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The purpose of this prospective case-control study is to investigate differences in quantitative autofluorescence (qAF) in clinically affected and unaffected eyes of patients with inactive posterior uveitis compared to healthy, age-matched controls. Patients with posterior uveitis and healthy controls were imaged using fundus autofluorescence (488 nm excitation; Spectralis HRA + OCT; Heidelberg Engineering) to measure qAF values using the proprietary HEYEX software. Mean background qAF (excluding vessels and retinal lesions) across all segments (as previously defined by Delori et al.) and in the segment with the highest mean qAF value were compared between affected and unaffected eyes from patients with posterior uveitis, and healthy age-matched control eyes using the Kruskal-Wallis-test. A total of 83 eyes from 83 patients were included: 33 affected eyes (33 patients with uni-/bilateral posterior uveitis), 21 clinically unaffected eyes (21 patients with unilateral posterior uveitis), and 29 healthy, age-matched control eyes (29 patients). Mean qAF values were significantly higher (p-value < 0.0001) in both clinically affected (177.0 ± 83.8 qAF arbitrary units [qAF a.u.]) and unaffected (173.8 ± 56.4 qAF a.u.) eyes compared to healthy, age-matched controls (135.7 ± 41.8 qAF a.u.). Likewise, mean qAF in the segment with the highest mean qAF value was significantly higher (p-value: <0.01) in affected (243.2 ± 103.1 qAF a.u.) and unaffected eyes (227.1 ± 63.4 qAF a.u.) in comparison to controls (168.9 ± 48.5 qAF a.u.). In conclusion, both clinically affected and unaffected eyes from patients with posterior uveitis demonstrated increased fundus autofluorescence. The results of our study could indicate subclinical inflammation in currently inactive and (yet) unaffected eyes of posterior uveitis patients. This could be caused by accumulation of fluorophores or an increased metabolic activity generated by low-grade inflammation. As these changes may precede future inflammation in yet unaffected eyes, additional longitudinal studies including analysis of eyes with active disease are warranted., Competing Interests: Declarations. Competing interests: ARVO disclosure codes: RPF: Apellis (C), Alimera (C), Allergan (C), Bayer (C, F), Biogen (F), Böhringer-Ingelheim (C), Caterna (C), Novartis (C), Opthea (C), ODOS (C), ProGenerika (C), Roche/Genentech (C), Stada Pharm (C) JJ: none MDJ: none JHT: Heidelberg Engineering (F), Optos (F), Zeiss (F), CenterVue (F), Novartis (R), Okko (R) FGH: Acucela (C, F), Alexion (C), Alzheon (C), Allergan (F), Apellis (C, F), Astellas (C), Bayer (C, F), Boehringer-Ingelheim (C), Bioeq/Formycon (F, C), CenterVue (F), Ellex (F) Roche/Genentech (C, F), Geuder (C, F), Graybug (C), Gyroscope (C), Heidelberg Engineering (C, F), IvericBio (C, F), Janssen (C), Kanghong (C, F), LinBioscience (C), NightStarX (F), Novartis (C, F), Optos (F), Oxurion (C), Pixium Vision (C, F), Oxurion (C), Stealth BioTherapeutics (C), Zeiss (F, C), GRADE Reading Center RL: none TA: Apellis (C), Bayer (C), Novartis (F, R), Roche (C), Heidelberg Engineering (C) MWMW: ASKIN & CO GmbH (R), Bayer AG (R), Baxter Healthcare Corporation (F), Berlin-Chemie AG (R, F), CenterVue SpA (F), Carl Zeiss Meditec (F), D-Eye Srl (F), DigiSight Technologies (R, F), Eyenuk, Inc. (F), glaucare GmbH (O, C), Heine Optotechnik GmbH (C, R, F), Heidelberg Engineering (R, F), Novartis Pharma GmbH (R, F), Optos (F) Pro Generika e.V. (R), Science Consulting in Diabetes GmbH (R)., (© 2025. The Author(s).)

For the conduct of future interventional age-related macular degeneration (AMD) trials, the availability of clinical study endpoints is key. However, no endpoints have been accepted by regulators for evaluation of treatment for intermediate (i) AMD, i.e. the AMD stage at highest risk of developing irreversible geographic atrophy or macular neovascularization. The European MACUSTAR consortium has recruited more than 700 individuals to develop and validate structural, functional and patient-reported endpoints, enabling future iAMD trials based on a prospective observational, multi-centre cohort study. Reliably assessing candidate endpoints in a setting that involves multiple clinical sites across countries comes with a plurality of challenges in the study set-up, quality of data, recruitment of participants and study conduct. Therefore, the MACUSTAR consortium has established a framework that successfully addresses these topics, provides relevant insights into the natural history of iAMD and its sub-phenotypes, and will open new regulatory pathways. The MACUSTAR study is registered on ClinicalTrials.gov under NCT03349801., Competing Interests: Competing interests: Jan Henrik Terheyden: Heidelberg Engineering, Optos, Zeiss, CenterVue (now iCare), Novartis, Okko. Hannah M. P. Dunbar: Boehringer Ingelheim. Steffen Schmitz-Valckenberg: AlphaRET, Apellis, Bayer, Carl Zeiss Meditec, eyeDNA, Formycon, Galimedix, Heidelberg Engineering, Katairo, Kubota Vision, Novartis, Perceivve Therapeutics, Pixium, Roche, Sparing Vision. Charlotte Behning: None. Cecília Martinho: None. Ulrich F.O. Luhmann: Employee of and financial interest in F. Hoffmann-La Roche Ltd. Marlene Saßmannshausen: Heidelberg Engineering, Optos, Zeiss. Anna Lüning: None. Alexandra Miliu: None. Inês Aires: None. Pier Basile: None. Joana Batuca: None. Matthias Schmid: Pixum Vision. Klaus-Peter Moll: Employee of Novartis. Nadia Zakaria: Employee of Novartis. Adnan Tufail: Allergan, Bayer, Kanghong, Heidelberg Engineering, Novartis, Roche/Genentech, Iveric Bio, Apellis, Theá. Alison Binns: Apparatus and method for retinal measurement; Patent number 9492081; Boehringer-Ingelheim. David P. Crabb: Apellis, Santen, Allergan/Abbvie, Janssen; Thea. Sergio Leal: Employee of Bayer Pharma AG. Robert P. Finger: Alimera, Apellis, Bayer, Boehringer-Ingelheim, Novartis, ODOS, Oxford Innovation, ProGenerika, Roche/Genentech, Biogen, Icare, Heidelberg Engineering, Carl Zeiss Meditec. Frank G. Holz: Allergan, Annexon, Alzheon, Apellis, Astellas, Bayer, Boehringer-Ingelheim, Bioeq/Formycon, CenterVue (now iCare), Roche/Genentech, 4D Molecular Therapeuticcs, Geuder, Grayburg, Heidelberg Engineering, IvericBio/Astellas, Janssen, LinBiosciences, NightStarX, Novartis, Optos, Oxurion, Pixium Vision, Stealth BioTherapeutics, Carl Zeiss Meditec, Grade Reading Center., (© 2025. The Author(s).)

