Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4

Abstract

Purpose: To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression.

Design: Consensus meeting.

Participants: Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists.

Methods: As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA.

Main outcome measures: Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates.

Results: OCT was used in cases of early and intermediate AMD as the base imaging method to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA.

Conclusions: An international consensus classification for OCT-defined anatomic features of iRORA are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly is essential to understand better the natural history of the disease, to identify high-risk signs of progression, and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavors, acknowledging that the classification will be refined as new data are generated.

Conflict of interest statement

Conflict of interest:

Dr. Guymer reports grants and personal fees from Novartis, personal fees from Bayer, Apellis, personal fees from Roche/Genentech, outside the submitted work.

Dr. Rosenfeld reports grants and personal fees from Carl Zeiss Meditec during the conduct of the study. He also received additional grant support from Genentech, and Tyrogenex. He has also received personal fees from Achillion Pharmaceuticals, Boehringer-Ingelheim, Carl Zeiss Meditec, Chengdu Kanghong Biotech, Healios K.K, Hemera Biosciences, F. Hoffmann-La Roche Ltd., Isarna Pharmaceuticals, Lin Bioscience, NGM Biopharmaceuticals, Ocunexus Therapeutics, Ocudyne, and Unity Biotechnology. Dr. Rosenfeld has equity interest in Apellis, Verana Health, and Ocudyne., outside the submitted work.

Dr. Curcio reports grants from Hoffman-LaRoche and Heidelberg Engineering.

Dr. Holz reports grants and personal fees from Heidelberg Engineering, grants and personal fees from Optos, grants from Zeiss, during the conduct of the study; grants and personal fees from Novartis, grants and personal fees from Bayer Healthcare, grants and personal fees from Genentech, grants and personal fees from Acucela, personal fees from Boehringer Ingelheim, grants and personal fees from Alcon, grants and personal fees from Allergan, outside the submitted work

Dr. Staurenghi reports personal fees and other from Heidelberg Engineering, grants, personal fees and other from Zeiss Meditec, grants from Optovue, grants and other from Optos, grants, personal fees and other from Centervue, grants from Nidek, grants, personal fees and other from Novartis, personal fees and other from Bayer, other from Boeheringer, other from Allergan, other from Alcon, outside the submitted work

Dr. Freund reports grants and personal fees from Genentech/Roche, personal fees from Heidelberg Engineering, personal fees from Optovue, personal fees from Allergan, personal fees from Novartis, personal fees from Carl Zeiss Meditec, during the conduct of the study.

Dr. Schmitz-Valckenberg reports grants from Acucela, grants and personal fees from Alcon/Novartis, grants and personal fees from Allergan, grants and personal fees from Bayer, grants and personal fees from Bioeq/Formycon, grants, personal fees and non-financial support from Carl Zeiss MediTec AG, grants and non-financial support from Centervue, personal fees from Galimedix, grants and non-financial support from Heidelberg Engineering, grants from Katairo, non-financial support from Optos, outside the submitted work.

Dr Sparrow reports grants from National Eye Institute (RO1EY024091, RO1EY12951. R24 EY027285, P30EY019007) Foundation Fighting Blindness, Research to Prevent Blindness, Heidelberg Engineering, Edward N and Della L. Thome Foundation; the Arnold and Mabel Beckman Initiative for Macular Research; Alcon, Alimera, Janssen Research and Development LLC, Baxter Healthcare Corporation, Othera Pharmaceuticals, Inc; personal fees from Bayer Healthcare, Pfizer; Astellas; outside the submitted work,

Dr. Spaide reports consulting fees and royalties from Topcon Medical Systems, consulting fees from Heidelberg Engineering, and royalties from DORC, outside the submitted work.

Dr. Tufail reports grants and personal fees from Novartis, personal fees from Roche, grants and personal fees from Bayer Healthcare, , personal fees from Allergan, grants and personal fees from Alcon, and personal fees from Heidelberg Engineering, personal feed from Kanghong, outside the submitted work. Supported in part from the National Institute for Health Research Biomedical Research Centre Moorfields Eye Hospital,.

Dr. Chakravarthy reports personal fees from Novartis, Bayer, Allergan and Heidelberg Engineeering.

Dr. Jaffe reports personal fees from Heidelberg Engineering, outside the submitted work.

Dr. Csaky reports personal fees from Genentech, Regeneron, Heidelberg Engineering, Gyroscope, Roche, Allergan, personal fees and grants from Ophthotech, Acucela, and equity interest in Apellis outside the submitted work..

