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Clinical science
Non-neovascular age-related macular degeneration with subretinal fluid
  1. Assaf Hilely1,
  2. Adrian Au2,
  3. K Bailey Freund3,
  4. Anat Loewenstein1,
  5. Eric H Souied4,
  6. Dinah Zur1,
  7. Riccardo Sacconi5,
  8. Enrico Borrelli5,
  9. Enrico Peiretti6,
  10. Claudio Iovino6,
  11. Yoshimi Sugiura7,
  12. Abdallah A Ellabban8,9,
  13. Jordi Monés10,
  14. Nadia K. Waheed11,
  15. Sengul Ozdek12,
  16. Duygu Yalinbas12,
  17. Sarah Thiele13,
  18. Luísa Salles de Moura Mendonça11,
  19. Mee Yon Lee14,
  20. Won Ki Lee15,
  21. Pierre Turcotte16,
  22. Vittorio Capuano4,
  23. Meryem Filali Ansary4,
  24. Usha Chakravarthy17,
  25. Albrecht Lommatzsch18,
  26. Frederic Gunnemann18,
  27. Daniel Pauleikhoff18,
  28. Michael S Ip19,
  29. Giuseppe Querques5,
  30. Frank G Holz13,
  31. Richard F Spaide3,
  32. SriniVas Sadda19,
  33. David Sarraf2,20
  1. 1 Division of Ophthalmology, Tel Aviv Ichilov-Sourasky Medical Center, Tel Aviv, Israel
  2. 2 Retinal Disorders and Ophthalmic Genetics Division, Stein Eye Institute, University of California, Los Angeles, Los Angeles, California, USA
  3. 3 Vitreous Retina Macula Consultants of New York, New York, New York, USA
  4. 4 Ophthalmology, Centre Hospitalier Intercommunal De Creteil, Creteil, France
  5. 5 Ophthalmology, Ospedale San Raffaele, Milano, Italy
  6. 6 Department of Surgical Sciences, Eye Clinic, University of Cagliari, Cagliari, Italy
  7. 7 Department of Ophthalmology, University of Tsukuba Faculty of Medicine, Tsukuba, Japan
  8. 8 Hull University Teaching Hospitals NHS Trust, Hull, UK
  9. 9 Suez Canal University Faculty of Medicine, Ismailia, Egypt
  10. 10 Barcelona Macula Foundation, Barcelona, Spain
  11. 11 New England Eye Center, Tufts University School of Medicine, Boston, Massachusetts, USA
  12. 12 Department of Ophthalmology, Gazi University, School of Medicine, Ankara, Turkey
  13. 13 Ophthalmology, University of Bonn, Bonn, Germany
  14. 14 Catholic University of Korea College of Medicine, Seoul, South Korea
  15. 15 Nune Eye Hospital, Seoul, South Korea
  16. 16 Private practice, Quebec City, Canada
  17. 17 Department of Ophthalmology, Queen’s University of Belfast, Belfast, UK
  18. 18 Department of Ophthalmology, Sankt Franziskus-Hospital Münster GmbH, Munster, Germany
  19. 19 Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, California, USA
  20. 20 Greater Los Angeles Veterans Affairs Healthcare Center, Los Angeles, California, USA
  1. Correspondence to David Sarraf, Stein Eye Institute, University of California, 100 Stein Plaza, Los Angeles, CA 90095, USA; dsarraf{at}ucla.edu

Abstract

Purpose To evaluate the various patterns of subretinal fluid (SRF) in eyes with age-related macular degeneration (AMD) in the absence of macular neovascularisation (MNV) and to assess the long-term outcomes in these eyes.

Methods This retrospective study included only eyes with non-neovascular AMD and associated SRF. Eyes with evidence of MNV were excluded. Spectral-domain optical coherence tomography (SD-OCT) was obtained at baseline and at follow-up, and qualitative and quantitative SD-OCT analysis of macular drusen including drusenoid pigment epithelial detachment (PED) and associated SRF was performed to determine anatomic outcomes.

Results Forty-five eyes (45 patients) were included in this analysis. Mean duration of follow-up was 49.7±36.7 months. SRF exhibited three different morphologies: crest of fluid over the apex of the drusenoid PED, pocket of fluid at the angle of a large druse or in the crypt of confluent drusen or drape of low-lying fluid over confluent drusen. Twenty-seven (60%) of the 45 eyes with fluid displayed collapse of the associated druse or drusenoid PED and 24 (53%) of the 45 eyes developed evidence of complete or incomplete retinal pigment epithelial and outer retinal atrophy.