Background: Until now, Schnabel's cavernous optic nerve atrophy (SCONA) has solely been a histopathological diagnosis exhibiting variable degrees of optic nerve (ON) atrophy with characteristic cavernous spaces filled with acid mucopolysaccharides. We report the first correlation of histopathologic findings with spectral domain-optical coherence tomography (SD-OCT) imaging in SCONA., Methods: We examined the eye of an index patient with histopathologically identified SCONA who had undergone multimodal imaging before enucleation for iris ring melanoma. The extent of SCONA in the index patient and three other enucleated eyes with SCONA were determined histopathologically. The histopathological findings of our index patient were correlated with in vivo SD-OCT images before enucleation and compared to representative images from eyes with a normal versus glaucomatous optic disc., Results: Histopathologic examination of our index patient showed a pre- and intralaminar extension of SCONA. Atrophy of the inner retinal layers was observed corresponding to the extent of SCONA. Correlation with SD-OCT showed small intralaminar hyporeflective pseudocysts which were detected in multiple scans corresponding to the histologically affected areas. These changes were neither visible in scans of patients with glaucomatous atrophy nor those with a normal ON., Conclusions: We present the first correlation of clinical and pathological findings in SCONA and were able to identify distinct SD-OCT characteristics for this condition. These findings may help to detect SCONA in vivo and to study this rare entity clinically with regard to its clinical course, risk factors, and pathogenesis. However, more cases of SCONA are needed to confirm our findings., Competing Interests: Competing interests: FGH, TA: Consultant for Heidelberg Engineering. MCH-C (non-financial): Secretary of the International Society of Ophthalmic Pathology (ISOP), Member of the section committee “Ophthalmic Pathology” within the German Ophthalmological Society (DOG), Member of the “Annual Meeting Program Committee” of ARVO for the section “Anatomy Pathology (AP)”. Ethics: This study involves human participants and was approved by an Ethics Committee. All our patients sign an informed consent that the histologic sections can be used for study purposes. This was approved by the Ethics Committee of the University of Bonn (328/16)., (© 2025. The Author(s).)

Competing Interests: Competing interests: Ashish Sharma; Consultant- Intas, Lupin, Bayer, Allergan, Novartis. Peter K Kaiser; Aerie, Allegro, Allergan, Allgenesis, Alzheon, Annexon Biosciences, AsclepiX, Aviceda, Bayer, Bausch and Lomb, Biogen Idec, Bionic Vision Technologies, Boehringer Ingelheim, Carl Zeiss Meditec, Clearside Biomedical, DelSiTech, DTx Pharma, Duet Therapeutics, Eyevensys, Galecto Biotech, Galimedix, Gemini Therapeutics, Glaukos, Innovent, iRenix, Iveric Bio, jCyte, Kanaph Therapeutics, Kanghong, Kodiak, LensGen, NGM Biopharmaceuticals, Inc., Novartis, Ocugenix, Oculis, Ocuphire, OcuTerra Therapeutics Inc., Omeros, Opthea, Oxurion, Palatin, Regeneron, RegenxBio, Retinal Sciences, Retrope, Roivant, Samsung Bioepis, Sandoz, Santen, Stealth Biotherapeutics, Sustained Nano Systems, Takeda, Théa, Ramin Tadayoni; AbbVie Allergan, Alcon, Apellis, Bayer, Boehringer Ingelheim, Genentech, Iveric Bio, KHB, Novartis, Oculis, Roche, Thea, Zeiss. Frank G Holz-F.G. Holz reports research grants and personal fees from Acucela, Allergan, Apellis, Bayer, Bioeq/Formycon, Roche/Genentech, Geuder, Heidelberg Engineering, ivericBio, Pixium Vision, Novartis, Zeiss; personal fees from Alexion, Grayburg Vision, LinBioscience, Stealth BioTherapeutics, Aerie, Oxurion. Luke Nicholson Optos (research funding), Bayer (Speaker fees), Abbvie (Speaker fees, advisory board), Roche (Speaker fees, Heidelberg (Speaker fees)). Clara Vazquez-Alfageme None. Sobha Sivaprasad- Dr Sivaprasad reported receiving financial support from AbbVie, Amgen, Apellis, Bayer, Biogen, Boehringer Ingelheim, Novartis, Eyebiotech, Eyepoint Phamaceuticals, Janssen Pharmaceuticals, Nova Nordisk, Optos, Ocular Therapeutix, Kriya Therapeutics, OcuTerra, Roche, Stealth Biotherapeutics. Dr Sivaprasad is Editor in Chief of Eye. Taku Wakabayashi; None. Se Joon Woo- Dr Woo reported serving as a consultant for Samsung Bioepis and Panolos Bioscience; being cofounder of Retimark; serving as an advisory board member of Novartis and Novelty Nobility; receiving grants and personal fees from Samsung Bioepis, Novartis, Novelty Nobility, Alteogen, Kookje, and Curacle; and receiving lecture fees from Novartis, Bayer, Allergan, AbbVie, Alcon, Taejoon, SCAI Therapeutics, and Alteogen. David Sarraf; Amgen, Bayer, Endogena Therapeutics, Genentech, Iveric Bio, Novartis and Optovue/Visionix and receives research grants from Amgen, Boehringer, Genentech, Heidelberg, Optovue/Visionix, Regeneron, and Topcon. Nilesh Kumar; Lupin and Intas. Nikulaa Parachuri-None. Carl D Regillo-Adverum, Allergan, Annexon, Bausch and Lomb, Clearside, Eyepoint, Genentech/Roche, Iveric, Novartis, Kodiak, Notal, Merck, Ocular therapeutics, Regenxbio, Stealth, Takeda, Zeiss and receives research support from Adverum, Allergan, Annexon, Eyepoint, Genentech/Roche, Novartis, Kodiak, Iveric, Regenxbio, Regeneron. Kourous A Rezaei- Consultant for Alcon Laboratories. Arshad M Khanani- Consultant: Adverum, Aerpio, Alimera, Allergan, Apellis, Asclepix, Aviceda, Bausch and Lomb, Broadwing Bio, Chengdu Kanghong, Cholgene, 4DMT, Dutch Ophthalmic Research Center, Gemini, Genentech, Glaukos, Graybug, Gyroscope, Iveric Bio, Janssen, Kato Pharma, Kodiak, Oculis, Opthea, Oxurion, Novartis, Polyphotonix, Recens Medical, Regeneron, Retrotope, Regenxbio, Roche, Surrozen, Thea, Unity Bio Research Support: Adverum, Apellis, Asclepix, Chengdu Kanghong, 4DMT, Gemini, Genentech, Graybug Vision, Gyroscope, Iveric Bio, Kodiak, Neurotech, NGM Bio, Ocular Therapeutix, Oculis, Opthea, Oxurion, Novartis, Recens Medical, Regenxbio, Roche, Unity Bio Equity: Aviceda, Gyroscope, Recens Medical, Retrotope, PolyphotonixSpeaker: Allergan, Genentech, Novartis. Francesco Bandello; CONSULTANT: Allergan, Bayer, Boehringer- Ingelheim, FidiaSooft, Hofmann La Roche, Novartis, NTC Pharma, Sifi, Thrombogenics, Zeiss. Mahesh Shanamugam; None. Lalit Verma; Consultant to Novartis, Bayer, Intas. Mangat Ram Dogra; None. NS Muralidhar; None. Manisha Agarwal; None. Anat Loewenstein; CONSULTANT: Allergan, Novartis, Roche, Notal Vision, Fiorsightslabs, Beyeonics, Bayer Health Care. Baruch D Kuppermann CLINICAL RESEARCH: Alcon, Alimera, Allegro, Allergan, Apellis, Clearside, Genentech, GSK, Ionis, jCyte, Novartis, Regeneron, ThromboGenics; CONSULTANT: Alimera, Allegro, Allergan, Cell Care, Dose, Eyedaptic, Galimedix, Genentech, Glaukos, Interface Biologics, jCyte, Novartis, Ophthotech, Regeneron, Revana, Theravance Biopharma, Dr Kuppermann acknowledges an unrestricted grant from Research to Prevent Blindness to the Gavin Herbert Eye Institute at the University of California, Irvine.

