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Age-related Macular Degeneration: Essential Pearls for Routine Practice

2 CPD in Australia | 0.5CD in New Zealand | 8 December 2018

By Dr. Smita Agarwal

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the industrialised world.1-3 In 2014, the worldwide prevalence of AMD was estimated to be 8.7 per cent. It is predicted that there will be 196 million people with AMD by 2020 and 288 million by 2040.4


1. Understand the types of macular degeneration and distinguish the different features
2. Be able to guide patients on the severity of macular degeneration and touch base on prognosis
3. Understand the pathophysiology of macular degeneration and its relevance to management
4. Understand possible etiology and associated risk factors to guide relatives of patients with AMD
5. Review clinical trials to understand treatment of patients with advanced macular degeneration
6. Managing non responders to help alleviate anxiety in patients who have not responded with the treatment.


Traditionally, two types of macular degeneration are recognised: dry and wet. The hallmark of the dry, or non-exudative form, is the deposition of extracellular material beneath the retinal pigment epithelium (RPE) causing the formation of drusen. This can lead to the loss of photoreceptors owing to the atrophic
and hypertrophic changes in the RPE underlying the central macula (Figure 1).

Patients with non-exudative AMD can progress to the wet, or exudative, form of AMD, in which choroidal neovascular membranes (CNVM) develop under the retina. The CNVM can cause visual disturbance manifested as vision reduction and/or distortion due to the leakage of fluid and/or blood, and can ultimately
cause a centrally blinding disciform scar that can form over a short span of time if left untreated. Approximately 10-20 per cent of patients with non-exudative AMD eventually progress to the exudative form,
which is responsible for the estimated 1.75 million cases of advanced AMD in the United States.5,6

Several classification systems are used to define AMD, both clinically and for research purposes. The Wisconsin Age-Related Maculopathy Grading System defined early AMD as the absence of advanced AMD and the presence of:
1. Soft indistinct or reticular drusen
2. Hard distinct or soft indistinct drusen with pigment abnormalities (RPE depigmentation or increased pigmentation).7

Late AMD is defined as the presence of either:
1. Geographic atrophy (GA) or
2. Exudative AMD.

Drusenoid pigment epithelial detachments (DPEDs), hallmark features of AMD, are a known precursor of geographic atrophy.9 This lesion can be distinguished from serous and haemorrhagic pigment epithelial detachment (i.e. exudative) by clinical appearance and fundus fluorescein angiography.10 The long term prognosis of DPED is poorer than the other types of PED. The Age-Related Eye Disease Study (AREDS) showed, in a large sample observed over five years or more, that 19 per cent of the eyes with DPED (defined as >350 μm in diameter) progressed to central GA, 57.8 per cent showed progressive fundus changes, and 39 per cent lost more than 15 letters of visual acuity.11

Exudative AMD is defined as the presence of any of the exudative lesions including:
1. Serous or haemorrhagic pigment epithelial detachment (PED)
2. Sub-retinal haemorrhage (Figure 2)
3. Sub-retinal scar
4. Prior laser scar for exudative AMD.7

The AREDS group developed an 11-step scale to document the severity of AMD based on features identifiable on fundus photographs.12 Patients were graded based on the presence or absence of drusen and their characteristics (i.e. size, shape, area), RPE abnormalities (i.e. hypopigmentation or hyperpigmentation and geographic atrophy) and retinal findings such as sub-retinal scarring, haemorrhage or detachment. Patients classed within steps one to three are considered not to have AMD, patients classed within steps four to eight were considered to have early AMD, and patients classed within steps nine to11
were considered to have advanced AMD.12

Based on data from the AREDS, a simplified version of the severity scale was developed to define patients with early AMD into risk categories predictive of the development of advanced AMD. The system assigns one risk factor each to the presence of one or more large (>125 μm) drusen, to the presence of any
pigmentary changes and to the presence of intermediate drusen in both eyes. These risk factors are added between both eyes to result in a score between zero and four. The approximate five-year risk of developing advanced AMD is then calculated as 0.5 per cent for those with 0 factors, 3 per cent for those with one factor,
12 per cent for those with two factors, 25 per cent for those with three factors and 50 per cent for those with four factors.12

