Continuing Education

In the latest in our CET series concerning macular disease, Krishnappa Madhusudhana and Richard Newsom discuss and compare the various ways of screening effectively for age-related macular degeneration in its various clinical presentations  (C3607, one standard CET point)

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Age-related macular degeneration (AMD) is the UK's leading cause of blindness.1 Its prevalence increases with age, peaking in the over-75s. The proportion of the population of over 65 years is expected to increase 29 per cent by year 2020, doubling the incidence of AMD.1, 2
Recent advances in choroidal neovascularisation (CNV) treatment mean that rapid referral has now become central to its management. Some have proposed a national screening programme to monitor high-risk patients.

Within this article we will review AMD epidemiology, screening strategies and the role of rapid referral pathways for patients with active CNV.

Epidemiology and Natural History of AMD
AMD or Stage 4 age-related maculopathy (ARM) occurs in two forms: dry AMD or wet AMD.

Although dry AMD accounts for 80 per cent of all diagnosed cases, wet AMD is responsible for up to 80 per cent of AMD-related blindness. The five-year incidence (number of new cases per year) of early ARM over the age of 75 is around 12 per cent, while that of AMD is 0.9 per cent, split equally between wet and dry types.3

The natural history of the two types of AMD has become clearer with the publication of several large prospective studies of AMD.
Dry AMD is characterised by the presence of drusen, retinal pigment epithelial atrophy and focal pigmentary changes in the macula.
CNV is the hallmark of wet AMD, presenting as greyish subretinal membrane associated with subretinal fluid, macular oedema, subretinal haemorrhage/exudates and pigment epithelial detachment (Figures 1a and 1b).

Features of dry AMD such as drusen and focal pigmentary changes are usually present in eyes manifesting CNV, as well as fellow eyes. However, CNV may occur without any of these precursor lesions.

Risk Factors for wet AMD
Various risk factors for the development of CNV have been identified. Systemic hypertension, carotid disease, family history, cataract surgery and smoking are some of the risk factors implicated. In the highest risk categories the incidence of CNV can reach 20 per cent per year. Some major risk factors are summarised in Table 1.

Onset of visual loss in dry AMD is sub-acute and is generally due to geographical atrophy involving the fovea. The incidence of visual loss in patients with dry AMD is relatively constant. The AREDS trial found a 5-7 per cent rate of visual loss in these patients, per annum.4 This was a relatively constant change over seven years. In contrast to this, wet AMD shows a more rapid progression of visual deterioration over the first three months.

Natural History of CNV
The rate of visual loss depends in part on the type of CNV and its location. The Macular Photocoagulation Study showed that in patients with extrafoveal classic lesions (<5 per cent of lesion types), severe visual loss (>6 lines of vision) occurs in 51 per cent of patients over two years, compared with 65 per cent in those with juxtafoveal classic lesions.5

These studies are of increasing historical interest, however, the TAP and VIP studies of Visudyne for sub-foveal CNV are perhaps more useful. They found that moderate visual loss (>3 lines of vision) occurs in 73 per cent of patients with pure classic CNV, 69 per cent in predominantly classic CNV and 67 per cent of patients with occult CNV over 12 months.6, 7 Most vision was lost in the first three months of the disease, particularly with active, classic CNV.

The Visudyne trials showed that there was improvement in vision in around 9 per cent of patients. However, it does slow the progression of the disease, stabilising or improving vision in 73 per cent of classic lesions and 67 per cent of predominantly classic, and 54 per cent of occult lesions.6, 7 These data show the importance of early referral of patients with active CNV before significant amount of vision is lost. This is also emphasised by the NICE guidance.

Screening for wet AMD
Low level of awareness of AMD in patients, limited mobility of elderly patients and delays in referral pathways can lead to delays in treatment of CNV.

Typically, a patient may be referred to the GP, then to a general ophthalmologist, and then to a specialist ophthalmologist at a regional centre. According to one study, 16 per cent of patients with wet AMD see retina specialists more than six months after the onset of symptoms.8 Delay in presentation reduces the time available for effective treatment, as PDT does not improve vision. For some patients the vision will fall outside the NICE guidelines by the time they are seen.

Cases such as these have renewed interest in developing rapid referral pathways. Some are even considering the possibility of screening high-risk patients. As the prevalence of blindness due to AMD increases with advancing age, screening protocols will need to concentrate on the high-risk elderly patients.

