AGE-RELATED MACULAR DEGENERATION: CURRENT CONCEPTS
From the 26th Annual Current Concepts in Ophthalmology, presented by the San Diego Eye Bank
Peter Custis, MD, Assistant Chief of Ophthalmology, Kaiser Permanente, San Diego, CA
Dry (Nonexudative) Age-related Macular Degeneration (AMD)
| Clinical features: drusen—hard small (<64 µ; excrescences at Bruch’s membrane underlying retinal pigment epithelium
[RPE]), intermediate, or large soft (associated with greater risk for advanced complications); confluent drusen identified
on optical coherence tomography (OCT); calcified drusen; geographic atrophy—well-defined areas of RPE
dropout, allowing visualization of underlying choriocapillaris; serous retinal pigment epithelial detachment (RPED; RPE
layer lifted off Bruch’s membrane); seen on angiography as pooling of fluorescein dye, filling serous pigment epithelial
detachment (PED) in early frames, but maintaining shape of area in late frames without leakage beyond original borders
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| Risk factors: relative risk—family history and genetics most significant; also increasing age, smoking, elevated serum
homocysteine, blue eyes, hyperopia, and white ethnicity; genetics— ≈50% of patients with AMD have same genetic defect
on chromosome 1 in area that codes for complement factor H (CFH; protects against oxidative-related damage); defect
associated with increased risk for AMD, especially if both alleles affected; other genetic markers
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 | CFH: AMD—CFH found in retina and produced in RPE and liver; genetic defect on chromosome 1 involves single
amino acid that substitutes tyrosine for histidine, resulting in abnormal CFH; CFH normally binds heparin and C-reactive
protein to prevent uncontrolled complement activation in alternative pathway; abnormal CFH may predispose individual
to increased cell damage; study—high levels of C3 and C5 found in drusen of patients with dry AMD;
concluded complement system plays role in AMD etiology; analysis of drusen in patients with AMD show high levels
of some end products of complement cascade (factors C3 and C5); factor C3a and C5a found in drusen in patients with
wet AMD; C3a and C5a induce vascular endothelial growth factor (VEGF) production in vitro and in vivo; C3a and
C5a generated early in animal models of choroidal neovascularization (CNV); genetic ablation of receptors for C3a
and C5a reduce VEGF expression in animal models; “two-hit theory”—defect in CFH locus not enough to cause
AMD; smoking (tar can trigger formation of deposits in Bruch’s membrane), infection, and other mediating factors
thought involved in development of AMD
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| Nutritional supplements: literature review concluded herbal medicines of no value in treating eye diseases; Age-Related
Eye Disease Study (AREDS) regimen proved efficacious in patients with AMD; efficacy of lutein, zeaxanthin, and
omega-3 fatty acids unproven; AREDS—patients given high-dose antioxidants ( β-carotene, vitamins C and E) and
zinc; study showed loss of visual acuity 25% less in experimental group; patients with advanced AMD in both eyes
benefited from AREDS regimen; severity of AMD associated with increased risk for death from myocardial infarction
(MI); lutein and zeaxanthin— β-carotenoids found in macula; obtained from fruits and vegetables; filter out blue
light and protect rods and cones from oxidative stress; case-controlled data and observational data suggest higher dietary
levels of lutein may have some protective benefit; omega-3 fatty acids—form of docosahexaenoic acid (DHA);
may help rebuild photoreceptor cells and retinal cell membranes; observational data show high intake associated with
lower risk for wet AMD; AREDS formula risks—vitamin A use in smokers may slightly increase risk for lung cancer;
vitamin E associated with higher risk for cardiovascular disease in patients who had daily intake >800 IU; side effects
associated with herbal supplements and nutritional medicines
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| Apheresis: plasma filtered to remove high molecular weight proteins (eg, complement factors) that may or may not damage
choroidal microcirculation, then filtered blood returned to patient’s other arm; expensive procedure; phase 3 trial
sponsored by National Institutes of Health (NIH) halted for lack of efficacy
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| Statins: patients with AMD have higher risk for cardiovascular disease, and lipids may play role in risk; observational
studies suggested patients on cholesterol-lowering drugs may have decreased incidence of wet AMD; recent study
found no association between statins and lower risk for AMD
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| AREDS 2: new multicenter randomized prospective trial; looking at whether macular xanthophylls with or without
omega-3 fatty acids decrease risk for advanced AMD, whether eliminating β-carotene has negative impact on risk for
advanced AMD, and whether reduction in dose of zinc negatively affects risk for advanced AMD; includes only patients
that have advanced dry AMD or wet AMD in at least 1 eye; long-term study
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| Preferential hyperacuity perimetry (PHP): based on concept of hyperacuity (ie, Vernier acuity; ability to detect subtle misalignment
