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Purpose: As part of the prospective, non-interventional OCEAN study, the ORCA module evaluated physicians' spectral domain optical coherence tomography (SD-OCT) image interpretations in the treatment of diabetic macular oedema (DME) or macular oedema (ME) secondary to retinal vein occlusion (RVO)., Methods: Presence of intraretinal fluid (IRF) and/or subretinal fluid (SRF) was evaluated independently by physicians and reading centres (RCs) on 1612 SD-OCT scans of 133 patients diagnosed with either DME or ME secondary to RVO. Agreement between physicians and RCs was calculated for both cohorts individually and as a combined ME cohort. Physicians' treatment decisions were analysed related to the results of the OCT-evaluations., Results: For the combined ME cohort, presence of IRF/SRF was recorded by RCs in 792/1612 (49.1%) visits and by physicians in 852/1612 (52.9%) visits, with an agreement regarding presence or absence of foveal fluid in 70.4% of cases. In 64.4% (510/792) of visits with RC-detected foveal IRF and/or SRF no injection was given. In 30.3% of these visits with foveal fluid no reason was identified for a 'watch and wait' approach indicating possible undertreatment. BCVA deterioration was seen in a quarter of these eyes at the following visit., Conclusion: Despite good agreement between physicians and RCs to recognize SRF and IRF, our data indicate that omitting injections despite foveal involvement of fluid is frequent in routine clinical practice. This may put patients at risk of undertreatment, which may negatively impact real-life BCVA outcomes., Trial Registration: www., Clinicaltrials: gov , identifier NCT02194803., (© 2024. The Author(s).)

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., (© 2022. The Author(s).)

Background: Empirical models have been an integral part of everyday clinical practice in ophthalmology since the introduction of the Sanders-Retzlaff-Kraff (SRK) formula. Recent developments in the field of statistical learning (artificial intelligence, AI) now enable an empirical approach to a wide range of ophthalmological questions with an unprecedented precision., Objective: Which criteria must be considered for the evaluation of AI-related studies in ophthalmology?, Material and Methods: Exemplary prediction of visual acuity (continuous outcome) and classification of healthy and diseased eyes (discrete outcome) using retrospectively compiled optical coherence tomography data (50 eyes of 50 patients, 50 healthy eyes of 50 subjects). The data were analyzed with nested cross-validation (for learning algorithm selection and hyperparameter optimization)., Results: Based on nested cross-validation for training, visual acuity could be predicted in the separate test data-set with a mean absolute error (MAE, 95% confidence interval, CI of 0.142 LogMAR [0.077; 0.207]). Healthy versus diseased eyes could be classified in the test data-set with an agreement of 0.92 (Cohen's kappa). The exemplary incorrect learning algorithm and variable selection resulted in an MAE for visual acuity prediction of 0.229 LogMAR [0.150; 0.309] for the test data-set. The drastic overfitting became obvious on comparison of the MAE with the null model MAE (0.235 LogMAR [0.148; 0.322])., Conclusion: Selection of an unsuitable measure of the goodness-of-fit, inadequate validation, or withholding of a null or reference model can obscure the actual goodness-of-fit of AI models. The illustrated pitfalls can help clinicians to identify such shortcomings.

Degenerative vitreous opacities (also known as myodesopsia) can cause permanent and relevant visual impairment. Neodymium-YAG laser vitreolysis is an alternative treatment option to pars plana vitrectomy for the treatment of disturbing degenerative vitreous opacities. This article critically discusses the different causes of vitreous opacities, the symptoms and functional impairments as well as clinical patient management. The aim is to support patient-oriented care and counselling of patients with vitreous opacities.

With the use of digital imaging systems and the possibilities of data exchange, the second opinion is becoming increasingly more important in retinal imaging. For a meaningful application, technical imaging requirements and medical assessment quality requirements have to be fulfilled. Responsibilities should be clearly defined. The aim must be to achieve a significant contribution to ensure high-quality patient care.

Background: Currently, no validated clinical endpoints for treatment studies exist for intermediate age-related macular degeneration (iAMD)., Objective: The European MACUSTAR study aims to develop and clinically validate adequate clinical endpoints for future treatment studies in iAMD and to identify early determinants of disease progression to late stage AMD., Material and Methods: The MACUSTAR study protocol was developed by an international consortium of researchers from academia, the pharmaceutical industry and medical device companies. The MACUSTAR project is funded by the Innovative Medicines Initiative 2 (IMI2) of the European Union., Results: The MACUSTAR study consists of a cross-sectional and a longitudinal investigation. A total of 750 subjects with early, intermediate and late AMD as well as control subjects with no signs of AMD will be included with a follow-up period of 3 years. Overall, 20 European study centers are involved., Conclusion: The MACUSTAR project will generate large high-quality datasets, which will allow clinical validation of novel endpoints for future interventional trials in iAMD. The aim is that these endpoints will be accepted as suitable for medication approval studies by the regulatory authorities and that understanding of the disease process will be improved.

