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Trial Ready AMD Cases: Establishing a Registry

2 CPD in Australia | .25CD + .25G in New Zealand | 1 November 2018

By Professor Robyn Guymer AM and Jeena Tan

The global prevalence of age related macular degeneration (AMD) continues to increase, impacting quality of life for patients, their families and carers. Early diagnosis and prompt management are essential to control the progress of this disease and minimise vision loss. Right now, a standardised classification system for AMD, new multimodal imaging techniques for diagnosis and management, and research into potential treatments are re-shaping the way this disease is diagnosed and managed.
It is hoped that a national AMD registry, that will provide the answers to remaining questions surrounding AMD, can be established, and give patients access to information and clinical trials as they become available in Australia and internationally.


  1. Be familiar with the Beckman classification of AMD.
  2. Understand that classification is based upon colour fundus images and relates to the risk of progression to vision loss
  3. Recognise the benefits of the proposed AMD research registry for researchers, clinicians and patients
  4. Know how optometrists and patients can become involved in the registry
  5. Recognise the significance of the recently concluded LEAD study.

Age-related macular degeneration (AMD) is the predominant cause of irreversible visual loss in people over 50 years of age in Western countries.1 AMD primarily impacts the ability to read, recognise faces and drive, with the late stages reducing quality of life and increasing the required level of care. Unsurprisingly, the risk of developing AMD increases with age, and as the population continues to age in Australia and other Western countries, we can only project an increase of the number of individuals affected by the disease, along with an increase of the impact to health care and demands on the public health system. This leads to AMD becoming a major health concern not only in Australia, but globally as well.

In the last decade, advances in the treatment of the neovascular form of late AMD (nAMD) have occurred with intraocular injections of anti-vascular endothelial growth factor (anti-VEGF). There are currently two approved anti-VEGF drugs that can be used in the clinical treatment of nAMD; these are Ranibizumab and Aflibercept. Bevacizumab is also used off label for this indication. Clinical trials of these drugs at regular four-weekly or two-monthly intervals, as well as using treat and extend protocols have dramatically reduced vision loss from this form of late AMD.2,3,4,5 However, long-term visual benefits are not always maintained despite treatment, with vision loss continuing to occur through atrophy or scar formation.6 There is also currently no treatment for the other late AMD complication of geographic atrophy (GA).

Apart from dietary supplements for subsets of individuals with AMD7 and general lifestyle modification, such as ceasing smoking and keeping a healthy weight,8 there is no specific intervention that prevents or slows progression from earlier, asymptomatic stages of AMD to the visually devastating complications of late AMD.

Once individuals reach the end stage of the disease and manifest the complication of geographic atrophy, vision and subsequent quality of life is greatly affected. Management of geographic atrophy currently involves supportive and monitoring interventions. These include regular review by an optometrist or ophthalmologist to closely monitor for any progression of the disease in the other eye (if only one eye is affected), referral to low vision services if required and lifestyle advice. As such, there is an urgent need for an effective intervention to slow or prevent the progression of the disease in its early stages.

The early, asymptomatic stages of AMD are diagnosed clinically by the presence of drusen within two disc diameters of the fovea. The clinical classification of AMD was updated in 2013 in the Beckman classification.9 The classification is based upon colour fundus images and relates to the risk of progression to vision loss. Size of any drusen present is confirmed as being very important to risk, with drusen that is <63µm (also known as druplets) being considered part of a normal age-related change. Having druplets with no other associated abnormalities in the retinal pigment carries the same risk of progressing to late AMD as having no drusen at all. This is why drusen that falls within this size range does not qualify as a classification of AMD.

Patients presenting with medium sized drusen at the macula, that is between 63–125µm, without abnormalities in the retinal pigment, are considered to have early AMD. Those with medium-sized drusen with abnormalities in the retinal pigment are considered to have intermediate AMD (iAMD).

Patients with large drusen (>125µm diameter) in both eyes, regardless of pigmentary abnormalities, are also considered to have iAMD and according to the Beckman classification, are at greater risk of progression to late AMD than those with smaller sized drusen.9 Patients presenting with early or intermediate stages of AMD can be asymptomatic and have no obvious loss to visual function.

