Reticular Pseudodrusen Can Help Foretell AMD Risk

Drusen are small yellow-white deposits commonly seen on retinal examination in patients older than 60 years of age. Drusen within the macula are one of the hallmark clinical findings in age-related macular degeneration (AMD), the leading cause of adult blindness in the developed world.¹ Although important in disease prognosis, this finding is traditionally viewed as benign in and of itself; however , new insights from advanced imaging studies and retrospective clinical reviews are highlighting important distinguishing factors amongst different types of drusen deposits with implications not only for vision but, potentially, for systemic health as well.

For these reasons, ophthalmology clinics must have a robust knowledge of the clinical implications of drusen, how to identify its presence, and the latest research into how drusen can be used as a biomarker for disease status. Applying these findings can assist physicians in understanding the experience of patients with drusen and inform decisions that can preserve vision and overall health.

Pathophysiology of Drusen

The formation and evolution of drusen likely involves disruption of normal retinal pigment epithelial (RPE) homeostasis at a micronutrient or biochemical level leading to activation of pro-inflammatory pathways and buildup of extracellular material which manifests as druse. They are made up of various proteins, polysaccharides, glycosaminoglycans and lipid, amyloid and complement factors that arise from inflammatory and immune responses to RPE cell damage.^2,3 Likely related to both genetic and environmental factors, elucidating the exact mechanisms of this process is an active area of research.^4-6

Drusen Characteristics

Drusen are classified by their size, shape and location within the retina/RPE complex. These characteristics were chosen due to their utility in stratifying risk for development of advanced AMD, namely neovascular AMD or geographic atrophy, or both. Small drusen are defined as smaller than 63 µm in diameter while large drusen are larger than 125 µm. Intermediate drusen are between 64 and 124 µm. Drusen are also classically described as hard, implying lesions with clearly defined edges and homogenous color, as opposed to soft which have poorly defined borders and variable color. Drusen may be distinct lesions or may coalesce into confluent patches.⁷ Drusen can be present anywhere within the fundus but only those within the macula have been associated with vision-threatening disease. Most drusen accumulate in the sub-RPE space between Bruch’s membrane and displaced RPE, though reticular pseudodrusen will deposit between the retina and RPE.⁶. These different characteristics are used when developing AMD clinical severity scores and risk calculators. Importantly, drusen are not stationary and may come and go. One study found between 20% and 34% of drusen disappear within a 5-to-7-year period.⁸ 

Clinical Implications of Drusen

Drusen typically produce no visual symptoms but rather indicate ongoing RPE dysfunction. Few small drusen may represent normal physiologic changes related to aging while presence of a large druse portends a significantly increased risk of AMD progression. Similarly, hard drusen have lower risk for progression compared with soft drusen.9,10

Reticular pseudodrusen can also pose a significant risk for developing advanced AMD.¹¹ These variable clinical risks based on the type of drusen have been included into clinical risk calculators for monitoring and educating patients regarding AMD. One of the most commonly used scales was developed by the Age-Related Eye Disease Studies  (AREDS/AREDS2) group which assigns a point value based on the presence of large drusen or macular pigmentary changes. Eyes are judged on a 4-point scale with increasing risk of developing advanced AMD with increasing point totals. One point is assigned for the presence of either a single large drusen or pigmentary changes for each eye. The total number of risk factors for both eyes are combined to give a total value out of 4. The risk of developing advanced AMD within 5 years for 0, 1, 2, 3 and 4 points was found to be 0.5%, 3%, 12%, 25% and 50%, respectively.⁹

Imaging Drusen

Optical coherence tomography (OCT) and fundus autofluorescence (FAF) have important roles in classifying drusen and monitoring for disease progression. OCT is the most sensitive modality for characterizing drusen structure and can often detect early drusen before they may be evident on clinical exam. Both hard and soft drusen present with hyperreflective sub-RPE lesions with soft drusen typically having a larger lesion size. Cuticular drusen show sawtoothed sub-RPE lesions with prolate shape and moderate hyperreflectivity. 

