Longitudinal structure-function analysis of molecularly-confirmed CYP4V2 Bietti Crystalline Dystrophy.

OBJECTIVES: Bietti Crystalline Dystrophy (BCD) is an autosomal recessive progressive retinal disease caused by mutations in CYP4V2. We have characterised the natural history including structural and functional measures to identify potential outcome metrics for future clinical trials. METHODS: Molecularly-confirmed BCD patients with biallelic variants in CYP4V2 were retrospectively identified from Moorfields Eye Hospital (UK). Clinical details including results of molecular genetic testing, best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography (OCT) scans were extracted. From OCT scans, ellipsoid zone (EZ) measures, foveal thickness of the whole retina, outer retina and choroid were measured. Age-related changes of clinical parameters were assessed with linear mixed models. RESULTS: Twenty-eight BCD patients were identified, with median age at baseline of 37 years (interquartile range [IQR]: 30-49.5). Median follow-up was 7.7 years (IQR: 3.4-14.5). Most patients (41.7%) showed chorioretinal atrophy at baseline. All OCT parameters showed significant age-related loss (p < 0.05), with EZ measures and choroidal thickness displaying the most rapid degeneration (2.3-3.3% per year vs 0.6-1.5% per year). Median BCVA was 0.2 LogMAR (IQR: 0-0.5) at baseline and showed small age-related loss ( + 0.016 LogMAR per year, p = 0.0019). Patients exhibited substantial phenotypic variability. CONCLUSIONS: BCD presents between age 25 and 40, and slowly progresses to an advanced chorioretinal atrophy and vision loss by age 60. BCVA may be preserved until late, and is seemingly poorly representative of disease progression. OCT parameters capturing EZ and choroid changes may afford more suitable trial outcome measures.

Longitudinal Changes of Retinal Structure in Molecularly Confirmed C1QTNF5 Patients With Late-Onset Retinal Degeneration.

Purpose: The purpose of this study was to present our findings on the natural history of late-onset retinal degeneration (LORD) in patients with molecularly confirmed C1QTNF5 heterozygous pathogenic variants and assess suitability of retinal structure parameters for disease monitoring. Methods: Sixteen patients with C1QTNF5-LORD were retrospectively identified from Moorfields Eye Hospital, UK. Fundus autofluorescence (FAF), optical coherence tomography (OCT) scans, and best-corrected visual acuity (BCVA) were collected. Area of atrophy (AA) was manually drawn in FAF images. Ellipsoid zone (EZ) width and foveal retinal thickness of the whole retina and outer retina were extracted from OCT scans. Age-related changes were tested with linear-mixed models. Results: Patients had median age of 62.3 years (interquartile range [IQR] = 58.8-65.4 years) at baseline, and median follow-up of 5.1 years (IQR = 2.6-7.6 years). AA, EZ width, and retinal thickness parameters remained unchanged until age 50 years, but showed significant change with age thereafter (all P < 0.0001). AA and EZ width progressed rapidly (dynamic range normalized rates = 4.3-4.5%/year) from age 53.9 and 50.8 years (estimated inflection points), respectively. Retinal thickness parameters showed slower progression rates (range = 1.6-2.5%/year) from age 60 to 62.3. BCVA (median = 0.3 LogMAR, IQR = 0.0-1.0 at baseline) showed a rapid decline (3.3%) from age 70 years. Findings from patients with earlier disease showed FAF atrophy manifests in the temporal retina initially, and then progresses nasally. Conclusions: Patients with LORD remained asymptomatic until age 50 years, before suffering rapid outer retinal degeneration. EZ width and AA showed rapid progression and high interocular correlation, representing promising outcome metrics. Clinical measures also capturing the temporal retina may be preferable, enabling earlier detection and better disease monitoring. Translational Relevance: Area of atrophy in FAF images and OCT-measured EZ width represent promising outcome metrics for disease monitoring in patients with C1QTNF5-LORD.

Foveal Hypoplasia in CRB1-Related Retinopathies.

