MACULAR DISEASE
| WHAT’S NEW AND HOT IN RETINA: AMD —Jennifer Lim, MD, Department of Ophthalmology, Keck School of
Medicine, University of Southern California, Los Angeles
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| Advancements in treatment of age-related macular degeneration (AMD): photodynamic therapy (PDT) with verteporfin
prevents disease progression and loss of vision; combretastatin A4 phosphate—tubulin-binding agent; endothelial
cells of immature blood vessels depend on tubulin for structure; intravenous (IV) delivery of drug causes loss of tubulin
structure; endothelial cells become round and effectively occlude lumen; phase 1 and 2 dose-escalation study found no
dose-limiting adverse effects; positive effects on neovascularization seen; phase 2 and 3 trials proceeding; PDT
monotherapy—limited use; vision rarely improved
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| PDT with triamcinolone: study using intravitreal injections looked at series of 26 eyes (13 naive to PDT; 13 previously
treated with PDT); visual acuity improved by 1.9 lines in newly treated eyes at 3 mo and by 2.5 lines at 1 yr; vision did
not significantly improve in eyes previously treated with PDT monotherapy; rate of retreatment low for both groups; adverse
effects of intravitreal steroids include cataracts and increased intraocular pressure (IOP); other studies did not find
improvements in vision; phase 3 clinical trials in progress
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| PDT with ranibizumab (rhuFab V2): nonbinding human sequence derived from mouse; sequence has high-affinity binding
epitopes for vascular endothelial growth factor (VEGF); molecule smaller than full-length antibody (concern that
full-length antibody would not cross retina), but potential for mouse antigenicity; study—phase 1 and 2 multicenter, single-blind
study compared PDT plus 0.5-mg injection of ranibizumab to PDT with sham injection; PDT given 7 days before
injection and repeated every 3 mo, if needed; 90.5% of patients given combination therapy but only ≈68% of patients
given PDT alone lost <15 letters; 23.8% of patients given combination therapy gained ≥3 lines of vision, compared to 5%
of patients on PDT alone
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| Ranibizumab monotherapy: ranibizumab vs PDT—phase 3 multicenter trial randomized 423 patients with predominantly
classic choroidal neovascularization (CNV) to 0.3 mg or 0.5 mg injections with ranibizumab or PDT monotherapy; 94% of
patients receiving 0.3 mg and 96% of patients receiving 0.5 mg ranibizumab lost <15 letters or gained ≥15 letters of vision,
compared to 64% of patients receiving PDT monotherapy; on average, patients treated with ranibizumab gained vision, but
patients treated with PDT lost vision; ranibizumab vs sham—716 patients with subfoveal CNV (minimally classic or occult)
randomized to 0.3 mg or 0.5 mg ranibizumab, or sham injection; 95% of patients in treatment groups lost <15 letters,
compared to 62% of patients in control group; 25% of patients receiving 0.3 mg and ≈34% of patients receiving 0.5 mg
ranibizumab gained ≥3 lines of vision, compared to 5% of patients in control group; on average, patients in treatment
groups gained 6.5 letters, whereas patients in control group lost 10.5 letters
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| Bevacizumab (Avastin): full-length anti-VEGF antibody; adverse effects include thromboembolic events and hypertension;
study—patients given 5 mg/kg IV Avastin; ≈67% of patients did not require retreatment; hypertension developed
or worsened in 56% of patients (controlled within 6 wk); vision improved at 3 mo (median, 9 letters; mean, 12 letters)
and 6 mo (median, 16 letters); retinal thickness (as measured by optical coherence tomography [OCT]) decreased at 3 mo
(median decrease 125 µ) and 6 mo (117 µ); problems with hypertension deterred further study; off-label intravitreal injection
of Avastin—study looked at alternative route of delivery; 1.25 mg Avastin (0.5 mL injection) reduced macular
edema and retinal thickness and partly restored foveal contour; response occurs within 1 wk; controlled studies needed
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| VEGF trap: molecule binds VEGF receptors 1 and 2 (VEGFR-1 and VEGFR-2); animal studies showed CNV decreased
by 85% over 10 days (CNV disappeared in many animals); phase 1 clinical trial compared treatment groups (IV injections
of 0.3 mg/kg, 1.0 mg/kg, and 5.0 mg/kg) to placebo; trend toward improved visual acuity and decreased retinal
thickness at higher doses, but problems with hypertension and proteinuria led to early withdrawal of some patients; phase
2 and 3 clinical trials anticipated
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| Other therapeutic strategies: receptor tyrosine kinase inhibitors (RTKIs)—local and systemic RTKIs directed at VEGF
receptors inhibited or improved laser-induced CNV in mice; hypoxic inducible factor (HIF)—molecules involved in intracellular
signaling, leading to production of VEGF; synthetic inhibitor of HIF-1 inhibited CNV in 60% of rats for up to
4 wk; squalamine—aminosterol antibiotic injected IV binds intracellular calmodulin, inhibiting endothelial cell migration,
VEGF signaling, and expression of integrin and cytoskeleton; phase 1 and phase 2 trials found stabilization or improvement
