Purpose:The purpose of this study was to evaluate the feasibility and utility of optical coherence tomography (OCT)-based, targeted microperimetry grids in assessing focal lesions in intermediate age-related macular degeneration (iAMD). Methods:The multicenter, prospective PINNACLE study enrolled 395 patients with iAMD aged 55 to 90 years across 12 international sites. Participants underwent imaging, including OCT and microperimetry, every 4 to 12 months over 3 years. Deep learning algorithms detected focal lesions and changes in OCT images, including drusen regression, EZ/IZ loss with hypertransmission, and subretinal fluid, guiding 5-point microperimetry targeted to lesion locations. Data were analyzed using linear mixed models to estimate differences between retinal sensitivity measured by the 5-point focal grids and sensitivity interpolated from the 24-point standard grids. Results:The final analysis included 93 eyes from 83 patients, assessing 605 of the 5-point targeted grids and standard grids across 235 focal lesions. The Pearson correlation between focally measured sensitivity and interpolated sensitivity was 0.76. However, interpolation from the standard grid could be erroneous, especially in central regions of lesions characterized by EZ/IZ loss with hypertransmission and subretinal fluid. Interpolation errors increased with distance to the nearest measurement point (slope = 2.20 dB per degree, 95% confidence interval [CI] = 1.52 to 2.87). A significant negative relationship was found between interpolation errors and retinal sensitivity, with the highest errors in areas of low sensitivity. Lesion size significantly impacted interpolation errors for EZ/IZ loss with hypertransmission (slope = -19.41 dB/mm², 95% CI = -29.63 to -9.18). Conclusions:Targeted grids improved the detection and understanding of how focal retinal changes affect visual function in patients with iAMD, supporting the development of therapeutic interventions.

Adaptive optics ophthalmoscopy (AOO) has the potential to provide insights into AMD pathology and to assess the risk of progression. We aim to utilise AOO to describe detailed features of intermediate AMD and to characterise microscopic changes during atrophy development. Patients with intermediate AMD were recruited into PINNACLE, a prospective observational cohort study. Participants underwent flood-illumination AOO using the commercially available rtx1 camera. AOO images were qualitatively assessed and correlated with clinical imaging including optical coherence tomography (OCT) and infrared scanning laser ophthalmoscopy. The visibility of cone mosaic was generally compromised in eyes with intermediate AMD. We observed an association between the visibility of cone mosaic on AOO and the detection of a well-defined normal interdigitation zone on OCT. Drusen subtypes were identified on AOO as variations in reflectance at the edge and/or the centre of the druse. The absence of a hyperreflective margin was associated with the loss of the overlying ellipsoid zone on OCT prior to the collapse of the druse. With progressive attenuation of the retinal pigment epithelium and loss of photoreceptor layers, the drusenoid lesion appeared more hyperreflective with very distinctive edges. This cross-sectional study supports the potential value of AOO for providing information on intermediate AMD and the development of atrophic lesions that cannot be seen in conventional imaging modalities. The ongoing longitudinal PINNACLE study is assessing the significance of the described findings.

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.Gly1961Glu). We optimized ABCA4 base editing in human models, including retinal organoids, induced pluripotent stem cell-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal explants and RPE/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in female nonhuman primates, with average editing of 75% of cones and 87% of RPE cells in vivo, which has the potential to translate to a clinical benefit. No off-target editing was detectable in human retinal explants and RPE/choroid explants. The high editing rates in primates show promise for efficient gene editing in other ocular diseases that are targetable by base editing.

