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Purpose To evaluate the effectiveness and safety of Selective Laser Trabeculoplasty (SLT) with the SLT mode of the VISULAS® green laser in patients with primary open-angle glaucoma (POAG). Methods This prospective, interventional multicenter clinical investigation included patients with POAG who either needed a treatment escalation because the individual intraocular pressure (IOP) target was not met or treatment initiation and had an IOP ≥ 17 mmHg at baseline in the study eye. The study was conducted in five research centers across Germany. Approximately 100 laser applications were delivered to 360° of the trabecular meshwork. Glaucoma medications were not modified during the 3-month follow-up to allow evaluation of the sole effect of VISULAS® green with SLT. Efficacy outcomes were postoperatively absolute and relative IOP changes at 1 and 3 months. Safety outcomes analyzed the rate of intra- and postoperative adverse events. Results Thirty-four eyes of 34 POAG patients were included. The overall mean number of preoperative glaucoma medications was 2.2 ± 1.4 in 29 treated eyes, 5 eyes were treatment naïve. Mean baseline IOP (mmHg) was 21.0 ± 2.69 and was reduced by − 3.53 ± 3.34 [95% CI − 4.61; − 2.45] and − 3.59 ± 3.41 [95% CI − 4.64; − 2.53] at the 1- and 3-month follow-up, respectively (p p Conclusions SLT performed with the VISULAS® green laser achieved clinically significant additional IOP reductions in medically treated as well as in treatment naïve eyes with POAG and there were no relevant safety issues. The results are comparable to other reported SLT studies.

Zusammenfassung Hintergrund Zahlreiche Studien haben eine mangelnde Therapieadhärenz als wichtigen Faktor identifiziert, der einer notwendigen Anzahl von Anti-VEGF-Behandlungen und somit einem besseren funktionellen Ergebnis entgegensteht. Fragestellung Der Beitrag diskutiert konkrete Maßnahmen, die das Risiko einer zu späten oder zu seltenen intravitrealen operativen Medikamenteneingabe (IVOM) im Sinne einer Unterbehandlung verringern. Material und Methode Im Rahmen einer Expertenrunde wurden relevante Parameter der Therapieadhärenz und Variablen identifiziert. Sinnvolle Abläufe strukturiert und organisatorischen Bereichen zugeordnet. Ergebnisse Die Zusammenstellung identifizierter Einflussfaktoren und sinnvoller Maßnahmen (Organisation, Transport, Kommunikation, Motivation) ermöglicht es Behandlern, die eigene Umsetzung der IVOM-Therapie in unterschiedlichen Bereichen zu optimieren. Regelmäßige Monitoring-Maßnahmen können den Umfang von Therapiepausen und -abbrüchen identifizieren. Für konkrete Kennzahlen (IVOM pro Zeitintervall, längstes Pausenintervall, Mindestabdeckung pro Zeit, Verzögerungen) wurde eine Auswirkung auf die Entwicklung der Sehfunktion nachgewiesen. Organisatorische Maßnahmen, die Schulung von Team und Zuweisern, die redundante und iterative Informationsweitergabe an Patienten haben sich in der Erfahrung von Experten bewährt. Die feste Integration dieser Prozesse in bestehende Strukturen wird durch die Arbeit mit Checklisten erleichtert. Schlussfolgerungen Eine Optimierung der Abläufe ist oft möglich, um die Adhärenz und somit die funktionellen Ergebnisse zu verbessern. Bisher fehlen jedoch noch interventionelle Studien, wie Adhärenz und Persistenz im deutschen Behandlungssetting erhöht werden.

