Think we’re seeing exudative AMD clearly? Maybe not. At EURETINA 2025, Dr. Steffen Schmitz-Valckenberg put our favorite imaging biomarkers under the microscope, challenging clinicians to zoom out, rethink what really matters and decide whether it’s time to refocus our view on what “seeing is believing” truly means.
As clinician-researchers, our days are split between two demanding callings: providing the best possible care for our patients and pushing the boundaries of what that care can become.
Anyone who has ever developed a research protocol knows how crucial it is to get every element right, from measuring the right things to defining outcomes that are scientifically sound and ensuring they truly matter for patients. The secret ingredient often lies in the biomarkers, those measurable indicators that reflect normal biological processes, disease states or response to therapy.
Thanks to leaps in imaging technology and our ever-deepening understanding of retinal structure and pathology, we now have more potential biomarkers than ever before. At EURETINA 2025, Dr. Steffen Schmitz-Valckenberg (USA) posed a thought-provoking question that many of us have quietly wondered, “Are we evaluating the right imaging biomarkers?”1
And if anyone is qualified to explore that question, it’s him. A professor of Ophthalmology and Visual Sciences at the University of Utah and co-founder and director of the Grading of Digital Fundus Examination Reading Center at the University of Bonn, Germany, Dr. Schmitz-Valckenberg has helped pioneer high-resolution retinal and fundus autofluorescence imaging techniques that have shaped modern retinal research around the world.
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Getting the lay of the land
Dr. Schmitz-Valckenberg began by framing the current landscape of exudative macular neovascularization (MNV)—the culprit behind irreversible visual impairment in individuals with age-related macular degeneration (AMD). The advent of anti-vascular endothelial growth factor (VEGF) therapy has dramatically reduced the number of patients experiencing severe vision loss. However, as most of us in clinic can attest, it comes at a price: an enormous assessment and treatment burden to sustain visual function.
Even with regular injections and vigilant follow-ups, not every patient hits the jackpot. Roughly 15% of eyes fall into the non- or suboptimal-responder category.2 That variability underscores why accurate imaging—and choosing the right biomarkers—matters more than ever.
Multimodal retinal imaging remains central to diagnosis, treatment monitoring and detecting complications. It also forms the foundation of numerous clinical endpoints. As Dr. Schmitz-Valckenberg explained, “When considering multimodal imaging in the context of MNV there are several practical considerations, such as the high volume of patients, as well as effective end analysis.”
To answer whether we are truly evaluating the right imaging biomarkers, he dissected the question from several angles…
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The art of differential diagnosis
“Not every macular exudation observed in an individual over the age of 55 is attributable to AMD,” Dr. Schmitz-Valckenberg noted, adding that most patients with exudative MNV secondary to AMD are over 70 years old. With a long list of possible differential diagnoses, multimodal imaging often holds the key to getting it right.
He referenced findings from the ORCA study,3 which showed that “the baseline diagnosis of the treating ophthalmologist was confirmed by the reading centers in eyes with neovascular AMD in 82.3%, or approximately four out of five physicians.”
The genetic lens
Next, Dr. Schmitz-Valckenberg explored how genetics intertwines with imaging. Two main AMD-associated genetic loci—CFH on chromosome 1 and ARMS2/HTRA1 on chromosome 10—significantly influence both the risk and the subtype of MNV.4
“Prior association of well-established imaging markers with age, genetic group and MNV subtype suggest that most imaging markers are rather unspecific when it comes to the signs of exudation, until later in the disease progression,” he explained.
Detecting trouble early
Early detection is where imaging earns its keep. Dr. Schmitz-Valckenberg questioned the minimal required B-scan density and compared the sensitivity of detecting intra- and subretinal fluid changes at 240 versus 120 microns, demonstrating just how easily lesions can be missed. “This is critical to disease detection and timely initiation of treatment,” he emphasized.
