C51856: Age related macular degeneration – a review

Age-related macular degeneration (AMD) is the leading cause of irreversible, progressive visual impairment in people over 60 in many Western countries, with severe vision loss affecting 10-15% of patients. It is a significant public health problem that presents a challenge for current economic models as populations grow and age.1 Dry AMD is characterised by deterioration of the photoreceptors and retinal pigment epithelium (RPE) in the central retina, caused by environmental and genetic factors. Wet AMD is caused by choroidal neovascularisation (CNV) growth under the RPE and central retina. Significant advances in our understanding of the condition have led to the development of revolutionary new therapies for wet AMD. While genetic screening and counselling may become important in terms of prevention of AMD, there is a need for new treatment options for dry AMD and to this end there is a range of promising treatments on the horizon.

Features, history and optometric management

Clinical features of AMD

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Dry AMD accounts for around 80% of all moderate/severe forms of the disease.1 Figure 1 shows the clinical features of AMD. These include discrete yellow spots at the macula (drusen), sharply demarcated areas of RPE depigmentation with focal hyperpigmentation.

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Although hard drusen are often found in ageing eyes, when they are observed in association with retinal pigment alterations and/or soft drusen, the risk of progression is increased. Areas of increased autofluorescence are comprised of lipofuscin accumulated within damaged RPE. They are considered a risk factor for progression of atrophy and vision loss. The late stage of dry AMD is also called geographic atrophy (GA) and it causes vision loss that may be mild to moderate and less often ‘severe’ as seen in wet AMD. GA is a sharply demarcated area of partial or complete depigmentation reflecting atrophy of the RPE. The margins of the depigmented area are usually scalloped and the large choroidal vessels are visible through the atrophic RPE. Vision loss particularly affects near vision and it usually takes several years from the onset of GA to cause visual loss.

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Exudative or neovascular AMD is typically caused by choroidal neovascularisation under the RPE. Neovascularisation can also arise in the neurosensory retina and is referred to as retinal angiomatous proliferation. The vessels can make contact with the choroidal vessels to form chorioretinal anastomoses. New vessels allow blood constituents to leak out causing separation of Bruch’s membrane, RPE and retina and also result in the accumulation of intraretinal fluid and thickening of the retina or in the formation of cystic spaces.

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Degenerative changes occur with cell loss and fibrosis. The end result is often a circular scar. In summary, the clinical features include atrophy of the RPE with visibility of the choroidal vessels, pigment epithelial detachment, with or without neurosensory detachment, neovascularisation, scar tissue, haemorrhage and exudates.

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A variant of AMD affecting all racial groups but with a higher representation in Asian populations is polypoidal choroidal vasculopathy.

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Aetiology of AMD

Age appears to be the most important risk factor and genetic, environmental factors and metabolic conditions also contribute to the development of AMD. Smoking is an important risk factor for dry AMD, possibly due to atherosclerotic changes and alteration in blood flow.1 In AMD, metabolic products accumulate in the extracellular space between Bruch’s membrane and the RPE, activating the complement system stimulating inflammation and increasing oxidative stress.1 An increase in oxidative stress can increase both the incidence and the progression of AMD.

Dietary carotenoids may be converted to macular pigment lutein and zeaxanthin which can reduce the risk of AMD. Certain genes such as complement factor H (CFH) have been associated with a higher risk of AMD 2 and an individual’s response to treatment may be affected by their genetic status, allowing for the possibility of creating biomarker profiles to guide treatment.

In a recent study, data from 31 population-based studies described as having populations similar to the middle-aged and older UK populations, were used to estimate the prevalence of late AMD. The estimated prevalence of late AMD was 4.8% (95% CI 3.4 to 6.6%) of those over 65 years and 12.2% (95% CI 8.8 to 16.3%) of those aged 80 years or more (Owen et al 2003).3 The prevalence of AMD may be higher in Caucasians. Other possible risk factors include sunlight exposure, cardiovascular disease and dyslipidaemia.4

Evaluation of patients at risk of AMD

The assessment of patients at risk of AMD should include taking a thorough history (including family history and any smoking history), visual acuity measured at distance and near, Amsler grid with appropriate refractive correction, visual fields and fundus evaluation using slit lamp binocular indirect ophthalmoscopy (BIO). More specialised tests such as preferential hyperacuity perimetry or PHP (Figure 2), macular pigment using heterochromic flicker photometry, if available, can provide additional information.

