Choroidal and Sub-Retinal Pigment Epithelium Caverns: Multimodal Imaging and Correspondence with Friedman Lipid Globules

Abstract

Purpose: To survey Friedman lipid globules by high-resolution histologic examination and to compare with multimodal imaging of hyporeflective caverns in eyes with geographic atrophy (GA) secondary to age-related macular (AMD) and other retinal diseases.

Design: Histologic survey of donor eyes with and without AMD. Clinical case series with multimodal imaging analysis.

Participants: Donor eyes (n = 139; 26 with early AMD, 13 with GA, 40 with nAMD, 52 with a healthy macula, and 8 with other or unknown characteristics) and 41 eyes of 28 participants with GA (n = 16), nAMD (n = 8), Stargardt disease (n = 4), cone dystrophy (n = 2), pachychoroid spectrum (n = 6), choroidal hemangioma (n = 1), and healthy eyes (n = 4).

Methods: Donor eyes were prepared for macula-wide epoxy resin sections through the foveal and perifoveal area. In patients, caverns were identified as nonreflective spaces on OCT images. Multimodal imaging included color and red-free fundus photography; fundus autofluorescence; fluorescein and, indocyanine green angiography; OCT angiography; near-infrared reflectance; and confocal multispectral (MultiColor [Spectralis, Heidelberg Engineering, Germany]) imaging.

Main outcome measures: Presence and morphologic features of globules, and presence and appearance of caverns on multimodal imaging.

Results: Globules were found primarily in the inner choroidal stroma (91.0%), but also localized to the sclera (4.9%) and neovascular membranes (2.1%). Mean diameters of solitary and multilobular globules were 58.9±37.8 μm and 65.4±27.9 μm, respectively. Globules showed morphologic signs of dynamism including pitting, dispersion, disintegration, and crystal formation. Evidence for inflammation in the surrounding tissue was absent. En face OCT rendered sharply delimited hyporeflective areas as large as choroidal vessels, frequently grouped around choroid vessels or in the neovascular tissue. Cross-sectional OCT revealed a characteristic posterior hypertransmission. OCT angiography showed absence of flow signal within caverns.

Conclusions: Based on prior literature documenting OCT signatures of tissue lipid in atheroma and nAMD, we speculate that caverns are lipid rich. Globules, with similar sizes and tissue locations in AMD and healthy persons, are candidates for histologic correlates of caverns. The role of globules in chorioretinal physiologic features, perhaps as a lipid depot for photoreceptor metabolism, is approachable through clinical imaging.

Figure 1:. Panoramic view of Friedman lipid globules in normal choroid and in a neovascular membrane.

A, B, C. 69-year-old woman, unremarkable macula; D. 90-year-old woman, choroidal neovascularization, and fibrovascular scar. A. Lipid globules line up along the inner choroid of foveal section (fuchsia arrowheads). ONH, optic nerve head; R, retina; C, choroid; S, sclera. B. Lipid globules line up along the inner choroid of perifoveal section (fuchsia arrowheads). C. Globules (fuchsia arrowheads) occupy half or more of choroidal thickness. From left to right, globules are multilobular, solitary, multilobular, solitary. INL, inner nuclear layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium; Ch, choroid; S, sclera. D. Globules (fuchsia arrowheads) track from the choroid into neovascular membranes. A large intraretinal cyst with lipid-containing fluid and phagocytes is also present (green arrowhead). R, retina; FV, fibrovascular scar; C, choroid.

Figure 2:. Morphology of lipid globules.

Submicrometer epoxy resin sections of OTAP-post-fixed tissue, toluidine blue stain. A. Solitary and well circumscribed globule, in an 82-year-old man with neovascular AMD. RPE, retinal pigment epithelium. Scale bar in H applies to all panels. B. A large double globule elevates Bruch’s membrane (red arrowheads) in a 75-year-old man with an unremarkable macula. C. Globule with pitting on its surface in a 71-year-old woman with an unremarkable macula. D. Multilobular globules form a chain in a fibrovascular scar just above Bruch’s membrane in a 77-year-old woman with neovascular AMD. E. Dispersing globules in an 87-year-old woman with neovascular AMD. Scar, fibrovascular scar. F. Disintegrating globules (yellow arrowhead) in an 89-year-old man with neovascular AMD. G. Crystalline changes in a globule located adjacent to blood vessel in the sclera in a 77-year-old woman with neovascular AMD. H. Dissolving globules within a disciform scar in an 87-year-old woman with neovascular AMD.

Figure 3.. Lipid globules are extracellular.

