Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration: A Nonrandomized Controlled Trial.

Importance: Existing therapies to slow geographic atrophy (GA) enlargement in age-related macular degeneration (AMD) have relatively modest anatomic efficacy, require intravitreal administration, and increase the risk of neovascular AMD. Additional therapeutic approaches are desirable. Objective: To evaluate the safety and possible anatomic efficacy of oral minocycline, a microglial inhibitor, for the treatment of GA in AMD. Design, Setting, and Participants: This was a phase 2, prospective, single-arm, 45-month, nonrandomized controlled trial conducted from December 2016 to April 2023. Patients with GA from AMD in 1 or both eyes were recruited from the National Institutes of Health (Bethesda, Maryland) and Bristol Eye Hospital (Bristol, UK). Study data were analyzed from September 2022 to May 2023. Intervention: After a 9-month run-in phase, participants began oral minocycline, 100 mg, twice daily for 3 years. Main Outcomes and Measures: The primary outcome measure was the difference in rate of change of square root GA area on fundus autofluorescence between the 24-month treatment phase and 9-month run-in phase. Results: Of the 37 participants enrolled (mean [SD] age, 74.3 [7.6] years; 21 female [57%]), 36 initiated the treatment phase. Of these participants, 21 (58%) completed at least 33 months, whereas 15 discontinued treatment (8 by request, 6 for adverse events/illness, and 1 death). Mean (SE) square root GA enlargement rate in study eyes was 0.31 (0.03) mm per year during the run-in phase and 0.28 (0.02) mm per year during the treatment phase. The primary outcome measure of mean (SE) difference in enlargement rates between the 2 phases was -0.03 (0.03) mm per year (P = .39). Similarly, secondary outcome measures of GA enlargement rate showed no differences between the 2 phases. The secondary outcome measures of mean difference in rate of change between 2 phases were 0.2 letter score per month (95% CI, -0.4 to 0.9; P = .44) for visual acuity and 0.7 µm per month (-0.4 to 1.8; P = .20) for subfoveal retinal thickness. Of the 129 treatment-emergent adverse events among 32 participants, 49 (38%) were related to minocycline (with no severe or ocular events), including elevated thyrotropin level (15 participants) and skin hyperpigmentation/discoloration (8 participants). Conclusions and Relevance: In this phase 2 nonrandomized controlled trial, oral minocycline was not associated with a decrease in GA enlargement over 24 months, compared with the run-in phase. This observation was consistent across primary and secondary outcome measures. Oral minocycline at this dose is likely not associated with slower rate of enlargement of GA in AMD.

Outer retinal microcavitations in Retinitis Pigmentosa: a novel OCT finding common in RP1-related retinopathy.

PURPOSE: To describe a novel optical coherence tomography (OCT) finding of outer retina microcavitations in RP1-related retinopathy and other retinal degenerations. METHODS: Medical charts and OCT images of 28 patients with either autosomal dominant (adRP) or recessive (arRP) RP1-related retinopathy were reviewed. Outer retina microcavitations were defined as hypo-reflective OCT structures of at least 30µm in diameter between the ellipsoid zone (EZ) and retinal pigment epithelium. Comparison was made based on the following metrics: (i) functional measures including best-corrected visual acuity (BCVA) and color discrimination errors on D-15 test; and (ii) structural measures, including central subfield (CSF), average macular thickness (AMT), and preserved transfoveal EZ width. Mann-Whitney tests were used for comparisons with significance set at P<0.05. The specificity of microcavitations for RP1-related retinopathy was estimated against 26 patients with non-RP1 RP. RESULTS: Among 15 included patients, microcavitations were found in at least one eye of all arR patients and 7/12 (58%) of adR patients. Patients with adR and microcavitations were older at the time of examination (51 vs. 43 years of age; p=0.04) and their eyes demonstrated worse BCVA (0.09 vs. 0 logMAR; p=0.008), reduced CSF (256 vs. 293µm; p=0.01), AMT (241 vs. 270µm; p=0.02) and shorter transfoveal EZ widths (1.67 vs. 4.98mm; p<0.0001). The finding of microcavitations showed a specificity of 0.92 for RP1-related retinopathy. CONCLUSION: A novel OCT finding of outer retina microcavitations was commonly observed in patients with RP1-related retinopathy. Eyes with outer retinal OCT microcavitations had worse visual function and more affected central retinal structure.

