Age Related Macular Degeneration

Synonyms: ARMD or AMD, macular degeneration, senile macular degeneration

This is the term given to ageing changes occurring without any obvious cause in the macula of individuals over the age of 50¹ associated with a risk of visual loss.² It is a disease of the macular area of the retina characterised by the deposition of small colloid bodies (drusen). These are found between the retinal pigment epithelium (RPE) and the underlying Bruch's membrane. They appear at about 45 years of age and increase in size and number. In the early stages, these changes are referred to as age-related maculopathy (ARM). When they reach a critical size and number in the macular area, they give rise to age related macular degeneration (ARMD). The risk of this progression leading to visual loss in the affected eye is of the order of 8% per year (this depends slightly on the exact nature of the drusen).

There are a number of different ways of defining and classifying the disease.² Based on the appearance of the drusen, it is said to be early, intermediate or advanced. In the latter, two forms are recognised:

• Atrophic (dry, non-exudative, geographic atrophy) - the presence of drusen results in progressive atrophy of the RPE, photoreceptors (overlying the RPE) and choriocapillaris (underlying the RPE). This is the commonest form of the disease, occurring in 90% of cases.
• Exudative (wet, neovascular) - in the remaining 10% of ARMD patients, there is a growth of choroidal vessels under and into the retina, resulting in a neovascular membrane, known as sub-retinal neovascularisation (SRNV). Serous fluid may accumulate here causing serous retinal detachment. Abnormal vessels can also form over the macula (retinal angiomatous proliferation). Both types of neovascularisation give rise to abnormal vessels that are fenestrated and prone to leakage. The end point of this type of ARMD is scar formation known as disciform macular degeneration (on account of its shape).

This is a bilateral but often asymmetrical disease with second eye involvement in over 60% of cases over 5 years.³

• This is the commonest cause of irreversible visual loss in patients over 50 years old, in the western world,⁴ accounting for almost 50% of those registered blind or partially sighted in the UK.²
• 10% of 65-75 year olds and 30% of over 75 year olds are affected to some degree.⁵
• 1.7% of the population over 50 years of age have severe disease (rising to 18% of the over 85 year olds).

Risk Factors¹

Ageing and smoking are the most consistent risk factors for the development of ARMD.²

• Ocular - the presence of ARM (described above) is the main ocular risk factor. There have been suggestions that hypermetropia, iris colour and pre-existing macular pigment are all linked but evidence remains mixed. There is also conflicting evidence relating to the effect of cataract surgery on ARMD at present.
• Medical - hypertension is a risk factor but antihypertensives do not reduce the risk. There is no association with diabetes and mixed reports of association with cardiovasculopathy.
• Genetic - there have been associations described between a number of genes and an increased risk of ARMD. Mutations of genes involved in the complement cascade and some genetic loci (particularly chromosome 10q locus) have been described. There also seems to be a relationship between genes and response to treatment.
• Lifestyle - smoking is a well established risk factor (there is a direct correlation between the the risk of developing advanced ARMD and the number of cigarettes smoked)² and, in theory, alcohol consumption should be too on account of the oxidative stress it places on the body. However, the latter is yet to be proven.
• Diet and nutrition - anti-oxidants and polyunsaturated fats have been extensively investigated in terms of prophylaxis (see below). Although there is not a clear, linear relationship, there is emerging evidence linking obesity to ARMD.
• Others - there is a marked ethnic difference in prevalence, with white people being more commonly affected. Women are said to be more affected in over 75 year olds (although some studies dispute this and there is the confounding factor of increased longevity). The relationship between sunlight exposure and ARMD is not clearcut although there is plenty of laboratory evidence demonstrating macular changes following UV light exposure. It therefore seems prudent to advise wearing sunglasses with 100% protection against UVA and UVB.

Symptoms

• Atrophic: progressive, steady decline of central vision (scotoma), difficulty in reading, seeing distant objects, distortion of straight lines ("Does the frame of the doorway look straight?"), micropsia or macropsia (seeing things smaller or bigger than they are). Getting around house is not affected as the peripheral vision spared.
• Exudative: as above but may suddenly deteriorate to profound central visual loss in the event of a bleed.

Signs

Discrete yellow deposits in the macular area, which may become paler, larger and confluent in patients progressing to exudative ARMD. There may have been a bleed, seen as a dark red, well-defined patch in the macular area. Late in the disease, a macular scar may develop: a thick yellow patch over the macular area.

