Optical Coherence Tomographic Imaging of Sub-Retinal Pigment Epithelium Lipid

CLINICAL SCIENCES

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Optical Coherence Tomographic Imagingof Sub−Retinal Pigment Epithelium LipidSri Krishna Mukkamala, MD; Rogerio A. Costa, MD, PhD; Adrian Fung, MD; David Sarraf, MD;Roberto Gallego-Pinazo, MD; K. Bailey Freund, MD

Objective: To describe an optical coherence tomo-graphic finding of layered hyperreflective bands be-neath the retinal pigment epithelium (RPE), the so-called onion sign believed to represent lipid within avascularized pigment epithelial detachment.

Methods: This retrospective observational case seriesinvolved reviewing clinical histories of patients with theonion sign. Imaging studies analyzed included spectral-domain optical coherence tomography, color and red-free photographs, near infrared reflectance, fundus au-tofluorescence, and blue-light fundus autofluorescence.

Results: A total of 22 eyes of 20 patients with sub-RPEhyperreflective bands were identified. There were 15women and 5 men with a mean patient age of 76 years(range, 60-92 years). Snellen best-corrected visual acu-ities ranged from 20/25 to counting fingers, with a me-dian of 20/80. Two patients had bilateral involvement,and 3 of 17 eyes had multifocal onion signs in the sameeye. All eyes had neovascular age-related macular de-generation, with type 1 (sub-RPE) neovascularization. In

all patients, the onion sign correlated with areas of yellow-gray exudates seen clinically that appeared bright on red-free and near infrared reflectance imaging. No specificfundus autofluorescence or blue-light fundus autofluo-rescence pattern was identified.

Conclusions: The onion sign refers to layered hyperre-flective bands in the sub-RPE space usually associatedwith chronic exudation from type 1 neovascularizationin patients with age-related macular degeneration. Withan associated bright near infrared reflectance, these bandsmay correspond to lipid, collagen, or fibrin. Because theonion sign colocalizes to areas of exudation that are knownto consist of lipoprotein, we propose that this finding mayrepresent layers of precipitated lipid in the sub-RPE space.To our knowledge, this is the first report of lipid de-tected in the sub-RPE space on clinical examination.

Arch Ophthalmol. 2012;130(12):1547-1553.Published online August 13, 2012.doi:10.1001/archophthalmol.2012.2491

S PECTRAL-DOMAIN (SD) OPTI-cal coherence tomography(OCT) has enhanced ourability to image the sub–retinal pigment epithelium

(RPE) space in retinal disorders associ-ated with pigment epithelial detach-ments (PEDs).1-6 With serial SD-OCTimaging, greater insight into the patho-genesis and natural history of PEDs maybe gained and may supplement older mo-dalities such as fluorescein angiography(FA), indocyanine green angiography(ICGA), and histopathology speci-mens.7-11 Using SD-OCT, we identified aunique finding associated with PEDs in pa-tients with neovascular age-related macu-lar degeneration (AMD)—the so-called on-ion sign. Reminiscent of the layers of anonion, this finding appears as layers of hy-perreflective bands between the RPE andBruch membrane within vascularized

PEDs. Coscas12 previously reported thisOCT finding as bands of fibrovascular tis-sue. However, we propose that these hy-perreflective bands likely represent sub-RPE lipid trapped within fibrovasculartissue that originates from type 1 neovas-cular exudation. Although intraretinal andsubretinal lipid are commonly present ina multitude of retinal diseases includingdiabetic retinopathy, retinal vein occlu-sions, hypertensive retinopathy, Coats dis-ease, macular telangiectasia type 1, radia-t ion ret inopathy, and Bartonel laneuroretinitis, we are not aware of otherconditions that commonly produce sub-RPE lipid.13-19

METHODS

We retrospectively reviewed clinical andimaging data from all eyes noted to have the

Author Affiliations are listed atthe end of this article.

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onion sign on SD-OCT performed as part of routine follow-upin patients with neovascular AMD. Patients were seen at theVitreous Retina Macula Consultants of New York, the Jules SteinEye Institute, the Centro Brasileiro de Ciencias Visuais, and theUniversity and Polytechnic Hospital. The Western Institu-tional Review Board approved this retrospective review, andpatients provided written informed consent for study partici-pation.