Dr. Sarraf reports grants and other from Genentech, grants from Heidelberg, grants from Regeneron, grants and other from Optovue, and grants from Topcon, personal fees from Bayer and Novartis and Optovue, outside the submitted work.

Dr. Monés reports grants from Eyerisk Consortium 2020, Novartis, Bayer, Alcon, Roche, Ophthotech, personal consultation fees from Novartis, Bayer, Alcon, Roche, Genentech, Cellcure, Reneuron and stock shareholder from ophthotech and Notalvision

Dr. Tadayoni reports grants and personal fees from Novartis, grants and personal fees from Bayer, grants and personal fees from Allergan, personal fees from Roche-Genetech, personal fees from Thea, personal fees from Alcon, grants from Zeiss, personal fees from Oculis, outside the submitted work;.

Dr. Grunwald has nothing to disclose.

Dr. Bottoni reports personal fees from Novartis, personal fees from Bayer, non-financial support from Allergan, non-financial support from Heidelberg Engineering, outside the submitted work

Dr. Liakopoulos reports personal fees and non-financial support from Heidelberg Engineering and Carl Zeiss Meditec, personal fees from Novartis, personal fees from Allergan, personal fees from Bayer, outside the submitted work.

Dr. Pauleikhoff discloses participation in clinical studies financed by Roche, Novartis and Bayer and consultation fees of Novartis and Bayer.

Dr Pagliarini reports personal fees and non-financial support from Novartis, Bayer, Allergan, Alcon, Heidelberg Engineering and Zeiss, outside of the submitted work.

Dr. Chew has nothing to disclose

Dr. Viola, has nothing to disclose

Dr. Fleckenstein reports grants, personal fees and non-financial support from Heidelberg Engineering, non-financial support from Zeiss Meditech, grants and non-financial support from Optos, personal fees from Novartis, personal fees from Bayer, grants and personal fees from Genentech, from Roche, outside the submitted work; In addition, Dr. Fleckenstein has a patent US20140303013 A1 pending

Dr. Blodi has nothing to disclose

Dr Lim reports non-financial support from Novartis and Heidelberg Engineering.

Dr Chong is an Boehringer Ingelheim International GmBH.

Dr Lutty has nothing to disclose

Dr. Bird has nothing to disclose.

Dr. Sadda reports grants and other from Optos, grants and other from Carl Zeiss Meditec, during the conduct of the study; grants and other from Allergan, grants and other from Carl Zeiss Meditec, other from Alcon, other from Allergan, other from Genentech, other from Regeneron, other from Novartis, outside the submitted work.

Copyright © 2019 American Academy of Ophthalmology. All rights reserved.

Figures

Figure 1.. Examples of multimodal imaging features of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA).

First column = color fundus photograph (CFP), second column = fundus autofluorescence (FAF), third column = near infrared reflectance (NIR), fourth column = optical coherence tomography (OCT) B-scan. A and B) CFP of the left maculae of two individual cases with large drusen. First column: CFP shows drusen and pigmentary changes without evidence of GA. Second column: FAF shows only small areas of hypo autofluorescence. Third column: NIR image illustrates no evidence of atrophy. Fourth column: OCT B-scan shows subsidence of the inner nuclear layer (INL) (large arrow) and outer plexiform layer (OPL). Note the hyporeflective wedge-shaped band within the limits of the Henle fibre layer (B) (arrow head). Note loss of photoreceptors as evidenced by outer nuclear layer (ONL) thinning and loss of external limiting membrane (ELM), ellipsoid zone (EZ) and interdigitation zone (IZ). Subjacent to the area of photoreceptor loss is a zone of attenuation and disruption of the RPE (

Figure 2.. Multimodal imaging of an AMD case illustrating progression from incomplete to complete retinal pigment epithelium and outer retinal atrophy (iRORA and cRORA) over 30 months.

First column = color fundus photograph (CFP), second column = fundus autofluorescence (FAF), third column = near infrared reflectance (NIR), fourth column = optical coherence tomography (OCT) B-scan. CFP of the left macula in a case with large drusen and hyperpigmentation, reticular pseudodrusen on FAF, and hyperreflective foci (#) on OCT at baseline. There is disruption of some outer retinal bands and the RPE, but no definite hypertransmission is present, so the criteria for iRORA are not met. At 6 months, there is hypertransmission into the choroid that is seen on OCT (small arrow), so iRORA criteria are now met. At 12 months, iRORA is more definitely seen on the OCT with RPE disruption 250 μm (*) showing a bare Bruch’s membrane (BrM) (arrowhead) and increased hypertransmission > 250 μm (small arrow). At 30 months, the initial atrophic area has changed little compared to 18 months, but additional areas of atrophy are becoming apparent on FAF and NIR. The hyporeflective space in the choroid at 18 and 30 months has been described as a choroidal cavern (%).

