Combined central serous chorioretinopathy, hypermetropia, short axial length, chorioretinal folds, enlarged/thickened ocular coats, with varying association of scleral changes (CHAFES).

PURPOSE: To describe a condition with the following features: chronic central serous chorioretinopathy (CCSC), chorioretinal folds, scleral changes (including any of the following flattened or 'squared off' posterior pole, 'T sign', or thickened ocular coats), accompanied by a short axial length and hypermetropia in a series of 7 patients. METHODS: The case notes of 7 patients presenting with a combination of CSC, choroidal folds scleral changes and hypermetropia were reviewed as part of a retrospective case series. Corrected visual acuities, serial refraction, colour imaging, fluorescein and indocyanine green angiography findings, together with B-ultrasound scan features were recorded, with axial length measurements as available (< 23.3 mm was defined as short). RESULTS: The study included 14 eyes of 7 subjects (2 females and 5 males) with a primary presentation of central vision disturbance. All patients showed signs of previous or current episodes of the following features in at least one eye: CSC (5/7 bilateral); choroidal folds (6/7 bilateral), thickening of ocular coats in the 5 in whom this was measured, at least one scleral abnormality on ultrasound in at least one eye. A short axial length at final appointment was recorded in 13/14 eyes. CONCLUSIONS AND RELEVANCE: The combination of CCSC with choroidal folds, hypermetropia with apparent shortening of the eyeball associated with one or more scleral abnormalities such as a flattened or 'squared off 'appearance of the B ultrasound may be a specific ocular condition. The aetiology of this particular combination of posterior segment manifestations is unknown; the choroid could be the primary focus of disease with secondary involvement of the sclera. Alternatively, the features observed may result from a chronic inflammatory process affecting the sclera with secondary effects on the choroid, retinal pigment epithelium and retina. In our case series, the final vision was not significantly different from vision at presentation.

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4.

PURPOSE: To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression. DESIGN: Consensus meeting. PARTICIPANTS: Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists. METHODS: As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA. MAIN OUTCOME MEASURES: Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. RESULTS: OCT was used in cases of early and intermediate AMD as the base imaging method to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA. CONCLUSIONS: An international consensus classification for OCT-defined anatomic features of iRORA are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly is essential to understand better the natural history of the disease, to identify high-risk signs of progression, and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavors, acknowledging that the classification will be refined as new data are generated.

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.

CHARACTERISTICS OF PIGMENTED LESIONS IN TYPE 2 IDIOPATHIC MACULAR TELANGIECTASIA.

PURPOSE: Pigment in the midretina is a characteristic sign in Type 2 idiopathic macular telangiectasia (MacTel) and is considered to characterize the late stage of the disease. Our aim was to investigate its incidence, and relationship with risk factors for MacTel, including outer retinal vascularization and subretinal neovascular proliferation (SRNV). METHODS: Pigment extent was measured in fundus autofluorescence images of 150 eyes of 75 MacTel probands, using the Region Finder tool of Heidelberg Eye Explorer. A linear mixed model was used to analyze the dynamics of pigment and its associations with other features of the phenotype. The relative incidence of pigment and of outer retinal outer retinal vascularization and SRNV was analyzed within the full MacTel Study cohort (1,244 probands). RESULTS: Mean pigment area at baseline was 0.157 mm (range = 0-1.295 mm, SD = 0.228 mm, n = 101). Progression demonstrated a nonlinear pattern (P < 0.001) at an overall rate of 0.0177 mm/year and was associated with the initial plaque size and with SRNV. There was a strong correlation between fellow eyes (P ≤ 0.0001). In approximately 25% of all SRNV cases, SRNV may coincide with or precede pigment. CONCLUSION: Our data may be useful for refining the current system for staging disease severity in MacTel.

CORRELATION OF STRUCTURAL AND FUNCTIONAL OUTCOME MEASURES IN A PHASE ONE TRIAL OF CILIARY NEUROTROPHIC FACTOR IN TYPE 2 IDIOPATHIC MACULAR TELANGIECTASIA.

