A. Epidemiology [1,2,3]

1. Major cause of blindness in developed nations
2. Most common cause of blindness in white Americans >65 years old
3. Deposition of drusen in macula, new blood vessel formation, progressive visual acuity loss
   1. AMD often leads to inability to read, recognize faces, and drive
   2. Severe visual loss occurs in ~10% of patients with AMD
   3. Of patients with blindness due to AMD, ~90% have wet (neovascular) form
4. Overall, dry or wet AMD in 1.6% of all persons, always age >50 years
   1. Prevalence age 55-64 0.2%
   2. Prevalence age 65-74 0.9%
   3. Prevalence age 75-84 is 4.6%
   4. Prevalence age >84 years is 13.1% [1]
5. ~10% of persons >65 years old have Drusen deposits, usually near macula
6. Risk Factors [2]
   1. Similar to those for cardiovascular disease [4]
   2. Age is most important risk factor (hence the name of the disease)
   3. Smoking increases AMD by 2-4X [5,6]
   4. AMD also increased with high cholesterol, obesity, hypertension, increased pulse pressure
   5. Inflammation believed to contribute strongly to AMD progression
   6. Increased C-reactive protein (marker for systemic inflammation) associated with AMD [4]
   7. Complement factor H (an inhibitor) polymorphism ascocatied with increased >2X risk for AMD [17]
   8. Complement C3 variant associated with 1.7X (heterozygotes) and 2.6X (homozygotes) increased risk for AMD [22]
   9. Dietary intake of antioxidants (Vitamins C and E, zinc, ß-carotone) inversely related to risk of AMD [3]
7. Progression of AMD associated with polymorphisms in CFH and LOC387715 genes [21]

B. Characteristics
[Figure] "Schematic of the Eye"

1. Types
   1. Non-Neovascular (dry) - usually early stage, with less visual acuity decline
   2. Neovascular (wet) - usually later stage, with more visual acuity decline, blindness
   3. Still controversial about whether the dry and wet forms are really the same disease
   4. Dry and wet forms can be found in the same patient in different eyes
   5. Dry and wet forms can morph into each other over time
2. Disease Stages
   1. Early: minimal visual impairment, large drusen, pigmentary abnormalities
   2. Late: two forms - atrophic (non-neovascular) and neovascular (exudative) forms
3. Dseases Characterized by Macular Changes
   1. Macula is central area of neural retina responsible for high acuity vision
   2. Bruch's membrane separates retinal pigment epithelium (RPE) from choroid
   3. AMD involves disruption of Bruch's membrane
   4. Focal deposition of extracellular material called drusen under RPE underlies pathology
   5. This drives new blood vessel formation (neovascularization) into macula
4. AMD ssociated with ~1.9X increased risk of stroke [16]

C. Pathophysiology [2]

1. Diseases of outer retina and choroid
   1. Deterioration of central portion of the retina
   2. Associated with senescent changes and drusen deposition
   3. Drusen deposition under RPE leads to localized atrophy or subretinal neovascularization
   4. RPE is the central element in pathogenesis of AMD
2. AMD Risk Factors
   1. Age
   2. Smoking within 20 years
   3. Family history / genetic factors
   4. Factor H (a complement inhibitor) polymorphisms (Tyr302His) independent AMD risk [17]
   5. White race
   6. LOC387715?ARMS2, Ala69Ser variant
   7. Obesity
   8. High dietary intake of vegetable fat
   9. Low dietary intake of antioxidants and zinc
   10. Inflammation is important component of AMD
3. Retinal Pigment Epithelium (RPE)
   1. Post-mitotic, cuboidal monolayer of cells, very high metabolic rate
   2. Numerous melanosomes within cytoplasm
   3. Functions to regenerate bleached visual pigments, especially rhodopsin
   4. Key in formation and maintenance of both Bruch's membrane and interphotoreceptor matrix
   5. Role in transport of fluids and ions between photoreceptors and choriocapillaris
   6. Capable of phagocytosis, essential for renewal of photoreceptors
   7. Tips of photoreceptors are shed from outer segments and engulfed and degraded by RPE
   8. Lipofuscin accumulation in RPE blocks lysosomal function, may herald RPE death
   9. Chromophores, which increase with age, also impair RPE lysosomal function
   10. Injured RPE attract dendrites from choroidal dendritic cells
   11. These choroidal dendritic cells constitute ~40% of drusen
4. Drusen Components
   1. Complement components (C') and regulators
   2. Immunoglobulins
   3. Anaphylatoxins
   4. Various chromophores, which can occupy ~20% of RPE cells (see above)
   5. Drusen Sizes: small (<63µm diameter), medium (63-124µm), or large (>124µm)
5. Abnormalities in Extracellular Matrix [7]
   1. Mutations in various fibulin genes associated with relatively rare forms of AMD
   2. Fibulins contain calcium binding domains that mediate interactions with elastin, laminin
   3. Bruch's membrane is a complex of extracellular matrix with elastic properties
   4. Bruch's membrane contains cross-linked elastic fibers in a collagenous matrix
   5. Various fibulin mutations are linked with phenotype of drusen
   6. Fibulin 5 mutations lead to many small drusen called basal laminar or cuticular drusen [11]
   7. Fibulin 5 missense mutations found in 1.7% of AMD cases [11]
6. May be related to juvenile onset macular degeneration, Stargardt's Disease
   1. Gene for Stargardt's Disease cloned, autosomal recessive inheritance (ABCR gene)
   2. AMD may be due, in part, to heterozygous loss of ABCR function
   3. ABCR protein is an ATP dependent pump protein