Figure 3.. Multimodal imaging of an AMD case illustrating progression from incomplete to complete retinal pigment epithelium and outer retinal atrophy (iRORA and cRORA) over 48 months.

First column = color fundus photograph (CFP), second column = fundus autofluorescence (FAF), third column = near infrared reflectance (NIR), fourth column = optical coherence tomography (OCT) B-scan. CFP of the left macula in a case illustrating large drusen and hyperpigmentation at baseline. FAF shows areas of hypo and hyper autofluorescence on FAF. The OCT at baseline shows a large druse, demonstrating hypertransmission into the choroid (small arrow). The external limiting membrane (ELM) is not clearly seen on top of this druse (large arrow) and the RPE appears intact. As such, the criteria for iRORA are not present. At 6 months, there is little change in CFP, FAF, and NIR, but on OCT, iRORA has developed, with subsidence of the inner nuclear (INL) and outer plexiform (OPL) layers (large arrow), thinning of the outer nuclear layer (ONL) and subsidence of the ELM which is still continuous. The ellipsoid zone (EZ) and RPE are discontinuous (*) and there is increased hypertransmission into the choroid (small arrow). At 18 months, whilst there is little change on the CFP, there is now a hypoautofluorescent area apparent on the FAF (small arrow). On OCT, there is a definite descent and disruption of the ELM on either side of the atrophic area, and in the midst of the atrophic area, OPL and INL subsidence (large arrow), further disruption of RPE, and possible BLamD remaining on Bruch’s membrane (BrM). At 30 months cRORA and atrophy on the FAF are evident, whilst the CFP does not demonstrate GA. The OCT has evidence of photoreceptor loss (subsidence of the INL and OPL, thinning of the ONL, discontinuous ELM descending on both sides of the atrophic area, discontinuity of the EZ and interdigitation zone (IZ) (large arrow), an area of complete RPE disruption (*) without residual BLamD > 250 μm in width and showing a bare BrM (arrowhead) and hypertransmission > 250 μm (small arrow). At 48 months, GA is identified on CFP (black arrow), enlarged area of atrophy on FAF is apparent, and atrophy is noted on the NIR image (white arrow). On OCT, the subsiding OPL within the atrophic area approaches BrM (large arrow).

Figure 4:. External limiting membrane (ELM) approaches druse apex due to photoreceptor shortening.

The histology in Fig 4 supports clinical imaging in Fig 2, 3 and illustrates changes in photoreceptor layers above a large druse as the atrophic process begins. A.Ex vivo imaging of the left eye of 85-year-old white female donor with geographic atrophy. Areas of absent autofluorescence signal (λ=787 nm) indicate complete retinal pigment epithelium (RPE) and outer retinal atrophy (cRORA). Yellow line crosses an area of mottled autofluorescence shown by histology. B, C. Submicrometer epoxy sections of osmium tannic acid paraphenylenediamine post-fixed tissue, stained with toluidine blue, at the plane indicated in A. B. Retina, RPE, and basal laminar deposit (BLamD) are artifactually detached from Bruch’s membrane (black arrowheads) at a soft druse and surrounding basal linear deposit (arrow). Framed area is magnified in C. NFL, nerve fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer; HFL, Henle fiber layer; ONL, outer nuclear layer; ELM, external limiting membrane; Ch, choroid; Sc, Sclera. g, Friedman lipid globule. C. An intact ELM (green arrowheads) skims close to the druse (d) apex, because photoreceptor outer segments are absent and inner segments are markedly shortened. RPE atop the druse is dysmorphic or absent. BLamD is thick with sublayers (L, late, E, early), including basal mounds (asterisk). Histology and figure prepared by J.D. Messinger DC from the Project MACULA resource http://projectmacula.cis.uab.edu/

Figure 5.. Evolution and clinicopathologic correlation of druse-associated atrophy.