PURPOSE: Macular telangiectasia Type 2 is a bilateral, progressive, potentially blinding retinal disease characterized by both vascular and neurodegenerative signs. Both the area of the break in the ellipsoid zone seen in "en face" optical coherence tomographic (OCT) images and microperimetric focal retinal sensitivity loss have been proposed as potential measures of progression in macular telangiectasia. The authors aimed to assess the characteristics and interrelationship of these structural and functional disease markers from the data collected in a phase one clinical trial of ciliary neurotrophic factor in macular telangiectasia. METHODS: Orthogonal topographic (en face) maps of the ellipsoid zone were generated from Heidelberg Spectralis OCT volume scans (15 × 10° area, 30-µm B-scan intervals) or Zeiss Cirrus HD-OCT 4000 512 × 128 cube scans. Mesopic microperimetry was performed on CenterVue MAIA perimeters, using a Goldmann III stimulus in a custom test grid. Structural and functional data were analyzed by two methods: by calculating aggregate loss and by simple thresholding. The alignment quality of structural and functional data was also evaluated. RESULTS: Overall, the break area showed a good correlation with aggregate sensitivity loss (ρ = 0.834, P < 0.0001, 95% confidence interval 0.716-0.906) but also with the number of test points below a threshold value (e.g., <20 dB: ρ = 0.843, P < 0.0001, 95% confidence interval 0.755-0.902). Significant misalignment of the MAIA test grid was apparent in 13/48 visits of 7/14 eyes. CONCLUSION: The authors found a good correlation between ellipsoid zone break area and function loss. En face OCT mapping of the ellipsoid zone appears to demonstrate structural change before mesopic microperimetry can detect a focal loss of retinal sensitivity. Thresholding offers a quick alternative to calculating aggregate sensitivity loss.

CORRELATION OF CLINICAL AND STRUCTURAL PROGRESSION WITH VISUAL ACUITY LOSS IN MACULAR TELANGIECTASIA TYPE 2: MacTel Project Report No. 6-The MacTel Research Group.

PURPOSE: To evaluate progression of macular telangiectasia Type 2 lesions and their correlation with visual acuity. METHODS: An international multicenter prospective study with annual examinations including best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, and optical coherence tomography images graded centrally. Mixed models were used to estimate progression rates, and a generalized linear model to compute the relative risk of BCVA loss, loss of ellipsoid zone (EZ) reflectivity, development of pigment plaques, or neovascularization. RESULTS: One thousand and fourteen eyes of 507 participants were followed for 4.2 ± 1.6 years. Best-corrected visual acuity decreased 1.07 ± 0.05 letters (mean ± SE) per year. Of all eyes, 15% lost ≥15 letters after 5 years. Of the eyes without EZ loss, 76% developed a noncentral loss. Of the eyes with noncentral loss, 45% progressed to central EZ loss. The rate of BCVA loss in eyes with noncentral EZ loss at baseline was similar to eyes without EZ loss. The rate of BCVA loss was significantly higher in eyes with central EZ loss at baseline (-1.40 ± 0.14 letters, P < 0.001). CONCLUSION: Ellipsoid zone loss is frequently found in macular telangiectasia Type 2 and is an important structural component reflecting visual function. Its presence in the fovea significantly correlates with worse visual prognosis.

LONGITUDINAL CORRELATION OF ELLIPSOID ZONE LOSS AND FUNCTIONAL LOSS IN MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To compare ellipsoid zone (EZ) loss and functional loss in macular telangiectasia (MacTel) type 2 longitudinally. METHODS: Prospective natural history study. Ellipsoid zone loss was measured in en-face images created from spectral domain optical coherence tomography. Functional loss was assessed by best-corrected visual acuity and microperimetry, counting the number of test points with impaired function. RESULTS: A total of 56 eyes of 31 participants were followed for 4.5 ± 1.2 years. Ellipsoid zone loss was 18,600 ± 3,917.3 pixel at baseline (≈0.59 mm) and increased 2,627.8 ± 427.9 pixel (≈0.08 mm) per year. Best-corrected visual acuity decreased 2.2 ± 0.9 letters per year. Change in EZ loss correlated significantly with change in relative and absolute scotomas (r = 0.62; P-value < 0.0001 and r = 0.72; P-value < 0.0001), but not with loss of best-corrected visual acuity. Functional loss showed a similar frequency of progression as EZ loss, but a higher rate of "regression," likely due to higher variability of the measurement, assuming a progressive neurodegenerative disease. CONCLUSION: The results of the authors support EZ loss as surrogate measure for visual function in MacTel type 2. Being objective, EZ loss might be considered more suitable than microperimetry as primary end point in future interventional trials.

ABNORMAL RETINAL REFLECTIVITY TO SHORT-WAVELENGTH LIGHT IN TYPE 2 IDIOPATHIC MACULAR TELANGIECTASIA.

