In the 6 available OCT volumes, the ELM descent was detectable in 8 to 9 of 10 B-scans crossing GA in 3 volumes, 2 to 3 of 10 scans in 2 volumes, and in no scans in one volume. Automatic real time function and quality values ranged from 7 to 11 and 3 to 27, respectively. Relative to B-scans with visible ELM descents, B-scans with invisible ELM descents had similar ART values (8.83 vs. 8.89; P = 0.960) and significantly lower-quality values (17.81 vs. 12.96 dB; P = 0.001).
Histology of the Retinal Pigment Epithelium–Deposit Complex
Geographic atrophy corresponded to a small, multilobular atrophic area in the nasal parafovea, 408 to 882 µm from the foveal center. Figures 5–9 correlate point-by-point ex vivo histology to in vivo clinical imaging. Table 2 and Supplemental Digital Contents 6–8 (See Tables 2–4, http://links.lww.com/IAE/A959, http://links.lww.com/IAE/A960, http://links.lww.com/IAE/A961) show cellular phenotype frequencies and layer thicknesses, for RPE–deposit complex, BrM–ChC, and outer retina, in order. To clarify relations with both photoreceptor topography and GA borders, Table 2 shows all RPE–deposit complex thicknesses, from nasal to temporal, across the histological sections.
Subretinal drusenoid deposit was widespread in the macula and beyond, yet absent in and near the atrophic areas and over subfoveal drusen (Figure 5 and Table 2). In 45 sections (mean length 7.35 ± 0.65 mm), coverage of macular RPE by SDD overall was 76.9% ± 9.9%. Because SDD was clearly visible in NIR only in temporal macula (Figures 3–4), we compared eccentricity-matched areas in temporal and nasal perifovea (Figure 5 and Table 2). In both places and consistent with previous reports,13,22,45,46 SDD comprised mounds of extracellular material consisting of a dispersed phase of small, regularly spaced, and gray-staining particles within a flocculent and light-staining continuous phase. Some deposits had caps of outer segment fragments (Figure 5B, yellow arrowhead). Infrequently, sloughed RPE and non-RPE cells were also present (Figure 5B, insets). In temporal perifovea, continuous SDD overlaid continuous RPE, punctuated by fascicles of RPE apical processes containing melanosomes and extending to contact outer segments (Figure 5A). Relative to temporal SDD (Figure 5A), nasal SDD (Figure 5B) was thinner, less intact, and flanked by RPE with apically projecting, organelle-filled extensions of cell bodies, sometimes bizarrely shaped, which embraced the deposits. Nasal SDD was also associated with significantly thicker BLamD (Table 2) and overlying photoreceptors with shorter outer segments (Figure 5B). At the nasal GA border, SDD thinned (Table 2).
Corresponding to subfoveal soft drusen on OCT (Figure 3I, red arrowheads) were RPE elevations containing a homogeneous, brown-stained material.47 Retinal pigment epithelium elevations containing similar material were found throughout the nonatrophic area of all sections and were continuous in the sub–RPE-BL space with BLinD. One soft druse end-stage is multilobular calcific nodules that replace the original lipid-rich contents in the sub–RPE-BL space,19 and these were common (18/45 sections). A histologic druse with nodules (Figure 6B) correlated to a druse with a hyporeflective interior on in vivo OCT in Figure 3III (green arrowhead).
In the sub–RPE-BL space of GA (30/45 sections) and extending beyond it under the fovea was a fibrotic material of undulating thickness, with few cells and no apparent vessels (avascular fibrosis, Figures 7–9). This fibrosis was continuous with soft drusen/BLinD, and individual RPE elevations could contain both materials (red arrowheads; See Figure 3, Supplemental Digital Content 3, http://links.lww.com/IAE/A956, showing contents of sub–RPE-BL space). Within fibrosis and not within soft drusen/BLinD were found clefts created by the extraction of cholesterol crystals by solvents during histological processing (Figures 7C and 9C). These correlated to hyperreflective lines above and parallel to BrM on OCT (Figures 7B and 8A, pink arrowheads) and intensely reflective plaques on NIR imaging (Figure 7A, pink arrowhead). In the sub–RPE-BL space in atrophic and nonatrophic areas were phagocytes, multinucleated giant cells, and subducted RPE (See Figure 4, Supplemental Digital Content 4, http://links.lww.com/IAE/A957). In the sub–RPE-BL space of the atrophic area (26/45 sections) were processes (Figure 9C, white arrow) resembling those of similar size and color internal to persistent BLamD in this and other GA eyes and considered Müller cells.7
Considering BLamD and RPE, BLamD was thick and present in early (palisade) and late (scalloped) forms in the nonatrophic area (Figures 6A, B, and 7C). Basal laminar deposit was persistent across GA but thinner (Figures 8C and 9C). In GA, more than half of sampled locations had dissociated RPE (Figures 8C and 9C). In nonatrophic areas, sloughed RPE in the subretinal space (Figures 7C and 8C, blue arrowhead) were hypertrophic and spherical, with moderately concentrated, greenish-stained lipofuscin and melanolipofuscin granules (Figure 7C). In severely nonuniform but still epithelial RPE in the same histologic section, granules were packed and stained bronze, indicating molecular differences between cells in these two states. Retinal pigment epithelium and RPE + BLamD thickened significantly (P < 0.0001) across the nonatrophic area toward the ELM descent, then declined on the atrophic side (Table 2). Near GA, sloughed RPE and individual melanosome/lipofuscin granules were found near the ELM descent only (See Table 2, Supplemental Digital Content 6, http://links.lww.com/IAE/A959), and no intraretinal RPE cells were detected.
