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To investigate the suitability of 6 rod- or cone-mediated dark adaptation (DA) parameters as outcome measures for clinical trials in age-related macular degeneration (AMD), including their retest reliability, association with age and disease severity, and measurable longitudinal change over time.Prospective, longitudinal study (Clinicaltrials.gov: NCT01352975).A total of 191 patients with AMD and older participants followed longitudinally over 5 years.Dark adaptation testing was performed using the AdaptDx dark adaptometer with a maximum test time of 40 minutes. A 2-part exponential-linear curve was fitted to obtain values for cone decay, cone plateau, time to rod-cone break, rod intercept time (RIT), rod adaptation rate (S2), and area under the curve. Intersession retest reliability was assessed in tests performed within 2 weeks using the Bland-Altman analysis. The relationship of DA parameters with age, AMD severity, and reticular pseudodrusen (RPD) presence was evaluated using linear mixed models.Retest reliability, association with disease severity, and longitudinal change of 6 DA parameters.A total of 1329 DA curves were analyzed. Rod intercept time was the parameter that showed the greatest reliability (intraclass correlation coefficient of 0.88) and greatest association with age, AMD severity, and RPD (marginal RAge-related macular degeneration severity and RPD presence are each associated with large differences in multiple DA curve parameters. In addition, substantial differences in some parameters occur with age, even accounting for AMD severity and RPD status. This supports the 2-hit hypothesis of age and disease status on DA (and perhaps AMD pathophysiology itself). Of the DA parameters, RIT has the highest retest reliability, closest correlation with AMD severity and RPD, and largest longitudinal changes. This underscores the suitability of RIT as an outcome measure in clinical trials. The cone plateau increases only in advanced stages of kinetic rod dysfunction, indicating rod dysfunction preceding cone dysfunction and degeneration in the temporal sequence of pathology in AMD.

Objective quantification of photoreceptor cell morphology, such as cell diameter and outer segment length, is crucial for early, accurate, and sensitive diagnosis and prognosis of retinal neurodegenerative diseases. Adaptive optics optical coherence tomography (AO-OCT) provides three-dimensional (3-D) visualization of photoreceptor cells in the living human eye. The current gold standard for extracting cell morphology from AO-OCT images involves the tedious process of 2-D manual marking. To automate this process and extend to 3-D analysis of the volumetric data, we propose a comprehensive deep learning framework to segment individual cone cells in AO-OCT scans. Our automated method achieved human-level performance in assessing cone photoreceptors of healthy and diseased participants captured with three different AO-OCT systems representing two different types of point scanning OCT: spectral domain and swept source.

To investigate potential associations between renal function and age-related macular degeneration (AMD) features as assessed with multimodal retinal imaging.A subset of participants included in a dark adaptation study with varying AMD severities had estimated glomerular filtration rate (eGFR) values (mL/min/1.73 m2) obtained from renal function laboratory testing of serum creatinine and cystatin C. Multimodal imaging from visit dates associated with serum samples was graded by the Wisconsin Reading Center for AMD features. Associations of eGFR with AMD features and severity grades, age, smoker status and rod-intercept time were investigated. Simple univariate analyses, age-corrected multivariate analyses, and a feature-selecting least absolute shrinkage and selection operator regression were performed for eGFR as a continuous dependent variable.A total of 110 patients (mean age, 75.1 ± 9.4 years; mean eGFR, 70.7 ± 18.2 mL/min/1.73 m2) were included. In univariate analyses age (estimate, -1.16 units/year; 95% confidence interval [CI], -1.46 to -0.87; P0.0001), rod-intercept time (estimate, -0.54 units/minute; 95% CI, -0.81 to -0.27; P0.001) and subretinal drusenoid deposits (-11.12 units for subretinal drusenoid deposit presence in either eye; 95% CI, -20.23 to -2.01; P = 0.017) were associated with decreased renal function. However, in age-corrected multivariate models, age was the only significant variable associated with renal function, confirmed by least absolute shrinkage and selection operator regression.Accounting for age, renal function parameters did not show an association with AMD features.Bruch's membrane of the eye and the glomerular basement membrane of the kidney share physiologic similarities such that decreased renal function may demonstrate associations with AMD phenotypes.

This case report of 2 patients describes peripheral Von Hippel-Lindau disease associated with a series of aflibercept injections.

