Publications by authors named "Angelos Kalitzeos"

40 Publications

Agreement Between Spectral-Domain and Swept-Source Optical Coherence Tomography Retinal Thickness Measurements in Macular and Retinal Disease.

Ophthalmol Ther 2021 Jul 29. Epub 2021 Jul 29.

NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, London, Institute of Ophthalmology, University College London, 162 City Road, London, EC1V 2PD, UK.

Introduction: To assess inter-device agreement in optical coherence tomography-derived retinal thickness measurements in patients with known macular conditions between spectral-domain and swept-source optical coherence tomography (OCT).

Methods: Two hundred seventy-two subjects were included in the study. They consisted of 91 male (33.5%) and 181 female (66.5%) subjects, and 132 left (48.5%) and 140 right (51.5%) eyes. Each subject underwent spectral-domain OCT (SD-OCT, Spectralis, Heidelberg Engineering; RTVue XR Avanti XR HD, Optovue) and swept-source OCT (SS-OCT; DRI-OCT-1, Atlantis, Topcon) in a single imaging session performed by the same clinical trial-certified technician. The comparison of retinal thickness reproducibility between devices was performed using Bland-Altman analyses and across the entire data set using the intraclass correlation coefficient (ICC).

Results: The ICC of the retinal thickness measurements (95% confidence interval) made using all three OCT instruments was 0.81 (0.77-0.84). The mean difference in mean retinal thickness between Spectralis SD-OCT and Topcon SS-OCT was 59.1 μm (95% limit of agreement [LoA] -21.7 to 139.8 μm). The mean difference in mean retinal thickness between Optovue SD-OCT and Topcon SS-OCT was 21.8 μm (95% LoA -34.7  to 78.3 μm).

Conclusions: Retinal layer thickness measurements vary between SS-OCT and SD-OCT devices. We describe inter-device agreement in retinal thickness between SS-OCT and SD-OCT in patients with macular conditions. Clinicians should be aware of the differences in retinal thickness values when imaging patients using different OCT devices and should consider using the same OCT device model in order to monitor clinical change.

Trial Registration: ClinicalTrials.gov Identifier (NCT02828215).
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http://dx.doi.org/10.1007/s40123-021-00377-8DOI Listing
July 2021

Novel disease-causing variant in presenting with autosomal dominant retinitis pigmentosa.

Br J Ophthalmol 2021 May 24. Epub 2021 May 24.

Cell and Gene Therapy, University College London Institute of Ophthalmology, London, UK

Aim: To describe the clinical and molecular features of a novel, autosomal dominant -retinopathy.

Methods: Retrospective cross-sectional study. Twelve individuals from a four-generation British pedigree underwent ophthalmic examination, genotyping using next generation sequencing, including whole genome sequencing and multimodal retinal imaging including fundus photography, optical coherence tomography (OCT), autofluorescence imaging and adaptive optics (AO) scanning light ophthalmoscopy were performed. Visual electrophysiology was performed in a subset.

Results: Eight family members were confirmed as affected by genotyping heterozygous for c.763delG. Visual acuity ranged from -0.1 to 0.2 logMAR. Affected individuals had constricted visual fields. A parafoveal and peripapillary ring of hyper-autofluorescence was seen initially, and with progression the area of perifoveal hypo-autofluorescence increased to involve the parafoveal area. Mild retinal thinning was identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness. Cone densities along the temporal meridian were reduced in affected individuals compared with normative values at all temporal eccentricities studied. One individual with incomplete penetrance, was identified as clinically affected primarily on the basis of AO imaging. Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction.

Conclusions: This novel heterozygous variant c.763delG is associated with a rod-cone dystrophy with variable expression. Determination of the degree of penetrance may depend on the modality employed to phenotypically characterise an individual. This rare and specific heterozygous (dominant) variant is predicted to result in a gain of function, that causes disease in a gene typically associated with biallelic (recessive) variants.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318034DOI Listing
May 2021

Long-Term Investigation of Retinal Function in Patients with Achromatopsia.

Invest Ophthalmol Vis Sci 2020 09;61(11):38

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

Purpose: To investigate the long-term natural history of retinal function of achromatopsia (ACHM).

Methods: Subjects with molecularly confirmed ACHM were recruited in a prospective cohort study of mesopic microperimetry. Coefficient of repeatability and intraclass correlation coefficient (ICC) of mean sensitivity (MS) were calculated. Best-corrected visual acuity (BCVA), bivariate contour ellipse area (BCEA), contrast sensitivity (CS), MS, total volume (VTOT), and central field volume (V5°) from volumetric and topographic analyses were acquired. Correlation of functional parameters with structural findings from optical coherence tomography (OCT) was performed.

Results: Eighteen subjects were recruited. Mean follow-up was 7.2 years. The MS test-retest repeatability coefficient was 1.65 decibels (dB), and the ICC was 0.973 (95% confidence interval, 0.837-0.98). Mean MS was similar for right and left eyes (16.97dB and 17.14dB, respectively). A negative significant correlation between logMAR BCVA and the retinal sensitivity indices (MS, VTOT, V5°) was found. A significant negative correlation between logCS and MS, VTOT, and V5° was also observed. BCVA and BCEA improved during follow-up. Mean CS, MS, VTOT, and V5° at final follow-up were similar to baseline. MS was similar between CNGA3- and CNGB3-ACHM. Patients with and without the presence of a foveal ellipsoid zone on OCT had similar MS (16.64 dB and 17.17 dB, respectively).

Conclusions: We demonstrate a highly reproducible assessment of MS. Retinal function including MS, volumetric indices, and CS are stable in ACHM. Improvement of fixation stability and small changes of BCVA over time may be part of the natural history of the disease.
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http://dx.doi.org/10.1167/iovs.61.11.38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509756PMC
September 2020

Intraobserver Repeatability and Interobserver Reproducibility of Foveal Cone Density Measurements in and -Associated Achromatopsia.

Transl Vis Sci Technol 2020 06 26;9(7):37. Epub 2020 Jun 26.

Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: To examine repeatability and reproducibility of foveal cone density measurements in patients with and -associated achromatopsia (ACHM) using split-detection adaptive optics scanning light ophthalmoscopy (AOSLO).

Methods: Thirty foveae from molecularly confirmed subjects with ACHM, half of whom harbored disease-causing variants in and half in underwent nonconfocal split-detection AOSLO imaging. Cone photoreceptors within the manually delineated rod-free zone were manually identified twice by two independent observers. The coordinates of the marked cones were used for quantifying foveal cone density. Cone density and difference maps were generated to compare cone topography between trials.

Results: We observed excellent intraobserver repeatability in foveal cone density estimates, with intraclass correlation coefficients (ICCs) ranging from 0.963 to 0.991 for and subjects. Interobserver reproducibility was also excellent for both (ICC = 0.952; 95% confidence interval [CI], 0.903-1.0) and (ICC = 0.968; 95% CI, 0.935-1.0). However, Bland-Altman analysis revealed bias between observers.

