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HomemieyecareHot Topics in Research: Reticular Pseudodrusen

Hot Topics in Research: Reticular Pseudodrusen

Researchers in Australia and around the world believe the presence of reticular pseudodrusen, as seen on optical coherence tomography, may provide valuable insights into a patient’s likely progression to late stage age-related macular degeneration (AMD). A global study aims to better understand the disease pathways behind the development of these drusen-like deposits in order to guide new treatment discovery.

Age-related macular degeneration (AMD) remains a leading cause of irreversible vision loss in Australia, and one in seven people over the age of 50 have signs of this disease.1 Drusen – focal accumulations of extracellular waste material below the retinal pigment epithelium (RPE) – are yellow deposits that, when present at the macula, are a hallmark sign of AMD.

Without your help in offering patients with AMD an opportunity to contribute to the efforts for finding an effective treatment, we will not be able to make headway in improving the lives of those with this potentially devastating condition

Figure 1. Example of a left eye with large drusen and reticular RPD as seen on a colour fundus photograph. (A) Note the faint network of broad interlacing ribbons of drusen-like deposits that represent RPD in the superior arcade (hard to discern). An OCT B-scan (B) was taken through the fovea (indicated by the white horizontal arrow), revealing the presence of RPD above the retinal pigment epithelium (RPE). White vertical arrows on the magnified inserts (C & D), correspond to the white dashed rectangles in (B) that were distinct from conventional drusen below the RPE (orange vertical arrow). Figure 2. Example of a right eye with large drusen and reticular pseudodrusen (RPD), as seen on a colour fundus photograph (A). Note the presence of pale-yellow, discrete deposits that represent RPD (but could be mistaken for small hard drusen). An OCT B-scan (B) was taken through the fovea (indicated by the white horizontal arrow). This revealed both (C) conventional drusen below the retinal pigment epithelium (orange vertical arrow), and (D) the presence of RPD above the RPE (white vertical arrows).

In more recent years, the advent of modern three-dimensional imaging modalities, such as optical coherence tomography (OCT), have revealed that drusen-like deposits can also be present above the RPE (Figure 1).2 These deposits are often found to be associated with a faint network of broad interlacing ribbons on colour fundus photographs (Figure 1), and have been termed ‘reticular pseudodrusen’ (RPD). This characteristic network pattern of drusen-like deposits was first described more than three decades ago by Mimoun et al,3 which they observed to be seen more clearly with blue light (“les pseudo-drusen visibles en lumière bleue”). Since then, OCT imaging has revealed that the same subretinal drusenoid deposits seen in eyes with these networks of interlacing ribbons can also be found to correspond with more discrete, pale-yellow deposits4 (Figure 2). Note that these deposits can resemble small hard drusen on clinical examination or on colour imaging.

Although the presence of these subretinal drusenoid deposits is clinically described as ‘reticular pseudodrusen’, recent histological studies have shown that their composition is distinct from conventional drusen.5,6 Indeed, our work7,8 at the Centre for Eye Research Australia (CERA) and the work of others9 has also shown that in people with AMD, those with coexistent RPD have substantially greater impairments in dark adaptation compared to those without, highlighting their distinct structural and associated functional differences.

Despite their distinctiveness, we and others, have shown that RPD are missed on the assessment of colour fundus photographs by experienced graders in 60% to 80% of eyes where they are detected on OCT imaging.10,11 Our studies and others have also shown that they are present in about 25% to 30% of individuals with intermediate AMD,10,11 and these findings together suggest that they are present more often than we may have previously realised.