In 1995, the International ARM Epidemiological Study Group redefined AMD; patients with minimal or moderate non-exudative age-related changes were classified as having age-related maculopathy (ARM) and advanced RPE atrophy (i.e. geographic atrophy) or choroidal neovascularisation (CNV) was required to make a diagnosis of nonexudative or exudative AMD respectively.13 Patients with ARM account for 85-90
per cent of individuals with negligible or minimal symptoms such as blurred central vision, and colour and contrast disturbances. The 10-15 per cent of patients with macular changes classified as AMD tend to have painless, progressive blurred central vison with moderate to severe metamorphopsia, which can be acute
or insidious in onset.13


AMD is a degenerative retinal disease, caused by both genetic and environmental factors. Strong association has been seen with age, race, sex and family history. In large epidemiological studies, modifiable risk factors are reported to be smoking, hypertension, obesity and dietary fat.14-16

The exact pathophysiology is poorly understood, however recent developments are increasing our understanding. The RPE is a metabolically active layer that supports the function of retinal photoreceptor cells and phagocytoses that shed outer segments of the photoreceptor cells. As the RPE cells age, they accumulate intracellular residual bodies containing lipofuscin,17 which can be seen by auto-fluorescence
imaging.18 The RPE cells extrude the waste material to be removed via choriocapillaries, however decreased RPE cell function and reduced permeability of the Bruch’s membrane leads to the formation
of deposits of material between the RPE and the chorio-capillaries known as drusen.

Recently, it has been reported that drusen formation may incite an inflammatory cascade involving the complement pathway via complement factor H(CFH) gene on chromosome 119 and the PLEKHA1 and
LOC387715 genes on chromosome 10.20

Drusen formation not only is a sign of RPE dysfunction, but is also thought to be a cause of RPE loss and, in turn, photoreceptor loss. RPE degeneration causes dysfunction in the Bruch’s membrane, which separates the choriocapillaries from the RPE. Breakdown of the Bruch’s membrane and a rise in vascular
endothelial growth factors (VEGFs) cause the growth of abnormal choroidal blood vessels beneath the RPE and potentially under the retina. These vessels cause bleeding and leak fluid before they eventually involute and result in scarring.


AMD results in significant visual morbidity and decreases all aspects of the patient’s quality of life21 as well as increasing the rate of depression22 and falls.23 The neovascular variant causes central blurring of vision. Even in dry AMD, despite relatively good vision, patients often report trouble adjusting to varying light conditions; they often complain of difficulty in adjusting their vision when moving from a dark
environment to a lighted one or vice versa.

Exudative AMD patients have a higher incidence of cerebrovascular incidents and cardiac disease.24 Geographic atrophy may be associated with cognitive impairment as assessed by mini-mental status exams. One case control study found a three-fold increase in mild cognitive impairment in patients with geographic atrophy when compared with normal controls, even when adjusted for age, visual acuity and
education level.25 In the AREDS trial involving 3,000 patients, patients with poorer vision performed worse in
cognitive tests.26

Etiology and Risk Factors

The deterioration of the macula causes loss of central vision only, while peripheral vision remains intact. Central vision is required to identify letters, numbers, facial features, border surfaces, angles and colours, reading, driving, watching TV and many other visual activities for which high definition is required.27,28 Since peripheral vision is intact, patients with AMD typically do not require canes or guide dogs.

The etiology is multifactorial and involves the interplay of genetic, environmental, metabolic, and functional factors. Various risk factors including age, female gender, sun exposure, family history, ethnicity,
smoking, alcohol consumption, high blood pressure, obesity, hypertension, diabetes, hypercholesterolemia and arteriosclerosis have been identified with varying degrees of association.29-36 Smoking and a higher
body mass index are two of the most common risk factors that contribute independently to the increase in the risk of developing AMD.37 Smoking has been clearly identified as increasing the risk of AMD by two-fold.37

Serum lipids were extensively studied regarding their relationship with AMD in the National Eye Institute-sponsored AREDS. One report suggests dietary intake of total omega-3 long chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with the development of neovascular AMD, although not non-exudative AMD.38

