Anthony Cavallerano, OD, FAAO

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Current Concepts in Age-related Macular
Degeneration and Nutrition
University of Milan at Bicocca June 2007

• Anthony Cavallerano, OD, FAAO
• VA Boston Health Care System
• New England College of Optometry
• Boston, Massachusetts
• Anthony.cavallerano_at_va.gov

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Course Outline

• Epidemiology
• Risk factors
• Biology of AMD
• Evidence based studies
• Diet/nutritional components to AMD
• Clinical application/recommendations

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Age-related Macular Degeneration

• 1874 - described in medical literature
• symmetrical central choroido-retinal disease
  occuring in senile persons
• Alternaltely referred to as senile,
  diskiform, or macular degeneration.
• 1980 age-related maculopathy
• End stage age-related macular degeneration

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Vision Impairment and Eye Disease

• A major public health problem
• Growing ever larger with the aging of the US
  population
• Disproportionately incident in underserved and
  minority populations
• A significant co-morbid condition
• Epidemic of diabetes
• Cardiovascular disease
• Treatments target the end stage of disease
• Accounts for 68 billion in direct costs in the
  US

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AMD and Functional Vision

• Reduced Central VA
• Central metamorphopsia
• Decreased contrast
• Decreased color

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Age-related Macular Degeneration

• Leading cause of irreversible blindness in older
  individuals in developed countries.
• In the US and other developed countries around
  the world it is reaching epidemic levels
• Patients with mild or moderate forms of the
  disease can develop metamorphopsia and visual
  impairment, whereas those with the advanced
  stages often experience loss of central vision
  leading to legal blindness.

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The Aging Phenomenon
Age-dependent Diseases causing loss of
Independence Alliance for Aging

• Alzheimers and related demented disorders
• Eye Disease
• AMD
• Diabetic Eye Disease
• Glaucoma
• Osteoporosis

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EpidemiologyPrevalence/Incidence

• Several studies provided information concerning
  the matter
• NHANES
• FRAMINGHAM EYE STUDY
• WATERMEN
• BEAVER DAM
• ROTTERDAM
• BLUE MOUNTAIN
• RURAL ITALY
• Prevalence
• In the US, 15 million people are affected
• 13.5 million with dry type
• 1.5 million with wet type
• As many as 200,000 new cases of neovascular (wet)
  AMD are diagnosed in the United States each year
  accounting for 90 of severe vision loss.
• No accepted treatment exists for millions of
  patients with (dry) AMD.

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Blindness from AMD A Growing Problem
As the population ages and lives longer, the
number of people suffering severe vision loss
will increase dramatically
Pharmacological Treatments for AMD, L.
Singerrman, M.D. Review of Ophthalmology,
10/03 Vision Problems in the U.S., Prevent
Blindness America, 1994
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Risk Factors

• Genetic
• Race
• Gender
• Age
• Hypertension/Diabetes
• Refractive error
• Lens opacities
• Sun exposure
• Smoking

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Risk Factors

• Genetic
• Studies have demonstrated familial aggregation.
• ABCR gene (linked to Stargardts disease) has
  been linked to some cases of AMD.
• Complement factor H Gene
• Proteins in CFH pathway found in drusen deposits
• Two- to four fold increased risk if gene variant
  is inherited from one parent
• Five- to seven fold increased risk from 2 parents
• Hagerman studied 3200 eyes with dry AMD
• Genetic component found in 75 of eyes
• Gene accounts for 30 to 50 of overall risk for
  developing AMD
• Protective form of the gene exists

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Risk Factors

• Race
• NHANES III reported a higher frequency in whites
  compared with blacks.
• In Baltimore Eye Survey AMD accounted for 30 of
  blindness among whites and 0 of blindness among
  blacks.
• Gender
• In the Beaver Dam study, only wet AMD was shown
  to be more frequent in women.
• Age

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AMD Is Directly Related To Age
Incidence of AMD Increases With Age
1 Beaver Dam Study Source Yanoff
Ophthalmology, First Edition, 1999 Clinical
Practice Guidelines, www.aoanet.org
www.allaboutvision.com
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Risk Factors

• Hypertension
• Role remains unclear
• Beaver Dam reported that systolic BP was
  associated with incidence of RPE depigmentation.
• Macular Photocoagulation Study reported an
  increased incidence of wet AMD associated with
  hypertension, in the 2nd eye of individuals with
  the disease in one eye at baseline.
• Diabetes
• Beaver Dam showed no relation, however,
  literature on the matter is otherwise scant.