RPD – A RISK FACTOR FOR PROGRESSION

We and others have previously shown that in the fellow eye of those with unilateral choroidal neovascularisation (CNV), the presence of RPD on multimodal imaging (including OCT imaging) was associated with an increased risk of progression to late AMD, independent of the conventional features of large drusen and pigmentary abnormalities in the eye without CNV.12,13 

A recent large study, looking at progression in people with only the early signs of AMD (n = 646), showed that RPD detected on fundus autofluorescence (FAF; an imaging modality that outperforms colour fundus photography for detecting RPD10) was also associated with an increased risk of progression.11 However, other studies, including our own (unpublished) have not observed RPD, as detected on OCT imaging, to be associated with an increased risk of progression in those with the early stages of AMD, although these studies included fewer participants than the abovementioned study.14,15 

The importance of RPD as a risk factor for progression to late AMD warrants further work to understand the disease mechanisms leading to its development and their progression to vision-threatening complications. This is required to guide the development of targeted treatments for those with RPD, which may well be different for this AMD phenotype compared to those with AMD but without RPD.

NEED TO FIND A TARGETED TREATMENT FOR RPD

The importance of finding a specific intervention for those with RPD is underscored by the findings from our Laser Intervention in the Early Stages of AMD (LEAD) study – a randomised-controlled trial examining the efficacy of a novel subthreshold nanosecond laser (SNL) for slowing disease progression in the early stages of AMD.16 The LEAD study showed that overall, those randomised to receive SNL treatment did not show a significantly slower rate of progression to late AMD when compared to those who were randomised to a sham treatment.

However, a post-hoc analysis revealed that there was a more than four-fold slowing in disease progression in the SNL compared to sham group for those who did not have coexistent RPD at baseline, while there was a more than two-fold increased rate of progression in those who did have coexistent RPD. It is well-recognised that post-hoc analyses in clinical trials should be interpreted with caution and require replication.17 Nonetheless, these findings demonstrate the possibility that treatments that may be useful for those without RPD may not necessarily be useful for those with RPD, and potentially the opposite will be true.

SYNERGY HIGH-RISK AMD STUDY

Our team at the CERA, in collaboration with other leading researchers at the University of Melbourne, Walter & Eliza Hall Institute and our collaborators in the UK, Europe and USA, have recently begun one of the world’s most comprehensive studies to understand the disease pathways behind the development of RPD. This study, funded by the National Health and Medical Research Council (AU$5 million over five years), brings together experts in eye health, artificial intelligence, genetics, stem cell research and bioinformatics to tackle RPD. This study has been named the ‘Synergy High-Risk AMD Study’.

One of the key goals of the study is to perform in-depth characterisation of a large cohort of individuals with the early stages of AMD, by using different risk factor questionnaires, new retinal imaging, visual function tests and by obtaining biological samples (e.g., blood to examine genes and skin biopsies for stem cell research). This will allow potential pathways that drive the development of RPD to be identified, and which will then enable us to identify new therapeutic strategies for people with this important AMD phenotype.

We are thus calling on the partnership of eye care professionals throughout Victoria to help identify people with nonneovascular AMD, and to offer them an opportunity to volunteer in taking part in the Synergy High-Risk AMD Study. This involves, at the most basic level, a once-off appointment at the Macular Research Unit, Centre for Eye Research Australia (co-located with the Royal Victorian Eye and Ear Hospital).

Without your help in offering patients with AMD an opportunity to contribute to the efforts for finding an effective treatment, we will not be able to make headway in improving the lives of those with this potentially devastating condition.

For further information, eligibility criteria, and referral pathways (including mail, fax or Oculo) for potential participants, visit www.cera.org.au/synergy-high-riskamd- study or contact the CERA research team on (AUS) 03 9929 8113 or amd-studies@cera.org.au.

Dr Zhichao Wu is an optometrist and Senior Research Fellow at the Centre for Eye Research Australia and Ophthalmology, Department of Surgery, The University of Melbourne. His research focusses on harnessing new technology to expedite treatment discovery and prevent irreversible vision loss from diseases such as agerelated macular degeneration and glaucoma. 

Dr Carla Abbott is a therapeutically-endorsed optometrist and Senior Research Fellow at the Centre for Eye Research Australia, conducting translational research studies. She is also a consultant optometrist and teaching clinician at the Australian College of Optometry, and Victorian practitioner member on the Optometry Board of Australia. 

