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.

Potential selection bias in candidates for stereotactic radiotherapy for neovascular AMD.

PURPOSE: Stereotactic radiotherapy (SRT, IRay) was able to reduce the need for intravitreal injections of anti-VEGF (IVI) in patients with neovascular AMD (nAMD) in a phase II randomized clinical trial. Certain morphologic characteristics, such as lesion size < 4 mm2 or lack of fibrosis, were associated with a better response. The purpose of this cross-sectional study was to investigate eligibility for SRT in a clinical routine setting and to compare clinical features of eligible and non-eligible patients. METHODS: Cross-sectional study of 468 patients treated for nAMD in one study center within a period of 4 months. Clinical features, such as visual acuity or number of IVI since diagnosis and within 6/12 months, as well as the presence for exclusion criteria for SRT were analyzed. Exclusion criteria were sub-divided into lesion-associated (relevant fibrosis, lesion size > 4 mm2, PE tear), ocular comorbidity (e.g., macular comorbidity, vascular disease) and systemic comorbidity (e.g., dementia or tremor). RESULTS: Exclusion criteria were met by 255 patients (54.5%). Exclusion was most dominantly associated with lesion-associated criteria (80.0%) and less often with ocular (20.8%) or systemic (9.4%) comorbidity. A total of 213 patients (45.5%) fulfilled eligibility criteria. Eligible patients had a better VA at time of analysis (0.36 vs. 0.56 logMAR, p < 0.0001) and at baseline (0.38 vs. 0.56 logMAR, p < 0.0001) compared to non-eligible patients. The numbers of previous intravitreal injections since diagnosis in strictly PRN-treated patients served as a surrogate marker for lesion activity and was comparable within the last 6/12 months. Non-eligible patients had a higher number of different anti-VEGF drugs (1.8 vs. 1.6, p = 0.038). CONCLUSIONS: SRT in addition to anti-VEGF can be an option in every second patient with nAMD. Due to morphological exclusion criteria, patients eligible for SRT had a better VA and a better clinical response compared to non-eligible patients.

Keratoconjunctivitis as a Single Entity in X-linked Agammaglobulinemia?

PURPOSE: To report a case of a male patient with a severe corneal and conjunctival immunopathy likely caused by an X-linked agammaglobulinemia. METHODS: A clinical case report with observation results from 2001-2021. RESULTS: A severe corneal immunopathy of both eyes is reported in a retrospective long-term observation of nearly twenty years in a 32-year-old male patient with X-linked agammaglobulinemia (XLA). A chronic progressive corneal scarring with a loss of visual acuity and typical symptoms of a phlyctenular keratoconjunctivitis were observed. CONCLUSION: Whereas steroid eye drops like dexamethasone could control the symptoms and the corneal scarring progression as short time therapy options, ciclosporin A eye drops showed problems in therapy adherence in long-time use. Antibiotic eye drops supported the anti-inflammatory therapy effects, but no typical pathogen was detected. Antineovascular subconjunctival application did not show any relevant effect in one-time use. Artificial tears were needed as basic therapy.

[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.

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.

[Extraction of features from clinical routine data using text mining]. / Merkmalsextraktion aus klinischen Routinedaten mittels Text-Mining.

BACKGROUND: Anti-VEGF drugs are currently used to treat macular diseases. This has led to a wealth of additional data, which could help understand and predict treatment courses; however, this information is usually only available in free text form. OBJECTIVE: A retrospective study was designed to analyze how far interpretable information can be obtained from clinical texts by automated extraction. The aim was to assess the suitability of a text mining method that was customized for this purpose. MATERIAL AND METHODS: Data on 3683 patients were available, including 40,485 discharge letters. Some of the data of interest, e.g. visual acuity (VA), intraocular pressure (IOP) and accompanying diagnoses, were not only recorded textually but also entered in a database and could thus serve as a gold standard for text analysis. The text was analyzed using the Averbis Health Discovery text mining platform. To optimize the extraction task, rule knowledge and a German language technical vocabulary linked to the international medical terminology standard systematized nomenclature of medicine (SNOMED CT) was manually added. RESULTS: The correspondence between extracted data and the structured database entries is described by the F1 value. There was agreement of 94.7% for VA, 98.3% for IOP and 94.7% for the accompanying diagnoses. Manual analysis of noncorresponding cases showed that in 50% text content did not match the database content for various reasons. After an adjustment, F1 values 1-3% above the previously determined values were obtained. CONCLUSION: Text mining procedures are very well suited for the considered discharge letter corpus and the problem described in order to extract contents from clinical texts in a structured manner for further evaluation.

Anti-VEGF injection frequency correlates with visual acuity outcomes in pro re nata neovascular AMD treatment.

Clinical trials report substantial gains in visual acuity (VA) for eyes treated with intravitreal anti-VEGF for neovascular AMD (nAMD). In clinical reality, VA outcomes are more variable. Here we investigate pro-re nata treatment frequencies and VA in a real-life cohort of 1382 eyes (1048 patients). Patients with nAMD and one year complete follow-up treated with pro-re nata anti-VEGF between 2009 and 2016 were included. Injection frequency and VA was analyzed clustered by year of first treatment. Baseline parameters were compared between years. Median injection frequency in the first year was 5 with an IQR (interquartile range) of 5 for patients treated in 2009 and 8 with an IQR of 3 for patients treated from 2012 onwards. Median VA outcomes at one year were -5 to ±0 letters for patients treated between 2009 and 2013 and ±0 to +2 letters for patients treated from 2013 onwards. This cohort comprises all severities and subtypes of nAMD. 39% of patients had baseline VA outside the range for the MARINA or ANCHOR clinical trials. Higher treatment frequency was associated with improved VA in our real-life nAMD cohort. With adequate injection frequency, almost 90% of eyes had stable or improved VA over one year. Median VA gains, however, were lower compared to clinical trials. This may be due to a wider range of baseline characteristics in real-life cohorts.