Background:During the first wave of the COVID-19 pandemic, the need of treatment of urgent ophthalmological diseases and the possible risk of a SARS-CoV-2 infection had to be weighed against each other. In this questionnaire study, we aimed to analyze potential barriers and patients’ health beliefs during and after the lockdown early 2020 in a tertiary referral center in Kiel, Germany.Methods:Patients admitted for the treatment of urgent ophthalmic diseases between March 1st, 2020, and June 3rd, 2020, were asked to participate in a questionnaire study. After informed consent was obtained, patients were interviewed using a standardized questionnaire which addressed aspects of their medical history, their health beliefs concerning the COVID-19 pandemic and barriers on their way to the treatment center. The study group was subdivided into two subgroups, depending on the occurrence of their symptoms, before and after the lockdown was ended on April 20th, 2020.Results:Ninety-three patients were included, 43 in subgroup A (before April 20th) and 50 in subgroup B (April 20th or later). Retinal disorders were most common (approximately 60%), with retinal detachments being the most singular reason for admission. Only 8 patients (8.6%) experienced a delay between their decision to visit a doctor until the actual examination. Every fourth patient was afraid of a COVID-19 infection, and expected a higher likelihood for an infection at the hospital. Patients with comorbidities tended to be more likely to be afraid of an infection (correlation coefficient 0.183, p=0.0785) and were significantly more likely to be concerned about problems with organizing follow-up care (corr. coefficient 0.222, p=0.0328). Higher age was negatively correlated with fear of infection (corr. coefficient -0.218, p-value 0.034).Conclusion:In this questionnaire study, only a minority of patients indicated a delay in treatment, regardless of whether symptoms occurred before or after the lockdown before April 20th. While patients with comorbidities were more concerned about infection and problems during follow-up care, patients of higher age – who have a higher mortality – were less afraid. Protection of high-risk groups should be prioritized during the SARS-CoV-2 pandemic.Trial registration:The study was registered as DRKS00021630 at the DRKS (Deutsches Register Klinischer Studien) before the conduction of the study on May 5th, 2020.

The treatment of macular diseases requires frequent monitoring by optical coherence tomography (OCT). Home monitoring would reduce the burden of frequent clinical visits and increase therapy adherence. In a pilot study with 47 patients having different macular diseases we tested a proprietary self-examination low-cost full-field OCT (SELFF-OCT). For comparison, scans with a standard clinical spectral domain OCT were taken. Data was graded by a reading center. Patients were able to successfully acquire images that were clinically gradable for 85% of the included eyes. The sensitivity and specificity for an anti-VEGF treatment decision based on the SELFF-OCT was 0.94 and 0.95, respectively.

Purpose The treatment guidelines for many macular diseases rely on frequent monitoring with optical coherence tomography (OCT). However, the burden of frequent disease control leads to low therapy adherence in real life. OCT home monitoring would address this issue but requires an inexpensive and self-operable device. With self-examination low-cost full-field OCT (SELFF-OCT), our group has introduced a novel technology that may fulfill both requirements. In this pilot study, we report the initial experiences with a clinical prototype. Methods Fifty-one patients with different macular diseases were recruited in a cross-sectional study. The most common diseases were age-related macular degeneration (AMD; 39/51), diabetic macular edema (DME; 6/51), and retinal vein occlusion (RVO; 3/51). Patients received a short training in device usage and then performed multiple self-scans with the SELFF-OCT device. For comparison, scans with a standard clinical spectral domain (SD-)OCT were taken. Results After a brief training, 77% of the patients were able to successfully acquire images that were clinically gradable. No significant influence on success could be found for age (p = 0.08) or BCVA (p = 0.97). Relevant disease biomarkers in the most common retinal diseases could be detected. Conclusions SELFF-OCT was used successfully for retinal self-examination and in the future could be used for retinal home monitoring. Future improvements in technology are expected to improve success rates and image quality. Trial registration The Trial was registered in the German Trial Register under the number DRKS00013755 on 14.03.2018.

Current algorithms for automated computer interpretation of optical coherence tomography (OCT) imaging of patients suffering from neovascular age-related macular degeneration (AMD) mostly rely on fluid detection. However, fluid detection itself and correct interpretation of the fluid currently limits diagnostic accuracy. We therefore performed a detailed analysis of the requirements that would have to be met for fluid detection approaches. We further investigated if monitoring retinal volume would be a viable alternative to detect disease activity. Retrospective analysis and manual grading of 764 OCT volume scans of 44 patients with exudative AMD treated with intravitreal anti-VEGF injections at a pro-re-nata (PRN) treatment regimen for at least 24 months. Detection of subretinal fluid (SRF) or intraretinal fluid (IRF) alone is not sufficient for disease detection. A combination of SRF and IRF can detect disease activity with a sensitivity of 98.6% and a specificity of 82%. With further characterization of IRF into exudative and degenerative cysts, specificity can be increased to 100%. However, correct characterization is currently not achieved by published fluid detection approaches. Change of macular retinal volume (MRV) can depict disease activity with sensitivity of 88.4% and specificity of 89.6%. Combination with the detection of SRF can further improve diagnostic accuracy to a specificity of 93.3% and sensitivity of 93.9% without relying on IRF or IRF characterization. Fluid detection without further characterization is not sufficient for AMD monitoring. Either further distinction between exudative and degenerative cysts is necessary, or other activity markers have to be taken into account. MRV offers good potential to fill this diagnostic gap and might become an important monitoring marker.

