[Effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration]. / Effektivnost' i bezopasnost' brolutsizumaba v lechenii neovaskulyarnoi vozrastnoi makulyarnoi degeneratsii.

PURPOSE: This study analyzes the effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration (nAMD) in real clinical practice. MATERIAL AND METHODS: The study included patients with nAMD who received brolucizumab treatment and evaluated the changes in best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume, as well as the number of injections and adverse events. RESULT: The group of previously treated patients included 28 subjects (28 eyes) that were switched to brolucizumab with a loading phase. By 12 months, BCVA changed from 0.43±0.29 to 0.33±0.27 LogMAR (p=0.11), CRT decreased from 281.5±58.2 to 239.9±45.6 µm (p=0.02). The group of previously untreated patients included 29 subjects (29 eyes). By 12 months, BCVA changed from 0.47±0.32 to 0.40±0.30 LogMAR (p=0.09), CRT decreased from 333.2±77.3 to 226.2±49.6 µm (p<0.001). Patients received 6.3±0.7 injections. In this group, baseline choroidal thickness showed a statistically significant correlation with final visual acuity (r=0.54; p<0.05) and CRT (r= -0.5; p<0.05). The group of previously treated patients switched without a loading phase included 18 patients (18 eyes). By 6 months, BCVA changed from 0.42±0.2 to 0.37±0.26 LogMAR (p=0.42). CRT remained stable at 285.6±56.9 µm (p=0.97). No adverse events related to intraocular inflammation were reported during the course of 385 injections. CONCLUSION: Brolucizumab therapy helps achieve significant anatomical and functional improvements in real clinical practice both in patients switched from previous treatments and in treatment-naïve patients. Greater baseline choroidal thickness may be associated with better anatomical and functional outcomes with brolucizumab treatment.

A Novel Artificial Intelligence-Based Classification of Highly Myopic Eyes Based on Visual Function and Fundus Features.

Purpose: To develop a novel classification of highly myopic eyes using artificial intelligence (AI) and investigate its relationship with contrast sensitivity function (CSF) and fundus features. Methods: We enrolled 616 highly myopic eyes of 616 patients. CSF was measured using the quantitative CSF method. Myopic macular degeneration (MMD) was graded according to the International META-PM Classification. Thickness of the macula and peripapillary retinal nerve fiber layer (p-RNFL) were assessed by fundus photography and optical coherence tomography, respectively. Classification was performed by combining CSF and fundus features with principal component analysis and k-means clustering. Results: With 83.35% total variance explained, highly myopic eyes were classified into four AI categories. The percentages of AI categories 1 to 4 were 14.9%, 37.5%, 36.2%, and 11.4%, respectively. Contrast acuity of the eyes in AI category 1 was the highest, which decreased by half in AI category 2. For AI categories 2 to 4, every increase in category led to a decrease of 0.23 logarithm of the minimum angle of resolution in contrast acuity. Compared with those in AI category 1, eyes in AI category 2 presented a higher percentage of MMD2 and thinner temporal p-RNFL. Eyes in AI categories 3 and 4 presented significantly higher percentage of MMD ≥ 3, thinner nasal macular thickness and p-RNFL (P < 0.05). Multivariate regression showed AI category 4 had higher MMD grades and thinner macular compared with AI category 3. Conclusions: We proposed an AI-based classification of highly myopic eyes with clear relevance to visual function and fundus features. Translational Relevance: This classification helps to discover the early hidden visual deficits of highly myopic patients, becoming a useful tool to evaluate the disease comprehensively.

Age-related macular degeneration.

ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of visual impairment in patients age 50 and older, with an estimated 200 million people affected worldwide and a projected 288 million by 2040. This article provides an overview of the epidemiology, risk factors, pathophysiology, clinical manifestations, diagnosis, management, and nursing considerations for AMD to equip nurses with the knowledge to play a crucial role in the early detection of this disease.

