The Progression of Stargardt Disease as Determined by Spectral-Domain Optical Coherence Tomography over a 24-Month Period (ProgStar Report No. 18).

INTRODUCTION: The aim of this study was to evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed ABCA4-associated Stargardt disease type 1 (STGD1) over a 24-month period in a multicenter prospective cohort study. METHODS: SD-OCT images from 428 eyes of 236 patients were analyzed. Change of mean thickness (MT) and intact area were estimated after semiautomated segmentation for the following individual layers in the central subfield (CS), inner ring (IR), and outer ring (OR) of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OSs), inner segments (IS), outer nuclear layer (ONL) inner retina (IR), and total retina. RESULTS: Statistically significant decreases of all outer retinal layers (RPE, OS, IS, and ONL) could be observed over a 24-month period both in decline of mean retinal thickness and intact area (p < 0.0001, respectively), whereas the IR showed an increase of retinal thickness in the CS and IR and remained unchanged in the OR. CONCLUSIONS: Significant loss could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with STGD1. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of STGD1.

Effects of Miosis on the Visual Acuity Space under Varying Conditions of Contrast and Ambient Luminance in Presbyopia.

Background: Presbyopia is an age-related ocular condition, typically affecting individuals aged over 40 years, characterized by a gradual and irreversible decline in the eye's ability to focus on nearby objects. Correction methods for presbyopia encompass the use of corrective lenses, surgical interventions (corneal or lens based), and, more recently, the FDA-approved topical administration of 1.25% pilocarpine. While prior research has demonstrated the efficacy of daily pilocarpine eye drop application in enhancing near visual acuity by increasing the depth of focus leveraging the pinhole effect, limited knowledge exists regarding its influence on visual acuity under varying conditions of contrast and ambient luminance. Methods: This study aims to investigate the impact of these variables on visual acuity, employing the VA-CAL test, among 11 emmetropic and 11 presbyopic volunteers who reported subjective difficulties with near vision. This study includes evaluations under natural conditions with a pinhole occluder (diameter of 2 mm), and subsequent administration of 1% pilocarpine (Pilomann, Bausch + Lomb, Laval, Canada). Results: The VA-CAL results demonstrate the expected, statistically significant effects of contrast and ambient luminance on visual acuity in both emmetropic and presbyopic volunteers. Furthermore, in emmetropic individuals, the application of pilocarpine resulted in a statistically significant reduction in visual acuity. In contrast, presbyopes did not exhibit statistically significant differences in the visual acuity space under either the pinhole or pilocarpine conditions when compared to natural conditions. Conclusions: The pharmacological treatment of presbyopia with pilocarpine eye drops, intended to enhance near vision, does not adversely affect visual acuity in presbyopes. This suggests that pilocarpine may offer a viable alternative for individuals averse to wearing corrective eyewear.

Sustained Extracellular Electrical Stimulation Modulates the Permeability of Gap Junctions in rd1 Mouse Retina with Photoreceptor Degeneration.

Neurons build vast gap junction-coupled networks (GJ-nets) that are permeable to ions or small molecules, enabling lateral signaling. Herein, we investigate (1) the effect of blinding diseases on GJ-nets in mouse retinas and (2) the impact of electrical stimulation on GJ permeability. GJ permeability was traced in the acute retinal explants of blind retinal degeneration 1 (rd1) mice using the GJ tracer neurobiotin. The tracer was introduced via the edge cut method into the GJ-net, and its spread was visualized in histological preparations (fluorescent tagged) using microscopy. Sustained stimulation was applied to modulate GJ permeability using a single large electrode. Our findings are: (1) The blind rd1 retinas displayed extensive intercellular coupling via open GJs. Three GJ-nets were identified: horizontal, amacrine, and ganglion cell networks. (2) Sustained stimulation significantly diminished the tracer spread through the GJs in all the cell layers, as occurs with pharmaceutical inhibition with carbenoxolone. We concluded that the GJ-nets of rd1 retinas remain coupled and functional after blinding disease and that their permeability is regulatable by sustained stimulation. These findings are essential for understanding molecular signaling in diseases over coupled networks and therapeutic approaches using electrical implants, such as eliciting visual sensations or suppressing cortical seizures.