of object, compared to other objects in field of view); potential for use in detecting patients at greater risk for
more advanced dry AMD or early development of wet AMD; test tries to determine which patients with visual defects at
higher risk for advanced AMD; sensitivity (ability to detect advanced AMD and/or wet AMD when disease present)
80%; specificity (ability to rule out false positives) 85%; specificity not better than Amsler grid testing; role in management
currently uncertain; currently, 40% of patients presenting with wet AMD already legally blind at time of diagnosis;
need diagnostic test to detect these patients earlier or even detect patients at risk for AMD earlier, so intervention with
newer therapies possible before patients lose vision
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| Laser therapy: unknown whether reabsorption of drusen improves visual acuity and reduces risk for wet AMD
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| Anecortave: modified steroid; no steroid side effects; lasts ≈6 mo; inhibits proteases required for vascular endothelial cell
migration; study looking at whether anecortave reduces risk of developing CNV microcirculation in fellow dry eye in
patients with wet AMD
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| Ciliary neurotrophic factor (CNTF): natural neuroprotective protein protects against loss of photoreceptors; implant developed
that contains genetically modified human RPE cells with upregulated production of CNTF; surgically implanted
in eye to see whether it can prevent further visual acuity loss in patients with dry AMD and geographic
atrophy; unique meshwork allows diffusion of O2 into donor RPE cells and expression of CNTF into eye; implant acts
as barrier to prevent host immune system from attacking donor RPE cells
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Wet (exudative) AMD
| Clinical features: CNV defined by location and angiographic appearance; all forms of CNV contribute to vision damage;
classic CNV—early hyperfluorescence with late leakage; occult CNV—late leakage of undetermined source; fibrovascular
pigment epithelial detachment (FVPED)—occult CNV; refers to stippled hyperfluorescence appearing in earlier
frames and oozing in later frames; retinal angiomatous proliferation (RAP)—vascularization develops intraretinally, as
opposed to starting in choroidal area; proliferation develops within retina and gradually extends to subretinal space, eventually
forming anastomosis with choroidal circulation; has full-thickness choroidal neovascular membrane; polypoidal choroidal
vasculopathy—presents clinically with large area of hemorrhage and lipid; may see bulbous dilatations of
vasculature within choroid on angiography; end-stage disease—dry disciform scar with or without chronic exudative
changes with lipid, fluid, and blood; angiographic classifications— ≈20% of patients present with predominantly classic
lesions; ≈7% present with minimally classic lesions; 73% of patients present with occult lesions only
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| Cataract surgery: AREDS demonstrates no association between cataract surgery and risk for CNV
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| Pathogenesis: angiogenesis—various factors lead to development of angiogenesis, including VEGF; variety of agents
act to negate development of CNV; current theory—initiating stimuli lead to upregulation of VEGF; VEGF leads to development
of new vessels and CNV membranes, which results in recruitment of inflammatory cells that contribute to
breakdown of blood-retinal barrier; cyclic pathway; initiating stimuli unknown; contributing factors (eg, oxidative stress,
inflammatory damage, vasculopathy) lead to ischemia and damage to Bruch’s membrane; common pathway hypoxia inducible
factor (HIF) found in RPE cells and stimulates release of VEGF; VEGF—multifunctional protein; variety of
VEGF proteins (groups A,B,C,D,E and placental growth factor; VEGF-A most potent subtype in eye and in AMD; 5 isomers
of VEGF-A, most common isomer VEGF165 ; VEGF leads to vascular endothelial cell proliferation and helps maintain
existing new blood vessel growth, increases vascular permeability, and acts as chemotactic factor for macrophages;
VEGF upregulated in RPE and outer nuclear layer of rods and cones when CNV present; exerts its effects by binding to 2
types of tyrosine kinase receptors (VEGFR-1 and VEGFR-2) found on endothelial cells to start angiogenesis cascade
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| Treatment: involves efforts to block production of VEGF, interfering with VEGF already produced, trying to close off existing
blood vessels, and to reduce risk for inflammation and scar tissue that lead to end-stage disease; combination
therapy—CNV 2-component process; vascular component mediated by VEGF and others that cause production of new
blood vessels; extravascular component includes inflammatory cells and other factors that lead to end-stage disease; several
mediators present so >1 drug type appropriate; steroids—only therapy that targets end products of inflammatory
process and scar tissue; use continues in treatment of AMD
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| Thermal laser: designed to ablate abnormal blood vessels but also destroys photoreceptors; still may be appropriate for
