A recent literature review published in Ophthalmology and Therapy assessed the role of retinal fluid in neovascular age-related macular degeneration (nAMD) disease outcomes and whether it may be beneficial to leave retinal fluid untreated.
Give me some background.
Intraretinal fluid (IRF) and subretinal fluid (SRF) are important biomarkers of disease activity in nAMD, though the exact role of SRF in guiding treatment decisions remains unclear.
- Note: Retinal fluid resolution is a common clinical trial endpoint for anti-VEGF therapy.
Key differences between the two include:
- IRF:
- Found in an estimated 40-68% of nAMD patients
- Defined on optical coherence tomography (OCT) as minimally reflective round spaces within the neurosensory retina
- Associated with poorer visual outcomes and increased risk of developing atrophy and fibrosis
- Typically concentrated at the foveal center
- SRF:
- Found in an estimated 80-90% of nAMD patients
- Defined on OCT as the dark, nonreflective space between the neurosensory retina and the retinal pigment epithelium (RPE)
- Post-hoc analyses of clinical trials showed that eyes with SRF at baseline had favorable visual acuity (VA) outcomes after anti-VEGF therapy
- Diffusely affects the macula in nAMD, extending throughout the entire macular region
- Note: Not all cases of SRF are due to neovascularization; some may occur overlying a serous pigment epithelial detachment (PED) or accompany concomitant drusen
Now, talk about the study.
In this literature review, investigators identified relevant publications on Pubmed with a cut-off date of March 2024 about the appearance of retinal fluid or changes to retinal fluid in nAMD patients.
Findings?
A previous study of nAMD patients found marginally lower rates of fibrosis in eyes with SRF compared to IRF.
- “Therefore, it can be hypothesized that the presence of SRF in eyes with nAMD may be a protective biomarker against atrophy, fibrosis, and progression of vision loss,” the study authors noted.
A potential mechanism for this protective effect: Changes to its composition (either innately or with treatment) in response to choroidal neovascularization (CNV) more closely mimic the normal extracellular milieu of photoreceptors—acting as a survival response against macular atrophy.
Tell me more about visual outcomes with residual SRF.
The FLUID Study found that best-corrected visual acuity (BCVA) outcomes were noninferior if some residual SRF was tolerated compared to total resolution.
However: While mild SRF may be protective in nAMD, the cause and effect of SRF on reduced or slowed atrophy has not yet been proven and requires further research.Meaning: When evaluating if residual SRF can be tolerated without clinical worsening, investigators recommended weighing the patient's treatment goals with risk factors for poor treatment responses, such as:
- Type of macular neovascularization (MNV)
- Subretinal hyperreflective material (SHRM)
- Fibrosis
- Atrophy
How does this information translate to the clinic?
The study authors proposed an algorithm for the diagnosis, prognosis, and treatment of SRF and IRF in nAMD:
- Diagnosis
- Establish retinal fluid location via OCT
- Confirm retinal fluid type and origin via differential diagnoses
- Nonexudative fluids will not be resolved by anti-VEGF therapy
- Determine the MNV type
- Prognosis
- Consider the prognostic implications of retinal fluid distribution
- IRF is a negative prognostic factor
- The relationship between sub-RPE fluid and visual prognosis is currently unclear
- Correlate retinal fluid location with MNV type
- Consider other factors that may affect visual function (i.e., fibrosis, atrophy)
- Treatment
- Treatment should be given for the most aggressive component
- When both IRF and SRF are present, treatment should be given to resolve IRF
- IRF should be treated to full resolution
- Low levels of SRF can be tolerated (up to 150-200 μm in thickness), especially if the external limiting membrane is intact and may be protective depending on its volatility
Take home.
SRF and IRF are key biomarkers of disease progression in nAMD, and the resolution of IRF should be aggressive as it is associated with worse visual outcomes and an increased risk of developing atrophy and fibrosis.
Interestingly, a growing body of evidence has suggested that SRF may be associated with improved visual outcomes by reducing the risk of development and progression of macular atrophy and fibrosis.
However: Further studies are required to validate these observations about the protective effect of SRF on nAMD.