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Early lesions may, however, not be detectable even with slit lamp BIO. Whenever wet AMD is suspected, fluorescein angiography (FA) and optical coherence tomography (OCT) are used to confirm the diagnosis (Figures 3a and b).

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While dry AMD is usually a slowly progressive disease, wet AMD progresses more rapidly and can cause severe vision loss over a matter of days or weeks. Research has shown that current techniques in the treatment of wet AMD are more likely to be successful and halt vision loss or reverse vision loss with smaller and less central lesions. The larger the lesion at baseline, the smaller the benefit in terms of the level of vision at two years after treatment is initiated. Thus early detection of AMD lesions is critical in management. The transition to wet AMD is often spotted late, leading to irreversible vision loss.

Detection may involve advising patients to report symptoms such as distortion of lines, blur, reduced vision, dark areas in the visual field or the use of the Amsler grid. Recent onset metamorphopsia, scotomas or micropsia should be investigated although researchers have suggested that patients who notice these symptoms or alterations to the appearance of the Amsler grid, are often detected late, ie when a large scotoma is already present. The original Amsler test was intended for use under normal illumination although a variation where the task lighting is reduced can make the test more sensitive to detecting small CNV lesions causing relative, not absolute scotomata. The common practice of providing patients with printed copies of the grid (black grids on white paper) may lead to anomalous results and compliance with self-monitoring has been reported to be poor. The most commonly presenting symptom of wet AMD is blur and distorted vision when reading, rather than changes on the Amsler chart. It has been suggested that around 50% of scotomata in the macular region remain undetected by Amsler grids. Nevertheless, patients should be asked to self-monitor their vision between clinic visits.

Changes in refractive error, increase in hyperopia or reduction in myopia, coupled with risk factors for AMD, could be indicative of elevation of the RPE or neurosensory retina. This can be investigated with slit lamp BIO, OCT and referral for ophthalmological opinion. Questions on whether the patient has noted any metamorphopsia/micropsia may be helpful in the differential diagnosis.

Retinal imaging

Angiography was the main diagnostic and follow up tool for AMD for many years. Indocyanine green angiography or ICGA (Figure 4) uses an alternative dye to fluorescein used to visualise the choroidal circulation, although its usefulness is limited if there is very thick blood or pigment as this can block transmission of the infrared wavelengths.

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It is useful when assessing patients suspected of having retinal angiomatous proliferative lesions, idiopathic polypoidal choroidopathy or central serous retinopathy. A dose of 25mg of ICG in aqueous solutions is usually injected intravenously and images acquired for up to 30 minutes. Non-invasive techniques such as fundus photography, OCT and autofluorescence imaging are also useful diagnostic tools and high resolution OCT in particular has become the most common method of making an initial diagnosis of wet AMD and is very useful for disease monitoring. Fluorescein angiography FA (Figure 5) continues to play a role in the diagnostic process by visualising the retinal vessels and choroidal neovascularisation as well as providing information on perfusion and exudation. Once the diagnosis of choroidal neovascular membrane has been made, monitoring of the effects of therapy can typically be undertaken using spectral domain OCT in terms of both qualitative changes and quantitative measures. A commonly used metric is variation in central retinal thickness. Other features include new haemorrhage visible clinically. Corrected distance visual acuity is an indicator but in itself is not sufficient to detect recurrence of activity of the neovascular membranes in wet AMD.

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Management

Dry AMD management options consist of modifications to lifestyle, nutritional supplements and supportive measures such as low vision rehabilitation.