The PONS study was conceived to analyze the extent of nonpersistence (NP) and nonadherence (NA) in the treatment of patients with neovascular age-related macular degeneration in everyday clinical practice in Germany. Further objectives were to identify factors that can affect NP and NA and to analyze clinical outcomes under everyday conditions.Nonpersistence (no contact with doctor for at least 3 months) and NA (no treatment or follow-up for at least 6 weeks) as well as clinical data were analyzed up to 24 months retrospectively and 12 months prospectively in 480 patients with neovascular age-related macular degeneration in 23 treatment centers. Patients were interviewed for factors possibly affecting NP and NA.One third of patients fulfilled criteria of NA in the first 3 months and two thirds after 6 months. The NP was 18.8% after 12 months. Treatment exclusively at one center, a higher number of patients with neovascular age-related macular degeneration at the treating center, and fixed appointments were associated with a lower risk for NP. An initial gain in visual acuity after upload was not preserved after 12 months (mean change -0.5 Early Treatment Diabetic Retinopathy Study letters). Whereas visual acuity declined by 7.5 Early Treatment Diabetic Retinopathy Study letters in patients with good baseline visual acuity20/40, visual acuity improved by 8.5 letters in patients with baseline visual acuity of ≤20/200. Only 7.5% of patients underwent an optical coherence tomography scan after 3 upload injections, and only 2.0 optical coherence tomographies were performed in the first 12 months.The NP and NA were high in our study population and are likely to have contributed to a suboptimal clinical outcome compared with randomized clinical trials. Shortcomings in the management of patients with neovascular age-related macular degeneration, including restrictions in the timely and adequate follow-up (including optical coherence tomography) and retreatment, appear to be constraining factors in Germany.

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 mmCross-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 mmExclusion 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).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.

Chronic central serous chorioretinopathy (CSC) is a vision-threatening eye disease for which there is still no approved treatment. Recent studies suggest that the corticosteroid pathway in the choroid is implicated in CSC pathogenesis, and that therapy with the aldosterone antagonist eplerenone improves clinical outcomes. However, there is still little clinical data to support this hypothesis. We performed a retrospective chart review to further investigate the clinical value of eplerenone treatment in patients with chronic CSC and to identify possible response predictors. Twenty-four patients with chronic CSC resistant to conventional therapy over at least 4 months were included in this retrospective study. Patients were initially treated with 25 mg/day of eplerenone administered orally for 1 week, followed by a sustained daily dose of 50 mg. The primary outcome measure was percentage of eyes achieving complete resolution of subretinal fluid (SRF), recorded by spectral domain optical coherence tomography (SD-OCT). Secondary outcomes included changes in central macular thickness (CMT) and best-corrected visual acuity (BCVA). Baseline SD-OCT images were also evaluated as possible predictors of treatment response. Twenty-nine percent of patients experienced complete resolution of SRF after a median of 106 days of treatment, while 33 % of patients showed a transient initial decrease in SRF, and 25 % failed to respond to treatment. Treatment had to be stopped in 13 % of patients because of adverse effects of the eplerenone treatment. In the study population, CMT decreased from 342 to 275 μm after treatment, which was associated with a modest improvement in mean BCVA from 0.35 to 0.3 logMar. The integrity of the ellipsoid zone and the retinal pigment epithelium (RPE) at baseline were associated with a tendency towards a favourable visual outcome. This study confirms the proposed clinical value of eplerenone for treating patients with therapy-resistant CSC. However, patients presenting widespread RPE changes are less likely to benefit from eplerenone treatment, which may argue for an earlier intervention. Larger studies are needed to characterise patient subgroups that may benefit the most from eplerenone treatment.