Electrical Input Filters of Ganglion Cells in Wild Type and Degenerating rd10 Mouse Retina as a Template for Selective Electrical Stimulation.

Bionic vision systems are currently limited by indiscriminate activation of all retinal ganglion cells (RGCs)- despite the dozens of known RGC types which each encode a different visual message. Here, we use spike-triggered averaging to explore how electrical responsiveness varies across RGC types toward the goal of using this variation to create type-selective electrical stimuli. A battery of visual stimuli and a randomly distributed sequence of electrical pulses were delivered to healthy and degenerating (4-week-old rd10) mouse retinas. Ganglion cell spike trains were recorded during stimulation using a 60-channel microelectrode array. Hierarchical clustering divided the recorded RGC populations according to their visual and electrical response patterns. Novel electrical stimuli were presented to assess type-specific selectivity. In healthy retinas, responses fell into 35 visual patterns and 14 electrical patterns. In degenerating retinas, responses fell into 12 visual and 23 electrical patterns. Few correspondences between electrical and visual response patterns were found except for the known correspondence of ON visual type with upward deflecting electrical type and OFF cells with downward electrical profiles. Further refinement of the approach presented here may yet yield the elusive nuances necessary for type-selective stimulation. This study greatly deepens our understanding of electrical input filters in the context of detailed visual response characterization and includes the most complete examination yet of degenerating electrical input filters.

Artificial Vision: The High-Frequency Electrical Stimulation of the Blind Mouse Retina Decay Spike Generation and Electrogenically Clamped Intracellular Ca2+ at Elevated Levels.

BACKGROUND: The electrical stimulation (stim) of retinal neurons enables blind patients to experience limited artificial vision. A rapid response outage of the stimulated ganglion cells (GCs) allows for a low visual sensation rate. Hence, to elucidate the underlying mechanism, we investigated different stim parameters and the role of the neuromodulator calcium (Ca2+). METHODS: Subretinal stim was applied on retinal explants (blind rd1 mouse) using multielectrode arrays (MEAs) or single metal electrodes, and the GC activity was recorded using Ca2+ imaging or MEA, respectively. Stim parameters, including voltage, phase polarity, and frequency, were investigated using specific blockers. RESULTS: At lower stim frequencies (<5 Hz), GCs responded synaptically according to the stim pulses (stim: biphasic, cathodic-first, -1.6/+1.5 V). In contrast, higher stim frequencies (≥5 Hz) also activated GCs directly and induced a rapid GC spike response outage (<500 ms, MEA recordings), while in Ca2+ imaging at the same frequencies, increased intracellular Ca2+ levels were observed. CONCLUSIONS: Our study elucidated the mechanisms involved in stim-dependent GC spike response outage: sustained high-frequency stim-induced spike outage, accompanied by electrogenically clamped intracellular Ca2+ levels at elevated levels. These findings will guide future studies optimizing stim paradigms for electrical implant applications for interfacing neurons.

The VA-CAL Test Quantifies Improvement of Visual Acuity in Achromatopsia by Means of Short-Wave Cutoff Filter Glasses in Daily Living Conditions.

Purpose: To quantify visual performance of patients with achromatopsia at various contrast and luminance combinations typical for daily living conditions, in comparison to controls, and to measure beneficial effects of short-wavelength cutoff filter glasses used by patients with achromatopsia to reduce glare sensation. Methods: Best-corrected visual acuity (BCVA) was tested with Landolt rings using an automated device (VA-CAL test). The visual acuity space was assessed for each participant with and without filter glasses (transmission >550 nm) at 46 contrast-luminance combinations (18%-95%; 0-10,000 cd/m2). The BCVA differences between both conditions were calculated for each combination as absolute values and relative to individual standard BCVA. Results: Fourteen achromats (mean ± SD: 37.9 ± 17.6 years) and 14 normally sighted controls (mean ± SD: 25.2 ± 2.8 years) were included in the study. Without filter glasses, achromats' BCVA was best at 30 cd/m2 (mean ± SEM: 0.76 ± 0.046 logarithm of the minimum angle of resolution [logMAR], contrast = 89%) and worst at 10,000 cd/m2 (mean ± SEM: 1.41 ± 0.08 logMAR, contrast = 18%), a deterioration up to 0.6 logMAR due to increased luminance and decreased contrast. Filter glasses improved achromats' BCVA for almost all luminances by about 0.2 logMAR but lowered controls' BCVA by about 0.1 logMAR. Conclusions: The VA-CAL test provides numerical proof that short-wavelength cutoff filter glasses can help patients with achromatopsia in everyday life, avoiding the common situation of severe visual impairment at certain daily object contrasts and ambient luminances. Translational Relevance: The VA-CAL test discovers losses of spatial resolution in the visual acuity space not seen in standardized BCVA assessment. Filter glasses improve the patients' daily visual performance, rendering them a strongly recommended visual aid in achromatopsia.

