Medical Bulletin

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Updates in the Management of Age-Related Macular Degeneration

Dr. Timothy YY Lai

IntroductionAge-related macular degeneration (AMD) is the leading cause of visual impairment and blindness among elderly patients in western countries and its prevalence is increasing due to aging of the population.1-4 In the United Kingdom, it has been estimated that around 3.5% of the population aged 75 years or older are visually impaired due to AMD.4 Due to westernisation of the Asian populations, the prevalence of AMD is also rising in various Asian countries. Therefore, clinicians should be aware of the recent developments in the management of AMD. This review aims to summarise some of the advancements in order to assist clinicians to have a better understanding in the management of this sight-damaging disease.

Classification of AMDAMD can be broadly classified into the dry (non-exudative) and the wet (exudative) forms. Early AMD is characterised by the presence of drusens with or without pigmentary changes of the retinal pigment epithelium (RPE) or the neurosensory retina. Drusens are acellular debris within the RPE basement membrane and are seen as yellow spots at the macula on ophthalmoscopy. Small drusens are commonly seen in normal individuals as signs of aging, whereas higher number of large drusens are associated with AMD (Figure 1). In more advanced non-exudative AMD, patients may develop severe visual loss due to localised area of RPE atrophy known as geographic atrophy. The wet or exudative form of AMD is also known as neovascular AMD and is characterised by the development of choroidal neovascularisation (CNV) (Figure 2), pigment epithelial detachment (PED), and disciform scar formation in advanced cases. Although neovascular AMD only occurs in around 10% of patients with AMD, it disproportionately accounts for 90% of patients with severe visual loss caused by AMD.

The diagnosis of exudative AMD with CNV is established on fundus fluorescence angiography which involves intravenous injection of fluorescence sodium solution followed by a series of retinal photographs obtained using a special fundus camera. Visual prognosis of patients with neovascular AMD depends on the location and classification of the CNV. The Macular Photocoagulation Study (MPS) has previously demonstrated that direct laser photocoagulation may be

useful in the treatment of CNV located outside the fovea (extrafoveal CNV).5,6 However, the visual prognosis of patients with CNV located at the central fovea (subfoveal CNV) is very guarded since 70% of patients with subfoveal CNV will have visual acuity of 20/200 or worse within two years.5-7 Laser photocoagulation is also not useful in these cases since the recurrence rate of CNV is high and patients will develop immediate loss of central vision after treatment.5,6 Therefore, until the development of photodynamic therapy (PDT) recently, there has been no effective treatment for patients with subfoveal CNV due to AMD.

Dr. Timothy YY Lai MBBS, MMedSc, MRCSEd, FCOphthHK, FHKAM (Ophthalmology)Specialist in Ophthalmology, Hong Kong Eye Hospital, Kowloon, Hong Kong.

Figure 1. Fundus photograph of a patient with dry (non-exudative) AMD characterised by drusen at the macula.

Figure 2. Fundus photograph of a patient with wet (exudative) AMD characterised by choroidal neovascularisation and scar formation at the macula.

Photodynamic therapy for neovascular AMDPhotodynamic therapy (PDT) is a two-steps procedure involving infusion and activation of a photosensitiser. It has the advantage over conventional direct laser photocoagulation due to its selective damage on the CNV while sparing any damage to the overlying neurosensory retina and RPE. This selective action is caused by preferential binding of the photosensitising agent to the low-density lipoprotein receptors present on CNV endothelial cells.8,9 After infusion of the photosensitising agent, a low-energy diode laser is used for activation of the drug, resulting in generation of highly reactive oxygen species such as free oxygen radicals and singlet oxygen molecules, thereby causing thrombosis and damage to the CNV.10

