment increased moderately but statistically significantly over the years. The most prevalent ROP severity stage at treatment was stage 3+ in zone II (76.6% of all treated eyes). Treatment patterns changed considerably from predominantly laser treatments in 2011 (75% of all treated eyes) to predominantly ranibizumab treatments in 2020 (60.9% of all treated eyes). The overall retreatment rate was 15.6%. Retreatment rates differed between initial treatment modalities (14.1% after laser coagulation, 12% after bevacizumab and 24.5% after ranibizumab). Treatment-associated systemic or ophthalmic complications were rare. CONCLUSIONS: This data analysis represents one of the largest documented cohorts of infants treated for ROP. The data on demographic parameters and treatment patterns provide useful information for further improvement of ROP management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Assessment of Retinopathy of Prematurity Regression and Reactivation Using an Artificial Intelligence-Based Vascular Severity Score.

Importance: One of the biggest challenges when using anti-vascular endothelial growth factor (VEGF) agents to treat retinopathy of prematurity (ROP) is the need to perform long-term follow-up examinations to identify eyes at risk of ROP reactivation requiring retreatment. Objective: To evaluate whether an artificial intelligence (AI)-based vascular severity score (VSS) can be used to analyze ROP regression and reactivation after anti-VEGF treatment and potentially identify eyes at risk of ROP reactivation requiring retreatment. Design, Setting, and Participants: This prognostic study was a secondary analysis of posterior pole fundus images collected during the multicenter, double-blind, investigator-initiated Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) randomized clinical trial, which compared 2 different doses of ranibizumab (0.12 mg vs 0.20 mg) for the treatment of ROP. The CARE-ROP trial screened and enrolled infants between September 5, 2014, and July 14, 2016. A total of 1046 wide-angle fundus images obtained from 19 infants at predefined study time points were analyzed. The analyses of VSS were performed between January 20, 2021, and November 18, 2022. Interventions: An AI-based algorithm assigned a VSS between 1 (normal) and 9 (most severe) to fundus images. Main Outcomes and Measures: Analysis of VSS in infants with ROP over time and VSS comparisons between the 2 treatment groups (0.12 mg vs 0.20 mg of ranibizumab) and between infants who did and did not receive retreatment for ROP reactivation. Results: Among 19 infants with ROP in the CARE-ROP randomized clinical trial, the median (range) postmenstrual age at first treatment was 36.4 (34.7-39.7) weeks; 10 infants (52.6%) were male, and 18 (94.7%) were White. The mean (SD) VSS was 6.7 (1.9) at baseline and significantly decreased to 2.7 (1.9) at week 1 (P < .001) and 2.9 (1.3) at week 4 (P < .001). The mean (SD) VSS of infants with ROP reactivation requiring retreatment was 6.5 (1.9) at the time of retreatment, which was significantly higher than the VSS at week 4 (P < .001). No significant difference was found in VSS between the 2 treatment groups, but the change in VSS between baseline and week 1 was higher for infants who later required retreatment (mean [SD], 7.8 [1.3] at baseline vs 1.7 [0.7] at week 1) vs infants who did not (mean [SD], 6.4 [1.9] at baseline vs 3.0 [2.0] at week 1). In eyes requiring retreatment, higher baseline VSS was correlated with earlier time of retreatment (Pearson r = -0.9997; P < .001). Conclusions and Relevance: In this study, VSS decreased after ranibizumab treatment, consistent with clinical disease regression. In cases of ROP reactivation requiring retreatment, VSS increased again to values comparable with baseline values. In addition, a greater change in VSS during the first week after initial treatment was found to be associated with a higher risk of later ROP reactivation, and high baseline VSS was correlated with earlier retreatment. These findings may have implications for monitoring ROP regression and reactivation after anti-VEGF treatment.

Ranibizumab in retinopathy of prematurity - one-year follow-up of ophthalmic outcomes and two-year follow-up of neurodevelopmental outcomes from the CARE-ROP study.