• Rule out diabetes (diabetic maculopathy).
• Type 2 membranoproliferative glomerulonephritis.
• Various rare ophthalmic conditions to be ruled out by ophthalmology team.

• Slit lamp examination (bio-microscopy) is needed.
• Patients with a suspected neovascular membrane will have fluorescein angiography to assess suitability for treatment.
• Some patients may need other investigations such as optical coherence tomography (OCT) which provides a cross-sectional view of different layers of the retina.

The aim of management is to minimise visual loss and to retain the greatest degree of independence possible. There is no effective treatment for dry ARMD;⁴ the focus of management in these patients should be visual rehabilitation.

It is the choroidal neovascularisation (CNV) that is amenable to treatment if caught early enough. Patients have to fulfill certain clinical criteria (known to suggest a positive outcome for treatment) and are specifically excluded from treatment if permanent structural damage to the fovea is noted on examination and investigation.¹ Hypersensitivity to the drugs used is also another exclusion criterion.

All types of ARMD

The phrase 'nothing can be done' may be devastating and is rarely true.¹

Rehabilitation

This is going to be the mainstay of management for the majority of patients with ARMD. It revolves around maximising any remaining visual function and assisting the person to maintain an independent life for as long as possible. It may involve:

• Refraction (i.e. glasses check at optician) - to make sure that any remaining vision is the best it can be.
• Low visual aid clinic referral which will provide practical training and coping strategies and help with the provision of:
  • Magnifiers for near vision, telescopes for distance vision.
  • Large print books, talking tapes etc.
  • Variety of gadgets to help with household tasks.

Counselling

• Reassure them that they will not go totally blind: peripheral vision is preserved.
• Check whether they are driving and if so, advise them to inform DVLA (document this). The onus is on the patient - not yourself - to talk to the DVLA. The DVLA may want some documentary evidence of their visual function which can often be provided by the optician.

Other

• It is worth telling them about the excellent patient support groups available (see further reading list below) - these may be as much support to the family as to the affected person.
• Registration as blind or partially sighted can only be done by an ophthalmologist and will give access to a degree of financial support. For more detail on this, please go to our record on Blindness and Partial Sight.

Wet ARMD¹

Treatment is carried out by ophthalmologists with a special interest in retinal and macular problems. Interventional treatment (i.e. all those described below other than laser treatment alone) takes place either in theatre or in a designated treatment 'clean room'. It is carried out under local anaesthetic.

Laser photocoagulation

This type of treatment needs to be carried out quickly - within a week following confirmation of eligibility on fluorescein angiography. It is suitable for the treatment of pathology that is situated away from the fovea (the most central area of the macula). However, it results in a scotoma reflecting the area treated. The CNV can re-occur, the majority doing so within a year of treatment.

Photodynamic therapy (PDT) with verteporfin

The principle of treatment is to destroy the neovascular membrane without damaging the overlying neurosensory retina. It involves intravenous injection of verteporfin which is then activated by an argon laser beam. The activated molecules destroy the vessels but spare the photoreceptors.

As with laser therapy, this treatment needs to be carried out soon after fluorescein angiography (1-2 weeks). It is carried out in selected cases with a minimum amount of vision (only refer if best corrected vision of 6/60).⁶ The treatment has limited success rates (stabilisation is aimed for, improvement is unusual) and needs to be repeated approximately every three months. In 1-4% of cases, it can result in a temporary loss of vision and in a small number of these patients, the loss can be severe and permanent.

Idiosynchratic back pain can develop during the infusion (1-2% of patients). Direct sunlight exposure should be avoided for 48 hours.

Anti-VEGFs⁷

An important new line of treatment are the anti-VEGF drugs. These are agents that interfere with angiogenesis by binding to vascular endothelial growth factors to prevent endothelial cell proliferation.⁴ The administration is intra-ocular and drugs that have been used in the United States are pegaptanib (Macugen™) and ranibizumab (Lucentis™).

Currently, it seems that ranibizumab is the more effective of the two and was licensed for use in the UK in June 2008. There are a number of specific criteria identified in a nationally used protocol, prepared by the Royal College of Ophthalmologists and endorsed by NICE, guiding the administration ± discontinuation of this drug. Once the patient has been identified as a suitable candidate (as assessed by slit-lamp examination, fluorescein angiography and optical coherence tomography), the drug is administered four-weekly. Severe hypersensitivity reactions have been reported up to an hour after administration so patients should be observed for this time.

