Overview
Nonexudative macular neovascularization (neMNV) is an early, often silent form of abnormal blood vessel growth beneath the retina in age-related macular degeneration (AMD). Unlike exudative AMD, it does not yet show leakage of fluid or blood, but it can signal a higher risk of later vision-threatening activity. One imaging feature often used as an indirect clue is the double-layer sign (DLS) on optical coherence tomography (OCT), which shows a separation between the retinal pigment epithelium and Bruch’s membrane. However, whether DLS reliably identifies neMNV has remained uncertain.
This multicenter prospective study examined fellow eyes of patients who had newly diagnosed exudative AMD in one eye. The goal was to determine how often DLS on OCT actually corresponded to neMNV on OCT angiography (OCT-A), a more direct imaging method for detecting abnormal blood flow.
Why this matters
In patients with unilateral exudative AMD, the other eye is at meaningful risk of developing neovascular disease. Identifying neMNV early could be useful for monitoring, counseling, and designing future clinical trials aimed at delaying or preventing exudation. If DLS were a dependable surrogate marker, clinicians could use standard OCT to estimate risk more easily. But if DLS is only loosely associated with neMNV, relying on it could lead to overestimation or underestimation of true disease prevalence.
Study design
This was a prospective observational cohort study conducted at multiple centers in the United Kingdom from January 2021 through June 2025. The analysis included 862 participants who had both OCT and OCT-A within 3 months of starting anti-vascular endothelial growth factor (anti-VEGF) treatment in the first eye. Of these, 550 participants had imaging in the fellow eye within 30 days of the first anti-VEGF injection, making them the main analytic group.
The study evaluated the prevalence of DLS and neMNV at baseline and used logistic regression to examine associations between imaging findings and the presence of neMNV. The investigators also compared outcomes in eyes with thick versus thin DLS.
Key findings
Among the 550 fellow eyes analyzed, the average participant age was 78.0 years, and 57.3% were women. DLS was present in 112 eyes, representing 20.4% of the cohort. neMNV was identified in 47 eyes, or 8.5% overall.
Most neMNV cases were located within the DLS region: 42 of 47 eyes with neMNV, or 89.36%, had neMNV inside a DLS. The remaining cases were found in other AMD-related structural changes, including fibrovascular irregular shallow pigment epithelial detachment in 3 eyes and beneath drusen in 2 eyes.
A particularly important result was that neMNV was much more common in eyes with thick DLS than in those with thin DLS. In eyes with thick DLS, neMNV was present in 48% of cases, compared with 16.2% in eyes with thin DLS. This difference was statistically significant. Even so, the overall prevalence of neMNV among all eyes with DLS was only about 40%.
Interpretation
These findings show that DLS is associated with neMNV, but it is not a reliable stand-alone surrogate marker. In other words, many eyes with DLS do not have neMNV when examined with OCT-A, and some eyes without a clear DLS may still have neMNV.
This distinction is clinically important. OCT is widely used in routine AMD care because it is fast, noninvasive, and readily available. OCT-A, while more informative for detecting flow, is more specialized and may not be accessible in every setting. If clinicians assume that DLS automatically means neMNV, they may overestimate disease burden or misjudge the risk of progression.
The study suggests that DLS should be viewed as a clue that prompts further evaluation rather than as proof of neovascularization. OCT-A remains the better tool for confirming neMNV.
Clinical implications
For retina specialists, this study reinforces several practical points:
First, patients with unilateral exudative AMD should be monitored closely in the fellow eye, especially if OCT shows DLS or other suspicious structural changes.
Second, the presence of DLS, especially thick DLS, may justify OCT-A to look for neMNV.
Third, the absence of DLS does not rule out neMNV. Clinical decisions should not rely on OCT morphology alone when the question is whether abnormal vessels are present.
Fourth, the study provides useful prevalence data for future research and clinical trial planning. Knowing that neMNV was present in 8.5% of fellow eyes overall, but only 40% of DLS-positive eyes, helps researchers calculate sample sizes and choose appropriate imaging endpoints.
Background on AMD and neMNV
Age-related macular degeneration is a major cause of central vision loss in older adults. In the neovascular form, new blood vessels grow from the choroid into or under the retina. These vessels can leak fluid or blood, causing distortion of central vision and potentially irreversible damage if not treated.
Anti-VEGF therapy has transformed treatment of exudative AMD by reducing leakage and preserving vision in many patients. However, anti-VEGF treatment is reactive rather than preventive: it treats disease after exudation begins. That is why there is increasing interest in detecting the nonexudative stage, when vessels are present but not yet leaking.
The term nonexudative macular neovascularization refers to this subclinical state. OCT-A, which visualizes blood flow without dye injection, has made it possible to detect these lesions earlier than conventional angiography in many cases.
What the study adds
This research adds several important points to current AMD practice. It confirms that neMNV is not rare in fellow eyes of patients with new-onset exudative AMD in the first eye. It also shows that DLS is common enough to be noticed in routine OCT, but not specific enough to be used as a dependable replacement for OCT-A.
The finding that most neMNV lesions were within DLS supports an anatomical relationship between the two features, but the mismatch in prevalence makes clear that the relationship is incomplete. DLS may reflect underlying structural remodeling, drusen, or early vascular change, but not every DLS corresponds to active nonexudative neovascularization.
Limitations and caution
As with all imaging studies, there are limitations. The results depend on image quality, timing of imaging relative to treatment initiation, and interpretation of OCT-A findings. Some lesions may be too small, too slow-flowing, or otherwise difficult to detect. Also, the study population consisted of patients with unilateral new-exudative AMD in the first eye, so the findings may not apply to all AMD populations.
Still, the multicenter prospective design strengthens the conclusions, and the sample size is relatively robust for this question.
Conclusion
In this multicenter study of fellow eyes from patients with unilateral new-onset exudative AMD, DLS on OCT was common, but true neMNV on OCT-A was much less common. Although neMNV was frequently located within DLS, only about 40% of DLS-positive eyes had neMNV. These results indicate that DLS should not be used as a substitute for OCT-A when evaluating for nonexudative macular neovascularization.
For clinicians, the message is straightforward: DLS is a useful warning sign, but it is not definitive. For researchers, the study provides valuable prevalence estimates and supports the need for direct vascular imaging when studying early neovascular AMD.