Clinical Presentation

In its early stages, AMD is usually asymptomatic and often goes unnoticed for a long time if routine dilated examinations are not performed. Patients with AMD usually report a family history of poor vision late in life, have difficulty with night vision and with changing light conditions, and complain of visual fluctuations when
reading. Some patients may complain of acute vision loss, blurred vision, scotomas, metamorphopsia or chronic visual distortion.27 Metamorphopsia and changes on Amsler grid examination are late features
of the disease. About 13 per cent of patients with AMD present with Charles Bonnet syndrome, in which mentally healthy patients complain of loss of vision and visual hallucinations. They report seeing
clear, well defined, organised images over which the patient has little or no control.39

Fundus Exam

Drusen, often the hallmark of AMD, can be seen in the early stages of the disease and are usually confluent with pigmentary changes and the accumulation of pigment in the posterior pole. The RPE often appears atrophic with an easier visualisation of the choroidal plexus. Drusen are focal deposits of extracellular
debris that typically form between the basal lamina of RPE and the inner collagenous layer of the Bruch’s membrane and are classified as soft and hard (Figure 3). Soft drusen are more commonly found in the
macula and pose a higher risk of AMD.35,40 They are slightly larger than hard drusen and do not have well-defined margins.41 Hard drusen tend to be smaller and well defined. In advanced stages of dry AMD,
these focal islands of atrophy coalesce and form large areas of atrophy, classified as geographic atrophy (GA), which severely affects vision.

The main indication of exudative AMD is the formation of a chorio-retinal neovascular membrane (CNVM). Eyes with exudative AMD present with sub-retinal fluid, retinal pigment epithelial detachment, sub-retinal haemorrhage, and occasionally, sub-retinal lipid deposits. Additionally, RPE hypertrophy, RPE atrophy and drusen are usually present. The CNVM may appear as yellow-green sub-retinal discolouration, occasionally surrounded by a pigment ring. Sub-retinal haemorrhage typically develops at the margins of the CNVM and may obscure the entire complex (Figure 4). In some cases, the sub-retinal haemorrhage can progress and lead to vitreous haemorrhage. Sub-retinal disciform scarring of the macula is common the end-stage of the disease.


History and a dilated fundus exam with accurate fundus photography is useful when assessing AMD. However, the cornerstone to evaluate dry AMD is to check visual acuity and to perform Amsler charting. Studies have shown that if the Amsler grid check is performed properly, it is quite sensitive in detecting any change.

Novel computing systems using mobile handheld devices have been tested to monitor the retinal visual function of patients with AMD.42

Optical coherence tomography (OCT) and OCT angiography (OCT-A) allow for the valuable non-invasive examination of the retinal and superficial choroidal blood vessels within the macula, providing a cross-sectional view of the retina that can be used to identify soft drusen, RPE detachments, sub-retinal and intra-retinal fluid, CNV and cystoid macular oedema, as well as to assess the integrity of the photoreceptor and RPE layers (Figure 5).43 It can also be useful in monitoring the therapeutic response,44 and OCT-A can be
particularly useful in the early detection of conversion to wet AMD. Fundus autofluorescence (FAF) is a non-invasive retinal imaging modality that provides a density map of lipofuscin in the RPE.

The biggest treatable cause of vision loss in dry AMD is the development of CNVM. Performing fundus fluorescein angiography (FFA) on a routine basis is not imperative, however any new metamorphopsia is a
good indication and performing FFA may be warranted.


Given increasing life expectancy, the impact of macular degeneration will become even greater in the future, hence the need to develop strategies to prevent it and effective treatment options to slow the progression of vision loss. Various life style changes, including reducing smoking, controlling obesity and maintaining dietary modifications have been established to have a beneficial effect on preventing the disease and retarding its progression.45

It is also recommended that patients who have signs of advanced AMD in one eye should take multi-vitamins that contain lutein. According to Age-Related Eye Disease Study 2 (AREDS2), oral supplements with macular xanthophylls (lutein 10mg/d plus zeaxanthin 2mg/d) are superior to lutein alone in regards
to retarding the progression of AMD.46

In this study, family members of patients with AMD did not show any significant benefit with AREDS multivitamin supplements, with the risks associated with long-term intake not necessarily overcoming the benefits of taking them.