High-resolution digital color photographs, red-free (RF) pho-tographs, and FA were obtained in each patient. Near infraredreflectance (NIR) using a light stimulus of 815 nm, blue-lightautofluorescence (bFAF) using a light stimulus of 488 nm, fun-dus autofluorescence (FAF) using an excitation light band-width from 535 to 585 nm, and SD-OCT examinations wereobtained with the Spectralis HRA � OCT (Heidelberg Engi-neering). For each scan, qualitative data including location,shape, relative orientation of the hyperreflective bands, and thepresence of posterior optical shadowing were recorded.

RESULTS

Twenty-two eyes of 20 consecutive patients were iden-tified as having sub-RPE hyperreflective bands, the on-ion sign. Two patients had bilateral involvement and 3of 22 eyes had multifocal involvement in the same eye(Figure 1). There were 15 women and 5 men, with a

mean age of 76 years (range, 60-92 years). Snellen best-corrected visual acuity at the most recent visit ranged from20/25 to counting fingers, with a median of 20/80. Re-view of medical histories revealed 13 patients (65%) withhypertension, 5 (20%) with hypercholesterolemia, and5 (20%) with type 2 diabetes mellitus.

All eyes had been diagnosed as having neovascularAMD. Of the 22 eyes, 11 were receiving injections of in-travitreal ranibizumab, 5 of intravitreal bevacizumab, 2of both intravitreal ranibizumab and bevacizumab(sequentially), and 4 were being observed without treat-ment. The length of treatment with intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapyprior to detection of the onion sign ranged from 3 monthsto 54 months. One eye had been treated for 3 months, 1for 6 months, 2 for 12 months, 1 for 18 months, and 14for more than 24 months. Six eyes had evidence of cho-rioretinal anastomosis, 1 had a RPE tear, 1 had reticularmacular disease (subretinal drusenoid deposits), and 1had angiographic evidence of polypoidal choroidal vas-culopathy.

On SD-OCT, the layered hyperreflective bands werefound to localize to beneath the hyperreflective RPE bandand above the hyperreflective band believed to repre-

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Figure 1. Multifocal onion sign in the left eye of an 80-year-old woman with neovascular age-related macular degeneration. Simultaneously acquired near infraredreflectance (NIR) images (A, C, and E) with their corresponding spectral-domain optical coherence tomographic (SD-OCT) raster scans (B, D, and F). In each pair,the scan traverses an area of increased NIR that correlates to sub–retinal pigment epithelium hyperreflective bands on SD-OCT (arrows). Scans show the inferiormacula (A and C) and the inferotemporal quadrant just outside the macula (E).




sent the Bruch membrane (Figure 2). The onion signwas not detected in the neurosensory retina, subretinalspace, or beneath the Bruch membrane in the choroidor sclera. The horizontal length of the bands appearedto correlate with the size of the overlying PED. The shapeof the bands varied from straight to curvilinear. Eyes withlarger PEDs had straighter bands, while eyes with flatterPEDs had more curvilinear bands. The hyperreflectivebands did not produce posterior optical shadowing of theunderlying tissues as is seen with calcification. The totalnumber of bands per eye was difficult to estimate be-cause SD-OCT spatial resolution was insufficient to dis-tinguish bands when stacked closely together.

The sub-RPE hyperreflective bands seen on SD-OCTcorrelated with deep yellow-gray deposits on clinical ex-amination and color photographs (Figure 3). On clini-cal examination and color photography alone, it was dif-ficult to appreciate the sub-RPE location of these deposits.Within these yellow-gray deposits, there were glisten-ing patches that appeared to represent crystalline mate-rial. In several eyes, we were able to document the de-velopment of an onion sign in funduscopic locationswhere prior color photography had documented an ab-sence of this finding.

When available, we reviewed RF, NIR, FAF, and bFAFimages. In all eyes, the onion sign correlated with areasof hyper-reflectance on RF and NIR images. When bothimaging modalities were available, the area of hyper-reflectance was larger in the NIR images than in the RFimages. In 6 of 11 eyes in which bFAF images were avail-able, the onion sign was associated with areas of mildhypo-autofluoresence. In the remaining 5 eyes, there wereno discernable findings correlating with these lesions(Figure 4).

