Prosthetic Visual Acuity with the PRIMA System in Patients with Atrophic Age-related Macular Degeneration at 4 years follow-up.

Objective: To assess the efficacy and safety of the PRIMA subretinal neurostimulation system 48-months post-implantation for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months post-implantation. Design: First-in-human clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.gov NCT03333954). Subjects: Five patients with GA, no foveal light perception and VA of logMAR 1.3 to 1.7 in their worse-seeing "study" eye. Methods: In patients implanted with a subretinal photovoltaic neurostimulation array containing 378 pixels of 100 µm in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 meter. The system's external components: augmented reality glasses and pocket computer, provide image processing capabilities, including zoom. Main Outcome Measures: VA using ETDRS charts with and without the system. Light sensitivity in the central visual field, as measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and optical coherence tomography up to 48-months post-implantation. Results: All five subjects met the primary endpoint of light perception elicited by the implant in the scotoma area. In one patient the implant was incorrectly inserted into the choroid. One subject died 18-months post-implantation due to study-unrelated reason. ETDRS VA results for the remaining three subjects are reported herein. Without zoom, VA closely matched the pixel size of the implant: 1.17 ± 0.13 pixels, corresponding to mean logMAR 1.39, or Snellen 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (SE 5.1) 95% CI[13.4,49.9], p<0.0001. Natural peripheral visual function in the treated eye did not decline after surgery compared to the fellow eye (p=0.08) during the 48 months follow-up period. Conclusions: Subretinal implantation of PRIMA in subjects with GA suffering from profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48-months. Using prosthetic central vision through photovoltaic neurostimulation, patients reliably recognized letters and sequences of letters,and with zoom it provided a clinically meaningful improvement in VA of up to eight ETDRS lines.

[Bottlenecks in the availability of ophthalmological medications : Initiative of the Working Group on Ethics in Ophthalmology of the DOG and the University Eye Clinic Bonn]. / Engpässe bei der Verfügbarkeit von ophthalmologischen Medikamenten : Initiative der Arbeitsgemeinschaft Ethik in der Augenheilkunde der DOG und der Universitäts-Augenklinik Bonn.

BACKGROUND: Bottlenecks in drug supply in the field of ophthalmological are continuously increasing in Germany. So far, these have hardly been communicated and discussed. We see the transparent presentation of the problem as a first step in compiling concepts to counteract this development. AIM OF THE WORK: Presentation of the supply shortages in ophthalmological drugs. MATERIAL AND METHODS: A listing and discussion of the shortages in drug supply to the best of our knowledge are presented. RESULTS: We distinguish between the problems in (1) supply shortages, (2) discontinuation of production, (3) lack of availability in Germany and (4) manufacture of drugs in specialized pharmacies often lacking approval for the ophthalmological indications. DISCUSSION: The reasons for drug supply shortages in ophthalmology are complex and therefore no easy solutions can be expected; however, industrial and regulatory authorities at the national and European levels are called upon to analyze the underlying problems and to find appropriate solutions.

A randomized, open-label, multicenter study of switching to brolucizumab with or without a loading dose for patients with suboptimal anatomically controlled neovascular age-related macular degeneration-the FALCON study.