To determine whether reticular pseudodrusen (RPD) status and/or ARMS2/HTRA1 genotype are associated with altered geographic atrophy (GA) enlargement rate, and to analyze potential mediation of genetic effects by RPD status.Post hoc analysis of a cohort within the Age-Related Eye Disease Study 2 (AREDS2) controlled clinical trial.771 eyes (563 participants, mean age 74.8 years) with GA.GA area was measured by planimetry from color fundus photographs at annual visits. RPD presence was graded from fundus autofluorescence images. Mixed-model regression of square root GA area was performed according to RPD status and/or ARMS2 genotype, including mediation analysis.Change in square root GA area over time.GA enlargement was significantly faster in eyes with RPD (P0.0001), at 0.379 (95% CI 0.329-0.430) versus 0.273 mm/year (0.256-0.289). The rate was also significantly faster in individuals carrying ARMS2 risk alleles (P0.0001), at 0.224 (95% CI 0.198-0.250), 0.287 (0.263-0.310), and 0.307 mm/year (0.273-0.341), in those with 0-2 risk alleles, respectively. In mediation analysis, the direct effect of ARMS2 genotype on GA enlargement was 0.074 mm/year (95% CI 0.009-0.139, P=0.025), whereas the indirect effect of ARMS2 genotype via RPD status was 0.002 mm/year (95% CI -0.006-0.009, P=0.64). In eyes with incident GA, RPD presence was not associated with altered likelihood of central involvement (P=0.29) or multifocality (P=0.16) at incidence. In eyes with incident non-central GA, RPD presence was associated with faster GA progression to the central macula (P=0.009), at 157 (95% CI 126-188) versus 111 μm/year (97-125). Similar findings were observed in the AREDS, as a validation dataset.GA enlargement is faster in eyes with RPD and in individuals carrying ARMS2 risk alleles. However, RPD status does not mediate the association between ARMS2 genotype and faster enlargement. RPD presence and ARMS2 genotype are relatively independent risk factors and must lead to faster enlargement by distinct mechanisms. RPD presence does not predict central involvement or multifocality at GA incidence, but is associated with faster progression towards the central macula. These findings have implications for clinical trials and clinical practice; RPD status should be considered for improved predictions of enlargement rate.

The purpose of this study was to investigate scotopic contour deformation detection (sCDD), and its structural determinants, in participants with intermediate age-related macular degeneration (iAMD) with or without reticular pseudodrusen (RPD).Forty-one participants (aged 58-89 years), including 9 with iAMD and RPD, 16 with iAMD only, and 16 controls, underwent functional testing. The sCDD was evaluated with radial frequency arcs presented at 4 loci: ±4 degrees and 8 degrees vertical eccentricity. Scotopic thresholds and dark adaptation (DA) were measured at the same loci. Retinal layers of spectral domain optical coherence tomography (SD-OCT) volume scans were segmented. To establish the concurrent validity of the functional test, we evaluated the fraction of variability in sCDD thresholds explained by SD-OCT data.The iAMD group had significantly worse sCDD thresholds compared with controls (8 degrees inferior retina: P = 0.004 and the 4 degrees loci: P0.02 for both). Elevated sCDD thresholds were observed in iAMD and RPD eyes at loci with normal scotopic thresholds; the opposite was rarely encountered. Elevated sCDD thresholds were also observed in iAMD eyes with normal DA. Elevated sCDD thresholds were associated with increased age and presence of late AMD in the fellow eye. The optimal machine learning model predicted 16% of variability (cross-validated R2) in sCDD thresholds at 8 degrees.A novel scotopic contour deformation task can provide unique information about rod dysfunction in participants with iAMD and RPD not observed with structural and other functional assessments. Rod dysfunction observed with scotopic contour deformation testing was associated with factors linked to risk of AMD progression.

The retinal dystrophy phenotype associated with CDHR1 retinopathy is clinically heterogenous. In this study, we describe the clinical and molecular findings of a retinal dystrophy cohort (10 patients) attributed to autosomal recessive CDHR1 and report novel variants in populations not previously identified with CDHR1-related retinopathy. Seven patients had evaluations covering at least a three-year period. The mean age of individuals at first symptoms was 36 ± 8.5 years (range 5–45 years). Visual acuity at the last visit ranged from 20/20 to 20/2000 (mean LogMAR 0.8 or 20/125). Three clinical subgroups were identified: rod–cone dystrophy (RCD), cone–rod dystrophy (CRD), and maculopathy. Extinguished scotopic electroretinography responses were noted in the RCD patients. Macular involvement was noted in all patients and documented on color fundus photography, fundus autofluorescence, and optical coherence tomography. Notable asymmetry of the degree of macular atrophy was present in two patients. The possible association between CDHR1 variants and clinical findings was predicted using molecular modeling.