Conclusion Non-neovascular AMD with SRF is an important clinical entity to recognise to avoid unnecessary anti-vascular endothelial growth factor therapy. Clinicians should be aware that SRF can be associated with drusen or drusenoid PED in the absence of MNV and may be the result of retinal pigment epithelial (RPE) decompensation and RPE pump failure.

  • Retina
  • Angiogenesis
  • Choroid
  • Degeneration
  • Macula

https://doi.org/10.1136/bjophthalmol-2020-317326

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    INTRODUCTION

    Traditionally, the presence of subretinal fluid (SRF) has been considered a biomarker of neovascularisation in patients with age-related macular degeneration (AMD). However, it is becoming more evident that fluid may be encountered in the setting of non-neovascular AMD.1–4 Sikorski et al 2 identified SRF in the angle or crypt between confluent drusen and attributed this to a mechanical effect of fluid accumulation, and Querques et al 4 noted the presence of SRF at the apex of an avascular serous pigment epithelial detachment (PED) in eyes with AMD. Lek et al 1 introduced the term non-exudative detachment of the neurosensory retina in 12 eyes with intermediate AMD and described low-lying SRF draping over confluent drusen in the absence of choroidal neovascularisation (CNV).5

    The aim of this study was to analyse the various patterns of SRF in the absence of macular neovascularisation (MNV) in eyes with intermediate AMD and to assess the long-term outcomes in these eyes with non-neovascular AMD and SRF.

    METHODS

    Study design

    This was an international multicentre, retrospective, observational cohort study, comprised of study sites affiliated with the various contributing authors. Institutional review board (IRB) approval was obtained from the University of California, Los Angeles (UCLA) IRB Office of Human Protection (DS). For the other coauthors, IRB approval and patient consent for retrospective analysis of de-identified data were obtained according to the requirements of the respective affiliated institutions. The study was conducted in compliance with the Health Insurance Portability and Accountability Act of 1996 and the Declaration of Helsinki.

    Inclusion/exclusion criteria

    Patients were included in this study if they were diagnosed with non-neovascular intermediate AMD associated with SRF. To be eligible for inclusion, eyes needed to fulfil the criteria for intermediate AMD, that is, macular drusen ≥125 μm in diameter6 or drusenoid PED (defined as a druse ≥350 μm in diameter7), and no evidence of MNV by examination and multimodal imaging at baseline or follow-up, despite the presence of SRF. Follow-up examination with spectral-domain optical coherence tomography (SD-OCT) retinal imaging for a minimum of 3 months was also required for inclusion in the study. If both eyes met the inclusion criteria, the right eye was selected for evaluation and analysis. All the images were analysed by two graders (AH and DS) at one site (UCLA) in order to ensure a uniform grading analysis.

    Eyes were excluded with any history of laser therapy or anti-vascular endothelial growth factor (anti-VEGF) injection. Additional exclusion criteria included any evidence of neovascularisation determined by the presence of macular haemorrhage on examination or imaging. Signs of MNV with fluorescein angiography (FA), indocyanine green angiography (ICGA) and OCT angiography (OCTA) were also criteria for exclusion at any time during the patient’s baseline or follow-up evaluation. FA definition of MNV included an early well-defined area of lacy hyperfluorescence with progressive late leakage or a PED with pooling and an associated hot spot or an irregular elevation of the retinal pigment epithelium (RPE) with progressive stippled leakage or a late leakage from an undetermined source.8 9 ICGA definition of MNV included a hot spot or plaque.10 OCTA definition of MNV included a high flow area of either small-calibre capillaries or a highly organised vascular complex with vessels branching from a core trunk.11 12 Any signs of neovascularisation identified with SD-OCT volumetric and B-scan review such as shallow irregular elevation of the RPE,13 heterogenous hyper-reflective material in the sub-RPE space14 or subretinal hyper-reflective material15 were also considered as criteria for exclusion. In addition, we excluded eyes with purely serous PED,16 17 eyes with findings of central serous chorioretinopathy and those with pachychoroid disease findings, that is, drusenoid deposits typical of pachydrusen, dilated choroidal veins and/or choroidal hyperpermeability on ICGA.18 Patients with incomplete demographic data or poor-quality imaging scans were also excluded.