Using Micro-Electrode-Array Recordings and Retinal Disease Models to Elucidate Visual Functions: Simultaneous Recording of Local Electroretinograms and Ganglion Cell Action Potentials Reveals the Origin of Retinal Oscillatory Potentials.

BACKGROUND: The electroretinogram (ERG) is an essential diagnostic tool for visual function, both in clinical and research settings. Here, we establish an advanced in vitro approach to assess cell-type-specific ERG signal components. METHODS: Retinal explant cultures, maintained under entirely controlled conditions, were derived from wild-type mice and rd10 rod- and cpfl1 cone-degeneration mouse models. Local micro-ERG (µERG) and simultaneous ganglion cell (GC) recordings were obtained from the retinal explants using multi-electrode arrays. Band-pass filtering was employed to distinguish photoreceptor, bipolar cell, amacrine cell (AC), and GC responses. RESULTS: Scotopic and photopic stimulation discriminated between rod and cone responses in wild-type and mutant retina. The 25 kHz sampling rate allowed the visualization of oscillatory potentials (OPs) in extraordinary detail, revealing temporal correlations between OPs and GC responses. Pharmacological isolation of different retinal circuits found that OPs are generated by inner retinal AC electrical synapses. Importantly, this AC activity helped synchronise GC activity. CONCLUSION: Our µERG protocol simultaneously records the light-dependent activities of the first-, second-, and third-order neurons within the native neuronal circuitry, providing unprecedented insights into retinal physiology and pathophysiology. This method now also enables complete in vitro retinal function testing of therapeutic interventions, providing critical guidance for later in vivo investigations.

Genetic and Clinical Profile of Retinopathies Due to Disease-Causing Variants in Leber Congenital Amaurosis (LCA)-Associated Genes in a Large German Cohort.

To report the spectrum of Leber congenital amaurosis (LCA) associated genes in a large German cohort and to delineate their associated phenotype. Local databases were screened for patients with a clinical diagnosis of LCA and for patients with disease-causing variants in known LCA-associated genes independent of their clinical diagnosis. Patients with a mere clinical diagnosis were invited for genetic testing. Genomic DNA was either analyzed in a diagnostic-genetic or research setup using various capture panels for syndromic and non-syndromic IRD (inherited retinal dystrophy) genes. Clinical data was obtained mainly retrospectively. Patients with genetic and phenotypic information were eventually included. Descriptive statistical data analysis was performed. A total of 105 patients (53 female, 52 male, age 3-76 years at the time of data collection) with disease-causing variants in 16 LCA-associated genes were included. The genetic spectrum displayed variants in the following genes: CEP290 (21%), CRB1 (21%), RPE65 (14%), RDH12 (13%), AIPL1 (6%), TULP1 (6%), and IQCB1 (5%), and few cases harbored pathogenic variants in LRAT, CABP4, NMNAT1, RPGRIP1, SPATA7, CRX, IFT140, LCA5, and RD3 (altogether accounting for 14%). The most common clinical diagnosis was LCA (53%, 56/105) followed by retinitis pigmentosa (RP, 40%, 42/105), but also other IRDs were seen (cone-rod dystrophy, 5%; congenital stationary night blindness, 2%). Among LCA patients, 50% were caused by variants in CEP290 (29%) and RPE65 (21%), whereas variants in other genes were much less frequent (CRB1 11%, AIPL1 11%, IQCB1 9%, and RDH12 7%, and sporadically LRAT, NMNAT1, CRX, RD3, and RPGRIP1). In general, the patients showed a severe phenotype hallmarked by severely reduced visual acuity, concentric narrowing of the visual field, and extinguished electroretinograms. However, there were also exceptional cases with best corrected visual acuity as high as 0.8 (Snellen), well-preserved visual fields, and preserved photoreceptors in spectral domain optical coherence tomography. Phenotypic variability was seen between and within genetic subgroups. The study we are presenting pertains to a considerable LCA group, furnishing valuable comprehension of the genetic and phenotypic spectrum. This knowledge holds significance for impending gene therapeutic trials. In this German cohort, CEP290 and CRB1 are the most frequently mutated genes. However, LCA is genetically highly heterogeneous and exhibits clinical variability, showing overlap with other IRDs. For any therapeutic gene intervention, the disease-causing genotype is the primary criterion for treatment access, but the clinical diagnosis, state of the retina, number of to be treated target cells, and the time point of treatment will be crucial.