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Ocular Risk Factors

• Refractive error
• Increased risk with hyperopia
• Lens opacities
• Beaver Dam revealed nuclear sclerosis associated
  with increased risk of early AMD but not late
  stages of the disease.
• FES found no relationship.
• Aphakia
• In studies of unilateral aphakia, surgical eye
  had more advanced disease when compared to
  contralateral eye.

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Environmental Risk Factors

• Sun exposure controversial risk factor
• Watermen study revealed a weak association
  between advanced AMD and exposure to visible
  light.
• UV light did not seem to be related in the Beaver
  Dam, Watermen and Blue Mountain studies.

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Sun Exposure
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Environmental Risk Factors

• Smoking
• Strong positive association between smoking and
  the dry and wet form.
• In the Nurses Health Study risk increased as
  pack years of smoking increased indicating a dose
  dependent relationship.

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AMD IS A MULTIFACTORIALDISEASE

• Genetic Factors Chr. 1, 2, 5, 9 22
• Cardiovascular Factors
• Environmental Smoking, nutrition and
• sunlight exposure Hx

50 percent of AMD can be explained by variations
in a gene called Complement Factor H (CFH). This
gene makes a protein that regulates the immune
and inflammatory responses of the body.
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What About Diet and Nutrition?
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USA Dietary Patterns (1890-2006)

• High simple carbohydrate consumption
• Soda -3.5 cans/day (only 25 diet) - started
  in 1890
• White Flour Baked goods - started in 1890
• Potatoes - French Fries as 1 vegetable
• Low Fruit Vegetable (micronutrient/fiber)
  consumption
• 201 imbalance W6W3 fatty acids
• 5-10 calories from trans fats
• Grain-fed fattened cows, pigs, chickens -and
  stable, (perhaps slightly lower ) saturated fat
  consumption
• Progressive increase in calories to 3700/capita
  in 1990s (fast food and meal
  super-sizing)

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Obesity Trends Among U.S. Adults1990
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 2024 25
www.cdc.gov
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Obesity Trends Among U.S. Adults2004
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 2024 25
www.cdc.gov
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AMD - Classification

• Nonexudative (geographic, non-neovascular, dry)
  involves outer retinal complex
• Choriocapillaris
• RPE
• Photoreceptors
• Exudative (neovascular, wet)
• Choroidal NV
• Serous or hemorrhagic neurosensory or RPE
  detachment
• Both types can lead to visual loss

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Classification Definition

• 2 clinical forms
• Dry

• Exudative

• Both types can lead to visual loss.
• Currently less than 1 is successfully treated

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Dry AMD Natural Course
Drusen ? RPE cell change
(apoptosis) ? 2ary atrophy of the
choriocapillaris ? 2ary atrophy of the outer
retina ? Geographic atrophy
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Choroidal Neovascular Membrane

• Clinical features
• hemorrhage
• lipid exudation
• serous elevation of RPE and sensory retina
• subretinal hemorrhage
• gray or green (dirty brown) lesion (appearance as
  seen through the RPE)

Exudative AMD
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Wet AMD
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Subretinal Fibrosis
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Clinical Features of Exudative AMD

• Classic CNVM (30 of CNVM)

-Pattern is mainly differentiated by FA
findings -Early phase reveals staining of a well
demarcated lesion. -Late phase reveals leak, at
times beyond the lesion borders.
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Clinical Features of Exudative AMD