Population screening is reserved for conditions that pose a considerable public health threat, have a known natural history, reasonable treatment, and occur asymptomatically in defined populations. Screening tests need to be simple, easy-to-perform, non-invasive and cost-effective. They should also demonstrate a high degree of sensitivity and specificity.9

Unlike screening for diabetic retinopathy, specific protocols for screening for wet AMD are yet to be established. Individuals at risk for wet AMD are largely asymptomatic and are identified primarily by retinal examination. The therapeutic window for wet AMD is relatively narrow, and until recently CNV lacked effective treatment.

Within the following section we will review the Amsler grid, Preferential Hyperacuity Perimetry, colour vision testing, slit-lamp biomicroscopy and photography as possible candidates for CNV screening.

Amsler chart monitoring
The Amsler chart (also known as the Amsler grid) is an important qualitative tool for the evaluation of central field of vision.

The patients, using their reading correction, fixate on the central dot of a black grid on a white background held at a distance of 30cm. Regions of blurring, distortion, micropsia, and metamorphopsia are noted. Micropsia is caused by leakage of subretinal fluid, elevating the retina and separating the photoreceptors, distortion by displacement of the photoreceptors, metamorphopsia by a combination of the two, while a scotoma is caused by photoreceptor death or sub-retinal blood (see Figure 2).

However, there are problems with Amsler chart screening. Several studies have evaluated the Amsler chart as a surveillance tool for AMD and have questioned the validity of Amsler chart screening.10, 11 The Amsler grid could not detect up to 70 per cent of scotomas that are six degrees or less in diameter.10

Zaidi et al found that the Amsler chart could detect only a third of patients who needed treatment of CNV.12 Due to this variability, others have developed the Macular Mapping Test (MMT, see Figure 3) and a 3D modelling of the Amsler grid.

Both of these have advantages over the Amsler grid, but are not so portable.13, 14 Some advise using the original Amsler grid (white lines on a black background) to improve the sensitivity of the test.15 Others have used red on black to further improve the sensitivity; however there is little data on this. In summary, this is a widely used but unreliable test for small scotoma and early disease. Poor technique by patients and varying levels of concentration and fatigue during self-monitoring at home could lead to highly variable results. However, in the absence of a definitive screening tool, Amsler chart screening continues to offer inexpensive, qualitative surveillance for CNV.

Preferential Hyperacuity Perimetry
The Preferential Hyperacuity Perimeter (PHP) has been developed as a response to the limitations of the Amsler grid for CNV screening (Figure 4).

PHP tests the central 14 degrees of the visual field. The stimulus is a dotted line with an artificially-generated distortion flashed in a predetermined order. The stimulus is projected on the screen and the patient registers distortion on the line using a pen on the touch-sensitive screen. The algorithm determines depth of visual field defect and by comparing with a normative database, determines whether progression to advanced AMD is suspected. A recent prospective study has evaluated the use of PHP in detecting recent-onset CNV.16 PHP was found to have a sensitivity and specificity of 82 per cent and 88 per cent respectively, in detecting CNV. Authors suggest periodic monitoring with PHP, of patients with intermediate stages of AMD.

On initial evaluation in the community it detected patients with branch retinal vein occlusion, dry AMD and macular holes. PHP is certainly a sensitive tool for assessing macular changes, however, as yet, the algorithm is not specific enough for widespread use in the community and direct referral to the hospital. As the software develops, however, this could be a novel method of detecting macular disease.

Colour vision testing
Colour contrast losses are known to occur in patients with asymptomatic AMD.

Holz et al demonstrated increased thresholds for foveal blue-colour contrast sensitivity in patients with age-related maculopathy.17 A loss of short wavelength sensitive (SWS) cone pathway sensitivity is found in most patients with early ARM, despite good visual acuity.18 These studies have suggested the use of colour contrast sensitivity tests to assess the progression of AMD. However, the tests need to be performed with a computerised method. Standard colour vision testing with Ishihara colour plates or the 100-hue test is not useful.

Although colour contrast sensitivity tests are quick and easy to conduct, they can detect only progression of AMD prior to the development of CNV or geographical atrophy and hence are not of much value in screening for CNV.

