Recent literature has increasingly reported on a clinical entity found in the fellow eyes of patients undergoing treatment for unilateral exudative neovascular age-related macular degeneration (nAMD). Multiple terms have been used to describe it, including nonexudative macular neovascularisation (neMNV), subclinical choroidal neovascularisation and quiescent choroidal neovascularisation1. Each term implies the presence of new vessels in the macula tissue without signs of exudation, such as intraretinal fluid, subretinal fluid, and subretinal pigment epithelial fluid2.
Detection on retinal imaging
The typical fundus findings in patients with neMNV are macular drusen and pigmentary abnormalities3. Large case series using indocyanine green angiography (ICG) have reported the presence of late-staining macular plaques without any leakage identified on fluorescein angiography. These plaques were considered to be quiescent subretinal neovascular complexes, such as neMNV4,5. ICG is no longer necessary to identify neMNV, since swept-source optical coherence tomography angiography (SS-OCTA) has been shown to be equally effective in detecting these complexes3,5.
The OCT features of neMNV include retinal pigment epithelium (RPE) elevations and intraretinal hyper reflective foci, but no evidence of intraretinal or subretinal fluid6,7. Identifying a double-layer sign on OCT images is a powerful predictor of neMNV, with a specificity of 87% and sensitivity of 88%8. The double-layer sign refers to two highly reflective layers that correspond to a separation between the RPE and Bruch’s membrane (see Fig 1).
Fig 1. Cross sectional OCT image showing a shallow, irregular retinal pigment epithelium elevation
(double-layer sign) with no evidence of fluid
When the double-layer sign is present on OCT, along with other features such as a transverse linear dimension ≥1,000μm, an irregular RPE layer with a height of predominantly <100μm and non-homogenous internal reflectivity, these collective features are termed ‘SIRE’ – shallow, irregular RPE elevation9. Presence of SIRE has a sensitivity of 100% and specificity of 92% for detecting neMNV9. Thus, OCT is a useful monitoring tool for neMNV where OCTA is unavailable.
OCTA has become invaluable for AMD as it is a non-invasive, safe and fast for directly visualising MNV. Most neMNV lesions have been categorised as type 1 MNVs, however some type 3 MNVs have also been detected10,11. An OCTA feature that helps to confirm an MNV within a double-layer sign is the flow overlay where decorrelation signals corresponding to flow are created and superimposed over the structural OCT image (see Fig 2a). Flow beneath RPE and above Bruch’s membrane indicates likely type 1 MNV3,12. When combined with accurate segmentation, neovascular complexes can be seen in the en face image of the segmentation slabs of the avascular slab (avascular area from outer nuclear layer to RPE) (see Fig 2b) and choriocapillaris slab (includes Bruch’s membrane and 20μm below).
Fig 2. Cross sectional OCTA scans through the fovea showing (A) slightly undulating retinal pigment epithelial
line with flow overlay demonstrating flow underneath the RPE and above Bruch’s membrane (yellow colour showing
flow above the red dotted line, denoting Bruch’s membrane); and (B) the avascular segmentation slab, showing MNV complex
With the increasing availability of OCTA in clinical practice, further research on the incidence, prevalence and natural history of neMNV in asymptomatic eyes with AMD has been possible.
Prevalence and natural history
Patients with neMNV are often asymptomatic and the effect on their best corrected visual acuity is minimal3,12. The pathophysiology of neMNV is not clear but it has been hypothesised that these neovascular complexes may provide nutritional support for the overlying RPE and photoreceptors13 and have a protective effect in slowing geographic atrophy progression2.
neMNV is now known to be much more prevalent in patients with AMD than we had initially anticipated, with rates of 6.25%-27% in patients with unilateral exudative AMD14. In a study of patients with geographic atrophy, 11% were found to have nonexudative MNV15.
The presence of nonexudative MNV is a powerful predictor of exudative disease. Eyes with neMNV identified on OCTA at the time of presentation have a 15 times greater risk of exudation compared to eyes with no detectable MNV at presentation16. However, incidence of conversion to exudation appears variable, with rates of 20-24% at 12-15 months16,17 and 26.3-34.5% by 20-24 months17,18. Bailey et al19 found up to 80% of neMNV lesions converted to exudation in two years, preceded by rapid growth of the lesion on OCTA19. An increase in the size of the vascular complex on OCTA seems to be a consistent finding in many studies7,15,17,19 as a hallmark of impending exudation. However, not all studies have reported this biomarker change18.
Treatment vs monitoring
Whether these subclinical lesions should be treated prophylactically with vascular endothelial growth factor (VEGF) inhibitors to prevent the onset of exudation has been the subject of ongoing debate. Recent evidence from the Pro-con and Prevent trials20,21 has provided greater clarity. Over a two-year period, 12 weekly prophylactic injections with aflibercept or ranibizumab in the high-risk fellow eyes of patients being treated for unilateral exudative AMD did not prevent progression to exudation nor benefit visual acuity outcomes.
Until we have further evidence on the predictors for conversion from neMNV to exudative MNV, vigilance will be needed in monitoring patients with this clinical entity. Educating our patients to identify symptoms of exudation via home monitoring using an Amsler grid or embracing new technologies such as home OCT monitoring, plus regular OCT/ OCTA imaging reviews in clinic will continue to be the mainstays of management.
Conclusion
Although the natural history and biomarkers for impending exudation are incompletely understood, neMNV is a prevalent condition that can be identified using OCT and OCTA. As a precursor to exudative MNV, close monitoring is recommended to facilitate timely anti-VEGF treatment, since the unpredictability of this condition makes its management challenging.
References
Dr Sophie Hill is a consultant ophthalmologist at the Greenlane Clinical Centre, specialising in medical retina and cataract surgery. She is also an honorary senior lecturer at the University of Auckland and works in private practice at Eye Institute.