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Review
. 2025 Mar;14(3):489-514.
doi: 10.1007/s40123-025-01093-3. Epub 2025 Feb 4.

To Treat or Not to Treat? Resolving the Question of Subretinal and Intraretinal Fluid in Age-Related Macular Degeneration: A Narrative Review

Alexander J E Foss  1 , David Almeida  2 , Chui Ming Gemmy Cheung  3   4 , Yuichiro Ogura  5 , Eduard de Cock  6 , Theo Empeslidis  6
Affiliations
Review

To Treat or Not to Treat? Resolving the Question of Subretinal and Intraretinal Fluid in Age-Related Macular Degeneration: A Narrative Review

Alexander J E Foss et al. Ophthalmol Ther. 2025 Mar.

Abstract

Neovascular age-related macular degeneration (nAMD) is associated with considerable quality of life and economic burden. nAMD is characterized by pathological neovascularization, leading to the accumulation of retinal fluid. Intraretinal fluid (IRF) is a major contributor to vision loss and may predict response to treatment. In contrast, the role of subretinal fluid (SRF) is less clear. Nevertheless, complete resolution of retinal fluid accumulation is often stated to be a key goal of therapy for nAMD, even though some eyes may never achieve a fluid-free macula despite regular anti-vascular endothelial growth factor treatment. In this article, we review the current literature regarding the role of retinal fluid in nAMD disease outcomes and assess whether and when it may be beneficial to leave retinal fluid untreated. In this context, we highlight the importance of correctly identifying retinal fluid types in nAMD and avoiding confusion with other optical coherence tomography signs that may respond differently to therapy, such as subretinal pseudocysts. Current evidence shows that IRF is associated with poor outcomes and an increased risk of developing atrophy and fibrosis; resolution of this retinal fluid type should remain a treatment target. However, the literature around SRF indicates that low levels of this fluid type, potentially up to 150-200 µm in thickness, may be tolerated with minimal impact on vision, and that SRF could be protective against the development and progression of macular atrophy and fibrosis. Although mild SRF may be protective in nAMD, cause and effect between SRF and reduced or slowed atrophy has not yet been proven and requires further research. Treatment should be given for the most aggressive component; when both IRF and SRF are present, treatment should be given for IRF.

Keywords: Anti-vascular endothelial growth factor (anti-VEGF); Intraretinal fluid (IRF); Macular atrophy; Neovascular age-related macular degeneration (nAMD); Prognosis; Sub-retinal fluid (SRF); Sub-retinal pigment epithelium fluid (sub-RPE fluid); Treatment response.

Plain language summary

Neovascular age-related macular degeneration (nAMD) is a progressive eye disease and a major cause of vision loss. In nAMD, new blood vessels grow into the light-sensitive layer at the back of the eye called the retina and can leak fluid. Fluid leaked into the retina is known as intraretinal fluid, and behind the retina is known as subretinal fluid. It is known that intraretinal fluid contributes to vision loss, but the impact of subretinal fluid is less clear. One aim of treatment for nAMD is to dry up retinal fluid, but in some eyes, this treatment is ineffective. This article summarizes previous research on identifying retinal fluid, the effect of retinal fluid on nAMD progression, and how the presence of retinal fluid impacts how patients respond to nAMD treatment. Findings from previous research showed that compared with eyes without intraretinal fluid, eyes with intraretinal fluid have worse vision, and this is more likely to decline further over time. Therefore, treatment should aim to dry up intraretinal fluid. Interestingly, the literature also suggested that a low level of subretinal fluid has little impact on vision and might even protect against nAMD worsening. The impact of mild subretinal fluid has not been proven yet and requires further study. Therefore, when both intraretinal fluid and subretinal fluid are present, treatment should be given for intraretinal fluid.

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Conflict of interest statement

Declarations. Conflict of Interest: The authors did not receive payment related to the development of this manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Alexander JE Foss has received writing support from Boehringer Ingelheim. David Almeida is Co-Founder and Chief Medical Advisor of Citrus Therapeutics and holds equity with this company. David Almeida declares involvement with AbbVie, ACELYRIN, Alcon, Alimera Sciences, Allergan, Bausch + Lomb, Bayer, Boehringer Ingelheim, Dutch Ophthalmics, EyePoint Pharmaceuticals, Genentech, Gyroscope Therapeutics, Novartis, Opthea, Regeneron, REGENXBIO, Roche, Samsara Vision and Spherix Consulting Group. Chui Ming Gemmy Cheung declares involvement with Bayer, Boehringer Ingelheim, Iveric Bio, Novartis, Roche, Topcon, and Zeiss. Yuichiro Ogura declares consultancy for Alcon Japan, Apellis, Bayer, Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd, HOYA, Iveric Bio, Kyoto Drug Discovery & Development, Novartis, Senju; research support from Bayer, Kowa, Nikon Healthcare, Novartis, Santen, Topcon, and ZEISS; and is an employee of Genentech, Inc. Eduard de Cock and Theo Empeslidis are employees of Boehringer Ingelheim. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Figures

Fig. 1
Fig. 1
OCT scan illustrating the appearance of CNV, SRF, and IRF in nAMD, and presence of outer retinal tabulation. CNV choroidal neovascularization, IRF intraretinal fluid, nAMD neovascular age-related macular degeneration, OCT optical coherence tomography, SRF subretinal fluid
Fig. 2
Fig. 2
The characteristics and treatment of MNV types. The characteristics, fluid distribution, and treatment recommendations for MNV type 1 [48, 95, 96, 123], type 2 [48, 95], and type 3  [48, 123]. *Due to the presence of large, mature vessels in the neovasculature, which may produce persistent SRF or SRF with inadequate response. IRF intraretinal fluid, MNV macular neovascularization, RPE retinal pigment epithelium, SRF subretinal fluid, VEGF vascular endothelial growth factor
Fig. 3
Fig. 3
Proposed algorithm for diagnosis, prognosis, and treatment of SRF and IRF in nAMD. IRF intraretinal fluid, MNV macular neovascularization, nAMD neovascular age-related macular degeneration, RPE retinal pigment epithelium, SRF subretinal fluid, VEGF vascular endothelial growth factor
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