PURPOSE: Macular telangiectasia Type 2 (MacTel) is a bilateral, progressive, potentially blinding retinal disease characterized by vascular and neurodegenerative signs, including an increased parafoveal reflectivity to blue light. Our aim was to investigate the relationship of this sign with other signs of macular telangiectasia Type 2 in multiple imaging modalities. METHODS: Participants were selected from the MacTel Type 2 study, based on a confirmed diagnosis and the availability of images. The extent of signs in blue-light reflectance, fluorescein angiographic, optical coherence tomographic, and single- and dual-wavelength autofluorescence images were analyzed. RESULTS: A well-defined abnormality of the perifovea is demonstrated by dual-wavelength autofluorescence and blue-light reflectance in early disease. The agreement in area size of the abnormalities in dual-wavelength autofluorescence and in blue-light reflectance images was excellent: for right eyes: ρ = 0.917 (P < 0.0001, 95% confidence interval 0.855-0.954, n = 46) and for left eyes: ρ = 0.952 (P < 0.0001, 95% confidence interval 0.916-0.973, n = 49). Other changes are less extensive initially and expand later to occupy that area and do not extend beyond it. CONCLUSION: Our findings indicate that abnormal metabolic handling of luteal pigment and physical changes giving rise to increased reflectance are widespread in the macula throughout the natural history of the disease, precede other changes, and are relevant to early diagnosis.

Potential Effects of Hormone Therapy in Type 2 Idiopathic Macular Telangiectasia.

PURPOSE: To investigate the influence of hormone therapy with tamoxifen or estrogens on morphological changes in macular telangiectasia (MacTel) type 2 patients as revealed clinically in multiple imaging modalities. METHODS: Patients with a history of tamoxifen or estrogen use were selected from the cohort of the MacTel Study. A race-, age- and best-corrected visual acuity-matched group of MacTel participants not under hormone therapy served as the comparison group. The frequencies of typical features of the MacTel phenotype apparent in color fundus, red-free, fluorescein angiographic and optical coherence tomographic images were graded and analyzed statistically. RESULTS: Thirty-nine MacTel patients were included in the analyses, of whom 13 were receiving tamoxifen, 13 estrogens and 13 patients no hormone treatment. Patients treated with estrogens showed significantly fewer breaks in the ellipsoid zone on optical coherence tomography (7 eyes, 29.1%, vs. tamoxifen: 14 eyes, 53.8%, and vs. controls: 14 eyes, 53.8%, p = 0.04 in both analyses, Fisher exact test). Retinal crystalline deposits were significantly more frequent in patients receiving estrogens (12 eyes, 16.2%, vs. 2 eyes, 2.7%, p = 0.003, Fisher exact test). No significant between-group differences were apparent with regard to other features of the phenotype (extent of retinal low reflective spaces, late hyperfluorescence on fluorescein angiography or retinal thickness). CONCLUSIONS: Tamoxifen treatment does not seem to accentuate structural changes in patients with MacTel type 2. Treatment with estrogens may exhibit a neuroprotective effect as suggested by the decreased frequency of ellipsoid zone breaks in corresponding patients, although corroborative studies are warranted to confirm these exploratory data.

Peripheral Retinal Imaging Biomarkers for Alzheimer's Disease: A Pilot Study.

PURPOSE: To examine whether ultra-widefield (UWF) retinal imaging can identify biomarkers for Alzheimer's disease (AD) and its progression. METHODS: Images were taken using a UWF scanning laser ophthalmoscope (Optos P200C AF) to determine phenotypic variations in 59 patients with AD and 48 healthy controls at baseline (BL). All living participants were invited for a follow-up (FU) after 2 years and imaged again (if still able to participate). All participants had blood taken for genotyping at BL. Images were graded for the prevalence of age-related macular degeneration-like pathologies and retinal vascular parameters. Comparison between AD patients and controls was made using the Student t test and the χ2 test. RESULTS: Analysis at BL revealed a significantly higher prevalence of a hard drusen phenotype in the periphery of AD patients (14/55; 25.4%) compared to controls (2/48; 4.2%) [χ2 = 9.9, df = 4, p = 0.04]. A markedly increased drusen number was observed at the 2-year FU in patients with AD compared to controls. There was a significant increase in venular width gradient at BL (zone C: 8.425 × 10-3 ± 2.865 × 10-3 vs. 6.375 × 10-3 ± 1.532 × 10-3, p = 0.008; entire image: 8.235 × 10-3 ± 2.839 × 10-3 vs. 6.050 × 10-3 ± 1.414 × 10-3, p = 0.004) and a significant decrease in arterial fractal dimension in AD at BL (entire image: 1.250 ± 0.086 vs. 1.304 ± 0.089, p = 0.049) with a trend for both at FU. CONCLUSIONS: UWF retinal imaging revealed a significant association between AD and peripheral hard drusen formation and changes to the vasculature beyond the posterior pole, at BL and after clinical progression over 2 years, suggesting that monitoring pathological changes in the peripheral retina might become a valuable tool in AD monitoring.

