Reticular pseudodrusen in AMD: Update for optometrists

Reticular Pseudodrusen in Age-Related Macular Degeneration: An Update for Optometrists

Zhichao Wu, BAppSc(Optom), PhD; Dr Himeesh Kumar, MBBS; Robyn H. Guymer, MBBS, PhD

Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia

Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Australia

Corresponding Author

Zhichao Wu

Centre for Eye Research Australia

Level 7, 32 Gisborne Street

East Melbourne, VIC 3002, Australia

Email: [email protected]

Financial Disclosure(s):

RHG reports personal fees from Bayer, Novartis, Roche Genentech and Apellis outside the submitted work and research grant from Bayer outside the submitted work. ZW and HK report nothing to disclose.

Funding Support:

Supported by the National Health & Medical Research Council of Australia (APP1181010 [RHG and ZW]) and the Macular Disease Foundation Australia (MDFA). MDFA had no role in the preparation, review, or approval of this manuscript.

Age-Related Macular Degeneration

Age-related macular degeneration (AMD) remains a leading cause of irreversible vision loss, and one in seven Australians have the early signs of AMD.¹ These individuals are at risk of developing vision-threatening, late complications including choroidal neovascularisation (CNV) or geographic atrophy (GA). There are currently no specific interventions that can effectively slow or prevent the development of late AMD in those with the early signs of AMD, apart from general lifestyle advice² or nutritional supplements.^3,4 For those who develop GA, there are also no treatments available to slow or prevent the progressive enlargement of atrophy.

Fortunately, treatments are now available for CNV based on intravitreal injections of antiangiogenic agents, but their long-term effectiveness is highly dependent on visual acuity at presentation for treatment.^5,6 Early detection of CNV before vision is affected is thus a key part of the management of those with the early stages of AMD by optometrists. This is paramount given the recognition that retinal fluid (that may be indicative of CNV) can be present in those deemed only to have the early stages of AMD on colour fundus photography.⁷ Therefore, more frequent monitoring of those with the early stages of AMD using modern imaging techniques like optical coherence tomography (OCT) could thus enable the earlier detection of CNV.

However, it is likely not cost-effective to monitor every one of the approximately two million Australians estimated to have the early signs of AMD¹ more frequently than considered appropriate as part of standard-of-care, in order to enable the early detection of CNV. Instead, there is a need to identify those at high-risk of disease progression to target for careful surveillance. Assessment of the risk of progression has conventionally been based on clinical severity classification schemes, where the presence of large drusen or pigmentary abnormalities are key risk factors.⁸ In recent years, a new clinical feature has become increasingly recognised that warrants recognition by optometrists in their clinical assessment of AMD – the presence of reticular pseudodrusen.

Reticular Pseudodrusen – What Are They?

Three decades ago, Mimoun and colleagues⁹ described a peculiar pattern of drusen-like deposits characterised by having a faint network of broad interlacing ribbons (forming a “reticular” pattern), which were seen more clearly with blue light (“les pseudo-drusen visibles en lumière bleue”). It was only with modern OCT imaging that revealed that this peculiar pattern represented deposits that were localised to the subretinal space (i.e. above the retinal pigment epithelium [RPE], rather than below the RPE, where conventional drusen are typically located; Fig. 1).¹⁰ Recent histological studies have also revealed that their composition is distinct from conventional drusen.^11,12

Figure 1: Example of an eye with large drusen and reticular pseudodrusen (RPD) as seen on a colour fundus photograph (A); note the faint network of broad interlacing ribbons of drusen-like deposits that represent RPD. An optical coherence tomography (OCT) B-scan (B) was taken through the fovea (indicated by the white horizontal arrow), and it reveals the presence of RPD above the retinal pigment epithelium (RPE; white vertical arrows on the magnified inserts in C and D, corresponding to the white dashed rectangles in B) that were distinct from conventional drusen below the RPE (orange vertical arrow).

These subretinal drusenoid deposits have since been observed to be present not simply with eyes with the peculiar faint-interlacing pattern of drusen-like deposits (described as “reticular”), but that they also corresponded with more discrete dots with a pale yellow appearance (that can resemble small, hard drusen; Fig. 2). Nonetheless, these deposits are clinically referred to as “reticular pseudodrusen” (RPD). However, we and others have also shown that RPD can be missed on colour fundus photographs between 58%¹³ to 79%¹⁴ of the time. There are thus present more frequently than might be expected, with our study and others indicating that they are present in 26%¹⁴ to 29%¹³ of individuals with intermediate AMD.

