Significant advances in the diagnosis and management of age related macular degeneration over the past several years have led to new protocols for management of the condition by primary health practitioners such as optometrists.
Age-related macular degeneration (AMD) remains one of the most common causes of visual impairment in Australia,1 with the recent National Eye Health Survey reporting the weighted prevalence of AMD in Australians aged over 50 years as 14.8 per cent.2
There have been significant advances in the treatment of AMD over the past decade. In particular, the discovery of the therapeutic potential of anti-vascular endothelial growth factor (anti-VEGF) compounds led to a dramatic reduction in the rates of legal blindness from neovascular AMD (nAMD). However, early diagnosis and prompt referral of nAMD remains essential and is the key to ensuring the best long term visual outcomes.3 As such, it is important that primary eye care practitioners are aware of the latest research discoveries,
in order to optimise the management of their patients with AMD.
Latest Developments in the Treatment of nAMD
In the past decade, anti-VEGF injections have become the mainstay treatment for nAMD and have been shown to have great success for many patients. However, there remain a proportion of patients who still lose vision despite treatment, and real-world data has, in many cases not matched the promising results of the large pivotal multicentre clinical trials that led to the commercial release of the drugs. This is most likely due to the fact that real-world treatments do not always follow the recommended protocols (for example, the required drug may not be given at the right time interval, due to factors such as cost, patient compliance and other logistics).
One of the best indicators for predicting long term outcomes is the presenting visual acuity
One of the best indicators for predicting long term outcomes is the presenting visual acuity; the earlier a person receives treatment, the better their chances of maintaining or improving their vision. Hence, early detection and treatment are vital.
In addition to a greater emphasis on early management, there have been several new VEGF inhibitors developed recently that seek to address these issues, and provide improved long-term outcomes. None of these are available clinically at this time, but do show the future potential options of anti-VEFG treatment. Examples of new treatments under investigation are;
1) Brolucizumab – a new generation anti-VEGF compound, which is a humanised single-cain antibody fragment that inhibits VEGF-A and has the smallest molecular weight to date (26kDa). It has been shown that brolucizumab has a similar efficacy to aflibercept when given every eight weeks, and so there is hope that it might be able to be given every 12-weeks,4 reducing the demand on both patients and practitioners.
2) RG7716 – an antibody that binds to both VEGF and angiopoietin 2 (ANG2). The latter is a proangiogenic cytokine which is elevated in both the aqueous and vitreous humor in patients with nAMD. Phase one studies have shown promising results, with phase two trials underway at present.
3) Designed ankyrin repeat proteins (DARPins) – VEGF inhibitors that have shown significant improvements over ranibizumab in phase two trials.
In addition to ongoing work with anti-VEGF compounds, work continues into the development of gene therapy for nAMD. In these treatments, viral vectors are used to deliver genes for VEGF inhibitors directly into the cells, and phase one data has been promising. While exciting, this process is more complex than the direct application of a pharmaceutical agent. Additionally, there is some concern that administration of VEGF inhibitors may also exacerbate the atrophic process, speeding up development of geographic atrophy. This particularly leads to caution when treating patients who have signs of both neovascular and atrophic AMD.
In summary, the best initial management for nAMD is early diagnosis and prompt referral to an ophthalmologist for treatment. The earlier the treatment, the better the outcome, and hence speed of appropriate referral is of essence for these patients.
Latest Developments in the Treatment of Atrophic AMD
Currently there are no pharmaceutical treatments proven to be effective for atrophic AMD, but there is intense research into this area, with a number of large scale clinical trials being conducted, including the following:
Lampalizimab is a complement inhibitor (specifically targeting complement factor D), composed of an antigen-binding fragment of a humanised monoclonal antibody. Unfortunately two recent international phase three trials of over 1000 participants failed to show any difference in geographic atrophy lesion size.5
APL-2 is another complement inhibitor, which is injected intravitreally monthly, and has had better success in clinical trials, with a reduction in the rate of geographic atrophy progression of 29 per cent noted over 12 months.6
An international multicentre trial – the BEACON Study – is currently investigating the efficacy of an intravitreal implant of this alpha-adrenergic neuroprotective agent for treatment of geographic atrophy. Results are pending.
