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Retinal Physician

Article

Mechanisms of Fluid Development in AMD

Consider the multiple pathways when creating treatment plans.

By: Assaf Hilely, MD, Adrian Au, MD, SriniVas R. Sadda, MD, David Sarraf, MD
Retinal Physician January 2, 2021 Vol 18, Issue January/February 2021 Page(s): 20, 22

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Hydrostatic mechanisms are critical to maintaining the retina in an exquisitely dry environment and optimizing visual function. Various cells are tasked with this important function, including the retinal pigment epithelium (RPE) and Muller cells. RPE cells, connected by tight junctions, create an effective water-tight seal and remove subretinal fluid (SRF) through an energy-intensive pump in which a Na+/K+ gradient is created.1,2 Bulk movement of fluid flows from the vitreous cavity through the inner and outer compartments of the retina and is directed toward the choriocapillaris by the pumping capacity of the RPE.3–5 Muller cells also mediate hydrostasis by removing intraretinal fluid (IRF) through intracellular ion, water, and bicarbonate transfer mechanisms.6

Fluid leakage in human tissues occurs through 2 pathways: transudation and exudation. Transudation results from increased hydrostatic or decreased oncotic pressure, which causes fluid to shift across an intact capillary endothelial cell membrane.7,8 Exudation, differentiated from transudation by a higher composition of proteins and cholesterol content,9 occurs as a result of the diffusion of fluid across an impaired capillary endothelial membrane. Pleural effusion can illustrate these concepts. Transudative effusion develops due to an increase in capillary hydrostatic pressure or a decrease in colloid oncotic pressure, commonly the result of congestive heart failure. By contrast, exudative effusions arise as a result of pleural inflammation, infection, injury, or lymphatic obstruction.8

EXUDATIVE PATHWAYS

In the eye, diabetic macular edema is the classic example of the exudative pathway in which hyperglycemia-mediated endothelial cell injury leads to retinal capillary plexus impairment and the development of IRF. Evidence of IRF includes the presence of cystoid macular edema, as identified with optical coherence tomography (OCT), and petaloid leakage, as demonstrated by dye-based fluorescein angiography.10,11 Exudation can also be commonly observed in eyes with neovascular age-related macular degeneration (AMD) in which leakage occurs from choroidal neovascular complexes that are comprised of impaired capillary endothelial cells. Vascular endothelial growth factor (VEGF)-dependent angiogenesis creates immature neovascular complexes that are prone to hyperpermeability, bleeding, and exudation.12,13 Evidence of exudation includes the presence of fluid (intraretinal or subretinal) or subretinal hyper-reflective exudation,14 which may represent fibrin or blood that can be associated with macular neovascularization. Subretinal hyper-reflective exudation is a subset of subretinal hyper-reflective material, which can also include type 2 macular neovascularization and/or subretinal fibrosis.15

TRANSUDATIVE PATHWAYS

Can intraretinal and subretinal fluid develop in eyes in the absence of true exudation? It is well known that degenerative microcysts or pseudocysts can develop over areas of complete RPE and outer retinal atrophy,16 as illustrated with OCT, in the absence macular neovascularization and in association with an intact retinal vascular endothelium. Further, SRF can be identified at the apex or angle of a drusenoid pigment epithelial detachment or as a drape overlying large drusen in eyes with non-neovascular AMD.17 Oxygen diffusion can be impaired due to the increased distance between the choriocapillaris-Bruch’s complex and the RPE and outer retina.18,19 The apex of the drusenoid PED represents the greatest separation from the choriocapillaris and the most likely location of RPE atrophy.20 The RPE may lose pumping function capacity prior to death, leading to fluid accumulation in the subretinal space.1,2 Alternatively, the diffuse accumulation of lipophilic material associated with basal linear and basal laminar deposit may lead to hydrophobicity of Bruch’s membrane with subsequent loss of hydraulic conductivity and impairment of the RPE pumping capacity.21

