Faster Sensitivity Loss around Dense Scotomas than for Overall Macular Sensitivity in Stargardt Disease: ProgStar Report No. 14

Purpose: Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS. Design: Multicenter, international, prospective cohort study: ProgStar Study. Methods: Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS). Results: Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (β = −1.33; P < .001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (β = .09; P = .461). Conclusions: In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts

Optical Coherence Tomography in the UK Biobank Study – Rapid Automated Analysis of Retinal Thickness for Large Population-Based Studies

Purpose: To describe an approach to the use of optical coherence tomography (OCT) imaging in large, population-based studies, including methods for OCT image acquisition, storage, and the remote, rapid, automated analysis of retinal thickness. Methods: In UK Biobank, OCT images were acquired between 2009 and 2010 using a commercially available “spectral domain” OCT device (3D OCT-1000, Topcon). Images were obtained using a raster scan protocol, 6 mm x 6 mm in area, and consisting of 128 B-scans. OCT image sets were stored on UK Biobank servers in a central repository, adjacent to high performance computers. Rapid, automated analysis of retinal thickness was performed using custom image segmentation software developed by the Topcon Advanced Biomedical Imaging Laboratory (TABIL). This software employs dual-scale gradient information to allow for automated segmentation of nine intraretinal boundaries in a rapid fashion. Results: 67,321 participants (134,642 eyes) in UK Biobank underwent OCT imaging of both eyes as part of the ocular module. 134,611 images were successfully processed with 31 images failing segmentation analysis due to corrupted OCT files or withdrawal of subject consent for UKBB study participation. Average time taken to call up an image from the database and complete segmentation analysis was approximately 120 seconds per data set per login, and analysis of the entire dataset was completed in approximately 28 days. Conclusions: We report an approach to the rapid, automated measurement of retinal thickness from nearly 140,000 OCT image sets from the UK Biobank. In the near future, these measurements will be publically available for utilization by researchers around the world, and thus for correlation with the wealth of other data collected in UK Biobank. The automated analysis approaches we describe may be of utility for future large population-based epidemiological studies, clinical trials, and screening programs that employ OCT imaging

Calcified nodules in retinal drusen are associated with disease progression in age-related macular degeneration

Drusen are lipid-, mineral-, and protein-containing extracellular deposits that accumulate between the basal lamina of the retinal pigment epithelium (RPE) and Bruch’s membrane (BrM) of the human eye. They are a defining feature of age-related macular degeneration (AMD), a common sight-threatening disease of older adults. The appearance of heterogeneous internal reflectivity within drusen (HIRD) on optical coherence tomography (OCT) images has been suggested to indicate an increased risk of progression to advanced AMD. Here, in a cohort of patients with AMD and drusen, we show that HIRD indicated an increased risk of developing advanced AMD within 1 year. Using multimodal imaging in an independent cohort, we demonstrate that progression to AMD was associated with increasing degeneration of the RPE overlying HIRD. Morphological analysis of clinically imaged cadaveric human eye samples revealed that HIRD was formed by multilobular nodules. Nanoanalytical methods showed that nodules were composed of hydroxyapatite and that they differed from spherules and BrM plaques, other refractile features also found in the retinas of patients with AMD. These findings suggest that hydroxyapatite nodules may be indicators of progression to advanced AMD and that using multimodal clinical imaging to determine the composition of macular calcifications may help to direct therapeutic strategies and outcome measures in AMD

SDOCT Imaging to Identify Macular Pathology in Patients Diagnosed with Diabetic Maculopathy by a Digital Photographic Retinal Screening Programme