VEGF and ELAVL1/HuR protein levels are increased in dry and wet AMD patients. A new tile in the pathophysiologic mechanisms underlying RPE degeneration?

Age-related macular degeneration (AMD) is a common retinal pathology characterized by degeneration of macula's retinal pigment epithelium (RPE) and photoreceptors, visual impairment, or loss. Compared to wet AMD, dry AMD is more common, but lacks cures; therefore, identification of new potential therapeutic targets and treatments is urgent. Increased oxidative stress and declining antioxidant, detoxifying systems contribute to the pathophysiologic mechanisms underlying AMD. The present work shows that the Embryonic Lethal Abnormal Vision-Like 1/Human antigen R (ELAVL1/HuR) and the Vascular Endothelial Growth Factor (VEGF) protein levels are higher in the RPE of both dry and wet AMD patients compared to healthy subjects. Moreover, increased HuR protein levels are detected in the retina, and especially in the RPE layer, of a dry AMD model, the nuclear factor erythroid 2-related factor 2 (Nrf2) / peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) double knock-out mouse. The crosstalk among Nrf2, HuR and VEGF has been also studied in ARPE-19 cells in basal and stressful conditions related to the AMD context (i.e., oxidative stress, autophagy impairment, Nrf2 deficit), offering new evidence of the mutual influence between Nrf2 and HuR, of the dependence of VEGF expression and secretion by these two factors, and of the increased susceptibility of cells to stressful conditions in Nrf2- or HuR-impaired contexts. Overall, this study shows evidence of the interplay among Nrf2, HuR and VEGF, essential factors for RPE homeostasis, and represents an additional piece in the understanding of the complex pathophysiologic mechanisms underlying AMD.

The role of immune modulators in age-related macular degeneration.

We provide an overview of the expanding literature on the role of cytokines and immune mediators in pathophysiology of age-related macular degeneration (AMD). Although many immunological mediators have been linked to AMD pathophysiology, the broader mechanistic picture remains unclear with substantial variations in the levels of evidence supporting these mediators. Therefore, we reviewed the literature considering the varying levels of supporting evidence. A Medical Subject Headings (MeSH) term-based literature research was conducted in September, 2023, consisting of the MeSH terms "cytokine" and "Age-related macular degeneration" connected by the operator "AND". After screening the publications by title, abstract, and full text, a total of 146 publications were included. The proinflammatory cytokines IL-1ß (especially in basic research studies), IL-6, IL-8, IL-18, TNF-α, and MCP-1 are the most extensively characterised cytokines/chemokines, highlighting the role of local inflammasome activation and altered macrophage function in the AMD pathophysiology. Among the antiinflammatory mediators IL-4, IL-10, and TGF-ß were found to be the most extensively characterised, with IL-4 driving and IL-10 and TGF-ß suppressing disease progression. Despite the extensive literature on this topic, a profound understanding of AMD pathophysiology has not yet been achieved. Therefore, further studies are needed to identify potential therapeutic targets, followed by clinical studies.

Varied clinical presentations of RP1L1 variants in Chinese patients: a study of occult macular dystrophy and vitelliform macular dystrophy.

BACKGROUND: Occult Macular Dystrophy (OMD), primarily caused by retinitis pigmentosa 1-like 1 (RP1L1) variants, is a complex retinal disease characterised by progressive vision loss and a normal fundus appearance. This study aims to investigate the diverse phenotypic expressions and genotypic correlations of OMD in Chinese patients, including a rare case of Vitelliform Macular Dystrophy (VMD) associated with RP1L1. METHODS: We analysed seven OMD patients and one VMD patient, all with heterozygous pathogenic RP1L1 variants. Clinical assessments included Best Corrected Visual Acuity (BCVA), visual field testing, Spectral Domain Optical Coherence Tomography (SD-OCT), multifocal Electroretinograms (mfERGs), and microperimetry. Next-generation sequencing was utilised for genetic analysis. RESULTS: The OMD patients displayed a range of phenotypic variability. Most (5 out of 7) had the RP1L1 variant c.133 C > T; p.R45W, associated with central vision loss and specific patterns in SD-OCT and mfERG. Two patients exhibited different RP1L1 variants (c.3599G > T; p.G1200V and c.2880G > C; p.W960C), presenting milder phenotypes. SD-OCT revealed photoreceptor layer changes, with most patients showing decreased mfERG responses in the central rings. Interestingly, a unique case of VMD linked to the RP1L1 variant was observed, distinct from traditional OMD presentations. CONCLUSIONS: This study highlights the phenotypic diversity within OMD and the broader spectrum of RP1L1-associated macular dystrophies, including a novel association with VMD. The findings emphasise the complexity of RP1L1 variants in determining clinical manifestations, underscoring the need for comprehensive genetic and clinical evaluations in macular dystrophies.