As previously mentioned, late AMD is classified when the individual develops choroidal neovascularisation and/or shows signs of any geographic atrophy. Geographic atrophy is characterised by progressive degeneration – the death of the photoreceptors and retinal pigment epithelium (RPE)9 – leading to a decline in visual function that is irreversible with no treatment currently available.

Neovascular AMD is characterised by the growth of new, fragile blood vessels that originate from the choroid beneath the retina. Leakage from these new vessels causes the accumulation of blood and fluid in the sub-retinal space, potentially causing RPE or retinal detachment and scarring. If not treated in a timely manner, acute severe vision loss can become permanent.

It is important for individuals with AMD to be aware that the complication of neovascular AMD can develop at any stage during disease progression. Due to the treatments available for nAMD, communicating this to patients with any stage of AMD is vital. It is essential that eye care professionals advise their patients to carefully monitor their vision for any sudden changes, including visual blur, reduction or distortion. An Amsler grid can also be provided to the patient, with instructions to self-assess central vision at regular intervals. The patient should also be advised to seek urgent and immediate care from an eye health professional if they start to notice any of the above sudden changes.

Figure 1. SD-OCT showing hyper reflective foci over drusen


New multimodal imaging (MMI) techniques, such as optical coherence tomography (OCT), fundus autofluorescence (FAF) and near infrared (IR) imaging have also revealed new anatomical features that are important when assessing AMD and an individual’s risk of vision loss. For example, hyper-reflective foci are often seen above drusen on Spectral-domain optical coherence tomography (SD-OCT) imaging and are thought to reflect the hyperpigmentary changes seen on colour fundus photography (CFP)10 (Figure 1). On SD-OCT, debris located above the RPE, so called subretinal drusenoid deposits (SDD), are also well seen and appear much more prevalent than previously appreciated on CFP (Figure 2). They can also be identified on other MMI modalities such as FAF and Near IR far more often than seen clinically or on CFP11 (Figure 3). Clinically, these deposits are called reticular pseudo drusen (RPD), and are considered important in disease pathogenesis as they are frequently present in late stage disease.12,13

Figure 2. SD-OCT showing typical drusen on the left and reticular pseudo-drusen on the right

Figure 3. A macula, imaged on colour photography, auto fluorescence and near infrared imaging showing extensive reticularpseudo-drusen


The SD-OCT has the advantage of being able to visualise specific retinal layers affected by a disease process. Recently we introduced the term nascent GA (nGA) to describe a collection of OCT findings that are thought to be the first signs of cell loss in AMD when atrophy begins.14 Findings include loss or thinning of the photoreceptor layer as evidenced by outer nuclear layer (ONL) thinning, subsidence of the outer plexiform layer (OPL) and inner nuclear layer (INL). Also found is the development of a hypo-reflective wedge-shaped band within the limits of the OPL. These changes are often associated with external limiting membrane (ELM) loss, or ellipsoid zone (EZ) or interdigitation zone (IZ) loss. Usually underlying the photoreceptor loss is a zone of attenuation or disruption of the RPE. A region of hyper-transmission of the signal into the choroid is also seen. This constellation of signs (not all present all the time) makes up nGA (Figure 4). These additional OCT signs add to the phenotypic profile of people with the early stages of AMD, before late AMD of CNV or GA develop. By using OCT, we will help define different risk profiles that are likely to be important when novel interventions are being trialled.

Figure 4. SD-OCT showing signs of nascent geographic atrophy


The Need For An AMD Registry

Currently there are researchers active in the international community working to find interventions that help people with AMD. To ensure that Australia is ready to participate in new trials of novel interventions that will target specific stages and risk profiles of AMD, there is a clear need to establish a database of AMD patients, or an AMD registry. This registry will consist of well-phenotyped individuals whose AMD status has been determined and who have consented to being contacted if an appropriate trial is recruiting in Australia.

The vast majority of earlier AMD cases are fully involved in the community and would usually be in contact with optometrists, rather than ophthalmologists, as they do not have significant ocular health issues and may also have no obvious signs or symptoms on presentation. Therefore, individuals with AMD need to be diagnosed in a primary eye care setting, provided with appropriate information about their condition and the appropriate management plan, phenotyped as to their risk and then, if they are interested and provide their consent, have their information forwarded onto a trial registry, ready for potential participation in future clinical trials.