Conclusions: Foveal cone density can be measured using the described method with good repeatability and reproducibility both for - and -associated ACHM. Any degree of bias observed among the observers is of uncertain clinical significance but should be evaluated on a study-specific basis.

Translational Relevance: This approach could be used to explore disease natural history, as well as to facilitate stratification of patients and monitor efficacy of interventions for ongoing and upcoming ACHM gene therapy trials.
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http://dx.doi.org/10.1167/tvst.9.7.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414701PMC
June 2020

Quantifying the Separation Between the Retinal Pigment Epithelium and Bruch's Membrane using Optical Coherence Tomography in Patients with Inherited Macular Degeneration.

Transl Vis Sci Technol 2020 05 23;9(6):26. Epub 2020 May 23.

Medical Retina Service, Moorfields Eye Hospital, London, UK.

Purpose: To describe and quantify Bruch's membrane (BM) and retinal pigment epithelium (RPE) separation using spectral-domain (SD) optical coherence tomography (OCT) in patients affected by inherited macular degenerations associated with BM thickening.

Methods: Patients with molecularly confirmed Sorsby fundus dystrophy (SFD), dominant drusen (DD), and late-onset retinal degeneration (L-ORD) were included in this retrospective study. Each disease was classed as early stage if subjects were asymptomatic, intermediate stage if they had nyctalopia alone, and late stage if they described loss of central vision. The main outcome was measurement of BM-RPE separation on SD-OCT. The BM-RPE separation measurements were compared against those in normal age-matched controls.

Results: Seventeen patients with SFD, 22 with DD, and eight with L-ORD were included. BM-RPE separation on SD-OCT demonstrated a high test-retest and interobserver reproducibility (intraclass correlation coefficients >0.9). BM-RPE separation was not identified in normal subjects. In SFD, there was greater BM-RPE separation in late-stage disease compared with intermediate-stage patients both at subfoveal ( < 0.05) and juxtafoveal ( < 0.01) locations. In DD, there was increased BM-RPE separation in late-stage disease compared with early stage at subfoveal ( < 0.001) and juxtafoveal ( < 0.05) topographies. There was no significant difference in BM-RPE separation between disease stages in L-ORD.

Conclusions: BM-RPE separation is a novel, quantifiable phenotype in the three monogenic macular dystrophies studied, and may be an optical correlate of the histopathological thickening in BM that is known to occur. BM-RPE separation, as measured by OCT, varies with stage of disease in SFD and DD, but not in L-ORD.

Translational Relevance: SFD, DD, and L-ORD are associated with BM thickening. In this group of patients, OCT assessment of macular structure identifies a separation of the usually single, hyperreflective line thought to represent BM and the overlying RPE. This separation is a novel and quantifiable feature of disease staging in SFD and DD.
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http://dx.doi.org/10.1167/tvst.9.6.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409156PMC
May 2020

Longitudinal Assessment of Remnant Foveal Cone Structure in a Case Series of Early Macular Telangiectasia Type 2.

Transl Vis Sci Technol 2020 03 30;9(4):27. Epub 2020 Mar 30.

Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Purpose: To determine the extent of remnant cone structure within early foveal ellipsoid zone (EZ) lesions in macular telangiectasia type 2 longitudinally using both confocal and split detector adaptive optics scanning light ophthalmoscopy (AOSLO).

Methods: Spectral domain optical coherence tomography (SDOCT), confocal and split detector AOSLO were acquired from seven patients (10 eyes) with small (early) EZ lesions on SDOCT secondary to macular telangiectasia type 2 at baseline, 6 months, and 12 months. The presence of cone structure on AOSLO in areas of EZ loss as well as cones at 1° eccentricity, and their change over time were quantified.

Results: By split detector AOSLO, remnant cone structure was identified within and on the borders of all foveal EZ lesions. Within the extent of these lesions, cone spacing ranged from 4.97 to 9.95 µm at baseline, 5.30 to 6.10 µm at 6 months, and 4.99 to 7.12 µm at 12 months. Four eyes with significantly smaller EZ lesions showed evidence of recovery of EZ reflectivity on SDOCT B-scans. Remnant cone structure was identified in some areas where EZ reflectivity recovered at the following time point. Eyes that showed recovery of EZ reflectivity had a continuous external limiting membrane.

Conclusions: Remnant cone structure can persist within small SDOCT-defined EZ lesions, which can wax and wane in appearance over time. AOSLO can help to inform the interpretation of SDOCT imaging.

Translational Relevance: The absence of EZ in early macular telangiectasia type 2 and other retinal conditions needs careful interpretation because it does not always indicate an absence of underlying cone structure. The integrity of the external limiting membrane may better predict the presence of remnant cone structure and recovery of EZ reflectivity.
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http://dx.doi.org/10.1167/tvst.9.4.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396184PMC
March 2020

Retinal Structure in RPE65-Associated Retinal Dystrophy.

Invest Ophthalmol Vis Sci 2020 04;61(4):47

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Purpose: RPE65-associated retinal dystrophy (RPE65-RD) is an early onset, progressive, severe retinal dystrophy. We sought to characterize the natural history of retinal degeneration in affected individuals.

Methods: We performed cross-sectional and longitudinal quantitative and qualitative assessments of retinal architecture in RPE65-RD using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Twenty-six subjects (mean age, 14.8 years, range, 5-24 years) with RPE65-RD underwent SD-OCT and FAF imaging, of whom 14 subjects were followed up over time. Foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW), and ellipsoid zone area (EZA) were calculated where possible. These were correlated with age, best corrected visual acuity (BCVA), and central 30° retinal sensitivity (V30). Intra-observer agreement, test-retest repeatability, and interocular symmetry were also investigated.

Results: We identified structural interocular symmetry, the presence of autofluorescence in 46% (12/26) of subjects, and the presence of foveal hypoplasia (associated with significantly worse BCVA) in 50% of subjects. EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of eyes, respectively, with both demonstrating good agreement on repeated measurement. The annual rate of progression using EZW was -300.63 µm/year, and -1.17 mm2/year in EZA. EZW was found to have a statistically significant correlation with BCVA and V30.

Conclusions: We identified the presence of autofluorescence in half of our subjects, with foveal hypoplasia also noted in half of our cohort. EZW, and to a lesser extent EZA, were robust measures of retinal degeneration and represent valuable metrics to determine the impact of intervention. (ClinicalTrials.gov number NCT02714816.).
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http://dx.doi.org/10.1167/iovs.61.4.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401957PMC
April 2020

Photoreceptor Structure in GNAT2-Associated Achromatopsia.

Invest Ophthalmol Vis Sci 2020 03;61(3):40

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Purpose: The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic window for potential intervention.