Reticular pseudodrusen in contrast are present between the RPE and ellipsoid zone. As these reticular lesions progress, they may break through the ellipsoid zone and eventually fade leading to hyperreflective stripes into the underlying choroid. On FAF, hard and soft drusen both show variable to mild hyperautofluorescence while reticular pseudodrusen demonstrate hypofluorescence or no change in autofluorescent signal. Cuticular drusen show a distinct starry sky type hyperautofluorescence which may be present before lesions are visible on clinical exam.^6,12

Evolving Understanding of Reticular Pseudodrusen

Researchers are increasingly recognizing the value of monitoring reticular pseudodrusen for determining AMD prognosis. Recently, the AREDS/AREDS2 research group published a post-hoc clinical trial analysis regarding the risk of reticular pseudodrusen present on the development of advanced AMD. Independent of the presence of other high-risk features, namely soft drusen and pigmentary abnormalities, reticular pseudodrusen were associated with an increased risk of developing advanced AMD, in particular geographic atrophy.¹¹ 

Interestingly, the risk appears higher in patients who lack other high-risk features. The study, which took into account 3355 eyes of 2056 participants, found reticular pseudodrusen considered in isolation from a 9-point severity scale is associated with a significantly higher risk of AMD progression (HR, 2.21; 95% CI, 1.85–2.64; P <.0001).¹¹

Additionally, researchers considered the effect of reticular pseudodrusen independent of the 4-point modified simplified severity scale and found a higher likelihood for progression to geographic atrophy (95% CI, 1.47–2.86; P <.0001).¹¹

This led to the conclusion that reticular pseudodrusen are an independent risk factor for AMD progression.¹¹ 

Presence of reticular pseudodrusen is likely a significant risk factor in patients who would be otherwise classified as mild or moderate disease on established AMD disease severity scales. Patients with reticular pseudodrusen may also demonstrate a different disease phenotype with distinct symptomatic and progression patterns.

Perhaps equally important is the recent association of reticular pseudodrusen with underlying systemic disease. Numerous reports have found connections between the presence of reticular pseudodrusen and cardiovascular disease, including coronary artery disease and hypertension.^13-16 

Patients with reticular pseudodrusen-associated AMD also have higher rates of all-cause mortality compared with patients without, a 2022 study shows.¹¹ Though no causal link has been established thus far, shared inflammatory or ischemic microvascular mechanisms have been proposed and are currently under investigation.¹⁷ 

Patient Education and Counseling

Patients who present with asymptomatic drusen concerning for non-exudative AMD should be counseled regarding the risk of developing advanced AMD based on the extent and composition of their drusen. They should also be advised to mitigate other risk factors associated with AMD progression, specifically to avoid smoking and manage other cardiovascular risk factors such as hypertension and hypercholesterolemia. Regular follow up and self-monitoring with Amsler grid for acute changes in central vision or metamorphopsia should be encouraged. Patients with intermediate and advanced AMD should receive AREDS2 vitamin supplementation twice daily to slow the risk of progression. Conversion to exudative AMD should prompt referral to a vitreoretinal specialist for consideration of anti-VEGF intravitreal therapy.

Future Directions

Developing more accurate prediction models is an area of active research. Artificial intelligence models are under development using primarily OCT imaging data.¹⁸ These may provide more accurate and detailed information and potentially allow for earlier diagnosis and treatment. Novel treatments, particularly for advanced non-exudative AMD, are under investigation. In February 2023, pegcetacoplan became the first FDA-approved treatment for patients with geographic atrophy. 

Other treatment modalities such as immunotherapy, gene therapy and sustained drug delivery devices are currently under clinical investigation.¹⁹ Treatment for AMD may very well change significantly in the coming decade depending on the outcomes of these studies.

Andrew J. Clark, MD PhD is a first-year vitreoretinal surgery fellow at the USC Roski Eye Institute/Retina-Vitreous Associates in Los Angeles.

Drs Boyer and Su are retinal surgeons at Retina-Vitreous Associates Medical Group in Los Angeles.