Prevalence and determinants of subretinal drusenoid deposits in patients' first-degree relatives.

PURPOSE: Subretinal drusenoid deposits (SDDs) are distinct extracellular alteration anterior to the retinal pigment epithelium (RPE). Given their commonly uniform phenotype, a hereditary predisposition seems likely. Hence, we aim to investigate prevalence and determinants in patients' first-degree relatives. METHODS: We recruited SDD outpatients at their visits to our clinic and invited their relatives. We performed a full ophthalmic examination including spectral domain-optical coherence tomography (SD-OCT) and graded presence, disease stage of SDD as well as percentage of infrared (IR) en face area affected by SDD. Moreover, we performed genetic sequencing and calculated a polygenic risk score (PRS) for AMD. We conducted multivariable regression models to assess potential determinants of SDD and associations of SDD with PRS. RESULTS: We included 195 participants, 123 patients (mean age 81.4 ± 7.2 years) and 72 relatives (mean age 52.2 ± 14.2 years), of which 7 presented SDD, resulting in a prevalence of 9.7%. We found older age to be associated with SDD presence and area in the total cohort and a borderline association of higher body mass index (BMI) with SDD presence in the relatives. Individuals with SDD tended to have a higher PRS, which, however, was not statistically significant in the multivariable regression. CONCLUSION: Our study indicates a potential hereditary aspect of SDD and confirms the strong association with age. Based on our results, relatives of SDD patients ought to be closely monitored for retinal alterations, particularly at an older age. Further longitudinal studies with larger sample size and older relatives are needed to confirm or refute our findings.

Visual impairment and retinal and brain neurodegeneration: A population-based study.

Visual impairment and retinal neurodegeneration are intrinsically connected and both have been associated with cognitive impairment and brain atrophy, but the underlying mechanisms remain unclear. To investigate whether transneuronal degeneration is implicated, we systematically assessed the relation between visual function and retinal, visual pathway, hippocampal and brain degeneration. We analyzed baseline data from 3316 eligible Rhineland Study participants with visual acuity (VA), optical coherence tomography (OCT), and magnetic resonance imaging (MRI) data available. Regional volumes, cortical volume, and fractional anisotropy (FA) were derived from T1-weighted and diffusion-weighted 3 T MRI scans. Statistical analyses were performed using multivariable linear regression and structural equation modeling. VA and ganglion cell layer (GCL) thinning were both associated with global brain atrophy (SD effect size [95% CI] -0.090 [-0.118 to -0.062] and 0.066 [0.053-0.080], respectively), and hippocampal atrophy (-0.029 [-0.055 to -0.003] and 0.114 [0.087-0.141], respectively). The effect of VA on whole brain and hippocampal volume was partly mediated by retinal neurodegeneration. Similarly, the effect of retinal neurodegeneration on brain and hippocampal atrophy was mediated through intermediate visual tracts, accounting for 5.2%-23.9% of the effect. Visual impairment and retinal neurodegeneration were robustly associated with worse brain atrophy, FA, and hippocampal atrophy, partly mediated through disintegration of intermediate visual tracts. Our findings support the use of OCT-derived retinal measures as markers of neurodegeneration, and indicate that both general and transneuronal neurodegeneration along the visual pathway, partly reflecting visual impairment, account for the association between retinal neurodegeneration and brain atrophy.

Systemic and Ocular Determinants of Peripapillary Retinal Nerve Fiber Layer Thickness Measurements in the European Eye Epidemiology (E3) Population.