Monocular transcorneal electrical stimulation induces ciliary muscle thickening in contralateral eye.

Transcorneal electrical stimulation (TES) is used as therapy for retinal diseases such as retinitis pigmentosa (RP) and was suggested for assessing retinal sensitivity by determining phosphene thresholds, subjective luminance impressions caused by retinal stimulation. Further applications concerned the accommodation process, revealing an improved accommodative amplitude in presbyopic eyes after TES treatment. The respective changes of the ciliary muscle (CM), the structure most important for near vision, during TES are yet unknown. In a pilot study, we aimed to assess whether monocular TES leads to morphological and functional CM changes and whether central accommodation control is affected. Ten healthy, near-emmetropic adults participated in the trial (4 females, age 26.3 ± 3.6 years). Using a wavefront and a stimulus generator, a biphasic square-wave stimulus (2 s positive and 6 s negative amplitude) of 0 µA average current was produced and transferred to the eye by means of a Dawson-Trick & Litzkow electrode. Prior to the stimulation, an individual determination of phosphene thresholds served to define individual TES current amplitudes, which ranged between 60 and 100 µA. Optical coherence tomography (OCT) imaging of the right eye's temporal ciliary muscle was performed before and during ipsi- as well as contralateral monocular TES in randomized order in the morning and afternoon of the same day. During imaging, subjects fixated a target at 4 m distance and refraction was simultaneously recorded via eccentric infrared photorefraction. OCT images were assessed using previously published custom-developed software, allowing the definition of selective CM thickness (CMT) readings, and plotting of continuous CMT profiles along the muscle border. CMT profiles revealed that both stimulations, on the ipsi- and contralateral eye, induced a thickening of the CM compared to the non-stimulated state. The selective CMT readings confirmed a significant increase with ipsi- (31 ± 30 µm; p = 0.010) and contralateral (25 ± 16 µm; p = 0.001) TES. However, refraction during far vision was not significantly affected by either stimulation (ipsilateral [n = 5]: median Δw/-w/o = 0 D; contralateral [n = 7]: Δw/-w/o = 0.13 D). Pupil size on average increased during TES, but without reaching significance (ipsilateral [n = 5] median Δw/-w/o = 0.23 mm, contralateral [n = 7] Δw/-w/o = 0.39 mm). Ipsilateral CM thickening could be explained by local changes within the stimulated ciliary muscle, such as increased blood flow or interstitial fluid rise induced by TES. However, the CMT increase in the right eye when TES was performed contralaterally, on the left eye, indicates an involvement of the central control circuit of accommodation. Further possible explanations for this finding are a synchronization of neuronal activities in the visual pathway, the release of vasoactive neuropeptides, or effects on the central blood pressure regulation. Given a neuromodulation effect on the CM function, TES might have implications for children with accommodation insufficiencies and as additional therapy in myopia control management, e.g. in combination with multifocal contact lens treatment. Our study is important for the clinical application of TES, and the outcome might add crucial knowledge to the current understanding of the accommodation process and inform research and treatment of both myopia and presbyopia.

