Clinical Review - Macular degeneration

Contributed by Professor Usha Chakravarthy, professor of ophthalmology and vision sciences, Queen's University of Belfast.

Fundus photograph showing drusen (yellow-coloured flecks)
Fundus photograph showing drusen (yellow-coloured flecks)

SECTION 1: Epidemiology and aetiology
Age-related macular degeneration (AMD) is a condition that affects people aged 50 years and older.

In the early stages of AMD, examination of the fundus of the eye using an ophthalmoscope will reveal yellowish-coloured deposits called drusen and/or focal changes in pigmentation which may be reduced or increased.

Drusen and pigmentary irregularities are typically concentrated in the macular region of the fundus although the peripheral regions are also affected.

These clinical features are generally compatible with normal visual function and are often detected on fundus examination in elderly patients attending for routine eye checks. These features are referred to as early AMD. Epidemiological studies show that small drusen (<63 microns) are common and affect one half of all people aged 55 years and older whereas large drusen (>125 microns) and pigmentary irregularities are uncommon in those under 65 years.1 Longitudinal epidemiological surveys reveal that 5 per cent of those with early AMD will progress to more severe stages of AMD.2

However, when patients with marked features of early AMD are observed longitudinally, as in the age-related eye disease study (AREDS), around half of those at most risk developed late disease within five years in at least one eye.3 Therefore drusen and pigmentary irregularities are considered to be precursors for more advanced dystrophic changes in the macula.

Types of AMD
In a proportion of patients, early AMD changes give way to a confluent atrophy of the constituent macular tissues (choriocapillaris, Bruch's membrane, retinal pigment epithelium and photoreceptors of the outer retina) which because of its scalloped edges is termed geographic atrophy (GA), also known as dry AMD.

GA is an advanced form of AMD.
Another manifestation of AMD is the development of an exudate in the macular tissues, known as neovascular (or wet) AMD. The exudation comes from abnormal neovascular complexes that form within the choroid and subsequently invade the subretinal pigment epithelial and subretinal spaces after breaching Bruch's membrane.

These complexes are termed choroidal neovascular membranes. In addition, neovascular complexes may arise de novo within the retina and are referred to as retinal angiomatous proliferations.

Another type of neovascular complex which also falls within the spectrum of neovascular AMD is polypoidal choroidopathy in which intrachoroidal telangiectactic new vessels with focal dilations form and result in the elevation of the retinal pigment epithelium.

In population-based surveys the prevalence of late AMD is around 35 per cent for people aged 85 years and older, with GA accounting for one third and neovascular AMD for two thirds of all cases.2

SECTION 2: Making the diagnosis
Early AMD is easily recognised by fundoscopy. This may be achieved through using a hand-held ophthalmoscope or by slit lamp biomicroscopy.

Pupillary dilation is usually required and the latter method allows a stereoscopic assessment of the macular features under high magnification and although technically more demanding than direct ophthalmoscopy, is the option preferred by retinal specialists.

Drusen are amorphous yellowish coloured flecks that are typically located in the macular region of the fundus (see image above). If the margins are well delineated they are termed distinct drusen. When the margins are poorly defined they are called indistinct drusen. Drusen can merge and become confluent with each other.

Alongside drusen, changes in macular colour (hypopigmentation) and focal clumping of pigment (hyperpigmentation) may be present.

A clinical scale has been described which assigns levels of severity to these features based on the characteristics and extent of both drusen and pigmentary irregularities.3 This scale is predictive of progression to the late AMD features of GA and neovascularisation.

GA is the term used to describe a sharply demarcated hypopigmented area of the fundus with a characteristic lobular contour and scalloped edges within which large choroidal vessels and the underlying sclera are visible.

Scattered areas of GA between which islands of normal fundus exist may be seen. If GA involves the central macula, vision may be impaired.

Neovascular AMD is instantly recognisable because it is an acutely exudative pathology. An elevation of the neural retina or the retinal pigment epithelium may be seen.

In addition, haemorrhage is a predominant feature and can be found in multiple tissue planes, within the retina, subretinal, subpigment epithelial and intrachoroidal.

Lipid that has seeped out of leaking blood vessels can also form amorphous yellowish collections within the retina and the underlying tissues. The exudative lesion assumes a circular shape so this condition is known as disciform macular degeneration.

Investigations
The definitive diagnostic test is a contrast based imaging of the macula known as fluorescein angiography (FA).

This involves injecting fluorescein dye into a peripheral vein and capturing its transit through the retinal and choroidal circulation by means of a specially adapted camera after dilation of the pupil.