PURPOSE: To investigate systemic and ocular determinants of peripapillary retinal nerve fiber layer thickness (pRNFLT) in the European population. DESIGN: Cross-sectional meta-analysis. PARTICIPANTS: A total of 16 084 European adults from 8 cohort studies (mean age range, 56.9±12.3-82.1±4.2 years) of the European Eye Epidemiology (E3) consortium. METHODS: We examined associations with pRNFLT measured by spectral-domain OCT in each study using multivariable linear regression and pooled results using random effects meta-analysis. MAIN OUTCOME MEASURES: Determinants of pRNFLT. RESULTS: Mean pRNFLT ranged from 86.8±21.4 µm in the Rotterdam Study I to 104.7±12.5 µm in the Rotterdam Study III. We found the following factors to be associated with reduced pRNFLT: Older age (ß = -0.38 µm/year; 95% confidence interval [CI], -0.57 to -0.18), higher intraocular pressure (IOP) (ß = -0.36 µm/mmHg; 95% CI, -0.56 to -0.15), visual impairment (ß = -5.50 µm; 95% CI, -9.37 to -1.64), and history of systemic hypertension (ß = -0.54 µm; 95% CI, -1.01 to -0.07) and stroke (ß = -1.94 µm; 95% CI, -3.17 to -0.72). A suggestive, albeit nonsignificant, association was observed for dementia (ß = -3.11 µm; 95% CI, -6.22 to 0.01). Higher pRNFLT was associated with more hyperopic spherical equivalent (ß = 1.39 µm/diopter; 95% CI, 1.19-1.59) and smoking (ß = 1.53 µm; 95% CI, 1.00-2.06 for current smokers compared with never-smokers). CONCLUSIONS: In addition to previously described determinants such as age and refraction, we found that systemic vascular and neurovascular diseases were associated with reduced pRNFLT. These may be of clinical relevance, especially in glaucoma monitoring of patients with newly occurring vascular comorbidities.

Directional Kinetics of Geographic Atrophy Progression in Age-Related Macular Degeneration with Foveal Sparing.

PURPOSE: To describe the directional kinetics of the spread of geographic atrophy (GA) spread in eyes with age-related macular degeneration and foveal sparing. DESIGN: Prospective, noninterventional natural history study: Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM; clinicaltrials.gov identifier, NCT00393692). SUBJECTS: Participants of the FAM study exhibiting foveal sparing of GA. METHODS: Eyes were examined longitudinally with fundus autofluorescence (FAF; excitation wavelength, 488 nm; emission wavelength, >500 nm) and near infrared (NIR) reflectance imaging (Spectralis HRA+OCT or HRA2; Heidelberg Engineering, Heidelberg, Germany). Areas of foveal sparing and GA were measured by 2 independent readers using a semiautomated software tool that allows for combined NIR reflectance and FAF image grading (RegionFinder; Heidelberg Engineering). A linear mixed effect model was used to model GA kinetics over time. MAIN OUTCOME MEASURE: Change of GA lesion size over time (central vs. peripheral progression). RESULTS: A total of 47 eyes of 36 patients (mean age, 73.8±7.5 years) met the inclusion criteria. Mean follow-up time was 25.2±16.9 months (range, 5.9-74.6 months). Interreader agreement for measurements of GA and foveal-sparing size were 0.995 and 0.946, respectively. Mean area progression of GA toward the periphery was 2.27±0.22 mm(2)/year and 0.25±0.03 mm(2)/year toward the center. Analysis of square root-transformed data revealed a 2.8-fold faster atrophy progression toward the periphery than toward the fovea. Faster atrophy progression toward the fovea correlated with faster progression toward the periphery in presence of marked interindividual differences. CONCLUSIONS: The results demonstrate a significantly faster centrifugal than centripetal GA spread in eyes with GA and foveal sparing. Although the underlying pathomechanisms for differential GA progression remain unknown, local factors may be operative that protect the foveal retina-retinal pigment epithelial complex. Quantification of directional spread characteristics and modeling may be useful in the design of interventional clinical trials aiming to prolong foveal survival in eyes with GA.

Fundus Autofluorescence in Posterior and Panuveitis-An Under-Estimated Imaging Technique: A Review and Case Series.

Fundus autofluorescence (FAF) is a prompt and non-invasive imaging modality helpful in detecting pathological abnormalities within the retina and the choroid. This narrative review and case series provides an overview on the current application of FAF in posterior and panuveitis. The literature was reviewed for articles on lesion characteristics on FAF of specific posterior and panuveitis entities as well as benefits and limitations of FAF for diagnosing and monitoring disease. FAF characteristics are described for non-infectious and infectious uveitis forms as well as masquerade syndromes. Dependent on the uveitis entity, FAF is of diagnostic value in detecting disease and following the clinical course. Currently available FAF modalities which differ in excitation wavelengths can provide different pathological insights depending on disease entity and activity. Further studies on the comparison of FAF modalities and their individual value for uveitis diagnosis and monitoring are warranted.

Implementing strabismus-specific psychosocial questionnaires in everyday clinical practice: mental health and quality of life in the context of strabismus surgery.

