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CASE REPORT: Prognostic biomarkers in intermediate AMD


Angelica Ly
BOptom (Hons) GradCertOcTher
Senior Staff Optometrist, PhD candidate, Centre for Eye Health


Age-related macular degeneration (AMD) is a leading cause of blindness in Australia.1 As practising clinicians, we face the challenge of accurately identifying and managing as early as possible patients with or at risk of vision loss. While neovascular AMD mandates immediate referral to an ophthalmologist, determining risk of progression in earlier stages is fundamental to appropriate management.

In the past few years phenotyping of the disease has become highly refined, staging and nomenclature of the disease have been clarified and treatment options have expanded. The 2013 Beckman initiative for macular research clinical classification scale2 recommends subdividing the disease into early, intermediate and late stages.

Late AMD represents the most advanced form associated with visual impairment due to geographic atrophy (GA) or choroidal neovascularisation (CNV). It has an estimated incidence of 6.8 per cent over 15 years in an Australian population.3 Intermediate AMD is typically asymptomatic and may vary dramatically in presentation from one eye to the next. The hallmark signs are large drusen greater than 125 µm in diameter, or pigmentary changes within the macular area. Patients with intermediate AMD in one or both eyes hold a wide-ranging three per cent to 53 per cent risk of progression to advanced AMD in five years, depending on the combination of clinical signs present.4

With the advent of advanced imaging, in particular optical coherence tomography (OCT), a growing number of indicators have been associated with an increased risk of AMD progression. Practitioners should be aware of these indicators and incorporate them into routine clinical practice. 



An 85-year-old Caucasian male was referred to Centre for Eye Health (CFEH) for a macular assessment due to bilateral drusen. He reported a history of bilateral cataract surgery one year prior to presentation. General health was remarkable for hypertension, managed using ramipril. He was a non-smoker and there was no known family history of AMD.

Entering unaided acuities were 6/9.5-1 OD and 6/9.5-2 OS, improving to 6/6-2 OD and 6/7.6-1 OS with pinhole. Amsler grid was unremarkable in each eye. Contrast sensitivity was within normal limits at 1.56 units in each eye tested monocularly using the MARS test (normal range 1.52 to 1.76 log units for patients older than 60 years).

Funduscopy, retinal photography and Spectralis OCT revealed extensive, small to large drusen OU. Hyperpigmentary changes at the macula were also present OU. There was no evidence in either eye of any geographic atrophy, choroidal neovascularisation or exudative changes, including intraretinal, subretinal or sub-RPE fluid.

Additional, structural signs that may portend the development of late AMD were also identified including:

1. reticular pseudodrusen, also known as subretinal drusenoid deposits,5-7 at the superonasal macula OU

2. hyper-reflective foci8-10 using OCT corresponding with hyperpigmentary changes OU

3. L-type or low reflective core OCT reflective drusen substructures11 OU

4. focal apposition and disruption of the ellipsoid zone and external limiting membrane overlying a relatively high drusen load OU.8,9,12 (Figures 1 and 2)



Figure 1. Imaging results from the patient’s baseline visit in the right eye. Top left: Colour fundus photograph, Top middle: Fundus autofluorescence image, Top right: Cirrus OCT advanced RPE analysis result, Bottom: OCT B-scans extracted from a Spectralis OCT macular cube scan illustrating additional high risk signs for progression.



Figure 2. Corresponding imaging results from the patient’s baseline visit in the left eye. The results are presented in the same order as described in Figure 1.


Fundus autofluorescence imaging also revealed a variety of patterns OU. In particular, alterations associated with a higher risk of conversion to late AMD including the patchy and reticular patterns were noted OU.13 Drusen volume measured 0.12 mm3 OD and OS in the central 3 mm using Cirrus OCT advanced RPE analysis (drusen volumes greater than 0.03 mm3 have been associated with a four-fold higher risk of progression to late AMD).14

In summary, these baseline findings are consistent with intermediate AMD in both eyes and a 53 per cent probability of progression to late AMD within the next five years according to the AREDS simplified severity scale.4 Structural changes including high drusen volume, reticular pseudodrusen, hyper-reflective foci, OCT reflective drusen substructures and abnormal FAF patterns were also identified, which may suggest a relatively greater risk of progressing to late AMD. His additional historical risk factors for progression include age and a medical history of hypertension.15

Current clinical guidelines recommended a review period in intermediate AMD between six and 24 months.16,17 In this instance, due to the additional risk factors identified, the patient was reviewed in conjunction with the referring optometrist every six months. Follow-up assessments facilitated by advanced imaging revealed evidence of drusen progression, followed by regression, indicative of overall disease progression.18 Progression to presumed late AMD was identified 28 months later OS (Figure 3) at which point the patient was referred promptly for ophthalmological care.

Early detection of progression to neovascular AMD is critical to maximising visual and functional outcomes.19 The progression to CNV may have been missed or the diagnosis delayed had it not been for several factors: the utility of ocular imaging, evidence-based practice and the CFEH collaborative care model.



Figure 3. Top: Follow-up findings using colour fundus photography, Bottom: Imaging results from the final follow-up visit including fundus autofluorescence (left) and an OCT line scan through the central macula (right). Both show exudative changes, including intraretinal fluid (arrowhead), signifying the likely conversion to neovascular AMD.



This case report highlights foremost the utility of ocular imaging in clinical practice. On the whole, imaging technologies have empowered eye-care professionals by allowing us to deliver more individualised care. Several evidence-based practice guidelines,16,17,20 including the most recent iteration edited by the Royal Australian and New Zealand College of Ophthalmologists,21 outline the importance of early detection using imaging and the role of optometrists in AMD screening, stratification and management. As illustrated in the case study, ‘full phenotyping’ of each AMD case is now possible with the widespread clinical availability of ocular imaging, especially OCT.21-24

CFEH Chair-side Reference

There is an onus on us as clinicians to systematically diagnose and stage ocular disease in order to determine a patient’s risk of vision loss and to ensure timely referral for treatment. Once a diagnosis has been made, we can then tailor the management plan according to the patient’s prognosis or risk of progression. This will require identifying the subtler disease-specific signs that herald a negative prognosis, many of which have been characterised only recently in the literature. Other signs relevant to AMD not described in the case study above include: nascent geographic atrophy,8 sub-RPE hyper-reflective columns25 and small pockets of subretinal fluid located in the depression between confluent drusen in the absence of CNV.26

With the incidence of diseases such as AMD rising, it is now more imperative than ever before that eye-care professionals collaborate to meet the demands of an ageing population. To deliver the best possible care to our patients, it is critical for practitioners to keep pace with the literature, apply and interpret ocular imaging appropriately, and refer for management advice and treatment in a judicious and timely manner. For challenging cases, patients can be referred to organisations with a special interest in ocular disease, such as CFEH. Such organisations are available to aid practising professionals by providing additional patient management advice.


The author thanks Michael Yapp, Professor Michael Kalloniatis and Paula Katalinic for reviewing the manuscript and Tyson Xu for his assistance in the literature search and for identifying the case images. 


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