Macular Telangiectasia Type 2 (MacTel) is a chronic, progressive disease of the central retina characterized by vascular and neurodegenerative changes. As there is currently no treatment for non-neovascular MacTel, there is a dearth for biomarkers identifying eyes with an increased risk for disease progression for patient counseling and clinical trial recruitment. Eyes were classified to be stable or progressive, defined by the fundus photography-based grading system by Gass and Blodi. First, structural differences between these two groups were assessed, employing optical coherence tomography (OCT) and OCT-angiography. Univariate regression analyses revealed evidence towards a lower superficial retinal layer (SRL) vessel density (VD), skeleton density (SD) and deep retinal layer (DRL) SD in progressing compared to stable eyes (p = 0.05, p = 0.05, p = 0.07). Second, a multivariable predictive model was employed to examine the predictive value of structural and functional parameters for disease progression. Baseline best corrected visual acuity (BCVA) and SRL SD are prognostic for disease progression (p < 0.001, p = 0.05). The presence of ellipsoid zone (EZ) loss is prognostic for future central retinal thickness (p < 0.01). We propose SRL SD, BCVA, and EZ loss as prognostic biomarkers and as possible outcome measures in future interventional studies in MacTel., (© 2024. The Author(s).)

As most rare diseases, intermediate uveitis lacks reliable endpoints necessary for randomized clinical trials. Therefore, we investigated longitudinal changes of retinal and choriocapillaris perfusion on optical coherence tomography angiography (OCT-A) in intermediate uveitis and their prognostic value for future best corrected visual acuity (BCVA) and central retinal thickness (CRT). In this retrospective, longitudinal cohort study eyes of patients with intermediate uveitis were imaged by swept-source OCT-A (macula-centered 3 × 3 mm; PLEX Elite 9000, Zeiss) and stratified into clinically stable, worsened and improved based on changes in clinical parameters. Superficial (SRL) and deep retinal layers (DRL) were automatically analyzed for vessel density (VD) and choriocapillaris layer for non-perfused area (CCNPA) using ImageJ. Mixed-effects regression analysis controlling for age, sex, and OCT-A signal strength index (SSI) was used to evaluate the prognostic value of OCT-A parameters. 91 eyes (62 stable, 12 worsened, and 17 improved) were included in the analysis and mean follow-up time was 296 days. Longitudinal changes of VD were different between all three groups (p = 0.002 for SRL and p = 0.017 for DRL). Clinically worsened eyes showed a decrease in VD (- 0.032 ± 0.055 for SRL and - 0.027 ± 0.025 for DRL), whereas clinically improved eyes showed an increase in VD (0.037 ± 0.039 for SRL and 0.001 ± 0.023 for DRL). No difference was found for CCNPA. When controlling for age, sex, and SSI, observed differences held true in clinically worsened eyes for DRL (p = 0.011) and in clinically improved eyes for SRL (p = 0.002). An increase of CCNPA in clinically worsened eyes (p = 0.03) compared to clinically stable and improved eyes was evident. Predictive analysis revealed an association of VD in SRL and DRL at baseline with BCVA at follow-up (p = 0.039 and p = 0.047, respectively) and of VD in SRL at baseline with CRT at follow-up (p = 0.046). Alterations in retinal perfusion on OCT-A in intermediate uveitis are partly reversible and OCT-A VD may serve to predict future BCVA and CRT. Thus, perfusion parameters on OCT-A might aid monitoring and serve as prognostic imaging-biomarker., (© 2024. The Author(s).)

This study aimed to determine the retest variability of quantitative fundus autofluorescence (QAF) in patients with and without age-related macular degeneration (AMD) and evaluate the predictive value of patient reliability indices on retest reliability. A total of 132 eyes from 68 patients were examined, including healthy individuals and those with various stages of AMD. Duplicate QAF imaging was conducted at baseline and 2 weeks later across six study sites. Intraclass correlation (ICC) analysis was used to evaluate the consistency of imaging, and mean opinion scores (MOS) of image quality were generated by two researchers. The contribution of MOS and other factors to retest variation was assessed using mixed-effect linear models. Additionally, a Random Forest Regressor was trained to evaluate the extent to which manual image grading of image quality could be replaced by automated assessment (inferred MOS). The results showed that ICC values were high for all QAF images, with slightly lower values in AMD-affected eyes. The average inter-day ICC was found to be 0.77 for QAF segments within the QAF8 ring and 0.74 for peripheral segments. Image quality was predicted with a mean absolute error of 0.27 on a 5-point scale, and of all evaluated reliability indices, MOS/inferred MOS proved most important. The findings suggest that QAF allows for reliable testing of autofluorescence levels at the posterior pole in patients with AMD in a multicenter, multioperator setting. Patient reliability indices could serve as eligibility criteria for clinical trials, helping identify patients with adequate retest reliability., (© 2023. Springer Nature Limited.)

This systematic review and meta-analysis investigated the impact of anti-vascular endothelial growth factor (VEGF) treatment in management of eyes with non-proliferative diabetic retinopathy (NPDR) without centre involving diabetic macular oedema (CI-DMO). We searched multiple databases for all randomised clinical trials (RCTs) that evaluated anti-VEGF treatment versus observation in eyes with NPDR without CI-DMO. Data was collected for six outcomes (best corrected visual acuity (BCVA) improvement, diabetic retinopathy severity score (DRSS), central subfield thickness, progression to vision threatening complications (VTCs), ocular adverse events and quality of life measures). Risk of bias was assessed using Cochrane risk-of-bias tool for randomised trials (RoB 2) and certainty of evidence was assessed using Grade of Recommendations, Assessment, Development and Evaluation (GRADE). We identified a total of 2 unique RCTs that compared aflibercept and sham to treat a total of 811 eyes. For BCVA change, there was a small, clinically insignificant benefit for aflibercept treatment at year 2 (MD 0.70, 95% CI 0.02-1.38, GRADE rating: MODERATE). DRSS demonstrated a statistically significant improvement with aflibercept use at year 2 (RR 3.76, 95% CI 2.75-5.13, GRADE rating: MODERATE). VTCs were significantly less in aflibercept arm at year 2 (RR 0.30, 95% CI 0.23-0.40, GRADE rating: MODERATE). In conclusion, aflibercept treatment versus observation in eyes with NPDR without CI-DMO can result in reduced risk of development of VTCs and regression of DRSS score over 2 years. Future trials are needed to increase the precision of the treatment effect and to provide data on quality-of-life metrics.PROSPERO Registration: CRD42021288608., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

The aim of this review is to identify the common characteristics and prognoses of different subtypes of neovascular age-related macular degeneration (nAMD). We also propose recommendations on how to tailor treatments to the subtype of neovessels to optimise patient outcomes. The authors, selected members of the Vision Academy, met to discuss treatment outcomes in nAMD according to macular neovascularisation (MNV) subtypes, using evidence from a literature search conducted on the PubMed database (cut-off date: March 2019). This review article summarises the recommendations of the Vision Academy on how the characterisation of MNV subtypes can optimise treatment outcomes in nAMD. The identification of MNV subtypes has been facilitated by the advent of multimodal imaging. Findings from fluorescein angiography, indocyanine green angiography and spectral-domain optical coherence tomography collectively help refine and standardise the determination of the MNV subtype. To date, three subtypes have been described in the literature and have specific characteristics, as identified by imaging. Type 1 MNV is associated with better long-term outcomes but usually requires more intense anti-vascular endothelial growth factor dosing. Type 2 MNV typically responds quickly to treatment but is more prone to the development of fibrotic scars, which may be associated with poorer outcomes. Type 3 MNV tends to be highly sensitive to anti-vascular endothelial growth factor treatment but may be associated with a higher incidence of outer retinal atrophy, compared with other subtypes. Accurately assessing the MNV subtype provides information on prognosis and helps to optimise the management of patients with nAMD., (© 2022. The Author(s).)

