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The human population is steadily growing with increased life expectancy, impacting the prevalence of age-dependent diseases, including age-related macular degeneration (AMD). Health care systems are confronted with an increasing burden with rising patient numbers accompanied by ongoing developments of therapeutic approaches. Concurrent advances in imaging modalities provide eye care professionals with a large amount of data for each patient. Furthermore, with continuous progress in therapeutics, there is an unmet need for reliable structural and functional biomarkers in clinical trials and practice to optimize personalized patient care and evaluate individual responses to treatment. A fast and objective solution is Artificial intelligence (AI), which has revolutionized assessment of AMD in all disease stages. Reliable and validated AI-algorithms can aid to overcome the growing number of patients, visits and necessary treatments as well as maximize the benefits of multimodal imaging in clinical trials. Therefore, there are ongoing efforts to develop and validate automated algorithms to unlock more information from datasets allowing automated assessment of disease activity and disease progression. This review aims to present selected AI algorithms, their development, applications and challenges regarding assessment and prediction of AMD progression., Competing Interests: Competing interests SF, KB, SR: No financial disclosures. GSR: Apellis (C), Bayer (C), RetInSight (F), Roche (C), Boehringer Ingelheim (C). US-E: Abbvie (C), Apellis Pharmaceuticals (F, C), Aviceda (C), Complement therapeutics (C), Galimedix (C), Genentech (F), Janssen (C), Heidelberg Engineering (C, F), Kodiak (F), Kriya (C), Novartis (F), ONL (C), Roche (C, F), RetInSight (C), Stealth Therapeutics (C), Topcon (F, C)., (© 2024. The Author(s).)

To examine the morphological impact of deep learning (DL)-quantified biomarkers on point-wise sensitivity (PWS) using microperimetry (MP) and optical coherence tomography (OCT) in intermediate AMD (iAMD). Patients with iAMD were examined by OCT (Spectralis). DL-based algorithms quantified ellipsoid zone (EZ)-thickness, hyperreflective foci (HRF) and drusen volume. Outer nuclear layer (ONL)-thickness and subretinal drusenoid deposits (SDD) were quantified by human experts. All patients completed four MP examinations using an identical custom 45 stimuli grid on MP-3 (NIDEK) and MAIA (CenterVue). MP stimuli were co-registered with corresponding OCT using image registration algorithms. Multivariable mixed-effect models were calculated. 3.600 PWS from 20 eyes of 20 patients were analyzed. Decreased EZ thickness, decreased ONL thickness, increased HRF and increased drusen volume had a significant negative effect on PWS (all p < 0.001) with significant interaction with eccentricity (p < 0.001). Mean PWS was 26.25 ± 3.43 dB on MP3 and 22.63 ± 3.69 dB on MAIA. Univariate analyses revealed a negative association of PWS and SDD (p < 0.001). Subclinical changes in EZ integrity, HRF and drusen volume are quantifiable structural biomarkers associated with reduced retinal function. Topographic co-registration between structure on OCT volumes and sensitivity in MP broadens the understanding of pathognomonic biomarkers with potential for evaluation of quantifiable functional endpoints., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Growing interest in microperimetry (MP) or fundus-controlled perimetry (FCP) as targeted psychometric testing method in geographic atrophy (GA) is warranted due to the disease subclinical/extra-foveal appearance or preexisting foveal loss with visual acuity becoming unreliable. We provide comprehensive pointwise test-retest repeatability reference values on the most widely used MP devices and combine them with targeted testing in areas of retinal pigment epithelium (RPE) as well as photoreceptor (PR) integrity loss, guiding the interpretation of sensitivity loss during the long-term follow-up of GA patients., Design: Prospective reliability study METHODS: Patients with GA underwent consecutive testing on CenterVue (iCare) MAIA and NIDEK MP3 devices. Obtained PWS measurements were spatially co-registered to an optical coherence tomography (OCT) volume scan acquired during the same visit. Areas with RPE and PR integrity loss, drusen and PR thickness as well as the volume of hyperreflective foci (HRF) where identified and quantified using a set of validated deep learning-based algorithms. Test-retest repeatability was assessed according to areas defined by biomarker-specific morphologic changes using Bland-Altmann coefficients of repeatability (CoR). Furthermore, the inter-device correlation, the repeatability of scotoma point detection as well as any potential effects on fixation stability were assessed., Results: 900 stimuli per device from twenty subjects were included. Identical overall PWS test-retest variance could be detected for MAIA (±6.57) and MP3 (±6.59). PR integrity loss was associated with a higher test-retest variance on both devices (MAIA: p=0.002; MP3: p<0.001). Higher CoR for stimuli in areas presenting RPE loss (±10.99 vs ±5.34) or HRF (±9.21 vs ±6.25) could only be detected on MP3 examinations (p<0.001 and p=0.01, respectively). An excellent intra-device correlation (MAIA: 0.94[0.93-0.95] MP3: 0.94[0.94-0.95]) and a good mean inter-device correlation (0.84[0.53-0.92]) could be demonstrated. The chosen device, run order or absence of foveal sparing had no significant effect on fixation stability., Conclusion: Areas presenting automatically quantified PR integrity loss with and without underlying RPE loss are associated with higher test-retest variance for both MAIA and MP3. These findings are crucial for an accurate interpretation of GA progression during long-term follow-up and the planning of future trials with microperimetry testing as functional study endpoint., Competing Interests: Conflicts of interest none, (Copyright © 2024. Published by Elsevier Inc.)