The drug which is currently available for PDT in the treatment of CNV is verteporfin (Visudyne, Novartis, Switzerland). Treatment involves infusion of the 6mg/m2 verteporfin over 10 minutes, followed by application of low-energy laser to the area of CNV for 83 seconds at 15 minutes from the commencement of infusion for drug activation. Repeat PDT with verteporfin is usually performed at 3-monthly intervals in patients with active CNV on fluorescein angiography. The safety and efficacy of PDT with verteporfin in the treatment of neovascular AMD has been demonstrated by two large multi-centred randomised placebo-controlled clinical trails, namely the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) and the Verteporfin in Photodynamic Therapy (VIP) studies.11-13 Both the TAP and VIP studies demonstrated that patients who received PDT with verteporfin had significant reduction in the risk of visual loss compared with placebo. On average, patients will require two to three treatments in the first year and around one to two treatments in the second year. PDT with verteporfin is generally well tolerated and complications associated with PDT are uncommon.14 Around 3% of patients however might develop acute severe visual loss following PDT. Nonetheless, PDT with verteporfin remains the treatment of choice in patients with neovascular AMD at present.

Newer treatment modalities for neovascular AMDDespite the efficacy of PDT with verteporfin, a substantial proportion of patients with CNV due to AMD will still develop significant visual loss. Another limitation of PDT is the high number of retreatment in some patients. Therefore, adjunctive and newer treatments have been proposed to improve the outcome in these patients. Studies have shown that combined PDT with verteporfin and intravitreal injection of triamcinolone acetonide may have a beneficial role in treating CNV due to AMD.15-17

Preliminary results in using inhibitors of vascular endothelial growth factor (VEGF) such as pegaptanib and ranibizumab for the treatment of neovascular

AMD are also encouraging and these agents will certainly increase the armament for the treatment of neovascular AMD in the near future.18,19

Prevention and prophylaxis for AMD disease progressionAs the visual outcome following treatment of AMD is generally poor, management of AMD should also include controlling the risk factors for disease progression as well as early detection of disease progression. Patients with high risk clinical features of AMD like large number of soft drusens or neovascular AMD in the fellow eye should be educated with the symptoms of AMD progression such as new onset of scotoma or metamorphopsia. An Amsler grid is a simple but useful tool for self-examination and all patients with AMD should be taught how to use the grid to detect new onset of symptoms which might be indicative of CNV or disease progression (Figure 3). When new symptoms arise, patients should seek specialist care as soon as possible for dilated fundus examination and further investigations since early detection of CNV might allow better visual outcome after treatment.

Various epidemiological studies have also evaluated the risk factors for the development of AMD. Cigarette smoking is one of the most important risk factor for AMD and the risk of both non-exudative and exudative AMD development is higher in current smokers than ex-smokers.20-23 Therefore, all patients with AMD regardless of type should be advised to stop smoking. Recent evidence has also suggested that exposure to second-hand smoke will also increase the risk of AMD by nearly two-fold.23 Systemic hypertension is also an important risk factor for the development of neovascular AMD and patients with hypertension should be followed more carefully for the development of advanced AMD.24

Figure 3. Amsler grid for self-examination

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Other modifiable risk factors for AMD include hyperlipidemia and cardiovascular diseases and these co-morbidities should be kept under optimal control.25

Antioxidants have been proposed to have an important role in the development of AMD and might be useful for prophylaxis of AMD. The Age-related Eye Disease Study (AREDS) is a multi-center randomized controlled clinical trial which investigated the role of high dose vitamin antioxidant supplementations in the prevention of AMD progression.26 The results showed that high dose supplements of vitamin C (500mg), vitamin E (400 IU), beta-carotene (15mg), zinc (80mg) and copper (2mg) could delay the progression of intermediate AMD to advanced AMD. It was also beneficial in delaying AMD progression in the good eye in patients with advanced AMD in the fellow eye. This antioxidant formulation should therefore be considered in patients with moderate AMD or with advanced AMD in one eye for prophylaxis treatment of AMD. Patients who smoke should be warned of the potential risk of beta-carotene supplements due to increased risk of lung cancer among smokers found in previous randomized controlled trials.27,28

ConclusionsThe impact of AMD in our society is likely to increase in the near future due to aging and westernization of the population. In view of the substantial burden of disease caused by visual impairment, it is important for all clinicians to be aware of the disease as early detection of AMD especially neovascular AMD may improve the visual outcome after treatment. More effective treatment modalities are becoming available and will have the potential to further improve the visual outcome in these patients who were untreatable just less than a decade ago.