Background: Pigment epithelial detachments (PEDs) occur in association with various chorioretinal diseases. With respect to the broad clinical spectrum of PEDs we describe fundus autofluorescence (FAF) characteristics of PEDs., Methods: Ninety-three eyes of 66 patients (mean age 71.9 ± 11.1) with uni- or bilateral PED ( ≥ 350 µm) were included in a retrospective cross-sectional study. PEDs were secondary to age-related macular degeneration (n = 79), central serous chorioretinopathy (n = 7), polypoidal choroidal vasculopathy (n = 2), pattern dystrophy (n = 3) or idiopathic PED (n = 2). FAF images were recorded using confocal scanning laser ophthalmoscopy (488 nm excitation wavelength, detection of emission >500 nm). Diagnosis of PED was confirmed using spectral-domain optical coherence tomography. A qualitative FAF grading system was established, and grading was performed by two independent readers., Results: PEDs showed highly variable characteristics on FAF imaging. FAF within the area of PED was found to be irregular/granular (n = 59, 63.4%), increased (n = 28, 30.1%), decreased (n = 3, 3.2 %), or normal (n = 3, 3.2%). Accompanying FAF changes included condensation of macular pigment (n = 67, 72.0%), focally increased FAF at the PED apex (n = 14, 15.1%) or elsewhere (n = 52, 55.9%), focally decreased FAF (n = 23, 24.7%), a cartwheel-like pattern (n = 10, 10.8%), a doughnut sign (n = 6, 6.5%), and a halo of decreased FAF encircling the PED (completely n = 20, 21.5% or incompletely n = 20, 21.5%)., Conclusions: PEDs show a variety of abnormal patterns on FAF imaging. These changes in FAF signals may be secondary to morphological and metabolic alterations within corresponding retinal layers and do not necessarily correspond with the underlying PED subtype or a specific pathology., (© 2022. The Author(s).)

Drusen are hallmarks of early and intermediate age-related macular degeneration (AMD) but their quantification remains a challenge. We compared automated drusen volume measurements between different OCT devices. We included 380 eyes from 200 individuals with bilateral intermediate (iAMD, n = 126), early (eAMD, n = 25) or no AMD (n = 49) from the MACUSTAR study. We assessed OCT scans from Cirrus (200 × 200 macular cube, 6 × 6 mm; Zeiss Meditec, CA) and Spectralis (20° × 20°, 25 B-scans; 30° × 25°, 241 B-scans; Heidelberg Engineering, Germany) devices. Sensitivity and specificity for drusen detection and differences between modalities were assessed with intra-class correlation coefficients (ICCs) and mean difference in a 5 mm diameter fovea-centered circle. Specificity was > 90% in the three modalities. In eAMD, we observed highest sensitivity in the denser Spectralis scan (68.1). The two different Spectralis modalities showed a significantly higher agreement in quantifying drusen volume in iAMD (ICC 0.993 [0.991-0.994]) than the dense Spectralis with Cirrus scan (ICC 0.807 [0.757-0.847]). Formulae for drusen volume conversion in iAMD between the two devices are provided. Automated drusen volume measures are not interchangeable between devices and softwares and need to be interpreted with the used imaging devices and software in mind. Accounting for systematic difference between methods increases comparability and conversion formulae are provided. Less dense scans did not affect drusen volume measurements in iAMD but decreased sensitivity for medium drusen in eAMD.Trial registration: ClinicalTrials.gov NCT03349801. Registered on 22 November 2017., (© 2022. The Author(s).)

Preservation of photoreceptors beyond areas of retinal pigment epithelium atrophy is a critical treatment goal in eyes with geographic atrophy (GA) to prevent vision loss. Thus, we assessed the association of treatment with the complement C3 inhibitor pegcetacoplan with optical coherence tomography (OCT)-based photoreceptor laminae thicknesses in this post hoc analysis of the FILLY trial (NCT02503332). Retinal layers in OCT were segmented using a deep-learning-based pipeline and extracted along evenly spaced contour-lines surrounding areas of GA. The primary outcome measure was change from baseline in (standardized) outer nuclear layer (ONL) thickness at the 5.16°-contour-line at month 12. Participants treated with pegcetacoplan monthly had a thicker ONL along the 5.16° contour-line compared to the pooled sham arm (mean difference [95% CI] + 0.29 z-score units [0.16, 0.42], P < 0.001). The same was evident for eyes treated with pegcetacoplan every other month (+ 0.26 z-score units [0.13, 0.4], P < 0.001). Additionally, eyes treated with pegcetacoplan exhibited a thicker photoreceptor inner segment layer along the 5.16°-contour-line at month 12. These findings suggest that pegcetacoplan could slow GA progression and lead to reduced thinning of photoreceptor layers beyond the GA boundary. Future trials in earlier disease stages, i.e., intermediate AMD, aiming to slow photoreceptor degeneration warrant consideration., (© 2022. The Author(s).)

Quantification of the relative ellipsoid zone reflectivity (rEZR) might be a structural surrogate parameter for an early disease progression in the context of age-related macular degeneration (AMD). Within the European multicenter, cross-sectional MACUSTAR study, we have devised an automatic approach to determine the mean rEZR [arbitrary units, AU] at two independent visits in SD-OCT volume scans in study participants. Linear mixed-effects models were applied to analyze the association of AMD stage and AMD associated high-risk features including presence of pigmentary abnormalities, reticular pseudodrusen (RPD), volume of the retinal-pigment-epithelial-drusenoid-complex (RPEDC) with the rEZR. Intra-class correlation coefficients (ICC) were determined for rEZR reliability analysis. Within the overall study cohort (301 participants), we could observe decreased rEZR values (coefficient estimate ± standard error) of - 8.05 ± 2.44 AU (p = 0.0011) in the intermediate and of - 22.35 ± 3.28 AU (p &lt; 0.0001) in the late AMD group. RPD presence was significantly associated with the rEZR in iAMD eyes (- 6.49 ± 3.14 AU; p = 0.0403), while there was a good ICC of 0.846 (95% confidence interval: 0.809; 0.876) in the overall study cohort. This study showed an association of rEZR with increasing disease severity and the presence of iAMD high-risk features. Further studies are necessary to evaluate the rEZR's value as a novel biomarker for AMD and disease progression., (© 2022. The Author(s).)

Clinical discrimination of posterior uveitis entities remains a challenge. This exploratory, cross-sectional study investigated the green (GEFC) and red emission fluorescent components (REFC) of retinal and choroidal lesions in posterior uveitis to facilitate discrimination of the different entities. Eyes were imaged by color fundus photography, spectrally resolved fundus autofluorescence (Color-FAF) and optical coherence tomography. Retinal/choroidal lesions' intensities of GEFC (500-560 nm) and REFC (560-700 nm) were determined, and intensity-normalized Color-FAF images were compared for birdshot chorioretinopathy, ocular sarcoidosis, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), and punctate inner choroidopathy (PIC). Multivariable regression analyses were performed to reveal possible confounders. 76 eyes of 45 patients were included with a total of 845 lesions. Mean GEFC/REFC ratios were 0.82 ± 0.10, 0.92 ± 0.11, 0.86 ± 0.10, and 1.09 ± 0.19 for birdshot chorioretinopathy, sarcoidosis, APMPPE, and PIC lesions, respectively, and were significantly different in repeated measures ANOVA (p < 0.0001). Non-pigmented retinal/choroidal lesions, macular neovascularizations, and fundus areas of choroidal thinning featured predominantly GEFC, and pigmented retinal lesions predominantly REFC. Color-FAF imaging revealed involvement of both, short- and long-wavelength emission fluorophores in posterior uveitis. The GEFC/REFC ratio of retinal and choroidal lesions was significantly different between distinct subgroups. Hence, this novel imaging biomarker could aid diagnosis and differentiation of posterior uveitis entities., (© 2022. The Author(s).)