The retinal dystrophy phenotype associated with

For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders.

To identify features correlating with drusenoid pigment epithelial detachment (DPED) progression in the Age-Related Eye Disease Study 2 Ancillary spectral-domain optical coherence tomography study cohort.In this retrospective analysis of a prospective longitudinal study, eyes with intermediate age-related macular degeneration and DPEDs were followed longitudinally with annual multimodal imaging.Thirty-one eyes of 25 participants (mean age 72.6 years) in the Age-Related Eye Disease Study 2 Ancillary spectral-domain OCT substudy (A2A study) had DPED identified in color fundus images. Spectral-domain optical coherence tomography inspection confirmed a subretinal pigment epithelium drusenoid elevation of ≥433 µm diameter in 25 eyes (80.6%). Twenty-four of these eyes were followed longitudinally (median 4.0 years), during which 7 eyes (29.2%) underwent DPED collapse (with 3/7 further progressing to geographic atrophy), 6 (25.0%) developing neovascular age-related macular degeneration, and 11 (45.8%) maintaining DPED persistence without late age-related macular degeneration. On Kaplan-Meier analysis, mean time to DPED collapse was 3.9 years. Both DPED collapse and progression to neovascular age-related macular degeneration were preceded by the presence of hyperreflective foci over the DPED.The natural history of DPED comprises collapse (sometimes followed by the development of atrophy), vascularization followed by exudation, or DPED persistence. Spectral-domain optical coherence tomography can confirm retinal pigment epithelial elevation caused by drusenoid accumulation and facilitate the identification of high-risk features that correlate with progression.

Dark adaptation (DA) refers to the slow recovery of visual sensitivity in darkness following exposure to intense or prolonged illumination, which bleaches a significant amount of the rhodopsin. This natural process also offers an opportunity to understand cellular function in the outer retina and evaluate for presence of disease. How our eyes adapt to darkness can be a key indicator of retinal health, which can be altered in the presence of certain diseases, such as age-related macular degeneration (AMD). A specific focus on clinical aspects of DA measurement and its significance to furthering our understanding of AMD has revealed essential findings underlying the pathobiology of the disease. The process of dark adaptation involves phototransduction taking place mainly between the photoreceptor outer segments and the retinal pigment epithelial (RPE) layer. DA occurs over a large range of luminance and is modulated by both cone and rod photoreceptors. In the photopic ranges, rods are saturated and cone cells adapt to the high luminance levels. However, under scotopic ranges, cones are unable to respond to the dim luminance and rods modulate the responses to lower levels of light as they can respond to even a single photon. Since the cone visual cycle is also based on the Muller cells, measuring the impairment in rod-based dark adaptation is thought to be particularly relevant to diseases such as AMD, which involves both photoreceptors and RPE. Dark adaptation parameters are metrics derived from curve-fitting dark adaptation sensitivities over time and can represent specific cellular function. Parameters such as the cone-rod break (CRB) and rod intercept time (RIT) are particularly sensitive to changes in the outer retina. There is some structural and functional continuum between normal aging and the AMD pathology. Many studies have shown an increase of the rod intercept time (RIT), i.e., delays in rod-mediated DA in AMD patients with increasing disease severity determined by increased drusen grade, pigment changes and the presence of subretinal drusenoid deposits (SDD) and association with certain morphological features in the peripheral retina. Specifications of spatial testing location, repeatability of the testing, ease and availability of the testing device in clinical settings, and test duration in elderly population are also important. We provide a detailed overview in light of all these factors.