Purpose The objective of our study was to investigate preferences of patients with neovascular age-related macular degeneration (nAMD) for different anti-vascular endothelial growth factor (VEGF) treatment schemes. Design We used a discrete choice experiment (DCE) design as part of a telephone interview. Participants Patients with nAMD aged at least 50 years were included in the study. Methods Telephone interviews were done between November 2012 and October 2013. Main Outcome Measures In our DCE survey, we measured patient preferences toward specific levels of attributes that describe different options in the everyday intravitreal injection treatment setting: (1) treatment scheme; (2) change of visual acuity (VA); and (3) time the patient needs for each visit to the eye specialist. Results A total of 284 patients with nAMD with a mean age of 77.4±7.1 years (women: 59.9%) completed the DCE interviews. Of them, 22.9% had poor VA at study inclusion, 54.9% had moderate VA, and 14.1% had good VA; VA was not available for 8.1% of the patients. Generally, patients preferred the attribute levels "improvement in VA" and "short time per specialist visit." The results for the attribute "treatment scheme" were inconclusive because none of the attribute levels (injections every 4 weeks, every 8 weeks, and pro re nata) were associated with statistically significant utility differences. This also mirrors the relative importance of the different attributes in patient decisions: "Change of VA" influenced decision making for a treatment option in 73.6% of cases; "waiting, treatment, and travel time" influenced decision making in 21.0% of cases; and "treatment scheme" influenced decision making for a treatment option in 5.4% of cases. To obtain improved VA instead of a worsening VA, patients in our study stated to be willing to accept a very long time needed per physician visit of 21.2 hours (8.5 hours for improved rather than stable VA and 12.7 hours for stable VA rather than worsening VA). Conclusions To prevent deterioration of VA, patients with nAMD seem to be willing to accept a high treatment burden with regular intravitreal injections at short intervals and long periods of waiting, treatment, and traveling for their consultations.

Christoph Ehlken,1,2 Mandy Helms,1 Daniel Böhringer,1 Hansjürgen T Agostini,1 Andreas Stahl1 1Ophthalmology, Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, 2Ophthalmology, Eye Center, University Hospital Schleswig-Holstein, Campus Kiel, Germany Purpose: Real-life clinical outcomes of patients treated with anti-VEGF drugs for neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), or macular edema secondary to branch retinal vein occlusion (BRVO) are often inferior to results from randomized clinical trials. This observational cohort study investigates treatment adherence and real-life clinical outcomes within the first year of treatment.Patients and methods: A total of 708 treatment-naïve patients (466 nAMD, 134 DME, and 108 BRVO) were included. Patients were followed with a PRN treatment protocol with three intravitreal injections (IVIs) and a series of 3 monthly injections in case of persistent or recurrent disease activity, as determined by monthly follow-up exams including optical coherence tomographies. Occurrence of gaps of >56 days between treatments or follow-up (nonadherence [NA]) and the reasons for NA (patient- or center-associated) as well as disease activity within the first 12 months of treatment were analyzed. Visual acuity (VA) as well as numbers and dates of optical coherence tomography and IVI were extracted from medical records.Results: NA occurred significantly more often in patients with DME (44%) than nAMD (32%) or BRVO (25%, p0.05).Conclusion: NA to treatment and follow-up regimens is a common problem in the management of patients with AMD and DME and limits clinical treatment outcomes under real-life conditions. Patients with DME have the highest risk of patient-associated NA, associated with a higher risk for significant VA loss. Keywords: AMD, RVO, DME, adherence, anti-VEGF, PRN, follow-up

Patients with exudative maculopathies (neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO)) are faced with a high burden of examinations and treatments. This study was conceived to analyze the accuracy of a subjective evaluation of visual acuity (VA) and metamorphopsia to detect disease reactivation, compared to morphological signs of reactivation assessed by means of SD-OCT.Retrospective study of 888 patients treated for nAMD (n = 638), DME (84), BRVO (110), and CRVO (56) was conducted. Subjective evaluation of the patient at an examination (i.e., change of VA and/or metamorphopsia) was compared to clinical evaluation of disease activity as assessed by SD-OCT. Sensitivity and specificity, negative and positive predictive values (PPV/NPV) for detection of active disease were calculated. Factors associated with false-negative subjective evaluation were analyzed by regression analysis.The sensitivity of the subjective evaluation to detect disease reactivation was 0.50 in all exudative maculopathies. Sensitivity was increased to ≥ 0.60 by combining subjective worsening with loss of 1 line in the VA test in RVO, but not in DME and nAMD. The specificity was 0.85 in all patients. PPV was 0.85 in patients with RVO. Regression analysis did not reveal any factors that could reliably identify patient subgroups in which OCT could be omitted, though CRVO patients with a visual acuity of 0.3 logMAR had an odds ratio of 0.20 for false-negative subjective evaluation (p = 0.009).The accuracy of subjective evaluation to discriminate disease activity in patients with different exudative maculopathies was low and cannot substitute for frequent SD-OCT exams. Routinely assessed clinical parameters such as age, visual acuity, or treatment experience were of no use to predict the validity of subjective evaluation of disease activity.This trial was registered at the DRKS (Deutsches Register Klinischer Studien, drks.de; No 00006851) prior to the inclusion of the first patient.