Purpose To evaluate retinal sensitivity in subfields and its association with the novel quick contrast sensitivity function (qCSF) in patients with early age-related macular degeneration (eAMD), in patients with intermediate AMD (iAMD), and in healthy controls. Methods In this prospective longitudinal study retinal sensitivity of a customized 24-point grid was assessed by microperimetry Macular Integrity Assessment (MAIA, CenterVue, Padova, Italy) and divided into different subfields. The Multiple Contrast Vision Meter (Adaptive Sensory Technology, San Diego, CA) was used for qCSF testing. Linear models were used to test the association of functional metrics with variables of interest. Results 92 study eyes from 92 participants were analyzed (13 eAMD, 31 iAMD, and 48 controls). Microperimetry subfield comparison showed significant differences (p<0.0001) in the control group between superior and inferior hemifield as well as between central and peripheral subfields. For eAMD significant differences were found between central and peripheral subfields (p<0.001) and specific subfields (p<0.05) and finally for iAMD between specific quadrants (p<0.05) and specific squares (p<0.05). Significant associations of retinal sensitivity with qCSF metrics were found for the area underneath the logarithmic contrast sensitivity function (AULCSF), contrast acuity (CA) and for the contrast sensitivity at specific spatial frequencies. Conclusions This study showed significant differences in the evaluated retinal sensitivity subfields providing localized natural history data for retinal sensitivity in healthy controls, and patients with eAMD and iAMD.

Purpose:The purpose of this study was to describe, validate, and compare the contrast sensitivity functions (CSFs) acquired with the novel quick CSF (qCSF) method from patients with early and intermediate age-related macular degeneration (eAMD and iAMD) and healthy controls. Methods:This is a cross-sectional analysis of contrast sensitivity (CS) and visual acuity (VA) baseline data from the prospective Multimodal Functional and Structural Visual System Characterization (MUMOVI) study. The qCSF testing was conducted with the manifold contrast vision meter (Adaptive Sensory Technology, San Diego, CA, USA). CS levels at spatial frequencies from 1 cycle per degree (CPD) to 18 CPD, the area underneath the logarithmic contrast sensitivity function (AULCSF), and contrast acuity (CA) were analyzed. The association of functional metrics with variables of interest was tested with linear models. Results:Ninety-four study eyes from 94 study patients were included in the analysis (13 patients with eAMD, 33 patients with iAMD, and 48 healthy controls). Significant differences between the eAMD and the iAMD model estimates were only found for CS at 1 CPD (t value = -2.9, P value = 0.006) and CS at 1.5 CPD (-2.7, 0.01). A specific association between smoking years and CS at 1 CPD (P = 0.02) and CS at 1.5 CPD (P = 0.03) could be described in patients with AMD. Conclusions:The qCSF testing allows the fast measurement of the whole CSF, enabling the integration into clinical routine. We showed that novel qCSF-derived metrics detect slight functional differences between AMD stages, which testing by Pelli-Robson charts or VA testing would miss. This study, therefore, yields novel qCSF-derived candidate metrics for therapeutic trials in AMD.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Current grading systems based on imaging biomarkers only coarsely group disease stages into broad categories and are unable to predict future disease progression. It is widely believed that this is due to their focus on a single point in time, disregarding the dynamic nature of the disease. In this work, we present the first method to automatically discover biomarkers that capture temporal dynamics of disease progression. Our method represents patient time series as trajectories in a latent feature space built with contrastive learning. Then, individual trajectories are partitioned into atomic sub-sequences that encode transitions between disease states. These are clustered using a newly introduced distance metric. In quantitative experiments we found our method yields temporal biomarkers that are predictive of conversion to late AMD. Furthermore, these clusters were highly interpretable to ophthalmologists who confirmed that many of the clusters represent dynamics that have previously been linked to the progression of AMD, even though they are currently not included in any clinical grading system.