BACKGROUND: Strabismus can have a great negative impact on the quality of life and the well-being of affected patients. In the past, these aspects were often neglected and, compared with somatic functioning, placed in the background. The aim of our study is to elicit factors influencing satisfaction with strabismus surgery, quality of life and expectations of surgery in order to better predict who will benefit the most and who may need further support. METHODS: We made a selection of suitable questionnaires to assess psychosocial aspects of strabismus and decided for Adult Strabismus 20 Questionnaire, Amblyopia and Strabismus Questionnaire, Diplopia Questionnaire, Expectations of Strabismus Surgery Questionnaire and Hospital Anxiety and Depression Scale. We then translated these measures (if not available in German). The patients filled out these forms as part of their preoperative orthoptic and ophthalmological assessment as well as approximately 3 months after strabismus surgery. RESULTS: We enrolled 59 patients in this study. Postoperative strabismus-related quality of life was higher after surgery and anxiety and depression levels were lower. Satisfaction with surgery was lower with higher postoperative angle and diplopia; the latter was also a determinant of lower postoperative quality of life. Higher expectations of strabismus surgery were present with higher depression levels and higher preoperative strabismus angle. CONCLUSION: Our data indicate that strabismus surgery may cause a significant improvement in several psychosocial domains. There is evidence that psychosocial factors can have significant impact on expectations with surgery. Hence, it is important to consider mental health aspects of this disease in order to treat patients in the best possible way.

Association of lipid-lowering drugs and antidiabetic drugs with age-related macular degeneration: a meta-analysis in Europeans.

BACKGROUND/AIMS: To investigate the association of commonly used systemic medications with prevalent age-related macular degeneration (AMD) in the general population. METHODS: We included 38 694 adults from 14 population-based and hospital-based studies from the European Eye Epidemiology consortium. We examined associations between the use of systemic medications and any prevalent AMD as well as any late AMD using multivariable logistic regression modelling per study and pooled results using random effects meta-analysis. RESULTS: Between studies, mean age ranged from 61.5±7.1 to 82.6±3.8 years and prevalence ranged from 12.1% to 64.5% and from 0.5% to 35.5% for any and late AMD, respectively. In the meta-analysis of fully adjusted multivariable models, lipid-lowering drugs (LLD) and antidiabetic drugs were associated with lower prevalent any AMD (OR 0.85, 95% CI=0.79 to 0.91 and OR 0.78, 95% CI=0.66 to 0.91). We found no association with late AMD or with any other medication. CONCLUSION: Our study indicates a potential beneficial effect of LLD and antidiabetic drug use on prevalence of AMD across multiple European cohorts. Our findings support the importance of metabolic processes in the multifactorial aetiology of AMD.

Age-Related Macular Degeneration and Cardiovascular Diseases: Revisiting the Common Soil Theory.

ABSTRACT: Age-related macular degeneration (AMD), a complex disease associated with aging, remains one of the leading causes of visual loss in high-income countries and its prevalence is expected to increase over the next decades. Polypoidal choroidal vasculopathy has been considered a variant of neovascular AMD and is highly prevalent in Asian populations. Similarly, cardiovascular disease (CVD)-another complex disease associated with aging-is a leading cause of morbidity and mortality in high-income countries and its prevalence is also expected to increase due to population aging. Previous studies reported an increased risk for CVD in AMD patients, indicating an underlying "common soil." Reviewing the current literature, consistent evidence for common risk factors and mutual comorbidity was identified for both diseases. Cardiovascular risk factors include smoking, diet, and low levels of physical activity, which also play a role in AMD pathogenesis. Several studies demonstrated AMD patients to be at higher risk for CVD compared to the general older population. The complexity of both diseases, however, complicates research on their relation, and thus studies ought to be interpreted with caution. Herein we present an overview of selected studies and their main "take-home messages" on this topic, and hypothesize on the patho-etiologic "common ground" of these 2 diseases.

Neurofilament light chain and retinal layers' determinants and association: A population-based study.