Histology of the BrM, Choriocapillaris, and Choroid
BrM was notable for the absence of refractile unstained patches that signify calcification. As shown in Table 2, BrM was thick in the perifovea (1.89 ± 0.25, 1.82 ± 0.27 µm) and thinned across the ELM descent into GA (1.77 ± 0.27, 1.58 ± 0.38, 1.40 ± 0.23 µm; P = 0.0053). Figures 6B, 7C, 8C, and 9C show relatively intact ChC in nonatrophic and atrophic areas, with few retracted capillaries or ghost capillaries. Choriocapillaris density was similar at approximately 0.60 in the perifovea and parafovea (Table 2) and across ELM descent into GA (Table 2). The frequency of unremarkable ChC was high throughout, and depillared BrM was not detected (See Table 3, Supplemental Digital Content 7, http://links.lww.com/IAE/A960). Corresponding to the OCT B-scans, the choroid was found to have relatively preserved thickness (Figure 8, A and B). The stroma was edematous, and large vessels contained blood, likely due to fixation by infusion.28 Friedman lipid globules44 were common in the choroid and in sclera (42/45 and 20/45 sections, respectively; not shown).
Histology of Neurosensory Retina
By both in vivo OCT and ex vivo histology, the atrophic areas (Figures 8 and 9) had ELM descents at the nasal and temporal aspects, with subsidence of OPL and inner nuclear layer between. External limiting membrane descents delimited the atrophic area (Figure 9C, green arrowheads), and between them, the ONL was completely atrophic, and there was no ELM. Optical coherence tomography shows hyporeflective wedges48 on the atrophic sides of each ELM descent (Figure 8A). Histology (Figure 8, B and C) revealed Henle fiber layer (HFL) that is ordered (i.e., parallel fibers), despite artifactual separation of individual fibers, and lacking cellular infiltration (Figure 8C). Internal to the wedge, the inner nuclear layer sagged downward (Figure 8B). On the nonatrophic side of the ELM descent (Figure 9, A–C) were a loss of outer segments, progressive shortening of inner segments, and inward translocation of mitochondria toward the cell body. Dyslamination of HFL/ONL and outer retinal tubulation/photoreceptor islands, two severe forms of photoreceptor degeneration and gliosis,7 were not detected in this eye.
Photoreceptor layer phenotypes and thicknesses are shown in Supplemental Digital Content 8 (see Table 4, http://links.lww.com/IAE/A961). Ectopic photoreceptor nuclei in OPL/HFL were common at the nonatrophic side of the ELM descent, as were ectopic photoreceptor nuclei in the inner segment. Five measures of photoreceptor abundance and health declined significantly (P < 0.0001) to zero on the atrophic side of the ELM descent (frequency of unremarkable ONL, frequency of continuous ONL, ONL thickness, rows of ONL nuclei, and inner segment myoid thickness). Absence of continuous ONL, ELM, and RPE layers (Figure 8C) correlates to GA (Figure 8A) on OCT.