Optical coherence tomography (OCT) is another test and is entirely non-invasive as injection of contrast is not required.

Diagnosis
The simplest method of establishing the diagnosis is fundoscopy, which will permit distinction of early and late forms of AMD.

Confirmation is by OCT and if an exudative lesion is present, separation of the tissue layers and fluid accumulation within the tissue layers is evident. Fluorescein and/or indocyanine green angiography is used to further refine the diagnosis and will reveal the location of the abnormal blood vessels and permit classification of these vascular complexes into defined clinical subtypes.

SECTION 3: Managing the condition
Progression rates from early AMD to late AMD are typically low, and only one clinical trial has shown a benefit of oral antioxidants (vitamins A, C, E and zinc) in the progression from early to late AMD.4

Therefore, there is considerable controversy about whether treatment should be offered to patients with early AMD features. If early AMD features are present in one eye and late AMD in the other eye, antioxidant supplements are sometimes prescribed.

There are no licensed treatments that reverse GA or prevent its progression, although a number of clinical trials are ongoing. Patients should be offered appropriate magnification aids to maximise reading ability.

Photodynamic therapy
The management of neovascular AMD has changed dramatically over the past decade.

Thermal laser was the mainstay of treatment for many years and this was replaced by photodynamic therapy (PDT).

A major drawback of thermal laser therapy was the recurrence of the neovascular lesion at the edge of the scar and furthermore expansion invariably occurred in the direction of the fovea.

PDT is a treatment which gained popularity in the late 1990s when it was demonstrated that treatment improved visual outcomes compared with the natural history of the condition.5

PDT involves the application of an infrared laser to the area of the lesion which activates the drug verteporfin which has been infused into the patient. However as with thermal laser, recurrence of exudation from the lesion was common and there was eventual progression to central macular scarring and sight loss.

Ranibizumab
The knowledge that vascular endothelial growth factor (VEGF) is a key driver for ocular neovascularisation resulted in the testing of antibodies against this protein. Two pivotal clinical trials,6,7 the ANCHOR and MARINA studies, randomised patients to ranibizumab or standard care (in ANCHOR this was PDT, while in MARINA it was observation).

The test drug was administered by injection into the vitreous cavity of the eye every month over a two-year period.

The results exceeded all expectations and established without doubt that treatment with ranibizumab yielded outcomes that were far superior to any that had been observed previously. Thus at present ranibizumab therapy has become the standard of care for neovascular AMD. However, this form of therapy has its own drawbacks.8 First, the drug has to be administered into the vitreous cavity, which involves penetration of the globe under conditions of strict asepsis.

Second, the therapeutic effects only last a month, and its administration has to be continued on a monthly basis for many years, with a huge impact on resources. Third, there is concern that side-effects may emerge from chronic inhibition of VEGF in the eye.

The Royal College of Ophthalmologists' guidelines suggest that at present VEGF inhibition by monthly intraocular administration of ranibizumab is accepted as the standard of care.9

A cheaper unlicensed alternative is bevacizumab, a drug originally developed for the treatment of cancer, and it is shown to be similarly effective in maintaining function and reducing the exudative manifestations of neovascular AMD.10

Guidelines
The currently accepted algorithm for the management of patients with AMD is shown in the diagram above.

SECTION 4: Prognosis
Most patients with early AMD merely require reassurance as few will progress to sight threatening AMD. However those with extensive early AMD features in both eyes can progress more rapidly to late AMD.

In this context the AREDS trial suggested that the risk of progression might be reduced by micronutrient supplementation.

However, owing to the lack of conclusive evidence, supplementation with antioxidants is not generally recommended in the UK.

It is important that patients with early AMD are appropriately counselled and advised with regard to lifestyle modifications and prevention.

There are no treatments that have been proven to be effective in preventing or reversing the expansion of GA. Studies have revealed the inexorable progression of the area of atrophy towards the fovea and its involvement usually results in severe reduction in the ability of the affected eye to see.

Follow-up
Patients with early AMD do not require follow-up in secondary care and are usually managed in primary care with regular annual refraction, visual acuity testing and fundus examination by a qualified optometrist.

If progression to more severe involvement of the macula with confluent and/or increasing drusen area is noted, and particularly if accompanied by subtle falls in visual acuity, referral to a retinal specialist should be made for imaging using high resolution OCT.

Although there is no treatment for GA, these patients remain at risk of developing neovascular manifestations which may go unrecognised, particularly if there is pre-existing visual impairment.

