Elsevier

Ophthalmology

Volume 122, Issue 11, November 2015, Pages 2316-2326
Ophthalmology

Original article
The Onion Sign in Neovascular Age-Related Macular Degeneration Represents Cholesterol Crystals

Presented at: Association for Research in Vision and Ophthalmology Annual Meeting, 2015, Denver, Colorado.
https://doi.org/10.1016/j.ophtha.2015.07.008Get rights and content

Purpose

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).

Design

Retrospective observational cohort study and experimental laboratory study.

Participants

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.

Main Outcome Measures

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.

Section snippets

Methods

The Western Institutional Review Board and the Institutional Review Board at University of Alabama at Birmingham approved the retrospective, observational cohort study and the experimental study, respectively. Research complied with the Health Insurance Portability and Accountability Act and adhered to the tenets of the Declaration of Helsinki.

Clinical Imaging and Associations

A cohort of 230 eyes of 150 consecutive patients (mean age, 84 years; 108 women and 42 men) with neovascular AMD was identified. Of these, 16 eyes of 15 patients (7.0%; mean age, 82 years; 13 women and 2 men) were found to exhibit the onion sign with SD OCT imaging. The onion sign corresponded to refractile yellow-gray exudates on color fundus photography and hyperreflective lesions on NIR SLO imaging in all 16 eyes (Fig 1).

Qualitative analysis of serial SD OCT scans revealed that the onion

Discussion

To our knowledge, this study is the first to report frequency, natural history, and histologic correlates of the onion sign in neovascular AMD. A long-lasting yet dynamic structure, the onion sign was visible in approximately 5% to 7% of neovascular AMD eyes and associated positively with intraretinal or subretinal hyperreflective foci and intraretinal fluid. A possible association between the onion sign and systemic hypercholesterolemia was suggested by a significantly higher use of

Acknowledgments

The authors thank the personnel of the Alabama Eye Bank (Doyce V. Williams, Executive Director, and Alan S. Blake, Chief Technical Officer) for timely retrieval of donor eyes and Giovanni Staurenghi, MD, for facilitating the participation of Dr. Zanzottera.

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    Supplemental material is available at www.aaojournal.org.

    Financial Disclosure(s): The author(s) have made the following disclosure(s):

    K.B.F.: Consultant - Genentech; Optos; Heidelberg Engineering; Thrombogenics; Optovue

    Supported by the Macula Foundation (New York, NY); the LuEsther T. Mertz Retinal Research Center (New York, NY); the National Institutes of Health (NIH), Bethesda, Maryland (grant no.: R01 EY06109), and the National Eye Institute, NIH (grant no.: P30 EY003039); Research to Prevent Blindness, Inc., New York, New York; EyeSight Foundation of Alabama (Birmingham AL); the International Retinal Research Foundation (Birmingham AL); and the Arnold and Mabel Beckman Initiative for Macular Research (Irvine CA). Project MACULA received additional support from the Edward N. and Della L. Thome Memorial Foundation (Boston MA), and the International Retinal Research Foundation (Birmingham AL). The funding organizations had no role in the design and conduct of this study.

    Author Contributions:

    Conception and design: Pang, Messinger, Freund, Curcio

    Analysis and interpretation: Pang, Messinger, Zanzottera, Curcio

    Data collection: Pang, Messinger, Zanzottera, Curcio

    Obtained funding: Curcio

    Overall responsibility: Pang, Freund, Curcio

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