BACKGROUND: Treatment initiation with brolucizumab, a new potent anti-vascular endothelial growth factor (VEGF) agent, is typically performed with three monthly injections (loading dose) and has been well studied in treatment-naïve patients. However, no clinical data are available yet on whether or not anti-VEGF pretreated patients also benefit from a loading dose. In the clinical setting, different heterogeneous treatment patterns are used as no clinical trial has addressed this so far in a head-to-head comparison. Therefore, the FALCON study is investigating whether patients with unsatisfactory response to previous anti-VEGF treatments benefit from a loading dose at the switch to brolucizumab treatment. METHODS: FALCON is a 52-week, two-arm, randomized, open-label, multicenter, multinational study in patients with residually active neovascular age-related macular degeneration (nAMD) who will be randomized 1:1 and started with brolucizumab 6 mg loading (three monthly loading doses) or brolucizumab 6 mg non-loading (one initial injection) and consecutive treatment every 12 weeks, respectively. The primary objective is to demonstrate non-inferiority of the non-loading vs. loading arm in mean change of best-corrected visual acuity (BCVA) from baseline to the mean value at week 40 to week 52. Secondary objectives include the assessment of anatomical outcomes, treatment intervals, safety and tolerability. RESULTS: FALCON will be the first study to assess treatment initiation with an anti-VEGF agent in a switch situation with or without loading dose in patients with nAMD. CONCLUSIONS: The results will support the optimization of treatment of patients with previous unsatisfactory anti-VEGF response. Therefore, we expect to see an impact on current clinical practice which has been established for more than a decade. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04679935, date of registration-22-Dec 2020; EUDRACT number: 2019-004763-53, date of registration-03 Dec 2019.

Clinico-pathological correlation of lacrimal caruncle tumors: a retrospective analysis over 22 years at the University Eye Hospital Bonn.

PURPOSE: The lacrimal caruncle is composed of numerous structures including different glands as well as hair follicles. Accordingly, the spectrum of benign and malignant lesions is broad, and the clinical diagnosis is often challenging. Here we systematically analyzed excised caruncular tumors over the past 22 years with special emphasis on the clinico-pathological correlation to provide a guidance for clinicians. METHODS: Retrospective evaluation with clinico-pathologic correlation of surgically removed caruncular tumors between 1998 and 2020 at a tertiary referral center. RESULTS: Eighty-two caruncular tumors were identified in the respective period. The patients were between 11 and 85 years of age (mean, 46.8 years; median, 49 years). Nevi (n = 35), cystic lesions (n = 14), oncocytoma (n = 9), papilloma (n = 8), sebaceous gland hyperplasia (n = 8), and reactive lymphoid hyperplasia (n = 4) were observed most frequently. Besides, we are the first reporting herniated orbital fat accompanied by a pyogenic granuloma. 2.4% (n = 2) were malignant tumors (sebaceous gland carcinoma, conjunctival intraepithelial neoplasia with pyogenic granuloma). CONCLUSION: Caruncular tumors show a broad spectrum of mostly benign tumors. They can occur in patients of any age. However, 8/9 oncocytomas and both malignant lesions were detected in patients older than 60 years. Although the clinical diagnosis was confirmed in only 68.3% by the histopathological analysis, the two malignant lesions were identified as such already clinically. Caruncular lesions with a history of growth or other signs of malignancy should be excised followed by detailed histopathological examination to allow a final diagnosis and exclude rare malignant tumors with lethal potential.

[Intraocular inflammation with brolucizumab use : Patient management-diagnosis-therapy]. / Intraokulare Entzündungen bei Brolucizumab-Anwendung : Patientenmanagement ­ Diagnose ­ Therapie.

The anti-vascular endothelial growth factor (anti-VEGF) agent brolucizumab has been approved in the USA in October 2019 and in Europe in February 2020 for the treatment of neovascular age-related macular degeneration (nAMD). The approval was based on the randomized, double-blind phase III studies HAWK and HARRIER with a total of 1817 patients. Brolucizumab 6 mg (administered every 12 or 8 weeks depending on the activity of the disease) showed a non-inferior efficacy in terms of best-corrected visual acuity compared to aflibercept 2 mg (administered every 8 weeks). Initial reports on the use of brolucizumab after its approval in the USA indicated a safety signal of rare adverse events termed as retinal vasculitis and/or retinal vascular occlusion that may result in severe loss of vision. Typically, these events occurred in the presence of intraocular inflammation (IOI). A safety review committee (SRC) subsequently carried out an independent analysis of data from the pivotal studies. This article sets out the current state of knowledge and aims to provide users with orientation-from the authors' perspective-in treating brolucizumab-associated IOI. It appears mandatory to provide patients with information about possible symptoms of IOI. Even though the case reports and the SRC review of HAWK/HARRIER may not yet provide sufficient evidence for any final conclusions, it seems crucial to educate patients about signs and symptoms to ensure an early detection and diagnosis in cases of IOI. Once a patient is diagnosed with IOI, retinal vasculitis, and/or retinal vascular occlusive events, physicians should act promptly with an adequate and intensive anti-inflammatory treatment and brolucizumab treatment should be discontinued. It is important to note that these recommendations are primarily based on the authors' expert opinions and should be considered as guidance in managing these events rather than a formal protocol or guidelines.