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye.

Accumulation of protein- and lipid-containing deposits external to the retinal pigment epithelium (RPE) is common in the aging eye, and has long been viewed as the hallmark of age-related macular degeneration (AMD). The cause for the accumulation and retention of molecules in the sub-RPE space, however, remains an enigma. Here, we present fluorescence microscopy and X-ray diffraction evidence for the formation of small (0.5-20 µm in diameter), hollow, hydroxyapatite (HAP) spherules in Bruch's membrane in human eyes. These spherules are distinct in form, placement, and staining from the well-known calcification of the elastin layer of the aging Bruch's membrane. Secondary ion mass spectrometry (SIMS) imaging confirmed the presence of calcium phosphate in the spherules and identified cholesterol enrichment in their core. Using HAP-selective fluorescent dyes, we show that all types of sub-RPE deposits in the macula, as well as in the periphery, contain numerous HAP spherules. Immunohistochemical labeling for proteins characteristic of sub-RPE deposits, such as complement factor H, vitronectin, and amyloid beta, revealed that HAP spherules were coated with these proteins. HAP spherules were also found outside the sub-RPE deposits, ready to bind proteins at the RPE/choroid interface. Based on these results, we propose a novel mechanism for the growth, and possibly even the formation, of sub-RPE deposits, namely, that the deposit growth and formation begin with the deposition of insoluble HAP shells around naturally occurring, cholesterol-containing extracellular lipid droplets at the RPE/choroid interface; proteins and lipids then attach to these shells, initiating or supporting the growth of sub-RPE deposits.

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.

A Population-Based Ultra-Widefield Digital Image Grading Study for Age-Related Macular Degeneration-Like Lesions at the Peripheral Retina.

PURPOSE: Our understanding of the relevance of peripheral retinal abnormalities to disease in general and in age-related macular degeneration (AMD) in particular is limited by the lack of detailed peripheral imaging studies. The purpose of this study was to develop image grading protocols suited to ultra-widefield imaging (UWFI) in an aged population. DESIGN: A cross-sectional study of a random population sample in which UWFI was introduced at the 12-year review of the Reykjavik Eye Study in Iceland. PARTICIPANTS: Five hundred seventy-six subjects 62 years of age or older. METHODS: Ultra-widefield (up to 200°) color and autofluorescence images were obtained using the Optos P200CAF laser scanning ophthalmoscope (Optos plc, Dunfermline, Scotland). The images were graded at Moorfields Eye Hospital Reading Centre primarily based on the International Classification for AMD. Macular and peripheral changes were graded using a standardized grid developed for this imaging method. MAIN OUTCOME MEASURES: Presence or absence of hard, crystalline, and soft drusen; retinal pigment epithelial changes; choroidal neovascularization (CNV); atrophy; and hypoautofluorescence and hyperautofluorescence were graded in the peripheral retina. RESULTS: Of the eyes examined, 81.1% had AMD-like changes in the macula alone (13.6%), periphery alone (10.1%), and both periphery and macula (57.4%). There was no AMD-like CNV or pigment epithelial detachment in the periphery except in those cases in which these clearly originated from the macula. Seven patients had AMD-like atrophy in the periphery without end-stage disease in the macula. One patient with end-stage disease in the macula had normal periphery results on the color images. While analyzing the eyes, we detected pathologic appearances that were very reliably identified by graders. CONCLUSIONS: Phenotyping the retinal periphery using the categories defined by the International Classification confirmed the presence of wide-ranging AMD-like pathologic changes even in those without central sight-threatening macular disease. Based on our observations, we propose here new, reliably identifiable grading categories that may be more suited for population-based UWFI.

Multimodal imaging in type 2 idiopathic macular telangiectasia.