Purpose: Anti-angiogenic treatment is well established in the management of exudative age-related macular degeneration (AMD), but not sufficient in all patients. The characterisation of factors driving this chronic disease could serve to identify additional treatment options. The purpose of this study was to assess gene expression patterns and distinct changes in cells derived from surgically extracted choroidal neovascularisation (CNV) membranes. Materials and Methods: The expression of >11,000 genes was analysed by means of a microarray in cells cultured from 2 late-stage CNV membranes compared to primary human retinal pigment epithelium (RPE) and ARPE-19 cells. A pathway analysis was performed to identify gene expression patterns associated with exudative AMD. Results: The analysis revealed significant alterations in gene sets associated with inflammatory processes in CNV-derived cells, involving the upregulation of pro-inflammatory factors IL6, C3, and C5, and downregulation of anti-inflammatory complement factor B and complement factor I. Factors associated with angiogenesis, such as VEGFA or ANGPT2, were not significantly regulated in the 2 RPE-derived cell lines. Conclusion: In late-stage CNV membrane-derived RPE, gene expression was shifted towards a pro-inflammatory state. Angiogenesis-associated factors were regulated differently in the 2 CNV-derived RPE membranes. While inflammation seems to be continuously stimulated by RPE associated with late exudative AMD, this appears not to be the case with regard to angioregulatory mechanisms.

Purpose To compare the complication spectrum and rate of 23-G and 20-G vitrectomy for macular surgery. Methods This was a retrospective comparative analysis of 20-G and 23-G vitrectomy (introduced in 2007) for macular surgery due to macular pucker or macular hole performed between 2006 and 2010 in 61 and 59 eyes, respectively, by 2 experienced surgeons and 2 trainees. We assessed the adjusted hazard ratio for vitrectomy 23-G vs 20-G with a Cox proportional hazard model. We counted retinal detachment, vitreous hemorrhage, endophthalmitis (as early postoperative complications), or cataract progression (as late postoperative complication) as endpoint. We adjusted for indication, surgeon, retinopexy method, and the endotamponade. Results Follow-up averaged 712 days. Median time to first event was 385 days in the 23-G group and 342 days in the 20-G group. Cox proportional hazard analysis showed no significant difference between vitrectomy 23-G vs 20-G with regard to postoperative complications (hazard ratio 0.79, 95% confidence interval 0.41-1.52). The other covariates did not exert a statistically significant effect on the risk of adverse events. Looking at individual complications, retinal detachment was exclusively found after 20-G. Conclusions In this homogenous large cohort, we did not find a statistically significant difference in rates of complications between 23-G and 20-G vitrectomy techniques for macular surgery. Trainees performed equally well as experienced surgeons.

Background Anti vascular endothelial growth factor (VEGF) therapy is an established treatment for various retinal diseases. Long-term data on injection frequencies and visual acuity (VA), however, are still rare. Methods Five-year analysis of real-life VA developments and injection patterns from 2072 patients (2577 eyes; 33 187 injections) with chronically active disease undergoing pro-re-nata treatment for age-related macular degeneration (AMD), diabetic macular oedema (DME), retinal vein occlusion (RVO) and myopic choroidal neovascularisation (CNV). Results Maximum mean VA gain in year 1 was+5.2 letters in AMD, +6.2 in DME, +10 in RVO and+7.2 in myopic CNV. Over 5 years, however, VA in patients with AMD declined. By year 5, 34% of patients with AMD had experienced VA loss of >15 letters, 56% had remained stable and 10% had gained >15 letters. Long-term VA developments in DME and RVO were more favourable with 81% of DME and 79% of patients with RVO gaining or maintaining vision at 5 years. In AMD, median injection frequency was six in year 1 and between four and five in consecutive years. In DME and RVO, median injection frequency was six in year 1 but lower compared with AMD in consecutive years. Injection frequency in DME was weakly associated with patient age (r s =0.1; p=0.03). Conclusions In AMD, the initial VA gain was not maintained long term despite higher injection numbers compared with DME, RVO and myopic CNV. The presented real-world data provide a peer-group-based estimate of VA developments and injection frequencies for counselling patients undergoing long-term anti-VEGF therapy.