• Occult CNVM (70 of CNVM)

- 2 patterns recognized -Fibrovascular
PED -Late leakage of undetermined source
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Clinical Features of Exudative AMD

• RPE elevation

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Clinical Features of Exudative AMD

• Heme in AMD
• Sub-RPE
• Sub-retinal
• Vitreous

• Other features
• Intraretinal and subretinal lipids
• Cystic changes in the sensory retina

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Exudative AMD Natural Course
Dry AMD
changes ?
?
CNVM CNVM Disciform scar ?
occult ? classic ? Disciform scar
?
?
PED PED
? ?
Serous RD
Serous RD
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VEGF

• A naturally occurring protein
• Stimulates angiogenesis
• Proinflammatory
• Macugen is the only FDA approved at this point to
  treat AMD
• Others being studied
• Current route of administration is injection
• IV administration likely to be next

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VEGF in the Normal Eye

• VEGF and VEGF receptors expressed in normal eye
• Receptors present in neural elements of inner
  retina
• High VEGF expression in retinal pigment
  endothelium
• Researchers hypothesize VEGF may be important for
  choriocapillaris survival and/or fenestrae
  maintenance
• Role of normal VEGF expression in the eye is
  unknown

Kim et al. IOVS. 1999 Witmer et al. Prog Ret
Eye Res. 2002 Adamis Shima. In press.
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VEGF in the Diseased Eye

• VEGF is implicated in
• Choroidal neovascularization (CNV)/ AMD
• Diabetic retinopathy
• Retinal vein occlusion
• Retinopathy of prematurity
• Corneal neovascularization
• Iris neovascularization

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Age Related Macular Degeneration A Pervasive
ProblemAn Elusive Solution

• Oxidative damage to the retina may be a causative
  factor.
• Until recently a lack of convincing clinical
  trial data had obscured a possible association
  between antioxidant/zinc supplementation and
  reduced AMD risk.
• The need for a large, randomized,
  placebo-controlled clinical trial was clear.
• NEI AREDS Study began

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Age-Related Eye Disease Study (AREDS)AMD Study
Objective

• To evaluate the effect of high-dose vitamins C
  and E, beta-carotene and zinc formulations on
  age-related macular degeneration (AMD)
  progression and visual acuity.

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AREDS AMD Study Protocol

• Double-masked trial
• Enrollment started November 1992
• Enrolled 3,640 study participants
• Subjects were 55-80 years of age
• Subject were followed every 6 months until April
  2001
• Average follow-up was 6.3 years
• 57 of subjects already taking multivitamins 67
  chose to add Centrum

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Population Classifications Utilized in Study
No AMD Essentially free of AMD, with less than 5
small drusen (lt63 u) and 20/32 vision or better
in both eyes Mild AMD Mild or borderline AMD
(multiple small drusen, single or nonextensive
intermediate drusen (63 or 124 u pigment
abnormalities, or any combination of these) in
one or both eyes, with 20/32 vision or better in
both eyes Moderate AMD Absence of advanced AMD
in both eyes and at least one eye with 20/32
vision or better with at least one large drusen
(125 u), extensive intermediate drusen,
geographic atrophy not involving the center of
the macula, or any combination of these Advanced
AMD Visual acuity of 20/32 or better and no
advanced AMD (geographic atrophy involving the
center of the macula or features of choroidal
neovascularization) in the study eye fellow eye
had either lesions of advanced AMD or lt20/32
vision and AMD abnormalities sufficient to
explain reduced visual acuity.
Category 1 Category 2 Category
3 Category 4
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No AMD - Very Low Risk
Category 1 - No or Few Drusen
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Early AMD - Low Risk2 rate of progression to
advanced AMD at 5 years
Category 2 - multiple small drusen, single or
nonextensive intermediate drusen (63 or 124 u)
pigment abnormalities.
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Intermediate AMD
Category 3 large drusen
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Advanced AMD
Neovascular
Geographic Atrophy
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AREDS US Public Health Impact

• Estimate the 5 year risk reduction with an
  intervention with an (OR of 0.75) or 25 risk
  reduction.
• 8 million at risk for advanced AMD
• 1.3 million would develop advanced AMD in the
  next 5 years
• 328,788 patients would avoid advanced AMD (2/3
  Neovascular and 1/3 geographic) with
  antioxidants.
• ARVO 2002 2903 Bressler et al.