INTRODUCTION: Diabetic macular edema (DME) is an important cause of vision loss. England has a national systematic photographic retinal screening programme to identify patients with diabetic eye disease. Grading retinal photographs according to this national protocol identifies surrogate markers for DME. We audited a care pathway using a spectral-domain optical coherence tomography (SDOCT) clinic to identify macular pathology in this subset of patients. METHODS: A prospective audit was performed of patients referred from screening with mild to moderate non-proliferative diabetic retinopathy (R1) and surrogate markers for diabetic macular edema (M1) attending an SDOCT clinic. The SDOCT images were graded by an ophthalmologist as SDOCT positive, borderline or negative. SDOCT positive patients were referred to the medical retina clinic. SDOCT negative and borderline patients were further reviewed in the SDOCT clinic in 6 months. RESULTS: From a registered screening population of 17 551 patients with diabetes mellitus, 311 patients met the inclusion criteria between (March 2008 and September 2009). We analyzed images from 311 patients' SDOCT clinic episodes. There were 131 SDOCT negative and 12 borderline patients booked for revisit in the OCT clinic. Twenty-four were referred back to photographic screening for a variety of reasons. A total of 144 were referred to ophthalmology with OCT evidence of definite macular pathology requiring review by an ophthalmologist. DISCUSSION: This analysis shows that patients with diabetes, mild to moderate non-proliferative diabetic retinopathy (R1) and evidence of diabetic maculopathy on non-stereoscopic retinal photographs (M1) have a 42.1% chance of having no macular edema on SDOCT imaging as defined by standard OCT definitions of DME when graded by a retinal specialist. SDOCT imaging is a useful adjunct to colour fundus photography in screening for referable diabetic maculopathy in our screening population

The effect of incorrect scanning distance on boundary detection errors and macular thickness measurements by spectral domain optical coherence tomography: a cross sectional study

BACKGROUND: To investigate the influence of scan distance on retinal boundary detection errors (RBDEs) and retinal thickness measurements by spectral domain optical coherence tomography (SD-OCT). METHODS: 10 eyes of healthy subjects, 10 eyes with diabetic macular edema (DME) and 10 eyes with neovascular age-related macular degeneration (AMD) were examined with RTVue SD-OCT. The MM5 protocol was used in two consecutive sessions to scan the macula. For the first session, the device was set 3.5 cm from the eye in order to obtain detectable signal with low fundus image quality (suboptimal setting) while in the second session a distance of 2.5 cm was set with a good quality fundus image. The signal strength (SSI) value was recorded. The score for retinal boundary detection errors (RBDE) was calculated for ten scans of each examination. RBDE scores were recorded for the whole scan and also for the peripheral 1.0 mm region. RBDE scores, regional retinal thickness values and SSI values between the two sessions were compared. The correlation between SSI and the number of RBDEs was also examined. RESULTS: The SSI was significantly lower with suboptimal settings compared to optimal settings (63.9+/-12.0 vs. 68.3+/-12.2, respectively, p = 0.001) and the number of RBDEs was significantly higher with suboptimal settings in the "all-eyes" group along with the group of healthy subjects and eyes with DME (9.1+/-6.5 vs. 6.8+/-6.3, p = 0.007; 4.4+/-2.6 vs. 2.5+/-1.6, p = 0.035 and 9.7+/-3.3 vs. 5.1+/-3.7, p = 0.008, respectively). For these groups, significant negative correlation was found between the SSI and the number of RBDEs. In the AMD group, the number of RBDEs was markedly higher compared to the other groups and there was no difference in RBDEs between optimal and suboptimal settings with the errors being independent of the SSI. There were significantly less peripheral RBDEs with optimal settings in the "all-eyes" group and the DME subgroup (2.7+/-2.6 vs. 4.2+/-2.8, p = 0.001 and 1.4+/-1.7 vs. 4.1+/-2.2, p = 0.007, respectively). Retinal thickness in the two settings was significantly different only in the outer-superior region in DME. CONCLUSIONS: Optimal distance settings improve SD-OCT SSI with a decrease in RBDEs while retinal thickness measurements are independent of scanning distance

Investigating Tissue Optical Properties and Texture Descriptors of the Retina in Patients with Multiple Sclerosis