Local and Global Associations of Reticular Pseudodrusen in Age-Related Macular Degeneration.

PURPOSE: To investigate the spatial distribution of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD) and their correlation with functional measures, retinal thickness, and changes over time. DESIGN: Longitudinal, cohort study. PARTICIPANTS: Thirty-five participants with RPD and spectrum of AMD severity (including no AMD). METHODS: Multimodal imaging was graded by a reading center, including evaluation of color fundus imaging to assess AMD severity scores. Reticular pseudodrusen presence on OCT volumes was confirmed on en face imaging and the RPD extent was contoured on infrared images. One study eye per participant underwent rod-mediated dark adaptation, measuring rod intercept time (RIT) at 5° and/or 12° superior to the fovea. MAIN OUTCOME MEASURES: The primary outcome was RIT and OCT thickness measures which were correlated with RPD area. RESULTS: A total of 51 eyes had ≥ 1 visit with RPD detected (mean follow-up, 2.19 ± 2.04 years; range, 0-5 years), totaling 169 eye-based visits with RPD. Of the 51 eyes with RPD, 5 (9.8%) developed geographic atrophy and 17 (33.3%) progressed to neovascular AMD. Larger RPD areas were detected more frequently in AMD severity scores 6-7. Reticular pseudodrusen area within an eye generally increased over time. The lesion distribution showed a predilection for the superior retina, especially the outer superior subfield of the ETDRS grid, with the central subfield having least involvement. Reticular pseudodrusen area was inversely correlated with central subfield thickness and positively correlated with RIT at 5° (P = 0.001; r2 = 0.01) and 12° (P = 0.004; r2 = 0.01). Rod-mediated dark adaptation at 5° reached the test ceiling in > 85% of visits, irrespective of RPD lesion presence/absence at the test location. Retinal thickness decreased monotonically, with the central subfield demonstrating the greatest percentage change over 5 years (Δ = -5.47%). CONCLUSIONS: In AMD, RPD involve predominantly the superior retina but can involve all ETDRS subfields and evolve over time. Eyes with RPD exhibit structural and functional impairments that can be measured beyond the boundaries of the RPD lesions, suggesting changes associated with RPD are associated with both local changes and a more widespread process. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Critical Dependence on Area in Relationship between ARMS2/HTRA1 Genotype and Faster Geographic Atrophy Enlargement: Age-Related Eye Disease Study 2 Report Number 33.