A 64-year-old woman had bilateral neovascular AMD.Medical history was significant for hypercholesterol-emia treated with atorvastatin and osteopenia treated withoral alendronate. On presentation, best-corrected visualacuity was 20/25 OD and 20/20 OS.

At the initiation of monthly intravitreal anti-VEGFtherapy, clinical examination and color photographs ofthe right eye showed parafoveal pigmentary changes anddrusen but no evidence of yellow-gray deposits or re-fractile material in the temporal macula (Figure 5). De-spite monthly treatment with intravitreal ranibizumab,

0.5 mg/0.05 mL, every 3 to 5 weeks for 3 years, this eyehad SD-OCT evidence of continued growth of type 1 neo-vascularization with persistent fluid noted at each monthlyexamination. One year later, a new PED was noted in theinferotemporal macula that flattened following a RPE tear.During the next 4 months, a well-defined area of yellow-gray deposits with foci of brighter refractile material wasnoted to develop temporal to the RPE tear.

Serial eye-tracked SD-OCT B-scan images through thisarea documented the changes resulting in the appear-ance of the yellow-gray lesions. A predominantly serousPED noted 24 months after initiating intravitreal anti-VEGF therapy developed, increasing internal reflectiv-ity during the ensuing 4 months. This increase in reflec-tivity initially appeared to represent increasing vascularity,or type 1 neovascularization, between the RPE and theBruch membrane, but later it appeared as intense, lay-ered linear bands believed to represent lipid-rich mate-rial. Simultaneous SD-OCT and NIR imaging localizedthe clinically apparent yellow-gray material to the sub-RPE space above the Bruch membrane.

COMMENT

The onion sign is a novel SD-OCT finding characterizedby the presence of hyperreflective bands detected withinvascularized PEDs. We believe this finding may repre-sent lipid-rich material due to chronic leakage from type1 neovascularization, most commonly occurring in eyeswith AMD. To our knowledge, sub-RPE lipid has not beenpreviously described as a clinical or OCT finding. As thereare no published clinicopathologic reports describing thisfinding, speculation about the etiology is based on in-sights provided by multimodal imaging techniques.

Clinically, the onion sign correlates with matte yellow-gray deposits with interspersed refractile areas localiz-ing to type 1 neovascular tissue. Punctate yellow-whitecrystalline deposits have been described in eyes with neo-vascular AMD.20 On OCT, these deposits appear as hy-perreflective foci and localize more superficially withinthe outer nuclear and outer plexiform layers of the neu-rosensory retina. Lima and colleagues20 proposed thatthese deposits could represent lipid or degenerated Mul-ler cells.

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Figure 2. Left eye of a 75-year-old woman with neovascular age-related macular degeneration receiving ranibizumab injections as needed for 3 years. A, Colorphotograph shows central retinal pigment epithelium (RPE) changes with surrounding yellow-gray material consistent with lipid (arrowhead). B, Spectral-domainoptical coherence tomographic B-scan line shows hyperreflective bands (arrowhead) beneath the RPE correlating to the yellow-gray material in part A.




In eyes with diabetic macular edema, similar exuda-tive deposits can be seen as hyperreflective foci on OCTin all retinal layers. When confluent, these foci can formplaques in the outer plexiform layer on OCT that corre-late to areas of hard exudates seen clinically. These hy-perreflective foci and plaques are thought to representlipid-rich deposits.13,19,21-23

While eyes with retinal vascular disease develop in-traretinal lipid, the eyes in our study appeared to accu-mulate sub-RPE lipid within vascularized PEDs (Figure 4).This localization of our findings to the sub-RPE space isunique. Just as a breakdown of the inner blood-retina bar-rier results in exudation anterior to the external limit-ing membrane in diabetes, exudation through the fenes-trated endothelium of a type 1 neovascular membrane

could result in buildup of lipoprotein-rich deposits boundanteriorly by the RPE. Perhaps precipitation or crystal-lization of the lipid components of these deposits ap-pears as hyperreflective bands on OCT. Phases of inter-mittent exudation could result in layers of parallelhyperreflective bands similar to strata of deposited sedi-mentary rock seen on a mountainside. We have ob-served similar bands above the RPE in patients with dia-betic macular edema with hard exudates.