Purpose To investigate and compare novel volumetric microperimetry (MP)–derived metrics in intermediate age-related macular degeneration (iAMD), as current MP metrics show high variability and low sensitivity. Methods This is a cross-sectional analysis of microperimetry baseline data from the multicenter, prospective PINNACLE study (ClinicalTrials.gov NCT04269304). The Visual Field Modeling and Analysis (VFMA) software and an open-source implementation (OSI) were applied to calculate MP-derived hill-of-vison (HOV) surface plots and the total volume (VTOT) beneath the plots. Bland–Altman plots were used for methodologic comparison, and the association of retinal sensitivity metrics with explanatory variables was tested with mixed-effects models. Results In total, 247 eyes of 189 participants (75 ± 7.3 years) were included in the analysis. The VTOT output of VFMA and OSI exhibited a significant difference (P < 0.0001). VFMA yielded slightly higher coefficients of determination than OSI and mean sensitivity (MS) in univariable and multivariable modeling, for example, in association with low-luminance visual acuity (LLVA) (marginal R2/conditional R2: VFMA 0.171/0.771, OSI 0.162/0.765, MS 0.133/0.755). In the multivariable analysis, LLVA was the only demonstrable predictor of VFMA VTOT (t-value, P-value: −7.5, <0.001) and MS (−6.5, <0.001). Conclusions The HOV-derived metric of VTOT exhibits favorable characteristics compared to MS in evaluating retinal sensitivity. The output of VFMA and OSI is not exactly interchangeable in this cross-sectional analysis. Longitudinal analysis is necessary to assess their performance in ability-to-detect change. Translational Relevance This study explores new volumetric MP endpoints for future application in therapeutic trials in iAMD and reports specific characteristics of the available HOV software applications.

Introduction: The aim of this study is to describe the design and the participants' baseline characteristics of a prospective natural-history study of geographic atrophy (GA) secondary to age-related macular degeneration.Methods: The optical coherence tomography (OCT) and microperimetry biomarker evaluation in patients with GA (OMEGA) study was conducted at a tertiary referral center (ClinicalTrials.gov identifier: NCT05963646). Participants were followed for 12 months during 4 visits (baseline and follow-up exams at weeks 12, 24, and 48) with best-corrected ETDRS visual acuity, low-luminance visual acuity, and quick contrast sensitivity function (qCSF) testing. Further, participants underwent spectral-domain OCT, OCT angiography, fundus autofluorescence (FAF) imaging, and mesopic microperimetry testing.Results: Thirty participants (median [IQR] age of 79 [77, 84] years) and 37 study eyes were included with a (median [IQR]) GA area of 1.40 mm(2) [0.49, 5.24] at baseline. Out of 37 study eyes, six developed macular neovascularizations (16%). The study-eye BCVA was (median [IQR]) 0.18 logMAR [0.06, 0.26], LLVA 0.66 logMAR [0.36, 0.88], and the microperimetry mean sensitivity 18.4 dB [9.21, 20.9]. The highest correlation between square root GA area and a visual function test was evident for LLVA (R-2 of 0.578), followed by AULCSF (0.519) and microperimetral retinal sensitivity (0.487).Conclusion: This report lays out the design and baseline characteristics of the OMEGA study, which aims to contribute to the understanding of the natural history of GA. The OMEGA study will provide estimates of the ability-to-detect change and retest reliability for a panel of structure and function assessments.

There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently, clinicians cannot provide individualised prognoses of disease progression. Moreover, enriching clinical trials with rapid progressors may facilitate delivery of shorter intervention trials aimed at delaying or preventing progression to late AMD. Thus, we performed a systematic review to outline and assess the accuracy of reporting prognostic factors for the progression of intermediate to late AMD. A meta-analysis was originally planned. Synonyms of AMD and disease progression were used to search Medline and EMBASE for articles investigating AMD progression published between 1991 and 2021. Initial search results included 3229 articles. Predetermined eligibility criteria were employed to systematically screen papers by two reviewers working independently and in duplicate. Quality appraisal and data extraction were performed by a team of reviewers. Only 6 studies met the eligibility criteria. Based on these articles, exploratory prognostic factors for progression of intermediate to late AMD included phenotypic features (e.g. location and size of drusen), age, smoking status, ocular and systemic co-morbidities, race, and genotype. Overall, study heterogeneity precluded reporting by forest plots and meta-analysis. The most commonly reported prognostic factors were baseline drusen volume/size, which was associated with progression to neovascular AMD, and outer retinal thinning linked to progression to geographic atrophy. In conclusion, poor methodological quality of included studies warrants cautious interpretation of our findings. Rigorous studies are warranted to provide robust evidence in the future.

AIMS:Age-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD. METHODS:The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55-90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models. CONCLUSIONS:This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.