Elaborate Evaluation of Farnsworth Dichotomous D-15 Panel Test Can Help Differentiate between Best Vitelliform Macular Dystrophy and Autosomal Recessive Bestrophinopathy.

INTRODUCTION: The colour vision in bestrophinopathies has not been assessed in detail so far. The aim of this study was to explore the extent to which distinct types of bestrophinopathies differ in regard to colour vision deficiencies using Farnsworth Dichotomous D-15 and Lanthony Desaturated D-15 panel tests. METHODS: Both D-15 tests were performed in 52 eyes of 26 patients with Best vitelliform macular dystrophy (BVMD) and 10 eyes of 5 patients with autosomal recessive bestrophinopathy (ARB). Two methods were used for a quantitative assessment of the colour vision deficiencies: moment of inertia method and Bowman method. The following parameters were calculated: confusion angle, confusion index (C-index), selectivity index (S-index), total error score (TES), and colour confusion index (CCI). RESULTS: The median value of confusion angle for all stages of BVMD fell into a narrow range around 62, indicating normal results. The median confusion angle value was 57 in ARB patients within a very wide range down to -82, indicating non-specific deficits. These differences were statistically significant. Significantly abnormal C-index and CCI values were found only in ARB patients, being 2.0 and 1.49, respectively. The majority of parameters of D-15 tests were independent of the visual acuity in both bestrophinopathies. CONCLUSIONS: Elaborate evaluation of the D-15 panel tests might help establish a differential diagnosis between different bestrophinopathies, as the pattern of the colour vision loss is different between BVMD and ARB. The quantitative parameters of colour vision tests in bestrophinopathies are independent of the visual acuity.

PandAcuity in paediatrics: a novel clinical measure of visual function based on the panda illusion.

BACKGROUND/AIMS: To evaluate the PandAcuity test for visual function testing in a paediatric cohort and to examine its agreement with conventional visual acuity (VA) testing. METHODS: PandAcuity scores were determined in 152 children (77 males) aged between 3 and 15 years after VA testing (LEATM-test, E-chart, Landolt-C-rings or numbers). The PandAcuity test consisted of illusions made up from silhouettes of animals 'hidden' within zig-zag-patterns of decreasing spatial frequencies. Correlation analyses between PandAcuity score and VA were performed. RESULTS: 150 children completed the test in at least one eye, 148 in both eyes. The PandAcuity test demonstrated good test-retest reliability (intraclass correlation coefficient=0.89) between two runs. VA and PandAcuity score showed a medium to large correlation (Spearman's ρ=0.52, p<0.0001). 93% of the children's visual impairment was classified in the same range by both test types. Receiver operating characteristic analysis of predicted visual impairment showed an excellent agreement with the classification based on VA testing (AUC=0.84). CONCLUSION: The PandAcuity test is rapid, simple and well accepted, rendering it a suitable supplement for the clinical assessment of VA in children. Because of its counterintuitive application (a higher number of correctly identified images means worse VA), it can be used to cross-validate conventional acuity tests to assure children's compliance.

Bioengineering strategies for restoring vision.

Late-stage retinal degenerative disease involving photoreceptor loss can be treated by optogenetic therapy, cell transplantation and retinal prostheses. These approaches aim to restore light sensitivity to the retina as well as visual perception by integrating neuronal responses for transmission to the cortex. In age-related macular degeneration, some cell-based therapies also aim to restore photoreceptor-supporting tissue to prevent complete photoreceptor loss. In the earlier stages of degeneration, gene-replacement therapy could attenuate retinal-disease progression and reverse loss of function. And gene-editing strategies aim to correct the underlying genetic defects. In this Review, we highlight the most promising gene therapies, cell therapies and retinal prostheses for the treatment of retinal disease, discuss the benefits and drawbacks of each treatment strategy and the factors influencing whether functional tissue is reconstructed and repaired or replaced with an electronic device, and summarize upcoming technologies for enhancing the restoration of vision.

