Non-neovascular fluid in age-related macular degeneration: observe-and-extend regimen in a case-series study

Published:September 12, 2022DOI:



      To describe the course of non-neovascular fluid in age-related macular degeneration (AMD) after anti–vascular endothelial growth factor (anti-VEGF) therapy or after observation without injections.


      Retrospective case series.


      AMD eyes with macular drusen and (or) drusenoid pigment epithelial detachment associated with non-neovascular fluid were included. Optical coherence tomography (OCT) angiography was performed in all eyes to exclude the presence of macular neovascularization. Subretinal fluid (SRF) was measured to determine the response after anti-VEGF therapy and after observation without injections.


      Ten eyes of 9 patients with intermediate AMD and SRF were studied over a median period of 59.5 months (range, 7–128 months). Six patients (6 eyes) had a history of anti-VEGF therapy. Median follow-up off injections was 13.5 months (range, 4–44 months). SRF thickness remained stable and unchanged during the follow-up off injections in all eyes (n = 6) with prior injection and in all eyes (n = 4) that had never been injected. Six eyes developed complete retinal pigment epithelial (RPE) and outer retinal atrophy, and 1 eye developed incomplete RPE and outer retinal atrophy. All eyes exhibited at least 2 OCT biomarkers associated with a high risk for progression to atrophy.


      This study provides preliminary data regarding the progression of non-neovascular fluid in AMD with or without anti-VEGF injections. A possible mechanism for fluid development may be related to RPE pump impairment. Distinguishing neovascular versus non-neovascular fluid using multimodal imaging, including OCT angiography, is essential to avoid unnecessary anti-VEGF therapy. An observe-and-extend regimen may be considered in AMD eyes with non-neovascular fluid.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Canadian Journal of Ophthalmology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Rosenfeld PJ.
        Optical coherence tomography and the development of antiangiogenic therapies in neovascular age-related macular degeneration.
        Invest Ophthalmol Vis Sci. 2016; 57 (OCT14–26)
        • Schmidt-Erfurth U
        • Waldstein S.
        A paradigm shift in imaging biomarkers in neovascular age-related macular degeneration.
        Prog Retin Eye Res. 2016; 50: 1-24
        • Hilely A
        • Au A
        • Freund KB
        • et al.
        Non-neovascular age-related macular degeneration with subretinal fluid.
        Br J Ophthalmol. 2021; 105: 1415-1420
        • Sikorski B
        • Bukowska D
        • Kaluzny J
        • Szkulmowski M
        • Kowalczyk A
        • Wojtkowski M.
        Drusen with accompanying fluid underneath the sensory retina.
        Ophthalmology. 2011; 118: 82-92
        • Cuesta-Lasso M
        • Vieira-Barros A
        • Dolz-Marco R
        • et al.
        Intravitreal therapies for non-neovascular age-related macular degeneration with intraretinal or subretinal fluid.
        Arch Soc Espanola Oftalmol. 2017; 92: 101-106
        • Lek J
        • Caruso E
        • Baglin E
        • et al.
        Interpretation of subretinal fluid using OCT in intermediate age-related macular degeneration.
        Ophthalmol Retina. 2018; 2: 792-802
        • Samanta A
        • Jhingan M
        • Arora S
        • et al.
        Intraretinal, sub-retinal, and sub-retinal pigmented epithelium fluid in non-exudative age-related macular degeneration: follow-up with OCT imaging.
        Eur J Ophthalmol. 2022; 32: 2419-2426
        • Bacci T
        • Essilfie J
        • Leong B
        • Freund K.
        Exudative non-neovascular age-related macular degeneration.
        Graefes Archr Clin Exp Ophthalmol. 2020; 259: 1123-1134
        • Cohen S
        • Dubois L
        • Nghiem-Buffet S
        • et al.
        Retinal pseudocysts in age-related geographic atrophy.
        Am J Ophthalmol. 2010; 150 (e1): 211-217
        • Ferris F
        • Wilkinson C
        • Bird A
        • et al.
        Clinical classification of age-related macular degeneration.
        Ophthalmology. 2013; 120: 844-851
        • Jaffe G
        • Chakravarthy U
        • Freund K
        • et al.
        Imaging features associated with progression to geographic atrophy in age-related macular degeneration.
        Ophthalmol Retina. 2021; 5: 855-867
        • Moseley H
        • Foulds WS
        • Allan D
        • Kyle PM.
        Routes of clearance of radioactive water from the rabbit vitreous.
        Br J Ophthalmol. 1984; 68: 145-151
        • Sharma A
        • Kumar N
        • Parachuri N
        • et al.
        Understanding the mechanisms of fluid development in age-related macular degeneration.
        Ophthalmol Retina. 2021; 5: 105-107
        • Schmidt-Erfurth U
        • Reiter GS
        • Riedl S
        • et al.
        AI-based monitoring of retinal fluid in disease activity and under therapy.
        Prog Retin Eye Res. 2021; 86100972
        • Sharma S
        • Toth CA
        • Daniel E
        • et al.
        Macular morphology and visual acuity in the second year of the comparison of age-related macular degeneration treatments trials.
        Ophthalmology. 2016; 123: 865-875
        • Holekamp NM
        • Sadda S
        • Sarraf D
        • et al.
        Effect of residual retinal fluid on visual function in ranibizumab-treated neovascular age-related macular degeneration.
        Am J Ophthalmol. 2021; 233: 8-17
        • Freund KB
        • Laud K
        • Lima LH
        • Spaide RF
        • Zweifel S
        • Yannuzzi LA.
        Acquired vitelliform lesions: correlation of clinical findings and multiple imaging analyses.
        Retina. 2011; 31: 13-25
        • Adamis AP
        • Shima DT
        • Yeo KT
        • et al.
        Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells.
        Biochem Biophys Res Commun. 1993; 193: 631-638
        • Pober JS
        • Sessa WC.
        Evolving functions of endothelial cells in inflammation.
        Nat Rev Immunol. 2007; 7: 803-815
        • Schwesinger C
        • Yee C
        • Rohan RM
        • et al.
        Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium.
        Am J Pathol. 2001; 158: 1161-1172
        • Dugel PU
        • Koh A
        • Ogura Y
        • et al.
        HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration.
        Ophthalmology. 2020; 127: 72-84
        • Kunimoto D
        • Yoon YH
        • Wykoff CC
        • et al.
        Efficacy and safety of abicipar in neovascular age-related macular degeneration: 52-week results of phase 3 randomized controlled study.
        Ophthalmology. 2020; 127: 1331-1344
        • Martin DF
        • Maguire MG
        • et al.
        Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.
        Ophthalmology. 2012; 119: 1388-1398
        • Guymer RH
        • Markey CM
        • McAllister IL
        • et al.
        Tolerating subretinal fluid in neovascular age-related macular degeneration treated with ranibizumab using a treat-and-extend regimen: FLUID study 24-month results.
        Ophthalmology. 2019; 126: 723-734