Family members of patients with AMD should be advised to do the following:
• Do not smoke and avoid smoking places
• Protect eyes from direct sunlight with dark UV-protective sunglasses or hat
• Eat a well-balanced diet high in natural antioxidants
• Eat fresh baked fish two to three times a week
• Eat green leafy vegetables daily
• Consider a supplement of folic acid (2.5mg/d), pyridoxine (50mg/d), and cyanocobalamin (1mg/d).47

Although no pharmacological treatments have been approved to treat dry AMD, many compounds are in the later stages of clinical trials, most notably lampalizumab, a complement inhibitor, which is injected intraocularly. The prognosis for patients with neovascular AMD has improved significantly with the development of anti-angiogenic therapy (i.e. intravitreal ranibizumab, aflibercept and/or bevacizumab).

VEGF Inhibition

Animal and clinical studies have established VEGF as a key mediator in ocular angiogenesis.48 Based on the angiogenic role of VEGF in CNVM, VEGF inhibition has become one of the most successful therapies for neovascular AMD. Pegaptanib, an RNA- binding anti-VEGF165 aptamer, was the first anti-angiogenic agent tested.49 Its use has declined owing to the development of more potent agents, which are derived from the
same monoclonal antibody precursor.50 It has been shown that visual improvements of +6.9 letters to +11.3 letters can be achieved following treatment with bevacizumab (Avastin; Genentech U.S., Inc.), ranibizumab (Lucentis; Genentech U.S., Inc. and aflibercept (Eyelea; Regeneron) in patients with CNVM.51


Ranibizumab is an intravitreally injected, recombinant, humanised, monoclonal antibody fragment designed to actively bind and inhibit all isoforms of VEGF. It has been FDA-approved for the treatment of exudative AMD. The MARINA44 (for minimally classic/occult CNVM) and Anchor52 (for predominantly classic CNVM) trials have both shown improved or stable vision following regular monthly intravitreal injections with

The PIER data suggests that quarterly injections are less effective than monthly dosing.53 The HORIZON
extension study, including patients from the MARINA, ANCHOR, and FOCUS trials, documented adverse events and visual acuity results in patients treated with ranibizumab over four years or more.

Rates of stroke and myocardial infarction continued to be low with long-term treatment. However, visual acuity gains achieved with monthly treatments during the initial phases of the study were lost in some cases as patients were followed up and treated less frequently during the latter years of the HORIZON study.54

However, several studies including the PrONTO55 and the SUSTAIN trials,56 administered the treatment monthly for the first three treatments and on an as-needed basis thereafter, achieving visual improvements
parallel with monthly dosing with fewer injections. Macular changes in a patient following treatment with ranibizumab are shown in Figure 7.


Aflibercept is a fusion protein designed to bind all forms of VEGF-A that was approved for the treatment of neovascular AMD in 2011. Two phase three studies, the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW1 and 2) trials, compared the efficacy of aflibercept and ranibizumab. It was demonstrated
that the safety, tolerability and visual results of aflibercept were non-inferior to ranibizumab.57 Macular changes in a patient following treatment with aflibercept are shown in Figure 8.


Bevacizumab is an off-label, full-length humanised monoclonal antibody specific against human VEGF. It is commonly used for the treatment of neovascular AMD although it is not currently approved for this purpose. The National Eye Institute funded a large randomised controlled trial to directly compare the safety and efficacy of bevacizumab and ranibizumab in the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT). It was reported that both drugs have similar results on visual acuity following one year of treatment.58

Additionally, no significant differences were noted in the number of significant adverse events associated with each drug.59 Intravitreal injections carry a small risk of endophthalmitis with a reported risk of 0.009-0.541 per cent.60,61 It was reported that uncovered speech during the injection process can result in significant growth of streptococcal bacterial colonies, and it has since been suggested that practitioners wear a face mask or minimise speech while administering the injections.62

Higher risk of infections have also been reported with repackaged intravitreal injections of bevacizumab.63
Other complications include eye pain, conjunctival and retinal haemorrhage, increased IOP, vitreous detachment and retinal atrophy.64,65

A current trial, the RIVAL trial, aims to compare change in baseline visual acuity at 12 months and change in the area of geographic atrophy at 24 months in patients with naïve wet AMD while undergoing treatment with
aflibercept or ranibizumab on a treat and extend basis.