Background: The ORCA module of the non-interventional OCEAN study investigated the use of retinal imaging diagnostics in the clinical treatment of patients undergoing vascular endothelial growth factor (VEGF) inhibitor treatment as part of routine clinical care. This article analyzes the agreement between the diagnosis documented by the treating ophthalmologist and the evaluation of reading centers at baseline as well as the effect on the response to treatment during the course., Methods: A total of 396 patients (age 75.4 years) were enrolled in which ranibizumab treatment was indicated by the treating ophthalmologist due to either diabetic macular edema (DME), neovascular age-related macular degeneration (nvAMD) or retinal venous occlusion (RVO). Over a period of 24 months, patient and examination data, treatments and interpretation of retinal imaging data by the treating ophthalmologist were systematically recorded. Furthermore, retinal imaging data were also evaluated by three reading centers., Results: In 338 out of 396 (85.4%) study eyes, the baseline diagnosis of the treating ophthalmologist was confirmed by the reading centers (DME 87.5%, nvAMD 82.3%, RVO 94.9%). In 17 of the remaining 58 eyes with a discrepant diagnosis, there was at least a consensus with respect to the indications for VEGF inhibitor therapy. The differential diagnoses included a variety of different retinal diseases. During follow-up of up to 3 months, eyes with a consistent diagnosis showed a clear increase in visual acuity (6.4 versus 2.7 letters, p = 0.05) and greater decrease in central retinal thickness (-112.3 versus -24.4 μm, p < 0.0001)., Discussion: The initial treatment decision for anti-VEGF therapy with consideration of the differential diagnoses can be challenging. Accurate evaluation of the clinical and imaging findings along with appropriate expertise appear to be important. The observation of superior initial response in eyes with a consensus of the diagnosis at baseline underlines the relevance of an adequate initial assessment for a successful treatment outcome.

YAG laser vitreolysis is an innovative procedure to treat symptomatic vitreous floaters. The treatment decision is based on taking a comprehensive patient history, thorough clinical examination, realistic expectations, and detailed patient information including risk of the procedure. Manifestation of vitreous opacities and possible subjective impairments are considerably variable. Dynamic changes over time are possible. Therefore, not all vitreous opacities are suitable for laser treatment. A classification according to histoanatomical origin can aid the treatment decision. In comparison to other ophthalmic YAG laser applications, YAG laser vitreolysis differs predominantly by its specific technical equipment requirements. In addition, treatment is more complex and time consuming, requires appropriate experience and knowledge of the surgeon, and should be carried out with utmost care and accuracy.

Purpose: In daily practice, vitreomacular traction (VMT) is described by the horizontal diameter of its attachment site implying a regular round shape of VMT. We investigated the deviation from this circular area of vitreous traction in patients with VMT., Methods: A retrospective analysis of optical coherence tomography (OCT) scans was performed. The area of vitreomacular attachment was determined using six radial OCT scans (A measured ). The assumed circular area of traction was calculated based on measuring the maximal horizontal diameter for comparison (A circular )., Results: Thirty-seven eyes of 37 patients with pure VMT were included. Patients' mean age was 72.8 ± 8.2 years. Mean horizontal VMT diameter was 400.8 ± 230.5 μm (median 361 μm; range 44-991 μm). While there was no difference between mean areas of traction for A circular and A measured (P = 0.93), the individual difference (|A circular  - A measured |) was 0.042 (± 0.044) mm 2 in mean or relative 73.0% (± 135.8%). A difference of ≥ 30% of A measured to A circular was found in 16 eyes (43.2%) and ≥ 100% in 7 eyes (18.9%), respectively., Conclusion: Vitreous attachment sites possess an irregular non-circular shape in a significant number of eyes with VMT. Consequently, the area of traction appears inaccurately described by its horizontal VMT diameter alone. As the area of traction is important for therapeutic recommendation, our results emphasize the need for a more precise description of the area of traction in eyes with VMT.