OCT Angiography of the Choriocapillaris in Central Serous Chorioretinopathy: A Quantitative Subgroup Analysis.

INTRODUCTION: To quantify optical coherence tomography angiography (OCTA) signal changes at the level of the choriocapillaris (CC) in patients with different stages of central serous chorioretinopathy (CSC) and to explore any correlation between subretinal fluid (SRF) and retinal pigment epithelium (RPE) alterations and the OCTA CC signal. METHODS: One hundred one CSC eyes and 42 healthy control eyes were included in this retrospective study. CSC patients were allocated into four groups: acute, non-resolving, chronic atrophic and inactive CSC. CC OCTA images (AngioPlex®, Zeiss) were automatically quantified using an image-processing algorithm. Spatial correlation analysis of OCTA signals was performed by overlapping macular edema heatmaps and fundus autofluorescence images with corresponding OCTA images. RESULTS: Active CSC subgroups demonstrated significantly more increased and decreased flow pixels in the CC compared with controls (p < 0.0001). No significant OCTA changes were seen within the active CSC groups or between the inactive and healthy subgroup. Spatial correlation analysis revealed a decreased OCTA signal in the SRF area and an increased signal outside the SRF area in acute CSC. Areas of RPE atrophy co-localized with areas of increased choriocapillaris OCTA signal, while areas with RPE alterations exhibited a normal signal compared with unaffected RPE. CONCLUSION: The decreased OCTA signal in the area of SRF in acute CSC could be evidence of localized CC hypoperfusion or due to shadowing artifacts. The missing CC OCTA changes in altered RPE adjacent to atrophy argues against CC injury. Studies with higher resolution and optimized image acquisition are warranted to further validate our findings.

Increased expression of angiogenic and inflammatory proteins in the vitreous of patients with ischemic central retinal vein occlusion.

BACKGROUND: Central retinal vein occlusion (CRVO) is a common disease characterized by a disrupted retinal blood supply and a high risk of subsequent vision loss due to retinal edema and neovascular disease. This study was designed to assess the concentrations of selected signaling proteins in the vitreous and blood of patients with ischemic CRVO. METHODS: Vitreous and blood samples were collected from patients undergoing surgery for ischemic CRVO (radial optic neurotomy (RON), n = 13), epiretinal gliosis or macular hole (control group, n = 13). Concentrations of 40 different proteins were determined by an ELISA-type antibody microarray. RESULTS: Expression of proteins enriched in the vitreous (CCL2, IGFBP2, MMP10, HGF, TNFRSF11B (OPG)) was localized by immunohistochemistry in eyes of patients with severe ischemic CRVO followed by secondary glaucoma. Vitreal expression levels were higher in CRVO patients than in the control group (CRVO / control; p < 0.05) for ADIPOQ (13.6), ANGPT2 (20.5), CCL2 (MCP1) (3.2), HGF (4.7), IFNG (13.9), IGFBP1 (14.7), IGFBP2 (1.8), IGFBP3 (4.1), IGFBP4 (1.7), IL6 (10.8), LEP (3.4), MMP3 (4.3), MMP9 (3.6), MMP10 (5.4), PPBP (CXCL7 or NAP2) (11.8), TIMP4 (3.8), and VEGFA (85.3). In CRVO patients, vitreal levels of CCL2 (4.2), HGF (23.3), IGFBP2 (1.23), MMP10 (2.47), TNFRSF11B (2.96), and VEGFA (29.2) were higher than the blood levels (vitreous / blood, p < 0.05). Expression of CCL2, IGFBP2, MMP10, HGF, and TNFRSF11B was preferentially localized to the retina and the retinal pigment epithelium (RPE). CONCLUSION: Proteins related to hypoxia, angiogenesis, and inflammation were significantly elevated in the vitreous of CRVO patients. Moreover, some markers known to indicate atherosclerosis may be related to a basic vascular disease underlying RVO. This would imply that local therapeutic targeting might not be sufficient for a long term therapy in a systemic disease but hypothetically reduce local changes as an initial therapeutic approach.

Levels of VEGF but not VEGF(165b) are increased in the vitreous of patients with retinal vein occlusion.

PURPOSE: To determine the concentration of the pro-angiogenic vascular endothelial growth factor VEGF(165) (VEGF) and the anti-angiogenic VEGF(165b) in vitreous samples of patients with branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) in comparison to patients without retinal occlusive disease. DESIGN: Experimental laboratory investigation. METHODS: Vitreous samples were collected from patients undergoing surgery for arteriovenous dissection after BRVO, radial optic neurotomy after CRVO in the occlusion group, or macular pucker or macular hole in the control group. Concentrations of VEGF and VEGF(165b) were determined by ELISA and an ELISA-type antibody microarray. RESULTS: Average vitreal concentration of VEGF was 8.6 ng/mL in the CRVO group and 2.0 ng/mL in the BRVO group as compared to 0.26 ng/mL in the control group. Average vitreal concentration of VEGF(165b) was 27 pg/mL in the CRVO group, 42 pg/mL in the BRVO group, and 49 pg/mL in the control group. In patients with CRVO and BRVO, the angiogenic balance was shifted towards angiogenic stimulation. CONCLUSION: The severity of RVO from BRVO to CRVO correlates with an increase of VEGF and the decrease of VEGF(165b), indicating a pro-angiogenic shift. Altering the ratio of VEGF(165b)/VEGF(165) might be a feasible approach for treating retinal occlusive diseases.