Sandra Liakopoulos

Evaluation of Age-related Macular Degeneration With Optical Coherence Tomography

Age-related macular degeneration (AMD) is the leading cause of severe visual loss in people aged 50 years or older in the developed world. In recent years, major advances have been made in the treatment of AMD, with the introduction of anti-angiogenic agents, offering the first hope of significant visual recovery for patients with neovascular AMD. In line with these advances, a new imaging modality-optical coherence tomography (OCT)-has emerged as an essential adjunct for the diagnosis and monitoring of patients with AMD. The ability to accurately interpret OCT images is thus a prerequisite for both retina specialists and comprehensive ophthalmologists. Despite this, the relatively recent introduction of OCT and the absence of formal training, coupled with rapid evolution of the technology, may make such interpretation difficult. These problems are compounded by the phenotypically heterogeneous nature of AMD and its complex morphology as visualized using OCT. We address these issues by summarizing the current understanding of OCT image interpretation in patients with AMD and describe how OCT can best be applied in clinical practice.

A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration

Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10−7). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10−10, resulting in OR = 3.65 and P = 8.8 × 10−16 for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.

Accuracy of retinal thickness measurements obtained with Cirrus optical coherence tomography

Aim: To report the frequency and severity of retinal thickness measurement errors in a Fourier domain optical coherence tomography (FDOCT) device, Cirrus OCT. Methods: Data from 209 eyes undergoing Cirrus OCT imaging with the Macular Cube protocol were collected. For each eye, the position of the automated retinal boundary lines used by the Cirrus OCT software for thickness calculations was assessed using a 6-point categorical scale. The presence of errors was correlated with various parameters including: retinal morphological features and disease diagnosis. Results: Errors of retinal boundary detection were observed in 57.5% of eyes but were severe in only 9.6% of eyes. The identification of subretinal fluid, subretinal tissue, pigment epithelium detachment or a diagnosis of choroidal neovascularisation was associated with more severe errors. Retinal cysts or a diagnosis of retinal vascular disease were less likely to be associated with significant error. Conclusions: Retinal thickness measurement errors appear to occur less frequently with Fourier domain OCT (Cirrus OCT), but segmentation errors remain a concern, particularly in assessment of eyes with structurally complex retinal disease. With the recent release of multiple FDOCT systems, assessment of segmentation error may be an important factor in determining the relative merits of these systems.

Evaluation of Serum Lipid Concentrations and Genetic Variants at High-Density Lipoprotein Metabolism Loci and TIMP3 in Age-Related Macular Degeneration

PURPOSE To analyze the association between polymorphisms in the TIMP3 gene and genes of the high-density lipoprotein (HDL) metabolism and age-related macular degeneration (AMD), and evaluate serum lipid and lipoprotein levels in AMD patients compared with control individuals. METHODS Single nucleotide polymorphisms in or near the TIMP3, ABCA1, FADS1-3, CETP, LIPC, and LPL genes were genotyped. Serum levels of apolipoprotein B (ApoB), apolipoprotein A1, lipoprotein a, cholesterol, triglycerides, and HDL-cholesterol were determined. RESULTS Significant associations were found between AMD and variants in ABCA1 and FADS1-3, and a nearly significant association in TIMP3. No significant associations were observed for variants in LPL, LIPC, and CETP. We also observed a significant elevation of ApoB levels in serum of AMD patients. Other lipids and lipoproteins were not significantly altered. CONCLUSIONS These results confirm associations of AMD with variants near the TIMP3 gene and at loci involved in HDL metabolism. They further highlight a role of the extracellular matrix and the HDL metabolism in the pathogenesis of AMD. This study identified increased ApoB levels as a possible new serum biomarker for AMD.

Comparison of the optical coherence tomographic features of choroidal neovascular membranes in pathological myopia versus age-related macular degeneration, using quantitative subanalysis

Aim: To compare the retinal morphological characteristics of eyes with choroidal neovascularisation (CNV) secondary to pathological myopia versus eyes with CNV secondary to age-related macular degeneration (AMD), using quantitative optical coherence tomography (OCT) subanalysis. Methods: Twenty-one eyes of 21 patients newly diagnosed as having CNV secondary to pathological myopia, and 43 consecutive cases of eyes with newly diagnosed subfoveal CNV secondary to AMD were retrospectively collected. In all patients, StratusOCT images and fluorescein angiograms (FA) were available for analysis. StratusOCT images were analysed using custom software (termed “OCTOR”), which allowed calculation of the thickness/volume of the neurosensory retina, subretinal fluid (SRF), subretinal tissue (SRT) and pigment epithelial detachments (PEDs). FA images were used to calculate CNV leakage area and CNV lesion size for each eye. Results: The total volume of neurosensory retina in the pathological myopia group was significantly less than in the AMD group (7.10 (SD 0.50) mm3 vs 7.76 (0.93) mm3, p = 0.004). The total volume of SRF in the pathological myopia group was less than in the AMD group, but the difference was not statistically significant (0.33 (1.38) mm3 vs 0.55 (0.82) mm3, p = 0.434). The total volume of SRT in the pathological myopia group was less than in the AMD group, but the difference was not statistically significant (0.16 (0.15) mm3 vs 0.36 (0.60) mm3, p = 0.144). The total volume of PED in the pathological myopia group was markedly less than in the AMD group (0.01 (0.03) mm3 vs 1.09 (1.89) mm3, p<0.001). On FA, the total leakage of CNV in the AMD group was significantly greater than in the pathological myopia group (4.17 (3.29) DAs vs 0.53 (0.58) DAs, p<0.001). Conclusions: CNV lesions in pathological myopia were associated with considerably less retinal oedema, SRF and SRT compared with CNV associated with AMD. PEDs were almost negligible in myopic lesions compared with AMD. These findings are consistent with previous clinical and angiographic descriptions of myopic CNV as relatively small lesions with modest exudation.