Figure 5. RANZCO collaborative guidelines for age-related macular degeneration. Click on image to enlarge.


According to the recent Royal Australian and New Zealand College of Ophthalmologists (RANZCO) collaborative care guidelines (Figure 5), referral to an ophthalmologist is only suggested for younger patients with early/intermediate AMD, or clearly indicated within one or two weeks for patients with signs suggesting choroidal neovascularisation, and for suspected or definite choroidal neovascularisation. Hence, for cases of the early stages of AMD, it is critical that optometry is involved in this initiative.

In the recently produced RANZCO collaborative care guidelines for AMD, the Beckman classification of AMD stage is the centre point of the guidelines. Eye care professionals are required to identify patients during routine examination that may be at risk of having or developing AMD. Once assessment of these patients is completed, there are five main groups that they can be classified, or phenotyped to. These are:

  1. No macula change or normal ageing changes
  2. Early AMD (drusen between 63µm and 125µm), with no pigment changes
  3. Intermediate AMD (drusen > 125µm or drusen 63-125µm AND pigment changes
  4. Late AMD – geographic atrophy
  5. Late AMD – choroidal neovascularisation

The RANZCO collaborative care guidelines were developed with the purpose of reaching a consistent way to classify patients, in turn leading to a more consistent approach to treatment and management of sight-threatening conditions. Additionally, consistent and accurate classification of disease should ensure that patients receive timely and appropriate treatment from the most appropriate health professional. Finally, as there is an increasing focus on the need to develop interventions to stop or slow progression of disease when AMD is in its early stages, correct classification of patients is important to enable appropriate inclusion in clinical trials and research.

The ultimate aim is to have community eye care professionals recognising all cases of AMD and categorising them according to the Beckman classification. After confirmation by an ophthalmologist, or specifically set up reading centre involved in the registry, the case will be placed on the trial registry for easy identification when new trials start recruiting.

Another key achievement would be beginning to recognise the additional MMI signs that further characterise the disease. It is something that, as collaborative eye care and eye health professionals, we should be working towards.

To work towards this end, CERA, Specsavers and Oculo have joined forces to conduct a pilot study led by Professor Robyn Guymer. The first aim of this trial is to determine the accuracy and consistency of stage classification in AMD, using the Beckman classification as a standard. The pilot will commence with a small group of Specsavers stores in Australia. This group will receive training on the Beckman classification by Professor Guymer as well as discussion on the SD-OCT signs seen in AMD that further contribute to the risk of vision loss; in particular associated with nascent geographic atrophy (nGA), hyper reflective foci and reticular pseudo drusen (RPD). An important secondary outcome is to assess the effectiveness of this training and feedback on the ability to stratify disease phenotype and risk of vision loss.

To achieve these outcomes, participating optometrists will be able to send their classification of clinical images, via Oculo, to the research unit at CERA. For patients who give their informed consent, there will also be the option to be placed on a research registry. Within this study, optometrists would also be able to seek feedback on any additional signs noted on OCT or on digital retinal photography. The clinical notes and the AMD grade indicated by the optometrist will be reviewed by Professor Gymer at CERA and feedback will be given on whether the classification by the optometrist was correct, as well as reporting back any corrections and including any additional findings of significance.

It is expected that by conducting this process, participating optometrists will become more proficient, over a short period of time, as to whether they have correctly identified and classified the presentation of disease. Additionally, the opportunity to inform patients of the research registry will help identify and increase AMD cases that are willing to be contacted for potential trials. Finally, there is also an opportunity to raise patient awareness of AMD as they are diagnosed, be aware of the opportunity to be involved in a national registry of AMD patients, be provided with consistent management advice after confirmation of their disease classification, and to better manage their disease.