A. A solitary lipid globule with pitting on one aspect is located near scleral vessels, 3 mm nasal to the fovea in an 80-year-old woman with RPE detachment. The red arrowhead indicates the part of the globule surface examined by transmission electron microscopy. B. Electron micrograph of lipid globule surface indicated in panel A. Globule surface topology is not consistent with delimitation by a membrane. For comparison, a nuclear membrane is indicated (blue arrowhead).

Figure 4.. Choroidal caverns in a case of geographic atrophy due to atrophic age-related macular degeneration.

A. En face structural optical coherence tomography (OCT) reconstruction at the level of the choroid showing hyporeflective round lesions corresponding with choroidal caverns (arrowheads). B. Infrared reflectance (IR) does not show changes within the area of the caverns. C. Fundus autofluorescence (FAF) shows an area of hypoautofluorescence. D. On indocyanine green angiography (ICGA) the caverns appear hyperfluorescent (arrowheads). E. Structural cross-sectional OCT scan at the corresponding area on panels A-D (black/white line). Pink lines show the level of choroidal segmentation. Choroidal caverns (arrowheads) are seen on panel A and E as irregular non-reflective structures located next to choroidal vessels and associated with a marked posterior increase on OCT signal (choroidal hypertransmission).

Figure 5.. Choroidal caverns and refractile drusen in a case of geographic atrophy due to age-related macular degeneration.

A. Color fundus photograph. B. MultiColor reflectance. C. Fundus autofluorescence. D. Near infrared reflectance. E. En face structural optical coherence tomography (OCT) reconstruction at the level of the choroid at the corresponding area on panels A-D (white box). I-II. Structural cross-sectional OCT scans at the corresponding area on panel E (green lines). Choroidal caverns (black arrows) and refractile drusen (white arrows) are seen on panels A and B as highly refractile structures and on panel D as hyperreflective dots. On panel E, choroidal caverns appear as well-defined, round, non-reflective features with sharp boundaries, whereas refractile drusen are represented by irregular mildly hyporeflective structures with ill-defined boundaries. On scan I, a choroidal cavern appears within the choroid as non-reflective spaces with a characteristic hyperreflective tail, whereas on scan II, refractile drusen are heterogeneous hyperreflective structures with marked posterior shadowing in the outer retina.

Figure 6.. Choroidal caverns in geographic atrophy secondary to Stargardt disease.

A. En face structural optical coherence tomography (OCT) reconstruction at the level of the choroid showing multiple round hyporeflective structures suggestive of choroidal caverns. One of the lesions is pointed (arrowhead). B. Infrared reflectance (IR) demonstrates the cavern to be hyperreflective (arrowhead). C. Fundus autofluorescence (FAF) showing a marked area of hypoautofluorescence. D. Indocyanine green angiography (ICGA) demonstrates hypofluorescence in the area of atrophy. E. Structural cross-sectional OCT scan at the corresponding area on panels A-D (black/white line). Horizontal red lines show the level of choroidal segmentation. Vertical red line shows the location of a choroidal cavern (arrowhead) that appears as a non-reflective structure associated with a posterior choroidal increase on OCT signal (choroidal hypertransmission). Choroidal caverns are in close relationship with choroidal vessels as seen in panel A.

Figure 7.. Multimodal imaging of the left eye of a 68-year-old male diagnosed with pachychoroid neovasculopathy.

A. Color fundus photograph. B. Red free image. C. En face optical coherence tomography (OCT) reconstruction at the level of the choroid showing a non-reflective lesion superior and temporal to the macula (blue and pink lines). D. Magnification of the area on the black box on image D. E. Cross-sectional swept-source OCT scan at the corresponding area on panel E. Yellow lines show the area of segmentation for image C. F. Magnification of the area on the white box on image E. The non-reflective lesion appears irregular-shaped and associates a tail of posterior choroidal hypertransmission (white arrowheads), whereas the retinal vessels demonstrate shadowing of the OCT signal (black arrowheads). The correspondence of vessels and caverns is made on panels D and F (white dashed lines)

Figure 8.. Multimodal imaging of the right eye of an 84-year-old woman diagnosed with neovascular age-related macular degeneration.

A, Color fundus photograph. B, Fundus autofluorescence (FAF) image. C, Red-free (RF) image. D, Infrared reflectance (IR) image. E, En face structural OCT and F, en face OCT angiography (OCTA) reconstructions at the level of the choroid at the corresponding areas on A–D (white-dashed box). G, Structural cross-sectional OCT scan at the corresponding area on (E) (blue line). Red lines show the area of segmentation for (E–F). H, Cross-sectional OCTA image with flow signal overlay. The nonreflective structures are located within the neovascular tissue, along vessels with the characteristic tail of hypertransmission (arrowhead), but now showing flow signal on OCTA.