PURPOSE: The primary endpoint results from the comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity (CARE-ROP) core study identified ranibizumab as an effective treatment to control acute retinopathy of prematurity (ROP). This study reports the 1- and 2-year follow-up data focusing on long-term functional outcomes and safety. METHODS: The CARE-ROP trial compared 0.12 mg versus 0.20 mg ranibizumab in 20 infants with ROP in a multicentric, prospective, randomized, double-blind, controlled study design. Sixteen patients entered the follow-up period. An ophthalmologic assessment at one year postbaseline was acquired from all 16 patients and a neurodevelopmental assessment at two years postbaseline was acquired from 15 patients. RESULTS: Fifteen of 16 infants were able to fixate and follow moving objects at one year postbaseline treatment. One child progressed to stage 5 ROP bilaterally between the end of the core study and the 1-year follow-up (first seen at PMA 75 weeks). Mean spherical equivalents were -1.9 diopters (D) and -0.75 D in the 0.12 mg and the 0.20 mg treatment arms. Strabismus was present in seven and nystagmus in five out of 16 infants. Mental development scores were within normal limits in six out of ten patients with available data. No statistically significant difference was observed between the two treatment arms. CONCLUSION: Neurodevelopmental and functional ocular outcomes 1 and 2 years after treatment with ranibizumab are reassuring regarding long-term safety. Late reactivation of ROP, however, represents a challenge during the follow-up phase and it is of utmost importance that regular follow-ups are maintained.

[Use of artificial intelligence in screening for diabetic retinopathy at a tertiary diabetes center]. / Einsatz von künstlicher Intelligenz im Screening auf diabetische Retinopathie an einer diabetologischen Schwerpunktklinik.

BACKGROUND: In 2018, IDx-DR was approved as a method to determine the degree of diabetic retinopathy (DR) using artificial intelligence (AI) by the FDA. METHODS: We integrated IDx-DR into the consultation at a diabetology focus clinic and report the agreement between IDx-DR and fundoscopy as well as IDx-DR and ophthalmological image assessment and the influence of different camera systems. RESULTS: Adequate image quality in miosis was achieved more frequently with the Topcon camera (n = 456; NW400, Topcon Medical Systems, Oakland, NJ, USA) compared with the Zeiss camera (n = 47; Zeiss VISUCAM 500, Carl Zeiss Meditec AG, Jena, Germany). Overall, IDx-DR analysis in miosis was possible in approximately 60% of the patients. All patients in whom IDx-DR analysis in miosis was not possible could be assessed by fundoscopy with dilated pupils. Within the group of images that could be evaluated, there was agreement between IDx-DR and ophthalmic fundoscopy in approximately 55%, overestimation of severity by IDx-DR in approximately 40% and underestimation in approximately 4%. The sensitivity (specificity) for detecting severe retinopathy requiring treatment was 95.7% (89.1%) for cases with fundus images that could be evaluated and 65.2% (66.7%) when all cases were considered (including those without images in miosis which could be evaluated). The kappa coefficient of 0.334 (p < 0.001) shows sufficient agreement between IDx-DR and physician's image analysis based on the fundus photograph, considering all patients with IDx-DR analysis that could be evaluated. The comparison between IDx-DR and the physician's funduscopy under the same conditions shows a low agreement with a kappa value of 0.168 (p < 0.001). CONCLUSION: The present study shows the possibilities and limitations of AI-assisted DR screening. A major limitation is that sufficient images cannot be obtained in miosis in approximately 40% of patients. When sufficient images were available the IDx-DR and ophthalmological diagnosis matched in more than 50% of cases. Underestimation of severity by IDx-DR occurred only rarely. For integration into an ophthalmologist's practice, this system seems suitable. Without access to an ophthalmologist the high rate of insufficient images in miosis represents an important limitation.

Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity.

BACKGROUND/AIMS: Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights. METHODS: Data, including infants born at 24-30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6-14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions. RESULTS: ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6-14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%. CONCLUSIONS: DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24-30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.

Real-life medium term follow-up data for intravitreal dexamethasone implant in retinal vein occlusion.