[ANDROMEDA-an investigation of factors influencing the adherence of patients with neovascular age-related macular degeneration using the newly developed patient questionnaire LAF-IVT]. / ANDROMEDA ­ Eine Untersuchung von Einflussfaktoren auf die Adhärenz von Patienten mit neovaskulärer altersabhängiger Makuladegeneration mithilfe des neu konzipierten Patientenfragebogens LAF-IVT.

BACKGROUND: Lack of adherence to treatment is a widespread problem in the anti-VEGF (Vascular Endothelial Growth Factor) treatment of patients with neovascular age-related macular degeneration (nAMD). In contrast to the extent of the lack of treatment adherence, there is so far insufficient evidence for elucidating the causes of nonadherence. The ANDROMEDA study was initiated to investigate the influencing factors on the adherence of nAMD patients to treatment. The focus of the study was on patient reported endpoints, as the perceptions and experiences of the patients are of enormous importance for the investigation of the various aspects of adherence to treatment. OBJECTIVE: This publication presents the design of the ANDROMEDA study as well as the development of a new patient questionnaire for the assessment of barriers to treatment within the design of the study. MATERIAL AND METHODS: This prospective noninterventional observational study to assess the compliance of patients with nAMD and anti-VEGF treatment was started at the end of January 2019. It is planned to include 1000 patients in 120 study centers throughout Germany with an observational period of 24 months. Patient interviews on general and vision-related quality of life, treatment satisfaction and possible barriers to treatment will be conducted at the beginning and after 4, 12 and 24 months. All patient visits will be documented by the study centers as part of the clinical routine. To date, there has been no suitable instrument for recording patient-related circumstances and potential barriers to anti-VEGF treatment. Therefore, a specific patient questionnaire for longitudinal assessment of adherence factors to intravitreal (anti-VEGF) therapy (LAF-IVT) was developed as part of the study concept. The questionnaire, developed by an expert panel, was tested via qualitative interviews for its cognitive characteristics ahead of its use. RESULTS: The results of the study are expected in early 2023. The cognitive examination of the LAF-IVT confirmed the feasibility of the new questionnaire. The practicability and significance of the new instrument can be assessed after completion of the quantitative data collection. CONCLUSION: The symptoms, barriers, burdens and quality of life effects experienced by patients influence the adherence to treatment and thus the outcome. A better understanding of the patient's views and experiences is the basis for long-term optimization of care.

Awareness of Age-Related Macular Degeneration in Community-Dwelling Elderly Persons in Germany.

Background: Due to current demographic trends age-related macular degeneration (AMD) is becoming more prevalent. When disease progresses to late-stage neovascular AMD, rapid initiation of treatment is required to achieve optimal outcomes. However, many affected individuals may be unaware of their disease impeding and delaying care seeking. Therefore, in an exploratory study we assessed whether elderly persons living independently in the community were aware of their AMD. Methods: Participants were recruited in eleven seniors' community centers. Participants underwent a standardized interview followed by non-mydriatic fundus photography of the macula and the optic disc in both eyes (Canon CR-2AF, Canon, New York, USA). The images were graded by an ophthalmologist and the data were analyzed descriptively. Results: A total of 281 participants (73.9 ± 8.1 years; 71.9% women) underwent bilateral fundus photography. The fundus photographs of 208 participants (74%; 73.6 ± 7.0 years; 73.1% women) could be graded. In a third (32.2%, n = 67) no pathological changes were detected. AMD was present in 24.5% of the examined subjects (n = 51). Half of the cases had early (47.1%), followed by intermediate (41.2%) and late (11.7%) AMD. Only one third (n = 16, 31.4%) were aware of their disease. Conclusions: A quarter of community dwelling elderly had AMD but only a third of these were aware of being affected with AMD. This confirms previous studies demonstrating low awareness for age-related eye diseases in the community. Considering the increase in population aging, awareness campaigns for AMD are needed.