Regulatory approval of the first two therapeutic substances for the management of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is a major breakthrough following failure of numerous previous trials. However, in the absence of therapeutic standards, diagnostic tools are a key challenge as functional parameters in GA are hard to provide. The majority of anatomical biomarkers are subclinical, necessitating advanced and sensitive image analyses. In contrast to fundus autofluorescence (FAF), optical coherence tomography (OCT) provides high-resolution visualization of neurosensory layers, including photoreceptors, and other features that are beyond the scope of human expert assessment. Artificial intelligence (AI)-based methodology strongly enhances identification and quantification of clinically relevant GA-related sub-phenotypes. Introduction of OCT-based biomarker analysis provides novel insight into the pathomechanisms of disease progression and therapeutic, moving beyond the limitations of conventional descriptive assessment. Accordingly, the Food and Drug Administration (FDA) has provided a paradigm-shift in recognizing ellipsoid zone (EZ) attenuation as a primary outcome measure in GA clinical trials. In this review, the transition from previous to future GA classification and management is described. With the advent of AI tools, diagnostic and therapeutic concepts have changed substantially in monitoring and screening of GA disease. Novel technology combined with pathophysiological knowledge and understanding of the therapeutic response to GA treatments, is currently opening the path for an automated, efficient and individualized patient care with great potential to improve access to timely treatment and reduce health disparities., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To evaluate the intra- and interdevice repeatability of microperimetry (MP) assessments in patients with diabetic macular edema (DME) two consecutive MP testings (45 fovea-centered stimuli, 4-2 staircase strategy) were performed using MP3 (NIDEK, Aichi, Japan) and MAIA (CenterVue, Padova, Italy), respectively. Intraretinal fluid (IRF) and ellipsoid zone (EZ) thickness were automatically segmented by published deep learning algorithms. Hard exudates (HEs) were annotated semi-automatically and disorganization of retinal inner layers (DRIL) was segmented manually. Point-to-point registration of MP stimuli to corresponding spectral-domain OCT (Spectralis, Heidelberg Engineering, Germany) locations was performed for both devices. Repeatability was assessed overall and in areas of disease-specific OCT biomarkers using Bland-Altmann coefficients of repeatability (CoR). A total of 3600 microperimetry stimuli were tested in 20 eyes with DME. Global CoR was high using both devices (MP3: ± 6.55 dB, MAIA: ± 7.69 dB). Higher retest variances were observed in stimuli with IRF (MP3: CoR ± 7.4 dB vs. ± 6.0 dB, p = 0.001, MAIA: CoR ± 9.2dB vs. ± 6.8 dB, p = 0.002) and DRIL on MP3 (CoR ± 6.9 dB vs. ± 3.2 dB, p < 0.001) compared to stimuli without. Repeatabilities were reduced in areas with thinner EZ layers (both p < 0.05). Fixation (Fuji classification) was relatively unstable independent of device and run. These findings emphasize taking higher caution using MP in patients with DME., (© 2024. The Author(s).)