Im Sommersemester 2006 wurde an der Universitats-Augenklinik Freiburg ein vorlesungsbegleitendes, internetbasiertes E-Learning-Modul fur Studierende eingerichtet. Den Studierenden begegnen im E-Learning-Modul die aus der Vorlesung bekannten Fallbeispiele quasi-interaktiv im Frage-Antwort-Modus. Inhalte, Format, Bedienbarkeit und Lerneffekt des E-Learnings wurden uber 2 Semester durch die Studierenden evaluiert. Von insgesamt 307 Studierenden im Augenkurs nutzten 272 das E-Learning-Angebot. Pro Nutzer wurden durchschnittlich 94% der angebotenen Inhalte bearbeitet. Uber 75% der Studierenden gaben an, Spas bei der Bearbeitung des E-Learnings gehabt zu haben. Studierende mit uberdurchschnittlicher E-Learning-Nutzung erreichten tendenziell bessere Ergebnisse in der Abschlussprufung. E-Learning als sinnvolle Erganzung zur Prasenzlehre wird von den Studierenden sehr gut angenommen. Fur die Lehrenden stellt es eine Moglichkeit dar, mit vergleichsweise geringem Aufwand die Inhalte der Prasenzlehre zur Wiederholung und Vertiefung anzubieten.

The objective of our study was to investigate preferences of patients with neovascular age-related macular degeneration (nAMD) for different anti-vascular endothelial growth factor (VEGF) treatment schemes.We used a discrete choice experiment (DCE) design as part of a telephone interview.Patients with nAMD aged at least 50 years were included in the study.Telephone interviews were done between November 2012 and October 2013.In our DCE survey, we measured patient preferences toward specific levels of attributes that describe different options in the everyday intravitreal injection treatment setting: (1) treatment scheme; (2) change of visual acuity (VA); and (3) time the patient needs for each visit to the eye specialist.A total of 284 patients with nAMD with a mean age of 77.4±7.1 years (women: 59.9%) completed the DCE interviews. Of them, 22.9% had poor VA at study inclusion, 54.9% had moderate VA, and 14.1% had good VA; VA was not available for 8.1% of the patients. Generally, patients preferred the attribute levels "improvement in VA" and "short time per specialist visit." The results for the attribute "treatment scheme" were inconclusive because none of the attribute levels (injections every 4 weeks, every 8 weeks, and pro re nata) were associated with statistically significant utility differences. This also mirrors the relative importance of the different attributes in patient decisions: "Change of VA" influenced decision making for a treatment option in 73.6% of cases; "waiting, treatment, and travel time" influenced decision making in 21.0% of cases; and "treatment scheme" influenced decision making for a treatment option in 5.4% of cases. To obtain improved VA instead of a worsening VA, patients in our study stated to be willing to accept a very long time needed per physician visit of 21.2 hours (8.5 hours for improved rather than stable VA and 12.7 hours for stable VA rather than worsening VA).To prevent deterioration of VA, patients with nAMD seem to be willing to accept a high treatment burden with regular intravitreal injections at short intervals and long periods of waiting, treatment, and traveling for their consultations.

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. peerReviewed

Although anti-VEGF therapy of exudative AMD with bevacizumab and ranibizumab proved efficacious in the majority of patients, CNV activity does not respond to continued treatment after repeated injections in a considerable amount of patients. These are referred to as nonresponders. A change of the drug to bevacizumab or ranibizumab could possibly offer an alternative option for the treatment of nonresponding exudative AMD. A total of 138 nonresponders who switched therapy from bevacizumab to ranibizumab (n=114) or vice versa (n=24) were included in a retrospective study. Visual acuity (VA) and foveal thickness before and after the switch of therapy were compared. By means of linear regression analysis, we analyzed possible prognostic factors associated with a favorable outcome for visual acuity. Linear regression analysis revealed a statistically significant benefit for nonresponders when treatment was changed to a different anti-VEGF drug (bevacizumab or ranibizumab). VA at the time of the switch was positively correlated with a beneficial development of VA after changing the drug. There was no significant correlation with age, macular thickness, number of injections before the switch, or the development of VA under treatment before the switch. Both patients switching to Avastin and Lucentis benefitted without statistically significant differences. An exchange of bevacizumab with ranibizumab or vice versa should be considered in nonresponders in the treatment of exudative AMD. Further prognostic factors may help to identify patients who might benefit from a switch. These factors should be investigated in further studies.