• Reducing body mass index, particularly in those who are obese, may reduce the risk of developing AMD. There is a decreased risk of AMD in patients with high intake of omega-3 polyunsaturated fatty acids.
• Smoking cessation may decrease oxidative stress and improve choroidal blood flow, reducing ischaemia, hypoxia, microinfarctions and damage to the RPE.1 Support is available from primary care physicians.
• Physical activity reduces systemic inflammation and endothelial dysfunction both of which play a role in AMD pathogenesis.
• Some studies suggest that excessive alcohol consumption may be associated with AMD and therefore should be avoided.
• Low vision rehabilitation includes assessment of residual functional vision, identification of the preferred retinal loci (PRL) and training on the use of the PRL. Education on the use of low vision aids and advice to assist with undertaking day-to-day tasks should be offered.
• Some clinics offer continued co-monitoring with an ophthalmologist for patients who have a family history/ risk factors eg obese with genetic markers/early signs or symptoms of AMD. Additional genetic information can reveal an individual’s overall risk profile. This monitoring approach can provide ongoing advice, support and reassurance. Diet, macular pigment levels and changes in autofluoresence or OCT patterns may be monitored to provide information on disease progression and the benefit of proposed interventions.
• Dry AMD can be monitored in optometric practice and updating the refraction can often improve visual acuity. As stated above an Amsler grid can be issued to the patient for self-assessment at home. The patient should be advised on the risks of progression and what to do in the event of a sudden onset of distortion. Any advice given should be recorded. Provision of patient leaflets, out of hours’ protocols and/or directions/map(s) of the local eye clinics should an ‘emergency’ situation arise can be helpful. A patient with dry AMD may require referral to assess progression, to access LVA services, assess the likely outcome of cataract extraction, for other eye disease management or to register as sight impaired or severely sight impaired. Information on both local and national support services should be provided (preferably in large print). Patients should inform the DVLA if they have AMD in both eyes or in one eye if a bus, coach or lorry driver. Patients with AMD should consider notifying siblings as there is an increased incidence if a first degree relative has AMD. Advising patients to eat a diet rich in green leafy vegetables, oily fish, nuts, seeds and free range eggs is useful. Those with a poor diet may take supplementsincluding lutein and zeaxanthin.

Referral pathways

Dry AMD if visually significant, is typically a routine referral through the GP. A GOC regulatory requirement is that a written statement outlining the reasons for referral is provided following the sight test, along with copy Rx. A copy of the referral letter should be given to the patient. If referring directly to the hospital or for local enhanced services, a report should be sent for information to the GP. Wet AMD will need urgent referral to a hospital eye service (preferably a fast track macular clinic or medical retina clinic). All potentially treatable wet AMD patients should have a faxed/email referral in line with local access arrangements. The Royal College of Ophthalmologists recommend that patients with suspected wet AMD are seen by an ophthalmologist within 48 hours of referral, and that treatment, if appropriate, commences within the next week.

Wet AMD treatment eligibility

To be eligible for ranibizumab or aflibercept on the NHS the following must apply

• Presence of CNV secondary to AMD
• VA greater than 6/96 (1.2 LogMAR) and VA less than 6/12
• Lesion less than 12 disc areas in size
• No structural damage to the fovea
• Blood in less than 50% of the lesion area
• Evidence of recent progression

In brief, if the diagnosis is confirmed following OCT and fluorescein angiography, the patient is then injected for three consecutive months. This is the ‘loading dose’. They are then monitored or treatment continued depending on the drug and the individualised treatment regime. Treatment decisions are guided by LogMAR VA, OCT and clinical evaluation. If there is evidence of activity an injection is given. Depending on the treatment regime patients without active disease may still be injected if they are following a fixed treatment or ‘treat and extend’ approach and observed if following an

‘as needed’ approach.

Advances in our understanding of the pathogenesis of early AMD are identifying new therapeutic targets. This, together with advances in detection and monitoring progression, offers promise in future strategies for blocking or reversing early AMD.

Medical and surgical interventions

AMD has a profound effect on the quality of life of those affected and is a major challenge for society due to the increase in life expectancy and environmental risks. Advances in medical and surgical therapies has led to an improvement in the outlook, particularly for patients affected by wet AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, there remain unresolved issues relating to the rapidly growing costs and the challenges of real world clinical management and monitoring of these patients. This section provides a brief overview of current and future treatment options, opportunities and challenges.

Current treatments for dry AMD

At present the treatment for dry AMD is consumption of antioxidant formulations and lifestyle modification (as outlined above). Possible therapeutic targets to prevent further damage, or to repair or regenerate damaged cells, include blocking or preventing the formation of drusen, reducing inflammation, since complement components and inflammatory molecules are found in drusen, preventing accumulation of by-products in the retina, reducing oxidative stress, improving choroidal perfusion and replacing, repairing or regenerating damaged RPE cells and photoreceptors and gene therapy.1 Anti-complement component antibodies and antioxidant therapies are under evaluation and future AMD medical therapies may be designed for intravitreal administration by injection or inserts, subcutaneous injection or maybe even topical application.

