New study examines soft drusen regression without atrophy and drusen ooze

The investigators retrospectively reviewed images from 640 consecutive eyes of 320 patients who had been followed for 2 years or longer. Image credit: AdobeStock/meenon

A new study tackled the topic of drusen regression without accompanying atrophy and forwarded the “drusen ooze” hypothesis to explain this phenomenon, ie, that the content of the drusen moves to the subretinal space through defects in the retinal pigment epithelium (RPE), which may explain drusen collapse with atrophy (DCwA) and (DRwoA),¹ reported Jordi Monés, MD, PhD. He is affiliated with the Institut de la Macula, Centro Medico Teknon, and the Barcelona Macula Foundation, both in Barcelona, and the John A Moran Eye Center, University of Utah, Salt Lake City.

He and his colleagues explained that while great strides have been made in the understanding of the biologic processes that precede the development of atrophy of RPE and photoreceptors, they recognized a subset of atrophy that results from the collapse of soft drusen, marking a crucial stage in disease progression.

“Although considerable attention has been focused on elucidating the mechanisms underlying drusen collapse and subsequent atrophy, a curious phenomenon has been poorly explained: drusen regression without accompanying atrophy. Despite its well-documented occurrence, it lacks a comprehensive explanation,^2-5” the investigators stated in the Ophthalmology Retina article.

Retrospective imaging study

They conducted this study to determine how often and why spontaneous soft drusen regresses without atrophy (DRwoA) in patients who had intermediate or atrophic age-related macular degeneration (AMD).

The investigators retrospectively reviewed images from 640 consecutive eyes of 320 patients who had been followed for 2 years or longer. Among these, 427 eyes of 262 patients were identified who had intermediate or atrophic AMD and no present or past exudative AMD.

The main outcome measures were DRwoA with integrity of the RPE and repositioning over Bruch’s membrane; DCwA in the same area simultaneously referred to as “sentinel” DCwA; and the reversibility of features of incomplete RPE, outer retinal atrophy (iRORA), and the areas (“halos”) of DRwoA around the sentinel drusen.

Evaluation of the images obtained from the 427 eyes identified 53 occurrences of DRwoA, representing 24.17% of the eyes with soft drusen. In 50 of the cases (94.33%), a nearby sentinel DCwA was seen. In 58% of the cases, a well-identifiable halo of drusen disappearance around the sentinel DCwA was clearly visible, the investigators reported.

Investigator commentary

A previous study theorized that “drusen formation and reabsorption are dynamic processes that can occur concurrently in the macula.⁶In addition, the potential prognostic implications of drusen regression and its therapeutic implications for macular alteration have been pointed out.⁶”

Monés and colleagues explained that the most accepted hypothesis for the disappearance of drusen material during drusen regression “is reduced secretion by altered RPE, especially when it dies, causing it to stop producing drusen material and leading to the collapse of the drusen.⁷”

Those authors reported in a separate study that “RPE cells on the drusen apex either migrate into the retina or die, and the drusen collapses because the RPE is not present to maintain it.”⁸

However, Monés and colleagues countered that that hypothesis does not explain drusen regression with the disappearance of drusen material with normal underlying RPE.

In the study under discussion, they identified a clear spatial and time relationship with DRwoA and DCwA, with at least 96% of the DRwoA having a close DCwA, and they occurred simultaneously, they said, indicating that both phenomena are related.

They explained further that in small soft drusen the connection may occur via a thin layer of drusen material, making the passage of material between drusen plausible, especially in low-density soft drusen, which has high fluid content, as represented by the drusenoid pigment epithelium detachment (PED) formed by coalescing drusen and accompanying surrounding soft drusen.

“The DRwoA around a collapsing drusenoid PED with atrophy is a typical phenomenon that can be observed in almost every case in daily practice to some extent. In drusen that will undergo DCwA, there invariably is an RPE defect at the apex of the drusen. This defect is a constant preceding stage in which hyperreflective dots are seen.^9,10 On the other hand, this RPE defect allows the connection between the sub-RPE drusen material and the subretinal space and the inner retina circulation. A plausible pathway for this material could be via the deep vascular complex of the retina, especially given the way-out challenges of the thickened Bruch's membrane.”

Monés and colleagues previously reported features suggesting movement of drusen material into the subretinal space through defects in the RPE above the drusen, which they referred to as “drusen ooze.” Both the presence of the same isoreflective material on both sides of the RPE, through the RPE defects accompanying the hyperreflective dots, and heterogeneous hyperreflectivity in the drusen, suggested the movement of material from the drusen to the subretinal space.

Although they advised that the drusen ooze hypothesis is not intended to replace established mechanisms such as RPE cell death, macrophage involvement, and glial activation, it presents a complementary perspective, especially in cases with high fluid, low-density soft drusen.

References:

1. Monés J, Pagani F, Santamaria JF, et al. Spontaneous soft drusen regression without atrophy and the drusen ooze. Ophthalmol Retina. 2025;9:828-37. https://www.ophthalmologyretina.org/article/S2468-6530(25)00093-4/fulltext

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