Preliminary data presented at the EURETINA Congress in Barcelona in 2017 showed that vision increased
by an average of 7.1 letters for patients receiving ranibizumab compared to 4.9 letters for those receiving aflibercept.66 The 12 month interim results are expected to be released in 2018.


Brolucizumab (RTH258) is a small human antibody fragment specific to all VEGF-A isoforms that is currently
under development for the treatment of neovascular AMD. Early results report noninferiority in regards to change in central subfield thickness compared to treatment with ranibizumab, with a significantly longer period of time between treatments.67

Preliminary results from two large ongoing clinical trials, the HAWK and HARRIER trials, have shown that the majority of patients can be maintained with treatments of brolucizumab every 12 weeks compared to every eight weeks for aflibercept.68


For patients that have not responded to anti-VEGF monotherapy, there are other approaches available including dual therapy with anti-VEGF agents and steroids. In one study, patients that did not respond to anti-VEGF monotherapy who were treated with intravitreal anti-VEGF injections combined with a dexamethasone
implant showed a decrease in average central foveal thickness and macula cube volume, with 33 per cent of patients experiencing an improvement in vision.69

Another study that compared aflibercept monotherapy with aflibercept combined with bromfenac reported an improvement in visual acuity, but no significant anatomical changes such as decreases in central retinal thickness (CRT).70 It was noted however, that CRT does not reliably correlate with visual acuity. Anti-VEGF
treatments have also been combined with photodynamic therapy; patients that received intravitreal ranibizumab injections combined with photodynamic therapy showed greater improvements in visual acuity and CRT compared to patients who received ranibizumab alone.71

It has also been reported that patients who did not respond to treatment with aflibercept monotherapy experienced an increase in visual acuity when switched to either ranibizumab or bevacizumab monotherapy, suggesting that such patients may also benefit from switching the type of anti-VEGF agent used.72

The results of various trials comparing the safety and efficacy of anti-VEGF agents are summarised in Table 1.

Table 1: Summary of trial studies compared safety and efficacy of various anti-VEGF treatments and regimens.

Patient Education

AMD is the primary cause of irreversible blindness in the western world. The etiology is largely unknown and is thought to involve a number of modifiable and un-modifiable risk factors. Frequent dilated fundus exams and weekly Amsler grid checks help in monitoring and detecting any early changes for prompt treatment
if needed. When visual acuity is reduced, patients have twice the risk of falling23 and two-fold the risk of depression.79

Patients with central atrophy often report trouble reading and doing fine motor tasks. Magnifiers and better contrast are the best solutions for such visual dysfunction. In contrast, patients with foveal sparing may be able to see 20/20, but are unable to navigate. For these patients, excess magnification will be detrimental.
Increased contrast and magnification, by the way of increased illumination and reverse telescopes respectively, may be beneficial for these patients, who should be referred to Vision Australia (www.visionaustralia.org) for visual rehabilitation with low vision aids. Macular Disease Foundation Australia has free information available for eye care professionals to provide their patients and a comprehensive
website (www.mdfoundation.com.au).

The Foundation offers free patient education sessions and has a helpline (freecall 1800 111 709).


 Dr. Smita Agarwal MBBS, MS, Grad Dip Med-Ref Surgery (USyd), FRANZCO, is a comprehensive ophthalmologist with special interests in refractive cataract surgery, glaucoma, retinal and anterior segment eye diseases. Dr. Agarwal is the Head of Ophthalmology Department at Wollongong and Shellharbour Public Hospitals, a senior lecturer at University of Sydney and University of Wollongong and a Visiting Medical Officer at a number of private hospitals. She is actively involved in the teaching of optometrists, GPs and medical students. She also performs laser eye surgery at Vision Eye Institute, Hurstville.

Dr. Agarwal has authored several research papers and case reports in Australia and overseas, including Journal of Cataract and Refractive Surgery, Journal of Ophthalmic and Plastic Surgery and Medical Journal
of Australia.   

This education article was sponsored by Novartis.

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