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  1. Age-related macular degeneration (AMD) is the leading cause of irreversible blindness.The disease adversely affects quality of life and activities of daily living, causing many affected individuals to lose their independence in their retirement years.

  2. Despite the introduction of new therapies for prevention and treatment of AMD, the prevalence of AMD is expected to increase by 97% by the year 2050.

  3. The only proven treatment available for the dry or nonexudative forms of this disease, comprising 85% of cases, is an antioxidant/mineral supplement which can slow the progression of the disease by 25% over 5 years.

  4. For the wet form of the disease, anti-vascular endothelial growth factor (VEGF) treatments have been very effective in preventing severe vision loss.

  5. Classification Macular degenerative changes have typically been classified into two clinical forms, dry or wet, both of which can lead to visual loss.

  6. In the early or intermediate dry forms visual loss is infrequent, and when it occurs it is usually gradual. Ophthalmoscopy reveals yellow subretinal deposits called drusen, or retinal pigment epithelial (RPE) irregularities, including hyperpigmentation or hypopigmentary changes. Larger drusen may become confluent and evolve into drusenoid RPE detachments. These drusenoid RPE detachments often progress to geographic atrophy and less frequently to neovascular AMD.

  7. In the wet form, vision loss can appear to occur suddenly, when a choroidalneovascular membrane leaks fluid or blood into the subpigment epithelial or subretinal space. Serous RPE detachments with or without coexisting choroidal neovascularization (CNV) are also classified as the wet form.

  8. Quality of life More recently in one study of well-being, patients with AMD had lower scores than patients with chronic obstructive pulmonary disease and acquired immunodeficiency syndrome (AIDS); the lower quality of life in patients with AMD was related to greater emotional distress, worse self-reported general health, and greater difficulty carrying out daily activities.

  9. Not only is AMD associated with a higher rate of depression in the community-dwelling adult population when compared to the unaffected adult population,but depression also exacerbates the effects of AMD.

  10. Risk Factors

  11. Antioxidants, vitamins, and minerals The role of antioxidant vitamins in the pathogenesis of AMD has received a great deal of attention. Antioxidants, which include vitamin C (ascorbic acid), vitamin E (alpha-tocopherol), and the carotenoids (including alpha-carotene, beta-carotene, cryptoxanthin, lutein, and zeaxanthin), may be relevant to AMD because of their physiologic functions and the location of some of these nutrients in the retina.

  12. Lutein and zeaxanthin, in particular, are associated with macular pigment.

  13. Trace minerals such as zinc, selenium, copper, and manganese may also be involved in antioxidant functions of the retina.

  14. Antioxidants could prevent oxidative damage to the retina, which could in turn prevent development of AMD.

  15. Damage to retinal photoreceptor cells could be caused by photo-oxidation or by free radical-induced lipid peroxidation.Thiscould lead to impaired function of the RPE and eventually to degeneration involving the macula.

  16. The deposit of oxidized compounds in healthy tissue may result in cell death because they are indigestible by cellular enzymes. Antioxidants may scavenge, decompose, or reduce the formation of harmful compounds.

  17. The AREDS confirmed that antioxidant and zinc supplementation can decrease the risk of AMD progression and vision loss. This study included a double-blind clinical trial in 11 centers around the USA, randomly assigning 3640 participants to take daily oral supplements of antioxidants, zinc, antioxidants and zinc, or placebo.

  18. Both zinc alone and antioxidants and zinc together significantly reduced the odds of developing advanced AMD in participants with intermediate signs of AMD

  19. The zinc supplement included zinc (80 mg) as zinc oxide, and copper (2 mg) as cupric oxide; the antioxidant supplement included vitamin C (500 mg), vitamin E (400 IU), and beta-carotene (15 mg).

  20. If the AREDS formulation were used to treat the 8 million individuals in the USA who are at increased risk for developing advanced AMD, the AREDS group authors estimate that more than 300,000 would avoid advanced AMD and the associated vision loss during the next 5 years.

  21. AREDS-type supplements are a cost-effective way of reducing visual loss due to the progression of AMD.

  22. The effect of dietary antioxidants on the incidence of early AMD has not been established and there are questions about the effect of beta-carotene supplements on AMD since there is none in the retina, and high doses of zinc could have side-effects.

  23. Diets high in antioxidant-rich fruits and vegetables may be related to a lower risk of exudative AMD. The first study launched to evaluate diet and AMD, the Dietary Intake Study, ancillary to the EDCCS, showed an inverse association between exudative AMD and dietary intake of carotenoids from foods.

  24. In that study reported in 1994, a diet rich in green leafy vegetables containing the carotenoids lutein and zeaxanthin was associated with a reduction in the risk of exudative AMD.