Topographic Measurement of the Subretinal Pigment Epithelium Space in Normal Aging and Age-Related Macular Degeneration Using High-Resolution OCT.

Purpose: A micrometer scale hyporeflective band within the retinal pigment epithelium basal lamina - Bruch's membrane complex (RPE-BL-BrM) was topographically measured in aging and age-related macular degeneration (AMD). Methods: In a prospective cross-sectional study, 90 normal eyes from 76 subjects (range = 23-90 years) and 53 dry AMD eyes from 47 subjects (range = 62-91 years) were enrolled. Isotropic volume raster scans over 6 mm × 6 mm (500 × 500 A-scans) were acquired using a high-resolution (2.7 µm axial resolution) spectral-domain optical coherence tomography (SD-OCT) prototype instrument. Six consecutive optical coherence tomography (OCT) volumes were computationally motion-corrected and fused to improve feature visibility. A boundary regression neural network was developed to measure hyporeflective band thickness. Topographic dependence was evaluated over a 6-mm-diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Results: The hyporeflective band thickness map (median of 4.3 µm and 7.8 µm in normal and AMD eyes, respectively) is thicker below and radially symmetric around the fovea. In normal eyes, age-associated differences occur within 0.7 to 2.3 mm from the foveal center (P < 0.05). In AMD eyes, the hyporeflective band is hypothesized to be basal laminar deposits (BLamDs) and is thicker within the 3-mm ETDRS circle (P < 0.0002) compared with normal eyes. The inner ring is the most sensitive location to detect age versus AMD-associated changes within the RPE-BL-BrM. AMD eyes with subretinal drusenoid deposits (SDDs) have a significantly thicker hyporeflective band (P < 0.001) than those without SDDs. Conclusions: The hyporeflective band is a quantifiable biomarker which differentiates AMD from aging. Longitudinal studies are warranted. The hyporeflective band may be a useful biomarker for risk stratification and disease progression.