membrane far enough removed from fovea
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| Transpupil thermotherapy: minimal benefit
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| Submacular surgery: more risks than benefits
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| Photodynamic therapy (PDT): intravenous (IV) injection of photosensitizing dye taken up by abnormal blood vessels;
low-energy laser light used to stimulate dye; results in formation of reactive O2 that damages abnormal blood vessels,
leading to thrombosis and CNV vessel occlusion; multiple treatments required to achieve benefit; best outcomes with
classic and smaller-sized lesions; consider use in combination therapy with steroids; studies show efficacy of PDT as
part of combination therapy 90% (however, large percentage of patients experience recurrence of disease); compared
to PDT alone, combination therapy offers better stabilization of vision and short-term improvement in vision in 10% to
20% of patients; cataracts and glaucoma potential side effects; patients begin to show atrophy in RPE, suggesting progression
of disease despite PDT, or delayed toxicity at follow-up; triamcinolone can cause toxicity to photoreceptors;
benefit of steroids may disappear if toxicity becomes issue 1 to 2 yr after treatment
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| Anecortave: no proven benefit in wet AMD
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| Pegaptanib (Macugen): aptamer (synthetic fragment of genetic material) that selectively binds VEGF165 ; requires intravitreal
injection; expensive; given every 6 wk for 1 to 2 yr; study data—overall, 15% reduction in vision loss, compared
to placebo; not associated with vision improvement; looking at pegaptanib as maintenance therapy to prevent
recurrence after PDT (selective anti-VEGF targeting)
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| Ranibizumab (Lucentis): study data—3 studies show ≈90% of patients experienced stability in vision loss, and up to
one third of patients had improvement in vision loss; excellent safety profile; not as many patients with improvement
in vision with less frequent dosing
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| Bevacizumab (Avastin): full-length humanized monoclonal antibody directed against 5 isomers of VEGF-A; given IV;
works to block development of new blood vessels; off-label use in wet AMD; systemic IV therapy effective in reducing
leakage in patients with wet AMD, but associated with hypertension and higher risk for thromboembolic events; study
group derived appropriate intraocular dose for intravitreal injection to circumvent side effects; found intravitreal injection
effective and reasonably safe in noncontrolled studies; advantages include similar efficacy, availability, and inexpensiveness;
disadvantages include off-label use, increasing potential for liability issues, unproven long-term safety and efficacy;
consider use as monotherapy, salvage therapy, in combination therapy, and in non-AMD diseases; because of 20-day half-
life, may space injections further apart (every 6 to 8 wk); studies show no safety concerns, eg, intraocular toxicity
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| Squalamine (Evizon): first drug in class of naturally occurring molecules called aminosterols synthesized chemically;
acts within endothelial cells to inhibit VEGF nonselectively and other angiogenesis mediators; given IV q 4 wk; results
of phase 1 and 2 trials show 25% improvement in vision and favorable stability
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| VEGF trap: soluble decoy receptor has VEGF receptors bound to human IgG; trap binds free VEGF not yet bound to real
VEGFR-1 and VEGFR-2 receptors on endothelial cells; phase 1 study ongoing
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| Pigment epithelium-derived factor (PEDF): naturally occurring protein in eye inhibits ocular neovascularization and promotes
survival of retinal and RPE cells; when attached to adenovirus vector, vector delivers PEDF to RPE and retinal cells; phase
1 study demonstrates safety and temporary regression in CNV
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| Kinase inhibitors: type of VEGF receptor inhibitor blocks activation of endothelial cells; ongoing study looking at use in
conjunction with PDT
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| Small interfering RNA (siRNA): blocks production of VEGF; siRNA synthetically produced agent injected intravitreally
and absorbed into cytoplasm of retina and RPE cells; once inside cells, undergo change that allows it to attack mRNA
produced by cell coded to make VEGF; siRNA binds in specific location to endogenous mRNA from cell nucleus;
binding mediates cleavage of endogenous mRNA by “slicer” component of siRNA; cleaved endogenous mRNA now
recognized by cell as aberrant and destroyed; 2 drugs (Cand5 and Sirna-027) undergoing phase 1 studies; preliminary
results show good safety, ability to stabilize vision loss, and vision improvement in some patients
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Educational Objectives
| The goal of this activity is to provide the listener with a better understanding of age-related macular degeneration (AMD).