But, as he cautioned, not every subretinal hyporeflective space equates to fluid secondary to MNV. To illustrate, he shared seven years of longitudinal imaging from an asymptomatic 59-year-old woman whose subretinal changes resolved without treatment—a benign evolution of subretinal changes.
Managing for the long haul
With an ever-growing number of patients under long-term monitoring and anti-VEGF treatment, the conversation inevitably turns to chronic management. “There are a high number of patients with remarkably good to moderate vision,” Dr. Schmitz-Valckenberg explained. “But when there are complaints from patients associated with losing vision over time, often, this means that atrophy or fibrosis has developed.”
That’s when en face imaging and autofluorescence come to the forefront. Identifying and visualizing fibrosis can be tricky, and once it’s present, there are no targeted therapies yet (though research continues).
He also highlighted the work of Gemmy Cheung and colleagues, “that describe how it is important to look at the integrity of the outer neurosensory retina, preservation of the ELM and level of fibrosis relative to the RPE” as key indicators of preserved vision.5
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Beyond the pixels
At the end of the day, imaging alone doesn’t tell the full story. “Visual function is about more than visual acuity and there is a need for more sensitive tools,” Dr. Schmitz-Valckenberg reminded the audience.
He shared how artificial intelligence can estimate retinal function from imaging data, introducing the term inferred sensitivity to describe this approach.6 “This can be used as a quasi function surrogate endpoint in future clinical trials… providing more precise evaluation of treatment effects that goes beyond BCVA [best-corrected visual acuity] testing.”
In the eye of the beholder
As Dr. Schmitz-Valckenberg wrapped up his lecture, he circled back to his opening question: are we truly evaluating the right imaging biomarkers? The answer, it seems, lies in embracing the interplay of multiple imaging modalities, coupled with genetic and functional insights.
“Further insights into disease processes can be obtained when multimodal imaging is utilized in combination with other findings, particularly those related to genetics and visual function,” he concluded.
In other words, it’s not just about what we see. It’s about how we see it…and how well that vision aligns with the reality of our patients’ outcomes.
Editor’s Note: Prof. Steffen Schmitz-Valckenberg’s insights in this article are based on his Day 3 presentation at EURETINA 2025 Paris, titled “Exudative AMD: Are we evaluating the right imaging biomarkers?”. This content is intended exclusively for healthcare professionals. It is not intended for the general public. Products or therapies discussed may not be registered or approved in all jurisdictions, including Singapore. A version of this article was first published in PIE Issue 37.
References
- Schmitz-Valckenberg S. Exudative AMD: Are we evaluating the right imaging biomarkers? Lecture at EURETINA 2025. Paris, France. September 6, 2025.
- Finger RP, Wickremasinghe SS, Baird PN, et al. Predictors of anti-VEGF treatment response in neovascular age-related macular degeneration. Surv Ophthalmol. 2014;59(1):1-18.
- Brinkmann CK, Chang P, Schmitz-Valckenberg S, et al. Baseline diagnostics and initial treatment decision for anti-vascular endothelial growth factor treatment in retinal diseases: Comparison between results by study physician and reading centers (ORCA/OCEAN study). Ophthalmologe. 2019;116(8):753-765.
- Solinsky B, Schmitz Valckenberg S, Zouache MA, et al. Clinical manifestation of macular neovascularization in age-related macular degeneration among individuals homozygous for risk alleles on chromosome 1 (CFH-CFHR5), on chromosome 10 (ARMS2/HTRA1) or both. IOVS. 2024;65(7):2788.
- Cheung GCM, Grewal DS, Teo KYC, et al. The evolution of fibrosis and atrophy and their relationship with visual outcomes in Asian persons with neovascular age-related macular degeneration. Ophthalmol Retina. 2019;3(12):1045-1055.
- von der Emde L, Pfau M, Schmitz-Valckenberg S, et al. AI-based structure-function correlation in age-related macular degeneration. Eye (Lond). 2021;35(8):2110-2118.