Retinal assessments have been discussed as biomarkers for brain atrophy. However, available studies did not investigate all retinal layers due to older technology, reported inconsistent results, or were based on small sample sizes. We included 2872 eligible participants of the Rhineland Study with data on spectral domain-optical coherence tomography (SD-OCT) and brain magnetic resonance imaging (MRI). We used multiple linear regression to examine relationships between retinal measurements and volumetric brain measures as well as fractional anisotropy (FA) as measure of microstructural integrity of white matter (WM) for different brain regions. Mean (SD) age was 53.8 ± 13.2 years (range 30-94) and 57% were women. Volumes of the inner retina were associated with total brain and grey matter (GM) volume, and even stronger with WM volume and FA. In contrast, the outer retina was mainly associated with GM volume, while both, inner and outer retina, were associated with hippocampus volume. While we extend previously reported associations between the inner retina and brain measures, we found additional associations of the outer retina with parts of the brain. This indicates that easily accessible retinal SD-OCT assessments may serve as biomarkers for clinical monitoring of neurodegenerative diseases and merit further research., (© 2022. The Author(s).)

Peripheral arterial disease (PAD) is caused by atherosclerosis and is a common disease of the elderly leading to excess morbidity and mortality. Early PAD diagnosis is important, as the only available causal therapy is addressing risk factors like smoking, hypercholesterolemia or hypertension. However, current diagnostic techniques often do not detect early stages of PAD. We theorize that PAD's underlying cause atherosclerosis can be detected on color fundus photography (CFP) images with a convolutional neural network architecture, which might aid earlier PAD diagnosis and improve disease monitoring. In this explorative study a deep attention-based Multiple Instance Learning (MIL) architecture is used to capture retinal imaging biomarkers on CFP images of 135 examinations. To capture subtle variations in vascular structures, higher image resolution can be utilized by partitioning the CFP into patches. Our architecture converts each patch into a feature vector, and determines its relative importance via an automatically computed attention weight. Our best model achieves an ROC AUC score of 0.890. Visualizing these attention weights provides insights about the network's decision and suggests ocular involvement in PAD. Statistical analysis confirms that the optic disc and the temporal arcades are weighted significantly higher (p < 0.001) than retinal background. Our results support the feasibility of detecting the presence of PAD with a modern deep learning approach., (© 2022. The Author(s).)

Refined understanding of the association of retinal microstructure with current and future (post-treatment) function in chronic central serous chorioretinopathy (cCSC) may help to identify patients that would benefit most from treatment. In this post-hoc analysis of data from the prospective, randomized PLACE trial (NCT01797861), we aimed to determine the accuracy of AI-based inference of retinal function from retinal morphology in cCSC. Longitudinal spectral-domain optical coherence tomography (SD-OCT) data from 57 eyes of 57 patients from baseline, week 6-8 and month 7-8 post-treatment were segmented using deep-learning software. Fundus-controlled perimetry data were aligned to the SD-OCT data to extract layer thickness and reflectivity values for each test point. Point-wise retinal sensitivity could be inferred with a (leave-one-out) cross-validated mean absolute error (MAE) [95% CI] of 2.93 dB [2.40-3.46] (scenario 1) using random forest regression. With addition of patient-specific baseline data (scenario 2), retinal sensitivity at remaining follow-up visits was estimated even more accurately with a MAE of 1.07 dB [1.06-1.08]. In scenario 3, month 7-8 post-treatment retinal sensitivity was predicted from baseline SD-OCT data with a MAE of 3.38 dB [2.82-3.94]. Our study shows that localized retinal sensitivity can be inferred from retinal structure in cCSC using machine-learning. Especially, prediction of month 7-8 post-treatment sensitivity with consideration of the treatment as explanatory variable constitutes an important step toward personalized treatment decisions in cCSC., (© 2021. The Author(s).)

Background: A variety of treatment strategies have been proposed for macular holes that persist or recur after surgery, and the debate about the best re-treatment approach is ongoing. To allow for a comparison with alternative surgical therapies, we assessed the anatomical and functional outcome of a temporary tamponade with conventional silicone oil in persistent or recurrent full-thickness macular holes., Methods: We retrospectively investigated consecutive patients with full-thickness macular holes that persisted or recurred following vitrectomy with internal limiting membrane peeling and gas tamponade. All patients received re-treatment by temporary tamponade of silicone oil and were allowed free postoperative positioning. Anatomical closure rate was assessed by optical coherence tomography, and change of best-corrected visual acuity (BCVA) was analyzed., Results: A total of 33 eyes of 33 consecutive patients were included. Macular hole closure following silicone oil tamponade was achieved in 30 of 33 eyes (90.9%). Median BCVA improved from 1.00 logMAR (interquartile range, 0.60-1.00) to 0.65 logMAR (0.49-1.00; p = 0.010) after silicone oil removal. In patients with macular hole closure, 61.3% exhibited functional improvement with median BCVA changing from 1.00 logMAR (0.70-1.00) to 0.60 logMAR (0.49-1.00; p = 0.0005). Mean minimal linear diameter of macular holes before primary surgery was 391.0 µm (±137.8; range 133-630), and 48.5% of macular holes were >400 µm in diameter., Conclusions: Treatment of persistent or recurrent full-thickness macular holes by temporary conventional silicone oil tamponade without postoperative positioning results in a high closure rate and a significant mean improvement of visual acuity., (© 2020. The Author(s).)

Current guidelines on the management of patients with neovascular age-related macular degeneration (nAMD) lack clear recommendations on the interpretation of fluid as seen on optical coherence tomography (OCT) imaging and the incorporation of this information into an ongoing disease treatment strategy. Our objective was to review current guidelines and scientific evidence on the role of fluid as a biomarker in the management of nAMD, and develop a clinically oriented, practical algorithm for diagnosis and management based on a consensus of expert European retinal specialists. PubMed was searched for articles published since 2006 relating to the role of fluid in nAMD. A total of 654 publications were screened for relevance and 66 publications were included for review. Of these, 14 were treatment guidelines, consensus statements and systematic reviews or meta-analyses, in which OCT was consistently recommended as an important tool in the initial diagnosis and ongoing management of nAMD. However, few guidelines distinguished between types of fluid when providing recommendations. A total of 52 publications reported primary evidence from clinical trials, studies, and chart reviews. Observations from these were sometimes inconsistent, but trends were observed with regard to features reported as being predictive of visual outcomes. Based on these findings, diagnostic recommendations and a treatment algorithm based on a treat-and-extend (T&E) regimen were developed. These provide guidance on the diagnosis of nAMD as well as a simple treatment pathway based on the T&E regimen, with treatment decisions made according to the observations of fluid as a critical biomarker for disease activity., (© 2021. The Author(s).)

Sensitive and robust outcome measures of retinal function are pivotal for clinical trials in age-related macular degeneration (AMD). A recent development is the implementation of artificial intelligence (AI) to infer results of psychophysical examinations based on findings derived from multimodal imaging. We conducted a review of the current literature referenced in PubMed and Web of Science among others with the keywords 'artificial intelligence' and 'machine learning' in combination with 'perimetry', 'best-corrected visual acuity (BCVA)', 'retinal function' and 'age-related macular degeneration'. So far AI-based structure-function correlations have been applied to infer conventional visual field, fundus-controlled perimetry, and electroretinography data, as well as BCVA, and patient-reported outcome measures (PROM). In neovascular AMD, inference of BCVA (hereafter termed inferred BCVA) can estimate BCVA results with a root mean squared error of ~7-11 letters, which is comparable to the accuracy of actual visual acuity assessment. Further, AI-based structure-function correlation can successfully infer fundus-controlled perimetry (FCP) results both for mesopic as well as dark-adapted (DA) cyan and red testing (hereafter termed inferred sensitivity). Accuracy of inferred sensitivity can be augmented by adding short FCP examinations and reach mean absolute errors (MAE) of ~3-5 dB for mesopic, DA cyan and DA red testing. Inferred BCVA, and inferred retinal sensitivity, based on multimodal imaging, may be considered as a quasi-functional surrogate endpoint for future interventional clinical trials in the future., (© 2021. The Author(s).)