D. Non-Neovascular AMD

1. Also called geographic atrophy
   1. Begins with round or oval hypopigmented spot, often juxtafovial
   2. Large choroidal vessels often visible in the hypopigmented spot
   3. Initial symptoms usually gaps in image (as if letters dropped out of line of text)
2. Drusen
   1. Pale, yellow-white deposits with amorphous, ill-defined borders = soft drusen
   2. Located between the RPE basement membrane and Bruch's membrane
   3. Contain vesicles and abnormal collagen on electron microscopy
   4. Apparent only when RPE becomes hypopigmented (diffuse drusen)
   5. Also apparent with serous RPE detachement (soft drusen)
   6. Not associated with visual acuity loss unless atrophy occurs
   7. However, soft drusen are a significant risk factor for subsequent develpment of choroidal neovascularization
3. Atrophy of RPE
   1. Multifocal areas of depigmented RPE; most prevalent in 8th-9th decades
   2. Often with focal clumps of hyperpigmentation, thinning of overlying senory retina
   3. Atrophy may be due to replacement of Drusen by fibrous tissue and dystrophic calcification
   4. Bruch's membrane calcifies and doubles in thickness between ages 10 and 90 years
   5. Beginning age ~30, lipid accumulates in Bruch's membrane
   6. WIth calcification, lipid deposition, thickening, fluid permeability severeal compromised
   7. These changes cause inflammation and/or inhibition of RPE, leading to atrophy of RPE
   8. Atrophy of central macula leads to visual loss (central scotoma) = geographic atrophy
4. Apoptosis of Photoreceptors [9]
   1. Intense light causes damage and apoptosis of photoreceptors
   2. Retinal hypoxia combined with less intense light also induces damage, apoptosis
   3. Erythropoietin (EPO) may be protective against photoreceptor apoptosis
   4. However, EPO can stimulate neovascularization which is detrimental to vision

E. Neovascular

1. Choroidal Neovascularization (CNV)
   1. Soft drusen appears to predispose to breaks in Bruch's membrane, detaching from RPE
   2. Drusen may cause serous or hemorrhagic fluid leakage, causing these breaks
   3. Detachment disturbs fine arrangement of photoreceptors, leading to image distortion
   4. This image distortion is called metamorphopsia, usually first symptoms of wet AMD
   5. Detachment leads to ingrowth of choroidal capillaries (neovascularization)
   6. New vessels can leak or bleed, leading to vision-threatening complications
2. Complications of Neovascularization
   1. Detachment of RPE from Bruch's Membrane
   2. Detachment of sensory retina
   3. Subretinal Hemorrhage - appears grey/green in color
   4. Lipid Preciptiations in retina
3. Disciform Scarring
   1. Fibrocytes accompany choroidal neovascularization (CNV)
   2. Laying down of fibro(vascular) tissue
   3. RPE and Photoreceptors destroyed
   4. Usually produces severe visual loss
   5. If associated with hemorrhage, can appear to be choroidal melanoma
4. Symptoms of CNV Changes
   1. Retinal Detachment leading to Metamorphopsia (detect on Amsler Grid)
   2. Hemorrhage with sudden onset of Central Scotomas (difficult for patient to identify)
   3. Gradual blurriness due to macular edema
   4. Severe central visual loss (usually from disciform scarring)