The Age Related Eye Disease Study

AREDS 5 was a major clinical trial sponsored by the National Eye Institute, one of the US federal government’s National Institutes of Health and based in Washington DC.

The AREDS was designed to tell us more about the natural history and risk factors of AMD and cataract and to evaluate the effect of high doses of vitamin C, vitamin E, beta-carotene and zinc on the progression of AMD and cataract.

The AREDS study categorised AMD as summarised in Table 1.

In the AREDS study, vitamin C (500mg), vitamin E (400 IU), beta-carotene (15mg), zinc (80mg) and copper (2mg) were tested against placebo. Antioxidants may prevent retinal damage by counteracting reactive oxygen species limiting oxidative stress. Zinc may lower excessive systemic complement activations, although the benefit of zinc in AMD prevention is yet to be confirmed. Copper is a scavenger of free radicals although its role in AMD protection is still unclear. Results from the AREDS showed that high levels of antioxidants and zinc significantly reduce the risk of advanced AMD and its associated vision loss in category 3 and 4 patients. These same nutrients had no significant effect on the development or progression of cataract.

The reduction was more significant with extensive intermediate drusen, geographic atrophy not at the centre of the macula, or at least one large drusen and in those with advanced AMD or VA <6/9 in one eye.

In AREDS 2, the risk of progression from early to advanced AMD was investigated. Three formulations were evaluated, one formulation without beta-carotene (due to a risk of lung cancer in smokers or previous smokers), one with reduced zinc concentration (25mg) and a third with a combination of no beta-carotene and reduced zinc. The results showed that adding lutein and zeaxanthin, omega-3 polyunsaturated fatty acids or both to the AREDS had no effect on progression to advanced AMD in addition to the benefit already achieved in AREDS 1. It was shown that lutein and zeaxanthin may be a useful substitute in the AREDS formulation in smokers and former smokers.

Other antioxidants, vitamins and minerals have also been studied with some of these agents. Chong et al 6 concluded that vitamin A, vitamin C, vitamin E, zinc, lutein, zeaxanthin, alpha and beta-carotene, beta-cryptoxanthin and lycopene had little effect in the prevention of early AMD. These authors, however, reported that consumption of omega-3 polyunsaturated fatty acids protect against AMD progression.

In summary, improving lifestyle and reducing modifiable risk factors are strategies that can prevent development and progression of the disease. Research suggests that antioxidants together with some essential elements have not proved effective in prevention of AMD. The use of antioxidants, plus zinc and copper have reduced the risk of progression of stage 3 and 4 AREDS patients to advanced AMD; the AREDS 2 formulation is recommended in such patients.

Therapies for dry AMD

Focal laser treatment to areas of large drusen have been observed to make them disappear but a Cochrane review of studies using focal laser to treat drusen with the intention of preventing progression to late stage AMD found that despite the disappearance of drusen, there was no evidence of prevention of late stage AMD and vision loss.7 Studies using large spot size diffuse lasers rather than focal lasers are ongoing.

Lowering lipid accumulation in Bruch’s membrane may also be an efficient way to treat AMD in the early stages although the results of statin efficacy in AMD were inconclusive.8

Lampalizumab (anti-Factor D Fab, Roche) is an antibody binding fragment of humanized monoclonal antibody which binds to and inhibits complement factor D (CFD), so reducing chronic inflammation. Phase 2 clinical trials showed that intravitreal lampalizumab reduced progression of geographic atrophy in patients with advanced dry AMD.9 Phase 3 clinical trials for treatment of geographic atrophy secondary to AMD are ongoing.

Fluocinolone acetonide (Iluvien, Alimera Sciences) is a non-bioerodible polyamide tube containing corticosteroid with a broad anti-inflammatory target. An ongoing study aims to evaluate intravitreal administration in GA.

The RPE could be an ideal tissue for transplantation in AMD although attempts at transplanting RPE cells in degenerated areas have largely been unsuccessful. Studies using human embryonic stem cell-derived RPE transplantation in AMD and Stargardt’s macular dystrophy patients, however, found increased macular pigmentation and improved visual acuity in treated compared with non-treated eyes and is a potential future therapy option.10 Using pluripotent stem cells that can differentiate into RPE and photoreceptor cells is an exciting approach. Trials are underway.