    Data collected

    Patients’ charts were reviewed between the years 2012 and 2019. All patients underwent a complete ophthalmologic examination including retinal imaging. Presence or absence of haemorrhage in or under the retina was determined by a designated clinician at the contributing site. Registered and tracked SD-OCT scans from the first and last available visits were obtained. FA, ICGA and OCTA images were also collected and analysed, if available, to rule out neovascularisation of any type. Demographic information including patient age, gender, medical history, medications and history of intravitreal anti-VEGF injections were all included in the analysis. Snellen visual acuity (VA) (converted into logarithm of the minimum angle of resolution (LogMAR) for statistical analysis) at baseline and final follow-up was also analysed.

    Image analysis

    SD-OCT volume scans of the retina, including enhanced depth imaging of the choroid, were obtained and performed using one of two spectral domain systems (Heidelberg Spectralis, Heidelberg Engineering, Franklin, Massachusetts, USA) or Zeiss Angioplex (Carl Zeiss Meditec, Dublin, California, USA). The SD-OCT volume scans were acquired in the high-resolution mode and using a scan density of either 97 B-scans or 25 B-scans with line spacing of 61 μm and 251 μm, respectively, with the Heidelberg Spectralis system, and using a scan density of 128 B-scans with line spacing of 47 μm with the Zeiss OCT system, with sufficient high quality to permit the analysis. All included cases adhered to one of the two imaging protocols.

    Qualitative and quantitative SD-OCT analysis of various morphological features was performed. The measurements were made using the built-in calliper in the SD-OCT machine software or assessed by exporting and analysing SD-OCT scans in ImageJ version 1.52a (National Institutes of Health, Bethesda, Maryland, USA).

    SRF was defined as a hyporeflective space located between the external limiting membrane (ELM) of the photoreceptors and the RPE. The thickness of SRF was quantitated by measuring the maximum distance (after analysis of all the B-scans in the volume) between the RPE band and the posterior border of the neurosensory retina and was termed SRF thickness.19

    Drusenoid PED was defined as a large druse with a basal diameter greater than 350 μm.7 Drusenoid PED height was measured as the maximum distance between Bruch’s membrane and the outer boundary of the RPE.20 Drusenoid PED height was measured at the baseline and follow-up visits using tracked SD-OCT scans and the SD-OCT calliper tool to obtain the maximum PED height as previously noted. A decrease of 50% or more in the drusenoid PED height as measured between the baseline and follow-up visit was defined as a collapse in the height of the drusenoid PED.

    Additional qualitative SD-OCT features were identified and analysed and are defined below. Many of these OCT structural biomarkers have been noted to be risk factors for progression to atrophy.21 22

    Hyper-reflective foci were defined as intraretinal hyperreflective dot-like or punctate lesions overlying the RPE layer of a druse or drusenoid PED and attributed to dissociated RPE cells.22 An RPE plume was defined as a hyper-reflective lesion radially migrating and tracking along the Henle fibre layer.22 Focal RPE thickening was defined as focal or band-like hyper-reflective thickening of the RPE layer of a druse or drusenoid PED.22 Drusenoid PED hyporeflectivity was defined as hyporeflective spaces located in the sub-RPE compartment of a drusenoid PED.21

    Acquired vitelliform lesion (AVL) overlying drusen and drusenoid PEDs was defined as a homogenous accumulation of hyper-reflective material between the RPE and the neurosensory retina located above the hyporeflective band of SRF. Cases of adult-onset vitelliform dystrophy or other non-AMD causes of AVL were excluded.23

    SRF with an AVL was defined as a multilayered accumulation of material comprised of a hyporeflective layer immediately above the RPE and a hyper-reflective band (ie, AVL) immediately beneath the neurosensory retina.24

    Choroidal hypertransmission was defined as vertical bands of increased reflectivity extending deep to the level of the RPE and extending into the choroid as a result of underlying regions of RPE disruption or atrophy.22

    Complete RPE and outer retinal atrophy (cRORA) was defined as a zone of attenuation or disruption of the RPE band of ≥250 μm associated with evidence of overlying photoreceptor degeneration including outer nuclear layer (ONL) thinning, ELM, ellipsoid zone (EZ) and interdigitation zone (IZ) loss.25 Incomplete RPE and outer retinal atrophy (iRORA) was defined as cRORA, however with a zone of attenuation or disruption of the RPE band of ≤250 μm.25

