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BackgroundCharacterization of retinal degeneration (RD) using high-resolution retinal imaging and exome sequencing may identify phenotypic features that correspond with specific genetic defects.Materials and methodsSix members from a non-consanguineous Indian family (three affected siblings, their asymptomatic parents and an asymptomatic child) were characterized clinically, using visual acuity, perimetry, full-field electroretinography (ERG), optical coherence tomography and cone structure as outcome measures. Cone photoreceptors were imaged in the proband using adaptive optics scanning laser ophthalmoscopy. The exome was captured using Nimblegen SeqCap EZ V3.0 probes and sequenced using lllumina HiSeq. Reads were mapped to reference hg19. Confirmation of variants and segregation analysis was performed using dideoxy sequencing.ResultsAnalysis of exome variants using exomeSuite identified five homozygous variants in four genes known to be associated with RD. Further analysis revealed a homozygous nonsense mutation, c.1105 C > T, p.Arg335Ter, in the FAM161A gene segregating with RD. Three additional variants were found to occur at high frequency. Affected members showed a range of disease severity beginning at different ages, but all developed severe visual field and outer retinal loss.ConclusionsExome analysis revealed a nonsense homozygous mutation in FAM161A segregating with RD with severe vision loss and a range of disease onset and progression. Loss of outer retinal structures demonstrated with high-resolution retinal imaging suggests FAM161A is important for normal photoreceptor structure and survival. Exome sequencing may identify causative genetic variants in autosomal recessive RD families when other genetic test strategies fail to identify a mutation.

PurposeWe studied the correlation between outer nuclear layer (ONL) thickness and cone density in normal eyes and eyes with retinitis pigmentosa (RP).MethodsSpectral-domain optical coherence tomography (SD-OCT) scans were acquired using a displaced pupil entry position of the scanning beam to distinguish Henle's fiber layer from the ONL in 20 normal eyes (10 subjects) and 12 eyes with RP (7 patients). Cone photoreceptors were imaged using adaptive optics scanning laser ophthalmoscopy. The ONL thickness and cone density were measured at 0.5° intervals along the horizontal meridian through the fovea nasally and temporally. The ONL thickness and cone density were correlated using Spearman's rank correlation coefficient r.ResultsCone densities averaged over the central 6° were lower in eyes with RP than normal, but showed high variability in both groups. The ONL thickness and cone density were significantly correlated when all retinal eccentricities were combined (r = 0.74); the correlation for regions within 0.5° to 1.5° eccentricity was stronger (r = 0.67) than between 1.5° and 3.0° eccentricity (r = 0.23). Although cone densities were lower between 0.5° and 1.5° in eyes with RP, ONL thickness measures at identical retinal locations were similar in the two groups (P = 0.31), and interindividual variation was high for ONL and cone density measures. Although ONL thickness and retinal eccentricity were important predictors of cone density, eccentricity was over 3 times more important.ConclusionsThe ONL thickness and cone density were correlated in normal eyes and eyes with RP, but both were strongly correlated with retinal eccentricity, precluding estimation of cone density from ONL thickness. (ClinicalTrials.gov number, NCT00254605.).

PurposeWe studied the correlation between outer nuclear layer (ONL) thickness and cone density in normal eyes and eyes with retinitis pigmentosa (RP).MethodsSpectral-domain optical coherence tomography (SD-OCT) scans were acquired using a displaced pupil entry position of the scanning beam to distinguish Henle's fiber layer from the ONL in 20 normal eyes (10 subjects) and 12 eyes with RP (7 patients). Cone photoreceptors were imaged using adaptive optics scanning laser ophthalmoscopy. The ONL thickness and cone density were measured at 0.5° intervals along the horizontal meridian through the fovea nasally and temporally. The ONL thickness and cone density were correlated using Spearman's rank correlation coefficient r.ResultsCone densities averaged over the central 6° were lower in eyes with RP than normal, but showed high variability in both groups. The ONL thickness and cone density were significantly correlated when all retinal eccentricities were combined (r = 0.74); the correlation for regions within 0.5° to 1.5° eccentricity was stronger (r = 0.67) than between 1.5° and 3.0° eccentricity (r = 0.23). Although cone densities were lower between 0.5° and 1.5° in eyes with RP, ONL thickness measures at identical retinal locations were similar in the two groups (P = 0.31), and interindividual variation was high for ONL and cone density measures. Although ONL thickness and retinal eccentricity were important predictors of cone density, eccentricity was over 3 times more important.ConclusionsThe ONL thickness and cone density were correlated in normal eyes and eyes with RP, but both were strongly correlated with retinal eccentricity, precluding estimation of cone density from ONL thickness. (ClinicalTrials.gov number, NCT00254605.).