After hearing and assimilating this program, the clinician will be better able to describe the:
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| 1. Clinical features of dry and wet AMD and the angiographic features of wet AMD.
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| 2. Most recent scientific discoveries linking genetic defects to onset of dry AMD.
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| 3. Current and emerging trends in treatment of dry AMD.
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| 4. Current understanding of the stimuli and mediators of choroidal neovascularization (CNV).
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| 5. Current and emerging trends in treatment of wet AMD.
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Discussed on This Program
Anecortave acetate (investigational) [Retaane]
Bevacizumab [Avastin]
Pegaptanib sodium [Macugen]
Ranibizumab (RhuFab V2) [Lucentis] (investigational)
Squalamine (investigational) [Evizon]
Triamcinolone acetonide [Aristocort, Aristocort A, Azmacort, Delta-Tritex, Flutex, Kenaject-40, Kenalog-10, Kenalog,
Kenalog in Orabase, Kenalog-40, Kenalog-H, Kenonel, Nasacort AQ, Nasocort HFA, Oralone Dental, Tac-3, Tac-40,
Tri-Kort, Tri-Nasal, Triacet, Triam-A, Triamonide 40, Triderm, Trilog]
Suggested Reading
Bashshur ZF et al: Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular
degeneration. Am J Ophthalmol. 142(1):1, 2006; Chopdar A et al: Age-related macular degeneration. BMJ.
326(7387):485, 2003; Despriet DD et al: Complement factor H polymorphism, complement activators, and risk of age-
related macular degeneration. JAMA. 296(3):301, 2006; Ergun E et al: Photodynamic therapy with verteporfin and intravitreal
triamcinolone acetonide in the treatment of neovascular age-related macular degeneration. Am J Ophthalmol.
142(1):10, 2006; Gottlieb JL: Age-related macular degeneration. JAMA. 288(18):2233, 2002; Holz FG et al: Pathogenesis
of lesions in late age-related macular disease. Am J Ophthalmol. 137(3):504, 2004; Klein R et al: The epidemiology
of age-related macular degeneration. Am J Ophthalmol. 137(3):486, 2004; Rosenfeld PJ: Intravitreal avastin: the
low cost alternative to lucentis? Am J Ophthalmol. 142(1):141, 2006; Sternberg P Jr et al: Photodynamic therapy for
age-related macular degeneration: a candid appraisal. Am J Ophthalmol. 137(3):483, 2004; van Leeuwen R et al: Dietary
intake of antioxidants and risk of age-related macular degeneration. JAMA. 294(24):3101, 2005; van Wijngaarden
P et al: Inhibitors of ocular neovascularization: promises and potential problems. JAMA. 293(12):1509, 2005;
Wiggs JL: Complement factor H and macular degeneration: the genome yields an important clue. Arch Ophthalmol.
124(4):577, 2006; Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol
. 122(4):598, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Custis was recorded July 29, 2006, in San Diego, CA, at the 26th Annual Current Concepts in Ophthalmology,
sponsored by the San Diego Eye Bank. The Audio-Digest Foundation thanks Dr. Custis and the San Diego Eye Bank
for their cooperation in the production of this program.
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