[Pro re nata anti-VEGF treatment results for neovascular age-related macular degeneration in routine clinical treatment: comparison of single with triple injections]. / Pro-re-nata-anti-VEGF-Behandlungsergebnisse bei neovaskulärer altersabhängiger Makuladegeneration in der klinischen Routineversorgung: Vergleich von Einzel- mit 3er-Injektionen.

BACKGROUND: Different injection regimens from continuous to pro re nata (PRN) have been proposed for treatment of neovascular age-related macular degeneration (nAMD). So far the PRN single injection on reactivation regimen has not been compared to the PRN triple injection on reactivation regimen (IVAN scheme). OBJECTIVE: Comparison of the two nAMD PRN injection regimens with single and triple injections on reactivation in a real-world setting in a retrospective case series in two German treatment centers. MATERIAL AND METHODS: Naïve nAMD patients, who started treatment according to either the single or triple injection regimen were included. Endpoints were best corrected visual acuity (LogMAR), central retinal thickness on optical coherence tomography (µm) and number of injections, all at 3, 6, 12, 18 and 24 months after treatment initiation. RESULTS: A total of 146 patients with single injection and 148 patients with triple injection regimens were included. There were no significant differences between the two treatment regimens in best corrected visual acuity (single vs. triple injection scheme: 0.50 ± 0.42 vs. 0.56 ± 0.42, p = 0.14), central retinal thickness (303 ± 76.2 vs. 306 ± 110, p = 0.79) and number of injections (13 ± 4.4 vs. 12 ± 5.4, p = 0.31). This was the case for all analyzed time points. CONCLUSION: There were no significant functional or morphological differences between the two PRN injection regimens with single and triple injections on reactivation after 24 months. For evaluation of long-term therapy results further studies are warranted.

[Long-term effects of anti-VEGF therapy for retinopathy of prematurity]. / Langzeiteffekte der Anti-VEGF-Therapie bei Frühgeborenenretinopathie.

BACKGROUND: Intravitreal anti-VEGF therapy is a highly efficacious new treatment option for retinopathy of prematurity (ROP) with significant advantages over conventional therapy using retinal laser coagulation in selected cases. With growing experience in the clinical application over the last years, data about the potential long-term effects of this therapeutic approach are increasingly becoming available, such as those related to ROP-associated myopia, neurodevelopment and late recurrences of ROP. Knowledge of these effects is of direct relevance for the clinical management of affected children. METHODS: The article is based on a literature review of the covered topics. RESULTS: In addition to its therapeutic effect on retinal pathology, anti-VEGF therapy in ROP can also reduce ROP-associated myopia, most likely due to a normalization of anterior segment development. As the unresolved question of potential negative effects of bevacizumab on neurodevelopment remains of concern, the use of alternative treatment options, such as ranibizumab or laser coagulation should be considered. Treatment-requiring recurrences of ROP following anti-VEGF therapy have been reported as late as 69 weeks postmenstrual age, indicating that long-term frequent ophthalmological follow-up examinations are required. CONCLUSION: Long-term effects of anti-VEGF therapy in ROP differ significantly from alternative treatment options such as laser coagulation. These differences are of relevance for the choice of treatment modality and the follow-up regimen of treated children.