PurposeTo evaluate cone spacing using adaptive optics scanning laser ophthalmoscopy (AOSLO) in eyes with nonneovascular AMD, and to correlate progression of AOSLO-derived cone measures with standard measures of macular structure.MethodsAdaptive optics scanning laser ophthalmoscopy images were obtained over 12 to 21 months from seven patients with AMD including four eyes with geographic atrophy (GA) and four eyes with drusen. Adaptive optics scanning laser ophthalmoscopy images were overlaid with color, infrared, and autofluorescence fundus photographs and spectral domain optical coherence tomography (SD-OCT) images to allow direct correlation of cone parameters with macular structure. Cone spacing was measured for each visit in selected regions including areas over drusen (n = 29), at GA margins (n = 14), and regions without drusen or GA (n = 13) and compared with normal, age-similar values.ResultsAdaptive optics scanning laser ophthalmoscopy imaging revealed continuous cone mosaics up to the GA edge and overlying drusen, although reduced cone reflectivity often resulted in hyporeflective AOSLO signals at these locations. Baseline cone spacing measures were normal in 13/13 unaffected regions, 26/28 drusen regions, and 12/14 GA margin regions. Although standard clinical measures showed progression of GA in all study eyes, cone spacing remained within normal ranges in most drusen regions and all GA margin regions.ConclusionsAdaptive optics scanning laser ophthalmoscopy provides adequate resolution for quantitative measurement of cone spacing at the margin of GA and over drusen in eyes with AMD. Although cone spacing was often normal at baseline and remained normal over time, these regions showed focal areas of decreased cone reflectivity. These findings may provide insight into the pathophysiology of AMD progression. (ClinicalTrials.gov number, NCT00254605).

Background Loss of photoreceptors cause degeneration in areas of the retina beyond the photoreceptors. The pattern of changes has implications for disease monitoring and measurement of functional changes. The aim of the study was to study the changes in inner retinal structure associated with photoreceptor disease, and the impact of these on microperimetry threshold. Methods This retrospective cohort study was conducted on optical coherence tomography (OCT) images and microperimetry tests collected between 2013 and 2019. 22 eyes with RPGR retinitis pigmentosa completed both OCT imaging and microperimetry assessment. 18 control eyes underwent OCT imaging. Photoreceptor layer and inner retinal thickness calculated for different eccentric areas were obtained. The relationship between the photoreceptor layer and inner retinal thickness, and microperimetry threshold was explored. Results Central 1° photoreceptor layer and inner retinal thickness were 96±34 and 139±75 μm in RPGR patients, and 139±15 and 62±14 μm in controls. Photoreceptor layer thickness differed between patient and control groups across increasing visual field areas (p<0.01, Kruskal-Wallis 1-way ANOVA), whereas the inner retinal thickness significantly differed between groups for the central 1° and 3° only. Microperimetry thresholds were explained by a combination of photoreceptor thickness (coefficient 0.15, 95% CI 0.13 to 0.18) and inner retinal thickness (coefficient 0.05, 95% CI 0.03 to 0.06). Conclusion OCT shows evidence of remodelling in the inner retinal layers secondary to photoreceptor disease. This appears to have an impact on microperimetry threshold measurements. [ABSTRACT FROM AUTHOR]