Methods: Patients with GNAT2-ACHM were recruited from a single tertiary referral eye center (Moorfields Eye Hospital, London, UK). We performed longitudinal clinical evaluation and ophthalmic examination, and multimodal retinal imaging, including adaptive optics scanning light ophthalmoscopy, quantitative analysis of the cone mosaic, and outer nuclear layer (ONL) thickness, including cone densities evaluation in selected regions of interest and comparison with reported healthy controls.

Results: All nine subjects (3 women) presented with nystagmus, decreased visual acuity (VA), light sensitivity, and highly variable color vision loss. One patient had normal color vision and better VA. Mean VA was 1.01 (±0.10) logarithms of the minimal angle of resolution (LogMAR) at baseline, and 1.04 (±0.10) LogMAR after a mean follow-up (range) of 7.6 years (1.7-12.8 years). Optical coherence tomography showed preservation of the foveal ellipsoid zone (EZ; n = 8; 88.9%), and EZ disruption (n = 1; 11.1%). Mean ONL thickness (range, ± SD) was 84.72 µm (28.57-113.33, ± 25.46 µm) and 86.47 µm (28.57-113.33, ± 24.65 µm) for right and left eyes, respectively. Mean cone densities (±SD) at 190 µm, 350 µm, and 500 µm from the foveal center, were 48.4 (±24.6), 37.8 (±14.7), and 30.7 (±9.9), ×103 cones/mm2, respectively. Mean cone densities were lower than these of unaffected individuals, but with an overlap.

Conclusions: The cone mosaic in GNAT2-ACHM is relatively well preserved, potentially allowing for a wide therapeutic window for cone-directed interventions.
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http://dx.doi.org/10.1167/iovs.61.3.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401776PMC
March 2020

Interocular Symmetry of Foveal Cone Topography in Congenital Achromatopsia.

Curr Eye Res 2020 10 13;45(10):1257-1264. Epub 2020 Mar 13.

Ophthalmology & Visual Sciences, Medical College of Wisconsin , Milwaukee, Wisconsin, USA.

: To determine the interocular symmetry of foveal cone topography in achromatopsia (ACHM) using non-confocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). : Split-detector AOSLO images of the foveal cone mosaic were acquired from both eyes of 26 subjects (mean age 24.3 years; range 8-44 years, 14 females) with genetically confirmed - or -associated ACHM. Cones were identified within a manually delineated rod-free zone. Peak cone density (PCD) was determined using an 80 × 80 μm sampling window within the rod-free zone. The mean and standard deviation (SD) of inter-cell distance (ICD) were calculated to derive the coefficient of variation (CV). Cone density difference maps were generated to compare cone topography between eyes. : PCD (mean ± SD) was 17,530 ± 9,614 cones/mm and 17,638 ± 9,753 cones/mm for right and left eyes, respectively ( = .677, Wilcoxon test). The mean (± SD) for ICD was 9.05 ± 2.55 µm and 9.24 ± 2.55 µm for right and left eyes, respectively ( = .410, paired -test). The mean (± SD) for CV of ICD was 0.16 ± 0.03 µm and 0.16 ± 0.04 µm for right and left eyes, respectively ( = .562, paired -test). Cone density maps demonstrated that cone topography of the ACHM fovea is non-uniform with local variations in cone density between eyes. : These results demonstrate the interocular symmetry of the foveal cone mosaic (both density and packing) in ACHM. As cone topography can differ between eyes of a subject, PCD does not completely describe the foveal cone mosaic in ACHM. Nonetheless, these findings are of value in longitudinal monitoring of patients during treatment trials and further suggest that both eyes of a given subject may have similar therapeutic potential and non-study eye can be used as a control.
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http://dx.doi.org/10.1080/02713683.2020.1737138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487033PMC
October 2020

Prospective exploratory study to assess the safety and efficacy of aflibercept in cystoid macular oedema associated with retinitis pigmentosa.

Br J Ophthalmol 2020 09 10;104(9):1203-1208. Epub 2020 Feb 10.

UCL Institute of Ophthalmology, University College London, London, UK

Aims: To report the safety and efficacy of intravitreal aflibercept (Eylea) (ivA) for retinitis pigmentosa-associated cystoid macular oedema (RP-CMO) at 12 months via mean central macular thickness (CMT) and reported adverse events.

Methods: A prospective, exploratory, phase II, non-randomised, single-centre, open-label, 1-arm clinical trial involving 30 eyes of 30 patients. Serial ivA was given via loading dose (three injections) followed by treat and extend protocol over 12 months.

Results: Twenty-nine out of 30 (96.7%) patients completed 12 months of follow-up. A total of four to 11 injections per patient were given over the 12 month study. No statistically significant reduction of CMT or visual acuity (VA) improvement was demonstrated in the group overall. Eleven out of 29 (37.9%) participants were considered as 'responders', demonstrating at least an 11% reduction of CMT at 12 months on spectral domain optical coherence tomography compared with baseline. A reduction of CMT by mean (SD) 28.1% (12.9 %) was observed in responders at 12 months, however, no statistically significant corresponding improvement in best corrected VA was seen. Baseline characteristics were similar between responder and non-responder groups. No clinically significant adverse events were deemed secondary to ivA.

Conclusion: This first prospective exploratory study demonstrates both the safety and acceptability of serial ivA in patients with RP-CMO, effective at reducing CMT in 37.9% of patients. All patients demonstrating anatomical response did so after their first injection. Longer duration of CMO did not negatively affect response to anti-VEGF. Further study in a larger cohort of patients with shorter CMO duration would be valuable to better establish the utility of VEGF blockade in RP-CMO.

Trial Registration Numbers: EudraCT (2015-003723-65); ClinicalTrials.gov (NCT02661711).
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http://dx.doi.org/10.1136/bjophthalmol-2019-315152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577098PMC
September 2020

Deep Phenotyping of PDE6C-Associated Achromatopsia.

Invest Ophthalmol Vis Sci 2019 12;60(15):5112-5123

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

Purpose: To perform deep phenotyping of subjects with PDE6C achromatopsia and examine disease natural history.

Methods: Eight subjects with disease-causing variants in PDE6C were assessed in detail, including clinical phenotype, best-corrected visual acuity, fundus autofluorescence, and optical coherence tomography. Six subjects also had confocal and nonconfocal adaptive optics scanning light ophthalmoscopy, axial length, international standard pattern and full-field electroretinography (ERG), short-wavelength flash (S-cone) ERGs, and color vision testing.

Results: All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia. We identified three novel disease-causing variants and provide phenotype data associated with nine variants for the first time. No subjects had foveal hypoplasia or residual ellipsoid zone (EZ) at the foveal center; one had an absent EZ, three had a hyporeflective zone, and four had outer retinal atrophy. The mean width of the central EZ lesion on optical coherence tomography at baseline was 1923 μm. The mean annual increase in EZ lesion size was 48.3 μm. Fundus autofluorescence revealed a central hypoautofluorescence with a surrounding ring of increased signal (n = 5). The mean hypoautofluorescent area at baseline was 3.33 mm2 and increased in size by a mean of 0.13 mm2/year. Nonconfocal adaptive optics scanning light ophthalmoscopy revealed residual foveal cones in only one of two cases. Full-field ERGs were consistent with severe generalized cone system dysfunction but with relative preservation of S-cone sensitivity.