Macular edema (ME) is the most frequent vision threatening consequence after retinal vein occlusion (RVO). In this study, we evaluate the effect of dexamethasone intravitreal implants (DII, Ozurdex) in a real-life cohort of 99 patients with ME due to RVO. All patients who received DII for ME following RVO between 2011 and 2016 at the University Eye Hospital Freiburg, Germany and who had fully accessible electronic medical records were eligible for this study. Most of the patients included in this study were not treatment-naïve: 61 eyes had received prior anti-VEGF drugs, 6 eyes had received intravitreal corticosteroids (triamcinolone) and 15 had been treated with both; 17 eyes were treatment-naïve. Mean follow-up was 312 ± 310 days. Mean visual acuity (VA) was maintained throughout the observation period (mean VA at baseline: 66.7 ± 23.5 letters; at last observation 64.9 ± 28.3). Central retinal thickness (CRT) decreased from 526 ± 179 µm at baseline to 431 ± 199 µm. Mean intraocular pressure (IOP) increased from 14.4 ± 3.1 mmHg at baseline to 17.1 ± 6.3 mmHg. Cataract surgery was performed in 22% of phakic eyes. DII was used as second-line treatment in the majority of cases in this cohort. The fact that mean VA remained unchanged while mean CRT decreased illustrates that morphologic improvement does not always translate into functional gain. Mean IOP was maintained within normal limits and cataract formation was as expected in this age group.

Individual Risk Prediction for Sight-Threatening Retinopathy of Prematurity Using Birth Characteristics.

Importance: To prevent blindness, repeated infant eye examinations are performed to detect severe retinopathy of prematurity (ROP), yet only a small fraction of those screened need treatment. Early individual risk stratification would improve screening timing and efficiency and potentially reduce the risk of blindness. Objectives: To create and validate an easy-to-use prediction model using only birth characteristics and to describe a continuous hazard function for ROP treatment. Design, Setting, and Participants: In this retrospective cohort study, Swedish National Patient Registry data from infants screened for ROP (born between January 1, 2007, and August 7, 2018) were analyzed with Poisson regression for time-varying data (postnatal age, gestational age [GA], sex, birth weight, and important interactions) to develop an individualized predictive model for ROP treatment (called DIGIROP-Birth [Digital ROP]). The model was validated internally and externally (in US and European cohorts) and compared with 4 published prediction models. Main Outcomes and Measures: The study outcome was ROP treatment. The measures were estimated momentary and cumulative risks, hazard ratios with 95% CIs, area under the receiver operating characteristic curve (hereinafter referred to as AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Among 7609 infants (54.6% boys; mean [SD] GA, 28.1 [2.1] weeks; mean [SD] birth weight, 1119 [353] g), 442 (5.8%) were treated for ROP, including 142 (40.1%) treated of 354 born at less than 24 gestational weeks. Irrespective of GA, the risk for receiving ROP treatment increased during postnatal weeks 8 through 12 and decreased thereafter. Validations of DIGIROP-Birth for 24 to 30 weeks' GA showed high predictive ability for the model overall (AUC, 0.90 [95% CI, 0.89-0.92] for internal validation, 0.94 [95% CI, 0.90-0.98] for temporal validation, 0.87 [95% CI, 0.84-0.89] for US external validation, and 0.90 [95% CI, 0.85-0.95] for European external validation) by calendar periods and by race/ethnicity. The sensitivity, specificity, PPV, and NPV were numerically at least as high as those obtained from CHOP-ROP (Children's Hospital of Philadelphia-ROP), OMA-ROP (Omaha-ROP), WINROP (weight, insulinlike growth factor 1, neonatal, ROP), and CO-ROP (Colorado-ROP), models requiring more complex postnatal data. Conclusions and Relevance: This study validated an individualized prediction model for infants born at 24 to 30 weeks' GA, enabling early risk prediction of ROP treatment based on birth characteristics data. Postnatal age rather than postmenstrual age was a better predictive variable for the temporal risk of ROP treatment. The model is an accessible online application that appears to be generalizable and to have at least as good test statistics as other models requiring longitudinal neonatal data not always readily available to ophthalmologists.