We build on foundational clinicopathologic correlation with panoramic electron microscopy by J.P. and S.H. Sarks and M. C. Killingsworth and a comprehensive OCT catalog by Fleckenstein et al.49 Our index case of GA secondary to AMD had a typical clinical presentation. The index case informs on the extent, topography, and end-stages of extracellular deposits central to AMD progression,50 photoreceptor depletion and gliosis, and the detection limits of current clinical imaging. Data are compared to other donor eyes with GA and clinicopathologic correlation of macular atrophy associated with neovascularization.7,28,29
Mound-shaped RPE elevations with homogeneous and mildly hyperreflective contents seen in OCT B-scans correlated with histologically identified soft drusen containing a homogeneous lipid-rich material–lacking cells and cellular fragments.17 Contents were interpreted as partly preserved membranous debris of Sarks et al,19 which itself is partly preserved masses of lipoprotein particles, both native and fused.47 Much evidence supports the idea that the RPE constitutively secretes large (∼80-nm diameter) apolipoprotein B, E-containing lipoprotein particles rich in esterified cholesterol that fill BrM throughout adulthood to form BLinD and soft drusen, as egress across the RPE–BrM–ChC complex is impaired, age-dependently.51,52 Very large drusen have a lifecycle of growth due to underclearance of these normally secreted RPE products and collapse after RPE migration and death terminates their production.23,46
Of soft druse end-stages described by the Sarks et al19 (reduced production, removal by macrophages, Müller cell processes penetrating BLamD, calcification, and replacement by collagen fibers), the index case exhibited the latter four, with calcification and fibrotic change visible by OCT. Within numerous RPE elevations were nodules, i.e., multilobed refractile structures 5 to 100 µm in diameter that are rich in a molecularly distinct hydroxyapatite. Nodules were recently confirmed as correlating to a heterogeneous internal reflectivity of drusen associated with 6-fold increased risk of progression to advanced disease.53,54 As seen by the Sarks, avascular fibrosis distinct from both fibrin deposition and exudation-associated fibrosis replaced soft drusen/BLinD while maintaining the shapes of drusenoid RPE elevations.55,56 We saw histologic evidence without imaging correlates for sub–RPE-BL cells potentially clearing drusen (Müller cells,7,20,57 subducted RPE, and probable macrophages).58
Within avascular fibrosis were single or sparse cholesterol crystals that could be correlated to intensely reflective areas in NIR and reflective lines in some OCT scans (Figures 3, 7, and 9, pink arrowheads). Fleckenstein et al49 and others59 attributed reflective horizontally oriented plaques to “densification” of BrM (e.g., electron density on transmission electron microscopy).19 Querques et al60 proposed that hyperreflective, variably oriented lines in regressing drusen resulted from either BrM splitting and bowing inward or a process “similar to the onion sign.”61 We subsequently correlated the onion sign in eyes with sub–RPE-BL hemorrhage and fluid to groups of cholesterol crystals,36 suggesting that an aqueous environment is required for super-saturation and precipitation. Conversion of the sub–RPE-BL environment from primarily lipid (soft drusen/BLinD) to nonlipidic (hemorrhage, fluid, and fibrosis) may promote cholesterol crystallization in the available fluid, e.g., the hydration water of collagen fibrils. Our data thus support crystallization as a biomarker for the replacement of soft drusen contents, while also not supporting BrM as a source of mirror-like reflectivity, because BrM in the index case lacked calcification. The Fleckenstein plaques49 may thus represent cholesterol crystals that are too close to BrM (<1.8–11.8 µm) to be resolved with present technology. Conversely, RPE elevations over avascular fibrosis can be distinguished from dome-shaped soft drusen by the slight irregularity of contour and content of reflective crystals (Figure 3).
Subretinal drusenoid deposit was extensive, thick, acellular, and undetectable under the fovea, consistent with a topography resembling that of rod photoreceptors.62 Solid extracellular deposits between photoreceptors and RPE account for reticular pseudodrusen, as established by direct clinicopathologic correlation,14,15 histological survey,13,45 and clinical OCT.16,63 In the index case, histologically detectable SDD was far more extensive than that seen in vivo. The rough texture seen on NIR and FAF (Figure 3, A and B) may thus signify confluent and degenerate25 SDD (Figure 5B). Building on our proposal that SDD entails dysregulation of the same lipid cycling system that produces drusen,13,52 we suggest that SDDs signify both progression risk and some functionality of participatory photoreceptors, RPE, and Müller glia. Subretinal drusenoid deposits also exhibit growth and regression.25 Without an obvious barrier to transport such as BrM, SDD may dissipate because of underproduction by these cells, as they degenerate. Subretinal drusenoid deposit has been misclassified as soft drusen or omitted from grading systems using color fundus photography;27 yet, photoreceptor degeneration and a distinctive RPE dysmorphia associated with SDD underscore its place in AMD.