Conclusions: PDE6C retinopathy is a severe cone dysfunction syndrome often presenting as typical achromatopsia but without foveal hypoplasia. Myopia and slowly progressive maculopathy are common features. There are few (if any) residual foveal cones for intervention in older adults.
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http://dx.doi.org/10.1167/iovs.19-27761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905659PMC
December 2019

Prospective Cohort Study of Childhood-Onset Stargardt Disease: Fundus Autofluorescence Imaging, Progression, Comparison with Adult-Onset Disease, and Disease Symmetry.

Am J Ophthalmol 2020 03 6;211:159-175. Epub 2019 Dec 6.

University College London Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom. Electronic address:

Purpose: To determine the reliability and repeatability of quantitative evaluation of areas of decreased autofluorescence (DAF) from fundus autofluorescence (FAF) images and track disease progression in children with Stargardt disease (STGD1), and to investigate clinical and genotype correlations, disease symmetry, and intrafamilial variability.

Design: Prospective cohort study.

Methods: Children and adults with molecularly confirmed STGD1 (n = 90) underwent longitudinal FAF imaging with subsequent semiautomated measurement of the area of DAF and calculation of the annual rate of progression. The age of disease onset was recorded for all subjects, as well as the electroretinography (ERG) group at baseline (n = 86). Patients were grouped for analysis based on the age at baseline and age of onset, into children (n = 56), adults with childhood-onset STGD1 (n = 15), and adults with adult-onset (n = 19). Fifty FAF images were selected randomly and analyzed by 2 observers to evaluate repeatability and reproducibility. Differences between groups, interocular symmetry, genotype-phenotype correlations, and intrafamilial variability were also investigated both for baseline measurements as well as progression rates. We measured visual acuity, molecular genetics, ERG group, FAF metrics, and their correlations.

Results: The mean age of onset ± SD was 9.6 ± 3.4 years for childhood-onset (n = 71) and 28.3 ± 7.8 years for adult-onset STGD1 (n = 19). The intra- and interobserver reliability of DAF quantification was excellent (intraclass correlation coefficients 0.995 and 0.987, respectively). DAF area was symmetric between eyes and the mean rate of progression (SD) was 0.69 (0.72), 0.78 (0.48), and 0.40 (0.36) mm/year for children, adults with childhood-onset, and adults with adult-onset disease, respectively. Patients belonging to a group 3 ERG phenotype (generalized cone and rod dysfunction) had a significantly greater progression rate. Limited intrafamilial variability was observed.

Conclusions: This is the first large prospective study of FAF in a cohort of molecularly confirmed children with STGD1. DAF area quantification was highly reliable and may thereby serve as a robust structural endpoint. A high rate of progression was observed in childhood-onset disease, making this subtype of STGD1 ideally suited to be considered for prioritization in clinical trials.
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http://dx.doi.org/10.1016/j.ajo.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082771PMC
March 2020

Assessing the Interocular Symmetry of Foveal Outer Nuclear Layer Thickness in Achromatopsia.

Transl Vis Sci Technol 2019 Sep 2;8(5):21. Epub 2019 Oct 2.

Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: We examine the interocular symmetry of foveal outer nuclear layer (ONL) thickness measurements in subjects with achromatopsia (ACHM).

Methods: Images from 76 subjects with - or -associated ACHM and 42 control subjects were included in the study. Line or volume scans through the fovea of each eye were acquired using optical coherence tomography (OCT). Image quality was assessed for each image included in the analysis using a previously-described maximum tissue contrast index (mTCI) metric. Three foveal ONL thickness measurements were made by a single observer and interocular symmetry was assessed using the average of the three measurements for each eye.

Results: Mean (± standard deviation) foveal ONL thickness for subjects with ACHM was 79.7 ± 18.3 μm (right eye) and 79.2 ± 18.7 μm (left eye) compared to 112.9 ± 15.2 (right eye) and 112.1 ± 13.9 μm (left eye) for controls. Foveal ONL thickness did not differ between eyes for ACHM ( = 0.636) or control subjects ( = 0.434). No significant relationship between mTCI and observer repeatability was observed for either control ( = 0.140) or ACHM ( = 0.351) images.

Conclusions: While foveal ONL thickness is reduced in ACHM compared to controls, the high interocular symmetry indicates that contralateral ONL measurements could be used as a negative control in early-phase monocular treatment trials.

Translational Relevance: Foveal ONL thickness can be measured using OCT images over a wide range of image quality. The interocular symmetry of foveal ONL thickness in ACHM and control populations supports the use of the non-study eye as a control for clinical trial purposes.
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http://dx.doi.org/10.1167/tvst.8.5.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779097PMC
September 2019

Characterization of Retinal Structure in ATF6-Associated Achromatopsia.

Invest Ophthalmol Vis Sci 2019 06;60(7):2631-2640

Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.

Purpose: Mutations in six genes have been associated with achromatopsia (ACHM): CNGA3, CNGB3, PDE6H, PDE6C, GNAT2, and ATF6. ATF6 is the most recent gene to be identified, though thorough phenotyping of this genetic subtype is lacking. Here, we sought to test the hypothesis that ATF6-associated ACHM is a structurally distinct form of congenital ACHM.

Methods: Seven genetically confirmed subjects from five nonconsanguineous families were recruited. Foveal hypoplasia and the integrity of the ellipsoid zone (EZ) band (a.k.a., IS/OS) were graded from optical coherence tomography (OCT) images. Images of the photoreceptor mosaic were acquired using confocal and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). Parafoveal cone and rod density values were calculated and compared to published normative data as well as data from two subjects harboring CNGA3 or CNGB3 mutations who were recruited for comparative purposes. Additionally, nonconfocal dark-field AOSLO images of the retinal pigment epithelium were obtained, with quantitative analysis performed in one subject with ATF6-ACHM.

Results: Foveal hypoplasia was observed in all subjects with ATF6 mutations. Absence of the EZ band within the foveal region (grade 3) or appearance of a hyporeflective zone (grade 4) was seen in all subjects with ATF6 using OCT. There was no evidence of remnant foveal cone structure using confocal AOSLO, although sporadic cone-like structures were seen in nonconfocal split-detection AOSLO. There was a lack of cone structure in the parafovea, in direct contrast to previous reports.

Conclusions: Our data demonstrate a near absence of cone structure in subjects harboring ATF6 mutations. This implicates ATF6 as having a major role in cone development and suggests that at least a subset of subjects with ATF6-ACHM have markedly fewer cellular targets for cone-directed gene therapies than do subjects with CNGA3- or CNGB3-ACHM.
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http://dx.doi.org/10.1167/iovs.19-27047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594318PMC
June 2019

Cross-Sectional and Longitudinal Assessment of the Ellipsoid Zone in Childhood-Onset Stargardt Disease.