With the recent rapid progression in research, the future holds great promise for patients affected with AMD and for scientists and clinicians involved in such studies. Genetics has provided a basic framework by identifying AMD risk variants and implicated pathways. Genes associated with AMD such as CFH or age-related maculopathy susceptibility 2 (ARMS2) have been identified and genetics are being used to help predict disease development/progression. As mentioned above, in the future it is envisaged that genetic analysis will be helpful in identifying the most suitable treatment options for individual patients.

In brief, treatment for dry AMD should be aimed at reducing noxious stimuli, protecting the remaining cells and repairing damaged cells. Continuing advances in understanding the molecular pathogenesis of early AMD are identifying new therapeutic targets and the future is promising.

Therapies for wet AMD

Until the advent of anti-vascular endothelial growth factor (anti-VEGF) drugs, therapy for wet AMD was limited to either argon laser photocoagulation or photodynamic therapy (PDT).

Laser photocoagulation

Randomised controlled trials undertaken by the Macular Photocoagulation Study (MPS) Group, found that laser photocoagulation with confluent argon laser to the CNV complex slowed or halted loss of visual acuity but did not improve it in people with juxta-foveal or extra-foveal lesions,11 but thermal laser treatment to sub-foveal lesions should be avoided due to the risk of laser-induced visual loss caused by the permanent scotoma. Laser photocoagulation is now no longer justified for most causes of wet AMD due to the introduction of anti-VEGF agents, but may still be useful for lesions well away from the fovea as it is a less costly and more convenient option.12

Photodynamic therapy (PDT) with verteporfin, (Visudyne, Novartis)

Intravenous Verteporfin is a photosensitive dye which binds to plasma low density lipoprotein which is then taken up by endothelial cells in new choroidal blood vessels and when activated by low energy thermal laser it causes damage to leaking vessels which seals them, therefore allowing a more targeted treatment of new vessels than laser. It is effective at reducing visual acuity loss in a sub-group of patients with predominantly classic lesions and occult lesions showing signs of recent progression, and idiopathic polypoidal choroidopathy.13

The NICE guidelines only recommend PDT for confirmed classic sub-foveal CNV, with no sign of occult, and visual acuity at least 6/60. PDT is not recommended where there is some occult component (NICE Technology Appraisal 2003).14 However, the Royal College of Ophthalmologists’ guidelines for treatment of age-related macular degeneration state that PDT is no longer justified as a monotherapy and is only recommended for idiopathic polypoidal choroidopathy.4

Steroids

Steroids are anti-angiogenic, anti-fibrotic, anti-inflammatory and they stabilise the blood retinal barrier, although the Royal College of Ophthalmologists advises that any potential role of triamcinolone as an adjunct of anti-VEGF therapy has yet to be established.4

Anti-angiogenic agents

Increased vascular endothelial growth factor (VEGF) in exudative AMD is the cause of growth of choroidal vessels through Bruch’s membrane to form a CNVM.15 New vessel growth occurs beneath the RPE and through the RPE to form a sub-retinal CNVM. As stated, new vessels leak, haemorrhage and fibro-vascular scarring occurs, causing rapid decline or loss of visual acuity.

VEGF can be targeted by anti-VEGF antibodies or soluble VEGF receptors and options include Pegaptanib, ranibizumab, bevacizumab, and aflibercept. Conbercept is an anti-VEGF drug approved for treating wet AMD in China. It has a higher binding affinity, lower dissociation rate and longer clearance time than other anti-VEGF agents and the company (Kanghong Biotech, Chengdu, China) is now in discussion with the FDA and European Medicines Agency.16

Pegaptanib sodium, (Macugen, EyeTech/Pfizer) is not cost-effective as a first line treatment in wet AMD and although licensed in the UK, in practice it is not recommended by NICE; however, funding may be sought from commissioners on an exceptional case basis, for example in the case of allergy to other anti-VEGF agents.4

Ranibizumab (Lucentis, Genetech Inc/Novartis) is a humanised fragment antibody binding (FAB), of a monoclonal antibody which binds to and inhibits all isoforms of VEGF A.