Health-related quality of life in patients with neovascular age-related macular degeneration: a prospective cohort study.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a common cause of visual impairment and blindness in the elderly with globally increasing prevalence. Vascular endothelial growth factor inhibitor (anti-VEGF) treatment has improved visual prognosis of nAMD, but continuous treatment may cause anxiety and stress, although increase in visual acuity (VA) may also have positive effects on patients' quality of life. The health care burden due to frequent treatment and monitoring is apparent, but the effect of anti-VEGF treatment on patients' quality of life is not fully understood. We evaluated the overall impact of nAMD and its treatment on newly diagnosed patients' health-related quality of life (HRQoL) in real-world setting. METHODS: The present prospective cohort study included newly diagnosed nAMD patients treated with anti-VEGF injections at Oulu University Hospital during 2019-2020. Data included parameters from comprehensive ophthalmic examination and fundus imaging, age at diagnosis, sex, comorbidities, visual acuity, and frequency of anti-VEGF injections. HRQoL was assessed by 15D questionnaire at diagnosis, 6 months, and 12 months. RESULTS: 95 nAMD patients were included. They were 78 ± 8 years old, 56 (59%) were female, and 74 (78%) had more than one comorbidity. The patients received 8 ± 3 anti-VEGF-injections. Visual acuity (VA) improved from 56 ± 18 to 61 ± 24 Early treatment diabetic retinopathy study (ETDRS) letters in 12 months. VA improved > 5 ETDRS letters in 45 (47%), remained stable in 30 (32%) and decreased > 5 letters in 17 (18%) eyes. The mean total 15D score reflecting overall HRQoL decreased from 0.850 ± 0.104 to 0.834 ± 0.103 in 12 months. Decreased HRQoL was associated with baseline best-corrected VA (BCVA) ≥ 70 ETDRS letters (p = 0.023) and more than one comorbidity (p = 0.034). HRQoL regarding visual function increased from 0.765 ± 0.194 to 0.789 ± 0.184 during the 12-month follow-up. CONCLUSIONS: In real world setting, HRQoL regarding visual function improved in anti-VEGF-treated nAMD patients during the first 12 months after the diagnosis and treatment initiation. Good baseline VA or several comorbidities were associated with decreased overall HRQoL during the follow-up. Despite the effectiveness of anti-VEGF treatment on visual function, several other aspects affecting elderly patients' everyday life should be considered when nAMD treatment is implemented.

Extent and Topography of Subretinal Drusenoid Deposits Associate With Rod-Mediated Vision in Aging and AMD: ALSTAR2 Baseline.

Purpose: In AMD, rod-mediated dark adaptation (RMDA) at 5° eccentricity is slower in eyes with subretinal drusenoid deposits (SDDs) than in eyes without. Here we quantified SDD burden using supervised deep learning for comparison to vision and photoreceptor topography. Methods: In persons ≥60 years from the Alabama Study on Early Age-Related Macular Degeneration 2, normal, early AMD, and intermediate AMD eyes were classified by the AREDS nine-step system. A convolutional neural network was trained on 55°-wide near-infrared reflectance images for SDD segmentation. Trained graders annotated ground truth (SDD yes/no). Predicted and true datasets agreed (Dice coefficient, 0.92). Inference was manually proofread using optical coherence tomography. The mean SDD area (mm2) was compared among diagnostic groups (linear regression) and to vision (age-adjusted Spearman correlations). Fundus autofluorescence images were used to mask large vessels in SDD maps. Results: In 428 eyes of 428 persons (normal, 218; early AMD, 120; intermediate AMD, 90), the mean SDD area differed by AMD severity (P < 0.0001): 0.16 ± 0.87 (normal), 2.48 ± 11.23 (early AMD), 11.97 ± 13.33 (intermediate AMD). Greater SDD area was associated with worse RMDA (r = 0.27; P < 0.0001), mesopic (r = -0.13; P = 0.02) and scotopic sensitivity (r = -0.17; P < 0.001). SDD topography peaked at 5° superior, extended beyond the Early Treatment of Diabetic Retinopathy Study grid and optic nerve, then decreased. Conclusions: SDD area is associated with degraded rod-mediated vision. RMDA 5° (superior retina) probes where SDD is maximal, closer to the foveal center than the rod peak at 3 to 6 mm (10.4°-20.8°) superior and the further eccentric peak of rod:cone ratio. Topographic data imply that factors in addition to rod density influence SDD formation.

Aging of the eye: Lessons from cataracts and age-related macular degeneration.

Aging is the greatest risk factor for chronic human diseases, including many eye diseases. Geroscience aims to understand the effects of the aging process on these diseases, including the genetic, molecular, and cellular mechanisms that underlie the increased risk of disease over the lifetime. Understanding of the aging eye increases general knowledge of the cellular physiology impacted by aging processes at various biological extremes. Two major diseases, age-related cataract and age-related macular degeneration (AMD) are caused by dysfunction of the lens and retina, respectively. Lens transparency and light refraction are mediated by lens fiber cells lacking nuclei and other organelles, which provides a unique opportunity to study a single aging hallmark, i.e., loss of proteostasis, within an environment of limited metabolism. In AMD, local dysfunction of the photoreceptors/retinal pigmented epithelium/Bruch's membrane/choriocapillaris complex in the macula leads to the loss of photoreceptors and eventually loss of central vision, and is driven by nearly all the hallmarks of aging and shares features with Alzheimer's disease, Parkinson's disease, cardiovascular disease, and diabetes. The aging eye can function as a model for studying basic mechanisms of aging and, vice versa, well-defined hallmarks of aging can be used as tools to understand age-related eye disease.