Figure 2: Example of another 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. An optical coherence tomography (OCT) B-scan (B) was taken through the fovea (indicated by the white horizontal arrow), and again reveals the presence of RPD above the retinal pigment epithelium (RPE; white vertical arrows on the magnified inserts in D, corresponding to the white dashed rectangles in B) that were distinct from conventional drusen below the RPE (orange vertical arrow in C).

Reticular Pseudodrusen – So What?

What is the significance of this often hard-to-detect feature? Here are three key reasons:

1. Risk Factor for Progression: we have previously shown that in those with unilateral CNV, the presence of RPD confers an increased risk of AMD progression independently of the conventional features of large drusen and pigmentary abnormalities in the eye without CNV.¹⁵ A meta-analysis of several other studies have since confirmed these findings.¹⁶ However, it has only been recently established that RPD detected on fundus autofluorescence (FAF; an imaging modality that outperforms colour fundus photography for detecting RPD¹³) is associated with an increased risk of progression in those with the early stages of AMD¹⁴ – the type of patients seen more frequently in optometry practices. However, this represents findings from only a single study that warrants confirmation in other cohorts, before evidence-based guidance can be provided in terms of whether, and how much more frequently, patients with RPD should be monitored by optometrists.

2. Impaired Dark Adaptation: our work^17,18 and others¹⁹ have recently revealed that those with RPD in particular experience a marked impairment in dark adaptation. Indeed, a recent study revealed that those with RPD had the lowest scores on a Low Luminance Questionnaire,²⁰ which is consistent with our anecdotal clinical observations that patients with RPD often report difficulties under and with adjusting to low light conditions. This knowledge can help optometrists in their counselling of patients with RPD.

3. Potentially Crucial Predictor of Treatment Response: we recently completed a randomised-controlled trial examining the efficacy of a novel subthreshold nanosecond laser (SNL) treatment aimed to prevent or slow late AMD in the early stages of AMD (the Laser Intervention in the Early Stages of AMD [LEAD] study).²¹ 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, whilst there was a more than two-fold increased rate of progression in those did have coexistent RPD. It is well-recognised that post-hoc analyses in clinical trials should be interpreted with caution and require replication.²² These findings highlight the possibility that treatments that may be useful for those without RPD may not necessarily be useful for those with RPD, and it may therefore be crucial to distinguish between those with and without RPD. As such, future preventative treatment trials are thus likely to include RPD as part of their eligibility criteria. It is thus imperative that optometrists become familiar with this important feature, so that they can provide a more accurate assessment and counselling when offering patients an opportunity to be involved in clinical trials to find a preventative treatment for AMD.

Reticular Pseudodrusen – Where to From Here?

Whilst we have come a long way in terms of distinguishing RPD from typical drusen and in terms of understanding their clinical implications, substantial efforts continue to be required to understand the disease mechanisms behind their development. This is urgently needed so that we can begin to develop targeted treatments for those with RPD. In 2020, we commenced a major project in Melbourne for exactly this purpose (which received $5 million from the National Health & Medical Research Council; APP1181010), bringing together experts in eye health, artificial intelligence, genetics, stem cell research and bioinformatics to tackle RPD.

In order to prevent irreversible vision loss in people with AMD, and especially the likely high-risk group with RPD, we are calling on the partnership of optometrists all throughout Victoria to identify those with the early stages of AMD and to offer them an opportunity to volunteer in taking part in our study. This involves, at the most basic level, a once-off appointment at the Macular Research Unit, Centre for Eye Research Australia where they will undergo new clinical imaging, assessment of visual function and to obtain a blood sample to examine their genetics.

Without the help of our optometry profession and without our advocacy for these patients by offering them 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.

CERA is also conducting numerous clinical studies and trials for individuals with AMD, including:

• (i) trials of laser interventions for those with the early stages of AMD (such as Laser LIGHT-01)

• (ii) trials of various treatments for those with geographic atrophy (such as OcuDyne #OC-1901 with a surgical intervention, GOLDEN with a subcutaneous drug, and ONL1204 with an intravitreal therapy)

We would appreciate the partnership of optometrists throughout Victoria to offer individuals with non-neovascular AMD an opportunity to participate in research studies to help us find new interventions for preventing irreversible vision loss from AMD.

For further information, please contact us on (03) 9929 8113 or [email protected].

For optometrists outside of Victoria, we recommend that you contact the Macular Disease Foundation Australia (MDFA) to find out more about how you can refer those with the early stages of AMD to those involved in AMD research in your local region.