Nature-inspired saccadic-like electrical stimulation paradigm promotes sustained retinal ganglion cell responses by spatiotemporally alternating activation of contiguous multi-electrode patterns.

Objective. Retinal electrical stimulation using multi-electrode arrays (MEAs) aims to restore visual object perception in blind patients. However, the rate and duration of the artificial visual sensations are limited due to the rapid response decay of the stimulated neurons. Hence, we investigated a novel nature-inspired saccadic-like stimulation paradigm (biomimetic) to evoke sustained retinal responses. For implementation, the macroelectrode was replaced by several contiguous microelectrodes and activated non-simultaneously but alternating topologically.Approach.MEAs with hexagonally arranged electrodes were utilized to simulate and record mouse retinal ganglion cells (RGCs). Two shapes were presented electrically using MEAs: a 6e-hexagon (six hexagonally arranged 10µm electrodes; 6e-hexagon diameter: 80µm) and a double-bar (180µm spaced, 320µm in length). Electrodes of each shape were activated in three different modes (simultaneous, circular, and biomimetic ('zig-zag')), stimulating at different frequencies (1-20 Hz).Main results.The biomimetic stimulation generated enhanced RGC responses increasing the activity rate by 87.78%. In the spatiotemporal context, the electrical representation of the 6e-hexagon produced sustained and local RGC responses (∼130µm corresponding to ∼2.5° of the human visual angle) for up to 90 s at 10 Hz stimulation and resolved the electrically presented double-bar. In contrast, during conventional simultaneous stimulation, the responses were poor and declined within seconds. Similarly, the applicability of the biomimetic mode for retinal implants (7 × 8 pixels) was successfully demonstrated. An object shape impersonating a smile was presented electrically, and the recorded data were used to emulate the implant's performance. The spatiotemporal pixel mapping of the activity produced a complete retinal image of the smile.Significance.The application of electrical stimulation in the biomimetic mode produced locally enhanced RGC responses with significantly reduced fading effects and yielded advanced spatiotemporal performance reflecting the presented electrode shapes in the mapped activity imprint. Therefore, it is likely that the RGC responses persist long enough to evoke visual perception and generate a seamless image, taking advantage of the flicker fusion. Hence, replacing the implant's macroelectrodes with microelectrodes and their activation in a topologically alternating biomimetic fashion may overcome the patient's perceptual image fading, thereby enhancing the spatiotemporal characteristics of artificial vision.

Ophthalmic and Genetic Features of Bardet Biedl Syndrome in a German Cohort.

The aim of this study was to characterize the ophthalmic and genetic features of Bardet Biedl (BBS) syndrome in a cohort of patients from a German specialized ophthalmic care center. Sixty-one patients, aged 5−56 years, underwent a detailed ophthalmic examination including visual acuity and color vision testing, electroretinography (ERG), visually evoked potential recording (VEP), fundus examination, and spectral domain optical coherence tomography (SD-OCT). Adaptive optics flood illumination ophthalmoscopy was performed in five patients. All patients had received diagnostic genetic testing and were selected upon the presence of apparent biallelic variants in known BBS-associated genes. All patients had retinal dystrophy with morphologic changes of the retina. Visual acuity decreased from ~0.2 (decimal) at age 5 to blindness 0 at 50 years. Visual field examination could be performed in only half of the patients and showed a concentric constriction with remaining islands of function in the periphery. ERG recordings were mostly extinguished whereas VEP recordings were reduced in about half of the patients. The cohort of patients showed 51 different likely biallelic mutations­of which 11 are novel­in 12 different BBS-associated genes. The most common associated genes were BBS10 (32.8%) and BBS1 (24.6%), and by far the most commonly observed variants were BBS10 c.271dup;p.C91Lfs*5 (21 alleles) and BBS1 c.1169T>G;p.M390R (18 alleles). The phenotype associated with the different BBS-associated genes and genotypes in our cohort is heterogeneous, with diverse features without genotype−phenotype correlation. The results confirm and expand our knowledge of this rare disease.

Comparison of CRT and LCD monitors for objective estimation of visual acuity using the sweep VEP.