For optometrists who are not involved in the pilot sites but are interested in becoming involved in this initiative, client details are able to be forwarded (once consent is given) to Professor Guymer at CERA for placement on the registry. However, at this time, the feedback via Oculo will only occur for the pilot sites. Optometrists are also reminded that the process outlined above for this pilot study is not a referral for ophthalmological consultation and does not replace a referral. For patients who require to be referred (as per the RANZCO guidelines) for clinical interventions or assessment by an ophthalmologist, optometrists should continue to refer according to usual referral practices. This also applies to any patient who consents to have their details and clinical images forwarded as part of the study; on the occasion a referral is also required, optometrists need to ensure this occurs as part of usual referral practice.

Ultimately if the pilot study is a success, the aim is to move to broaden its reach so that optometrists Australia-wide are able to contribute to the registry. It will take time to put processes in place, and funding to grow and maintain the registry. However AMD is an ongoing concern, so if an Australia-wide, well-characterised AMD trial registry can be established, Australia will be well-placed to participate in important, patient-based research. This will make a difference not only to the lives of people with AMD, but to the future population at risk of developing this disease.

Why This Registry Is Important Now

There is no specifically targeted intervention to slow AMD progression from early stages of the disease to late vision threatening complications. The Laser intervention in Early stages of Age-related macular Degeneration (LEAD) study is a proof of concept, investigation of the safety and efficacy of sub-threshold nanosecond laser (SNL) treatment as an intervention in iAMD to slow progression to late AMD. The LEAD study is also the first AMD trial to incorporate findings identified using several multi modal imaging (MMI) techniques, including OCT to define late AMD. The results of this Australian study are due to be published in the journal Ophthalmology soon and irrespective of the findings of the study, there is sure to be a need for ongoing research and further trials into this form of laser intervention. This study also highlights why there is a critical need for all eye care professionals involved in the assessment, detection and management of people with AMD to be able to properly identify their risk factors for progression, as identified on SD-OCT.

LEAD is a multi-centred, double-masked, randomised, sham-procedure controlled, exploratory clinical trial of sub-threshold nanosecond laser treatment (SNL). Participants with bilateral large drusen (> 125µm), best corrected visual acuity (BCVA) ≥ 20/40 were enrolled. Participants were randomly assigned (1:1) to receive SNL or sham laser treatment to the study eye at six-monthly visits over 36 months. The primary efficacy outcome is the number of study eyes progressing to a late AMD endpoint – either neovascular AMD (nAMD) or atrophic AMD.

Two hundred and ninety two participants were randomised to receive SNL or sham treatment. The median age of the participants at baseline was 70 years. A third (33.2 per cent) of the participants had pigmentary abnormalities and nearly a quarter (24 per cent) had definite RPD. Atrophic endpoints were defined as traditional GA based upon colour fundus photography, or FAF defined atrophy, or OCT defined atrophy or nascent GA. Neovascular endpoints were defined based upon FFA. The primary endpoint results were presented in September during the 2018 Euretina Congress in Vienna.

Prof. Guymer reported that the main outcome of the rate of progression to late AMD in the treated and sham groups, was not statistically significant, however, different clinical groups appeared to respond differently to the treatment. Patients with less severe signs of AMD (representing 76 per cent of the participants) showed a four-fold decrease in progression rate of their disease, whereas participants with more severe signs of disease at the beginning of the trial (24 per cent of participants) had a doubling of their progression rate to late stages of AMD when compared to participants who were not treated.

The results are important as this was the first RCT of nanosecond laser in iAMD, but also because it used MMI to determine the presence of earlier stages of drusen associated atrophy as part of an atrophic endpoint in AMD. Currently the OCT defined anatomical endpoints of atrophy are not recognised by regulatory authorities.

Researchers at CERA are keen to continue to explore further the possibilities that this sub threshold laser offers in the treatment of AMD. The clinical trial has been run alongside a major pre-clinical research effort at the University of Melbourne, led by Professor Erica Fletcher. Collectively, there is still much to do to understand the mechanism by which the laser treatment might be able to influence the disease.

If we can mutually establish a registry of early stage AMD cases who are keen to be involved in research, we will be well placed to answer all the remaining questions that the LEAD study poses, as well as being able to embrace any other early stage intervention trial that comes out of other research in Australia, or comes to Australia as part of multi centred international trials. Either way, our community of older Australians can only benefit from this initiative.