Transl Vis Sci Technol 2019 Mar 1;8(2). Epub 2019 Mar 1.

UCL Institute of Ophthalmology, University College London, London, UK.

Purpose: To evaluate the reliability of ellipsoid zone (EZ) loss width and area measurements from spectral-domain optical coherence tomography (SD-OCT) images and track disease progression in childhood-onset Stargardt disease (STGD1).

Methods: Children with molecularly confirmed STGD1 ( = 46, mean age 12.4 years) underwent SD-OCT for the measurement of the transverse (width) loss of the EZ and en face analysis to quantify the area of EZ loss. All scans were analyzed twice by two graders to evaluate reliability. The annual rate of EZ width and area loss were calculated.

Results: The intra- and intergrader reliability of transverse EZ loss and area of EZ loss measurements at baseline for both graders was 0.99. The mean annual rate of transverse EZ loss (±standard deviation) was 279.5 ± 259.9 μm/y. The mean rate of area of EZ loss (±standard deviation) was 1.20 ± 1.29 mm/y. The percentage transverse EZ loss was 10.2 ± 9.9%/y, which was significantly lower than the area of EZ loss at 19.4 ± 16.3%/y. High degree of interocular symmetry was observed.

Conclusions: This is a prospective study on the quantification of EZ loss in children with STGD1 and highlights the reliability of SD-OCT in measuring EZ loss. High intra- and intergrader reliability was observed, with good ability to detect changes over time.

Translational Relevance: Measuring the area of EZ loss was more sensitive compared with transverse EZ width loss measurements and will be valuable for natural history studies and clinical trials requiring sensitive and reliable structural endpoints.
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http://dx.doi.org/10.1167/tvst.8.2.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397016PMC
March 2019

Adaptive Optics Retinal Imaging in CNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability.

Invest Ophthalmol Vis Sci 2019 01;60(1):383-396

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

Purpose: To investigate retinal structure in subjects with CNGA3-associated achromatopsia and evaluate disease symmetry and intrafamilial variability.

Methods: Thirty-eight molecularly confirmed subjects underwent ocular examination, optical coherence tomography (OCT), and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). OCT scans were used for evaluating foveal hypoplasia, grading foveal ellipsoid zone (EZ) disruption, and measuring outer nuclear layer (ONL) thickness. AOSLO images were used to quantify peak foveal cone density, intercell distance (ICD), and the coefficient of variation (CV) of ICD.

Results: Mean (±SD) age was 25.9 (±13.1) years. Mean (± SD) best corrected visual acuity (BCVA) was 0.87 (±0.14) logarithm of the minimum angle of resolution. Examination with OCT showed variable disruption or loss of the EZ. Seven subjects were evaluated for disease symmetry, with peak foveal cone density, ICD, CV, ONL thickness, and BCVA not differing significantly between eyes. A cross-sectional evaluation of AOSLO imaging showed a mean (±SD) peak foveal cone density of 19,844 (±13,046) cones/mm2. There was a weak negative association between age and peak foveal cone density (r = -0.397, P = 0.102), as well as between EZ grade and age (P = 0.086).

Conclusions: The remnant cone mosaics were irregular and variably disrupted, with significantly lower peak foveal cone density than unaffected individuals. Variability was also seen among subjects with identical mutations. Therefore, subjects should be considered on an individual basis for stratification in clinical trials. Interocular symmetry suggests that both eyes have comparable therapeutic potential and the fellow eye can serve as a valid control. Longitudinal studies are needed, to further examine the weak negative association between age and foveal cone structure observed here.
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http://dx.doi.org/10.1167/iovs.18-25880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354941PMC
January 2019

Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy.

Br J Ophthalmol 2019 Jan 24. Epub 2019 Jan 24.

UCL Institute of Ophthalmology, University College London, London, UK

Progressive cone and cone-rod dystrophies are a clinically and genetically heterogeneous group of inherited retinal diseases characterised by cone photoreceptor degeneration, which may be followed by subsequent rod photoreceptor loss. These disorders typically present with progressive loss of central vision, colour vision disturbance and photophobia. Considerable progress has been made in elucidating the molecular genetics and genotype-phenotype correlations associated with these dystrophies, with mutations in at least 30 genes implicated in this group of disorders. We discuss the genetics, and clinical, psychophysical, electrophysiological and retinal imaging characteristics of cone and cone-rod dystrophies, focusing particularly on four of the most common disease-associated genes: , , and Additionally, we briefly review the current management of these disorders and the prospects for novel therapies.
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http://dx.doi.org/10.1136/bjophthalmol-2018-313278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709772PMC
January 2019

Fast adaptive optics scanning light ophthalmoscope retinal montaging.

Biomed Opt Express 2018 Sep 15;9(9):4317-4328. Epub 2018 Aug 15.

Wellcome/EPSRC Centre for Interventional and Surgical Sciences, University College London, London, UK.

The field of view of high-resolution ophthalmoscopes that require the use of adaptive optics (AO) wavefront correction is limited by the isoplanatic patch of the eye, which varies across individual eyes and with the portion of the pupil used for illumination and/or imaging. Therefore all current AO ophthalmoscopes have small fields of view comparable to, or smaller than, the isoplanatic patch, and the resulting images have to be stitched off-line to create larger montages. These montages are currently assembled either manually, by expert human graders, or automatically, often requiring several hours per montage. This arguably limits the applicability of AO ophthalmoscopy to studies with small cohorts and moreover, prevents the ability to review a real-time captured montage of all locations during image acquisition to further direct targeted imaging. In this work, we propose stitching the images with our novel algorithm, which uses oriented fast rotated brief (ORB) descriptors, local sensitivity hashing, and by searching for a 'good enough' transformation, rather than the best possible, to achieve processing times of 1-2 minutes per montage of 250 images. Moreover, the proposed method produces montages which are as accurate as previous methods, when considering the image similarity metrics: normalised mutual information (NMI), and normalised cross correlation (NCC).
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http://dx.doi.org/10.1364/BOE.9.004317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157757PMC
September 2018

Longitudinal Assessment of Retinal Structure in Achromatopsia Patients With Long-Term Follow-up.

Invest Ophthalmol Vis Sci 2018 12;59(15):5735-5744

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

Purpose: To longitudinally characterize structural retinal changes in achromatopsia (ACHM) over extended follow-up.

Methods: Fifty molecularly confirmed ACHM subjects underwent serial spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Foveal structure on SD-OCT was graded and compared for evidence of progression, and foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness were serially measured. FAF patterns were characterized and compared over time.