Bevacizumab (Avastin, Genetech Inc) is a humanised full-length antibody which binds to all isoforms of VEGF. The Comparison of AMD Treatment trials (CATT)17 and Alternative Treatments to Inhibit VEGF in Age-Related Choroidal Neovascularisation trials (IVAN)18 showed that bevacizumab has a similar efficacy to ranibizumab, but it is not licensed for use in the treatment of AMD in the UK.

Aflibercept (Eylea, Regeneron) is a fusion protein which inhibits all isoforms of VEGF A and placental growth factor (PGF) and was licensed in Europe for the treatment of wet AMD in 2012.19

Clinical trials

Two important randomised, masked, sham-controlled clinical trials, MARINA (Minimally Classic/Occult trial of the anti-VEGF antibody ranibizumab in the treatment of neovascular AMD)20 and ANCHOR (Anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularisation in AMD),21 followed by the PIER and FOCUS studies form the basis for licensing and subsequent NICE guidelines.

MARINA compared ranibizumab versus sham injections at monthly intervals in minimally classic/occult lesions. ANCHOR compared ranibizumab to PDT in eyes with predominantly classic choroidal neovascularisation. The main outcome (MARINA) was that 95% of those treated with ranibizumab, maintained VA (lost less than 15 letters logMAR with the EDTRS chart) compared with 62% in the sham injection group. Up to 34% had improved VA at one year (gained 15 letters or more) compared with 5% in the sham injection group. Patients treated with ranibizumab showed an improvement of 6.6 letters at two years compared with loss of 14.9 letters in the sham group.

ANCHOR showed those treated with ranibizumab had up to a 10. 7 letter gain at two years compared with a loss of 9.8 letters in the PDT group. Up to 40% of those treated with ranibizumab achieved VA of 0.3 logMAR (~6/12).

PIER evaluated the safety and efficacy of ranibizumab administered monthly for three months and then quarterly in patients with AMD. It was concluded that the benefits obtained with quarterly dosing were not as robust and those observed in previous studies with monthly dosing. In PrONTO ranibizumab was given on an as needed basis after initial stabilisation of the lesion. Results from the PrONTO study suggest that a less frequent dosage regimen using OCT metrics to direct treatment may give equally good visual results. The CATT studies compared monthly versus as needed treatment using ranibizumab and bevacizumab. These studies suggested that if monthly injection is superior to as needed treatment, the differences are not large. The European Medicines Agency suggested treating on an as needed basis. Less than monthly injections may be adequate for some but monthly assessment is the gold standard as it is not possible to accurately predict which patients are at risk of CNV recurrence.

In summary, all types of foveal choroidal neovascularisation (occult, classic, and mixed) are suitable for treatment with ranibizumab and aflibercept. Bevacizumab has similar functional efficacy to ranibizumab.

The requirement for monthly injections places a considerable burden on both patients and healthcare systems and many patients require long-term follow up. Studies have shown that aflibercept allowed less frequent dosing with no impact on efficacy and similar results to ranibizumab, so reducing the burden on patients, carers and the healthcare services.22 VIEW 1 and VIEW 2 studies were randomised controlled clinical trials comparing monthly and two monthly dosing regimes of intravitreal aflibercept with monthly intravitreal ranibizumab. Both regimes of aflibercept were found to be clinically equivalent to monthly ranibizumab with the added benefit of reduced burden and risks associated with monthly intravitreal injections.22

A treatment approach which attempts to take a more proactive approach at less than monthly intervals is the concept called ‘treat and extend’. This approach involves commencing treatment using a fixed monthly dosing approach until a dry retina or disease stability is achieved. The treatment is then continued and the review interval is extended sequentially at each visit in two week increments up to 12 weeks if there is disease stability. If signs of disease activity increase, the treatment interval is reduced. All visits therefore become treatment visits but with a variable interval tailored to the individual. Arnold et al23 have shown good results using this approach in routine clinical practice.

The NICE guidelines for the use of ranibizumab and aflibercept state that the drugs are recommended as an option for wet AMD if:

• Corrected distance visual acuity is between 6/12 and 6/96
• There is no permanent structural damage to the central fovea
• The lesion is less than or equal to 12 disc areas in greatest linear dimension
• There is evidence of presumed disease progression (blood vessel growth as indicated by fluorescein angiography, or recent visual acuity changes), and the cost beyond 14 injections is met by the manufacturer.