Both retinal atrophy measured through optical coherence tomography and plasma neurofilament light chain (NfL) levels are markers of neurodegeneration, but their relationship is unknown. Therefore, we assessed their determinants and association in 4369 participants of a population-based study. Both plasma NfL levels and inner retinal atrophy increased exponentially with age. In the presence of risk factors for neurodegeneration (including age, smoking, and a history of neurological disorders), plasma NfL levels were associated with inner retinal atrophy and outer retinal thickening. Our findings indicate that inner retinal atrophy can reflect neuroaxonal damage as mirrored by rising plasma NfL levels.

Retinal layer assessments as potential biomarkers for brain atrophy in the Rhineland Study.

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.

Physical Activity, Incidence, and Progression of Age-Related Macular Degeneration: A Multicohort Study.

PURPOSE: To investigate the impact of physical activity (PA) on the incidence or progression of age-related macular degeneration (AMD) in the general population. DESIGN: Meta-analysis of longitudinal cohort studies. METHODS: We included 14,630 adults with no or early AMD at baseline from 7 population-based studies and examined associations of PA with AMD incidence and progression using multistate models (MSM) per study and subsequent random effects meta-analysis. Age effects were assessed using meta-regression. The main outcome measure was the hazard ratio (HR) for incident early or progression to late AMD. RESULTS: At baseline, mean age was 60.7 ± 6.9 to 76.4 ± 4.3 years, and prevalence of early AMD was 7.7% (range, 3.6%-16.9%) between cohorts. During follow-up, 1461 and 189 events occurred for early and late AMD, respectively. In meta-analyses, no or low to moderate PA (high PA as reference) was associated with an increased risk for incident early AMD (HR, 1.19; 95% CI, 1.01-1.40; P = .04), but not for late AMD. In subsequent meta-regression, we found no association of age with the effect of PA on incident AMD. CONCLUSIONS: Our study suggests high levels of PA to be protective for the development of early AMD across several population-based cohort studies. Our results establish PA as a modifiable risk factor for AMD and inform further AMD prevention strategies to reduce its public health impact.

Yokoyama procedure for esotropia associated with high myopia: real-world data from a large-scale multicentre analysis.

PURPOSE: High myopic patients may develop strabismus due to globe dislocation out of the normal extraocular muscle cone. Surgical correction of this strabismus type is possible by joining the superior and lateral rectus muscles without the need for a scleral suture called the Yokoyama procedure. Data from large patient samples and the evaluation of a potential effect of an additional medial rectus recession (MRR) have been lacking so far. METHODS: We pooled retrospective patient data of 14 departments of ophthalmology in Germany and Switzerland and analysed determinants of postoperative results using multivariable regression models. RESULTS: We included 133 patients (mean age: 59.7 ± 13.4 years, surgery between 2008 and 2017) with a mean preoperative esotropia (both Yokoyama with and without MRR) of 23.8°±4.6°. The angle of preoperative esotropia increased with age. The postoperative esotropia was 8.7° ± 9.9°, and six patients were overcorrected. While preoperative esotropia was highly associated with postoperative results, we found no association of additional MRR with any of our postoperative outcome measures. The Yokoyama procedure had a higher absolute effect in patients with higher preoperative esotropia. CONCLUSION: Our study confirms the positive effect of the Yokoyama procedure on strabismus due to high myopia in large-scale real-world data. In some cases, MRR may be needed because of muscle contracture, although additional MRR statistically did not affect the postoperative outcome. In patients with bilateral high myopic strabismus, correction of both eyes seems beneficial. The effect size of the Yokoyama procedure appears to be mainly driven by preoperative esotropia.

Association of retinal layer measurements and adult cognitive function: A population-based study.

OBJECTIVE: To quantify the associations of peripapillary retinal nerve fiber layer (pRNFL) thickness and macular ganglion cell layer (mGCL) volume with cognitive functioning and to investigate how demographic and vascular health factors affect these associations in a population-based sample of adults. METHODS: The sample included the first 3,000 participants (age range 30-95 years) of the Rhineland Study (recruited from March 2016 to December 2018) who underwent spectral-domain optical coherence tomography and cognitive assessment at 1 of 2 identical study centers in Bonn, Germany. We used multiple linear regression models to examine the relationships between retinal layer measurements and cognitive functioning after adjustment for confounders, and we examined the moderating effects of demographic and vascular health factors. RESULTS: The analytical sample included 2,483 participants who were 54.3 years old (SD 13.8 years) on average. After full adjustment, each 1-SD decrease in mGCL volume was associated with a greater decrease in global function than that of pRNFL thickness (ß = -0.048 [95% confidence interval (CI) -0.077 to -0.018] vs ß = -0.021 [95% CI -0.049 to 0.007]). These relationships increased in strength with advancing age, were stronger in participants with hypertension, and were reversed in current smokers relative to nonsmokers. CONCLUSIONS: mGCL volume is more strongly related to adult cognitive functioning than pRNFL thickness, making it a better potential biomarker of neurodegeneration. Age and vascular health factors play important roles in determining the strength and direction of this association.