PURPOSE: To assess the differences in texture descriptors and optical properties of retinal tissue layers in patients with multiple sclerosis (MS) and to evaluate their usefulness in the detection of neurodegenerative changes using optical coherence tomography (OCT) image segmentation. PATIENTS AND METHODS: 38 patients with MS were examined using Stratus OCT. The raw macular OCT data were exported and processed using OCTRIMA software. The enrolled eyes were divided into two groups, based on the presence of optic neuritis (ON) in the history (MSON+ group, n = 36 and MSON- group, n = 31). Data of 29 eyes of 24 healthy subjects (H) were used as controls. A total of seven intraretinal layers were segmented and thickness as well as optical parameters such as contrast, fractal dimension, layer index and total reflectance were measured. Mixed-model ANOVA analysis was used for statistical comparisons. RESULTS: Significant thinning of the retinal nerve fiber layer (RNFL), ganglion cell/inner plexiform layer complex (GCL+IPL) and ganglion cell complex (GCC, RNFL+GCL+IPL) was observed between study groups in all comparisons. Significant difference was found in contrast in the RNFL, GCL+IPL, GCC, inner nuclear layer (INL) and outer plexiform layer when comparing MSON+ to the other groups. Higher fractal dimension values were observed in GCL+IPL and INL layers when comparing H vs. MSON+ groups. A significant difference was found in layer index in the RNFL, GCL+IPL and GCC layers in all comparisons. A significant difference was observed in total reflectance in the RNFL, GCL+IPL and GCC layers between the three examination groups. CONCLUSION: Texture and optical properties of the retinal tissue undergo pronounced changes in MS even without optic neuritis. Our results may help to further improve the diagnostic efficacy of OCT in MS and neurodegeneration

Anti-vascular endothelial growth factor therapy for the treatment of myopic choroidal neovascularization

Colin S Tan,1,2 SriniVas R Sadda3 1National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore; 2Fundus Image Reading Center, National Healthcare Group Eye Institute, Singapore; 3Doheny Eye Institute, University of California Los Angeles, CA, USA Abstract: Myopic choroidal neovascularization (CNV) is a sight-threatening condition which occurs in eyes with myopia, particularly in those with pathologic myopia. It is the most common cause of CNV among patients younger than 50 years. Hemorrhage and exudation from the CNV lesion may eventually result in scarring or chorioretinal atrophy. While myopic CNV was previously treated with focal laser photocoagulation or photodynamic therapy (PDT), the current treatment of choice is anti-vascular endothelial growth factor (VEGF) agents. Many studies have demonstrated the efficacy of intravitreal anti-VEGF agents in the treatment of myopic CNV. The RADIANCE study reported that intravitreal ranibizumab was superior to PDT in eyes with myopic CNV (at 3 months, both groups receiving intravitreal ranibizumab gained 10.5 and 10.6 letters vs 2.2 letters among patients receiving PDT). In addition, the study demonstrated similar visual outcomes in eyes treated on the basis of visual acuity stabilization or disease activity criteria. Other clinical studies have provided evidence for the efficacy of ranibizumab and aflibercept in the treatment of myopic CNV. This review addresses the epidemiology, pathophysiology, and imaging characteristics of myopic CNV, and discusses the evidence for the efficacy of anti-VEGF agents as compared to laser photocoagulation and PDT. Keywords: myopic choroidal neovascularization, ranibizumab, anti-vascular endothelial growth facto

Retinal vein occlusion and macular edema &amp;ndash; critical evaluation of the clinical value of ranibizumab

Pearse A Keane1, Srinivas R Sadda21NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK; 2Doheny Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USAAbstract: Retinal vein occlusions (RVOs) constitute the second most common cause of retinal vascular disease after diabetic retinopathy, with a prevalence of between 1% and 2% in persons older than 40 years of age. Despite the existence of numerous potential therapeutic options, none is entirely satisfactory, and many patients with RVO suffer irreversible visual loss. Fortunately however, the recent introduction of antivascular endothelial growth factor (VEGF) agents, such as ranibizumab (Lucentis&amp;reg;, Genentech, South San Francisco, CA) and bevacizumab (Avastin&amp;reg;, Genentech), offers a potentially new treatment approach for clinicians managing this disorder. The results of the BRAVO and CRUISE trials have provided the first definitive evidence for the efficacy and safety of ranibizumab in the treatment of RVO. As a result, ranibizumab has recently been approved by the US Food and Drug Administration for the treatment of RVO-associated macular edema. In this review, we provide a critical evaluation of clinical trial data for the safety and efficacy of ranibizumab, and address unresolved issues in the management of this disorder. Keywords: ranibizumab, retinal vein occlusion, vascular endothelial growth factor, macular edem