The CRB1 gene plays a role in retinal development and its maintenance. When disrupted, it gives a range of phenotypes such as early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone-rod dystrophy (CORD) and macular dystrophy (MD). Studies in CRB1 retinopathies have shown thickening and coarse lamination of retinal layers resembling an immature retina. Its role in foveal development has not yet been described; however, this retrospective study is the first to report foveal hypoplasia (FH) presence in a CRB1-related retinopathy cohort. Patients with pathogenic biallelic CRB1 variants from Moorfields Eye Hospital, London, UK, were collected. Demographic, clinical data and SD-OCT analyses with FH structural grading were performed. A total of 15 (48%) patients had EOSRD/LCA, 11 (35%) MD, 3 (9%) CORD and 2 (6%) RP. FH was observed in 20 (65%; CI: 0.47-0.79) patients, all of whom were grade 1. A significant difference in BCVA between patients with FH and without was found (p = 0.014). BCVA continued to worsen over time in both groups (p < 0.001), irrespective of FH. This study reports FH in a CRB1 cohort, supporting the role of CRB1 in foveal development. FH was associated with poorer BCVA and abnormal retinal morphology. Nonetheless, its presence did not alter the disease progression.

Physical Properties and Interaction With the Ocular Surface of Water-Gradient Contact Lenses.

ABSTRACT: Since the introduction of silicone hydrogel contact lenses, many silicone-hydrogel materials have been produced, including water-gradient contact lenses with a silicone hydrogel core and a thin hydrogel outer layer (e.g., delefilcon A, verofilcon A, and lehfilcon A). Their properties have been investigated in various studies assessing both the chemical-physical characteristics and the comfort, but the overall picture is not always consistent. In this study, water-gradient technology is reviewed by looking at basic physical properties both in vitro and in vivo and at the interaction with the human ocular surface. Surface and bulk dehydration, surface wetting and dewetting, shear stress, interaction with tear components and with other environmental compounds, and comfort are discussed.

Concordance of Objectively Detected Retinal Nerve Fiber Bundle Defects in En Face OCT Images with Conventional Structural and Functional Changes in Glaucoma.

PURPOSE: To assess how objectively detected defects in retinal nerve fiber bundle (RNFB) reflectance on en face OCT images relate to circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and visual field defects. DESIGN: Cross-sectional study. PARTICIPANTS: Sixteen participants with early glaucoma and 29 age-matched healthy controls, of whom 22 had usable en face images for the establishment of normative levels of RNFB reflectance. METHODS: All the participants underwent cpRNFLT scans, visual field examination, and wide-field OCT. En face reflectivity was assessed objectively using the Summary of Multiple Anatomically Adjusted Slabs method. En face defects were deemed concordant with cpRNFLT when they had at least 1 cpRNFLT point with P < 0.01, within ± 15° of the predicted insertion on the optic disc. Visual fields were examined using custom suprathreshold perimetry and SITA Standard 24-2. For each visual field location, the corresponding reflectance was deemed abnormal if any en face superpixel within ± 1° was abnormal. The overall, positive, and negative agreements were measured in each participant. MAIN OUTCOME MEASURES: Proportion of concordant defects between en face reflectance analysis and cpRNFLT (%) as well as overall, positive, and negative agreements between en face reflectance analysis and visual field results. RESULTS: Most en face abnormalities had concordant cpRNFLT defects in the mapped sector (median proportion concordant, 0.85; interquartile range, 0.74-0.95). In eyes with glaucoma, a median of 8.1% (range, 2.4%-23.7%) and 14.9% (range, 3.5%-29.1%) locations showed corresponding en face and visual field defects using 24-2 and custom perimetry, respectively. Both the perimetric strategies had moderate-to-good raw agreement with en face analysis (0.66-0.68), with stronger agreement on normal findings than on defects (0.77-0.78 and 0.4-0.44). CONCLUSIONS: Objectively extracted reflectance defects showed strong concordance with conventional cpRNFLT damage and good agreement with perimetry, which could be enhanced by further minimization of image artifacts.

A Natural History Study of RP2-Related Retinopathy.