Professor Robyn Guymer AM is the Deputy Director of the Centre for Eye Research Australia and Head of the Macular Research Unit, and Professor Ophthalmology, Department of Surgery at the University of Melbourne. She is a practising clinician-scientist and a retinal consultant at the Royal Victorian Eye and Ear Hospital. 

References 

  1. Keel S, Xie J, Foreman J, et al. Prevalence of Age- Related Macular Degeneration in Australia: The Australian National Eye Health Survey. JAMA Ophthalmology 2017;135:1242-9. 
  2. Zweifel SA, Spaide RF, Curcio CA, Malek G, Imamura Y. Reticular Pseudodrusen Are Subretinal Drusenoid Deposits. Ophthalmology 2010;117:303-12. 
  3. Mimoun G, Soubrane G, Coscas G. Macular Drusen. Journal Francais D Ophtalmologie 1990;13:511-30. 
  4. Suzuki M, Sato T, Spaide RF. Pseudodrusen Subtypes as Delineated by Multimodal Imaging of the Fundus. Am J Ophthalmol 2014;157:1005-12. 
  5. Greferath U, Guymer RH, Vessey KA, Brassington K, Fletcher EL. Correlation of histologic features with in vivo imaging of reticular pseudodrusen. Ophthalmology 2016;123:1320-31. 
  6. Chen L, Messinger JD, Zhang Y, et al. Subretinal drusenoid deposit in age-related macular degeneration: histologic insights into initiation, progression to atrophy, and imaging. Retina 2020;40:618-31. 
  7. Luu CD, Tan R, Caruso E, et al. Topographic Rod Recovery Profiles after a Prolonged Dark Adaptation in Subjects with Reticular Pseudodrusen. Ophthalmology Retina 2018;2:1206-17. 
  8. Tan R, Guymer RH, Luu CD. Subretinal Drusenoid Deposits and the Loss of Rod Function in Intermediate Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2018;59:4154-61. 
  9. Flamendorf J, Agrón E, Wong WT, et al. Impairments in dark adaptation are associated with age-related macular degeneration severity and reticular pseudodrusen. Ophthalmology 2015;122:2053-62. 
  10. Wu Z, Ayton LN, Luu CD, Baird PN, Guymer RH. Reticular Pseudodrusen in Intermediate Age-Related Macular Degeneration: Prevalence, Detection, Clinical, Environmental and Genetic Associations. Invest Ophthalmol Vis Sci 2016;57:1310-6. 
  11. Domalpally A, Agron E, Pak JW, et al. Prevalence, Risk and Genetic Association of Reticular Pseudodrusen in Age-related Macular Degeneration. AREDS2 Report 20. Ophthalmology 2019;126:1659-66. 
  12. Finger RP, Wu Z, Luu CD, et al. Reticular Pseudodrusen: A Risk Factor for Geographic Atrophy in Fellow Eyes of Individuals with Unilateral Choroidal Neovascularization. Ophthalmology 2014;121:1252-6. 
  13. Hogg RE, Silva R, Staurenghi G, et al. Clinical Characteristics of Reticular Pseudodrusen in the Fellow Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration. Ophthalmology 2014. 
  14. Sleiman K, Veerappan M, Winter KP, et al. Optical Coherence Tomography Predictors of Risk for Progression to Non-Neovascular Atrophic Age-Related Macular Degeneration. Ophthalmology 2017;124:1764-77. 
  15. Thiele S, Nadal J, Pfau M, et al. Prognostic Value of Retinal Layers in Comparison with Other Risk Factors for Conversion of Intermediate Age-related Macular Degeneration. Ophthalmology Retina 2020;4:31-40. 
  16. Guymer RH, Wu Z, Hodgson LAB, et al. Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial. Ophthalmology 2019;126:829-38. 
  17. Rothwell PM. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. The Lancet 2005;365:176-86.

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