In addition to deposition of lipid, other explanationsof these bands must be considered. Drusen regression canresult in calcification that may produce a crystalline ap-pearance with deposits just above the Bruch mem-brane.24-27 However, in the onion sign, bands are foundat many levels between the Bruch membrane and the RPE.

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Figure 3. Left eye of an 81-year-old woman with neovascular age-related macular degeneration receiving monthly alternating injections of ranibizumab andoff-label bevacizumab for 3 years. A, Color photograph shows a central vascularized pigment epithelial detachment with yellow-gray material at its margins. Thismaterial was not present at the initiation of anti–vascular endothelial growth factor therapy 2 years earlier. Laminar venous and recirculation phase fluoresceinangiography show an occult leakage pattern consistent with type 1 neovascularization (B and C). D, Red-free imaging shows areas of brightness corresponding tothe yellow-gray material present in the color photograph (A). Early and late phase indocyanine green angiography shows an early focal hotspot with late washoutconsistent with polypoidal choroidal vasculopathy (PCV) (E and F). The PCV lesion is found within a larger late staining plaque consistent with type 1neovascularization. Spectral-domain optical coherence tomographic B-scan lines show sub–retinal pigment epithelium hyperreflective bands (G and H) thatcorresponded to the yellow-gray areas in the color photograph (A) and areas of increased brightness on red-free image (D and inset).




This dissimilarity, along with the absence of posterior op-tical shadowing typically caused by calcification on OCT,makes the possibility of a calcified drusen less likely.

Other imaging modalities may be useful in identify-ing the onion sign. Both RF and NIR imaging highlightareas with an onion sign. When both of these modalitiesare available, the sign appeared larger and brighter onNIR when compared with RF images. Melanin, fibrin, andcollagen are bright on NIR images and should be in-cluded in a list of possible explanations of the onion sign.28

We did not observe any bFAF and FAF associated withthe onion sign in the sub-RPE space.

While there is no histopathologic evidence that mela-nin accumulates within type 1 neovascular tissue, fibrin andcollagen are possible contributors to the onion sign. Elec-tron micrographic evaluation of surgically excised choroi-dal neovascular (CNV) membranes revealed that 25-nmcollagen and fibrin bands were among the most com-monly seen extracellular components, found in 84% and79% of specimens, respectively.29 In 12% of specimens, therewas evidence of uncommon components including calci-fication and curvilinear filaments. Lafaut and colleagues30

analyzed 35 surgically removed CNV membranes and at-tempted to assess the distribution of fibrin deposition inthese specimens. They did not observe fibrin in curvilin-ear sub-RPE bands as seen on OCT in our patients.

Although fibrin is very common in excised CNVspecimens, the NIR images of our patients showed fi-brin may not be a major component of the onion sign.Typically, fibrin in occult CNV lesions is seen as punc-tate areas of increased NIR reflectance interspersedwithin an area of decreased NIR reflectance.28,31 By con-trast, the NIR images of all of our patients showed con-fluent areas of increased NIR reflectance. These areas ofincreased NIR reflectance are peculiar because PEDs,within which the onion signs are found, are usuallyassociated with decreased central NIR reflectance witha brighter halo.28 While fibrin is not seen on FA, ittypically stains with ICGA. In eyes in which FA andICGA were available, there was no finding consistentwith the more intense hyperfluorescent staining offibrin, only the late faint hyperfluorescence of type 1neovascularization commonly referred to as a plaque(Figure 5).

Collagen is another possible component of the onionsign, as it is a common component in sub-RPE depos-its.24,25 Knupp and colleagues32 investigated collagen inthe Bruch membrane and beneath the RPE. They showedthat collagen, particularly collagen VI, can aggregate intobands that form basal laminar deposits. However, colla-gen is inconsistent with the yellow-gray refractile depos-its seen on color fundus photographs.

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Figure 4. Left eye of a 68-year-old woman with the onion sign. A, Red-free (RF) imaging shows a ring of pigmentary changes in the macula. At the nasal edge ofthis ring, there is a focal area of increased brightness (arrowhead). B, On near infrared reflectance (NIR) imaging, this area of increased reflectance is larger whencompared with the RF image. C, Fundus autofluorescence (FAF) imaging shows a clearly delineated ring of mixed hyper-FAF and hypo-FAF around the fovea.However, there is no obvious alteration of FAF associated with the area of increased NIR. FAF image (D) with its corresponding raster spectral-domain opticalcoherence tomographic (SD-OCT) scan line (E). The SD-OCT reveals hyperreflective bands in the sub-retinal pigment epithelium space corresponding to the areaof brightness on RF and increased NIR images.