    Complete outer retinal atrophy (cORA) was defined as overlying photoreceptor degeneration including ONL thinning, ELM loss, EZ and IZ loss, without any RPE disruption in a zone of ≥250 μm.25 Incomplete outer retinal atrophy was defined as cORA, however within a zone of ≤250 μm.25

    Statistical analysis

    Statistical analysis was performed on R version 3.5.0 (www.r-project.org). Demographic data, outcomes and SD-OCT features of atrophy were reported as averages with SD (age, follow-up, fluid thickness, vision or PED height) or numerical counts with percentages (sex, eye, development of cRORA, iRORA, PED collapse or specific OCT features of atrophy). Paired Wilcoxon signed-rank test was performed for interval variables between two groups (baseline vs follow-up vision or PED height). Paired McNemar’s test was performed for categorical variables (baseline vs follow-up cRORA or iRORA). P value <0.05 was considered statistically significant.

    RESULTS

    Demographic data

    Forty-five eyes from 45 patients were identified with SRF associated with intermediate AMD and macular drusen or drusenoid PED and no evidence of neovascularisation. The average age of patients in the overall cohort was 72.8±11.0 years old (range 49–93 years old) and women comprised 29 (64.4%) of the 45 eyes of this group with the right eye involved in 27 (60.0%) cases. Mean follow-up was 49.7±36.7 months.

    Online supplemental table 1 summarises the modalities used to exclude MNV. A total of 26 (57.8%) patients underwent FA, 18 (40.0%) patients underwent OCTA and 13 (28.9%) patients underwent ICGA. Only three (6.7%) patients failed to undergo FA, OCTA or ICGA to rule out MNV, although close evaluation of the OCT volume scans failed to detect evidence of MNV in these cases. Of note, during the data collection process, eight patients were noted to harbour MNV and therefore were excluded from the dataset.

    Patterns of SRF in non-neovascular AMD

    Across the overall cohort, the average SRF thickness was 148±135.5 μm.

    There were three different patterns of SRF:

    1. Fluid located at the apex of a drusenoid PED in 26 (57.8%) of the 45 eyes (figure 1A,B).

    2. Fluid located at the angle of a large druse or drusenoid PED or within the pocket or crypt between confluent drusen in 11 (24.4%) of the 45 eyes (figure 1C,D).

    3. Fluid located in a shallow or low-lying drape over confluent drusen in 8 (17.8%) of the 45 eyes (figure 1E,F, online supplemental figure A,B).

    Figure 1
    Figure 1

    Three cases of non-neovascular intermediate age-related macular degeneration illustrating drusenoid pigment epithelial detachment (PED) and drusen associated with three different patterns of subretinal fluid (SRF) that progress to collapse and atrophy. (A) Spectral-domain optical coherence tomography (SD-OCT) illustrates drusenoid PED with crest of SRF associated with an acquired vitelliform lesion and focal retinal pigment epithelium (RPE) thickening, including intraretinal hyper-reflective foci. (B) At the 5-year follow-up visit, the drusenoid PED is collapsed with development of complete RPE and outer retinal atrophy (cRORA). (C) SD-OCT illustrates drusenoid PED with SRF located at the angle or crypt of the PED. (D) At the 10-month follow-up visit, the PED is collapsed with progression to cRORA. (E) SD-OCT illustrates drusenoid PED with low-lying drape of SRF. (F) At the 7-year follow-up visit, the drusenoid PED is collapsed with progression to cRORA.

    Figure 2
    Figure 2

    Case of non-neovascular intermediate age-related macular degeneration illustrating drusenoid pigment epithelium detachment (PED) associated with severe subretinal fluid (SRF) at the apex of the drusenoid PED with subsequent collapse and development of complete retinal pigment epithelial and outer retinal atrophy (cRORA). (A) Spectral-domain optical coherence tomography (SD-OCT) B-scan displays a large drusenoid PED with SRF at the crest at baseline. Note the associated findings of choroidal hypertransmission and a hyporeflective subretinal pigment epithelium (sub-RPE) space indicating a high risk for progressive RPE atrophy. (B) At the 3-year follow-up visit, severe apex fluid is noted associated with intraretinal hyper-reflective foci, focal RPE thickening and hyporeflective sub-RPE areas. (C) At the 4-year follow-up visit, note the development of intraretinal degenerative cysts. (D) At the 5-year follow-up visit, the drusenoid PED is collapsed with development of cRORA. Near-infrared (NIR) (A through D) and fundus autofluorescence (A and D) images illustrate the progressive development of RPE atrophy. The level of the SD-OCT B-scan is shown on the NIR images.

