Cause of Vision Loss in Patients with Neovascular AMD under Anti-VEGF Therapy
Fibrosis or Atrophy
The principle cause of vision loss in neovascular age related macula degeneration (AMD) can reflect the underlying mechanism of retinal damage. Subretinal fibrosis can represent under treatment with anti-VEGF, and more intensive therapy is required. In contrast, geographic atrophy represents progression of the underlying macula degeneration, which is not amendable to anti-VEGF therapy.
A new report from the AREDS group addressed the principle causes of vision loss in patients with new onset neovascular age related macula degeneration undergoing anti-VEGF therapy. In the study cohort of 594 eyes, 56 eyes (or almost 10%) had a visual acuity of 6/60 or less in 2 years despite treatment. It was determined that the principle cause of vision loss in these eyes was fibrosis in 40% of the cases and atrophy in the remaining 60% (graph above). The anti-VEGF therapy regime was not reported in this study.
The CATT study has reported a similar proportion of fibrosis as the cause of vision loss (44%) in patients with more than 3 line loss of acuity (6.9%) . In contrast, the real world data from New Zealand and Australia suggests that the rate of fibrosis in patients with <6/60 visual acuity is 28%, while in Switzerland this rate is 78%. Corresponding to this, the proportion of patients with less than 6/60 acuity is 14% in New Zealand and Australia, and 38% in Switzerland, likely due to less anti-VEGF injections being performed in Switzerland.
Types of macula neovascular membrane and fibrosis
A reanalysis of the data from the HARBOUR study showed a strong association between the fluorescein maculae neovascular membrane subtypes and the likelihood of fibrosis (Adrean et al., 2020). The likelihood of fibrosis is highest in predominately classic membranes (78.2%), followed by minimally classic (50.7%), then occult (19.8%).
It is now know that the classic component of a macula neovascular membrane largely correspond to the portion of the membrane located in the subretinal space (or using OCT terminology type II macula neovascular membrane), and it is this component that results in fibrosis. Macula neovascular membrane that are below the retinal pigment epithelium (type I macula neovascular membrane) do not tend to cause fibrosis (unless there is an associated rip or haemorrhage).
Atrophy and the protective effect of macula neovascularisation
In fact, type I macula neovascular membrane can be protective against future geographic atrophy. Type I membrane is associated with subretinal fluid, while type II and type III membrane are associated with both intraretinal and subretinal fluid. Initial evidence comes from the CATT study, where the presence of subretinal fluid is associated with better final visual acuity. This suggests that subretinal fluid is not the cause of vision loss in neovascular age related macular degeneration, and type I membrane may have a protective effect.
Further evidence comes from a study showing that type I membrane (whether active or not) retards the growth of geographic atrophy, and histology data showing the morphology of these sub-RPE membrane to be similar to choriocapillaris and may have a supportive function of RPE health.
Optimising anti-VEGF therapy in neovascular age related macular degeneration
Based on these data, it is clear that the primary role of anti-VEGF therapy is to prevent fibrosis. Fibrosis occurs when there is a type II macula neovascular membrane, and in age related macular degeneration, most type II membranes originate from an underlying, often poorly controlled, type I membrane. Ongoing injection therapy is to prevent the development of these type II membranes, and also to prevent haemorrhages or RPE rip. Small amount of subretinal fluid is tolerable and may not be detrimental.
Furthermore, many patients with neovascular age related macular degeneration and well controlled type I membranes will retain good vision over the longer term, as the risk of fibrosis is minimised by injections and the risk of atrophy mitigated by the presence of these membrane. Therefore, accurate classification of the macula neovascular membrane subtype will help inform our neovascular AMD patients about their future prognosis.