MIXED-MECHANISM PATHWAYS

Although classic exudative pathways may be the most important factor leading to fluid accumulation in neovascular AMD, it is important to understand that alternative pathways, including transudative mechanisms, may also be at work. Persistent fluid after anti-VEGF therapy is a major challenge in the management of neovascular AMD. Across the entire CATT trial cohort,22 at 5 years, 37.7% of eyes exhibited persistent subretinal fluid and 61.0% displayed intraretinal fluid. In the VIEW-2 cohort,23 at 52 weeks, 27.6% to 39.7% of eyes exhibited residual fluid. In the HAWK and HARRIER trials, rates of persistent IRF/SRF at week 48 were noted in 25.8% to 34.1% of eyes in the brolucizumab arm and 43.9% to 44.7% of eyes in the aflibercept arm.24 Therefore, it is possible that this recalcitrant fluid, which does not completely resolve with anti-VEGF therapy, may be caused by mixed mechanisms and may not be solely the result of exudation. The loss of RPE pumping capacity or the disruption of Muller cells may be additional factors to consider in understanding the nature of persistent fluid in eyes with neovascular AMD.

The FLUID study25 compared treat-and-extend regimens but used a 200 µ threshold of SRF for 1 of the arms of the investigation. The study found that there was no difference in visual outcomes between the 2 groups and that patients with 200 µ of SRF or less who were given extended follow-up visits experienced comparable visual outcomes to the group that was extended only with the complete absence of fluid. The favorable outcomes encountered in the group in which fluid was tolerated can be interpreted in different ways. Mild residual fluid may be an indicator of exudative activity but it is possible that it can be tolerated without adverse outcome, at least in the short term. It is also possible that this mild residual fluid may be the result of alternative pathways of leakage, including impaired RPE pumping capacity, and therefore anti-VEGF treatment may not be essential, because persistent fluid may not be solely the result of exudative mechanisms related to active angiogenic disease.

CONCLUSION

The evaluation of fluid in eyes with non-neovascular and neovascular AMD requires thoughtful consideration of the various pathways of leakage. It is critical to identify fluid, both intraretinal and subretinal, as a biomarker of exudation and angiogenic activity to expedite timely treatment and optimize visual and anatomic outcomes and guide further therapy. However, it is important to appreciate additional pathways of fluid development in eyes with AMD. Muller cells and RPE cells are critical elements of the hydrostatic pathway in the retina, and impairment of these cells can lead to fluid accumulation in both the non-neovascular and neovascular forms of AMD. RP

Assaf Hilely, MD, is a retina specialist in the Retinal Disorders and Ophthalmic Genetics Division, Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, and the Division of Ophthalmology, Tel Aviv Ichilov-Sourasky Medical Center, Tel Aviv, Israel. Dr. Hilely reports no related disclosures. Adrian Au, MD, is a retina specialist in the Retinal Disorders and Ophthalmic Genetics Division, Stein Eye Institute, David Geffen School of Medicine at UCLA. Dr. Au reports no related disclosures. SriniVas Sadda, MD, is a retina specialist at the Doheny Image Reading Center, Doheny Eye Institute in Los Angeles. Dr. Sadda reports consultancy to Amgen, Allergan, Bayer, Regeneron, Novartis Roche/Genentech, Merck, 4DMT, Heidelberg Engineering, Centervue, and Optos. David Sarraf, MD, is a retina specialist in the Retinal Disorders and Ophthalmic Genetics Division, Stein Eye Institute, David Geffen School of Medicine at UCLA, and with the Greater Los Angeles VA Healthcare Center. Dr. Sarraf reports consultancy to Amgen, Bayer, Novartis, and Optovue; speakers’ fees from Novartis and Optovue; and research for Amgen, Genentech, Heidelberg, Optovue, Regeneron, and Topcon. Reach Dr. Sarraf at sarraf@jsei.ucla.edu.

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