Results: Mean SD-OCT follow-up was 61.6 months (age range at baseline, 6-52 years). Forty-five of the subjects had serial FAF (mean follow-up: 48.5 months). Only 6 (12%) of the subjects demonstrated qualitative change on serial foveal SD-OCT scans. Among the entire cohort, there was no statistically significant change over time in FTRT (P = 0.2459) or hyporeflective zone (HRZ) diameter (P = 0.3737). There was a small-but statistically significant-increase in ONL thickness (P = 0.0084). Three different FAF patterns were observed: centrally increased FAF (13/45), normal FAF (14/45), and well-demarcated reduced FAF (18/45), with the latter group displaying a small gradual increase in the area of reduced FAF of 0.055 mm2 over 43.4 months (P = 0.0011).

Conclusions: This longitudinal study of retinal structure in ACHM represents the largest cohort and longest follow-up period to date. Our findings support the presiding notion that ACHM is essentially a stationary condition regarding retinal structure, and any change over time is likely to be small, slow, and variable across patients. This may potentially afford a wider window for therapeutic intervention.
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http://dx.doi.org/10.1167/iovs.18-25452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280917PMC
December 2018

Cross-Sectional and Longitudinal Assessment of Retinal Sensitivity in Patients With Childhood-Onset Stargardt Disease.

Transl Vis Sci Technol 2018 Nov 27;7(6):10. Epub 2018 Nov 27.

UCL Institute of Ophthalmology, University College London, London, UK.

Purpose: We assess cross-sectional and longitudinal microperimetry and full-field static perimetry-derived retinal sensitivity with conventional and volumetric indices of retinal function in childhood-onset Stargardt disease (STGD1).

Methods: Subjects with molecularly confirmed childhood-onset STGD1 underwent full-field static perimetry and/or microperimetry using custom designed grids. Mean sensitivity (MS) and total volume (V) were computed for each microperimetry test. MS, V, and central field volume (V) were computed for each full-field static perimetry test. Subjects under 18 years old at baseline were classified as children and subjects 18 years or older as adults.

Results: A total of 43 children (mean age at baseline, 13.0 years; range, 8-17) and 13 adults (mean age at baseline, 23.1 years; range, 18-32) were included in the analysis. For full-field static perimetry and microperimetry for both subgroups, intraclass correlation coefficient results for MS and volumetric indices were good to excellent, indicating strong test-retest reliability. Interocular symmetry in terms of baseline measurements and the annual rate of progression was observed. A greater rate of progression was observed in childhood.

Conclusions: To our knowledge, this is the first prospective study of retinal sensitivity in a large cohort of molecularly confirmed subjects with childhood-onset STGD1 demonstrating that children with STGD1 can reliably undertake detailed functional testing. Moreover, using custom designed grids and subsequent topographic analysis, volumetric indices of retinal function provide a reliable measure of retinal sensitivity.

Translational Relevance: This study highlights the use of microperimetry and full-field static perimetry, as well as volumetric indices of retinal function, in monitoring disease progression.
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http://dx.doi.org/10.1167/tvst.7.6.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262645PMC
November 2018

Natural History Study of Retinal Structure, Progression, and Symmetry Using Ellipzoid Zone Metrics in RPGR-Associated Retinopathy.

Am J Ophthalmol 2019 02 9;198:111-123. Epub 2018 Oct 9.

University College London Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom. Electronic address:

Purpose: This is a quantitative study of retinal structure, progression rates, and interocular symmetry in retinitis pigmentosa GTPase regulator gene (RPGR)-associated retinopathy using spectral-domain optical coherence tomography (OCT).

Design: Prospective, observational cohort study.

Methods: Thirty-eight subjects at Moorfields Eye Hospital in London were assessed with 2 spectral-domain OCT-derived ellipzoid zone (EZ) metrics with repeatability assessments. EZ width (EZW) measurements were made on transfoveal line scans. En face images of the EZ area (EZA) were generated from high-density macular volume scans and were quantified. Baseline size, progression rate, symmetry, associations with age and genotype, and baseline structure-function correlation were investigated.

Results: Baseline EZW and EZA measurements were 1963.6 μm and 3.70 mm, respectively. The mean EZW progression rate was 233.6 μm per year, and the mean EZA rate was 0.67 mm per year. Relative interocular difference as an index of symmetry was 3% for both metrics, indicating good baseline symmetry in general-although significant variation existed across the cohort. Analysis of variance found a significant effect of age but not genotype on EZ dimension and progression rates. Larger EZ dimension and greater progression were seen in younger subjects. A positive correlation between EZ dimension and progression was evident. Overall exponential decline rates of 8.2% with EZW and 15.5% with EZA were obtained. Good functional correlation was found with EZW demonstrating stronger correlation; however, EZA correlation with function was also significant.

Conclusions: EZ metrics are sensitive structural biomarkers for measuring residual extent and progression in RPGR-associated retinopathy. Our elucidation of the natural history will provide clinicians and patients with more knowledge about the condition and inform the design and interpretation of interventional trials.
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http://dx.doi.org/10.1016/j.ajo.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355316PMC
February 2019

Residual Cone Structure in Patients With X-Linked Cone Opsin Mutations.

Invest Ophthalmol Vis Sci 2018 08;59(10):4238-4248

University College London Institute of Ophthalmology, London, United Kingdom.

Purpose: To assess residual cone structure in subjects with mutations in exon 2, 3, and 4 of the OPN1LW or OPN1MW opsin.

Methods: Thirteen males had their OPN1LW/OPN1MW opsin genes characterized. The cone mosaic was imaged using both confocal and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO), and retinal thickness was evaluated using optical coherence tomography (OCT). Six subjects completed serial imaging over a maximum period of 18 months and cone density was measured across imaging sessions.

Results: Ten subjects had an OPN1LW/OPN1MW "interchange" opsin mutation designated as LIAVA or LVAVA, which both introduce exon 3 splicing defects leading to a lack of functional photopigment in cones expressing LIAVA and greatly reduced functional photopigment in cones expressing LVAVA. Despite disrupted cone reflectivity and reduced numerosity, residual inner segments could be visualized. Similar patterns were observed in individuals with an exon 2 insertion, or an exon 4 splice defect, both of which are also expected to produce cones that are devoid of functional opsin protein. OCT revealed variably reduced retinal thickness. A significant inverse relationship was found between the proportion of waveguiding cones and axial length.

Conclusions: Split-detection imaging revealed that the altered appearance of the cone mosaic in confocal images for subjects with exon 2, 3, and 4 mutations was generally due to disrupted waveguiding, rather than structural loss, making them possible candidates for gene therapy to restore cone function. The relative fraction of waveguiding cones was highly variable across subjects, which appears to influence emmetropization in these subjects.
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http://dx.doi.org/10.1167/iovs.18-24699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103386PMC
August 2018

A Cross-Sectional and Longitudinal Study of Retinal Sensitivity in RPE65-Associated Leber Congenital Amaurosis.

Invest Ophthalmol Vis Sci 2018 07;59(8):3330-3339

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

Purpose: RPE65-associated Leber congenital amaurosis (RPE65-LCA) is an early-onset severe retinal dystrophy associated with progressive visual field loss. Phase I/II and III gene therapy trials have identified improved retinal sensitivity but little is known about the natural history of retinal sensitivity in RPE65-LCA.

