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The latest treatment approaches to age-related macular degeneration

Case report 1

A 72-year-old retired construction worker was referred to the ophthalmology outpatients department by his local optometrist with a six-month history of a deterioration in the vision from his right eye that was not corrected by his new spectacles.

This man’s Snellen visual acuity with his spectacles was right eye 6/9 and left eye 6/6. Anterior segment examination was normal. Dilated fundus examination of the right eye revealed parafoveal geographic atrophy with associated pigment clumping and hard drusen temporal to the macula. These findings are shown in Figure 1A. Dilated fundus examination of the left fundus revealed hard drusen temporal to the macula. The findings at both fundi were consistent with dry age-related macular degeneration (AMD).

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Figure 1A: Colour fundus photograph of the right eye. Para-foveal geographic-type atrophy with associated pigment clumping indicated by the red arrow. Hard drusen are indicated by the arrow

Optical coherence tomography (OCT) imaging of the right eye, a representative image from which can be seen in Figure 1B, showed disruption of the retinal pigment epithelium (RPE).

””Figure 1B: OCT image right macala. A segment of RPE atrophy lies between the blue arrows. Increased reflectivity i nchoroid due to RPE atrophy is indicated by the red arrow

This patient was advised to eat a diet rich in green leafy vegetables and oily fish. He was commenced on eye supplements. Nine months later, his visual acuity and fundus appearance were unchanged.

Case report 2

A 69-year-old farmer was referred to the eye casualty department by his GP with a two-day history of reduced vision from his right eye.

He had a past ocular history of dry AMD, for which he underwent annual review in the ophthalmology outpatients department. His last review had been one month previously.

This man’s Snellen visual acuity with his spectacles was right eye 6/18 and left eye 6/7.5. Anterior segment examination revealed mild cataract bilaterally. Dilated fundus examination of the right eye revealed a circular, elevated, hypopigmented area of approximately 1.5 disc diameters with central pigment clumping close to the fovea. These findings are shown in Figure 2A. They were suggestive of wet AMD. Dilated fundus examination of the left eye revealed soft drusen consistent with dry AMD.

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Figure 2A: Colour fundus photograph right eye. Circular, elevated, hypopigmented area with cenrtal pigment clumping is indicated by the blue arrow

OCT imaging of the right eye, a representative image from which can be seen in Figure 2B,revealed a small, solid pigment epithelial detachment and sub-RPE fluid.

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Figure 2B: OCT image right macala. A small solid pigment epithelial detachment is indicated by the blue arrow. Sub-RPE fluid is indicated by the red arrow

This patient received three intravitreal injections of the anti-vascular endothelial growth factor (anti-VEGF) agent bevacizumab to his right eye, each injection separated by four weeks. He was also given dietary advice and commenced on supplements.

After his anti-VEGF therapy, this man had a Snellen visual acuity of 6/9 from his right eye. OCT confirmed resolution of the aforementioned sub-RPE fluid. His next review is scheduled for six weeks.

Discussion

The prevalence of AMD worldwide is estimated to be 8.69 per cent in those aged between 45-85 years. AMD is the leading cause of permanent vision loss in people aged over 50 years in Ireland. The number of people with AMD will rise dramatically here in the next 10 years with an increase in our ageing population.

Early dry AMD is characterised by drusen, hyperpigmentation and/or hypopigmentation at the macula. Late dry AMD is characterised by larger areas of ‘geographic’ atrophy at the macula. As Figure 3 shows, about 20 per cent of patients with dry AMD will develop wet or ‘exudative’ AMD. Anomalous blood vessels from the choroid grow through the RPE to the retina. Vision may deteriorate rapidly and dramatically when these vessels leak and/or haemorrhage.

Nutritional supplements for AMD

The Age-Related Eye Disease Studies (AREDS 1 and AREDS 2) were large, randomised, controlled clinical trials (RCTs) completed in 2001 and 2013, respectively. The studies examined the influence of nutritional supplementation on the progression of AMD. Three groups were analysed:

Group 1: Early AMD: Several small or medium-sized drusen in one or both eyes.

Group 2: Intermediate AMD: Many medium-sized drusen or one or more large drusen in one or both eyes.

Group 3: Late dry or exudative AMD in one eye but good vision in the fellow eye.