Based on the clinical progression of our patients, wehypothesize that the onion sign resulted from layers ofdeposited lipid within type 1 neovascular tissue. Clini-cally, these patients, all with neovascular AMD, had areaswhere chronic exudation preceded the development ofthese hyperreflective bands on OCT. Histopathology ofhard exudates has revealed the presence of lipoproteinmaterial and lipid-laden macrophages.22 These lipid exu-dates can appear as foci of extreme NIR hyper-

reflectance in neovascular AMD, as seen in our pa-tients.31 Multiple physical forms of sub-RPE lipid-richdeposits have been observed by apolipoprotein immu-nofluorescence. However, to our knowledge, the pres-ence of cholesterol crystals or stacked linear bands hasnever been reported.33-36

In summary, we report a novel SD-OCT finding wecall the onion sign appearing as hyperreflective bandswithin vascularized PEDs detected in the setting of on-going exudation in eyes with neovascular AMD. Thesebands appear to be related to lipoprotein exudation andlikely represent layers of lipid-rich material trapped withintype 1 neovascular tissue. Based on NIR findings, colla-gen and/or fibrin may also contribute to this finding. Toour knowledge, this is the first report of sub-RPE lipidthat can be detected on OCT examination.

Submitted for Publication: April 12, 2012; final revi-sion received April 12, 2012; accepted May 20, 2012.Published Online: August 13, 2012. doi:10.1001/archophthalmol.2012.2491Author Affiliations: Vitreous Retina Macula Consultantsof New York, New York (Drs Mukkamala, Fung, andFreund), LuEsther T. Mertz Retinal Research Center, NewYork (Drs Mukkamala, Fung, and Freund), Department ofOphthalmology,NewYorkUniversity,NewYork(DrsMuk-kamala and Freund), Edward S. Harkness Eye Institute, Co-lumbiaUniversity,NewYork(DrsMukkamalaandFreund),New York; Centro Brasileiro de Ciencias Visuais, Belo Hori-zonte, Minas Gerais, Brazil (Dr Costa); Retinal Disordersand Ophthalmic Genetics Division, Jules Stein Eye Insti-tute, University of California, Los Angeles (Dr Sarraf),Greater Los Angeles VA Healthcare Center (Dr Sarraf), LosAngeles, California; and Department of Ophthalmology,University and Polytechnic Hospital, La Fe, Valencia, Spain(Dr Gallego-Pinazo).Correspondence: K. Bailey Freund, MD, Vitreous RetinaMacula Consultants of New York, 460 Park Ave, 5th Fl,New York, NY 10022 ([email protected]).Financial Disclosure: None reported.Funding/Support: This study was supported by fund-ing from the LuEsther T. Mertz Retinal Research Cen-ter; the Manhattan Eye, Ear, and Throat Institute; theMacula Foundation Inc; and the Karl Kirchgessner Foun-dation Ophthalmology Endowment Fund to Dr Sarraf.

REFERENCES

1. Spaide RF. Enhanced depth imaging optical coherence tomography of retinal pig-ment epithelial detachment in age-related macular degeneration. Am J Ophthalmol.2009;147(4):644-652.

2. Ahlers C, Michels S, Beckendorf A, Birngruber R, Schmidt-Erfurth U. Three-dimensional imaging of pigment epithelial detachment in age-related macular de-generation using optical coherence tomography, retinal thickness analysis andtopographic angiography. Graefes Arch Clin Exp Ophthalmol. 2006;244(10):1233-1239.

3. Coscas F, Coscas G, Souied E, Tick S, Soubrane G. Optical coherence tomogra-phy identification of occult choroidal neovascularization in age-related maculardegeneration. Am J Ophthalmol. 2007;144(4):592-599.

4. Sato T, Iida T, Hagimura N, Kishi S. Correlation of optical coherence tomogra-phy with angiography in retinal pigment epithelial detachment associated withage-related macular degeneration. Retina. 2004;24(6):910-914.