Introduction: Introduction of retinal gene therapy requires established outcome measures along with thorough understanding of the pathophysiology. Evidence of early, thinned outer segments in RPGR X-linked retinitis pigmentosa could help understand how the level of cone photoreceptor involvement translates to visual potential. Objective: Analysis of foveal photoreceptor outer segment length in a young cohort of RPGR patients to help clarify the reason for absent maximal visual acuity seen. Methods: Case-control study of RPGR patients. Quantitative measurement of photoreceptor outer segment by OCT. Results: Eighteen male RPGR patients and 30 normal subjects were included. Outer segment thickness differed significantly between the RPGR and normal eyes (p < 0.0005). Mean outer segment values were 35.6 ± 2.3 µm and 35.4 ± 2.6 µm for RPGR right and left eyes, respectively. In normal eyes, the mean outer segment thickness was 61.4 ± 0.7 µm for right eyes and 62.4 ± 0.7 µm for left eyes. Conclusions: Patients with RPGR X-linked retinitis pigmentosa show thinning of the foveal photoreceptor outer segment thickness early in the disease course, which could be an explanation for the lower maximum visual acuity seen. These findings must be taken into consideration when assessing efficacy outcome measures in retinal gene therapy trials. [ABSTRACT FROM AUTHOR]

Importance: All automated image quality indicators for en face optical coherence tomography angiography (OCTA) images require gold standard validation for determining optimum thresholds. Background: A manual grading system (gold standard) for OCTA images was validated and compared to two automated image quality indicators: signal strength index (SSI) and scan quality index (SQI) generated by different software versions of the Optovue OCTA device. Design: Retrospective cross‐sectional study. Participants: A total of 52 eyes of 52 healthy individual and 77 eyes of 51 patients with retinal vascular diseases. Methods: A total of 129 OCTA images of the superficial vascular plexus were graded manually by three independent examiners. Each image was assigned grades 1 to 4 (1‐2, unacceptable; 3‐4, acceptable) masked to the software‐generated quality indicators. Main Outcome Measures: Inter‐grader agreement and comparison of the utility of SSI and SQI in discriminating between acceptable and unacceptable OCTA images. Results: There was a substantial agreement between the three graders (κ = 0.63). Mean SSI and SQI was significantly different between acceptable and unacceptable images (P <.001). SQI outperformed SSI in separating acceptable from unacceptable images (areas under the receiver operating characteristic curve: 0.87 vs 0.80) and the optimum cut‐off was ≥7 for SQI and ≥70 for SSI for acceptable images. Up to 30% of images with quality indicators reaching the optimum SQI and SSI cut‐off thresholds still had unacceptable quality on manual grading. Unacceptable images were found in 33% and 66% of healthy and diseased eyes, respectively. Conclusions and Relevance: SQI is closely related to manual grading but we caution reliance on the optimized threshold to determine image quality. SQI is superior to SSI in discriminating between acceptable and unacceptable images. [ABSTRACT FROM AUTHOR]

Purpose: To report a novel optical coherence tomography sign in the context of CRB1 -related maculopathy termed outer retinal columnar abnormalities (ORCA)., Methods: Retrospective, multicenter, observational case series of 14 eyes of eight patients with molecularly confirmed CRB1 -related maculopathy and ORCA. Multimodal imaging scans and medical records of patients with CRB1 -related maculopathy were reviewed. Outcome measures included best-corrected visual acuity, central subfield thickness on spectral-domain optical coherence tomography, presence of ORCAs, and analysis of their change in appearance over time., Results: At baseline, mean age was 18±10 years (range 9-36 years). All patients had an isolated macular dystrophy except for 1 case harboring a triallelic pathogenic variant. Variant c.498&#95;506del was found in 9 cases (88%). At presentation, ORCA were visible on macular spectral-domain optical coherence tomography in all cases as multiform, vertical, hyperreflective, columnar alterations extending from the ellipsoid to the outer plexiform layer, with a variable degree of hyporeflective cystic spaces in the outer and inner nuclear layers. Over 6±4.7 follow-up years, the presence of ORCA varied greatly with a decrease in ORCA associated with sequential development of retinal atrophy., Conclusion: A high suspicion for CRB1 -associated retinal dystrophy should arise in the presence of ORCA on spectral-domain optical coherence tomography, prompting genetic testing.