PURPOSE: To analyze ARMS2/HTRA1 as a risk factor for faster geographic atrophy (GA) enlargement according to (1) GA area and (2) contiguous enlargement versus progression to multifocality. DESIGN: Age-Related Eye Disease Study 2 (AREDS2) cohort analysis. PARTICIPANTS: Eyes with GA: 546 eyes of 406 participants. METHODS: Geographic atrophy area was measured from color fundus photographs at annual visits. Mixed-model regression of square root of GA area and proportional hazards regression of progression to multifocality were analyzed by ARMS2 genotype. MAIN OUTCOME MEASURES: Change in square root GA area and progression to multifocality. RESULTS: Geographic atrophy enlargement was significantly faster with ARMS2 risk alleles (P < 0.0001) at 0.224 mm/year (95% CI, 0.195-0.252 mm/year), 0.298 mm/year (95% CI, 0.271-0.324 mm/year), and 0.317 mm/year (95% CI, 0.279-0.355 mm/year), for 0 to 2 risk alleles, respectively. However, a significant interaction (P = 0.011) was observed between genotype and baseline area. In eyes with very small area (< 1.9 mm2), enlargement was significantly faster with ARMS2 risk alleles (P < 0.0001) at 0.193 mm/year (95% CI, 0.162-0.225 mm/year) versus 0.304 mm/year (95% CI, 0.280-0.329 mm/year) for 0 versus 1 to 2 risk alleles, respectively. With moderately small (1.9-3.8 mm2) or medium to large (≥ 3.8 mm2) area, enlargement was not significantly faster with ARMS2 risk alleles (P = 0.66 and P = 0.70, respectively). In nonmultifocal GA, enlargement was significantly faster with ARMS2 risk alleles (P = 0.001) at 0.175 mm/year (95% CI, 0.142-0.209 mm/year), 0.226 mm/year (95% CI, 0.193-0.259 mm/year), and 0.287 mm/year (95% CI, 0.237-0.337 mm/year) with 0 to 2 risk alleles, respectively. ARMS2 genotype was not associated significantly with progression to multifocal GA. CONCLUSIONS: The relationship between ARMS2/HTRA1 genotype and faster GA enlargement depends critically on GA area: risk alleles represent a strong risk factor for faster enlargement only in eyes with very small area. They increase the growth rate more through contiguous enlargement than progression to multifocality. ARMS2/HTRA1 genotype is more important in increasing risk of progression to GA and initial GA enlargement (contiguously) than in subsequent enlargement or progression to multifocality. These findings may explain some discrepancies between previous studies and have implications for both research and clinical practice. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The qMini assay identifies an overlooked class of splice variants.

Splice variants are known to cause diseases by utilizing alternative splice sites, potentially resulting in protein truncation or mRNA degradation by nonsense-mediated decay. Splice variants are verified when altered mature mRNA sequences are identified in RNA analyses or minigene assays. Using a quantitative minigene assay, qMini, we uncovered a previously overlooked class of disease-associated splice variants that did not alter mRNA sequence but decreased mature mRNA level, suggesting a potentially new pathogenic mechanism.

RPGR: Deep Phenotyping and Genetic Characterization With Findings Specific to the 3'-end of ORF15.

Purpose: To describe a group of patients with retinitis pigmentosa GTPase regulator (RPGR)-related retinopathy with a tapetal-like retinal sheen and corresponding changes in the reflectivity of the ellipsoid zone on optical coherence tomography (OCT) imaging. Methods: A retrospective case series of 66 patients with a disease-causing variant in RPGR was performed. An expert examiner, masked to patient demographics, clinical evaluations, and specific RPGR variant, analyzed color fundus photographs for the presence of a tapetal-like retinal sheen and assessed OCT images for the presence of an abnormally broad hyper-reflective band in the outer retina. Longitudinal reflectivity profiles were generated and compared with healthy controls. Results: Twelve patients (18.2%) had a retinal sheen on color images that cosegregated with an abnormally broad hyper-reflective ellipsoid zone band on OCT imaging. Three-fourths of these patients were male, had a cone-rod dystrophy, and had pathogenic RPGR variants located toward the 3'-end of ORF15. This group had a different longitudinal reflectivity profile signature compared with controls. After a period of prolonged dark adaptation, the abnormal hyper-reflective band on OCT became less apparent, and the outer retinal layers adopted a more normal appearance. Conclusions: RPGR-related retinopathy should be considered for males presenting with retinal sheen, abnormal ellipsoid zone hyper-reflectivity, and cone or cone-rod dysfunction on ERG, and pursued with molecular testing. Our results have implications for understanding the role of the C-terminal domain encoded by RPGR ORF15 in the phototransduction cascade. Further, the findings may be important to incorporate into both inclusion criteria and outcome measure developments in future RPGR-related cone or cone-rod dystrophy clinical trials.

Genotype-Phenotype Association in ABCA4-Associated Retinopathy.