Pegaptanib is not the recommended first line treatment option but is used by some. The treatment pattern is very similar to ranibizumab's but the injections are given at six weekly intervals.

Bevacizumab (Avastin™) - a similar drug developed for the systemic treatment of colorectal cancer - is cheaper but is not currently licensed for intra-ocular use. Early studies look promising with regards to its effects in wet ARMD. However, it is not yet licensed for use in the eye on account of the paucity of information regarding optimum dose and administration frequency.⁸ Although it may be used off-licence, NICE and the Royal College of Ophthalmologists stress the lack of data surrounding its long-term efficacy and safety record.

Combination therapy: PDT and anti-VEGF

There are ongoing trials assessing this treatment option. Results are promising so far, suggesting improved efficacy, reduced frequency of re-treatments and reduced toxicity. However, there is as yet insufficient evidence available to recommend this line of treatment as routine.

Other

Other combination therapies (e.g. verteporfin and triamcinolone) have been tried with little evidence of success. Excision of subfoveal neovascular membranes or repositioning of the macula away from the membranes is also being investigated⁹ but there is risk of complications and severe visual loss (worse than experienced with conservative management). Other treatment options that have been considered are radiotherapy¹⁰ and transpupillary thermotherapy¹¹ but these remain very unusual options.

Serous retinal detachment, haemorrhage (both in exudative ARMD only). There are also recognised complications of the treatment of this condition including:⁷

• Hypersensitivity reaction to drug
• Endophthalmitis
• Retinal detachment
• Severe uncontrolled uveitis
• Ongoing periocular infections
• Other serious ocular complications attributable to ranibizumab or injection procedure
• Thrombo-embolic phenomena
• Traumatic cataract

This is a progressive, irreversible disease affecting central vision only. The process tends to be a slow one in dry ARMD, unless concurrent pathology develops in the same or fellow eye, when the decline becomes more apparent. For the minority of wet ARMD patients who fulfill the criteria for treatment, the outlook is better but not much more so:

• A study showed that at 5 years, about 20% of both treated and untreated patients experienced visual loss although laser treatment did seem to delay the development of CNV.²
• Laser photocoagulation is associated with a reduction in visual loss in the 15-20% of patients with exudative ARMD who have particular characteristics amenable to this kind of treatment.² However, there are high recurrence rates and a significant risk of eventual visual loss associated with lasering near the fovea.
• Photodynamic therapy - where indicated (again: certain patient subgroups only show any benefit) - is also associated with serious potential visual side effects.
• Anti-VEGFs are promising but treatment with these drugs is an involved process involving intravitreal injections on repeated occasions (with the attendant risks) and long-term follow up (two years and beyond). Ranibizumab improves vision in a third of patients; most will maintain their existing vision and about 10% deteriorate. Pegaptanib reduces the risk of visual loss but there will be some decline over two years. The challenge of going through the treatment (for the few for whom it is an option) and its limited success may be poorly understood by patients pressing for treatment of their ARMD.

Given the importance of this condition and the growing proportion of older people in the population and the small numbers of people suitable for treatment, much work is being carried out in the identification of risk factors and preventative measures. Much of these focus around dietary issues.

• The main work is based on the fact that the oxygen-rich retina is exposed to light and therefore vulnerable to oxidative damage. It is thought that this leads to a cumulative oxidative stress.⁴
  • Antioxidants (e.g. vitamin C, vitamin E, various types of carotenoids and zinc) or dietary supplements (e.g. vitamin E and β-carotene) have been studied as potentially protective.
  • There has been somewhat conflicting evidence surrounding their efficacy but a recent meta-analysis concluded that high antioxidant levels in the healthy retina do little to prevent ARMD in well nourished western populations.¹² There is also evidence to the contrary.
  • Currently, the Royal College of Ophthalmologists highlights the benefit of high dose antioxidants (vitamins C and E, β-carotene) and zinc in reducing the patient's relative risk of ARMD progression by 25% and it suggests that these supplements may be indicated in patients with advanced disease in the fellow eye.¹
• A further meta-analysis suggests that consumption of fish and foods rich in omega-3 fatty acids may be associated with a lower risk of ARMD.¹³ However, there is currently insufficient evidence to support their routine consumption as a preventative measure for ARMD particularly.

The strongest risk factor, age, is not preventable so currently the only firm advice remains to focus on modifiable risk factors, hypertension, weight and - as ever - to encourage your patient to stop smoking.⁴