[Reasons for delayed and discontinued therapy in age-related macular degeneration]. / Gründe für Therapieverzögerung und -abbruch bei altersabhängiger Makuladegeneration.

BACKGROUND: Critical prerequisites for successful therapy of neovascular age-related macular degeneration (nvAMD) are an early initiation and continuous monitoring; however, delays in starting therapy and non-medically indicated discontinuation of therapy are frequent, which limits therapy efficacy and, thus, visual outcomes. OBJECTIVE: To identify the reasons for delay in therapy and non-medically indicated termination of therapy. MATERIAL AND METHODS: Patients who had started a new therapy (starters) and those who independently terminated therapy (dropouts) were interviewed by telephone with a specific, standardized questionnaire. Results were summarized descriptively. RESULTS: A total of 100 starters and 55 dropouts were interviewed. The mean therapy delay was 22 (±28 SD) days. This was mainly due to the time until the decision to see an ophthalmologist was made. Main reasons for dropping out were: transportation issues (27%), poor general health (25%) and the assumption that there is no benefit from therapy (11%). Of the patients who dropped out 63% would have liked to continue therapy. CONCLUSION: There is potential for improvement in nvAMD management regarding therapy start as well as therapy maintenance. Sensitizing for initial nvAMD symptoms is important as is reduction of barriers to therapy maintenance, since most therapy dropouts would like to continue the therapy.

[Morphologic Corneal Changes after Crosslinking for Keratoconus]. / Morphologische Hornhautveränderungen nach Crosslinking bei Keratokonus.

Keratoconus is a relatively common (1 : 2000) bilateral disease leading to a change in biochemical and biomechanical corneal structure as well as thinning and ectasia. For more than 10 years, crosslinking has been a therapeutic option in cases of progression. Using riboflavin and UVA-radiation, the anterior corneal stroma (300 µm) gets stiffened by crosslinking of collagen fibers. When protocols and limitations are adhered, the procedure is described to be effective and of low-risk. This review gives an overview about physiologic and pathologic changes in keratoconic corneas before and after crosslinking. Based on histopathologic examination, the current knowledge in published literature is reviewed and is complemented by our own investigations.

[Collision tumor]. / Kollisionstumor.

A 65-year-old woman presented with a painless, partially pigmented and partially hyperkeratotic tumorous lesion on the lower eye lid. Histopathologic findings of the wedge resection showed a collision tumor of a highly differentiated squamous cell carcinoma and a fibrosing basal cell carcinoma. Collision tumors involving these two components are rare, particularly in the periocular region.

Genetic and epigenetic insights into uveal melanoma.

Uveal melanoma (UM) is the most frequent primary intraocular tumor in Caucasian adults and is potentially fatal if metastases develop. While several prognostic genetic changes have been identified in UM, epigenetic influences are now getting closer attention. Recent technological advances have allowed to exam the human genome to a greater extent and have improved our understanding of several diseases including malignant tumors. In this context, there has been tremendous progress in the field of UM pathogenesis. Herein, we review the literature with emphasis on genetic alterations, epigenetic modifications and signaling pathways as well as possible biomarkers in UM. In addition, different research models for UM are discussed. New insights and major challenges are outlined in order to evaluate the current status for this potentially devastating disease.

[Ophthalmological health care of the institutionalized elderly : The OVIS study]. / Ophthalmologische Versorgung in Seniorenheimen : Die OVIS-Studie.