Aim To conduct a systematic review in order to compare adverse effects (AE) and the reporting of harm in randomised controlled trials (RCTs) and non-RCTs evaluating intravitreal ranibizumab and bevacizumab in age-related macular degeneration. Methods Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. Studies which compared bevacizumab or ranibizumab as monotherapy with any other control group were included. Case series were included if they met predefined quality standards. Results The 2 year results of phase III trials evaluating ranibizumab show that the rates of serious ocular AE were low (≤2.1%) but indicate major safety concerns (RR 3.13, 95% CI 1.10 to 8.92). A possible signal with regard to thromboembolic events (RR 1.35, 95% CI 0.66 to 2.77) and a significant increase in non-ocular haemorrhage (RR 1.62, 95% CI 1.03 to 2.55) were also noted. In contrast to ranibizumab trials, the RCTs evaluating bevacizumab are of limited value. The main shortcomings are small sample sizes and an apparent lack of rigorous monitoring for AE. A critical assessment of the large number of published case series evaluating bevacizumab also shows that no reliable conclusions on safety can be drawn using this study design. Therefore, any perception that intravitreal bevacizumab injections are not associated with major ocular or systemic AE are not supported by reliable data. Conclusion The bevacizumab studies show too many methodological limitations to rule out any major safety concerns. Higher evidence from ranibizumab trials suggests signals for an increased ocular and systemic vascular and haemorrhagic risk which warrants further investigation.

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.

Purpose of review We conducted a systematic review to evaluate whether the existing evidence justifies the intravitreal use of bevacizumab in comparison to ranibizumab in age-related macular degeneration. Recent findings Compared with photodynamic therapy, bevacizumab shows a relative improvement in visual acuity that is of similar size as in the comparison of ranibizumab with photodynamic therapy (relative improvement from 30 to 35%). However, this finding is based on one randomized controlled trial including less than 50 patients treated with bevacizumab. Also, nothing is known about long-term (>12 months) improvements in visual acuity and optimal treatment intervals for bevacizumab.Regarding safety, the published literature indicates that ocular and systemic adverse effects are less frequent under bevacizumab than ranibizumab treatment. But the validity of this finding is strongly limited by inadequate reporting, an unsystematic evaluation of adverse effects and short follow-up times in studies evaluating bevacizumab. Summary Given the lack of controlled data, the widespread off-label use of bevacizumab is not justified in clinical practice. On the other hand, a major challenge in the management of patients who require repeated antivascular endothelial growth factor injections is the high cost of ranibizumab. This dilemma underlines the need for head-to-head studies comparing both vascular endothelial growth factor antibodies, or, at least, well conducted randomized controlled trials evaluating intravitreal bevacizumab.

Acta Ophthalmol. 2011: 89: 82–90 Abstract. Purpose: To investigate whether EphrinB2 (EfnB2) or EphB4 influence retinal angiogenesis under physiological or pathological conditions. Methods: Using the mouse model of oxygen-induced proliferative retinopathy (OIR), the expression of EfnB2, EphB4, vascular endothelial growth factor (VEGF), VEGFR1 and VEGFR2 was quantified by quantitative polymerase chain reaction (qPCR) and localized in EfnB2- and EphB4-lacZ mice. Angioproliferative retinopathy was manipulated by intravitreal injection of dimeric EfnB2 and monomeric or dimeric EphB4. Results: Dimeric EphB4 (EphB4-Fc) and EfnB2 (EfnB2-Fc) enhanced hypoxia-induced angioproliferative retinopathy but not physiological angiogenesis. Monomeric EphB4 (sEphB4) reduced angiogenesis. The messenger RNA (mRNA) level of EfnB2 increased significantly in the hyperoxic phase (P7–P12), while EphB4, VEGF, VEGFR1 and VEGFR2 showed a significant – up to fivefold – increased expression at P14, the start of morphologically visible vasoproliferation caused by relative hypoxia. Conclusion: The ephrin/Eph system is involved in angioproliferative retinopathy. Stimulation of EphB4 and EfnB2 signalling using EfnB2-Fc and EphB4-Fc, respectively, enhanced hypoxia-induced angiogenesis. In contrast, sEphB4 inhibited hypoxia-induced angiogenesis. Therefore, angiogenesis is enhanced by signalling through both EphB4 (forward) and EfnB2 (reverse). The distinction in the expression kinetics of EphB4 and EfnB2 indicates that they govern two different signalling pathways and are regulated in diverse ways. sEphB4 might be a useful drug for antiangiogenic therapy.