Methods: A total of 19 subjects (aged 9 to 23 years) undertook monocular full-field static perimetry of which 13 subjects were monitored longitudinally. Retinal sensitivity was measured as mean sensitivity (MS) and volumetrically quantified (in decibel-steradian) using visual field modeling and analysis software for the total (VTOT), central 30° (V30) and central 15° (V15) visual field. Correlation was evaluated between retinal sensitivity and age, best-corrected visual acuity (BCVA), contrast sensitivity, vision-related quality of life, and genotype. Test-retest reliability was also investigated.

Results: V30 was identified to have a strong, weak, and moderate correlation with age, BCVA and contrast sensitivity respectively. Furthermore, V30 was identified as having a weak linear relationship with the mobility and independence domains of the vision-related quality of life questionnaire. Longitudinal analysis demonstrated a slow loss of retinal sensitivity in this cohort. Subjects with at least one RPE65 nonsense variant appeared to show greater progressive loss of retinal sensitivity in the second decade of life than those without.

Conclusions: Volumetric assessment of central 30° visual field sensitivity, V30, is a useful independent measure of retinal function and, in our data, represented the best metric to monitor deterioration of retinal sensitivity in RPE65-LCA. Furthermore, functional correlation with genotype may enable more informed prognostic counseling. (ClinicalTrials.gov number, NCT02714816.)
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http://dx.doi.org/10.1167/iovs.18-23873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040235PMC
July 2018

Characterization of Visual Function, Interocular Variability and Progression Using Static Perimetry-Derived Metrics in RPGR-Associated Retinopathy.

Invest Ophthalmol Vis Sci 2018 05;59(6):2422-2436

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

Purpose: To characterize bilateral visual function, interocular variability and progression by using static perimetry-derived volumetric and pointwise metrics in subjects with retinitis pigmentosa associated with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene.

Methods: This was a prospective longitudinal observational study of 47 genetically confirmed subjects. Visual function was assessed with ETDRS and Pelli-Robson charts; and Octopus 900 static perimetry using a customized, radially oriented 185-point grid. Three-dimensional hill-of-vision topographic models were produced and interrogated with the Visual Field Modeling and Analysis software to obtain three volumetric metrics: VTotal, V30, and V5. These were analyzed together with Octopus mean sensitivity values. Interocular differences were assessed with the Bland-Altman method. Metric-specific exponential decline rates were calculated.

Results: Baseline symmetry was demonstrated by relative interocular difference values of 1% for VTotal and 8% with V30. Degree of symmetry varied between subjects and was quantified with the subject percentage interocular difference (SPID). SPID was 16% for VTotal and 17% for V30. Interocular symmetry in progression was greatest when quantified by VTotal and V30, with 73% and 64% of subjects possessing interocular rate differences smaller in magnitude than respective annual progression rates. Functional decline was evident with increasing age. An overall annual exponential decline of 6% was evident with both VTotal and V30.

Conclusions: In general, good interocular symmetry exists; however, there was both variation between subjects and with the use of various metrics. Our findings will guide patient selection and design of RPGR treatment trials, and provide clinicians with specific prognostic information to offer patients affected by this condition.
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http://dx.doi.org/10.1167/iovs.17-23739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947973PMC
May 2018

Automatic Cone Photoreceptor Localisation in Healthy and Stargardt Afflicted Retinas Using Deep Learning.

Sci Rep 2018 05 21;8(1):7911. Epub 2018 May 21.

Welcome/EPSRC Centre for Interventional and Surgical Sciences, London, UCL, UK.

We present a robust deep learning framework for the automatic localisation of cone photoreceptor cells in Adaptive Optics Scanning Light Ophthalmoscope (AOSLO) split-detection images. Monitoring cone photoreceptors with AOSLO imaging grants an excellent view into retinal structure and health, provides new perspectives into well known pathologies, and allows clinicians to monitor the effectiveness of experimental treatments. The MultiDimensional Recurrent Neural Network (MDRNN) approach developed in this paper is the first method capable of reliably and automatically identifying cones in both healthy retinas and retinas afflicted with Stargardt disease. Therefore, it represents a leap forward in the computational image processing of AOSLO images, and can provide clinical support in on-going longitudinal studies of disease progression and therapy. We validate our method using images from healthy subjects and subjects with the inherited retinal pathology Stargardt disease, which significantly alters image quality and cone density. We conduct a thorough comparison of our method with current state-of-the-art methods, and demonstrate that the proposed approach is both more accurate and appreciably faster in localizing cones. As further validation to the method's robustness, we demonstrate it can be successfully applied to images of retinas with pathologies not present in the training data: achromatopsia, and retinitis pigmentosa.
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http://dx.doi.org/10.1038/s41598-018-26350-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962538PMC
May 2018

Retrospective cohort study exploring whether an association exists between spatial distribution of cystoid spaces in cystoid macular oedema secondary to retinitis pigmentosa and response to treatment with carbonic anhydrase inhibitors.

Br J Ophthalmol 2019 02 29;103(2):233-237. Epub 2018 Apr 29.

UCL Institute of Ophthalmology, University College London, London, UK

Background: Carbonic anhydrase inhibitors (CAIs) are frequently used as an initial step to treat retinitis pigmentosa-associated cystoid macular oedema (RP-CMO). Interestingly, it has been postulated that CAIs might reduce outer nuclear layer (ONL) fluid more effectively than inner nuclear layer (INL) fluid due to better access to retinal pigment epithelium basolateral membrane than neurosensory retina. This retrospective cohort study explores if an association between spatial distribution of cystoid spaces in RP-CMO and CAI response exists.

Methods: Two independent graders reviewed pretreatment and post-treatment optical coherence tomography (OCT) images of 25 patients (43 eyes) initiated on topical and/or oral CAIs between January 2013 and December 2014. Documentation included the presence/absence of fluid (and layer(s) involved), external limiting membrane, epiretinal membrane (ERM), vitreomacular adhesion/traction, lamellar/full-thickness macular hole and central macular thickness (CMT)/volume.

Results: INL fluid was found in all study eyes. All 13 'responders' (at least 11% reduction of CMT after treatment) demonstrated pretreatment ONL fluid. In seven patients (four responders and three non-responders), complete clearance of ONL fluid was achieved despite persistence of INL fluid. ERM presence was similar in responders and non-responders.

Conclusion: In this study, INL fluid was found to be the most common spatial distribution of RP-CMO. However, patients who were classed as a 'responder' to CAI treatment all demonstrated coexisting ONL fluid on their pretreatment OCT scans. This may be explained by CAIs having better access to retinal pigment epithelium basolateral membrane than neurosensory retina. Our study also suggests a minimal impact on response to CAIs by ERM.
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http://dx.doi.org/10.1136/bjophthalmol-2017-311392DOI Listing
February 2019

Severe Loss of Tritan Color Discrimination in RPE65 Associated Leber Congenital Amaurosis.