Time points of clinical images are shown as months before death of this 90-year-old white woman. A-E, en face imaging shows developing atrophic spots (orange and yellow arrowheads). FAF, fundus autofluorescence (excitation wavelengths 488, 535–585, 532 nm in A,C,D respectively); RGB, color photograph; NIR, near-infrared reflectance. F-H, I-K, optical coherence tomography (OCT) B-scans through the orange and yellow atrophic spots, respectively. Upper and lower arrowheads in G-H and I-J indicate hyperreflectivity corresponding to gliosis and hypertransmission into the choroid, respectively; L-N, histologic sections through yellow and orange atrophic spots. In atrophic areas retina is attached to posterior tissues. Outside atrophic areas there is artifactual bacillary layer detachment. The HFL, in areas of minimal photoreceptor degeneration (asterisk in L), is pale-stained and ordered. In areas of photoreceptor loss, the HFL is stained medium-gray, with disordered fibers and evidence of Müller cell bodies (orange and yellow arrowheads), signifying gliosis. Green arrowheads, external limiting membrane (ELM). Black arrowheads, Bruch’s membrane. L, M, histologic sections 60 μm apart through the orange atrophic spot. In L is a base-down triangle of gliosis (upper arrowhead) and an area of absent ONL bounded by two ELM descents. The prior presence of a druse is indicated by calcific nodules under a blue-stained line of persistent BLamD (lower arrowhead in L). In M, the curved arrowhead indicates where processes from the HFL enter under the BLamD. N, O, two histologic sections 30 μm apart through the yellow atrophic spot. In the center are two drusen (D) with absent RPE and containing large calcific nodules. Through an interruption in the BLamD, gliotic processes enter from the HFL (yellow curved arrow, N). In the HFL are presumed Müller cell bodies (yellow arrowheads, N, O). On the left side of N is a small druse (d) with continuous RPE and ELM. In O, the ELM has descended onto the druse apex, which is covered with persistent BLamD. The RPE is absent. BLamD, basal laminar deposit. NFL, nerve fiber layer; GCL, Ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; HFL, Henle fiber layer; ONL, outer nuclear layer; IS/OS, inner and outer segments; RPE, retinal pigment epithelium; Ch, choroid. Prepared by J.D. Messinger DC and L. Chen MD PhD.

Figure 6:. Descent of the external limiting membrane (ELM) towards Bruch’s membrane.

The histology supports the clinical imaging in Figure 2,3, bottom row. The ELM descends in two curved lines on either side of a narrow isthmus of atrophy typically seen in iRORA. The ONL, HFL, OPL, and INL subside in parallel to the ELM, creating a funnel. The ONL is discontinuous, and the HFL is disordered. Where these ELM descents curve, surviving cone photoreceptors lack outer segments and have short inner segments. Layers: ELM, external limiting membrane (green arrowheads); ILM, inner limiting membrane; NFL, nerve fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; HFL, Henle fiber layer; ONL, outer nuclear layer; ChC, choriocapillaris; black arrowheads, Bruch’s Membrane. 87-year-old white male donor. Prepared by M. Li MD PhD and J.D. Messinger DC from the Project MACULA AMD histopathology resource: http://projectmacula.cis.uab.edu/

Figure 7.. Multimodal imaging of an AMD case illustrating retinal pigment epithelium loss without choroidal hypertransmission over 24 months.

First column = color fundus photograph (CFP), second column = fundus autofluorescence (FAF), third column = near infrared reflectance (NIR), fourth column = optical coherence tomography (OCT) B-scan. The right macula of a case demonstrating large drusen and pigmentary abnormalities on the CFP. At baseline the FAF demonstrates a mottled hypo- and hyperautofluorescent signal. The NIR also presents a mottled reflectance. The OCT demonstrates minimal subsidence of the inner nuclear layer (INL), outer plexiform layer; (OPL) but obvious hyporeflective wedges in Henle’s fiber layer (HFL) (large arrows). There is RPE attenuation (*) without obvious hypertransmission into the choroid. At 12 and 24 months, whilst there is increasing hypoautofluorescence on FAF imaging and progressive loss of the RPE (*) and a bare Bruch’s membreane (BrM). There is minimal hypertransmission into the choroid on the OCT, where greater hypertransmission would be expected to accompany the RPE loss. At no time point in this illustration were all the criteria met for iRORA.

Figure 8.. Multimodal imaging of an AMD case illustrating choroidal hypertransmission despite apparent presence of the retinal pigment epithelium.