5. Spaide RF, Curcio CA. Drusen characterization with multimodal imaging. Retina.2010;30(9):1441-1454.

B

D

A

C

Baseline

Wk 6

Wk 9

Wk 12

Wk 15

Wk 21

Wk 24

Wk 43

Wk 49

Wk 52

Wk 70

Figure 5. The right eye of a 64-year-old woman with neovascular age-relatedmacular degeneration. A, Color photograph at the onset of intravitrealranibizumab injections revealed parafoveal drusen. B, One year later, therewas a vascularized pigment epithelial detachment (PED) detected in theinferotemporal macula. The arrowhead shows its location in the colorphotographs and in the corresponding spectral-domain optical coherencetomographic scans (SD-OCT) (D). C, Three years after presentation, colorphotographs revealed pigment hyperplasia in the central macula. Theinferotemporal PED had flattened following a retinal pigment epithelium(RPE) tear, leaving an area of subretinal fibrosis. Temporal to the resolvedPED, a well-defined area of yellow-gray deposit with foci of brighter refractilematerial is shown (C, green arrow). D, The serial eye-tracked SD-OCTs showevolution of a second PED correlating with an accumulation of yellowishexudates (D, week 6, green arrow). The progression appears to be a gradualenlargement and vascularization of an initially serous PED with thedevelopment of sub-RPE hyperreflective bands, the onion sign.




6. Yasuno Y, Miura M, Kawana K, et al. Visualization of sub-retinal pigment epi-thelium morphologies of exudative macular diseases by high-penetration opti-cal coherence tomography. Invest Ophthalmol Vis Sci. 2009;50(1):405-413.

7. Hartnett ME, Weiter JJ, Garsd A, Jalkh AE. Classification of retinal pigment epi-thelial detachments associated with drusen. Graefes Arch Clin Exp Ophthalmol.1992;230(1):11-19.

8. Casswell AG, Kohen D, Bird AC. Retinal pigment epithelial detachments in theelderly: classification and outcome. Br J Ophthalmol. 1985;69(6):397-403.

9. Bressler NM, Silva JC, Bressler SB, Fine SL, Green WR. Clinicopathologic cor-relation of drusen and retinal pigment epithelial abnormalities in age-related macu-lar degeneration: 1994. Retina. 2005;25(5)(suppl):130-142.

10. Green WR, Enger C. Age-related macular degeneration histopathologic studies:the 1992 Lorenz E. Zimmerman lecture: 1992. Retina. 2005;25(5)(suppl):1519-1535.

11. Klein ML, Wilson DJ. Clinicopathologic correlation of choroidal and retinal neo-vascular lesions in age-related macular degeneration. Am J Ophthalmol. 2011;151(1):161-169.

12. Coscas G. Optical Coherence Tomography in Age-Related Macular Degeneration.Heidelberg, Germany: Springer Medizin Verlag; 2009.

13. Bolz M, Schmidt-Erfurth U, Deak G, Mylonas G, Kriechbaum K, Scholda C; Dia-betic Retinopathy Research Group Vienna. Optical coherence tomographic hy-perreflective foci: a morphologic sign of lipid extravasation in diabetic macularedema. Ophthalmology. 2009;116(5):914-920.

14. Nowilaty SR, Al-Shamsi HN, Al-Khars W. Idiopathic juxtafoveolar retinal telan-giectasis: a current review. Middle East Afr J Ophthalmol. 2010;17(3):224-241.

15. Gragoudas ES, Li W, Lane AM, Munzenrider J, Egan KM. Risk factors for radia-tion maculopathy and papillopathy after intraocular irradiation. Ophthalmology.1999;106(8):1571-1577, discussion 1577-1578.

16. Othman IS, Moussa M, Bouhaimed M. Management of lipid exudates in Coatsdisease by adjuvant intravitreal triamcinolone: effects and complications. Br JOphthalmol. 2010;94(5):606-610.

17. Fernandes BF, Odashiro AN, Maloney S, Zajdenweber ME, Lopes AG, BurnierMN Jr. Clinical-histopathological correlation in a case of Coats’ disease. DiagnPathol. 2006;1:24.