The AREDS 1 study found that by taking the supplement used therein, the details of which are found in Table 1, patients with intermediate and late AMD reduced their risk of progression to late AMD by 25 per cent and reduced their risk of central vision loss by 19 per cent.

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Table 1: AREDS 1 and AREDS 2 supplements and other commercially available supplements for AMD

The AREDS 2 study found that, when compared to patients not receiving these substances, patients who received the macular carotenoids lutein and xeathanthein as part of their supplement reduced by 9  per cent their risk of progression to late AMD. Patients with the lowest dietary intake of these compounds benefited most from their addition as a supplement. The addition of omega-3 fatty acids to the supplement was not found to be of benefit to vision.

The AREDS studies thus provided evidence that patients with established but non-advanced AMD benefit from supplementation with broad spectrum antioxidants that include the constituents of macular pigment.

Anti-VEGF treatment for wet AMD

To date, the treatments for wet AMD have concentrated, in the main, on opposing the effects of VEGF, which has a major role in the development of the abnormal blood vessels from the choroid that are associated with this condition.

Ranibizumab is a humanised recombinant antibody fragment that binds to VEGF and prevents it from binding to its receptors to produce the proliferation of vessels from the choroid. The MARINA trial compared intravitreal ranibizumab 0.5mg to sham injections. Participants in the treatment group on average gained 7.2 letters over a 24-month period. Participants in the control group on average lost 10.4 letters over the same period.

Bevacizumab is a humanised monoclonal antibody that also blocks angiogenesis by inhibiting VEGF. It is a much larger molecule than ranibizumab. Due to similar results and far less cost per treatment than ranibizumab, it is frequently used as an off-label treatment for wet AMD. The CATT trials discovered the mean number of letters gained per participant over a two-year period in those treated with these two anti-VEGF medications. The results are summarised in Table 2.

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Table 2: Results at two years of the CATT trial. Available supplements for AMD

Aflibercept is a recombinant fusion protein that consists of the VEGF-binding portions of the VEGF-A and VEGF-B receptors fused to the Fc portion of immunoglobulin G. The VIEW trial demonstrated that bi-monthly aflibercept was non-inferior to monthly ranibizumab. Aflibercept may be more appropriate for a treat-and-extend treatment regimen than ranibizumab and bevacizumab. Such a treatment strategy involves initial dosing every month for three months, with extension of the interval between doses thereafter. Aflibercept maintained anatomic and visual gains much more reliably than the other two treatments when adopting this approach.

Intravitreal injections are not without their risk. The ocular complications of these injections are inflammation, cataract, endophthalmitis and retinal detachments, all of which can result in a deterioration in vision. A number of systemic adverse effects occurred in trial participants but it is difficult to ascribe their occurrence completely to the administration of an anti-VEGF agent. As Table 3 shows, in the MARINA trial, patients who received sham injections had systemic adverse events, with a frequency comparable to those who had received ranibizumab injections.

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TABLE 3: MARINA trial. Adverse events occurring in those who received ‘sha’ injections and Ranibizumab injections

Currently, ranibizumab and aflibercept are licenced as first-line agents for the treatment of wet AMD. If a particular patient does not respond to one treatment, because these medications have related but somewhat different modes of action, switching to the other treatment should be considered and may be beneficial. There are, however, significant cost-savings associated with the off-label use of bevacizumab and given its similar efficacy to the other anti-VEGF treatments, it remains a very reasonable treatment for wet AMD.

Other considerations

Unfortunately, nutritional supplementation and/or intravitreal treatment with anti-VEGF agents will not alter the visual acuity of a proportion of patients with late AMD. AMD affects only central vision and so reassurance that peripheral vision will not be affected by this condition should be given. Such patients may be directed to the National Council for the Blind in Ireland, with which they may be registered and of whose low visual aid service they can avail.

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Figure 3: Little or no vision loss is associated with early and intermediate dry AMD. Late AMD shows moderate to severe vision loss

Lampalizumab, a complement inhibitor directed against complement factor D, which is given as an intravitreal injection, may in future prove an effective treatment for late dry AMD. Fovista, which prevents platelet-derived growth factor binding to blood vessel pericytes and in turn the formation of aberrant choroidal blood vessels when used in combination with current anti-VEGF medication, may further advance the treatment of wet AMD.

References available on request

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