Epidemiology

• This is the most common cause of irreversible visual loss in patients over 50 years old, in the western world,^[5] 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.^[6]
• 1.7% of the population over 50 years of age have severe disease (rising to 18% of the over 85 year-olds).
• Its prevalence is increasing in line with an ageing population.^[3]

Risk factors^[1]

Ageing and smoking are the most consistent risk factors for the development of AMD.^[2][3] A healthy lifestyle with regards to nutrition and physical activity is also associated with a decreased risk of developing age-related macular degeneration (AMD). A recent study has had compelling results, demonstrating that in the population studied (1,313 middle-aged women), a combination of healthy eating, physical activity and not smoking was associated with 71% lower odds for AMD compared with having high-risk behavioural scores.^[7]

• Ocular - the presence of age-related maculopathy (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. A history of cataract surgery may predispose individuals.^[8]
• Medical - cardiovascular risk factors are also associated with AMD;^[8] hypertension is a particular risk factor but antihypertensives do not reduce the risk. There is no association with diabetes.
• Genetic - a positive family history increases the risk of developing AMD.^[8] There have been associations described between a number of genes and an increased risk of AMD. Mutations of genes involved in the complement cascade (the first gene to be implicated was the complement factor H gene)^[3] 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 AMD 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. There is growing evidence that a high cumulative lifetime exposure to sunlight also increases the risk of developing AMD.^[3]
• Diet and nutrition - antioxidants and polyunsaturated fats have been extensively investigated in terms of prophylaxis (see under 'Prevention', below). Although there is not a clear, linear relationship, there is emerging evidence linking obesity to AMD.
• 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).

Presentation

Symptoms

Age-related macular degeneration (AMD) may be an incidental finding on a routine visit to the optometrist - particularly if only one eye is affected.^[9] Alternatively, patients may present with difficulty with tasks that require visual discrimination, such as driving, reading and recognising faces.^[3] Less common symptoms include night glare, photopsia (flickering or flashing lights), visual hallucinations (Charles Bonnet syndrome) and abnormal dark adaptation.^[9]

• Atrophic: in the early stages of development of geographic atrophy, diagnosis is often incidental.^[3] As the disease goes on, progressive, steady decline of central vision (black or grey scotoma) may be associated with 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 the house is not affected, as the peripheral vision is spared.
• Exudative: as above but may suddenly deteriorate to profound central visual loss in the event of a bleed. This may be preceded or accompanied by a shower of floaters.^[9]

Signs

Examination may reveal a normal or decreased visual acuity associated with distortion on the Amsler grid (see separate article Examination of the Eye). Fundus examination reveals discrete yellow deposits in the macular area, which may become paler, larger and confluent in patients progressing to exudative AMD. 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.

Differential diagnosis

Painless loss of vision can be caused by:^[9]

• Refractive errors.
• Cataracts.
• Some corneal diseases.
• Posterior vitreous detachment or retinal detachment.
• Retinal artery occlusion or retinal vein occlusion.
• Central serous retinopathy.
• Cerebrovascular disease.
• Pituitary and other neurological tumours.
• Some drugs or chemicals including methanol, chloroquine, hydroxychloroquine, isoniazid, thioridazine, isotretinoin, tetracycline, or ethambutol.

Other conditions to consider include:^[6]

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

Generally, the differential diagnosis will be considered by the ophthalmic team rather than the general practitioner.

Investigations

• Slit-lamp examination (bio-microscopy) is needed.
• Optical coherence tomography (OCT) is now commonly used to support the initial diagnosis and help assess the severity of the disease. This provides a cross-sectional view of the retina and the test can simply and painlessly be carried out in clinic in a few minutes. It is also a useful tool to assess response to treatment.^[3]
• Patients with a suspected neovascular membrane will have fluorescein angiography to assess suitability for treatment. Indocyanine green angiography is occasionally used to provide additional information to fluorescein angiography and also involves intravenous injection of a dye.

Management

The aim of management is to minimise visual loss in the early stages and to retain the greatest degree of independence possible through optimising remaining vision in the later stages.There is no effective treatment for dry age-related macular degeneration (AMD);^[5] 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 fulfil 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.