Invest Ophthalmol Vis Sci 2018 01;59(1):85-93

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

Purpose: RPE65-associated Leber congenital amaurosis (RPE65-LCA) is a progressive severe retinal dystrophy with early profound dysfunction of rod photoreceptors followed by progressive cone photoreceptor degeneration. We aim to provide detailed information about how cone dysfunction affects color discrimination.

Methods: Seven adults (aged 16-21) with RPE65-LCA underwent monocular color discrimination assessment using the Trivector and Ellipse versions of three computerized tests: Cambridge Colour Test (CCT), low vision version of the Cambridge Colour Test (lvvCCT), and the Universal Colour Discrimination Test (UCDT). For comparison, subjects were also tested using the American Optical Hardy Rand Rittler (AO-HRR) plates. Each assessment was repeated three times.

Results: The Trivector version of the tests demonstrated that color discrimination along the tritan axis was undetectable in four subjects, and severely reduced in three subjects. These findings were confirmed by the Ellipse version of the tests. Color discrimination along the protan and deutan axes was evident but reduced in six of seven subjects. Four of seven subjects were unable to read any of the HRR plates.

Conclusions: The computerized color vision tests adopted in this study provide detailed information about color discrimination in adult RPE65-LCA patients. The condition is associated with severe impairment of color discrimination, particularly along the tritan axis indicating possible early involvement of S-cones, with additional protan and deutan loss to a lesser extent. This psychophysical assessment strategy is likely to be valuable in measuring the impact of therapeutic intervention on cone function.
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http://dx.doi.org/10.1167/iovs.17-22905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769497PMC
January 2018

Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy.

Ophthalmology 2018 05 6;125(5):735-746. Epub 2018 Jan 6.

Department of Genetics, University College London Institute of Ophthalmology, University College London, London, United Kingdom; Medical Retina Service, Moorfields Eye Hospital, London, United Kingdom. Electronic address:

Purpose: To describe the earliest features of ABCA4-associated retinopathy.

Design: Case series.

Participants: Children with a clinical and molecular diagnosis of ABCA4-associated retinopathy without evidence of macular atrophy.

Methods: The retinal phenotype was characterized by color fundus photography, OCT, fundus autofluorescence (FAF) imaging, electroretinography, and in 2 patients, adaptive optics scanning laser ophthalmoscopy (AOSLO). Sequencing of the ABCA4 gene was performed in all patients.

Main Outcome Measures: Visual acuity, OCT, FAF, electroretinography, and AOSLO results.

Results: Eight children with ABCA4-associated retinopathy without macular atrophy were identified. Biallelic variants in ABCA4 were identified in all patients. Four children were asymptomatic, and 4 reported loss of VA. Patients were young (median age, 8.5 years; interquartile range, 6.8 years) with good visual acuity (median, 0.155 logarithm of the minimum angle of resolution [logMAR]; interquartile range, 0.29 logMAR). At presentation, the macula appeared normal (n = 3), had a subtly altered foveal reflex (n = 4), or demonstrated manifest fine yellow dots (n = 1). Fundus autofluorescence identified hyperautofluorescent dots in the central macula in 3 patients, 2 of whom showed a normal fundus appearance. Only 1 child had widespread hyperautofluorescent retinal flecks at presentation. OCT imaging identified hyperreflectivity at the base of the outer nuclear layer in all 8 patients. Where loss of outer nuclear volume was evident, this appeared to occur preferentially at a perifoveal locus. Longitudinal split-detector AOSLO imaging in 2 individuals confirmed that the greatest change in cone spacing occurred in the perifoveal, and not foveolar, photoreceptors. Electroretinography showed a reduced B-wave-to-A-wave ratio in 3 of 5 patients tested; in 2 children, recordings clearly showed electronegative results.

Conclusions: In childhood-onset ABCA4-associated retinopathy, the earliest stages of macular atrophy involve the parafovea and spare the foveola. In some cases, these changes are predated by tiny, foveal, yellow, hyperautofluorescent dots. Hyperreflectivity at the base of the outer nuclear layer, previously described as thickening of the external limiting membrane, is likely to represent a structural change at the level of the foveal cone nuclei. Electroretinography suggests that the initial site of retinal dysfunction may occur after phototransduction.
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http://dx.doi.org/10.1016/j.ophtha.2017.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917070PMC
May 2018

CELLULAR IMAGING OF THE TAPETAL-LIKE REFLEX IN CARRIERS OF RPGR-ASSOCIATED RETINOPATHY.

Retina 2019 Mar;39(3):570-580

Moorfields Eye Hospital, London, United Kingdom.

Purpose: To examine the features of the tapetal-like reflex (TLR) in female carriers of RPGR-associated retinopathy by means of adaptive optics scanning light ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography.

Methods: Nine molecularly confirmed RPGR carriers and three healthy controls underwent ocular examination and the following retinal imaging modalities: color photography, near-infrared reflectance, fundus autofluorescence, spectral domain optical coherence tomography, and AOSLO. After identifying TLR areas across all imaging modalities, normalized local contrast of outer retinal bands on spectral domain optical coherence tomography was calculated and AOSLO-acquired photoreceptor mosaic analysis was performed.

Results: Seven carriers had TLR areas, which colocalized with increased rod photoreceptor reflectivity on confocal AOSLO and reduced cone photoreceptor densities. Parafoveal TLR areas also exhibited reduced local contrast (i.e., increased reflectivity) of the outer retinal bands on spectral domain optical coherence tomography (inner segment ellipsoid zone and outer segment interdigitation zone). Healthy controls did not show TLR.

Conclusion: The cellular resolution provided by AOSLO affords the characterization of the photoreceptor mosaic in RPGR carriers with a TLR. Features revealed include reduced cone density, increased cone inner segment diameter, and increased rod outer segment reflectivity.
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http://dx.doi.org/10.1097/IAE.0000000000001965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963958PMC
March 2019

Adaptive optics imaging of inherited retinal diseases.

Br J Ophthalmol 2018 08 15;102(8):1028-1035. Epub 2017 Nov 15.

UCL Institute of Ophthalmology, University College London, London, UK.

Adaptive optics (AO) ophthalmoscopy allows for non-invasive retinal phenotyping on a microscopic scale, thereby helping to improve our understanding of retinal diseases. An increasing number of natural history studies and ongoing/planned interventional clinical trials exploit AO ophthalmoscopy both for participant selection, stratification and monitoring treatment safety and efficacy. In this review, we briefly discuss the evolution of AO ophthalmoscopy, recent developments and its application to a broad range of inherited retinal diseases, including Stargardt disease, retinitis pigmentosa and achromatopsia. Finally, we describe the impact of this microscopic imaging on our understanding of disease pathogenesis, clinical trial design and outcome metrics, while recognising the limitation of the small cohorts reported to date.
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http://dx.doi.org/10.1136/bjophthalmol-2017-311328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059037PMC
August 2018
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