Purpose: To evaluate the agreement and predictability of ocriplasmin treatment effects among retinal experts (raters) by assessment of retinal imaging data of eyes treated for vitreomacular traction in nine different centers in Germany and Austria., Methods: Retrospective cohort study. Combined confocal near-infrared scanning laser ophthalmoscopy and spectral-domain optical coherence tomography images (Spectralis® device, Heidelberg Engineering GmbH, Germany) from 136 eyes of 135 subjects were reviewed by 14 raters using an internet-based grading database and a standardized questionnaire. In addition to the images taken within 2 days prior to treatment, age, gender, and lens status were disclosed to the raters. Treatment success was defined as a complete cleavage of the posterior vitreous cortex at day 28±5. Main outcome was the agreement and predictability among raters for assessment of treatment success., Results: Raters generally accepted starting ocriplasmin treatment (chance for treatment success ≥ 1%) in 22.4 to 69.1% (median 53.2%) of eyes (moderate intra- and interrater agreements with kappa-values of 0.6 and 0.48). The likelihood for a high potential treatment success (equal or higher than 25%) was judged by the raters in 43.4% to 86.0% (median 62.6%) of eyes (moderate intra- and fair interrater agreements with kappa-values of 0.56 and 0.22). Allocating eyes for high potential treatment success overall increased the odds by 3.07, with odds ratios of single raters up to 4.06 to 6.16., Conclusions: These results underscore the importance of training health care providers in the evaluation of retinal imaging data and also to define characteristic morphological features better in the presence of vitreoretinal interface diseases. The better results of single raters in the predictability of treatment success by the allocation of eyes in the high-potential group indicates the high relevance of the meticulous analysis of retinal images.

Optical coherence tomography (OCT) imaging now plays an important role in the management of macular and retinal diseases. In addition to the many advantages of this noninvasive imaging modality, limitations and pitfalls should be taken into consideration. The aim of this review is to discuss several possible sources of error in the conduct and interpretation of OCT imaging. Ultimately, this article should add to a meaningful and focused use in clinical practice.

Background: Due to current demographic trends, the prevalence of mild cognitive impairment and dementia is expected to increase considerably. For potential new therapies it is important to identify patients at risk as early as possible. Currently, there is no population-based screening. Therefore, identification of biomarkers that will help screen the population at risk is urgently needed. Thus, a literature review on retinal pathology in neurodegenerative diseases was performed., Methods: PubMed was searched for studies published up to August 2016 using the following keywords: "mild cognitive impairment", "dementia", "eye", "ocular biomarkers", "OCT" and "OCT angiography". Relevant publications were selected and summarized qualitatively., Results: Multiple studies using noninvasive in vivo optical coherence tomography (OCT) imaging showed nonspecific retinal pathological changes in patients with neurodegenerative diseases such as mild cognitive impairment, Alzheimer's and Parkinson's disease. Pathological changes in macular volume, optic nerve fiber layer thickness and the ganglion cell complex were observed. However, based on available evidence, no ocular biomarkers for neurodegeneration which could be integrated in routine clinical diagnostics have been identified., Conclusion: The potential use of OCT in the early diagnostic workup and monitoring of progression of neurodegenerative diseases needs to be further explored in longitudinal studies with large cohorts.

Purpose: Optical coherence tomography angiography (OCT‑A) allows for the non-invasive, three-dimensional visualization of retinal and chorioidal vascular structures. In this study, this new imaging modality was evaluated in rats., Methods: In vivo imaging in Dark Agouti rats was performed using confocal scanning laser ophthalmoscopy (cSLO) and OCT‑A (Spectralis prototype, Heidelberg Engineering) after adjusting the length of the reference arm. The OCT‑A en-face images were compared to conventional fluorescein angiography cSLO images. The histological examination allowed for correlation of retinal and chorioidal plexus., Results: While the diagnostic device was developed for use in humans, OCT‑A and cSLO imaging can be applied in rodents after only minor hardware modifications. High-resolution and contrast-enhanced images enable a depth-selective visualization of the three retinal plexus and the inner and outer chorioidal vascular networks. In comparison to fluorescein angiography (FA), OCT‑A is characterized by higher resolution and more accurate three-dimensional localization of vascular structures, particularly in deep layers. A current limitation includes the relatively small area imaged by OCT‑A., Discussion: The recently developed OCT‑A imaging technology also allows for three-dimensional detection of retinal and chorioidal vascular changes in vivo without dye injection in rodents. OCT may potentially replace invasive FA for specific questions and will be useful in animal models for research of retinal and chorioidal angiogenic processes physiologically and during pharmacological interventions.