PURPOSE: To investigate the applicability of liquid crystal displays (LCD) as suitable replacement for cathode ray tube monitors (CRT) as stimulator for the sweep VEP for estimating visual acuity. METHODS: In a first experiment, sweep VEPs were recorded in 13 healthy volunteers with best-corrected visual acuity with an LCD and a CRT monitor, respectively. Time-to-peak after stimulus and peak-to-trough amplitudes as well as the visual acuity, estimated using a second-order polynomial and the modified Ricker model, were compared between both monitor types. In a second experiment, sweep VEPs were recorded in six healthy volunteers with two levels of stimulus contrast using artificially reduced visual acuities as well as best-corrected with the same monitors as in the first experiment and additionally, a modern LCD gaming monitor with a response time of 1 ms. Time-to-peak after stimulus and peak-to-trough amplitudes were compared between the different combinations of monitors and contrasts. Finally, visual acuities estimated using the modified Ricker model were compared to subjective visual acuities determined using the Freiburg Visual Acuity and Contrast Test (FrACT). RESULTS: In the first experiment, the time-to-peak after stimulus presentation was statistically significantly delayed for LCD displays (mean difference [confidence interval]: 60.0 [54.0, 65.9] ms; t(516) = 19.7096, p < 0.0001). Likewise, peak-to-trough amplitudes were statistically significantly smaller for the LCD stimulator, however, not clinically relevant (mean difference [confidence interval]: - 0.89 [- 1.59, - 0.20] µV; t(516) = - 2.5351, p = 0.0115). No statistically significant effect of the monitor type on the estimated visual acuity was found for neither method, second-order polynomial, nor the modified Ricker model. In the second experiment, statistically significant delays of the time-to-peak after stimulus onset were found for all combinations of monitor and contrast compared to the CRT monitor. A statistically significant, but not clinically relevant, difference of the peak-to-trough amplitudes was only found between the CRT monitor and the LCD gaming monitor (mean difference [confidence interval]: 2.6 [1.2, 4.0] µV; t(814) = 4.66, p < 0.0001). Visual acuities estimated from LCD stimulation significantly underestimated the subjective visual acuity up to 0.2 logMAR using the conversion formula of the first experiment. No statistically significant difference was found when using conversion formulas adjusted for each combination of monitor and contrast. CONCLUSIONS: Based on the results of this study, LCD monitors may substitute CRT monitors for presenting the stimuli for the sweep VEP to objectively estimate visual acuity. Nevertheless, it is advisable to perform a calibration and to collect normative data of healthy volunteers using best-corrected and artificially reduced visual acuity for establishing a conversion formula between sweep VEP outcome and the subjective visual acuity before replacing a CRT with an LCD stimulator.

The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying blue cone monochromacy.

Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families-all from the United States-showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no "region of overlap" among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.

Central Visual Function and Genotype-Phenotype Correlations in PDE6A-Associated Retinitis Pigmentosa.

Purpose: Autosomal recessive retinitis pigmentosa (arRP) can be caused by mutations in the phosphodiesterase 6A (PDE6A) gene. Here, we describe the natural course of disease progression with respect to central retinal function (i.e., visual acuity, contrast sensitivity, and color vision) and establish a detailed genotype--phenotype correlation. Methods: Forty-four patients (26 females; mean age ± SD, 43 ± 13 years) with a confirmed genetic diagnosis of PDE6A-associated arRP underwent comprehensive ophthalmological examinations including best-corrected visual acuity (BCVA) with Early Treatment Diabetic Retinopathy Study charts, contrast sensitivity (CS) with Pelli-Robson charts at distances of 3 m and 1 m, and color vision testing using Roth 28-Hue and Panel D-15 saturated color cups. Results: The most frequently observed variants were c.998+1G>A/p.?, c.304C>A/p.R102S, and c.2053G>A/p.V685M. Central retinal function in patients homozygous for variant c.304C>A/p.R102S was better when compared to patients homozygous for variant c.998+1G>A/p.?, although the former were older at baseline. Central retinal function was similar in patients homozygous for variant c.304C>A/p.R102S and patients heterozygous for variants c.304C>A/p.R102S and c.2053G>A/p.V685M, although the latter were younger at baseline. Annual decline rates in central retinal function were small. Conclusions: We conclude that the severity of the different disease-causing PDE6A mutations in humans with respect to central visual function may be ranked as follows: c.2053G>A/p.V685M in homozygous state (most severe) > c.998+1G>A/p.? in homozygous state > c.304C>A/p.R102S and c.2053G>A/p.V685M in compound-heterozygous state > c.304C>A/p.R102S in homozygous state (mildest). The assessment of treatment efficacy in interventional trials will remain challenging due to small annual decline rates in central retinal function.