Stargardt disease (STGD1) is the most common inherited retina degeneration. It is caused by biallelic ABCA4 variants, and no treatment is available to date. STGD1 shows marked phenotypic variability, especially regarding the age of onset. The underlying genotype can partially explain this variability. Notably, a subset of ABCA4 variants was previously associated with an earlier disease onset than truncating ABCA4 variants, pointing toward pathogenic mechanisms beyond the loss of gene function in these patients. On the other end of the spectrum, variants such as p.Gly1961Glu were associated with markedly slower extrafoveal disease progression. Given that these drastic differences in phenotype are based on genotype (resulting in important prognostic implications for patients), this chapter reviews previous approaches to genotype-phenotype correlation analyses in STGD1.

LOW-DOSE SUPPLEMENTATION WITH RETINOL IMPROVES RETINAL FUNCTION IN EYES WITH AGE-RELATED MACULAR DEGENERATION BUT WITHOUT RETICULAR PSEUDODRUSEN.

PURPOSE: The aim of this study was to determine the functional impact of oral vitamin A supplementation in patients with intermediate age-related macular degeneration with and without reticular pseudodrusen (RPD) demonstrating dysfunction in dark adaptation. METHODS: Five patients with intermediate age-related macular degeneration and without RPD (AMD group; mean ± SD age 78.0 ± 4.7 years) and seven with RPD (RPD group; age 74.1 ± 11.2 years) were supplemented with 16,000 IU of vitamin A palmitate for 8 weeks. Assessment at baseline, 4, 8, and 12 weeks included scotopic thresholds, dark adaptation, best-corrected and low luminance visual acuities, and the low-luminance quality of life questionnaire. RESULTS: In the linear mixed model, rod intercept time improved significantly in the AMD group (mean [95% CI] change -1.1 minutes [-1.8; -0.5] after 4 weeks ( P < 0.001) and -2.2 min [-2.9 to -1.6] after 8 weeks of vitamin A supplementation ( P < 0.001). The dark adaptation cone plateau also significantly improved (i.e., more sensitive cone threshold) at 4 and 8 weeks ( P = 0.026 and P = 0.001). No other parameters improved in the AMD group, and there was no significant improvement in any parameter in the RPD group despite significantly elevated serum vitamin A levels measurable in both groups after supplementation ( P = 0.024 and P = 0.013). CONCLUSION: Supplementation with 16,000 IU vitamin A, a lower dose than used in previous studies, partially overcomes the pathophysiologic functional changes in AMD eyes. The lack of improvement in the RPD group may indicate structural impediments to increasing vitamin A availability in these patients and/or may reflect the higher variability observed in the functional parameters for this group.

Natural History of Visual Dysfunction in ABCA4 Retinopathy and Its Genetic Correlates.

PURPOSE: To systematically assess the ability to detect change and retest reliability for a panel of visual function assessments in ABCA4 retinopathy. DESIGN: Prospective natural history study (NCT01736293). METHODS: Patients with at least 1 documented pathogenic ABCA4 variant and a clinical phenotype consistent with ABCA4 retinopathy were recruited from a tertiary referral center. Participants underwent longitudinal, multifaceted functional testing, including measures of function at fixation (best-corrected visual acuity, low-vision Cambridge Color Test), macular function (microperimetry), and retina-wide function (full-field electroretinography [ERG]). Two- and 5-year ability to detect change was determined based on the η2 statistic. RESULTS: A total of 134 eyes from 67 participants with a mean follow-up of 3.65 years were included. In the 2-year interval, the microperimetry-derived perilesional sensitivity (η2 of 0.73 [0.53, 0.83]; -1.79 dB/y [-2.2, -1.37]) and mean sensitivity (η2 of 0.62 [0.38, 0.76]; -1.28 dB/y [-1.67, -0.89]) showed most change over time, but could only be recorded in 71.6% of the participants. In the 5-year interval, the dark-adapted ERG a- and b-wave amplitude showed marked change over time as well (eg, DA 30 a-wave amplitude with an η2 of 0.54 [0.34, 0.68]; -0.02 log10(µV)/y [-0.02, -0.01]). The genotype explained a large fraction of variability in the ERG-based age of disease initiation (adjusted R2 of 0.73) CONCLUSIONS: Microperimetry-based clinical outcome assessments were most sensitive to change but could only be acquired in a subset of participants. Across a 5-year interval, the ERG DA 30 a-wave amplitude was sensitive to disease progression, potentially allowing for more inclusive clinical trial designs encompassing the whole ABCA4 retinopathy spectrum.