Choriocapillaris Impairment, Visual Function, and Distance to Fovea in Aging and Age-Related Macular Degeneration: ALSTAR2 Baseline.

Purpose: In aging and early-intermediate age-related macular degeneration (AMD), rod-mediated dark adaptation (RMDA) slows more at 5° superior than at 12°. Using optical coherence tomography angiography (OCTA), we asked whether choriocapillaris flow deficits are related to distance from the fovea. Methods: Persons ≥60 years stratified for AMD via the Age-Related Eye Disease Study's nine-step system underwent RMDA testing. Two adjacent 4.4° × 4.4° choriocapillaris OCTA slabs were centered on the fovea and 12° superior. Flow signal deficits (FD%) in concentric arcs (outer radii in mm, 0.5, 1.5, 2.2, 4.0, and 5.0 superior) were correlated with rod intercept time (RIT) and best-corrected visual acuity (BCVA). Results: In 366 eyes (170 normal, 111 early AMD, 85 intermediate AMD), FD% was significantly worse with greater AMD severity in all regions (overall P < 0.05) and poorest under the fovea (P < 0.0001). In pairwise comparisons, FD% worsened with greater AMD severity (P < 0.05) at distances <2.2 mm. At greater distances, eyes with intermediate, but not early AMD differed from normal eyes. Foveal FD% was more strongly associated with longer RIT at 5° (r = 0.52) than RIT at 12° (r = 0.39) and BCVA (r = 0.21; all P < 0.0001). Choroidal thickness was weakly associated with longer RIT at 5° and 12° (r = 0.10-0.20, P < 0.05) and not associated with AMD severity. Conclusions: Reduced transport across the choriocapillaris-Bruch's membrane-retinal pigment epithelium complex, which contributes to drusen formation under the macula lutea (and fovea), may also reduce retinoid resupply to rods encircling the high-risk area. FD% has potential as a functionally validated imaging biomarker for AMD emergence.

Quantifying Geographic Atrophy in Age-Related Macular Degeneration: A Comparative Analysis Across 12 Deep Learning Models.

Purpose: AI algorithms have shown impressive performance in segmenting geographic atrophy (GA) from fundus autofluorescence (FAF) images. However, selection of artificial intelligence (AI) architecture is an important variable in model development. Here, we explore 12 distinct AI architecture combinations to determine the most effective approach for GA segmentation. Methods: We investigated various AI architectures, each with distinct combinations of encoders and decoders. The architectures included three decoders-FPN (Feature Pyramid Network), UNet, and PSPNet (Pyramid Scene Parsing Network)-and serve as the foundation framework for segmentation task. Encoders including EfficientNet, ResNet (Residual Networks), VGG (Visual Geometry Group) and Mix Vision Transformer (mViT) have a role in extracting optimum latent features for accurate GA segmentation. Performance was measured through comparison of GA areas between human and AI predictions and Dice Coefficient (DC). Results: The training dataset included 601 FAF images from AREDS2 study and validation included 156 FAF images from the GlaxoSmithKline study. The mean absolute difference between grader measured and AI predicted areas ranged from -0.08 (95% CI = -1.35, 1.19) to 0.73 mm2 (95% CI = -5.75,4.29) and DC between 0.884-0.993. The best-performing models were UNet and FPN frameworks with mViT, and the least-performing models were PSPNet framework. Conclusions: The choice of AI architecture impacts GA segmentation performance. Vision transformers with FPN and UNet architectures demonstrate stronger suitability for this task compared to Convolutional Neural Network- and PSPNet-based models. Selecting an AI architecture must be tailored to the specific goals of the project, and developers should consider which architecture is ideal for their project.