Purpose: Investigating the sequence of morphological changes preceding outer plexiform layer (OPL) subsidence, a marker preceding geographic atrophy, in intermediate AMD (iAMD) using high-precision artificial intelligence (AI) quantifications on optical coherence tomography imaging., Methods: In this longitudinal observational study, individuals with bilateral iAMD participating in a multicenter clinical trial were screened for OPL subsidence and RPE and outer retinal atrophy. OPL subsidence was segmented on an A-scan basis in optical coherence tomography volumes, obtained 6-monthly with 36 months follow-up. AI-based quantification of photoreceptor (PR) and outer nuclear layer (ONL) thickness, drusen height and choroidal hypertransmission (HT) was performed. Changes were compared between topographic areas of OPL subsidence (AS), drusen (AD), and reference (AR)., Results: Of 280 eyes of 140 individuals, OPL subsidence occurred in 53 eyes from 43 individuals. Thirty-six eyes developed RPE and outer retinal atrophy subsequently. In the cohort of 53 eyes showing OPL subsidence, PR and ONL thicknesses were significantly decreased in AS compared with AD and AR 12 and 18 months before OPL subsidence occurred, respectively (PR: 20 µm vs. 23 µm and 27 µm [P < 0.009]; ONL, 84 µm vs. 94 µm and 98 µm [P < 0.008]). Accelerated thinning of PR (0.6 µm/month; P < 0.001) and ONL (0.8 µm/month; P < 0.001) was observed in AS compared with AD and AR. Concomitant drusen regression and hypertransmission increase at the occurrence of OPL subsidence underline the atrophic progress in areas affected by OPL subsidence., Conclusions: PR and ONL thinning are early subclinical features associated with subsequent OPL subsidence, an indicator of progression toward geographic atrophy. AI algorithms are able to predict and quantify morphological precursors of iAMD conversion and allow personalized risk stratification.

Objective: To compare the visibility and accessibility of the outer retina in neovascular age-related macular degeneration (nAMD) between 2 OCT devices., Methods: In this prospective, cross-sectional exploratory study, differences in thickness and loss of individual outer retinal layers in eyes with nAMD and in age-matched healthy eyes between a next-level High-Res OCT device and the conventional SPECTRALIS OCT (both Heidelberg Engineering GmbH, Heidelberg, Germany) were analyzed. Eyes with nAMD and at least 250 nL of retinal fluid, quantified by an approved deep-learning algorithm (Fluid Monitor, RetInSight, Vienna, Austria), fulfilled the inclusion criteria. The outer retinal layers were segmented using automated layer segmentation and were corrected manually. Layer loss and thickness were compared between both devices using a linear mixed-effects model and a paired t test., Results: Nineteen eyes of 17 patients with active nAMD and 17 healthy eyes were included. For nAMD eyes, the thickness of the retinal pigment epithelium (RPE) differed significantly between the devices (25.42 μm [95% CI, 14.24-36.61] and 27.31 μm [95% CI, 16.12-38.50] for high-resolution OCT and conventional OCT, respectively; p = 0.033). Furthermore, a significant difference was found in the mean relative external limiting membrane loss (p = 0.021). However, the thickness of photoreceptors, RPE integrity loss, and photoreceptor integrity loss did not differ significantly between devices in the central 3 mm. In healthy eyes, a significant difference in both RPE and photoreceptor thickness between devices was shown (p < 0.001)., Conclusion: Central RPE thickness was significantly thinner on high-resolution OCT compared with conventional OCT images explained by superior optical separation of the RPE and Bruch's membrane., Competing Interests: Footnotes and Disclosures Gregor Sebastian Reiter received grant support from RetInSight. Hrvoje Bogunovic received grant support from RetInSight and Apellis and as a speaker for Apellis, Roche, and Bayer. Ursula Schmidt-Erfurth served as a scientific consultant for Boehringer, Heidelberg Engineering, Kodiak, Roche (F), and Apellis Pharmaceuticals; received grants from Boehringer (C), Genentech (F), Heidelberg Engineering (F), Janssen, Kodiak (F, C), Novartis (F), Roche (F), RetInSight (F, C), and Apellis Pharmaceuticals (F, C); as a speaker for Apellis, Roche; and received meeting support from Apellis. The remaining authors have no disclosures., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)