The Royal College of Ophthalmologists statement on choice of anti-VEGF agents for wet AMD recommends that patients with vision >6/96 and active wet AMD are eligible for treatment with either ranibizumab or aflibercept under NICE guidance according to a variety of treatment regimes including:

• Treat and Extend
• Monitor
• Monitor and Extend
• Fixed dosing.

As more optometry practices acquire OCT instruments it may be possible to develop ‘hub and spoke’ models where accredited and trained community optometrists review patients then refer those who need treatment or advanced investigation to the hospital. In some parts of the country non-medical healthcare professionals including optometrists, administer anti VEGF injections to increase capacity. The Royal College of Ophthalmologists have published a statement on intravitreal injections of anti-VEGF agents by non-medical health care professionals. The view states that where circumstances and facilities allow, the injection should be given by a specialist doctor trained in the procedure, however it is reasonable for non-medical health care professionals to administer injections if certain stipulations are met. There are potentially serious adverse events associated with intravitreal injections; endophthalmitis, cataract, vitreous haemorrhage and retinal detachment. They should be carried out in a clean room or in theatre, resuscitation facilities must be readily available and a table or couch allowing the patient to be supine is necessary.

Sub-macular surgery and ionising radiation

Surgical interventions for AMD have been shown to be inferior to anti-VEGF therapy but may be considered where there are complications such as large sub-macular haemorrhage or in those unresponsive to anti-VEGF therapy.24 The Royal College of Ophthalmologists state that submacular surgery, macular translocation or radiation monotherapy are not recommended for the management of neovascular AMD.4

Ionising radiation can inactivate proliferating endothelial cells and can be delivered directly to a choroidal neovascular membrane. Oraya therapy applies stereo-tactic, low voltage x-rays to target CNVMs and is used on patients already receiving intravitreal anti-VEGF therapy. The INTREPID study was a randomised controlled trial which compared the Oraya therapy plus ranibizumab injections with sham treatment and ranibizumab.25 The study showed patients previously treated with anti-VEGF for wet AMD for a period of three years experienced a 32% reduction in need for injections compared to a control group at 12 months following radiation treatment. 25% needed no further injections.

Future treatments under investigation include complement inhibitors, mRNA and tyrosine kinase receptor inhibitors 26 and an anti-platelet derived growth factor called Fostiva.

End-stage treatments

Patients who have already finished anti-VEGF treatments and who have scarring of the central macular area may benefit from implantable devices. The IMT (Vision Care Ophthalmic Technologies) is the first FDA approved single device for AMD and the implantable miniature telescope (IMT Centrasight Treatment programme) comprises an implantable miniature telescope and rehabilitation programme for those with end stage AMD. The device is implanted into the capsular bag in one eye only, the other eye being used for mobility and navigation, ideally in those who have not already had cataract surgery.27

The IOL-VIP is a double lens system for dry AMD or stable wet AMD patients who have finished anti-VEGF treatment and have VA between 6/18 and 6/60. An in-the-bag implant and an anterior chamber implant with 1.3x magnification and prism incorporated to deviate the image away from the central scarred area.28

Summary

Advances in our understanding of the pathogenesis of AMD have identified new therapeutic targets. This coupled with the advances in diagnosis and monitoring techniques has greatly improved the prognosis for AMD patients. While there are many challenges and unmet needs, the optometrist as the trusted eyecare provider will continue to play a vital role in the diagnosis and management of these patients.

Optometrists Nigel Smith, Claire Mansell and Dr Clare O’Donnell work with Optegra Eye Sciences and Sajjad Mahmood is a consultant ophthalmologist at Optegra Eye Hospital Manchester and at Manchester Royal Eye Hospital

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16 Guttman Krader C: Novel anti-VEGF agent approved in China may reduce injection frequency; Ophthalmology Times 2015; April 1. Accessed 11 March 2016. http://bit.ly/1Whobrr.

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19 Brown DM et al. Primary endpoint results of a phase II study of vascular endothelial growth factor trap-eye in wet age-related macular degeneration. Ophthalmology, 2011; 118, 1089-97.

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21 Brown DM et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. New Engl J Medicine. 2006; 355, 1432-44.

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