BACKGROUND: Macular telangiectasia Type 2 is a bilateral, progressive potentially blinding retinal disease characterized by both vascular and neurodegenerative signs that have been documented using different imaging techniques. The correlation between macular telangiectasia Type 2 signs from various imaging modalities is unknown. Our aim was to investigate the relationship of various macular telangiectasia Type 2 signs using fundus fluorescein angiography, optical coherence tomography and dual-wavelength autofluorescence images. METHODS: Participants were selected from the macular telangiectasia Type 2 Natural History Observation Study, based on a confirmed diagnosis and the availability of images. Signs in fundus fluorescein angiography, dual-wavelength autofluorescence, and optical coherence tomography images were graded according to standardized categories, and agreement among the multimodel imaging was assessed statistically. RESULTS: One hundred and ninety-one eyes of 96 patients were examined. Significant correlations were found between early and late fundus fluorescein angiography (ρ = 0.82, P < 0.0001), luteal pigment loss and early/late fundus fluorescein angiography signs (ρ = 0.52, P < 0.0001 and ρ = 0.62, P < 0.0001, respectively), inner and outer segment break length and pigment loss (Class 1 vs. 2/3, P < 0.0001; Class 2 vs. 3, P = 0.04). Correlation between pigment loss and retinal spaces/atrophic retinal restructuring was fair (κ = 0.25-0.33). Bilateral symmetry was slight to substantial (κ = 0.18-0.62). CONCLUSION: Our data demonstrate the relative extent of neurodegenerative and vascular signs; it may be useful for designing systems for staging disease severity using multimodal imaging and may also provide clues to the pathogenesis of the disease.

Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3.

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.

Associations between autofluorescence abnormalities and visual acuity in idiopathic macular telangiectasia type 2: MacTel project report number 5.

PURPOSE: The aim of this study was to determine whether typical abnormalities seen on autofluorescence (AF) imaging in patients with macular telangiectasia (MacTel) type 2 are correlated with visual acuity at presentation and with progression of visual loss over a 2-year follow-up period. METHODS: A subgroup of 218 patients (413 eyes) enrolled in the MacTel study that underwent AF imaging was included in the present study. Images were graded at the Moorfields Eye Hospital Reading Center. Recorded AF abnormalities at baseline and at 2 years included the presence of increased AF because of loss of masking at the central macula, localized decreased AF at the end of a retinal vessel, and large area of decreased AF. Best-corrected visual acuity was measured using the Early Treatment for Diabetic Retinopathy chart at baseline and after 2 years. Statistical associations were sought by means of a generalized linear model. RESULTS: Presence of increased macular AF (P = 0.004), a large area of decreased AF (P < 0.001), or decreased AF at the end of a retinal vessel (P < 0.001) at baseline were significantly associated with worse best-corrected visual acuity. Presence of increased macular AF (P < 0.001) or of localized decreased AF at the end of a retinal vessel (P < 0.001) and the absence of a large area of decreased AF (P < 0.001) were predictive of a subtle but significant drop in best-corrected visual acuity at 2 years. CONCLUSIONS: Increased central AF at baseline heralds worse best-corrected visual acuity and predicts further subtle visual loss in a period of 2 years, which, however, does not stand out from the overall slowly progressive natural history of the disease.

Agreement between time-domain and spectral-domain optical coherence tomography in the assessment of macular thickness in patients with idiopathic macular telangiectasia type 2.

PURPOSE: To estimate the conversion factors to transpose macular thickness measurements on time-domain (TD) to various spectral-domain (SD) optical coherence tomography (OCT) machines in patients with macular telangiectasia type 2a (MacTel). PROCEDURES: Macular scans on TD- and SD-OCT were performed on patients at the same visit. The retinal thickness values in various ETDRS subfields and macular volume were compared between different OCT machines. RESULTS: The macular thickness and volume were significantly greater (p < 0.0001, r = 0.678-0.822) on SD-OCT. The mean differences in macular thickness between TD Stratus and SD-OCT by Spectralis, Cirrus and Topcon were 62, 41 and 20 µm, respectively. The conversion factor of macular thickness from TD-OCT to Spectralis, Cirrus and Topcon were +65, +39 and +25 µm, respectively. CONCLUSION AND MESSAGE: The estimates of conversion of macular thickness from TD- to SD-OCT using simple mean differences between machines and those by linear regression were similar suggesting that the former may be used for the longitudinal follow-up of MacTel patients.