of vision; phase 3 trial in progress; short interfering ribonucleic acid (RNA) technology—small double-
stranded RNA molecule interferes with production of RNA and down-regulates production of VEGF (effect 100-fold
greater than equivalent amount of antibody or aptomer); dose-dependent reduction in CNV and decrease in vascular leakage
seen in nonhuman primates
|
| Gene therapy: pigment epithelial-derived factor (PEDF)—potent antiangiogenic molecule; gene carried into cell by modified
adenovirus stimulates production of PEDF, which also promotes survival of photoreceptors and retinal pigment epithelium
(RPE); phase 1 study found no significant adverse effects (mild uveitis and increases in IOP seen in some
patients); positive effects seen on visual acuity and retinal thickness; other gene therapy—introduction of genes activated
by hypoxic conditions; genes encoding angiostatic proteins (endostatin and angiostatin) result in decreased CNV
when introduced into RPE of mice
|
| NUTRITION AND MACULAR DEGENERATION —Allan J. Flach, MD, PharmD, Professor of Ophthalmology, University
of California, San Francisco, School of Medicine
|
| Age-Related Eye Disease Study (AREDS): prospective randomized placebo-controlled clinical trial assessed efficacy of
AREDS formulation (500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene; 80 mg zinc oxide, 2 mg cupric oxide) for
prevention of AMD and vision loss; formulation recommended for patients >55 yr of age with extensive intermediate
drusen, ≥1 large drusen, and noncentral geographic atrophy in ≥1 eye, or advanced AMD or vision loss caused by AMD
in ≥1 eye; use of formulation in suitable patients prevents or slows advanced eye disease and vision loss
|
| Criticisms of study: study included only healthy, nonsmoking patients, many of whom took additional vitamin supplements
(may not reflect average patient population); formulation did not include lutein or zeaxanthin (considered more effective than
β-carotene); later formulation corrected this (results forthcoming)
|
| Availability of formulation: several preparations now available, but some require daily ingestion of 4 large tablets; annual
cost of $180 to $240 may deter some patients; many other formulations, not scientifically tested, marketed as beneficial
for ocular health
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| Efficacy: effect real, but modest in many patients; progression may continue in some patients; benefit occurs in patients with intermediate
or advanced AMD (ie, does not prevent onset of AMD)
|
| Toxicity: β-carotene increases risk for lung cancer in smokers (increased risk persists for 20 yr after cessation of smoking);
some preparations substitute lutein for β-carotene (safer, but efficacy unproven); AREDS study reported increased rate of
hospitalization for genitourinary tract infections (unexplained); zinc—when taken without copper, zinc may cause anemia
or aggravation of cardiovascular disease; immune dysfunction may occur when taken in daily doses >150 mg; risk
for prostate cancer may increase with daily doses >100 mg; 80 mg contained in formulation likely exceeds dose needed
for benefit; vitamin E—experts recommend avoidance in patients with RPE detachment; some question safety in patients
with macular degeneration; meta-analysis suggested high doses of antioxidants, including 400 IU of vitamin E,
may increase all-cause mortality, but retrospective analysis of AREDS data shows decrease in 5-yr mortality
|
| Dietary sources: 400 IU vitamin E—10 cups fortified cereal, 10 cups wheat germ, or 10 oz sunflower seeds; 500 mg vitamin
C—4 cups orange juice, 5 cups tomato juice, or 5 cups steamed broccoli; 15 mg β-carotene—0.5 cup dried tomatoes,
0.25 cup carrots, or 0.5 cup spinach; 80 mg zinc—80 cups brown rice or 80 slices whole wheat bread; 2 mg
copper—4 cups refried beans or 2 cups bran
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| Benefits: AREDS supplement reduces rate of progression of AMD by 25% over 5 yr; probability of loss of 15 letters of vision
over 5 yr—29% with placebo; 23% for AREDS formula; 25% for zinc and copper alone; 26% for antioxidants
alone; probability for progression to advanced AMD at 5 yr—28% for placebo; 20% for AREDS formula; 22% for zinc
and copper; 23% for antioxidants; probability of severe vision event at 5 yr—17% for placebo; 12% for AREDS formula;
13% for zinc and copper; 14% for antioxidants
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| Other issues of diet and lifestyle: smoking—increases risk for late AMD by 3 to 4 times (risk remains elevated for 20 yr
after cessation of smoking); associated with cataract, glaucoma, diabetic retinopathy, Grave’s disease, and dry eyes;
exercise—improves cardiovascular health, lipid levels, and insulin sensitivity; decreases blood pressure (BP), type 2 diabetes,
adipose mass, and insulin resistance; antioxidants—dark green leafy vegetables rich in antioxidants; increased dietary
intake reduces risk for advanced AMD by 43%; obesity—high body mass index (BMI); calculated as weight (kg)/
[height (m)]2 , increases risk for early and dry AMD; BMI >30 increases risk for late and pigmentary AMD; high BMI associated
with increased neovascularization
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| CURRENT TREATMENT STRATEGIES IN DIABETIC MACULAR EDEMA —Christina J. Flaxel, MD, Associate
