The story used to be so simple. Neovascular age-related macular degeneration is a leading cause of uncorrectable vision loss. In this context, intraretinal and subretinal fluid (SRF) is evidence of exudation from macular neovascularization (MNV). Treat every drop of fluid relentlessly with repeated injections. Unfortunately, this narrative is no longer so clear.

As we’ve observed, treated and studied countless eyes using optical coherence tomography and multimodal imaging, we’ve learned repeatedly that the truth is much more nuanced. In reality, not all fluid appears to be bad, and not all intraretinal and subretinal back-spaces are fluid that indicates an exudative process secondary to MNV. While these broad concepts are now well appreciated and essentially obvious to most retina specialists, it’s clear that we as a field still have much to learn about the meaning of all apparent fluid in AMD. Albert Einstein summarized the concept well: “The more I learn, the more I realize how much I don’t know.”

Take non-neovascular AMD. Defined by the absence of MNV, the simplistic view is that there should be no fluid present. Nevertheless, through a recent post hoc analysis of the Phase II FILLY trial studying pegcetacoplan (APL-2, Apellis) for the management of geographic atrophy, in which eyes developing investigator-determined exudative AMD were described, it was evident that a clinically relevant minority of patients had evidence of SRF or intraretinal cysts at baseline—fluid that was non-exudative in nature.

Such non-exudative intraretinal cystoid or cavitary spaces can occur within areas of retinal atrophy, potentially related to retinal pigment epithelium pump failure or Müller cell degeneration, the latter of which can be dramatic in some eyes with macular telangiectasia type 2. In comparison, non-exudative SRF can accumulate in eyes due to incomplete conformation of the outer retina to the underlying RPE, most commonly in the context of confluent drusen, in which fluid appears to accumulate in the valleys between drusen; or large drusenoid pigment epithelial detachments, in which fluid can accumulate at the apex of the lesion. The clinical implication of distinguishing such fluid from an MNV-driven exudative process is critical, and well summarized by Karen Jeng-Miller, MD, on page 30.

In exudative AMD, studies employing the Port Delivery System with ranibizumab (Genentech/ Roche) implant, the anti-VEGF gene therapies ADVM-022 (Adverum Biotechnologies) and RGX-314 (RegenxBio), and next-generation anti-VEGF pharmaceuticals such as KSI-301 (Kodiak Sciences), CLS-AX (Clearside Biomedical) and EYP1901 (EyePoint Pharmaceuticals), continue to shed light on the meaning of fluid and possibly more clinically impactful, fluid fluctuations.

While fluid in the context of AMD should raise a bright red flag indicating the possibility of associated MNV, beware that not all fluid is bad, and certainly not all fluid needs to be treated. RS