Quantification of the Dynamic Visual Acuity Space at Real-World Luminances and Contrasts: The VA-CAL Test.

Purpose: Best-corrected visual acuity (BCVA) is assessed at a single standardized luminance with maximum optotype contrast, not reflecting the constantly changing daily-life viewing conditions. For a more realistic estimation of visual performance at varying object contrasts (Cs) and ambient luminances (ALs), we developed a new VA test, VA-CAL. Methods: Landolt-C-rings between 18% and 95% Weber contrast, were presented at 1 m distance (8 Alternative Forced Choice) on a 5.7 degree field in the middle of a frosted glass screen (66 degrees), back-lit by 3060 LEDs (generating ambient luminances between 0-10,000 cd/m²). Visual acuity (VA) was measured in 14 normally sighted participants twice for 8 conditions of ambient luminance and 6 conditions of contrast using a QUEST staircase procedure. Results: VA improved continuously up to an ambient luminance of 3000 to 5000 cd/m² (best mean VA ± SEM: -0.47 ± 0.03 logMAR at C = 95%, AL = 3000 cd/m²), followed by a decline of VA at higher luminances with good test-retest variability. As expected, reduced contrast leads to a lower VA (worst mean VA ± SEM: -0.03 ± 0.03 logMAR at C = 18%, AL = 0 cd/m²). A 3D plot of these data shows the VA space (VAS) extending between the contrast and luminance axes, which describes the dynamics of VA continuously changing under varying everyday life conditions. Conclusions: VA-CAL, an automated device and procedure, allows for simultaneous evaluation of VA at various contrast-luminance combinations, thus providing a more comprehensive assessment of spatial vision problems not seen with standard BCVA tests. Translational Relevance: The new BCVA test VA-CAL incorporates a range of everyday contrast and ambient luminance conditions for a more realistic description of visual performance.

Three-Year Changes in Visual Function in the Placebo Group of a Randomized Double-Blind International Multicenter Safety Study: Analysis of Electroretinography, Perimetry, Color Vision, and Visual Acuity in Individuals With Chronic Stable Angina Pectoris.

Purpose: To determine whether significant deteriorations in objective (electroretinography [ERG]) and subjective (standard automated and semi-automated kinetic perimetry; color discrimination; and best-corrected visual acuity) tests of visual function, potentially attributable to aging, occurred in the group randomized to placebo of a 3-year prospective multicenter ocular safety study of ivabradine for chronic stable angina pectoris. Methods: The multicenter trial was conducted at 11 international ophthalmic centers. Changes in visual function between baseline and month 36 were analyzed by means of a two-tailed Wilcoxon signed-rank test, based on the Hodges and Lehman estimator of the median difference, with the 95% confidence intervals derived by Walsh averages. Results: Thirty-eight participants from the placebo group completed the study (mean [SD], age, 62.7 [8.1] years). The group exhibited in each eye small, but statistically significant, reductions in the amplitudes of the dark-adapted (DA) ERG 3.0 a-wave, and light-adapted (LA) 3.0 b-wave, as well as increases in peak time for the DA 0.01 b-wave, DA 3.0 a-wave, LA 3.0 b-wave, and LA 3.0 30-Hz flicker response and in the isopter area I3e of the visual field. Conclusions: Statistically significant deteriorations occurred in visual function over a period of 3 years, potentially attributable to age, within a group of individuals with chronic stable angina pectoris and unremarkable ophthalmological findings other than those attributable to age. Translational Relevance: A longitudinal correction factor for age-related change in visual function may be useful in future trials to determine whether an observed deterioration in visual function is related to intervention or to aging.