F. Differential Diagnosis of CNV

1. AMD - drusen are characteristic
2. Ocular Histoplasmosis
3. Severe Myopia leads to Lacquer Cracks
4. Angioid Streaks
   1. Pseudoxanthoma Elasticum
   2. Paget's Disease
   3. Sickle Cell Retinopathy
5. Trauma (blunt) with choroidal rupture
6. Excessively hot laser photocoagulation

G. Treatment

1. Non-Neovascular AMD
   1. Drusen - educate patient to monitor activity with Amsler grid; report changes quickly
   2. Atrophy - low vision aides
   3. Antioxidants - daily anti-oxidants (PreserVision®) reduced progression 25% over 5 years [1]
2. Neovascular AMD
   1. Fluorescein angiography to deliniate location and extent of CNV
   2. Treat with intense, confluent laser photocoagulation if area away from fovea
   3. Photodynamic therapy with verteporfin (Visudyne®) is also effective [8]
   4. Limitations: ~50% CNV have foveal center involved, poorly demarkated boundaries
   5. Frequent recurrence (~25%) of CNV to foveal center; need frequent follow up
   6. Inhibitors of vascular endothelial growth factor (VEGF) are active in neovascular AMD
   7. VEGF inhibitors may also be effective in diabetic retinopathy with neovascularization [13]
   8. Pegaptinib is approved (see below)
   9. Ranibizumab is approved (see below)
   10. Bevacizumab (Avastin®) is a full anti-VEGF mAb and is used off-label for wet AMD
   11. Thalidomide and Interferon alpha are being studied to suppress vascularization
3. Pegaptanib (Macugen®) [14]
   1. Anti-VEGF aptamer FDA approved for intravitreous injection for neovascular AMD
   2. Injected into each eye once every 6 weeks for 48 weeks slowed progression of neovascular ARMD compared with sham injection [12]
   3. Efficacy decreased in second year
   4. Inflammation, vitreous floaters and vitreous opacities occur
   5. Serious adverse effects: endophthalmitis (1.3%), retinal detachment (0.7%), cataract (0.6%)
4. Ranibizumab (Lucentis®) [13,18,19,20]
   1. Monoclonal anti-VEGF Ab fragment
   2. Most effective therapy currently available with clear data for up to 2 years
   3. Superior to verteporfin
   4. Intravitreal injection of 0.3mg or 0.5mg monthly for at least 1 year
   5. Serious adverse effects: endophthalmitis (1.4%), uveitis (0.7%)
   6. FDA approved for wet AMD
5. Disciform Scarring
   1. Almost always in central macula
   2. Assess low vision score
   3. At present, lost photoreceptors cannot be restored
   4. Experimental RPE and photoreceptor transplant studies in very early stages
6. Laser Therapy for Extrafoveal CNV [15]
   1. 5 years after diagnosis - 64% severe visual loss in untreated
   2. 5 years after diagnosis - 47% severe visual loss in treated
   3. Thus, ~25% reduction in blindness for treated patients
7. Laser Therapy for Subfoveal CNV [15]
   1. 2 years after diagnosis - 37% loss of 6 lnes of acuity in treated
   2. 2 years after diagnosis - 20% loss of 6 lnes of acuity in untreated
   3. However, large loss of visual acuity in treated patients due to closeness to fovea
   4. Difficult decision initially to treat these patients
   5. Photodynamic therpay with laser + verteporfin is more effective than laser alone [8]
   6. Laser therapy is not effective for nonneovascular ("dry") AMD
8. Diet
   1. High carotenoid intake decreased risk of developing advanced AMD in one study
   2. Vitamin A, C or E intake was not related to development of advanced AMD
   3. Zinc oxide (80mg/d) in combination with vitamins C and E may retard progression [10]
   4. Dietary intake of Vitamins C and E, zinc and ß-carotene inverseley related to AMD risk [2]
   5. Recommend that patients eat a balanced diet with fruits and leafy vegetables
   6. Consider supplements of vitamins A, C, ß-carotene, copper and zinc (PreserVision®)
9. Investigational Treatments
   1. Submacular Surgery - areas of CNV and blood are excised from subretinal space
   2. External beam radiation therapy
   3. Thalidomide - has anti-angiogenic activity
   4. Transplantation - retina or retinal pigment epithelial; highly experimental
   5. Retinal translocation
   6. Retinal prosthesis - highly experimental
   7. Anti-angiogenic agents - including antisense compounds, other VEGF antagonists
   8. Cholesterol Reduction - high cholesterol levels may increase risk of developing AMD

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