    Figure 3
    Figure 3

    Case of non-neovascular intermediate age-related macular degeneration illustrating drusenoid pigment epithelium detachment (PED) associated with severe subretinal fluid (SRF) at the apex of the drusenoid PED with subsequent collapse and development of complete retinal pigment epithelial and outer retinal atrophy (cRORA). (A) Spectral-domain optical coherence tomography B-scan illustrates a large drusenoid PED. (B) At the 7-year follow-up visit, evolving collapse of the drusenoid PED is evident with the development of severe SRF at the apex and high risk signs for the progression to atrophy including focal retinal pigment epithelial (RPE) thickening intraretinal hyper-reflective foci, choroidal hypertransmission and hyporeflective areas in the subRPE compartment. (C) At the 10-year follow-up visit, the drusenoid PED is collapsed with the development of cRORA.

    Functional and anatomical outcomes of non-neovascular AMD

    For the overall cohort, the mean baseline Snellen VA in LogMAR was 0.4±0.3 (Snellen 20/45). At final follow-up, the VA significantly decreased to 0.6±0.4 (Snellen 20/74, p<0.001). The average central PED height at baseline was 620.7±345.4 μm across the overall cohort. At final follow-up, central PED height significantly decreased to 199.7±271.3 μm (p<0.001) (table 1).

    In the total cohort, 27 (60.0%) of the 45 eyes with non-neovascular AMD and SRF exhibited collapse of the drusen or drusenoid PED and 22 (48.9%) of the 45 eyes progressed to cRORA and 2 (4.4%) of the 45 eyes progressed to iRORA (table 1). (figure 2 and figure 3).

    When we excluded patients with AVL, the outcomes were similar: 16 (55.2%) of the 29 eyes collapsed and 13 (44.8%) of the 29 progressed to cRORA.

    The follow-up period for the collapsed and the non-collapsed cases was 67.6 months and 22.8 months, respectively (p<0.001). For the cRORA and iRORA outcomes, the follow-up period was 69.5 months and 52.9 months, respectively.

    We calculated minimum threshold drusenoid PED height at baseline that predicted progression to iRORA and cRORA and this varied according to the specific location of fluid: 265 μm with apex fluid, 80 μm with draping fluid and 551 μm with angle/crypt fluid, with an average height of 701.0 μm, 793.5 μm and 271.3 μm, respectively.

    A number of different OCT biomarkers of atrophy were analysed (table 2). Of note, 43 (95.6%) of the 45 eyes with SRF displayed focal RPE thickening, 36 (80.0%) of the 45 displayed intraretinal hyperreflective foci and 26 (57.8%) of the 45 eyes displayed sub-RPE hyporeflective spaces.

    View this table:
    Table 1

    Functional and anatomical outcomes of total cohort with non-neovascular AMD and SRF

    View this table:
    Table 2

    SD-OCT features of atrophy and their rate of association with SRF in non-neovascular AMD

    DISCUSSION

    This study analysed the presence of SRF in eyes with non-neovascular AMD and the associated long-term outcomes. Three different patterns of fluid accumulation were noted in intermediate AMD. The most common pattern was a crest of SRF above the apex of a large drusenoid PED in 26 (57.8%) of the 45 eyes, which was associated with a high rate of collapse and eventual atrophy. SRF located at the angle or in the crypt between confluent drusen in 11 (24.4%) of the 45 eyes comprised the second pattern. A drape of low-lying fluid over confluent drusen in 8 (17.8%) of the 45 eyes comprised the third pattern. In total, 27 (60%) of all 45 eyes showed evidence of drusen or drusenoid PED collapse and 24 (53.3%) of all 45 eyes progressed to advanced forms of atrophy (cRORA/iRORA). Five-year rates of atrophy in eyes with drusenoid PEDs have been noted to be approximately 20%.7 24

    There are a number of OCT biomarkers of non-neovascular AMD that can predict the future development of RPE atrophy. In this study, SRF was associated with many of these features.21 22 In fact, 43 (95.6%) of the 45 cases in this study with intermediate AMD and SRF also displayed focal RPE thickening and 36 (80%) of the 45 cases displayed hyper-reflective intraretinal foci. However, without a comparative group of AMD patients without SRF, we were unable to determine whether SRF was an independent risk factor for atrophy.