ADVANCES IN PHOTORECEPTOR AND RETINAL PIGMENT EPITHELIUM QUANTIFICATIONS IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION: High-Res Versus Standard SPECTRALIS Optical Coherence Tomography.

PURPOSE: In this study, differences in retinal feature visualization of high-resolution optical coherence tomography (OCT) devices were investigated with different axial resolutions in quantifications of retinal pigment epithelium and photoreceptors (PRs) in intermediate age-related macular degeneration. METHODS: Patients were imaged with standard SPECTRALIS HRA + OCT and the investigational High-Res OCT device (both by Heidelberg Engineering, Heidelberg, Germany). Drusen, retinal pigment epithelium, and PR layers were segmented using validated artificial intelligence-based algorithms followed by manual corrections. Thickness and drusen maps were computed for all patients. Loss and thickness measurements were compared between devices, drusen versus nondrusen areas, and early treatment diabetic retinopathy study subfields using mixed-effects models. RESULTS: Thirty-three eyes from 28 patients with intermediate age-related macular degeneration were included. Normalized PR integrity loss was significantly higher with 4.6% for standard OCT compared with 2.5% for High-Res OCT. The central and parafoveal PR integrity loss was larger than the perifoveal loss (P < 0.05). Photoreceptor thickness was increased on High-Res OCT and in nondrusen regions (P < 0.001). Retinal pigment epithelium appeared thicker on standard OCT and above drusen (P < 0.01). CONCLUSION: Our study shows that High-Res OCT is able to identify the condition of investigated layers in intermediate age-related macular degeneration with higher precision. This improved in vivo imaging technology might promote our understanding of the pathophysiology and progression of age-related macular degeneration.

Microperimetry Characteristics of Regions With a Truly Nonresponding Location: Implications for Atrophic Age-Related Macular Degeneration.

Purpose: To understand the microperimetry response characteristics of regions with a truly nonresponding location, which will be useful when considering criteria for end-stage atrophic age-related macular degeneration (AMD). Methods: A simulation model was developed using data from 128 participants with bilateral large drusen at baseline seen over 36 months at 6-month intervals. One hundred thousand pairs of real-world microperimetry testing results were simulated separately with and without one truly nonresponding location, where the sensitivity of one randomly selected location for the former group was derived from the distribution of responses from a truly nonresponding location at the optic nerve head from 60 healthy participants. Results: Only 60% of the simulated test pairs with a truly nonresponding location had ≥1 location that was <0 decibel (dB) on both tests. In contrast, 91% of the simulated test pairs had ≥1 location that was ≤10 dB on both tests, and 87% had ≥1 location that was ≤10 dB on both tests and <0 dB for one of the tests. Of the simulated test pairs without a truly nonresponding location, there were 0.04%, 1.4%, and 0.4% that met these three above criteria, respectively. Conclusions: Regions with a truly nonresponding test location do not almost always show a repeatable absolute scotoma (<0 dB), but instead, much more often a deep visual sensitivity defect (≤10 dB), with or without having an absolute scotoma on one of the tests. These findings are crucial if functional criteria are to be considered as part of a definition of end-stage atrophic AMD.

Bruch's Membrane Opening Changes in Eyes With Myopic Macular Degeneration: AIER-SERI Adult High Myopia Study.

