Transcript Age-related Macular Degeneration and Acquired Macular

Current Concepts in Agerelated 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
[email protected]
Course Outline
Epidemiology
Risk factors
Biology of AMD
Evidence based studies
Diet/nutritional components to AMD
Clinical application/recommendations
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”
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
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Epidemic of diabetes
Cardiovascular disease
Treatments target the end stage of disease
Accounts for $68 billion in direct costs in the US
AMD and Functional Vision
Reduced Central VA
Central
metamorphopsia
Decreased contrast
Decreased color
20/40
20/80
20/200 or
worse
Driving privileges
Reading newspaper
print
Difficulty reading
large print
Legal blindness
Face recognition is
difficult
Ability to live
independently
is threatened
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.
The Aging Phenomenon
Age-dependent Diseases causing
loss of Independence – Alliance for Aging
Alzheimer’s and related demented
disorders
Eye Disease
 AMD
 Diabetic Eye Disease
 Glaucoma
Osteoporosis
Epidemiology
Prevalence/Incidence
Several studies provided information concerning the
matter:
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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.
Blindness from AMD – A Growing Problem
U.S.
2003
2030
Projected
Number of Legally Blind
New Cases Annually
1.2 Million
6.3 Million
200,000
500,000
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
Risk Factors
Genetic
Race
Gender
Age
Hypertension/Diabetes
Refractive error
Lens opacities
Sun exposure
Smoking
Risk Factors
Genetic
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Studies have demonstrated familial aggregation.
ABCR gene (linked to Stargardt’s 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
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Protective form of the gene exists
Risk Factors
Race
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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
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In the Beaver Dam study, only wet AMD was shown to
be more frequent in women.
Age
AMD Is Directly Related To Age
30%
12%
55 to 64
16%
65 to 74
Over 75
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
Risk Factors
Hypertension
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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
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Beaver Dam showed no relation, however,
literature on the matter is otherwise scant.
Ocular Risk Factors
Refractive error
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Increased risk with hyperopia
Lens opacities
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Beaver Dam revealed nuclear sclerosis
associated with increased risk of early AMD but
not late stages of the disease.
FES found no relationship.
Aphakia
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In studies of unilateral aphakia, surgical eye had
more advanced disease when compared to
contralateral eye.
Environmental Risk Factors
Sun exposure – controversial risk factor
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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.
Environmental Risk Factors
Smoking
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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.
AMD IS A MULTIFACTORIAL
DISEASE
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.
What About Diet and
Nutrition?
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
20:1 imbalance W6:W3 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)
Obesity Trends* Among U.S. Adults
1990
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data
www.cdc.gov
<10%
10%–14%
15%–19%
20%–24%
≥25%
Obesity Trends* Among U.S. Adults
2004
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data
www.cdc.gov
<10%
10%–14%
15%–19%
20%–24%
≥25%
AMD - Classification
Nonexudative (geographic, non-neovascular,
“dry”) involves outer retinal complex
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Choriocapillaris
RPE
Photoreceptors
Exudative (neovascular, “wet”)
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Choroidal NV
Serous or hemorrhagic neurosensory or RPE
detachment
Both types can lead to visual loss
Classification & Definition
2 clinical forms:
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Dry
Both
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Exudative
types can lead to visual loss.
Currently less than 1% is successfully treated
Dry AMD: Natural Course
Drusen
↓
RPE cell change (apoptosis)
↓
2ary atrophy of the choriocapillaris
↓
2ary atrophy of the outer retina
↓
Geographic atrophy
Choroidal Neovascular Membrane
Clinical features
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hemorrhage
lipid exudation
serous elevation of RPE and sensory
retina
subretinal hemorrhage
gray or green (dirty brown) lesion
(appearance as seen through the RPE)
Wet AMD
Subretinal Fibrosis
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.
Clinical Features of Exudative AMD
Occult CNVM (70% of CNVM)
- 2 patterns recognized:
-Fibrovascular PED
-Late leakage of undetermined source
Clinical Features of Exudative AMD
RPE elevation
VEGF
A naturally occurring protein
Stimulates angiogenesis
Proinflammatory
Macugen is the only FDA approved at this point to treat
AMD
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Others being studied
Current route of administration is injection
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IV administration likely to be next
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.