Determinants of Macular Layers and Optic Disc Characteristics on SD-OCT: The Rhineland Study.

PURPOSE: To investigate variation and determinants of macular layers, peripapillary retinal nerve fiber layer (pRNFL) and Bruch's membrane opening-minimum rim width (BMO-MRW) in the general population. METHODS: In 1306 participants, we performed spectral domain optical coherence tomography (SD-OCT) scans of the macula, pRNFL, and BMO-MRW, and assessed their determinants using multivariable regression. Intraindividual interocular differences were analyzed using Spearman's rank correlation analysis. RESULTS: Participant age ranged from 30 to 95 years (mean ± standard deviation, 56.1 ± 13.9) and 56% were women. Interocular correlation ranged from 0.63 to 0.93. Differences increased with age and were larger in persons with glaucoma or prior stroke. pRNFL and BMO-MRW decreased with increasing age. Except for RNFL, volumes of various inner macular layers and the outer nuclear layer (ONL) decreased with increasing age, more negative spherical equivalent (SE), and were lower in women compared to men. For some layers, age effects amplified over the life course. History of stroke was associated with smaller volumes of various layers, without reaching statistical significance. We found no association of further systemic parameters with any SD-OCT parameter. CONCLUSIONS: We provide large-scale normative data from a Caucasian general population for various SD-OCT measures. Interocular variability increased with age and specific pathology. Factors, such as age, sex, refraction, and a history of stroke, were associated with various retinal assessments. TRANSLATIONAL RELEVANCE: In clinical routine, our findings should be considered on a per eye basis when interpreting SD-OCT volumes, pRNFL, or BMO-MRW to avoid confounded results.

Impact of visual impairment on physical activity in early and late age-related macular degeneration.

BACKGROUND: Modifiable risk factors for age-related macular degeneration (AMD) include smoking, nutrition and likely physical activity (PA). Levels of PA, however, are impacted by any visual impairment which makes the assessment of any association with AMD difficult. PURPOSE: To assess the impact of visual impairment under both high and low luminance conditions on levels of PA in early and late AMD. METHODS: Ninety participants with early to late AMD underwent a clinical assessment including conventional best-corrected visual acuity, low luminance visual acuity, contrast sensitivity and the Moorfields acuity test. PA was recorded using a wrist-worn accelerometer (GENEActiv, Activeinsights) on seven consecutive days. Patient characteristics were compared with the Wilcoxon rank-sum test and determinants of moderate-to-vigorous-PA (MVPA) were assessed using linear regression models. RESULTS: Mean age was 73.9 ± 8.5 years (range 50-89) and 47 subjects (52.2%) were women. Average MVPA time was longer in the early (355.1 ± 252.0 minutes/week) compared to the late AMD group (162.2 ± 134.6 minutes/week; p<0.001). Using linear regression, age [ß = -0.25; 95% confidence interval (CI): -12.9; -0.8, p = 0.028] and AMD stage (ß = -0.28; 95% CI: -230.9, -25.0; p = 0.015) but not visual impairment on any of the employed tests were associated with MVPA (minutes/week). CONCLUSIONS: We found late AMD to be associated with reduced PA. As performance on any of the visual tests was not associated with PA, this association cannot entirely be explained by functional impairment. More research is needed to further explore the association of PA and AMD as PA may be a potentially modifiable risk factor.

Comparison of Green Versus Blue Fundus Autofluorescence in ABCA4-Related Retinopathy.