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Primary Vision Outcome
3 or More Line VA LossAMD Categories 3 and 4
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Placebo
Antioxidants
Zinc
30
Antioxidants Zinc
Estimated Probability
20
10
0
0
1
2
3
4
5
6
7
Years
A 19 Risk Reduction
Data on file, AREDS.
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Progression to Advanced AMD
AMD Categories 3 and 4 by Treatment Group
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28
30
Estimated Probability
20
20
10
P vs. AZ plt0.01
0
0
1
2
3
4
5
6
7
A 25 Risk Reduction
Years
Data on file, AREDS.
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AREDS - AMD TRIALNEI Conclusions and
Recommendations

• If they have
• extensive intermediate-sized drusen,
• at least one large drusen,
• non-central GA in one or both eyes,
• advanced AMD in one eye, or
• vision loss due to AMD in one eye, and
• they are without contraindications (smoking)
• they should consider taking a supplement of
  antioxidants plus zinc such as that used
  in the AREDS study

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AREDS 10/12/01 press release

• The supplements are not a cure for AMD, nor will
  they restore vision already lost from the
  disease..

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AREDS Recommendations

• Supplement
• Intermediate AMD
• Advanced AMD
• Excellent Safety
• Avoid beta carotene in smokers
• Encourage adherence

Advanced
Intermediate
Data on file, AREDS.
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Treatment Options for Dry AMD

• Dry Macular Degeneration
• AREDS Approx 25 decrease
  in risk of developing wet when
  one eye already wet
• Would mean approx. 300,000
  less people per year developing wet
• Formulation Vitamin C 500mg,
• Vit. E 400IU, Beta Carotene
• 15mg Zinc 80mg, Copper 2mg
• Note Smokers unable to take
• formulation increase risk of lung cancer
• with high dose beta-carotene
  

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Chance of Progressing to Advanced AMD
15 - 18 of intermediate AMD patients will
progress to advanced AMD within 5 years
Source Arch Ophthalmology, October, 2001
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Current Atrophic AMD intervention

• Decrease smoking
• Avoid obesity
• Exercise
• Avoid exposure to bright sunlight
• (blueblockers-yellow tint)
• Increase plant food (spinach) consumption
• Follow www. MyPyramid.Gov SuperFoods Rx book
  by Steve Pratt, MD
• Avoid or control hypertension.
• Avoid high Fe(II) intake give blood 3x/year
• (Lutein based multivitamin/multimineral)
• Omega 3 fatty acids
• A glass of red wine and blueberries/cherries
• Soy (genistein), oranges, bananas vitamin D
  against neovascularization (wet AMD)

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14 Super Foods

• Blueberries
• Sardine
• Citrus
• Pumpkin
• Yogurt
• Oats
• Legumes

• Spinach
• Turkey Breast
• Broccoli
• Walnuts
• Tomato
• Green Tea
• Soy

Daily sunlight and/or 1000 IU vitamin D daily
also is very important for general health
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Additional Emerging Epidemiological Associations

• Cardiovascular Disease
• Plant Food Consumption
• Obesity and Physical Inactivity
• C-reactive Protein

• Fish nut intake
• (vs. trans fat)
• Aspirin ?
• Cholesterol yes statins ?
• Alcohol
• Iron status

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Lycopene

• Carotenoid found in tomatoes
• Ten times more potent than Vitamin E
• Inherent putative anti-inflammatory effects
• Thought to be protective for
• AMD
• Prostate disease
• Cancers
• Cardiovascular disease

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National Eye InstituteAREDS II Study