    AVL is another known risk factor of RPE atrophy.26 However, a separate analysis excluding eyes with AVL was performed and outcomes were similar. A common pathway exists with the development of SRF and AVL, and vitelliform accumulation may represent a sequela of SRF persistence.27 Gradual RPE dysfunction secondary to long-term separation of the RPE from the underlying choriocapillaris may lead to the collection of SRF, impairment of outer segment phagocytosis and the deposition of AVL.27 Alternatively, ageing RPE cells may gradually lose the ability to clear photoreceptor outer segments and absorb fluid with resultant accumulation of vitelliform material over time in the subretinal space.23 RPE atrophy may be the final outcome in either scenario.

    The development of SRF in non-neovascular AMD has been previously investigated in smaller studies. Sikorski et al 2 evaluated six patients with SRF identified in the angle or crypts between confluent drusen and followed these patients for an average period of only 16.5 months. They showed no progression to future CNV or geographic atrophy due to limited follow-up and attributed the fluid to mechanical strain or tensile stress of the drusenoid PED on the outer retina leading to ‘tenting’ of the retina. Lek et al 1 described SRF in eyes with intermediate AMD in just 12 patients with long-term follow-up (30–54 months) but did not identify and study all the different patterns of non-neovascular fluid nor the association with atrophy.

    Various mechanisms may explain the accumulation of SRF in eyes with non-neovascular AMD.28–30 Impaired oxygen diffusion due to the increased distance between the choriocapillaris-Bruch’s complex and the RPE and outer retina can lead to RPE and photoreceptor dysfunction.31 32 The apex of the drusenoid PED represents the greatest separation from the choriocapillaris and the most likely location of RPE atrophy.24 The RPE may lose pumping function capacity prior to death leading to fluid or transudate accumulation in the subretinal space.33 This may explain the most common location of fluid development at the apex of the drusenoid PED and the threshold height for collapse of 265 microns noted in this study and the association with other biomarkers of atrophy. This significant hypoxic gradient may also induce VEGF production from the retina, causing endothelial incompetence and vascular leakage and exudation from the retinal capillary plexus.20

    In neovascular AMD, the presence of SRF is due to an exudative process, as VEGF-dependent angiogenesis leads to the development of neovascular complexes with immature endothelium that are prone to hyperpermeability and bleeding and exudation.20 In non-neovascular or ‘dry’ AMD, the development of fluid in the absence of MNV may be the result of either transudative (eg, RPE pump failure) or exudative (eg, retinal capillary leakage due to increased VEGF secretion) processes and underscores the importance of careful multimodal evaluation, including the use of OCTA to assess for MNV before reflex administration of anti-VEGF therapy with the identification of fluid.34 This study also challenges the use of nebulous terms such as dry or non-exudative AMD which are not sufficiently accurate in their description of the disease. Neovascular or non-neovascular AMD (with or without fluid) may be the most appropriate language to adopt.

    This study is limited by its retrospective and non-consecutive study design. As a result, this study was unable to provide the exact incidence of SRF complicating eyes with intermediate AMD. Patients included in this study did not have a uniform or standardised protocol of multimodal retinal imaging or consistent follow-up intervals. A prospective dataset with uniform multimodal retinal imaging to definitively exclude MNV at baseline and a comparative control group with long-term, consistent follow-up to properly assess for the development of atrophy are essential to validate the findings of this study. Nevertheless, this study highlights the important presentation of non-neovascular fluid in patients with AMD and indicates the need to further investigate the possible association of fluid as a risk factor for atrophy.

    In conclusion, this study analysed the presence of SRF in a relatively large cohort of eyes with non-neovascular AMD. We identified three different patterns of SRF development in the clinical setting of intermediate AMD. The most common pattern was the presence of a crest of SRF at the apex of a large druse or drusenoid PED that may signal the eventual collapse and atrophy of the PED. This pathway may be related to hypoxia-induced RPE pump failure due to the large distance of the outer retina and RPE from the underlying choroid. We recommend the term non-neovascular AMD with SRF to describe AMD eyes with fluid in the absence of documented evidence of MNV. It is important that practitioners are aware that various patterns of fluid can develop in eyes with non-neovascular intermediate AMD to avoid unnecessary anti-VEGF therapy and employ multimodal imaging, including non-invasive OCTA, to exclude the presence of neovascularisation in these clinical scenarios.