Thus regular review by qualified optometrists in the community setting is recommended.

Careful counselling
Patients with neovascular AMD who have embarked on a course of anti-VEGF therapy may expect improved outcomes compared with natural history.

However, before therapy, patients require careful counselling and managing of expectations because most will have a degree of visual impairment.

SECTION 5 Case study
A 75-year-old woman presented to her GP with a two-week history of blurred vision in her right eye and she was referred to ophthalmology.

She had no past ocular history of note and was in good health apart from controlled hypertension. On examination visual acuities were logMAR 0.8 (Snellen 6/36) in the right eye and logMAR 0.0 (Snellen 6/6) in the left. Anterior segments of both eyes were unremarkable apart from non-significant early cataracts. The fundus of the left eye showed multiple macular drusen.

The fundus of the right eye had a central exudative yellowish lesion with haemorrhage defining the boundaries.

FA confirmed the presence of a choroidal neovascular membrane and OCT revealed irregular thickening of the interface between the choroid, retinal pigment epithelium and retina.

There were pockets of fluid between the retina and its pigment epithelium (subretinal) and within the retina (intraretinal fluid), causing it to be markedly thickened.

The diagnosis was neovascular AMD involving the central macula. The patient was commenced on a course of intravitreal ranibizumab (0.5 mg) which was continued monthly.

At six months, visual acuity in the right eye had improved and the OCT confirmed the absence of fluid in the macular tissue compartments.

The patient will continue to be monitored as recurrence of neovascular AMD is common.

SECTION 6 Evidence base
Clinical trials

  • Brown DM, Kaiser PK, Michels M et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1432-44.7

This study compared monthly ranibizumab versus three-monthly verteporfin PDT in patients with angiographic subtype of classic or predominantly classic neovascular AMD.

At 12 months, 94.3 per cent of the group given 0.3mg of ranibizumab lost fewer than 15 letters of vision, compared with 64.3 per cent in the PDT group. Ranibizumab produced a highly significant treatment benefit over PDT (P<0.001).

  • Rosenfeld PJ, Brown DM, Heier JS et al. Ranibizumab for neovascular age-related macular degeneration.

N Engl J Med 2006; 355: 1419-31.

This study compared monthly ranibizumab versus observation in patients with the angiographic subtype of minimally classic or occult neovascular AMD.

At 12 months, 94.5 per cent of the group given 0.3mg of ranibizumab and 94.6 per cent given 0.5mg had lost fewer than 15 letters of vision, compared with 62.2 per cent in the control group.

All these results were highly significant (P<0.001) and were maintained at 24 months.

Guidelines

  • NICE. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. TA155. London, NICE, 2008. Available from http://guidance.nice.org.uk/TA155
  • The Royal College of Ophthalmologists. Age-related macular degeneration: guidelines for management. February 2009.

Pages 46 to 48 give useful details on the initiation of treatment and treatment delivery.

  • The Royal College of Ophthalmologists. Guidelines for intravitreal injections procedure, 2009.

There are potentially serious adverse events associated with intravitreal drug administration. The guidelines outline best practice procedures to avoid the complications relating to this route of drug delivery.

Online

The Macular Disease Society is a UK-based organisation which provides advice, information and help to patients who have AMD.

REFERENCES

1. Klein R, Klein BE, Linton KL. Ophthalmology 1992; 99: 933-43.

2. Wang JJ, Rochtchina E, Lee AJ et al. Ophthalmology 2007; 114: 92-8.

3. Ferris FL, Davis MD, Clemons TE et al. Age-Related Eye Disease Study (AREDS) Research Group. Arch Ophthalmol 2005; 123: 1570-4.

4. AREDS Research Group. Arch Ophthalmol 2001; 119: 1417-36.

5. Macular photocoagulation study group. Arch Ophthalmol 1982;100: 912-18.

6. TAP study group. Arch Ophthalmol 2001; 119: 198-207.

7. Brown DM, Kaiser PK, Michels M et al; ANCHOR Study Group. N Engl J Med 2006; 355: 1432-44.

8. Chakravarthy U, Lim J. BMJ 2007; 334: 269-70.

9. Royal College of Ophthalmologists guidelines: Age-Related Macular Degeneration Guidelines for Management. February 2009.

10. Chakravarthy U. BMJ 2010; 340: 2384.

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Spend a session at your local ophthalmology clinic and refine your skills using an ophthalmoscope.
  • Make a poster for your waiting room about AMD.
  • Offer to develop a protocol on the management of AMD in primary care within your consortium.

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