PURPOSE: To investigate the interreader and intermodality agreement for grading of retinal pigment epithelium (RPE) atrophy lesion size in ABCA4-related retinopathy using green (GAF) and blue fundus autofluorescence (BAF) imaging. METHODS: In this cross-sectional case series, 97 eyes of 49 patients with RPE atrophy secondary to ABCA4-related retinopathy underwent GAF- (518 nm excitation light) and BAF- (488 nm excitation light) imaging using confocal scanning laser ophthalmoscopy (Spectralis HRA, Heidelberg Engineering, Heidelberg, Germany). Lesions with definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) in GAF and BAF imaging were analyzed separately by five independent readers using semiautomated software (RegionFinder, Heidelberg Engineering). Intermodality and interreader agreements were assessed for the square-root lesion size, lesion perimeter, and circularity. RESULTS: GAF- and BAF-based measurements of DDAF and QDAF showed high intermodality and interreader agreement concerning square-root lesion size, as well as shape descriptive parameters (perimeter and circularity). Interreader agreement of square-root lesion size was slightly, hence not significantly higher for GAF-based grading ([95% coefficients of repeatability, intraclass correlation coefficient] DDAF: 0.215 mm, 0.997; QDAF: 0.712 mm, 0.981) compared to BAF-based grading (DDAF: 0.232 mm, 0.997; QDAF: 0.764 mm, 0.978). However, DDAF-measurements revealed distinctly more reproducible results than QDAF-measurements. Foveal sparing did not interfere with intermodality agreement. CONCLUSIONS: Both GAF- and BAF-based quantification of RPE atrophy showed very reliable results with possible superiority of GAF in the context of less energetic excitation light. TRANSLATIONAL RELEVANCE: The high interreader agreement qualifies the use of DDAF progression in GAF and BAF imaging as potential morphologic outcome measure for interventional clinical trials and disease monitoring.

The Impact of Lens Opacity on SD-OCT Retinal Nerve Fiber Layer and Bruch's Membrane Opening Measurements Using the Anatomical Positioning System (APS).

Purpose: To evaluate the impact of lens opacity on retinal nerve fiber layer thickness (RNFLT) and Bruch's membrane opening (BMO) measurements. Methods: Fifty-nine randomly selected patients without any other relevant ocular pathology undergoing elective routine cataract surgery in two specialized eye clinics were enrolled. RNFLT, BMO area, and BMO minimum rim width (BMO-MRW) were assessed with the Heidelberg Engineering Spectralis OCT using the anatomical positioning system (APS) prior to and 1 day after cataract surgery using a ring scan at different eccentricities of the disc (3.5, 4.1 and 4.7 mm). Lens opacity was quantified using densitometry based on Scheimpflug images (Oculus Pentacam AXL). Results: RNFLT, BMO area, and BMO-MRW were virtually identical before and following removal of the cataractous lens. This held when assessed overall, within the six sectors for the 3.5-mm scan, or at any other eccentricity. Baseline RNFLT was not associated with lens opacity. Conclusions: Using the APS, RNFLT remained unchanged following cataract surgery, contrary to results reported by previous studies. Our results imply that the APS may have contributed to more precise spectral-domain optical coherence measurements, minimizing the influence of cataract on RNFLT and BMO assessments in our cohort.

Combined Fundus Autofluorescence and Near Infrared Reflectance as Prognostic Biomarkers for Visual Acuity in Foveal-Sparing Geographic Atrophy.

Purpose: To identify predictors of best corrected visual acuity (BCVA) in eyes with foveal-sparing geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Methods: Best corrected visual acuity (Early Treatment Diabetic Retinopathy Study charts); serial fundus autofluorescence; and near-infrared reflectance images of patients participating in the FAM (NCT00393692) and DSGA (NCT02051998) studies were analyzed. The sizes of GA and spared fovea, and the minimal linear dimension of intact retinal pigment epithelium ("bridge") between the residual foveal island and the surrounding retina were quantified and associations with BCVA were assessed by local regression curves and mixed effects models. Results: A total of 65 eyes (51 patients, aged 75.68 ± 8.41 years) were included. Median time between baseline and last visit with detectable foveal sparing was 18 (quartiles: 12, 33) months. Median BCVA was 0.30 (0.20, 0.52) logMAR at baseline and 0.4 (0.3, 0.7) logMAR at follow-up. Local regression curves suggested no linear association of BCVA with GA size, sparing size or bridge size. Most contrasting values for BCVA were observed for >1.5 mm2 foveal-sparing size and for 400 µm bridge size. Employing these values as cutoff levels, mixed effects modeling revealed that both anatomic parameters, but not time, significantly impacted BCVA. Conclusions: During the review period eyes with foveal-sparing GA were likely to maintain the baseline BCVA. There was no linear correlation of BCVA with foveal-sparing size. Yet, BCVA was worse if the spared foveal area was <1.5 mm2 or if the bridge was smaller than 400 µm in width. These findings add to the understanding of the natural history of foveal-sparing GA and may support future clinical trial designs.