• The primary objective of AREDS II is to determine
  whether oral supplementation of lutein or
  omega-3, alone, together or in combination
  decrease the risk of progression to advanced AMD
  as compared to placebo
• 4,000 patients
• 40-60 sites
• 5 year study duration
• Start date April 2006

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AREDS II

• Effect on progression to Advanced AMD with lutein
  (10 mg and 2 mg of zeaxanthin) AND Omega-3 (1 gm
  daily)
• Refine formulation of original AREDS formula
  including
• Remove beta-carotene due to risk to smokers
• Reduce zinc from 80mg to 40mg daily
• Concern re ? Risk for Alzheimers disease

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AREDS II

• Randomized, clinical, trial
• Lutein/Zeaxanthin
• Omega-3 Fatty Acids
• Begin 2006

Lutein/Zeaxanthin
DHA/EPA
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AREDS II Local Sites

• Beth Israel Deaconess Medical CenterBoston,
  MAJorge Arroyo, MD, MPH 617-667-3391
  Massachusetts Eye and Ear Infirmary Boston,
  MAJohanna Seddon, MD617-573-4010 New England
  Medical Center Boston, MAElias Reichel, MD
  617-636-5489Ophthalmic Consultants of Boston
  Boston, MAJeffrey Heier, MD617-314-2608

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Zeaxanthin May Help to Reduce
Oxidative Stress
and Lutein
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Lutein (and Zeaxanthin)

• Anti-oxidant carotenoids in the vitamin A family,
  also known as xanthophylls
• Lutein can be converted to zeaxanthin in the body
  
• Most dominant pigments in the macular region of
  the retina
• Retinoprotective
• Lutein reduces blue light damage to
  photoreceptors by filtering blue light
• Protects against perioxidation of fatty acids in
  the photoreceptor membrane
• Protects the blood vessels supplying the macular
  region
• Protective for cataract

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LUTEIN BIOLOGICAL ACTIONS

• Only carotenoid found in ocular tissue
• Accumulates in both lens and macula
• Primary component of the yellow macular pigment
• Protects the macula by
• Filtering out blue light
• Acting as an antioxidant
• Providing structural integrity to photoreceptors
• The eye selectively concentrates Lutein (yellow
  colored pigment) in the macula region
• Macula Pigment Optical Density is the amount of
  Zeaxanthin Lutein in the macula
• The eye conserves these carotenoids

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KEY LUTEIN (macula pigment)

• Lutein is the key carotenoid in the diet.
• 6 mg. intake per day led to a 43 reduction in
  severe AMD prevalence (1994 JAMA study).
• Diet plays a role in lutein deposited in the
  macula.
• Lutein protects by blocking blue light and
  functioning as an antioxidant.
• AMD patients have less macula lutein in vivo or
  on autopsy.
• MPOD is 20 lower in females.
• MPOD is lower in individuals with light-colored
  irises.
• MPOD is lower in smokers.

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AREDS compatible Lutein based - Antioxidant
Supplements

• If you meet high risk AREDS criteria
• B L PreserVision w lutein gel caps 1 cap
  twice per day (or equivalent components dose
  used in the National Eye Institute AREDS study)
• General mail order comprehensive multivitamin
  with lutein
• www.PurityProducts.com Perfect MultiFormula
• 1-800-281-7781
• www. MedOp.com Whole Body Formula
• 1-800-358-7797
• www. Lef.org Two per day superior to Centrum
• 1-800-544-4440
• Fish (sardines, herring, salmon, chunk tuna) or
  cod liver oil

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Healthy Life Style

• Diet
• Exercise
• Smoking
• Alcohol consumption
• French paradox
• Blood pressure/lipid profile

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Conclusion

• Many new treatments
• Most likely will see combinations of different
  treatments along with more aggressive prevention
• Bottom line AMD is still debilitating, and we
  must be quick to diagnose, treat, and offer low
  vision when needed

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QUESTIONS

• THANK YOU