In the RPE layer, the index case is representative of the appearance and enlargement of GA, in the absence of neovascular findings. The index eye exhibited thickening of the RBB complex toward the ELM descent in OCT and histology (Table 2). This thickening is accounted for by progressive RPE dysmorphia atop a BLamD of relatively uniform thickness. Retinal pigment epithelium dysmorphia at the ELM descent was first described by the Sarks and recently quantified in donor eyes8,39 and in direct clinicopathologic correlation of macular atrophy.29 In the index eye, the retina remained attached at the atrophic area, a common finding in donor eyes with GA, possibly due to Müller cell interaction with persistent BLamD18 that may or may not itself be visible. The hyporeflective wedge of Monés48 is a reliable OCT signature in GA, sometimes visible internal to the entire border in en face OCT. Despite suboptimal tissue preservation, Müller fibers in the HFL remained parallel and ordered, without cellular infiltration, consistent with permissiveness to transmitted light and low reflectivity typical of a wedge. By contrast, punctate reflectivity20 in atrophic areas may result from disordered Müller processes, possibly predictive of atrophy expansion.64
Compared to similarly analyzed donor eyes with GA,7 the index eye differed by having undetectable HFL/ONL dyslamination or intraretinal RPE, relatively healthy ChC, noncalcified BrM, and prominent avascular fibrosis. Relative to the comparison cases, the index eye had a small multilobular atrophic area (See Table 1, Supplemental Digital Content 5, http://links.lww.com/IAE/A958), suggesting that a relatively recent onset of atrophy could underlie these differences. Like the fellow eye that progressed to Type 3 neovascularization,28 the index eye also had abundant extracellular deposits, relatively intact ChC, cells in the sub–RPE-BL space, and progression to advanced AMD at the same (parafoveal) eccentricity, supporting a causal relationship with the topography of outer retinal cells.62,65 However, although the index eye had sub–RPE-BL avascular fibrosis, in the fellow eye, Müller cell processes accompanied a neovascular stalk from the retina that implanted in this compartment.
We provide new information about device-independent and device-dependent visibility of specific pathologies. Both the atrophic zone and drusen were poorly visible in the NIR locator image. Light reflected from the sclera impacts the intensity of retinal reflectivity66 and autofluorescence,67 and eyes with thick choroids, like the index eye, show low NIR within areas of GA. Although BLamD was >11-µm thick under the fovea (Table 2), it could not be cleanly delimited from the RPE layer in OCT. The index eye had notably little focal hyperautofluorescence at the atrophy margin in baseline FAF and accordingly had relatively few sloughed and intraretinal RPE on histology 12 months later. Numerous histologic lipid globules did not manifest as numerous hyporeflective caverns44 because caverns are best seen in en face reconstruction of dense OCT B-scan raster patterns.
Our data help define imaging parameters necessary to consistently visualize the ELM descent, proposed as a histologically meaningful border of atrophy.7,8,39 Descents were visible in a scan with ART = 29 and quality = 24 dB (Figures 3-I) but not in scans with ART = 7 to 11 and quality = 11 to 19 dB (Figure 4, I and II). Separately, we showed that in macular atrophy, 100% of ELM descents were detected, with ART of 7 and quality of 33 dB.29 The invisibility of the ELM descent in color fundus photography and FAF imaging, in concert with inaccurate histologic quantification of outer retinal cells in GA,68 can lead to an overestimate of viable retina available for therapeutic rescue in the atrophic zone. The loss of relevant detail at quality ≤15 dB when ART is below 9 to 10 encourages heightened attention to these settings for accurate assessment of GA and its precursors.
Strengths of this study include serial eye-tracked OCT with the last clinic visit 4 months before tissue recovery, baseline FAF imaging, a detailed and comprehensive histology technique, multiscale viewing of both digital sections and OCT scans, and current nomenclature for both OCT and AMD pathology. Limitations include insufficient image quality in OCT volumes to reveal all relevant features, poor preservation of druse contents, and postmortem detachment that impeded comprehensive quantification of retinal morphology. Nevertheless, this is the first clinicopathologic correlation of GA with in vivo OCT, NIR, and FAF imaging, with the most complete accounting of currently recognized AMD layers since the Sarks' monumental description. Age-related macular degeneration's notorious complexity has been exacerbated by limitations of imaging technologies that could not reveal major pathology within and beyond the RPE layer. The catalog of histologically validated OCT signatures, expanded by this report, can serve as references for other modalities. A timeline from AMD precursors to end-stages visible clinically at the subcellular level is a holy grail for multifactorial diseases of aging. Recent trial imaging data can be interpreted to inform preventive measures and direct new therapies to disease stages before irreversible tissue damage.
The authors thank the Alabama Eye Bank for timely retrieval of donor eyes and C.A. Girkin, MD, MSPH, for making the index eye available for this study.
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age-related macular degeneration; basal laminar deposits; basal linear deposits; drusen; subretinal drusenoid deposits; external limiting membrane; outer retina; photoreceptors; retinal pigment epithelium; Müller cells; optical coherence tomography; fundus autofluorescence; histology; complete retinal pigment epithelium and outer retinal atrophy; geographic atrophy
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