Robyn Guymer is Professor of Ophthalmology at Melbourne University and a deputy director of the Centre for Eye Research Australia. She is also a senior retinal specialist at the Royal Victorian Eye and Ear Hospital. She is a clinician scientist who leads a team of 20 researchers primarily investigating AMD. Prof. Guymer is currently investigating new strategies for treating early stages of AMD with a nanosecond laser and is working to identify novel imaging and functional biomarkers and surrogate endpoints to improve the feasibility of conducting early intervention trials. She has been a principal investigator in many industry sponsored trials and serves on several pharmaceutical advisory boards. She is part of the International Mactel consortium, the Beckman/Ryan AMD initiative (USA) and the International Classification of Atrophy (CAM) group. She is a member of the Macular Society and an inaugural fellow of the Australian Academy of Health and Medical Sciences.  Professor Guymer was awarded the NHMRC’s 2016 Elizabeth Blackburn Fellowship for the top ranked female research fellowship in clinical medicine. In June 2018 she was awarded the Member of the Order of Australia (AM) for significant service to medicine in the field of ophthalmology, particularly age related macular degeneration as a clinician, academic and researcher.



Jeena Tan B.Optom (Therapeutics), completed her Bachelor of Optometry in 2011 from the University of Melbourne. She commenced clinical practice in Shepparton Victoria  before returning to a Specsavers practice in Melbourne after three years. While in clinical practice, Ms. Tan was also involved in peer mentoring graduate optometrists, and supervising optometry students from Deakin University and the University of Melbourne. Currently in the role of Optometry Development Consultant for Specsavers, Ms. Tan is working toward improving collaborative care of patients and is keenly interested in the enhancement of primary eye care through systematic, measurable interventions.



1. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. The Lancet 2012; 379(9827): 1728-38.
2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for Neovascular Age-Related Macular Degeneration. N Engl J Med 2006; 355(14): 1419-31.
3. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-44.
4. Martin DF, Maguire MG, Ying GS, Runwald JE, Fine SL, Jaffe GJ; CATT Research Group. Ranbizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897-908.
5. Heier, Jeffrey S. et al; Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-related Macular Degeneration. Ophthalmology 2012:119:12:2537 - 2548
6. Bhisitkul RB, Mendes TS, Rofagha S, et al. Macular Atrophy Progression and 7-Year Vision Outcomes in Subjects From the ANCHOR, MARINA, and HORIZON Studies: the SEVEN-UP Study*. Am J Ophthalmol 2015; 159(5): 915-24. e2.
7. 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(10): 1417-36.
8. Meyers KJ, Liu Z, Millen AE, et al. Joint associations of diet, lifestyle, and genes with age-related macular degeneration. Ophthalmology 2015; 122(11): 2286-94.
9. Ferris III FL, Wilkinson C, Bird A, et al. Clinical Classification of Age-Related Macular Degeneration. Ophthalmology 2013; 129(4): 844-51.
10. Wu Z. Wu Z, Cunefare D, Chiu E, et al.L Longitudinal Associations Between Microstructural Changes and Microperimetry in the Early Stages of Age-Related Macular Degeneration Longitudinal Structure and Function Associations in AMD. Invest Ophth Vis Sci. 2016;57(8):3714-22
11. Curcio CA, Messinger JD, Sloan KR, McGwin G, Medeiros NE, Spaide RF. Subretinal Drusenoid Deposits in Non-Neovacular Age-Related Macular Degeneration: Morphology, Prevalence, Topography, and Biogenesis Model. Retina 2013.
12.Zhou Q, Daniel E, Maguire MG, et al. Pseudodrusen and incidence of late age-related macular degeneration in fellow eyes in the Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology 2016; 123(7): 1530-40.
13.Schmitz-Valckenberg S, Alten F, Steinberg JS, et al. Reticular Drusen Associated with Geographic Atrophy in Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2011; 52(9): 5009-15.
14.Wu Z, Luu CD et al. Optical Coherence Tomography-Defined Changes Preceding the Development of Drusen-Associated Atrophy in AMD. Ophthalmology. 2014 8;121(12):2415-22.

' The ultimate aim is to have community eye care professionals recognising all cases of AMD, categorising them according to the Beckman classification and… placing them on the trial registry '