Purpose: The purpose of this study was to assess the choroidal thickness and the Bruch's membrane opening size and their relationship to visual acuity in eyes with myopic macular degeneration (MMD). Methods: This was a population-based, cross-sectional study. Patients over the age of 30 years with high myopia (spherical equivalent ≤-5 diopters [D]) were recruited. The eyes were grouped according to the International Meta-Analysis for Pathologic Myopia (META-PM) classification based on fundus photographs and diffuse atrophy was subdivided into peripapillary diffuse choroidal atrophy (PDCA) or macular diffuse choroidal atrophy (MDCA). Swept-source optical coherence tomography imaging was performed and then the subfoveal choroidal thickness (SFCT) and Bruch's membrane opening diameter (BMOD) were measured. Results: Of the 470 study participants recruited, 373 patients (691 eyes), with a mean age of 42.8 ± 7.2 years, were eligible for the study and included in the analysis. There was no significant difference in SFCT between MDCA and patchy atrophy (M3) groups (P = 1.000), and the BMOD enlarged significantly from no myopic macular lesions to M3 (the P values of multiple comparison tests were all <0.005). Simple linear regression analysis showed that BMOD correlated positively with age (P < 0.001) and axial length (P < 0.001). Multiple linear regression analysis showed that best corrected visual acuity (BCVA) was significantly correlated with age (P = 0.041), axial length (P = 0.001), and BMOD (P = 0.017), but not with SFCT (P = 0.231). Conclusions: The significant variation of BMOD among MMD groups and the correlation between BMOD and BCVA in MMD eyes suggest that BMOD may be an imaging biomarker for monitoring MMD.

Developing quantitative analysis program of blood flow velocity according to vessel diameter for neovascular age-related macular degeneration using OCTA-VISTA.

This study aimed to develop a quantitative analysis program of blood flow velocity by vessel diameter in neovascular age-related macular degeneration (nAMD) subjects using high-speed swept-source optical coherence tomography angiography. This retrospective, observational, cross-sectional study included 10 eyes of healthy volunteers and 4 eyes of patients with representative nAMD. Novel scan patterns and variable interscan time analysis were utilized to measure the flow parameter, a surrogate marker of blood flow velocity, by vessel diameter within different depths. Detected vessels at superficial and deep as well as outer retinal regions were categorized into three vessel diameters (major vessels (> 40 µm), medium vessels (20-40 µm), and capillaries (< 20 µm)). The flow parameter increased with enlarged vessel diameter in all participants at superficial and deep layer. All nAMD subjects, except for type 3 macular neovascularization (MNV), contained a structure dominated by medium vessels at outer retinal region. The mean flow parameter at outer retinal region was type 1 MNV (1.46 ms-1), type 1 + 2 MNV (0.98 ms-1), and polypoidal choroidal vasculopathy, including branching vascular networks (1.46 ms-1). This program provides the possibility to extract the blood flow information at different depths by vessel diameter types, which is considered to be useful tool for evaluating nAMD pathology and activity.

Retinal Sensitivity in Macular Subfields and Their Association with Contrast Sensitivity in Early and Intermediate Age-Related Macular Degeneration.

INTRODUCTION: The objective of this study was to evaluate retinal sensitivity in subfields and its association with the novel quantitative 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, USA) 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, contrast acuity 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.

Foveolar Drusen Decrease Fixation Stability in Pre-Symptomatic AMD.

Purpose: This study aims at linking subtle changes of fixational eye movements (FEM) in controls and in patients with foveal drusen using adaptive optics retinal imaging in order to find anatomo-functional markers for pre-symptomatic age-related macular degeneration (AMD). Methods: We recruited 7 young controls, 4 older controls, and 16 patients with presymptomatic AMD with foveal drusen from the Silversight Cohort. A high-speed research-grade adaptive optics flood illumination ophthalmoscope (AO-FIO) was used for monocular retinal tracking of fixational eye movements. The system allows for sub-arcminute resolution, and high-speed and distortion-free imaging of the foveal area. Foveal drusen position and size were documented using gaze-dependent imaging on a clinical-grade AO-FIO. Results: FEM were measured with high precision (RMS-S2S = 0.0015 degrees on human eyes) and small foveal drusen (median diameter = 60 µm) were detected with high contrast imaging. Microsaccade amplitude, drift diffusion coefficient, and ISOline area (ISOA) were significantly larger for patients with foveal drusen compared with controls. Among the drusen participants, microsaccade amplitude was correlated to drusen eccentricity from the center of the fovea. Conclusions: A novel high-speed high-precision retinal tracking technique allowed for the characterization of FEM at the microscopic level. Foveal drusen altered fixation stability, resulting in compensatory FEM changes. Particularly, drusen at the foveolar level seemed to have a stronger impact on microsaccade amplitudes and ISOA. The unexpected anatomo-functional link between small foveal drusen and fixation stability opens up a new perspective of detecting oculomotor signatures of eye diseases at the presymptomatic stage.