Purpose: To assess potential differences between central and eccentric cones in the aberrometric corneal profile and in visual and keratometric outcomes 6 months after intracorneal ring segment (ICRS) implantation for keratoconus. Methods: This study compared two groups consisting of 12 patients each, with central or eccentric keratoconus who were treated with femtosecond laser-assisted Keraring implantation. Uncorrected (UDVA) and corrected (CDVA) distance visual acuity, keratometric readings and higher order aberrations (HOAs) including high order aberrations root mean square (HOARMS), coma, spherical aberration and trefoil were measured preoperatively and 6 months after ICRS implantation. Results: Trefoil and spherical aberration were significantly reduced after ICRS implantation compared to preoperative values in eccentric keratoconus (Trefoil, p = 0.0049; Spherical aberration, p < 0.0001). In central keratoconus spherical aberration was reduced not significantly after ICRS implantation compared to preoperative values (p = 0.087). Coma showed a significant reduction in central (p = 0.0001) and in eccentric keratoconus (p = 0.0001). The reduction of spherical aberration in central keratoconus was significantly positively correlated to improvement in UDVA (Pearson's correlation coefficient, r = -0.66; p = 0.02). In eccentric keratoconus there was a significant positive correlation between reduction of trefoil and improvement in UDVA (Spearmans R, r = -0.69; p = 0.01). Conclusion: Patients both with central and eccentric keratoconus benefit from ICRS implantation. Specifically, our data provide a slightly higher gain in visual performance for eccentric cones 6 month after ICRS implantation, which is accentuated by a greater reduction in spherical aberration and trefoil. Improvements in UDVA are positively correlated with reductions in HOAs.

Intraocular lens (IOL) power calculation after corneal refractive surgery (CRS) becomes an expanding challenge for ophthalmologists as more and more cataract surgeries after CRS are required. These patients typically also have high expectations as to visual performance. Conventional IOL power calculation schemes frequently provide inaccurate results in these cases. This review aims to summarize and recommend currently available IOL power calculation methods for eyes with the most common CRS methods: radial keratotomy (RK), photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), and small incision lenticule extraction (SMILE). To this end, biometry measuring methods and IOL formulas will be explained and combinations of both are proposed. In synopsis, it is evident that the latest generation of vergence formulas exhibit favorable IOL power prediction accuracy in post-CRS eyes, even though the predictive precision of methods in eyes without CRS is not attained. Ray tracing computation, intraoperative aberrometry, and machine learning-based formulas hold potential to further improve refractive outcomes in post-CRS eyes.

Purpose To examine the effect of prolactin (PRL) on human corneal stromal fibroblasts (CSFs), derived from healthy individuals and from keratoconus (KC) patients, in vitro, specifically assessing physiological and elevated PRL concentrations as apparent during pregnancy. Methods Eye bank corneas of 3 female and 3 male healthy individuals as well as the corneal buttons of 3 female and 3 male KC patients were utilized for this study. The endothelium of the cornea was removed with sterile surgical scalpels, the probes were washed repeatedly with Dulbecco’s PBS and corneoscleral rims were trimmed off. Subsequently the corneal stroma was digested with collagenase type I and the harvested CSFs were cultured. We then examined (1) cell proliferation, (2) cell viability and (3) cytokine release of CSFs upon exposure to prolactin in vitro. Results With respect to viability and proliferation our experiments did not show significant differences between CSFs exposed to different PRL concentrations. Our data show a significantly lower IL-8 concentration in normal CSFs exposed to 10ng/ml PRL compared to 0ng/ml and 1000ng/ml at 5 hours post exposition. Moreover, we can report significantly lower secretion of IL-8, IL-6, HGF, VEGF and FGFb in KC CSFs compared to normal CSFs, independent of PRL exposure, as determined by cytokine ELISA. Conclusion Our data in part points towards corneal cytokine secretion as a possible link between altered stromal PRL concentrations and KC progression. However, in our small dataset a significant influence of PRL concentration on cytokine secretion can only be described for IL-8 in normal CSFs. Further our results contribute to existing reports on the importance of cytokines in KC development, with an emphasis on significantly lower cytokine secretion in KC CSFs compared to normal controls.