Smartphone-based fundus imaging (SBFI) is a low-cost approach for screening of various ophthalmic diseases and particularly suited to resource limited settings. Thus, we assessed how best to upskill alternative healthcare cadres in SBFI and whether quality of obtained images is comparable to ophthalmologists. Ophthalmic assistants and ophthalmologists received a standardized training to SBFI (Heine iC2 combined with an iPhone 6) and 10 training examinations for capturing central retinal images. Examination time, total number of images, image alignment, usable field-of-view, and image quality (sharpness/focus, reflex artifacts, contrast/illumination) were analyzed. Thirty examiners (14 ophthalmic assistants and 16 ophthalmologists) and 14 volunteer test subjects were included. Mean examination time (1st and 10th training, respectively: 2.17 ± 1.54 and 0.56 ± 0.51 min, p < .0001), usable field-of-view (92 ± 16% and 98 ± 6.0%, p = .003) and image quality in terms of sharpness/focus (p = .002) improved by the training. Examination time was significantly shorter for ophthalmologists compared to ophthalmic assistants (10th training: 0.35 ± 0.21 and 0.79 ± 0.65 min, p = .011), but there was no significant difference in usable field-of-view and image quality. This study demonstrates the high learnability of SBFI with a relatively short training and mostly comparable results across healthcare cadres. The results will aid implementing and planning further SBFI field studies.

The purpose of this prospective case-control study was to assess whether parameters of retinal and choriocapillaris perfusion are altered in patients with peripheral arterial disease (PAD). Patients with PAD and healthy controls were imaged with swept-source optical coherence tomography angiography (OCT-A). Macula centered 3 × 3 mm OCT-A scans were acquired, binarized and perfusion was evaluated for vessel density (VD) and choriocapillaris non-perfused area. Clinical examination and non-invasive assessment included Fontaine staging, ankle-brachial-pressure-index (ABI) and vascular color-coded Doppler sonography. Fifty-two patients with PAD and 23 healthy controls were included. Superficial retinal VD was reduced in patients compared to controls (difference =  - 0.013, p = 0.02), decreased with higher Fontaine stage (p = 0.01) and correlated with ABI (r = 0.42, p < 0.0001, 95% confidence interval [CI] 0.23-0.58). Choriocapillaris non-perfused area was larger in patients compared to controls (difference = 3.64%, p = 0.002, 95% CI 1.38-5.90%) and significantly correlated with ABI (r =  - 0.22, p = 0.03, 95% CI - 0.40- - 0.03). Multivariate multiple regression analysis revealed a significant association of all OCT-A parameters with ABI and of deep retinal vessel density and choriocapillaris non-perfused area with Fontaine stage. In this first study of retinal and choroidal perfusion in patients with PAD we found both retinal and choroidal perfusion to be significantly impaired. OCT-A parameters could aid as indirect imaging biomarkers for non-invasive PAD staging and monitoring.

Spatially-resolved retinal function can be measured by psychophysical testing like fundus-controlled perimetry (FCP or 'microperimetry'). It may serve as a performance outcome measure in emerging interventional clinical trials for macular diseases as requested by regulatory agencies. As FCP constitute laborious examinations, we have evaluated a machine-learning-based approach to predict spatially-resolved retinal function ('inferred sensitivity') based on microstructural imaging (obtained by spectral domain optical coherence tomography) and patient data in recessive Stargardt disease. Using nested cross-validation, prediction accuracies of (mean absolute error, MAE [95% CI]) 4.74 dB [4.48-4.99] were achieved. After additional inclusion of limited FCP data, the latter reached 3.89 dB [3.67-4.10] comparable to the test-retest MAE estimate of 3.51 dB [3.11-3.91]. Analysis of the permutation importance revealed, that the IS&OS and RPE thickness were the most important features for the prediction of retinal sensitivity. 'Inferred sensitivity', herein, enables to accurately estimate differential effects of retinal microstructure on spatially-resolved function in Stargardt disease, and might be used as quasi-functional surrogate marker for a refined and time-efficient investigation of possible functionally relevant treatment effects or disease progression.

Here, we investigate the extent to which re-implementing a previously published algorithm for OCT-based drusen quantification permits replicating the reported accuracy on an independent dataset. We refined that algorithm so that its accuracy is increased. Following a systematic literature search, an algorithm was selected based on its reported excellent results. Several steps were added to improve its accuracy. The replicated and refined algorithms were evaluated on an independent dataset with the same metrics as in the original publication. Accuracy of the refined algorithm (overlap ratio 36-52%) was significantly greater than the replicated one (overlap ratio 25-39%). In particular, separation of the retinal pigment epithelium and the ellipsoid zone could be improved by the refinement. However, accuracy was still lower than reported previously on different data (overlap ratio 67-76%). This is the first replication study of an algorithm for OCT image analysis. Its results indicate that current standards for algorithm validation do not provide a reliable estimate of algorithm performance on images that differ with respect to patient selection and image quality. In order to contribute to an improved reproducibility in this field, we publish both our replication and the refinement, as well as an exemplary dataset.

Retinopathy of prematurity (ROP) is a frequent cause of treatable childhood blindness. The current dependency of telemedicine-based ROP screening on cost-intensive equipment does not meet the needs in economically disadvantaged regions. Smartphone-based fundus imaging (SBFI) allows for affordable and mobile fundus examination and, therefore, could facilitate cost-effective telemedicine-based ROP screening in low-resources settings. We compared non-contact SBFI and conventional contact fundus imaging (CFI) in terms of feasibility for ROP screening and documentation. Twenty-six eyes were imaged with both SBFI and CFI. Field-of-view was smaller (ratio of diameters, 1:2.5), level of detail was equal, and examination time was longer for SBFI as compared to CFI (109.0 ± 57.8 vs. 75.9 ± 36.3 seconds, p < 0.01). Good agreement with clinical evaluation by indirect funduscopy was achieved for assessment of plus disease and ROP stage for both SBFI (squared Cohen's kappa, 0.88 and 0.81, respectively) and CFI (0.86 and 0.93). Likewise, sensitivity/specificity for detection of plus disease and ROP was high for both SBFI (90%/100% and 88%/93%, respectively) and CFI (80%/100% and 100%/96%). SBFI is a non-contact and low-cost alternative to CFI for ROP screening and documentation that has the potential to considerably improve ROP care in middle- and low-resources settings.

The purpose of this study was to assess which visual function measures are most strongly associated with vision-related quality of life (VRQoL) in age-related macular degeneration (AMD). A cross-sectional study of subjects with early AMD (n = 10), intermediate AMD (n = 42) and late AMD (n = 38) was conducted. Subjects were interviewed with the Impact of Vision Impairment (IVI) questionnaire. Functional tests performed included best-corrected visual acuity (BCVA), low luminance visual acuity (LLVA), visual acuity measured with the Moorfields Acuity Charts (MAC), contrast sensitivity, reading speed, mesopic and dark-adapted microperimetry. The relationship between VRQoL and visual function was assessed with multiple regressions controlling for confounders. Rasch analysis demonstrated the validity of the IVI to assess VRQoL through three subscales: reading and accessing information, mobility and independence, and emotional well-being. Subjects with late AMD had significant lower IVI scores on all subscales compared with intermediate and early AMD (p < 0.011). In the overall cohort, IVI subscales were associated with BCVA, LLVA, MAC-VA and contrast sensitivity (all p < 0.001). Among the subgroup of early and intermediate AMD subjects, reading and mobility subscales were significantly associated with MAC-VA (p < 0.013). These results suggest that MAC-VA is a useful, patient-relevant measure of visual impairment in AMD.

