title: The Onion Sign in Neovascular Age-Related Macular Degeneration Represents Cholesterol Crystals.
abstract: OBJECTIVE
  To investigate the frequency, natural evolution, and histologic correlates of layered, hyperreflective, subretinal pigment epithelium (sub-RPE) lines, known as the onion sign, in neovascular age-related macular degeneration (AMD).
  
  
  METHODS
  Retrospective observational cohort study and experimental laboratory study.
  
  
  METHODS
  Two hundred thirty eyes of 150 consecutive patients with neovascular AMD and 40 human donor eyes with histopathologic diagnosis of neovascular AMD.
  
  
  METHODS
  Spectral-domain optical coherence tomography (SD OCT), near-infrared reflectance (NIR), color fundus images, and medical charts were reviewed. Donor eyes underwent multimodal ex vivo imaging, including SD OCT, before processing for high-resolution histologic analysis.
  
  
  METHODS
  Presence of layered, hyperreflective sub-RPE lines, qualitative analysis of their change in appearance over time with SD OCT, histologic correlates of these lines, and associated findings within surrounding tissues.
  
  
  RESULTS
  Sixteen of 230 eyes of patients (7.0%) and 2 of 40 donor eyes (5.0%) with neovascular AMD had layered, hyperreflective sub-RPE lines on SD OCT imaging. These appeared as refractile, yellow-gray exudates on color imaging and as hyperreflective lesions on NIR. In all 16 patient eyes, the onion sign persisted in follow-up for up to 5 years, with fluctuations in the abundance of lines and association with intraretinal hyperreflective foci. Patients with the onion sign disproportionately were taking cholesterol-lowering medications (P=0.025). Histologic analysis of 2 donor eyes revealed that the hyperreflective lines correlated with clefts created by extraction of cholesterol crystals during tissue processing. The fluid surrounding the crystals contained lipid, yet was distinct from oily drusen. Intraretinal hyperreflective foci correlated with intraretinal RPE and lipid-filled cells of probable monocytic origin.
  
  
  CONCLUSIONS
  Persistent and dynamic, the onion sign represents sub-RPE cholesterol crystal precipitation in an aqueous environment. The frequency of the onion sign in neovascular AMD in a referral practice and a pathology archive is 5% to 7%. Associations include use of cholesterol-lowering medication and intraretinal hyperreflective foci attributable to RPE cells and lipid-filled cells of monocyte origin.
authors: Vitreous Retina Macula Consultants of New York, New York, New York.
authors: Claudine E
authors: CE
authors: Pang
authors: Department of Ophthalmology, University of Alabama School of Medicine, Birmingham, Alabama.
authors: Jeffrey D
authors: JD
authors: Messinger
authors: Department of Ophthalmology, University of Alabama School of Medicine, Birmingham, Alabama; Eye Clinic, Department of Clinical Science "Luigi Sacco," Sacco Hospital, University of Milan, Milan, Italy.
authors: Emma C
authors: EC
authors: Zanzottera
authors: Vitreous Retina Macula Consultants of New York, New York, New York; LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, New York, New York; Department of Ophthalmology, New York University School of Medicine, New York, New York.
authors: K Bailey
authors: KB
authors: Freund
authors: Department of Ophthalmology, University of Alabama School of Medicine, Birmingham, Alabama. Electronic address: curcio@uab.edu.
authors: Christine A
authors: CA
authors: Curcio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D002784:Cholesterol / Q000009:adverse effects*; D003460:Crystallization; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D015745:Granuloma, Foreign-Body / Q000175:diagnosis* / Q000209:etiology; D006801:Humans; D008297:Male; D064847:Multimodal Imaging; D055213:Retinal Pigment Epithelium / Q000473:pathology*; D012189:Retrospective Studies; D014019:Tissue Donors; D041623:Tomography, Optical Coherence; D057135:Wet Macular Degeneration / Q000175:diagnosis* / Q000209:etiology
chemical_list: D000924:Anticholesteremic Agents; D002784:Cholesterol