Green-Light Autofluorescence Versus Combined Blue-Light Autofluorescence and Near-Infrared Reflectance Imaging in Geographic Atrophy Secondary to Age-Related Macular Degeneration.

Purpose: To compare the intermodality and interreader agreement for geographic atrophy (GA) lesion size quantification in green-light fundus autofluorescence (GAF; excitation = 518 nm) versus combined blue-light fundus autofluorescence (BAF; excitation = 488 nm) and near-infrared reflectance (NIR; 820 nm) -based grading. Methods: Confocal scanning laser ophthalmoscopy (cSLO) GAF, BAF, and NIR images of 40 eyes from 29 patients (mean age 79.7 years) with GA secondary to AMD were recorded according to a standardized protocol. GA areas were analyzed in GAF, BAF combined with NIR (BAF+NIR), or BAF alone, by four independent readers using semiautomated software (RegionFinder; Heidelberg Engineering, Heidelberg, Germany). A mixed-effects model was used to assess the effect of image modality on the measured square-root lesion area. The coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were assessed for the square-root lesion area, lesion perimeter, and circularity. Results: GAF-based measurements were on average 0.062 mm (95% confidence interval [CI] 0.04-0.08 mm) larger than BAF+NIR-based measurements and 0.077 mm (95% CI 0.06 - 0.10 mm) larger than BAF-based measurements. Interreader agreement was highest for GAF-based analysis ([CR, ICC] 0.196 mm, 0.995) followed by BAF+NIR (0.232 mm, 0.992) and BAF alone (0.263 mm, 0.991). The same was noted for the lesion perimeter and circularity. Post hoc review revealed that interreader differences were associated with media opacification interfering with lesion boundary demarcation to a larger extent in BAF than in GAF. Conclusions: cSLO-based GAF and combined BAF+NIR imaging with semiautomated lesion delineation allow for an accurate and reproducible quantification of GA. The slightly better interreader agreement using cSLO GAF suggests that its use may be preferable in clinical trials examining the change in lesion size as a clinical endpoint.

Differential Disease Progression in Atrophic Age-Related Macular Degeneration and Late-Onset Stargardt Disease.

Purpose: To compare the disease course of retinal pigment epithelium (RPE) atrophy secondary to age-related macula degeneratio (AMD) and late-onset Stargardt disease (STGD1). Methods: Patients were examined longitudinally by fundus autofluorescence, near-infrared reflectance imaging, and best-corrected visual acuity (BCVA). Areas of RPE atrophy were quantified using semi-automated software, and the status of the fovea was evaluated based on autofluorescence and near-infrared reflectance images. Mixed-effects models were used to compare atrophy progression rates. BCVA loss and loss of foveal integrity were analyzed using Turnbull's estimator. Results: A total of 151 patients (226 eyes) with RPE atrophy secondary to AMD and 38 patients (66 eyes) with RPE atrophy secondary to late-onset STGD1 were examined for a median time of 2.3 years (interquartile range, 2.7). Mean baseline age was 74.2 years (SD, 7.6) in AMD and 63.4 (SD, 9.9) in late-onset STGD1 (P = 1.1 × 10-7). Square root atrophy progression was significantly faster in AMD when compared with late-onset STGD1 (0.28 mm/year [SE, 0.01] vs. 0.23 [SE, 0.03]; P = 0.030). In late-onset STGD1, the median survival of the fovea was significantly longer when compared with eyes with AMD (8.60 vs. 3.35 years; P = 0.005) with a trend to a later BCVA loss of ≥3 lines (5.97 vs. 4.37 years; P = 0.382). Conclusions: These natural history data indicate differential disease progression in AMD versus late-onset STGD1. The results underline the relevance of refined phenotyping in elderly patients presenting with RPE atrophy in regard to prognosis and design of interventional trials.