Spatially-resolved mapping of rod- and cone-function may facilitate monitoring of macular diseases and serve as a functional outcome parameter. However, mesopic and dark-adapted two-color fundus-controlled perimetry (FCP, also called "microperimetry") constitute laborious examinations. We have devised a machine-learning-based approach to predict mesopic and dark-adapted (DA) retinal sensitivity in eyes with neovascular age-related macular degeneration (nAMD). Extensive psychophysical testing and volumetric multimodal retinal imaging data were acquired including mesopic, DA red and DA cyan FCP, spectral-domain optical coherence tomography and confocal scanning laser ophthalmoscopy infrared reflectance and fundus autofluorescence imaging. With patient-wise leave-one-out cross-validation, we have been able to achieve prediction accuracies of (mean absolute error, MAE [95% CI]) 3.94 dB [3.38, 4.5] for mesopic, 4.93 dB [4.59, 5.27] for DA cyan and 4.02 dB [3.63, 4.42] for DA red testing. Partial addition of patient-specific sensitivity data decreased the cross-validated MAE to 2.8 dB [2.51, 3.09], 3.71 dB [3.46, 3.96], and 2.85 dB [2.62, 3.08]. The most important predictive feature was outer nuclear layer thickness. This artificial intelligence-based analysis strategy, termed "inferred sensitivity", herein, enables to estimate differential effects of retinal structural abnormalities on cone- and rod-function in nAMD, and may be used as quasi-functional surrogate endpoint in future clinical trials.

Purpose: To examine the feasibility and utility of dark-adapted two-color fundus-controlled perimetry (FCP) in patients with cuticular, reticular, and soft drusen, and to compare FCP data to microstructural spectral-domain optical coherence tomography (SD-OCT) data., Methods: Forty-four eyes (24 eyes of 24 patients with drusen, age 69.4 ± 12.6 years; 20 normal eyes of 16 subjects, 61.7 ± 12.4 years) underwent duplicate mesopic, dark-adapted cyan and dark-adapted red FCP within 14° of the central retina (total of 12 936 threshold tests) using the Scotopic Macular Integrity Assessment (S-MAIA, CenterVue, Padova, Italy) device. FCP data were registered to SD-OCT data to obtain outer nuclear layer, inner and outer photoreceptor segment, and retinal pigment epithelium drusen complex (RPEDC) thickness data spatially corresponding to the stimulus location and area (0.43°). Structure-function correlations were assessed using mixed-effects models., Results: Mean deviation values for eyes with cuticular, soft, and reticular drusen were similar for mesopic (-2.1, -3.4, and -3.6 dB) and dark-adapted red (-1.4, -2.6, and -3.3 dB) FCP. For the dark-adapted cyan FCP (0.1, -1.9, and -5.0 dB) and for the cyan-red sensitivity difference (+1.0, +0.5, and -2.4 dB), the mean deviation values differed significantly in dependence of the predominant drusen type (one-way ANOVA; p < 0.05). RPEDC thickness was associated with reduction of mesopic sensitivity (-0.34 dB/10 µm RPEDC thickening; p < 0.001), dark-adapted cyan sensitivity (-0.11 dB/10 µm RPEDC thickening; p = 0.003), and dark-adapted red sensitivity (-0.26 dB/10 µm RPEDC thickening; p < 0.001)., Conclusions: In contrast to mesopic FCP, dark-adapted two-color FCP allowed for meaningful differential testing of rod and cone function in patients with drusen indicating predominant cone dysfunction in eyes with cuticular drusen and predominant rod dysfunction in eyes with reticular drusen. RPEDC thickness was the strongest predictor of the evaluated SD-OCT biomarkers for point-wise sensitivity.

Smartphone-based fundus photography (SBFP) allows for a cheap and mobile fundus examination with the potential to revolutionize eye care especially in low income settings. The purpose of this study was to assess the impact of pupil dilation on image quality in optic nerve head (ONH) imaging and vertical cup-to-disc ratio (vCDR) evaluation with SBFP. Eyes with glaucoma or suspected to have glaucoma were imaged with conventional digital fundus photography (CFP) and SBFP undilated and following dilation, all monoscopically. SBFP was possible in 74% of eyes without dilation and in 98% following dilation. Better image quality on SBFP was achieved with dilation and complete visualization of the optic disc rim was possible in 46% of images without dilation and on 94% of images with dilation. VCDR measurements on images obtained following dilation highly correlated with measurements on CFP (coefficient of correlation r = 0.91, p < 0.001), whereas vCDR on images obtained without dilation correlated less well with CFP (r = 0.70, p < 0.001). SBFP for ONH evaluation is promising, however dilation appears mandatory to achieve results comparable to optic disc evaluation on CFP. ONH imaging with smartphones without dilation might bear the risk of underestimating the CDR and hence overlooking patients at risk for glaucoma.

Macular and cone/cone-rod dystrophies (MD/CCRD) demonstrate a broad genetic and phenotypic heterogeneity, with retinal alterations solely or predominantly involving the central retina. Targeted next-generation sequencing (NGS) is an efficient diagnostic tool for identifying mutations in patient with retinitis pigmentosa, which shows similar genetic heterogeneity. To detect the genetic causes of disease in patients with MD/CCRD, we implemented a two-tier procedure consisting of Sanger sequencing and targeted NGS including genes associated with clinically overlapping conditions. Disease-causing mutations were identified in 74% of 251 consecutive MD/CCRD patients (33% of the variants were novel). Mutations in ABCA4, PRPH2 and BEST1 accounted for 57% of disease cases. Further mutations were identified in CDHR1, GUCY2D, PROM1, CRX, GUCA1A, CERKL, MT-TL1, KIF11, RP1L1, MERTK, RDH5, CDH3, C1QTNF5, CRB1, JAG1, DRAM2, POC1B, NPHP1 and RPGR. We provide detailed illustrations of rare phenotypes, including autofluorescence and optical coherence tomography imaging. Targeted NGS also identified six potential novel genotype-phenotype correlations for FAM161A, INPP5E, MERTK, FBLN5, SEMA4A and IMPDH1. Clinical reassessment of genetically unsolved patients revealed subgroups with similar retinal phenotype, indicating a common molecular disease cause in each subgroup.

PurposeTo identify the strongest variable(s) linked with the number of ranibizumab injections and outcomes in AURA, and to identify ways to improve outcomes using this association.MethodsAURA was a large observational study that monitored visual acuity over a 2-year period in patients with neovascular age-related macular degeneration (AMD) who received ranibizumab injections. Baseline characteristics, resource use, and outcomes were analyzed using an instrumental variable approach and regression analysis.ResultsData were analyzed from 2227 patients enrolled in AURA. Optical coherence tomography (OCT) and ophthalmoscopy were the most common diagnostic tests used, and this combination was the strongest instrumental variable. Use of OCT and ophthalmoscopy affected the number of injections given and resulted in an increase in visual acuity gains from baseline of 17.6 letters in year 1 and 2.5 letters in year 2. Regression models using the instrumental variable (OCT and ophthalmoscopy combined) showed that ≥5.1 (95% CI: 3.3-11.4) ranibizumab injections were needed to maintain visual acuity from baseline to year 1 and ≥8.3 (95% CI: 5.3-18.8) injections were needed to maintain visual acuity from year 1 to year 2. To gain ≥15 letters, ≥7.9 (95% CI: 5.1-17.5) ranibizumab injections would be needed in year 1 and ≥16.1 (95% CI: 10.3-36.4) injections would be needed over 2 years.ConclusionsThese findings highlight the role that regular monitoring plays in guiding neovascular AMD therapy and they showed that the number of ranibizumab injections needed to maintain visual acuity is higher than that administered in AURA.

