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Jeffrey D Messinger, Claudine E Pang, Emma C. Zanzottera, K Bailey Freund, Christine A Curcio; Prevalence, natural history, associations, and histological correlate of the Onion sign in neovascular age-related macular degeneration (nvAMD). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3782.
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Purpose: To investigate the prevalence, natural history, associations, and histological correlates of layered, hyper-reflective (HR), sub-retinal pigment epithelium (sub-RPE) bands, known as the Onion Sign, in nvAMD (Mukkamala, Arch Ophthalmol 2012 130:1).
Methods: A retrospective observational cohort study included 230 eyes of 150 consecutive patients receiving anti-VEGF therapy for nvAMD. Spectral-domain optical coherence tomography (SD-OCT), near-infrared reflectance, color fundus images, and medical charts of all patients were reviewed. Outcomes were the presence of layered, HR sub-RPE bands, and qualitative analysis of their appearance with SD-OCT over time. An ex vivo imaging and histology study included 39 human donor eyes with nvAMD (http://projectmacula), unrelated to the clinic patients. All donor eyes underwent ex vivo SD-OCT imaging, color fundus photography, and processing for macula-wide high-resolution sections.
Results: Sixteen of 230 treated nvAMD eyes (7.0%) exhibited an Onion Sign on SD-OCT imaging. These also appeared as refractile, yellow-gray exudates on color imaging and HR lesions on near-infrared imaging. In all 16 eyes, the Onion Sign persisted up to 5 years of follow-up, with fluctuations in Onion volume. The Onion Sign was associated with the presence of systemic hypercholesterolemia (p = 0.025) and intraretinal HR foci. Two of 39 donor eyes (5.1%) exhibited sub-RPE brightly HR lines and intraretinal HR foci in ex vivo SD-OCT. The bands correlated with sub-RPE cholesterol crystals, as predicted (Christakopoulos, Acta Ophthalmologica 2013 91:248), and were evidenced by distinctive clefts created by crystal extraction during tissue processing. HR foci correlated with intraretinal RPE filled with melanosomes and lipofuscin and other cells filled with lipid droplets and sparse melanosomes.
Conclusions: A long-lasting and dynamic structure, the ‘onion sign’ was visible in ~5-7% anti-VEGF-treated nvAMD eyes and associated with the presence of systemic hypercholesterolemia and intraretinal HR foci. Sub-RPE cholesterol crystal precipitation due to super-saturation is distinct from sub-RPE oily cholesterol accumulation in drusen. Cells associated with intraretinal fluid are migrated RPE plus cells that appeared to have phagocytized RPE, possibly microglia.
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