Slit-lamp biomicroscopy
Slit-lamp biomicroscopy using a 60D lens is the standard examination technique used to diagnose AMD (Figure 5), while the decision to treat is based on findings of fundus fluorescein angiograms (Figure 1). While fluorescein angiography is offered in the hospital setting, slit-lamp biomicroscopy is a common examination technique in general practice. It is sensitive to sub-retinal blood and fluid associated with CNV. High-risk patients and those who require treatment can be referred to treatment centres. Drawbacks of this method of screening are the delays in referral pathways, need of patient transport to the hospital and the risk of unnecessary referrals clogging the clinics.

Photographic screening
Photographic screening (Figure 6) for wet AMD is drawing increased attention. Photographic screening involves capturing retinal images of 'high-risk' patients in the community; the images are transmitted electronically and evaluated by retinal experts.

This could hasten the process of patient referral and management. It could also reduce unnecessary travel, saving the direct and indirect costs of patient transport. Recently, several studies have evaluated this method as a screening tool.19, 20 Pirbhai et al found that digital, non-stereo colour fundus photographs had a sensitivity of 89 per cent in detecting CNV.21 They have suggested that combining digital colour images with red-free images or introduction of stereo images might reduce false-negatives.

Maberley et al found that colour fundus images using both stereo pairs and single images were adequate to detect most cases of CNV.19 The detection rate improved with the inclusion of clinical data in the screening programme. Recently, Zimmer-Galler et al evaluated an internet-based automated fundus camera (DigiScope) as a screening tool for AMD by comparing it with standard stereo fundus photographs and found an excellent agreement for high-risk lesions.20

So far, there have been no reported studies from the UK evaluating the use and effectiveness of photographic screening for wet AMD.
To address this issue, we conducted a prospective study at Southampton Eye Unit, to determine whether photographic screening of elderly patients could lead to higher detection treatment of CNV. The images were transmitted electronically and graded by a retina specialist (RSN) based on the classification used in the Age-Related Eye Disease Study (AREDS).4

The findings have yet to be formally presented, however, it was possible to identify patients with CNV (Grade 4 ARM) and have them referred for urgent assessment with fluorescein angiography and OCT. Non-targeted screening of elderly patients had a relatively low detection rate and some patients were reluctant to seek help. Other methods of targeted screening or telemedicine referral may be more appropriate in this group of patients.

Discussion
The development of photodynamic therapy and some of the new anti VEGF injectable treatments have given real hope to this needy group of patients.

Optimal management of wet AMD involves early detection and prompt referral of patients who need treatment. The patients need to be seen within the therapeutic window before a significant amount of vision is lost. Data from the UK show that nearly 45 per cent of patients with AMD first present to the optometrist, while many of them first consult GPs and general ophthalmologists.

In line with the NICE guidance on PDT, direct referral from the first point of NHS contact straight to a retina specialist is essential to achieve optimal treatment.22 Yet each year, treatment is delayed for about 3,000 patients because they are not directly referred to specialist centres and only half of patients reach the specialist centres in time.

Instead, they are passed around the systems between optometrists, GPs and general ophthalmologists.23 This highlights the urgent need of fast track referrals in the NHS to facilitate timely treatment of these patients.

Screening for diabetic retinopathy is well established and professional organisations recommend a sensitivity and specificity of at least 80 per cent and 95 per cent respectively for sight-threatening diabetic retinopathy. However, there are no clear guidelines as yet for screening in AMD.
Screening for wet AMD using accurate and non-invasive methods offers the opportunity for community-based screening and streamlining of patient referrals and further evaluation. There are several candidate methods of screening for AMD, but the most accurate and practical method is yet to be identified.

The success of photographic screening for diabetic retinopathy has prompted the potential use of a similar method of screening for wet AMD. Photographic screening could avoid 'controllable' delays in the diagnosis and treatment of CNV, facilitating detection of lesions at an early treatable stage.

However, non-targeted screening of asymptomatic patients in the community can lead to a low detection rate even with highly sensitive and specific screening methods. There are also other issues to be addressed, such as real benefits in terms of visual outcome, cost-effectiveness and medico-legal implications of telemedicine.

Further research is needed before screening for wet AMD can be incorporated into community practice. Till then, the successful management of wet AMD relies upon early referral of patients using fast-track referral pathways.