Professor of Ophthalmology, Oregon Health and Science University, Portland
|
| Epidemiology of diabetic eye disease: 25% of patients with diabetes have some signs of diabetic retinopathy; 5% have
proliferative disease; prevalence increases with duration of diabetes; >25% of patients with type 1 diabetes develop proliferative
disease (less common in patients with type 2 diabetes); nonproliferative disease responsible for 85% to 90% of
cases of visual impairment associated with diabetes, but rarely causes blindness; diabetes increases risk for blindness by
25 times; prevalence of diabetic macular edema (DME) also increases with duration of diabetes; prevention and
treatment—laser only approved treatment (not prophylactic); preventing damage important; current treatments cannot
reverse capillary instability and closure
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| VEGF protein: stimulates mitosis of vascular endothelial cells; increases permeability of blood vessels; stimulates vasodilation;
promotes migration of endothelial cells; inhibits apoptosis; enhances survival of endothelial cells; VEGF and
diabetes—levels elevated in retina in experimental diabetes; VEGF165 induces vascular leakage in primates; increased levels
found in vitreous of eyes with proliferative disease; diabetic patients have elevated levels in aqueous; VEGF-induced
permeability linked to diabetic and nondiabetic macular edema
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| Protein kinase C (PKC): family of enzymes involved in signaling of growth factors; PKC- β2 implicated in microvascular
damage associated with hyperglycemia; critical component of cascade initiated by VEGF; ruboxistaurin—inhibits PKC- β
prevents vascular complications of diabetes in animal models; prevents formation of new vessels; reduces vascular permeability
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| Diagnosis of DME: fluorescein angiography (FA) confirms diagnosis; OCT important for diagnosing macular edema; limits
of FA—degree of leakage does not correlate with visual acuity or clinical outcomes; technique does not show abnormalities
in vitreoretinal interface; fluorescein leakage not used as criteria for treatment in Early Treatment Diabetic Retinopathy
Study (ETDRS); OCT—more precise than slit-lamp examination for diagnosing macular edema (becoming more important
than FA)
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| Subtypes of DME: traditional—sponge-like swelling on OCT; increased retinal thickness correlates with loss of visual
acuity; moderate correlation with fluorescein leakage; good response to laser treatment (edema decreases and vision improves);
cystoid—cystoid spaces within retina; moderate response to laser treatment; serous retinal detachment without
traction on posterior hyaloid—uncommon subtype; not visible clinically; hard exudates remain after fluid recedes; poor
response to laser treatment; DME caused by traction on posterior hyaloid—retinal detachment may occur; no response
to laser treatment or intravitreal injections; surgery often effective; OCT important for diagnosis (large cystic spaces, serous
detachment, and traction)
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| Laser treatment: results of ETDRS show modest benefit; 3% of patients gained >3 lines of vision; 17% of patients had some
improvement over 5 yr; DME persisted for >1 yr in 35% of patients and >3 yr in 24% of patients; 40% of patients required retreatment
within 1 yr; treatment aimed at preserving, rather than improving, vision
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| Medical management: 3 large prospective studies show tight control of blood glucose (BG) levels reduces risk for clinically
significant DME, need for laser treatment, and progression of retinopathy; note—level of control used in study difficult
to achieve in many patients; tight control of BP also reduces risk for progression, vision loss, and need for laser
treatment
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| Steroids: decrease permeability and vasomotor response of blood vessels; stabilize lysosomal membranes and blood-retinal
barrier; inhibit VEGF and other inflammatory mediators; efficacy—case study shows elimination of cysts and reduction
of leakage in patient with diffuse cystoid macular edema; delivery—sub-Tenon’s injection (anterior and posterior); intravitreal
injection; sustained-release devices
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| Ruboxistaurin: oral agent results in systemic inhibition of PKC- β study found decreased risk for DME involving or threatening
center of macula, especially when BG controlled; another study found decreased vision loss associated with diabetic
retinopathy, but treatment had no effect on risk for progression
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| VEGF-inhibitors: Macugen, Lucentis, and VEGF Trap delivered by injection; Avastin used in patients with diabetes;
study found significant reduction in central macular thickness, compared to usual care (68 µ vs 3.7 µ), and also reduced
need for laser treatment
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Educational Objectives
| The goal of this activity is to update the clinician about recent advances and clinical research in the field of macular disease.