First column = color fundus photograph (CFP), second column = fundus autofluorescence (FAF), third column = near infrared reflectance (NIR), fourth column = optical coherence tomography (OCT) B-scan. The left macula of a case of intermediate AMD illustrating large drusen and pigment disturbance, including one area of hypopigmentation (black arrow), not obvious on FAF but seen as a circumscribed area on NIR. At baseline, the OCT demonstrates a large druse with hyperreflective foci (#) at the druse apex and hypertransmission into the choroid (small arrow) in a “bar code” appearance. The RPE is attenuated. There is no subsidence of the inner nuclear layer (INL), outer plexiform layer; (OPL), although the ONL is thinned, and the external limiting membrane (ELM) and ellipsoid zone (EZ) are discontinuous. At baseline all criteria for iRORA have been met. At 6 months, the druse has regressed, and there are two hyporeflective wedges in HFL, subsidence of the OPL and ONL, and a descent of the ELM bounding both sides of the atrophy (large arrows). However, the RPE now appears to remain intact, although there is hypertransmission clearly present (small arrow). As such, at this time point, all the criteria for iRORA are not met. As the CFP image has a corresponding area of hypopigmentation, one explanation for this RPE appearance is preferential loss of melanosomes from the RPE that reduces (but does not eliminate) backscatter.

Figure 9.. Multimodal imaging of an AMD case illustrating marked choroidal hypertransmission despite relatively intact retinal pigment epithelium and persistence of the druse contour.

First column = color fundus photograph (CFP), second column = fundus autofluorescence (FAF), third column = near infrared reflectance (NIR), fourth column = optical coherence tomography (OCT) B-scan The left macula of a case illustrating large drusen on CFP with some hypopigmentation at baseline (black arrow). FAF and NIR do not demonstrate areas of hypoautofluorscence on FAF or reduced NIR, respectively. On OCT at baseline a druse displays hypertransmission into the choroid (bar code appearance, white arrow). There is no subsidence of the the inner nuclear layer (INL), outer plexiform layer; (OPL), and the RPE is preserved, thus not fulfilling all criteria for iRORA. At 6 months, the druse has reduced in size and appears hyporeflective but the overlying RPE remains intact above it, yet there is hypertransmission of the signal into the choroid (small arrow). All the criteria for iRORA are still not met. Over time the druse contour and marked hypertransmission persist (small arrow), and internal reflectivity partially fills the druse, the RPE is now becoming attenuated, although still with potentially residual basal laminar deposit (BLamD). At 24 months, all the criteria for iRORA have been met. Despite the hypertransmission there is no obvious hypoautofluorescence on FAF, although this area is masked by luteal pigment. No hyporeflective areas are seen on NIR, nor is there any corresponding GA on CFP.

Figure 10.. Screening for iRORA using an en face slab with boundaries beneath the retinal pigment epithelium (RPE) to detect hypertransmission into the choroid using swept source (SS) OCT imaging

6×6 mm SS OCTA images of a right eye with large drusen. Panels A and B depict the eye at baseline and panels C and D show progression after 6 months. A:En face structure image using custom sub-RPE slab depicted by the purple boundary lines in B, and the bright area (yellow arrow) corresponds to the area of hypertransmission shown in B. B: SS-OCT B-scan showing a large druse with hypertransmission (yellow arrow). The boundary lines for the sub-RPE slab are shown beneath the RPE. There is loss of the photoreceptor-attributable bands, but the RPE remains intact, and as such, criteria for iRORA have not been met. C: Six months later, an en face structure image using the same custom sub-RPE slab depicted in panel A, but with a brighter area (blue arrow) corresponding to the area of hypertransmission shown in panel D. D: SS-OCT B-scan showing the collapse of the large druse with hypertransmission (lower blue arrow), disruption of the outer retinal layers (upper blue arrow) and a small disruption in the RPE can be seen. All criteria for iRORA have been reached.

Figure 11:. Screening for iRORA using an en face slab with boundaries beneath the retinal pigment epithelium to detect both hypo- and hypertransmission into the choroid using swept source (SS) OCT imaging

6×6 mm SS OCTA images in an eye with large drusen. Figures A and D represent the baseline visit, B and E at the 12 months’ follow-up visit, and C and F at the 20 months’ follow-up visit, where iRORA is evident (red arrow). A:En face structural image using a custom slab (purple lines) showing a hyporeflective area (yellow arrow) corresponding to pigment migration (hyperreflective foci) over the druse in D (yellow arrow). B-F:En face structure images using a custom slab showing a hyperreflective area (blue arrow in B and red arrow in C), which respectively corresponds to drusen (E, blue arrow) with hypertransmission (white arrow) (F), subsidence of the INL and OPL, and a faint wedge-shaped band in the HFL (red arrow). In E, there is subtle hypertransmission into the choroid, subsidence of the INL and OPL and attenuation of the RPE, fulfilling all the criteria for iRORA, and again in F, iRORA is present, and the druse has regressed completely.