Fluid fluctuation and visual outcomes in neovascular age-related macular degeneration: A systematic review and meta-analysis

Why clinicians should know about it

• Picked for Ophthalmology (paper of the day, 7 November 2026): Anti-VEGF fluid fluctuation predicts nAMD visual outcomes

Abstract

Fluctuation in retinal thickness and fluid during anti-vascular endothelial growrh factor (VEGF) therapy has emerged as a candidate prognostic biomarker in neovascular age-related macular degeneration (nAMD), but the evidence is heterogeneous and has not been quantitatively synthesized. We searched PubMed/MEDLINE, Scopus, and Web of Science from inception to December, 2025, for studies reporting retinal fluid or thickness fluctuation metrics and best-corrected visual acuity (BCVA) outcomes in eyes receiving anti-VEGF therapy for nAMD, including both observational studies and post hoc analyses of randomized trials. Between-group mean differences (MDs) in BCVA change were pooled using random-effects models, stratified by study design and OCT parameter, and certainty of evidence was assessed using GRADE. Seventeen studies comprising 19 reports and 9,873 eyes were included. Among observational studies at 24 months, eyes in the highest fluctuation category had significantly smaller BCVA gains than those in the lowest for every parameter examined: intraretinal fluid (MD -7.00 letters, 95% CI -10.27 to -3.72), subretinal fluid (-5.02, -8.09 to -1.95), pigment epithelial detachment (-8.41, -14.54 to -2.27), total fluid (-9.42, -12.69 to -6.15), and central subfield thickness (-10.56, -14.40 to -6.73), with low to moderate heterogeneity (I² 0-42.6%). Among post hoc analyses of randomized trials at 24 months, the pooled difference was -6.02 letters (-8.72 to -3.32), with substantial heterogeneity (I² = 77.2%) that leave-one-out analysis showed did not alter the direction or significance of the estimate. Greater fluctuation was additionally associated with approximately twice the odds of macular fibrosis and atrophy. Certainty of evidence was low to very low for most fluid compartments, limited principally by the non-randomized nature of the exposure and by the absence of a standardized definition of fluctuation across studies. Temporal anatomical stability, rather than the presence of fluid at any single visit, may therefore carry prognostic information beyond conventional measures of disease activity, though prospective evaluation using a common metric is required before stability can be adopted as a treatment target.

Abstract as published, via PubMed.