For both neovascular and atrophic AMD, the main method of treatment remains intravitreal injections. However, this carries some risk (such as endophthalmitis) and has led to an enormous logistic burden of delivering the drug at regular intervals. As such, research also continues into other methods of transferring drugs into the vitreous, such as reservoir systems and slow release capsules. Early work is underway into biodegradable implants that can provide slow release of pharmaceuticals, and then be absorbed into the vitreous without the need for surgical removal.
At present, none of these treatments are available commercially, but there are often opportunities for patients to be involved in early clinical trials. More details are available from research institutions such as the Centre for Eye Research Australia in Melbourne (www.cera.org.au), the Save Sight Institute in Sydney (www.savesightinstitute.org.au) and the Lions Eye Institute in Perth (www.lei.org.au).
Advances in Ocular Imaging and AMD
Over the past decade, optical coherence tomography (OCT) has become an essential imaging modality in the diagnosis and management of AMD. Not only does it allow the detection of signs of active nAMD (such as retinal fluid), it can also be used for monitoring the earliest signs of AMD such as drusen and pigment, and detecting signs of increased risk of vision loss such as reticular pseudodrusen (RPD)7 and nascent geographic atrophy.8
In addition to these capabilities, most OCT instruments also include the ability to use autofluorescence imaging (very useful for detection areas of atrophy and RPD), near infrared imaging (especially useful for RPD) and multichannel colour imaging (to provide additional information about the different retinal layers). Most have enhanced depth imaging modes (EDI), which provide higher resolution imaging of the choroidal layer, allowing choroidal thickness measurements.
Many optometric and ophthalmic practices now have a spectral-domain OCT which offers even greater resolution of sub clinical phenotypic details. Further advances in technology have led to the development of optical coherence angiography (OCT-A) and swept-source OCT.
OCT-A allows imaging of the retinal vasculature in vivo, without the need for the dye injections essential for traditional angiography. Additionally, OCT-A has the benefit of providing structural OCT information (via a line or cube OCT scan) at the same time as detecting retinal and choroidal blood flow characteristics. The research into OCT-A is still in its infancy, but has clear clinical advantages. It should be noted that OCT-A does not indicate blood vessel leakage, hence there is still a role for traditional angiography.
Swept-source OCT uses a longer wavelength (1050nm vs. 840nm in spectral-domain OCT) which allows better penetration and imaging of deep retinal structures (especially the choroid). Swept-source OCT is up to twice as fast as spectral-domain, and has specialised filters that improve detection of microvasculature.
Clinical trial protocol recommendations from the Classification of Atrophy Consensus meeting (CAM),9 published in 2017, were the first to have included OCT biomarkers. This is indicative of the importance OCT images now have in the diagnosis and management of AMD. Additionally, the CAM group recently published new OCT-defined atrophy definitions for AMD, which optometrists should be aware of (see Sadda et al. Consensus Definition for Atrophy Associated for Age Related Macular Degeneration on OCT: Classification of Atrophy Report Three, Ophthalmology).
RANZCO Optometry Management Guidelines
Published in November 2016, the RANZCO AMD management guidelines provide a useful reference for the diagnosis and management of AMD (Figure 1). The guidelines reference the Beckman classification of AMD, and provide recommendations on the best management for varying signs and symptoms.
One of the challenges in the field of AMD is to ensure new research advances are communicated to primary care health practitioners (normally optometrists) in a rapid and detailed manner. The authors of this article were recently awarded funding to complete a project aimed at improving communication channels between ophthalmology, optometry and clinical research, so that this information is passed on in an improved manner. This funding, a 2018 NHMRC Next Generation Clinical Researcher Fellowship to Dr. Ayton, aims to upskill optometrists in the newest advances in the field of AMD.
There are a number of challenges still to be faced to improve outcomes for those people with AMD, but progress in the past few years has been exponential, providing hope to those living with this condition. We strongly advise our colleagues to keep reading and keep up to date in this area, in order to provide the best clinical care to our patients with AMD.
Figure 1 (click on image to enlarge)
Dr. Lauren N. Ayton is an Honorary Senior Research Fellow at the Department of Surgery (Ophthalmology), University of Melbourne and a Director of Clinical and Regulatory Affairs, Bionic Eye Technologies Inc, New York, USA.
Professor Robyn H. Guymer is Deputy Director & Principal Investigator, Centre for Eye Research Australia, The University of Melbourne, Australia. She is a Professor, Department of Surgery (Ophthalmology), University of Melbourne.
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