Background: The prevalence of blindness as defined by law could be reduced by the introduction of anti-vascular endothelial growth factor (VEGF) therapy. Because the treatment is governed by patient needs, mostly using morphological criteria, imaging diagnostics are of particular importance. The non-interventional OCEAN study investigates the treatment with ranibizumab in the clinical routine practice. In a subgroup of patients the interpretation of spectral domain optical coherence tomography (SD-OCT) scans by the treating physicians will be analyzed (ORCA module)., Methods: Over a period of 24 months data from patients with exudative age-related macular degeneration (AMD), macular edema due to retinal vein occlusion or diabetes mellitus, who are receiving intravitreal injections of ranibizumab, will be assessed. Information on examinations, visual acuity, treatment and recordings from imaging techniques will be documented using a questionnaire. The SD-OCT scans, fluorescence angiography and fundus photography will be independently analyzed by the ophthalmologist of the study center and by three reading centers (CIRCL Cologne, GRADE Bonn and M3 Münster). Automated measurements of retinal thickness by the manufacturers' software will be checked and if necessary manually corrected. A qualitative interpretation in terms of morphological criteria for (further) treatment will be performed., Conclusion: A thorough assessment of SD-OCT images during anti-VEGF therapy provides the basis for the best possible needs-oriented treatment regimen. The control of the quality of data from daily routine practice may indicate possible weaknesses allowing explicit training and therefore optimization of patient treatment.

Background: The largest German prospective non-interventional ophthalmological study OCEAN (NCT02194803) investigates the treatment of retinal diseases with ranibizumab in routine patient care. A feature of this study is the participation of ophthalmic surgeons in surgical centers as well as general ophthalmologists who do not perform intravitreal injections themselves., Objectives: The functional outcome following administration of three intravitreal injections was analyzed with respect to the time from initial examination to the first injection (defined as treatment delay) as well as potentially confounding factors., Material and Methods: This interim analysis included only data from therapy naïve patients participating in the OCEAN study, who received at least three ranibizumab injections. The potential impact of various factors on treatment delay was analyzed by the χ(2)-test., Results: Data of 1333 patients were analyzed. The median delay before treatment was 15 days (range 0-90 days). Patients with a delay of more than 28 days showed a significantly lower gain in visual acuity than patients with a delay of less than 14 days. Age, gender and baseline visual acuity did not show an association with the treatment delay; however, referral from a primary care ophthalmologist, undertaking fluorescein angiography in an external practice and the underlying indications did affect the observed treatment delays., Conclusion: Every patient should be treated within 14 days, following recent recommendations of the ophthalmological societies. Liability issues have to be considered as the statistical evaluation of real life data showed unambiguous results.

Purpose: To determine fundus autofluorescence (FAF) signal variations and corresponding microstructural alterations on spectral-domain optical coherence tomography (SD-OCT) in areas of funduscopically visible drusen associated with age-related macular degeneration (AMD)., Methods: Thirty eyes from 22 patients with geographic atrophy (GA) secondary to AMD (median age 74, range 64-87 years), who had undergone retinal imaging including color fundus photography (CFP), FAF and SD-OCT (Spectralis HRA+OCT; Heidelberg Engineering GmbH, Heidelberg, Germany) were retrospectively analyzed. In each eye, at least one druse (≥ 63 μm) in the perilesional zone of GA recorded on CFP was analyzed. Relative FAF intensities and alterations in SD-OCT bands at the site of each druse were evaluated., Results: A total of 73 drusen were analyzed, which were associated with heterogeneous corresponding alterations on FAF and SD-OCT. The FAF signal was normal, increased, decreased or not evaluable in 32 (44 %), 27 (37 %), 12 (16 %), and 2 (3 %) drusen, respectively. Focal hyperreflectivity overlying drusen was most frequently spatially confined to increased FAF (present in 9 (33 %) of 27 drusen with increased FAF). Outer nuclear layer thinning and choroidal hyperreflectivity were associated with decreased FAF (present in 7 [58 %] of 12 and 6 [50 %] of 12 drusen with decreased FAF, respectively)., Conclusions: The appearance of soft drusen on CFP does not allow for differentiation between preserved and markedly compromised outer retinal integrity, including incipient atrophy and focal neurosensory alterations of reflectivity overlying extracellular sub-retinal pigment epithelium (RPE) deposits. Multimodal imaging reveals a broad spectrum of microstructural changes, which may reflect different stages in the evolution of drusen.