Oral minocycline for the treatment of retinitis pigmentosa-associated cystoid macular edema: results of a phase I/II clinical trial.

PURPOSE: The etiology of retinitis pigmentosa (RP)-associated cystoid macular edema (CME) has been related to retinal neuroinflammation and microglial activation. Minocycline, a drug FDA-approved for anti-microbial indications, also inhibits microglial activation and expression of inflammatory mediators. This study investigates the safety and efficacy of oral minocycline as primary treatment for RP-associated CME. METHODS: A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with RP-associated CME. Participants had lead-in assessments prior to the initiation of oral minocycline 100 mg twice daily for 12 months. Main outcome variables included changes in best-corrected visual acuity (BCVA) and retinal central subfield thickness (CST) measured using spectral domain optical coherence tomography relative to mean of pre-treatment measurements. RESULTS: The study drug was well tolerated and not associated with any severe adverse events. No significant changes in mean BCVA from study baseline were noted in either the study eye (+ 0.7 ± 4.1 letters at 6 months, - 1.1 ± 1.7 letters at 12 months) or the qualifying fellow eye (- 0.3 ± 3.4 letters at 6 months, - 0.3 ± 4.6 letters at 12 months) (p > 0.05 for all comparisons). Mean percentage changes in CST from baseline however decreased progressively with treatment (decreases at 6 and 12 months: study eyes 3.9 and 9.8%; qualifying fellow eyes 1.4 and 7.7%). Considering all eyes (n = 10), mean percentage CST decrease at 6 and 12 months was 2.7 ± 9.5% (p = 0.39) and 8.7 ± 9.5% (p = 0.02) respectively. CONCLUSION: Oral minocycline administration over 12 months was associated with no significant changes in mean BCVA and a small but progressive decrease in mean CST. TRIAL REGISTRATION: NCT02140164 (05/2014).

Deep learning-enabled volumetric cone photoreceptor segmentation in adaptive optics optical coherence tomography images of normal and diseased eyes.

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.

Hyperreflective Foci in Age-Related Macular Degeneration are Associated with Disease Severity and Functional Impairment.

PURPOSE: To analyze presence of hyperreflective foci (HRF) across different age-related macular degeneration (AMD) severities and examine its correlation with other structural and functional AMD features. DESIGN: Longitudinal, single-center, case-control study. PARTICIPANTS: One hundred and fifty-eight participants aged > 50 years old with varying AMD severities (including no AMD). METHODS: Color fundus imaging was used to assess AMD severity and hyperpigmentation (PGM) presence. Subretinal drusenoid deposits (SDD) and HRF were detected on OCT volumes. The correlations of HRF with additional AMD features were evaluated using linear and logistic mixed-effects models. One study eye per participant underwent dark adaptation (DA) testing to measure rod intercept time (RIT) for structure function associations. Eyes were followed longitudinally and changes in AMD severity and RIT were measured relative to HRF presence. MAIN OUTCOME MEASURES: The primary outcome was presence of HRF, which was compared with presence of other AMD features and DA impairment. RESULTS: One hundred and fifty-eight participants (median baseline age of 73.1 [interquartile range (IQR) = 66-79] years) contributing 1277 eye visits were included. Hyperreflective foci (HRF) were detected more frequently in higher AMD severities. Hyperreflective-foci presence was significantly associated with PGM presence (odds ratio 832.9, P < 0.001) and SDD presence (odds ratio 9.42, P = 0.017). Eyes with HRF demonstrated significantly longer DA (median 27.1 [IQR = 16-40] minutes) than those without HRF (13.5 [10-22] minutes) but less than eyes with SDD only (40 [28-40] minutes). Highest RIT values were found in eyes with both HRF and SDD (40.0 [40-40] minutes). Age and HRF explained a similar proportion of RIT variability as age and SDD. Eyes that developed HRF demonstrated baseline RITs closer to eyes with HRF at baseline, compared with eyes that never developed HRF (29.1 [16-40], 38.5 [22-40] versus 13.1 [10-22] minutes; Kruskal-Wallis P < 0.001). CONCLUSIONS: The progressively increased presence of HRF in higher AMD severities, and its correlation with previously associated AMD biomarkers, suggests HRF is an important OCT feature adding to the understanding of disease progression. Hyperreflective foci presence was associated with delays in DA, indicating HRF is a marker for visual cycle impairment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Reticular Pseudodrusen Status, ARMS2/HTRA1 Genotype, and Geographic Atrophy Enlargement: Age-Related Eye Disease Study 2 Report 32.