  25. A prospective double-masked study involving lutein and antioxidant supplementation in a group of 90 individuals showed that visual function was improved with 10 mg of lutein or a lutein/antioxidant formula.

  26. In a British study of 380 men and women, lower plasma levels of zeaxanthin were also found to be associated with an increased risk of AMD.

  27. A cross-sectional study using previously collected NHANES I data found a weak protective effect with increased consumption of fruits and vegetables rich in vitamin A.

  28. A prospective follow-up study has shown that fruit intake is inversely associated with exudative AMD.

  29. AREDS2, an ongoing trial of lutein, zeaxanthin, and omega 3 fatty acids and assessment of omission of beta-carotene and use of much lower doses of zinc for the prevention of AMD progression, may provide additional data regarding optimal vitamin supplement regimens for AMD patients.

  30. Age All studies demonstrate that the prevalence, incidence, and progression of all forms of AMD rise steeply with increasing age. There was a 17-fold increased risk of AMD comparing the oldest to the youngest age group in the Framingham Study.

  31. Gender Several studies have shown no overall difference in the frequency of AMD between men and women, after controlling for age. However, in NHANES III, men, regardless of race and age, had a lower prevalence of AMD than women.

  32. Race/ethnicity Overall, the literature to date suggests that early AMD is common among blacks and Hispanics, although less common than among non-Hispanic whites, whereas advanced AMD is much less common in these groups compared with non-Hispanic whites. Furthermore, differences in prevalence rates between non-Hispanic whites in different regions of the USA suggest that ethnicity is an important determinant of AMD.

  33. Socioeconomic status Less education and lower income have been shown to be related to increased morbidity and mortality from a number of diseases, and there are mixed findings for AMD.

  34. Furthermore, no associations were noted in another case–control study or in the FES, although different definitions of macular degeneration were used in those reports, compared with the more recent studies. It is possible that education is a surrogate marker for behaviors and lifestyles related to AMD.

  35. Refractive error Several case–control studies have shown an association between AMD and hyperopia.

  36. This association, therefore, might implicate structural and mechanical differences that render some eyes predisposed to maculopathy.

  37. Iris color Higher levels of ocular melanin may be protective against light-induced oxidative damage to the retina, since melanin can act as a free radical scavenger and may have an antiangiogenesis function.

  38. Lens opacities, cataracts, and cataract surgery Data regarding the relationship between cataracts and AMD are inconsistent. FES investigators found no relationship, whereas data from the NHANES did support a relationship between AMD and lens opacities. In the BDES, in which photographs of the lens and macula were graded, nuclear sclerosis was associated with increased odds of early AMD (OR 1.96; 95% CI 1.3–3.0) but not of late AMD. Neither cortical nor posterior subcapsular cataracts were related to AMD. A case–control study of 1844 cases and 1844 controls indicated that lens opacities or cataract surgery were associated with an increased risk of AMD.

  39. Although AMD-affected individuals reported better visual function and quality of life after cataract surgery, a history of cataract surgery has been found to be associated with an increased risk for advanced AMD in some earlier studies. Investigators have postulated that this association might arise because the cataractous lens can block damaging ultraviolet light.

  40. Inflammatory changes after cataract surgery may also cause progression of early to late AMD. In the BDES, previous cataract surgery at baseline was associated with a statistically significant increased risk for progression of AMD (OR 2.7) and for development of late AMD

  41. In the BDES, previous cataract surgery at baseline was associated with a statistically significant increased risk for progression of AMD (OR 2.7) and for development of late AMD .

  42. In more recent prospective studies, however, including the large AREDS study cohort, there was no evidence to support a higher rate of progression of AMD in patients who underwent cataract surgery.

  43. Cup-to-disc ratio The EDCCS demonstrated that eyes with larger cup-to-disc ratios had a reduced risk of exudative AMD. This effect persisted even after multivariate modeling, adjusting for known and potential confounding factors.

  44. Smoking The preponderance of epidemiologic evidence indicates a strong positive association between both wet and dry AMD and smoking.

  45. Smoking is an important, independent, modifiable risk factor for AMD.

  46. Mechanisms by which smoking may increase the risk of developing AMD include its adverse effect on blood lipids by decreasing levels of high-density lipoprotein (HDL) and increasing platelet aggregability and fibrinogen, increasing oxidative stress and lipid peroxidation, and reducing plasma levels of antioxidants.

  47. Alcohol intake Studies that have examined the relationship between AMD and alcohol consumption have yielded mixed results.

  48. In the EDCCS, no significant relationship between alcohol intake and exudative AMD was noted in univariateanalyses.