18. Ogino K, Murakami T, Tsujikawa A, et al. Characteristics of optical coherencetomographic hyperreflective foci in retinal vein occlusion. Retina. 2012;32(1):77-85.

19. Ota M, Nishijima K, Sakamoto A, et al. Optical coherence tomographic evalua-tion of foveal hard exudates in patients with diabetic maculopathy accompany-ing macular detachment. Ophthalmology. 2010;117(10):1996-2002.

20. Lima LH, Freund KB, Klancnik JM Jr, Spaide RF. Intraretinal crystalline depositsin neovascular age-related macular degeneration. Retina. 2010;30(4):542-547.

21. Deak GG, Bolz M, Kriechbaum K, et al; Diabetic Retinopathy Research Group Vi-enna. Effect of retinal photocoagulation on intraretinal lipid exudates in diabeticmacular edema documented by optical coherence tomography. Ophthalmology.2010;117(4):773-779.

22. Cusick M, Chew EY, Chan CC, Kruth HS, Murphy RP, Ferris FL III. Histopathol-ogy and regression of retinal hard exudates in diabetic retinopathy after reduc-tion of elevated serum lipid levels. Ophthalmology. 2003;110(11):2126-2133.

23. Otani T, Kishi S. Tomographic findings of foveal hard exudates in diabetic macu-lar edema. Am J Ophthalmol. 2001;131(1):50-54.

24. Burns RP, Feeney-Burns L. Clinico-morphologic correlations of drusen of Bruch’smembrane. Trans Am Ophthalmol Soc. 1980;78:206-225.

25. Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of theretinal pigment epithelium. Eye (Lond). 1988;2(pt 5):552-577.

26. Cukras C, Agron E, Klein ML, et al; Age-Related Eye Disease Study Research Group.Natural history of drusenoid pigment epithelial detachment in age-related macu-lar degeneration: Age-Related Eye Disease Study report no 28. Ophthalmology.2010;117(3):489-499.

27. Sarraf D, Gin T, Yu F, Brannon A, Owens SL, Bird AC. Long-term drusen study.Retina. 1999;19(6):513-519.

28. Holz FG, Spaide RF. Medical Retina: Focus on Retinal Imaging. Heidelberg, Ger-many: Springer Medizin Verlag; 2010.

29. Grossniklaus HE, Miskala PH, Green WR, et al. Histopathologic and ultrastruc-tural features of surgically excised subfoveal choroidal neovascular lesions: sub-macular surgery trials report no 7. Arch Ophthalmol. 2005;123(7):914-921.

30. Lafaut BA, Bartz-Schmidt KU, Vanden Broecke C, Aisenbrey S, De Laey JJ, Hei-mann K. Clinicopathological correlation in exudative age related macular degen-eration: histological differentiation between classic and occult choroidalneovascularisation. Br J Ophthalmol. 2000;84(3):239-243.

31. Theelen T, Berendschot TT, Hoyng CB, Boon CJ, Klevering BJ. Near-infrared re-flectance imaging of neovascular age-related macular degeneration. Graefes ArchClin Exp Ophthalmol. 2009;247(12):1625-1633.

32. Knupp C, Amin SZ, Munro PM, Luthert PJ, Squire JM. Collagen VI assemblies inage-related macular degeneration. J Struct Biol. 2002;139(3):181-189.

33. Malek G, Li CM, Guidry C, Medeiros NE, Curcio CA. Apolipoprotein B in cholesterol-containing drusen and basal deposits of human eyes with age-related maculopathy.Am J Pathol. 2003;162(2):413-425.

34. Curcio CA, Millican CL, Bailey T, Kruth HS. Accumulation of cholesterol with agein human Bruch’s membrane. Invest Ophthalmol Vis Sci. 2001;42(1):265-274.

35. Curcio CA, Presley JB, Malek G, Medeiros NE, Avery DV, Kruth HS. Esterifiedand unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy. Exp Eye Res. 2005;81(6):731-741.

36. Curcio CA, Johnson M, Huang JD, Rudolf M. Apolipoprotein B-containing lipo-proteins in retinal aging and age-related macular degeneration. J Lipid Res. 2010;51(3):451-467.




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Optical Coherence Tomographic Imaging of Sub-Retinal Pigment Epithelium Lipid