Purpose To measure the level of VEGF protein in serum and breast milk after intravitreal injection of bevacizumab and ranibizumab. Methods Serum and breast milk samples before and after repeated intravitreal injections of bevacizumab and ranibizumab were collected from a 35-year old female who was treated for CNV secondary to a chorioretinal scar and who was nursing her 4-month old son. Samples were analysed for the level of VEGF protein via ELISA. Results VEGF protein in the serum was reduced significantly to non-detectable levels after intravitreal injection of bevacizumab and started to recover only after 6 weeks. After intravitreal injection of ranibizumab, however, only a temporary dip 3 days after injection could be detected. VEGF in breast milk was reduced by approximately one third directly after injection of bevacizumab. After injection of ranibizumab, the level of VEGF protein remained unaltered. Conclusion Use of intravitreal VEGF inhibitors should be avoided during pregnancy or while nursing a baby. However, if necessary, ranibizumab seems to have a lower effect on VEGF in the serum or breast milk an should therefore be used.

Purpose EphrinB2 is predominantly expressed in arteries, while its ligand EphB4 is predominantly expressed in veins. Activation of ephrinB2 and EphB4 by receptor dimers have been shown to enhance neovascularization, whereas inhibition of EphB4 reduced neovascularization both in vitro and in vivo in a mouse model of oxygen-induced retinopathy (OIR). These data suggest a role of the ephrinB2-EphB4 system in retinal neovascularization. We looked for expression of these membrane-bound factors in a mouse model of OIR. Methods Heterogenic EphB4lacZ+/- mice were examined in a well-established mouse model of oxygen-induced retinopathy. Mice were kept in 75% oxygen for postnatal days P7-P12. Returned to room air, they underwent a relative hypoxia and developed a proliferative retinopathy within the next 5-7 days. Eyes were enucleated on P17-P19 during the peak of vascular proliferation, stained for LacZ, and embedded in paraffin. Sections were investigated for LacZ staining. Results Sections show a strong expression of EphB4 in preretinal neovascularization both in small and larger vessels. EphB4 is also mildly expressed in vessels in the inner plexiform layer and in the ganglion cell layer. Conclusion The expression pattern suggests a role of EphB4 in preretinal neovascularization in a mouse model of OIR. Further studies of the intracellular localisation of EphB4 are needed to add to understanding the role of the ephrin system in OIR.

Connective tissue growth factor (CTGF) is a member of the CCN family of growth factors. CTGF is important in scarring, wound healing, and fibrosis. It has also been implicated to play a role in angiogenesis, in addition to vascular endothelial growth factor (VEGF). In the eye, angiogenesis and subsequent fibrosis are the main causes of blindness in conditions such as diabetic retinopathy. We have applied three different models of angiogenesis to homozygous CTGF−/− and heterozygous CTGF+/− mice to establish involvement of CTGF in neovascularization. CTGF−/− mice die around birth. Therefore, embryonic CTGF−/−, CTGF+/−, and CTGF+/+ bone explants were used to study in vitro angiogenesis, and neonatal and mature CTGF+/− and CTGF+/+ mice were used in models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. Angiogenesis in vitro was independent of the CTGF genotype in both the presence and the absence of VEGF. Oxygen-induced vascular pathology in the retina, as determined semi-quantitatively, and laser-induced choroidal neovascularization, as determined quantitatively, were also not affected by the CTGF genotype. Our data show that downregulation of CTGF levels does not affect neovascularization, indicating distinct roles of VEGF and CTGF in angiogenesis and fibrosis in eye conditions.

The effect of the heparin analog 5-amino-2-naphthalenesulfonate (5-amino-2-NMS) on retinal neovascularization was investigated in the mouse model for oxygen-induced retinopathy (OIR). From postnatal day 7 (P7) until P12, mice were kept in a 75% oxygen environment. On P12, they received an intravitreal injection of 10mM 5-amino-2-NMS in one eye and PBS as control substance in the fellow eye. The animals were intracardially perfused with fluorescein-dextran solution on P17. Retinal whole mounts were prepared and ischemic retinopathy was evaluated in 30 animals using a standardized retinopathy score. A single intravitreal injection of 5-amino-2-NMS reduces significantly angioproliferative changes (blood vessel tufts, extra-retinal neovascularization, and blood vessel tortuosity) compared to the contralateral control eye (p=0.025). The median retinopathy score (maximal 13) for the 5-amino-2-NMS treated eyes was 6 versus 8 for the control eyes. 5-Amino-2-NMS binds to the heparin-binding site of FGF1 and FGF2 and thus may be a promising substance for the local treatment of retinal neovascularization.