PURPOSE: To determine whether reticular pseudodrusen (RPD) status, ARMS2/HTRA1 genotype, or both are associated with altered geographic atrophy (GA) enlargement rate and to analyze potential mediation of genetic effects by RPD status. DESIGN: Post hoc analysis of an Age-Related Eye Disease Study 2 cohort. PARTICIPANTS: Eyes with GA: n = 771 from 563 participants. METHODS: Geographic atrophy area was measured from fundus photographs at annual visits. Reticular pseudodrusen presence was graded from fundus autofluorescence images. Mixed-model regression of square root of GA area was performed by RPD status, ARMS2 genotype, or both. MAIN OUTCOME MEASURES: Change in square root of GA area. RESULTS: Geographic atrophy enlargement was significantly faster in eyes with RPD (P < 0.0001): 0.379 mm/year (95% confidence interval [CI], 0.329-0.430 mm/year) versus 0.273 mm/year (95% CI, 0.256-0.289 mm/year). Enlargement was also significantly faster in individuals carrying ARMS2 risk alleles (P < 0.0001): 0.224 mm/year (95% CI, 0.198-0.250 mm/year), 0.287 mm/year (95% CI, 0.263-0.310 mm/year), and 0.307 mm/year (95% CI, 0.273-0.341 mm/year) for 0, 1, and 2, respectively. In mediation analysis, the direct effect of ARMS2 genotype was 0.074 mm/year (95% CI, 0.009-0.139 mm/year), whereas the indirect effect of ARMS2 genotype via RPD status was 0.002 mm/year (95% CI, -0.006 to 0.009 mm/year). In eyes with incident GA, RPD presence was not associated with an altered likelihood of central involvement (P = 0.29) or multifocality (P = 0.16) at incidence. In eyes with incident noncentral GA, RPD presence was associated with faster GA progression to the central macula (P = 0.009): 157 µm/year (95% CI, 126-188 µm/year) versus 111 µm/year (95% CI, 97-125 µm/year). Similar findings were observed in the Age-Related Eye Disease Study. CONCLUSIONS: Geographic atrophy enlargement is faster in eyes with RPD and in individuals carrying ARMS2/HTRA1 risk alleles. However, RPD status does not mediate the association between ARMS2/HTRA1 genotype and faster enlargement. Reticular pseudodrusen presence and ARMS2/HTRA1 genotype are relatively independent risk factors, operating by distinct mechanisms. Reticular pseudodrusen presence does not predict central involvement or multifocality at GA incidence but is associated with faster progression toward the central macula. Reticular pseudodrusen status should be considered for improved predictions of enlargement rate. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Novel ophthalmic findings and deep phenotyping in Williams-Beuren syndrome.

BACKGROUND/AIMS: To characterise the ocular manifestations of Williams-Beuren syndrome (WBS) and compare these to patients with isolated elastin mediated supravalvular aortic stenosis (SVAS). METHODS: Fifty-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. RESULTS: Mean 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. CONCLUSION: WBS 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.

Quantitative analysis of optical coherence tomography imaging in patients with different severities of hydroxychloroquine toxicity.