Comparison of Clinically-Relevant Findings from High Speed Fourier Domain and Conventional Time Domain Optical Coherence Tomography

PURPOSE To compare the sensitivities of high-speed Fourier-domain optical coherence tomography (FD-OCT) and conventional time-domain (TD) OCT for the detection of clinical findings important in the management of common vitreoretinal disorders. DESIGN Prospective, observational study. METHODS FD-OCT scans (128 B scans x 512 A scans) were obtained using a prototype instrument (3 D-OCT; Topcon, Tokyo, Japan) in 50 eyes of 28 consecutive patients undergoing conventional high-resolution (6 B scans x 512 A scans) TD-OCT imaging (Stratus OCT; Carl Zeiss Meditec, Dublin, California, USA). Each image set was reviewed independently for the presence of clinical findings of interest, and device sensitivities were calculated. RESULTS The average sensitivity for detection of all features in this study was 94% for FD-OCT and 60% for TD-OCT. Clinical findings were identical between devices in 18% (9/50) of cases. FD-OCT detected features that were not visible on conventional OCT scans in 78% (39/50) of cases. FD-OCT was more sensitive than TD-OCT for the detection of multiple findings, including diffuse intraretinal edema (87% vs 60.9%), subretinal fluid (100% vs 46.2%), large pigment epithelium detachments (100% vs 81%), and subretinal tissue (100% vs 61.5%). CONCLUSIONS FD-OCT seems to be superior to TD-OCT for the detection of many clinically relevant features of vitreoretinal disease. The greater sensitivity of FD-OCT systems for the detection of intraretinal and subretinal fluid may be of particular importance for the treatment of patients with neovascular age-related macular edema. FD-OCT is likely to supplant TD-OCT as the standard of care for retinal specialists in the near future.

Grading of Age-Related Macular Degeneration: Comparison between Color Fundus Photography, Fluorescein Angiography, and Spectral Domain Optical Coherence Tomography

Purpose. To compare color fundus photography (FP), fluorescein angiography (FA), and spectral domain optical coherence tomography (SDOCT) for the detection of age-related macular degeneration (AMD), choroidal neovascularisation (CNV), and CNV activity. Methods. FPs, FAs, and SDOCT volume scans from 120 eyes of 66 AMD and control patients were randomly collected. Control eyes were required to show no AMD, but other retinal pathology was allowed. The presence of drusen, pigmentary changes, CNV, and signs for CNV activity was independently analyzed for all imaging modalities. Results. AMD was diagnosed based on FP in 75 eyes. SDOCT and FA showed sensitivity (specificity) of 89% (76%) and 92% (82%), respectively. CNV was present on FA in 68 eyes. Sensitivity (specificity) was 78% (100%) for FP and 94% (98%) for SDOCT. CNV activity was detected by SDOCT or FA in 60 eyes with an agreement in 46 eyes. Sensitivity was 88% for SDOCT and 88% for FA. FP showed sensitivity of 38% and specificity of 98%. Conclusions. CNV lesions and activity may be missed by FP alone, but FP may help identifying drusen and pigmentary changes. SDOCT is highly sensitive for the detection of AMD, CNV, and CNV activity; however, it cannot fully replace FA.

Imaging Protocols in Clinical Studies in Advanced Age-Related Macular Degeneration: Recommendations from Classification of Atrophy Consensus Meetings

PURPOSE To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. DESIGN Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. PARTICIPANTS A panel of retina specialists. METHODS During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held. MAIN OUTCOME MEASURES Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials. RESULTS Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions. CONCLUSIONS A multimodal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future.

Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT Classification of Atrophy Report 3

PURPOSE To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD). DESIGN Consensus meeting. PARTICIPANTS Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers. METHODS As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy. MAIN OUTCOME MEASURES A consensus classification system for atrophy and OCT-based criteria to identify atrophy. RESULTS OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 μm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 μm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear. CONCLUSIONS A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.

Effect of ranibizumab retreatment frequency on neurosensory retinal volume in neovascular amd.

Purpose: To determine the characteristics of patients with neovascular age-related macular degeneration who show initial anatomic improvements on optical coherence tomography in response to treatment with ranibizumab, but who subsequently regress toward their anatomic baseline. Methods: Data from 50 consecutive patients, receiving ranibizumab therapy for neovascular age-related macular degeneration, were collected. Raw StratusOCT images were analyzed using custom software (“OCTOR”). Changes in volume of neurosensory retina at months 1, 3, and 6 were calculated. Baseline demographic and morphologic characteristics were compared. Results: Forty-two patients (84%) showed a reduction in total retinal volume 1 month after initial treatment with ranibizumab. Of the patients that initially showed a reduction, 16 (38%) maintained this reduction through month 6, whereas 26 patients (62%) demonstrated a subsequent increase in retinal volume. Patients who maintained a reduction in edema received 3.75 ± 1.18 injections of ranibizumab versus 2.96 ± 1.34 injections for patients who did not (P = 0.049). Regression of initial anatomic improvements was associated with worsening of visual acuity (r = 0.599, P = 0.002). Conclusion: Patients receiving fewer injections of ranibizumab appeared less likely to maintain anatomic improvements achieved following commencement of ranibizumab therapy; regression of these improvements was associated with deterioration in visual acuity.