This study investigates deep-learning (DL) sequence modeling techniques to reliably fit dark adaptation (DA) curves and estimate their key parameters in patients with age-related macular degeneration (AMD) to improve robustness and curve predictions.A long-short-term memory autoencoder was used as the DL method to model the DA curve. The performance was compared against the classical nonlinear regression method using goodness-of-fit and repeatability metrics. Experiments were performed to predict the latter portion of the curve using data from early measurements. The prediction accuracy was quantified as the rod intercept time (RIT) prediction error between predicted and actual curves.The two models had comparable goodness-of-fit measures, with root mean squared error (RMSE; SD) = 0.11 (0.04) log-units (LU) for the classical model and RMSE = 0.13 (0.06) LU for the DL model. Repeatability of the curve fits evaluated after introduction of random perturbations, and after performing repeated testing, demonstrated superiority of the DL method, especially among parameters related to cone decay. The DL method exhibited superior ability to predict the curve and RIT using points prior to -2 LU, with 3.1 ± 3.1 minutes RIT prediction error, compared to 19.1 ± 18.6 minutes RIT error for the classical method.The parameters obtained from the DL method demonstrated superior robustness as well as predictability of the curve. These could provide important advances in using multiple DA curve parameters to characterize AMD severity.Dark adaptation is an important functional measure in studies of AMD and curve modeling using DL methods can lead to improved clinical trial end points.

IMPORTANCE: Sorsby fundus dystrophy is a typically adult-onset maculopathy with high risk for choroidal neovascularization. Sorsby fundus dystrophy, inherited as an autosomal dominant fully penetrant trait, is associated with TIMP3 variants that cause protein aggregation in the extracellular matrix. OBJECTIVE: To evaluate the phenotype and underlying biochemical mechanism of disease-causing TIMP3 variants altering the N-terminal signal peptide in 2 families who have early-onset diffuse maculopathy without choroidal neovascularization with cosegregation of TIMP3 variants in the signal peptide sequence. DESIGN, SETTING, AND PARTICIPANTS: This case series of 2 families with early-onset diffuse maculopathy was conducted at the National Eye Institute, National Institutes of Health Clinical Center. Data were collected and analyzed from October 2009 to December 2021. MAIN OUTCOMES AND MEASURES: Clinical imaging and molecular genetic testing were performed in 2 families with macular dystrophy. Cosegregation analysis of TIMP3 variants was performed in affected and unaffected family members. Candidate TIMP3 signal peptide variants were assessed for cleavage defects after transfection. RESULTS: Eleven individuals from 2 families with early-onset diffuse maculopathy without choroidal neovascularization harbor TIMP3 variants (L10H or G12R) in the N-terminal signaling peptide were analyzed. Cosegregation with phenotype was confirmed in additional family members. Biochemical analysis confirmed defects in both protein maturation and extracellular deposition. CONCLUSIONS AND RELEVANCE: This study found that TIMP3 variants altering signal peptide function deviated from classic Sorsby fundus dystrophy both in phenotypic features and underlying mechanism. These results suggest atypical patient presentations are caused by TIMP3 signal peptide defects, associated with impaired cleavage and deposition into the extracellular matrix, implicating a novel macular dystrophy disease.

Background/AimsTo characterise the ocular manifestations of Williams-Beuren syndrome (WBS) and compare these to patients with isolated elastin mediated supravalvular aortic stenosis (SVAS).MethodsFifty-seven patients with a diagnosis of WBS and five with SVAS underwent comprehensive ophthalmic evaluation at the National Institutes of Health from 2017 to 2020, including best-corrected visual acuity, slit-lamp biomicroscopy, optical biometry, dilated fundus examination, optical coherence tomography and colour fundus imaging.ResultsMean age of the 57 WBS patients was 20.3 years (range 3–60 years). Best-corrected visual acuity ranged from 20/20 to 20/400 with mean spherical equivalent near plano OU. Twenty-four eyes (21.8%) had an axial length (AL) less than 20.5 mm and 38 eyes (34.5%) had an AL measuring 20.5–22.0 mm. Stellate iris and retinal arteriolar tortuosity were noted in 30 (52.6%) and 51 (89.5%) WBS patients, respectively. Novel retinal findings in WBS included small hypopigmented retinal deposits (OD 29/57, OS 27/57) and broad foveal pit contour (OD 44/55, OS 42/51). Of the five patients with SVAS, none had stellate iris or broad foveal pit contour while 2/5 had retinal arteriolar tortuosity.ConclusionWBS is a complex multisystem genetic disorder with diverse ophthalmic findings that differ from those seen in isolated elastin mediated SVAS. These results suggest other genes within the WBS critical region, aside from ELN, may be involved in observed ocular phenotypes and perhaps broader ocular development. Furthermore, retinal arteriolar tortuosity may provide future insight into systemic vascular findings in WBS.