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
Age Related Macular Degeneration:
A Pervasive Problem…An Elusive Solution
Oxidative damage to the retina may be a
causative factor.
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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, placebocontrolled clinical trial was clear.
NEI AREDS Study began
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.
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®
Population Classifications Utilized in Study
Category 1:
Category 2:
Category 3:
Category 4:
No AMD: Essentially free of AMD, with less than 5 small
drusen (<63 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
<20/32 vision and AMD abnormalities sufficient to explain
reduced visual acuity.
No AMD - Very Low Risk
Category 1 - No or Few Drusen
Early AMD - Low Risk
2 % 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.
Intermediate AMD
Category 3 – large drusen
Advanced AMD
Neovascular
Geographic Atrophy
AREDS: US Public Health Impact
Estimate the 5 year risk reduction with
an intervention with an (OR of 0.75) or
25 % risk reduction.
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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.
Primary Vision Outcome
Estimated Probability
3 or More Line VA Loss—AMD Categories 3 and 4
40%
Placebo
Antioxidants
Zinc
Antioxidants + Zinc
30%
29%
20%
23%
10%
0%
A 19% Risk
Reduction
0
1
2
3
4
Years
5
6
7
Data on file, AREDS.
Progression to Advanced AMD
Estimated Probability
AMD Categories 3 and 4 by Treatment Group
40%
Placebo
Antioxidants
Zinc
28%
Antioxidants + Zinc
30%
20%
20%
10%
P vs. A+Z – p<0.01
0%
A 25% Risk
Reduction
0
1
2
3
4
Years
5
6
7
Data on file, AREDS.
AREDS - AMD TRIAL
NEI 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
AREDS
10/12/01 press release
“The supplements are not a
cure for AMD, nor will they
restore vision already lost from
the disease”………..
AREDS Recommendations
Supplement
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Intermediate AMD
Advanced AMD
Excellent Safety
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Avoid beta carotene in
smokers
Encourage adherence
Data on file, AREDS.
Intermediate
Advanced
Treatment Options for Dry AMD
Dry Macular Degeneration
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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
Chance of Progressing to
Advanced AMD
15 - 18%
0.3
Probability
of Advanced
AMD
Advanced
AMD
0.2
0.1
0
1
2
3
4
5
Years
15% - 18% of intermediate AMD patients will
progress to advanced AMD within 5 years
Source: Arch Ophthalmology, October, 2001
Current Atrophic AMD intervention
Decrease smoking
Avoid obesity
Exercise
Avoid exposure to bright sunlight
(blueblockers-yellow tint)
Increase plant food (spinach) consumption
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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)
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
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
Lycopene
Carotenoid found in tomatoes
Ten times more potent than Vitamin E
Inherent putative anti-inflammatory effects
Thought to be protective for:
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AMD
Prostate disease
Cancers
Cardiovascular disease
National Eye Institute
AREDS 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
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4,000 patients
40-60 sites
5 year study duration
Start date: April 2006
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
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Remove beta-carotene due to risk to smokers
Reduce zinc from 80mg to 40mg daily
Concern re: ? Risk for Alzheimer’s disease
AREDS II
Randomized, clinical,
trial
Lutein/Zeaxanthin
Lutein/Zeaxanthin
Omega-3 Fatty Acids
Begin 2006
DHA/EPA
AREDS II Local Sites
Beth Israel Deaconess Medical Center
Boston, MA
Jorge Arroyo, MD, MPH
617-667-3391
Massachusetts Eye and Ear Infirmary
Boston, MA
Johanna Seddon, MD
617-573-4010
New England Medical Center
Boston, MA
Elias Reichel, MD
617-636-5489
Ophthalmic Consultants of Boston
Boston, MA
Jeffrey Heier, MD
617-314-2608
Zeaxanthin and Lutein May Help to
Reduce Oxidative Stress
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
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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
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
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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
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.
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
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www. MedOp.com “Whole Body Formula”
1-800-358-7797
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www. Lef.org “Two per day” –superior to Centrum®
1-800-544-4440
Fish (sardines, herring, salmon, chunk tuna) or cod liver oil
Healthy Life Style
Diet
Exercise
Smoking
Alcohol consumption
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French paradox
Blood pressure/lipid profile
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
QUESTIONS
THANK YOU