After hearing and assimilating this program, the clinician will be better able to:
|
 | 1. Describe recent advances and investigational therapies for the treatment of age-related macular degeneration
(AMD).
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| 2. Discuss the application of gene therapy to the treatment of patients with AMD.
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| 3. Identify patients with AMD who may benefit from the Age-Related Eye Disease Study (AREDS)-formulation nutritional
supplements.
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| 4. Review the relationship between vascular endothelial growth factor (VEGF) and diabetic macular edema (DME).
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| 5. Discuss surgical and medical options for patients with DME.
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Discussed on This Program
Anecortave acetate (investigational)
Bevacizumab [Avastin]
Combretastatin A4 phosphate (investigational)
Pegaptanib sodium [Macugen]
Ranibizumab (rhuFab V2) [Lucentis] (investigational)
Ruboxistaurin mesylate (investigational)
Squalamine (orphan drug)
Triamcinolone acetonide (several trade names)
Verteporfin [Visudyne]
Suggested Reading
Adamis AP, et al: Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology
113:23, 2006; Anand A, et al: Persistent diabetic macular edema is associated with elevated hemoglobin A1c.
Am J Ophthalmol 140:960, 2005; Campochiaro PA, et al: Adenoviral vector-delivered pigment epithelium-derived factor
for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther 17:167, 2006; Chan
WM, et al: Combined photodynamic therapy and intravitreal triamcinolone injection for the treatment of subfoveal choroidal
neovascularization in age related macular degeneration: a comparative study. Br J Ophthalmol 90:337, 2006; Chieh JJ,
et al: Intravitreal triamcinolone acetonide for diabetic macular edema. Retina 25:828, 2005; Entezari M, et al: Posterior
sub-tenon triamcinolone for refractory diabetic macular edema: a randomized clinical trial. Eur J Ophthalmol 15:746, 2005;
Knudtson MD, et al: Age-related eye disease, visual impairment, and survival: the Beaver Dam Eye Study. Arch Ophthalmol
124:243, 2006; Metelitsina TI, et al: Effect of systemic hypertension of foveolar choroidal blood flow in age related
macular degeration. Br J Ophthalmol 90:342, 2006; Ng WT, Goggin M: Awareness of and compliance with recommended
dietary supplement among age-related macular degeneration patients. Clin Experiment Ophthalmol 34:9, 2006; Owens SL,
et al: Prophylactic laser treatment hastens choroidal neovascularization in unilateral age-related maculopathy: final results
of the drusen laser study. Am J Ophthalmol 141:276, 2006; Ozdemir H, et al: Early optical coherence tomography changes
after photodynamic therapy in patients with age-related macular degeneration. Am J Ophthalmol 141:574, 2006; Seddon
JM, et al: Evaluation of the clinical age-related maculopathy staging system. Ophthalmology 113:260, 2006; van Leeuwen
R, et al: Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA 294:3101, 2005; West AL, et
al: Evidence for the use of nutritional supplements and herbal medicines in common eye diseases. Am J Ophthalmol
141:157, 2006; Yasukawa T, et al: Intraocular sustained drug delivery using implantable polymeric devices. Adv Drug Deliv
Rev 57:2033, 2005.
Faculty Disclosure
In adherence with 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. Dr. Lim receives financial support
from Eye Tech, Genentech, Novartis, and Bausch and Lomb. Dr. Flaxel receives financial support from Eye Tech, Genentech,
Novartis, and Pfizer.
Dr. Lim was recorded in Los Angeles at Controversies in Ophthalmology, sponsored by Research Study Club of Los Angeles,
and held January 14, 2006; Dr. Flach was recorded in San Francisco at New Directions in Ocular Therapies, sponsored
by University of California, San Francisco, Beckman Vision Center, Department of Ophthalmology, and held December 1-
2, 2005; Dr. Flaxel was recorded in Memphis at Clinical Update for the Comprehensive Ophthalmologist, sponsored by
University of Tennessee, Health Science Center, Department of Ophthalmology, and held December 3-5, 2005. The Audio-
Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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