Macular Telangiectasia Type 2: A Classification System Using MultiModal Imaging MacTel Project Report Number 10.

Purpose: To develop a severity classification for macular telangiectasia type 2 (MacTel) disease using multimodal imaging. Design: An algorithm was used on data from a prospective natural history study of MacTel for classification development. Subjects: A total of 1733 participants enrolled in an international natural history study of MacTel. Methods: The Classification and Regression Trees (CART), a predictive nonparametric algorithm used in machine learning, analyzed the features of the multimodal imaging important for the development of a classification, including reading center gradings of the following digital images: stereoscopic color and red-free fundus photographs, fluorescein angiographic images, fundus autofluorescence images, and spectral-domain (SD)-OCT images. Regression models that used least square method created a decision tree using features of the ocular images into different categories of disease severity. Main Outcome Measures: The primary target of interest for the algorithm development by CART was the change in best-corrected visual acuity (BCVA) at baseline for the right and left eyes. These analyses using the algorithm were repeated for the BCVA obtained at the last study visit of the natural history study for the right and left eyes. Results: The CART analyses demonstrated 3 important features from the multimodal imaging for the classification: OCT hyper-reflectivity, pigment, and ellipsoid zone loss. By combining these 3 features (as absent, present, noncentral involvement, and central involvement of the macula), a 7-step scale was created, ranging from excellent to poor visual acuity. At grade 0, 3 features are not present. At the most severe grade, pigment and exudative neovascularization are present. To further validate the classification, using the Generalized Estimating Equation regression models, analyses for the annual relative risk of progression over a period of 5 years for vision loss and for progression along the scale were performed. Conclusions: This analysis using the data from current imaging modalities in participants followed in the MacTel natural history study informed a classification for MacTel disease severity featuring variables from SD-OCT. This classification is designed to provide better communications to other clinicians, researchers, and patients. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Identification of anti-retinal antibodies in patients with age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrial counties. Recent findings indicate that the autoimmunity is involved in the pathogenesis of the disease. However, there is no autoantibody biomarker applied in a clinical setting for diagnosis and prognosis of AMD. In order to reveal retinal antigens targeted by serum IgG from AMD patients, mouse retinal tissue proteins were separated by 2-dimensional electrophoresis and the proteins in the immunoblots that were specific for dry and wet AMD patients IgG were identified by LC-MS/MS. Retinol-binding protein 3 and aldolase C (ALDOC) were mainly recognized by IgG form wet AMD patients. Pyruvate kinase M2 (PKM2) was targeted by both dry and wet AMD and level of anti-PKM2 IgG antibody was correlated best with the stage of AMD. Expression of ALDOC and PKM2 was decreased in mouse retina from aging whereas PKM2 deposit on RPE was increased in aged mice. Our data demonstrate that sera of AMD patients contain autoantibodies against retinal proteins and anti-PKM2 IgG serves as a biomarker for diagnosis and prognosis of AMD. Further investigation of the association of anti-retinal antibody level with expression level of antigens in retina will be needed to reveal the disease pathogenesis.

Serum autoantibody biomarkers for age-related macular degeneration and possible regulators of neovascularization.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrial counties. Its pathogenesis is at least partially mediated by immunological factors, including a possible autoimmune response. To date, only a few antibodies have been identified in sera from patients with AMD. In order to reveal an autoantibody profile for AMD and identify biomarkers for progression of this disease, we have performed an antigen microarray analysis of serum samples from patients with AMD and healthy controls. Sera from the AMD groups contained high levels of IgG and IgM autoantibodies to some systemic antigens when compared to the normal group. Targeted antigens included cyclic nucleotide phosphodiesterase, phosphatidylserine (PS) and proliferating cell nuclear antigen. The IgG/IgM ratio for antibodies to PS was notably elevated in the AMD group compared to the normal group, and this ratio correlated best with the stage of AMD patients with an anti-PS ratio greater than the cut-off value had a 44-fold risk for advanced AMD with choroidal neovascularization. PS immunoreactivity was also elevated in AMD retina. Moreover, IgG autoantibodies purified from sera of AMD patients induced more tube formation on choroidal-retinal endothelial cells compared to those of healthy donors. Hence, sera from patients with AMD contain specific autoantibodies which may be used as biomarkers for AMD, and the IgG/M ratio for autoantibodies to PS might allow better monitoring of AMD progression.