Read another newly released journal article: Reticular pseudodrusen: A critical phenotype in age-related macular degeneration

Multiple choice questions

1. The early signs of AMD are present in approximately how many Australians:
a. One in seven people over 18 years of age
b. One in seventy people over 18 years of age
c. One in seven people over 50 years of age
d. One in seventy people over 50 years of age

2. Effective treatments are now available for…
a. Those with the early stages of AMD
b. Those who develop geographic atrophy (GA)
c. Those who develop choroidal neovascularisation (CNV)
d. All of the above

3. How can we minimise the risk of those with the early stages of AMD from experiencing irreversible vision loss from CNV?
a. Careful surveillance to enable early detection of CNV
b. Using optical coherence tomography to detect retinal fluid
c. Ensuring that appropriate and early treatments are initiated
d. All of the above

4. Reticular pseudodrusen (RPD) are…
a. Deposits localised below the retinal pigment epithelium
b. Deposits localised above the retinal pigment epithelium
c. Deposits that are always seen on a clinical examination
d. Deposits that are always present in those with the early stages of AMD

5. How often are RPD present in individuals with intermediate AMD?
a. Approximately 5-10%
b. Approximately 25-30%
c. Approximately 60-80%
d. Approximately 90-100%

6. How often are RPD missed on colour fundus photographs?
a. Approximately 5-10% of the time
b. Approximately 25-30% of the time
c. Approximately 60-80% of the time
d. Approximately 90-100% of the time

7. For patients with the early stages of AMD and RPD, they should be reviewed:
a. Every 3 months
b. Every 6 months
c. Every 12 months
d. Robust evidence-based guidance remains to be established

8. Patients with the early stages of AMD with RPD are often characterised by having:
a. No visual complaints
b. Markedly reduced visual acuity
c. Dark adaptation impairments
d. Severe peripheral visual field loss

9. Based on our current knowledge, the presence of RPD…
a. Will definitely not have any impact on the response of potential interventions
b. May have some impact on the response of potential interventions
c. Has been shown in several studies to predict the response of potential interventions
d. Will definitively predict the response of potential interventions

10. Which of the following is an appropriate strategy for the management of those with the early stages of AMD by optometrists?
a. Monitoring these patients for the development of CNV
b. Providing relevant counselling based on recognising the presence of RPD
c. Offering patients an opportunity to participate in research studies to find an effective preventative treatment
d. All of the above

For the answers to these questions, scroll to the bottom of this page, below the references.

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. Meyers KJ, Liu Z, Millen AE, et al. Joint associations of diet, lifestyle, and genes with age-related macular degeneration. Ophthalmology 2015;122:2286-94.

3. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS Report No. 8. Arch Ophthalmol 2001;119:1417-36.

4. The Age-Related Eye Disease Study 2 Research Group. Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration. JAMA 2013;309:2005-15.

5. Tufail A, Xing W, Johnston R, et al. The Neovascular Age-Related Macular Degeneration Database: Multicenter Study of 92 976 Ranibizumab Injections. Ophthalmology 2014;121:1092-101.

6. Gillies MC, Campain A, Barthelmes D, et al. Long-Term Outcomes of Treatment of Neovascular Age-Related Macular Degeneration. Ophthalmology 2015;122:1837-45.

7. Leuschen JN, Schuman SG, Winter KP, et al. Spectral-domain optical coherence tomography characteristics of intermediate age-related macular degeneration. Ophthalmology 2013;120:140-50.

8. Ferris III FL, Wilkinson C, Bird A, et al. Clinical Classification of Age-Related Macular Degeneration. Ophthalmology 2013;129:844-51.

9. Mimoun G, Soubrane G, Coscas G. Macular Drusen. Journal Francais D Ophtalmologie 1990;13:511-30.

10. Zweifel SA, Spaide RF, Curcio CA, Malek G, Imamura Y. Reticular Pseudodrusen Are Subretinal Drusenoid Deposits. Ophthalmology 2010;117:303-12.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. Zhou Q, Shaffer J, Ying G-s. Pseudodrusen in the fellow eye of patients with unilateral neovascular age-related macular degeneration: a meta-analysis. PLoS ONE 2016;11:e0149030.

17. 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.

18. 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.

19. 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.

20. Yazdanie M, Alvarez J, Agrón E, et al. Decreased visual function scores on a low luminance questionnaire is associated with impaired dark adaptation. Ophthalmology 2017;124:1332-9.

21. 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.

22. Rothwell PM. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. The Lancet 2005;365:176-86.

Multiple choice answers

1. C, 2. C, 3. D, 4. B, 5. B, 6. C, 7. D, 8. C, 9. B, 10. D

Posted: 21 February 2022