Three anti-vascular endothelial growth factor (VEGF) therapies are currently used for the treatment of patients with wet age-related macular degeneration (AMD): pegaptanib, ranibizumab, and bevacizumab. Ranibizumab is an antibody fragment approved for the treatment of wet AMD. Bevacizumab is a full-length antibody registered for use in oncology but unlicensed for wet AMD. However, it is used off-label worldwide not only for wet AMD but also for various other ocular diseases associated with macular edema and abnormal vessel growth. We consider aspects of ranibizumab and bevacizumab in relation to their molecular characteristics, in vitro and in vivo properties, and preclinical safety data. Before 2009, most studies described the short-term toxicity of bevacizumab in multiple cell types of the eye. Since 2009, an increasing number of studies have compared the properties of ranibizumab and bevacizumab and investigated their impact on retinal cell functioning. Compared with bevacizumab, ranibizumab neutralizes VEGF better at low concentrations, maintains efficacy for longer, and has a higher retinal penetration and potency. Studies in animals demonstrate ranibizumab to be better localized to the injected eye, whereas bevacizumab appears to have a greater effect in the fellow eye. In humans, a localized and systemic effect has been reported for both molecules. In conclusion, overlapping yet distinct pharmacological properties of ranibizumab and bevacizumab indicate that safety or efficacy data from one cannot be extrapolated to the other.

Purpose: To describe the occurrence of discrete arcs of increased fundus autofluorescence (FAF) associated with various retinal dystrophies and to assess their functional significance by fundus-controlled microperimetry., Methods: Seven patients, three with pigmented paravenous retinochoroidal atrophy (PPRCA), one with sector retinitis pigmentosa (RP), one with typical RP, and two with macular dystrophy were assessed by retinal imaging including FAF imaging. Serial images were obtained within a review period of 6 and 10 years in a patient with PPRCA and macular dystrophy, respectively. Fundus-controlled microperimetry was performed in eight eyes of five patients to determine light increment sensitivity., Results: A discrete arched line of increased FAF was observed without obvious correlate on fundus biomicroscopy. The orientation of this line differed from ring shape in RP and macular dystrophy, a semi-circle structure in sector RP to crescent shape with tiplike extensions towards branching retinal veins in PPRCA. Longitudinal investigation revealed slight migration of the arc in PPRCA and peripheral extension of the ring diameter in macular dystrophy. Microperimetry revealed that the arc of increased FAF sharply delineated areas of severely impaired retinal sensitivity., Conclusions: The findings indicate that arcs of increased FAF in PPRCA and other retinal dystrophies demarcate areas of impaired retinal function and may migrate over time. FAF imaging may therefore reveal the exact extent of neurosensory dysfunction that may exceed the dimensions anticipated by conventional examinations.

Purpose: To describe patients with full-thickness macular holes (FTMHs) and lamellar macular holes (LMHs) in association with type 2 idiopathic macular telangiectasia (type 2 IMT)., Methods: Six patients with either FTMH or LMH and type 2 IMT were evaluated by means of optical coherence tomography (OCT) imaging, funduscopy, and fluorescein angiography., Results: The age of the examined patients ranged from 57 to 70 years (mean 62.5+/-5.2), and best-corrected visual acuity of the affected eyes ranged from 20/50 to 20/200 (mean 20/100). All eyes showed macular abnormalities typical for nonproliferative type 2 IMT except for one eye with a proliferative disease stage. Three patients had an FTMH, one presenting with bilateral FTMH, and three had an LMH on OCT. In all cases of FTMH, the macular holes did not have elevated margins. Surgery was performed in two patients with a FTHM without subsequent functional improvement., Conclusions: The altered foveal anatomy with progressive atrophic changes within the neurosensory retina in type 2 IMT may predispose to the development of FTMH and LMH. Type 2 IMT should be considered in the differential diagnosis in patients presenting with macular holes. The association between the two may reflect alternative pathogenetic mechanisms in the development of macular holes.

Purpose: To assess the general feasibility of recording multifocal electroretinograms (mfERGs) with simultaneous fundus monitoring in a clinical setting., Methods: An mfERG system (RETIscan) and a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph) were connected to record mfERGs elicited by a pseudorandom binary m-sequence stimulus generated by a 514 nm laser source. Recordings were compared to a conventional mfERG system using monitor stimulation. A total of five subjects (two normal subjects and three patients) were examined., Results: In normal volunteers records obtained by the fundus-monitored mfERG showed highest response densities in the central fundus area and a decrease of response amplitudes towards the periphery paralleling cone receptor density. However, compared to the monitor stimulation, the drop-off of amplitudes as a function of eccentricity was not as clearly defined. The responses obtained from patients with retinal diseases were diminished in the areas of retinal dysfunction., Conclusions: These preliminary findings indicate that the technique of laser stimulation in principle allows for topographic retinal recording. This method might be useful, for example if the retinal position of the stimulus array is not centred onto the fovea but deviates due to fixation problems. However, further improvement of the technique appears necessary before considering routine clinical application.

Recently, the VMD2 gene has been identified as the causative gene in juvenile-onset vitelliform macular dystrophy (Best disease), a central retinopathy primarily characterised by an impaired function of the retinal pigment epithelium. In this study we have further characterised the spectrum of VMD2 mutations in a series of 41 unrelated Best disease patients. Furthermore we expanded our analysis to include 32 unrelated patients with adult vitelliform macular dystrophy (AVMD) and 200 patients with age-related macular degeneration (AMD). Both AVMD and AMD share some phenotypic features with Best disease such as abnormal subretinal accumulation of lipofuscin material, progressive geographic atrophy and choroidal neovascularisation, and may be the consequence of a common pathogenic mechanism. In total, we have identified 23 distinct disease-associated mutations in Best disease and four different mutations in AVMD. Two of the mutations found in the AVMD patients were also seen in Best disease suggesting a considerable overlap in the aetiology of these two disorders. There were no mutations found in the AMD group. In addition, four frequent intragenic polymorphisms did not reveal allelic association of the VMD2 locus with AMD. These data exclude a direct role of VMD2 in the predisposition to AMD.

Inherited retinal venous beading is a rare autosomal disorder. We describe three affected members in three generations of a single family. It is evident that there may be gross asymmetry of affection between the two eyes, and highly variable expressivity such that the diagnosis may not be evident without a family survey. One patient had remarkable spontaneous recovery of vision.

Acute zonal occult outer retinopathy (AZOOR) may be precipitated by various retinal disorders and is characterised by rapid loss of visual field which cannot be explained by the ophthalmoscopic changes consequent upon the initiating disease. The electroretinogram is abnormal, indicating that the field loss is due to retinal dysfunction. The phenomenon was first recognised in the multiple evanescent white dot syndrome (MEWDS) as the enlarged blind spot syndrome. It was subsequently described with multifocal inner choroidopathy and acute macular neuropathy (AMN). We have identified 7 patients who presented with widespread visual loss associated with multifocal inner choroidopathy in whom functional loss was documented with electroretinography and automated visual field testing. All patients were young, myopic, and otherwise healthy women. Initial photopsia was noted by 4 patients. Fundus findings included scattered small partially pigmented yellowish lesions resembling those in multifocal inner choroidopathy or pseudo presumed ocular histoplasmosis syndrome, disc swelling, vitritis, and secondary choroidal neovascularisation. Two patients had bilateral involvement. All patients had an enlargement of the blind spot, and widespread visual field loss which was not explained by fundus changes. All had an abnormal electroretinogram suggesting widespread retinal disease. In AZOOR retinal dysfunction occurs without corresponding visible retinal lesions. This disorder appears to be precipitated by several conditions, although the causal relationship between the initiating event and the widespread functional loss is unknown.