Assessment of local sensitivity in incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) lesions in intermediate age-related macular degeneration (iAMD).

Lesions of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) are associated with disease progression in age-related macular degeneration. However, the corresponding functional impact of these precursor lesions is unknown.We present a cross-sectional study of four patients employing clinical-grade MAIA (stimulus size: 0.43°, ~125 µm) and adaptive optics scanning light ophthalmoscope (AOSLO, stimulus size 0.07°, ~20 µm) based microperimetry (MP) to assess the specific impact of iRORA lesions on retinal sensitivity.AOSLO imaging showed overall reduced photoreceptor reflectivity and patches of hyporeflective regions at drusen with interspersed hyper-reflective foci in iRORA regions. MAIA-MP yielded an average retinal sensitivity loss of -7.3±3.1 dB at iRORA lesions compared with the in-eye control. With AOSLO-MP, the corresponding sensitivity loss was 20.1±4.8 dB.We demonstrated that iRORA lesions are associated with a severe impairment in retinal sensitivity. Larger cohort studies will be necessary to validate our findings.

Leading edge of the a-wave of the electroretinogram and sodium iodate-induced age-related macular degeneration: A model.

BACKGROUND: Iron-induced oxidative stress was thought to be the reason why the a-wave amplitude of the electroretinogram (ERG) dropped when iron ions were present. It is assumed that reactive oxygen species (ROS) are generated in the presence of iron ions, and this leads to a decrease in hyperpolarization of the photoreceptor. It is known that in age-related macular degeneration (AMD), sodium iodate can induce oxidative stress, apoptosis, and retinal damage, which mimic the effects of clinical AMD. Here, the reduction of the a-wave amplitude in mice with sodium iodate-induced age-related macular degeneration is explained. METHODS: The leading edge of the a-wave is divided into voltages developed by cones and rods. The same oxidative stress model is applied here since sodium iodate causes the creation of ROS in a manner similar to that caused by iron ions, with the exception that the retina is treated as a circuit of various resistances when computing the photoresponse. Moreover, sodium iodate also leads to apoptosis and, hence, may cause misalignment in cones (not in rods) during the initial stage of apoptosis in AMD. To include the effects of apoptosis and shortening in cones and rods, we have used a factor representing the fraction of total cones and rods that are alive. To include the effect of misalignment of cones on the reduction of the a-wave amplitude, we have used the Stiles-Crawford function to calculate the number of photoisomerizations occurring in a photoreceptor misaligned at an angle θ. The results are compared with experimental data. RESULTS: In sodium iodate-treated eyes, the ROS produced can attract calcium ions in the photoreceptor, which increases the calcium influx. In the case of the cones, the inclusion of the misalignment angle in the phototransduction process helps in determining the voltage and slope of the voltage vs. time graph.The smaller the fraction of active photoreceptors, the smaller the amplitude of the a-wave. The calcium influx, misaligned photoreceptors, and total photoreceptor loss all cause the amplitude of the a-wave to decrease, and at any time from the beginning of phototransduction cascade, the calcium influx causes the slope of the a-wave to increase. CONCLUSION: The reduction in the a-wave amplitude in the eyes of sodium iodate-treated mice is attributed to oxidative stress in both cones and rods and cone misalignment, which ultimately lead to apoptosis and vision loss in AMD.