PURPOSE: To determine the diagnostic validity of quantitative measures derived from optical coherence tomography (OCT) images in their ability to discriminate between cohorts of eyes unaffected by hydroxychloroquine (HCQ) and those with a range of toxicity severities, including mild toxicity. METHODS: Prospective, single-centre, case-control study conducted between August 2010 and May 2017. Participants were exposed to HCQ for at least 5 years (mean±SD =14±7.2 years) and classified into affected and unaffected cohorts based on the American Academy of Ophthalmology's 2016 recommendations. For affected eyes, severity (groups 1-4) was assigned based on the extent of ellipsoid zone loss. For all eyes, spectral domain-OCT scans were analysed quantitatively to compute inner retinal thickness (IRT), outer retinal thickness (ORT), and minimum signal intensity (MI) and compared across toxicity groups. RESULTS: Of the 85 participants (mean age 59±12 years, 93% female), 30 had retinal toxicity. Significant differences in ORT and MI were observed between each affected severity group and unaffected eyes. Significant differences in IRT were observed for groups 3-4 but not groups 1-2. ORT and MI were each able to discriminate between unaffected and group 1 eyes with the highest discrimination at the inner subfields (areas under the curve, AUC=0.96 for ORT and AUC=0.93 for MI). CONCLUSIONS: Quantitative analysis of OCT scans revealed significant differences between eyes with and without toxicity in two different measures. Each individual metric could discriminate between the unaffected and the lowest severity category, suggesting their potential utility in screening for HCQ toxicity in patients at risk.

Investigations of Renal Function and Age-Related Macular Degeneration Phenotypes.

Purpose: To investigate potential associations between renal function and age-related macular degeneration (AMD) features as assessed with multimodal retinal imaging. Methods: 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. Results: 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; P < 0.0001), rod-intercept time (estimate, -0.54 units/minute; 95% CI, -0.81 to -0.27; P < 0.001) 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. Conclusions: Accounting for age, renal function parameters did not show an association with AMD features. Translational Relevance: 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.

Assessment of Retinal Changes Following Intravitreal Aflibercept in 2 Patients With Von Hippel-Lindau Disease-Related Retinal Capillary Hemangioblastoma.

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

Deep Learning-Based Modeling of the Dark Adaptation Curve for Robust Parameter Estimation.

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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. Translational Relevance: 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.

Photoreceptor and Retinal Pigment Epithelium Relationships in Eyes With Vitelliform Macular Dystrophy Revealed by Multimodal Adaptive Optics Imaging.

Purpose: To assess the structure of cone photoreceptors and retinal pigment epithelial (RPE) cells in vitelliform macular dystrophy (VMD) arising from various genetic etiologies. Methods: Multimodal adaptive optics (AO) imaging was performed in 11 patients with VMD using a custom-assembled instrument. Non-confocal split detection and AO-enhanced indocyanine green were used to visualize the cone photoreceptor and RPE mosaics, respectively. Cone and RPE densities were measured and compared across BEST1-, PRPH2-, IMPG1-, and IMPG2-related VMD. Results: Within macular lesions associated with VMD, both cone and RPE densities were reduced below normal, to 37% of normal cone density (eccentricity 0.2 mm) and to 8.4% of normal RPE density (eccentricity 0.5 mm). Outside of lesions, cone and RPE densities were slightly reduced (both to 92% of normal values), but with high degree of variability in the individual measurements. Comparison of juxtalesional cone and RPE measurements (<1 mm from the lesion edge) revealed significant differences in RPE density across the four genes (P < 0.05). Overall, cones were affected to a greater extent than RPE in patients with IMPG1 and IMPG2 pathogenic variants, but RPE was affected more than cones in BEST1 and PRPH2 VMD. This trend was observed even in contralateral eyes from a subset of five patients who presented with macular lesions in only one eye. Conclusions: Assessment of cones and RPE in retinal locations outside of the macular lesions reveals a pattern of cone and RPE disruption that appears to be gene dependent in VMD. These findings provide insight into the cellular pathogenesis of disease in VMD.