X-linked retinitis pigmentosa (RP) is a severe form of RP, often with early macular involvement. This study aimed to characterise the natural history of patients with a diagnosis of X-linked RP due to RP2 mutations. Clinical details, best-corrected visual acuity (BCVA) and multimodal retinal imaging were retrospectively collected from patients with RP2 variants from Moorfields Eye Hospital (London, UK). Measures of the ellipsoid-zone (EZ) width, central retinal thickness (CRT), and thickness of the photoreceptor and retinal pigment epithelium complex (PR+RPE, taken between the external limiting membrane and RPE) were extracted from spectral-domain optical coherence tomography (SD-OCT) scans. A total of 47 affected males (median baseline age: 20 years, IQR: 12.5−36.5) were included, and 41 had two or more visits (median follow-up: 8.0 years, IQR: 3.2−14.5). A total of 24 RP2 variants were identified, 13 of which were novel. BCVA dropped from 0.66 LogMAR at baseline (IQR, 0.35−1.4) to 1.3 LogMAR at the most recent visit (IQR: 0.6−1.4). SD-OCT revealed a prevalent outer retinal atrophy (n = 23/35, 65.7%), and measurable EZ width at baseline in 34.3% of patients (n = 12). Age significantly affected all quantitative measures (p < 0.001) except EZ width (p = 0.58), with exponential decays of 46−49% and 12.6−33.9% per decade for BCVA and SD-OCT measures, respectively. RP2 patients exhibited rapid progression to outer retina atrophy and early macular involvement with substantial vision loss by age 30−40.

Enhanced Objective Detection of Retinal Nerve Fiber Bundle Defects in Glaucoma With a Novel Method for En Face OCT Slab Image Construction and Analysis.

Purpose: To introduce and evaluate the performance in detecting glaucomatous abnormalities of a novel method for extracting en face slab images (SMAS), which considers varying individual anatomy and configuration of retinal nerve fiber bundles. Methods: Dense central retinal spectral domain optical coherence tomography scans were acquired in 16 participants with glaucoma and 19 age-similar controls. Slab images were generated by averaging reflectivity over different depths below the inner limiting membrane according to several methods. SMAS considered multiple 16 µm thick slabs from 8 to 116 µm below the inner limiting membrane, whereas 5 alternative methods considered single summary slabs of various thicknesses and depths. Superpixels in eyes with glaucoma were considered abnormal if below the first percentile of distributions fitted to control data for each method. The ability to detect glaucoma defects was measured by the proportion of abnormal superpixels. Proportion of superpixels below the fitted first percentile in controls was used as a surrogate false-positive rate. The effects of slab methods on performance measures were evaluated with linear mixed models. Results: The ability to detect glaucoma defects varied between slab methods, χ2(5) = 120.9, P < 0.0001, with SMAS showing proportion of abnormal superpixels 0.05 to 0.09 greater than alternatives (all P < 0.0001). No slab method found abnormal superpixels in controls. Conclusions: SMAS outperformed alternatives in detecting abnormalities in eyes with glaucoma. SMAS evaluates all depths with potential retinal nerve fiber bundle presence by combining multiple slabs, resulting in greater detection of reflectance abnormalities with no increase in surrogate false positives. Translational Relevance: SMAS may be used to objectively detect glaucoma defects in en face optical coherence tomography images.

A Simple Subjective Evaluation of Enface OCT Reflectance Images Distinguishes Glaucoma From Healthy Eyes.

Purpose: We present a subjective approach to detecting glaucomatous defects in enface images and assess its diagnostic performance. We also test the hypothesis that if reflectivity changes precede thickness changes in glaucoma there should be reduced correlation between the modalities in glaucoma compared to controls. Methods: Twenty glaucoma participants and 20 age-matched controls underwent high-resolution OCT scans of one eye. 4 µm-thick enface slabs were constructed through the retina. Enface indices were depths of first gap in visible retinal nerve fiber bundles (RNFBs) and last visible bundle, subjectively evaluated in six sectors of a 3.5 mm circle around the optic disc. Retinal nerve fiber layer thickness (RNFLT) along the same circle was extracted at angles corresponding to enface indices. Between-group differences were tested by linear mixed models. Diagnostic performance was measured by partial receiver operating characteristic area (pAUC). Results: First gap and last visible bundle were closer to the inner limiting membrane in glaucoma eyes (both P < 0.0001). Enface indices showed excellent diagnostic performance (pAUCs 0.63-1.00), similar to RNFLT (pAUCs 0.63-0.95). Correlation between enface and RNFLT parameters was strong in healthy (r = 0.81-0.92) and glaucoma eyes (r = 0.73-0.80). Conclusions: This simple subjective method reliably identifies glaucomatous defects in enface images with diagnostic performance at least as good as existing thickness indices. Thickness and reflectivity were similarly related in healthy and glaucoma eyes, providing no strong evidence of reflectivity loss preceding thinning. Objective analyses may realize further potential of enface OCT images in glaucoma. Translational Relevance: Novel enface OCT indices may aid glaucoma diagnosis.