ReferencesKlein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology 1992;99:933-943.Vingerling JR, Dielemans I, Hofma A, et al. The prevalence of age-related maculopathy in the Rotterdam study. Ophthalmology 19095;102:205-210.Klein R, Klein BE, Cruickshanks KJ. The prevalence of age-related maculopathy by geographic region and ethnicity. Prog Retin Eye Res 1999;18:371-389.Owen CG, Fletcher AE, Donoghue M, Rudnicka AR. How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom? Br J Ophthalmol 2003;87:312-317.Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Arch Ophthalmol 1991; 109:1220-1231.Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Updated findings from two clinical trials. Arch Ophthalmol 1993;111:1200-1209.Bressler SB, Bressler NM, Fine SL. Natural course of choroidal neovascular membranes within the foveal avascular zone in senile macular degeneration. Am J Ophthalmol 1982;93:157-163.Flower RW. Expanded hypothesis on the mechanism of photodynamic therapy action on choroidal neovascularization. Retina 1999;19:365-369.Maziere JC, Morliere P, Santus R. The role of the low density lipoprotein receptor pathway in the delivery of lipophilic photosensitizers in the photodynamic therapy of tumours. J Photochem Photobiol B 1991;8:351-360.

1.

2.

3.

4.

5.

6.

7.

8.

9.

Schmidt-Erfurth U, Hasan T. Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macular degeneration. Surv Ophthalmol 2000;45:195-214.Treatment of Age-related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials--TAP report. Arch Ophthalmol 1999;117:1329-1345.Bressler NM; Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. P h o t o d y n a m i c t h e r a p y o f s u b f o v e a l c h o r o i d a l neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2. Arch Ophthalmol 2001;119:198-207.Verteporfin In Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization--verteporfin in photodynamic therapy report 2. Am J Ophthalmol 2001;131:541-560.Schnurrbusch UE, Jochmann C, Einbock W, Wolf S. Complications after photodynamic therapy. Arch Ophthalmol 2005;123:1347-1350.Rechtman E, Danis RP, Pratt LM, Harris A. Intravitreal triamcinolone with photodynamic therapy for subfoveal choroidal neovascularisation in age related macular degeneration. Br J Ophthalmol 2004;88:344-347.Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology. 2003;110:1517-1525.Chan WM, Lai TY, Wong AL, et al. Combined photodynamic therapy and intravitreal triamcinolone injection for the treatment of subfoveal choroidal neovascularisation in age-related macular degeneration: A comparative study. British Journal of Ophthalmology (in press).Husain D, Kim I, Gauthier D, et al. Safety and efficacy of intravitreal injection of ranibizumab in combination with verteporfin PDT on experimental choroidal neovascularization in the monkey. Arch Ophthalmol 2005;123:509-516.Gonzales CR; VEGF Inhibi t ion Study in Ocular Neovascularization (V.I.S.I.O.N.) linical Trial Group. Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis. Retina 2005;25:815-827.Klein R, Klein BEK, Linton KLP, et al. The Beaver Dam Eye Study: The relation of age-related maculopathy to smoking. Am J Epidemiol 1993;137:190-200.Smith W, Mitchell P, Leeder SR. Smoking and age-related maculopathy. Arch Ophthal 1996;114:1518-1523. Vingerling JR, Hofman A, Grobbee DE, de Jong PT. Age-Related Macular Degeneration and Smoking: the Rotterdam Study. Arch Ophthal 1996;114:1193-1196.Khan JC, Thurlby DA, Shahid H, et al. Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation. Br J Ophthalmol 2006;90:75-80.The Age-Related Eye Disease Study Research Group. Risk Factors Associated with Age-Related Macular Degeneration: A case-control study in the Age-Related Disease Study: Age-Related Eye Disease Study Report No. 3. Ophthalmology 2000;107:2224-2232.Pieramici DJ, Bressler SB. Age-related macular degeneration and risk factors for the development of choroidal neovascularization in the fellow eye. Curr Opin Ophthalmol 1998;9:38-46.Age-Related Eye Disease Study Research Group. A randomized, 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;119:1417-1436.The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-1035.Omenn GS, Goodman E, Thornquist MD, et al. Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-1155.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

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