A series of implanted miniature systems of lenses have been devised for patients with end-stage disease: either a single lens is used to magnify the image on the macula or a series of lenses are used to deflect the image on to a less damaged part of the retina. This seems to be associated with a relatively good visual outcome after visual rehabilitation. However, there are also serious safety concerns regarding the procedure, as studies have highlighted significant complications. Therefore, the National Institute of Health and Clinical Excellence (NICE) recommends that this treatment only be carried out in units where appropriate auditing mechanisms are in place.^[10]

Management in primary care^[9]

Suspected AMD

These patients should be managed in a secondary care setting. If you suspect that your patient has AMD, you should arrange for them to be seen by the local team within a week. The other option is for the patient to be seen by an optometrist within the week. If the optometrist makes a diagnosis of wet AMD, they should refer on directly to the ophthalmology team and not back to the GP for onward referral.

Confirmed AMD

An explanation of the disease process and management options should be provided at the point of diagnosis in secondary care but, often, the information needs to be re-iterated and audio or written information can be provided in primary care.

In addition:

• The patient should see their GP or optometrist as soon as possible should they develop worsening symptoms or problems in the other eye.
• Explain the role of smoking in progression of the disease and encourage/support the patient to stop.
• Advise the person to eat a healthy, balanced diet rich in antioxidant vitamins and carotenoids (found in green leafy vegetables such as spinach and kale, eggs, and fresh fruit).
• Discuss the use of high-dose vitamin and mineral supplements See ('Prevention' below). The groups who may be most likely to benefit include people with advanced AMD or vision loss due to AMD in one eye, and people with intermediate AMD who have extensive intermediate-sized drusen, at least one large drusen, or non-central geographic atrophy in one or both eyes.

All types of AMD

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 AMD. 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 (ie and optician checking the patient's glasses) - 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.
  • a 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 the Driver and Vehicle Licensing Agency (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 optometrist.

Other

• It is worth telling them that there are excellent patient support groups available - 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 see separate article Blindness and Partial Sight.

Wet AMD^[1]

Treatment is carried out by ophthalmologists with a special interest in retinal and macular problems. Interventional treatment (ie 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. For the past couple of decades, laser treatment and photodynamic therapy were the main treatment options for patients with neovascular AMD but now monotherapy with an anti-vascular endothelial growth factor (anti-VEGF) drug (administered into the vitreous) is the current standard of care.^[3]

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).^[11] 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-VEGFs^[12]

These are agents that interfere with angiogenesis by binding to vascular endothelial growth factors (VEGFs) to prevent endothelial cell proliferation.^[5] The administration is intraocular and drugs that have been used in the USA 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 (RCO) and endorsed by the National Institute for Health and Clinical Excellence (NICE), guiding the administration ± discontinuation of this drug. Once the patient has been identified as a suitable candidate (as assessed by visual acuity, 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. So far, the practical experience of starting ranibizumab has been comparable to trial outcomes in terms of clinical benefit, adverse effects and service delivery issues.^[13]

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 intraocular use. Early studies look promising with regards to its effects in wet AMD. However, it is not yet licensed for use in the eye on account of the paucity of information regarding optimum dose and administration frequency.^[14] Although it may be used off-licence, NICE and the RCO stress the lack of data surrounding its long-term efficacy and safety record. However it remains widely used around the world on account of its price, and results of ongoing international trials comparing it with ranibizumab are eagerly awaited.^[3]

Combination therapy: PDT and anti-VEGF

There are ongoing trials assessing this treatment option. Early results suggest improved efficacy, reduced frequency of re-treatments and reduced toxicity initially. However, the need for re-treatment 12 months on appears to be the same^[3] and there is, as yet, insufficient evidence available to recommend this line of treatment as routine.