References
1 Royal College of Ophthalmologists. A national research strategy for ophthalmology. Royal College of Ophthalmologists 2002.
2 Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE et al. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology, 2001; 108: 697-704.
3 Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology, 1997; 104 (1): 7-21.
4 Age-Related Eye Disease Study Research Group. A randomised placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS Report No. 8. Arch Ophthalmol, 2001; 119: 1417-36.
5 Macular Photocoagulation Study Group. Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for evaluation and treatment in the Macular Photocoagulation Study. Arch Ophthalmol, 1991; 109:1242-57.
6 Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group, Verteporfin in Photodynamic Therapy Study Group. Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularisation secondary to age-related macular degeneration: TAP and VIP report no. 1. Am J Ophthalmol, 2003; 136: 407-18.
7 Verteporfin in Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularisation in age-related macular degeneration: Two year results of a randomised clinical trial including lesions with occult with no classic choroidal neovascularisation- verteporfin in photodynamic therapy report 2. Am J Ophthalmol, 2001; 131(5): 541-60.
8 Haddad WM, Seres A, Coscas G, Soubrane G. Presentation delay in patients affected with age-related macular degeneration. Graefe's Arch Clin Exp Ophthalmol, 2002; 240(1): 31-4.
9 Hennekens CH, Buring J. Epidemiology in Medicine. Little Brown and Company: Boston/Toronto, 1987.
10 Schuchard RA. Validity and interpretation of Amsler grid reports. Arch Ophthalmol, 1993; 111: 776-80.
11 Archard OA, Safran AB, Duret FC, Ragama E. Role of the completion phenomenon in the evalauation of Amsler grid results. Am J Ophthalmol, 1995; 120: 322-9.
12 Zaidi FH, Cheong-Leen R, Gair EJ, et al. The Amsler chart is of doubtful value in retinal screening for early laser therapy of subretinal membranes. The West London Survey. Eye, 2004; 18: 503-8.
13 Nazemi PP, Fink W, Lim JI, Sadun AA. Scotomas of age-related macular degeneration detected and characterised by means of a novel three-dimensional computer-automated visual field test. Retina, 2005; 25 (4): 446-53.
14 Bartlett H, Davies LN and Eperjesi F. The macular mapping test: a reliability study. BMC Ophthalmology, 2005,5:18.
15 Augustin AJ, Offermann I, Lutz J, Schmidt-Erfurth U, Tornambe P. Comparison of the original Amsler grid with the modified Amsler grid: result for patients with age-related macular degeneration. Retina, 2005; 25 (4): 443-5.
16 Preferential Hyperacuity Perimetry Research Group. Preferential Hyperacuity Perimeter (Pre View PHP) for detecting choroidal neovascularisation study. Ophthalmology, 2005; 112(10): 1758-65.
17 Holz FG, Gross-Jendroska M, Eckstein A, et al. Colour contrast sensitivity in patients with age-related Bruch's membrane changes. Ger J Ophthalmol, 1995; 4 (6): 336-41.
18 Remky A, Elsner AE. Blue on yellow perimetry with scanning laser ophthalmoscopy in patients with age related macular disease. Br J Ophthalmol, 2005; 89 (4): 464-9.
19 Maberley DAL, Isbister C, MacKenzie P et al. An evaluation of photographic screening for neovascular age-related macular degeneration. Eye, 2005; 19: 611-6.
20 Zimmer-Galler IE, Zeimer R. Feasibility of screening for high-risk age-related macular degeneration with an internet-based automated fundus camera. Ophthalmic Surg Lasers Imaging, 2005; 36 (3): 228-36.
21 Pirbhai A, Sheidow T, Hooper P. Prospective evaluation of digital non-stereo colour fundus photography as a screening tool in age-related macular degeneration. Am J Ophthalmol, 2005; 139(3): 455-61.
22 National Institue for Health and Clinical Excellence (2003). Macular degeneration (age-related) Photodynamic therapy (Technology appraisal 68). http://www.nice.org.uk.
23 Survey carried out by Insight Research for Novartis Ophthalmics, 2005.

• Richard Newsom is consultant
  ophthalmic surgeon and Hon senior
  lecturer, Southampton Eye Unit where Krishnappa Madhusudhana is a research fellow

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