Aim: The aim of the study was the analysis of reticular drusen (RDR) in patients with age-related macular degeneration using simultaneous confocal scanning laser ophthalmoscopy (cSLO) and spectral domain optical coherence tomography (SD-OCT) at different time points., Methods: Included in this retrospective analysis were 47 eyes from 32 patients (median age 80.1 years, range 66-89 years) with RDR at baseline and at least one follow-up visit. Registration of the cSLO near-infrared reflectance image and the SD-OCT B-scan (Spectralis HRA + OCT, Heidelberg Engineering, Heidelberg) at different time points was carried out using the AutoRescan tool., Results: While either no alterations or increase in the RDR area (n=19 eyes) or RDR density (n=15) were seen by cSLO imaging, the analysis of the SD-OCT B-scans at different time points revealed a more complex picture. An increase in two well visible lesions at the baseline visit was detected in 8 eyes at the first follow-up and in 3 eyes at the second follow-up examination. A regression was seen in 5 eyes at the first follow-up and in 3 eyes at the second follow-up visit. In most eyes (n=23), an increase of one with a parallel decrease of the second RDR lesion in the identical B-scan was identified at the first follow-up visit, whereas individual RDR showed an increase at the second follow-up examination that had initially shown a decrease in size at the first follow-up visit., Conclusions: The results indicate underlying dynamic processes in the development and changes of RDR over time. For a more accurate analysis, the exact registration of SD-OCT B-scans at different time points and the use of high-resolution very dense volume scans would be helpful in order to assess such discrete changes of miniscule intraretinal lesions over time.

The development of imaging technologies has contributed to the understanding of the genesis and pathophysiological mechanisms of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Fundus autofluorescence (FAF) imaging allows accurate discrimination of the boundaries of atrophic patches. Furthermore, predictive markers for disease progression can be identified. Non-invasive FAF imaging now represents the gold standard for evaluating progressive enlargement of atrophic areas. By means of high resolution optical coherence tomography (OCT) microstructural retinal changes in GA can be identified. Anatomical endpoints are now being used in interventional GA trials and represent meaningful outcome parameters as surrogate markers in an overall slowly progressive disease which may not affect the fovea until later stages of the disease.

Geographic atrophy (GA) as the late stage manifestation of age-related macular degeneration (AMD) is a progressive disease process afflicting the retinal pigment epithelium, choriocapillaris and the outer neurosensory retina. GA represents a complex, multifactorial disease governed by the interdependence of genetic, endogenous and exogenous factors. Diagnosis and monitoring of GA progression is largely based on various retinal imaging modalities. After the breakthrough in the treatment of wet AMD GA represents a large clinical challenge. Recent studies have contributed to a better understanding of the pathophysiological pathways, natural history and predictive markers for progression.

Background: Fundus autofluorescence (AF) imaging using confocal scanning laser ophthalmoscopy (cSLO) has been shown to be superior to fundus photography or angiography for delineating areas of geographic atrophy (GA) in retinal pigment epithelium (RPE) and for recording variation over time. We have evaluated a method for automated computerized detection and quantitation of RPE atrophy., Methods: AF images in vivo were recorded with a confocal scanning laser ophthalmoscope (exc. 488 nm, em. >500 nm; Heidelberg Retina Angiograph). The intensity of AF in atrophic areas was markedly decreased. Two independent readers analysed these areas in 24 right eyes manually by outlining GA areas using a mouse-driven arrow (method A) and automatically by image analysis software (Global Lab Image/2) after subjective adjustment of thresholding (method B). Agreement between observers and between methods A and B was assessed by the Bland-Altman design for method-comparison studies., Results: Larger areas were measured using method A than B by both readers (agreement A/B: reader 1 mean difference 1.04 mm, 95% CI [0.66,1.42]; reader 2 mean difference 0.62 mm, 95% CI [0.43,0.81]). The agreement between the readers was mean difference 0.39 mm (95% CI [0.02,0.76]) for A and mean difference -0.03 mm (95% CI [-0.23,0.18]) for B. Features making the delineation of borders of GA difficult included large choroidal vessels with autofluorescent properties in the GA area and media opacities., Conclusions: Fundus AF cSLO imaging provides a reliable means to delineate areas of GA. The automated image analysis allows more accurate detection and quantitative documentation of atrophic areas than manual outlining. This method will be useful in longitudinal natural history studies and for monitoring effects of future therapeutic interventions to slow down GA progression in patients with advanced atrophic ARMD and other retinal diseases associated with outer retinal atrophy.