BACKGROUND: Due to demographic change and societal transformation the number of elderly persons living in retirement homes is growing in Germany. Access to health care is more complicated in the setting of nursing homes. Different regional studies suggest unmet ophthalmological health care needs in institutionalized elderly people. This study assessed the current ophthalmological health care structure and supply status in nursing homes in Germany. METHODS: This prospective, multicenter cross-sectional study was conducted by 14 study centers in Germany. Elderly people living in 32 nursing homes were included after approval by the local institutional review boards. A standardized examination was performed which included a detailed medical and ocular history, refraction, visual acuity testing, tonometry, biomicroscopy and dilated funduscopy. Unmet ophthalmological health care needs were documented and the data were analyzed descriptively and via logistic regression modelling. RESULTS: A total of 600 participants (434 women and 166 men) aged 50-104 years were examined of which 368 (61%) had ophthalmological conditions requiring treatment. The most prevalent findings were cataracts (315; 53%), disorders of the eyelids (127; 21%), dry eye disease (57; 10%) and posterior capsule opacification (43; 7%). In 63 (11%) of the participants glaucoma was suspected and 55 (9%) of the examined population had a known diagnosis of glaucoma, of whom one third was not on any or on insufficient anti-glaucomatous therapy. 236 (39%) showed signs of age-related macular degeneration (AMD). Only 52% of the examined cohort had been examined by an ophthalmologist within the last 5 years and 39% stated that they would currently not be able to consult an ophthalmologist. Reported barriers were mainly transport and lack of support. CONCLUSION: This study demonstrates considerable unmet ophthalmological health care needs of the institutionalized elderly in Germany. Novel and reformed models of specialist care provision have to be developed.

Demographics of patients receiving Intravitreal anti-VEGF treatment in real-world practice: healthcare research data versus randomized controlled trials.

BACKGROUND: While randomized controlled trials (RCTs) are based on strict inclusion/exclusion criteria, non-interventional studies (NISs) might provide additional information to guide management in patients more representative to the real-world setting. The aim of this study was to compare baseline characteristics of patients receiving intravitreal treatment in the NIS OCEAN with those from published RCTs. METHODS: The ongoing OCEAN study enrolled patients treated with ranibizumab for neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME) or branch/central retinal vein occlusion (B/CRVO). Baseline patient characteristics were compared by indication within the OCEAN cohort. Furthermore, the characteristics were set in reference to those of published RCTs in the same indications. Confidence intervals (CIs) were calculated and assessed for statistically significant differences as indicated by non-overlapping CIs. RESULTS: Patient characteristics in the NIS OCEAN were evaluated for 3,614 patients with nAMD, 1,211 with DME, 204 with BRVO and 121 with CRVO. Between these groups, significant differences in mean age, gender distributions, and mean baseline VA were seen, reflecting known differences between the indications. Compared to the patient characteristics of published RCTs (trials selected by literature search: nAMD: 13 RCTs, DME: 9, RVO: 5), the OCEAN patients' mean age was significantly higher in every indication. The gender distributions across the trials were comparable, with only few differences between OCEAN and the RCTs. Regarding the mean baseline VA, notable differences were found in nAMD and in DME, with VA significantly higher in some RCTs and lower in others. CONCLUSIONS: The described differences underline the complementarity of NISs and RCTs. OCEAN covers a broader spectrum and more variability of patients than do RCTs. As baseline values may have impact on the treatment response (ceiling effect), there is an ongoing need for research in all patient subgroups. Country-specific assessments of patient populations can better reflect the real-world situation. NISs can deliver insights that RCTs may not, as NISs can include non-typical patients, patients with comorbidities, a broader age spectrum and patients of various disease stages. TRIAL REGISTRATION: The NIS OCEAN was registered on www.clinicaltrials.gov (identifier: NCT02194803 ).

[Rare presentation of a scleral nevus with progression in size]. / Seltene Präsentation eines skleralen Nävus mit Größenprogredienz.

A 52-year-old male caucasian patient presented with a limbal subconjunctival pigmentation of unknown origin with progressive enlargement over the past years. Differential diagnoses included a malignant melanocytic lesion; therefore, an excisional biopsy was performed. Prior investigations showed no ciliary body or anterior chamber angle involvement. Histological and immunohistochemical analysis revealed the rare diagnosis of a scleral nevus. The clinical, histological and immunohistochemical findings as well as the relevant differential diagnoses are discussed.