Other

• Other combination therapies (eg verteporfin and triamcinolone) have been tried with little evidence of success.
• Other treatment possibilities that have been considered are radiotherapy^[15] and transpupillary thermotherapy^[16] but these remain very unusual options.
• Surgery has also been explored but is not commonly used:
  • A macular translocation with 360° retinotomy:^[17] essentially, the macula is detached with only a small strand of tissue connecting it to the optic disc, the underlying abnormal neovascularisation is removed from the choroid and the macula is re-attached, rotated away from the diseased site. This results in a distorted image (as the macula is in a different position) which is corrected by a further operation to rotate the globe, such that the image is correctly positioned again. However, NICE has concluded that there is insufficient evidence from randomised controlled trials on the effectiveness of macular translocation, which also carries important risks.
  • Limited macular translocation:^[18] this is a less invasive alternative to macular translocation with 360° retinotomy. The retina is detached from the underlying choroid and the sclera is folded and sutured so that a healthy piece of choroid is brought to lie under the macula. This procedure is also associated with potential complications and, as with the full macular translocation, should only be carried out where good auditing facilities are in place.
• There is new research into the use of ciliary neurotrophic growth factor which looks promising and there are new lines of investigation looking at immunomodulatory drugs which may slow or stop the progression of AMD from the early to late stages.^[3]
• There are a number of treatment options that have been examined where studies have either been inconclusive or of poor quality. These include looking at using statins and ginkgo biloba extracts (these contain flavonoids and terpenoids which have antioxidant properties) to slow disease progression. These are not treatment options used in the UK.

Treatment outcomes^[3]

Given the progressive nature of AMD and the evolving treatment options (which are not always accurately reported in the media), it is worth noting what patients can expect following treatment:

• About 80% of patients experience a slowing of the progression of vision loss.
• The aim is to preserve central vision but most patients will have some difficulty in reading small print and other visually demanding tasks, even if the structure of the fovea appears to have been restored.
• Metamorphopsia may be a persistent feature in some people.

Complications

Serous retinal detachment, haemorrhage (both in exudative age-related macular degeneration (AMD) only). There are also recognised complications of the treatment of this condition including:^[12]

• Hypersensitivity reaction to a 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.
• Ongoing visual loss (20% of patients).^[3]

Any patient suffering from sight loss later in life is also at risk of developing visual hallucinations (Charles Bonnet syndrome).

Prognosis

This is a progressive, irreversible disease affecting central vision only. The process tends to be a slow one in dry age-related macular degeneration (AMD), unless concurrent pathology develops in the same or fellow eye, when the decline becomes more apparent. Untreated wet AMD leads to significant visual loss (6/60 or worse) within 3 years.^[3] For the minority of wet AMD patients who fulfil 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 choroidal neovascularisation (CNV).^[2]
• Laser photocoagulation is associated with a reduction in visual loss in the 15-20% of patients with exudative AMD 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: only certain patient subgroups show any benefit) - is also associated with serious potential visual side-effects.
• Anti-vascular endothelial growth factor (anti-VEGF) drugs are promising but treatment with these 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 AMD.

Prevention

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.

• 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.^[5]
  • Antioxidants (eg vitamin C, vitamin E, various types of carotenoids and zinc) or dietary supplements (eg vitamin E and beta-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 age-related macular degeneration (AMD) in well-nourished western populations.^[19] There is also evidence to the contrary.
  • Currently, the RCO highlights the benefit of high-dose antioxidants (vitamins C and E, beta-carotene) and zinc in reducing the patient's relative risk of AMD progression by 25% and it suggests that these supplements may be indicated in patients with advanced disease in the fellow eye.^[1]
• It is worth noting that supplements are not without risks:^[9]
  • High doses of dietary supplements (particularly beta-carotene) may also be harmful to smokers (possible increased risk of lung cancer).^[3]
  • Additionally, people with diabetes or vascular disease are at an increased risk of heart failure associated with vitamin E supplementation.
  • This combination of supplements increases the risk of hospitalisation due to genitourinary conditions (for example, urinary tract infection, urinary stones [calculi], urinary retention, and prostatic hyperplasia) and long-term use could theoretically lead to zinc-induced anaemia (although the copper supplementation should prevent this).
  • It is worth noting that the high dose of beta-carotene may cause harmless yellowing of the skin (but the sclera remain white).
• 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 AMD.^[20] However, there is currently insufficient evidence to support their routine consumption as a preventative measure for AMD 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.^[5]