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.

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.

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.

For the wet form of the disease, anti-

vascular endothelial growth factor

(VEGF) treatments have been very

effective in preventing severe vision loss.

Classification

Macular degenerative changes have typically been

classified into two clinical forms, dry or wet, both of which

can lead to visual loss.

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.

In the wet form, vision loss can appear to occur suddenly,

when a choroidal neovascular 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.

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.

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.

Risk Factors

1. Age 8. Cup-to-disc ratio 15. Cardiovascular diseases

2.Gender 9. smoking 16. Blood pressure and hypertension

3. Race / ethnicity 10.Antioxidants,vitamins, and minerals

17. Cholesterol levels and dietary fat intake

4. Socioeconomic status 11. Alcohol intake 18. Diabetes and

hyperglycemia

5. Refractive error 12. Obesity and physical activity

19. Hormonal and reproductive factors

6. Iris color 13. Sun light exposure 20. Inflammatory factors

7.Lensopacities,cataracts, and cataract surgery 14. Medications 21. Genetic factors

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.

Lutein and zeaxanthin, in

particular, are associated

with macular pigment.

Trace minerals such as zinc, selenium, copper, and

manganese may also be involved in antioxidant

functions of the retina.

Antioxidants could prevent oxidative damage to

the retina, which could in turn prevent

development of AMD.

Damage to retinal photoreceptor cells could be

caused by photo-oxidation or by free radical-

induced lipid peroxidation.This could lead to

impaired function of the RPE and eventually to

degeneration involving the macula.

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.

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.

Both zinc alone and antioxidants and zinc

together significantly reduced the odds of

developing advanced AMD in participants

with intermediate signs of AMD

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).

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.

AREDS-type supplements are a cost-effective way of

reducing visual loss due to the progression of AMD.

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.

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.

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.

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.

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.

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.

A prospective follow-up study has shown

that fruit intake is inversely associated with

exudative AMD.

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.

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.

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.

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.

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.

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.

Refractive error

Several case–control studies have shown an association

between AMD and hyperopia.

This association, therefore, might implicate

structural and mechanical differences that render

some eyes predisposed to maculopathy.

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.

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.

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.

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

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 .

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.

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.

Smoking

The preponderance of epidemiologic evidence indicates a

strong positive association between both wet and dry AMD

and smoking.

Smoking is an important, independent,

modifiable risk factor for AMD.

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.

Alcohol intake

Studies that have examined the relationship between AMD

and alcohol consumption have yielded mixed results.

In the EDCCS, no significant relationship

between alcohol intake and exudative AMD

was noted in univariate analyses.

In a case–control study using

NHANES I data, moderate wine

consumption was associated with a

decreased risk of developing AMD.

In a large prospective study, no support was found for a

protective association between moderate alcohol

consumption and risk of AMD, although there was a

suggestion of a modest increased risk of AMD in heavier

drinkers.

The evidence to date suggests that alcohol intake does

not have a large effect on the development of AMD.

Obesity and physical activity

There is an association between AMD and overall

obesity and abdominal adiposity.

Obesity and physical activity are modifiable factors

that may alter an individual's risk of AMD incidence

and progression.

Sunlight exposure

The literature to date regarding the association between

sunlight exposure and AMD is conflicting. Overall, the data

do not support a strong association between ultraviolet

radiation exposure and risk of AMD, although a small effect

cannot be ruled out.

Medications

Some studies have shown borderline statistically

significant associations between increased risk of early

AMD with use of antihypertensive medication, especially

beta-blockers.

Other studies have shown a decreased rate of CNV

among AMD patients taking aspirin or cholesterol-

lowering drugs such as statins.

Cardiovascular diseases

Some studies have suggested an association between

AMD and clinical manifestations of cardiovascular disease

(CVD).

Blood pressure and hypertension

The role of blood pressure in the etiology of AMD remains

unclear.

Cholesterol levels and dietary fat intake

There is some evidence linking cholesterol level to AMD,

but not all results are consistent.

A case–control study showed that higher HDL

cholesterol levels tended to reduce the risk of

AMD.

Dietary fat intake was associated with an elevated

risk of exudative AMD in the Dietary Ancillary

Study of EDCCS.

A high intake of fish and omega-3 fatty acids reduced the

risk when linoleic acid intake was low.

Nuts have also been shown to decrease the risk of AMD

progression.

Diabetes and hyperglycemia

Many studies have investigated the relationship between

diabetes and/or hyperglycemia and AMD, and most have

found no significant relationships.

One difficulty with these studies is the uncertainty of

diagnosing AMD in the presence of diabetic retinopathy.

Also, many studies of AMD exclude persons with

diabetic retinopathy.