    Acknowledgments

    AH—no financial disclosures. AA—no financial disclosures. KBF—consultant to Genentech, Optovue, Zeiss, Heidelberg Engineering, Allergan, Bayer, Novartis. He receives research funding from Genentech/Roche. AL—consultant/advisor for the following companies: Allergan, Bayer, Beyeonics, ForSight Labs, Notal Vision, Novartis, Alcon, Almira. EHS—expert for Allergan, Novartis, Bayer, Roche. JM—consultant to Novartis, Bayer, Alcon, Roche, Genentech, Cell Cure, ReNeuron; financial support—Eyerisk Consortium 2020, Novartis, Bayer, Alcon, Roche, Ophthotech; equity owner— Ophthotech, Notalvision. Pierre Turcotte—educational grants (Bayer). DZ—consultant to Allergan, Bayer. EP—consultant to Bayer, Novartis, travel grants from SIFI, Allergen, Bausch and Lomb. CI—no financial disclosures. MYL—no financial disclosures. YS—no financial disclosures. RS—no financial disclosures. AAE—no financial disclosures. EB—Zeiss, CenterVue. U C—no financial disclosures. NW—Macula Vision Research Foundation, Carl Zeiss Meditec, Optovue, Topcon Medical Systems, Nidek Medical Products, Optovue, Regeneron, Genentech. SO—no financial disclosures. DY—nTo financial disclosures. ST—Heidelberg Engineering; Carl Zeiss Meditec; Optos; CenterVue; Bayer; Novartis; BONFOR Gerok Funding, Faculty of Medicine, University of Bonn Grant No O-137.0026. LSdMM—no financial disclosures. VC—no financial disclosures. MFA—no financial disclosures. AL—consultant: Bayer. Lecture fees/Honoraria: Bayer, Allergan, Novartis. FG—no financial disclosures. DP—advisory board and study support of Roche, Novartis, Bayer, Allergan. WKI—advisory boards for Novartis, Bayer, Allergan, Alcon, Santen and has received consultancy fees from these companies. He has received payments for lectures from Novartis, Bayer, Allergan, Alcon. MSI—consultant for Thrombogenics, Boehringer Ingelheim, RegenexBio, Amgen, Novartis, Allegro, Allergan, Lineage Cell Therapeutics, Clearside, Genentech. GQ—consultant for Alimera Sciences (Alpharetta, Georgia, USA), Allergan (Irvine, California, USA), Amgen (Thousand Oaks, California, USA), Bayer Shering-Pharma (Berlin, Germany), Heidelberg (Germany), KBH (Chengdu; China), LEH Pharma (London, UK), Lumithera (Poulsbo; USA), Novartis (Basel, Switzerland), Sandoz (Berlin, Germany), SIFI (Catania, Italy), Sooft-Fidea (Abano, Italy), Zeiss (Dublin, California, USA). FGH—Acucela, Allergan, Apellis, Bayer, Boehringer-Ingelheim, Bioeq/Formycon, CenterVue, Ellex, Roche/Genentech, Geuder, Grayburg Vision, Heidelberg Engineering, Kanghong, LinBioscience, NightStarX, Novartis, Optos, Pixium Vision, Oxurion, Stealth BioTherapeutics, Zeiss. RFS—consultant for Topcon Medical Systems, Heidelberg Engineering; Royalties—Topcon Medical Systems, DORC. SVS—Allergan, Carl Zeiss Meditec, CenterVue, Genentech, Heidelberg Engineering, Iconic, 4DMT, Novartis, Optos, Topcon, Oxurion. DS—Amgen, Bayer, Genentech, Heidelberg, Novartis, Optovue, Regeneron, Topcon.

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    Footnotes

    • The paper was presented at the 7th International Congress, Rome, Italy, December 2019.

    • Contributors No contributorship was associated with the study.

    • Funding This study was supported by the Research to Prevent Blindness (DS), New York, New York, USA and the Macula Foundation (DS, KBF), New York, New York, USA.

    • Competing interests None declared.

    • Ethics approval Institutional review board (IRB) approval was obtained from the UCLA IRB Office of Human Protection, IRB#11-000324.

    • Provenance and peer review Not commissioned; internally peer reviewed.

    • Data availability statement Data are available upon reasonable request.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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