Depth-resolved variations in visibility of retinal nerve fibre bundles across the retina in enface OCT images of healthy eyes.

PURPOSE: Recent developments in optical coherence tomography (OCT) technology enable direct enface visualisation of retinal nerve fibre bundle (RNFB) loss in glaucoma. However, the optimum depth at which to visualise RNFBs across the retina is unknown. We aimed to evaluate the range of depths and optimum depth at which RNFBs can be visualised across the retina in healthy eyes. METHODS: The central ± 25° retina of 10 healthy eyes from 10 people aged 57-75 years (median 68.5 years) were imaged with spectral domain OCT. Slab images of maximum axial resolution (4 µm) containing depth-resolved attenuation coefficients were extracted from 0 to 193.5 µm below the inner limiting membrane (ILM). Bundle visibility within 10 regions of a superimposed grid was assessed subjectively by trained optometrists (n = 8), according to written instructions. Anterior and posterior limits of RNFB visibility and depth of best visibility were identified for each grid sector. Effects of retinal location and individual eye on RNFB visibility were explored using linear mixed modelling with likelihood ratio tests. Intraclass correlation coefficient (ICC) was used to measure overall agreement and repeatability of grading. Spearman's correlation was used to measure correlation between depth range of visible RNFBs and retinal nerve fibre layer thickness (RNFLT). RESULTS: Retinal location and individual eye affected anterior limit of visibility (χ2(9)  = 58.6 and 60.5, both p < 0.0001), but none of the differences exceeded instrument resolution, making anterior limit consistent across the retina and different eyes. Greater differences were observed in the posterior limit of visibility across retinal areas (χ2(9)  = 1671.1, p < 0.0001) and different eyes (χ2(9)  = 88.7, p < 0.0001). Optimal depth for visualisation of RNFBs was around 20 µm below the ILM in most regions. It varied slightly with retinal location (χ2(9)  = 58.8, p < 0.0001), but it was not affected by individual eye (χ2(9)  = 10.7, p = 0.29). RNFB visibility showed good agreement between graders (ICC 0.89, 95%CI 0.87-0.91), and excellent repeatability (ICC 0.96-0.99). Depth range of visible RNFBs was highly correlated with RNFLT (ρ = 0.9, 95%CI: 0.86-0.95). CONCLUSIONS: The range of depths with visible RNFBs varies markedly across the healthy retina, consistently with RNFLT. To extract all RNFB information consistently across the retina, slab properties should account for differences across retinal locations and between individual eyes.

Global prevalence of diabetic retinopathy: protocol for a systematic review and meta-analysis.

INTRODUCTION: With increasing diabetes trends worldwide, morbidity, mortality and associated costs due to diabetes-related complications are a global public health concern. Diabetic retinopathy (DR) is among the leading causes of vision loss at the global level; accurate estimates of DR burden is of crucial importance for planning, implementing and evaluating DR prevention and care interventions.The available evidence on DR prevalence at the global level, dating back to 2008, only considered data from selected regions. Taking into account the rapidly changing patterns in DR epidemiology, the aim of the current study is to carry out a systematic review and meta-analysis to derive solid and updated estimates on global and setting-specific DR prevalence. METHODS AND ANALYSIS: The systematic review methods have been defined following PRISMA guidelines. Studies published from 2008 through 2018 will be identified searching the electronic databases Embase, Medline, Cochrane, ISI Web of Knowledge, as well as through grey literature search. Retrieved records will be independently screened by two authors and relevant data will be extracted from studies reporting data on DR prevalence among individuals with diabetes. Prevalence pooled estimates of any form of DR and vision-threatening DR will be computed applying random-effects meta-analysis. Interstudy heterogeneity will be assessed using the I2 statistic and explored through meta regressions and subgroup analyses. Depending on data availability, we plan to conduct subgroup analyses by study population, diabetes type, DR severity, geographical region and other selected clinical and sociodemographic variables of interest. Quality appraisal of the studies will be performed. ETHICS AND DISSEMINATION: Ethics approval is not required as this is a review of anonymised published data. Findings of the final report will be shared with the scientific community through publication in a peer-reviewed journal and presentation at conferences, as well as with key stakeholders, including national and international health authorities, health policy makers, healthcare professionals and the general population. CLINICAL TRIAL REGISTRATION: CRD42018085260.