RETINAL DISEASE
From the Ninth Annual Clinical Update for the Comprehensive Ophthalmologist, presented by the University of
Tennessee Health Science Center, Memphis
| THE ROLE OF INFLAMMATION IN AMD—Alessandro Iannaccone, MD, Associate Professor of Ophthalmology, University
of Tennessee Health Science Center College of Medicine, Hamilton Eye Institute, Memphis
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| Age-related macular degeneration (AMD): complex late-onset multifactorial condition; environmental, dietary, and
genetic factors, and concurrent conditions play role in determining likelihood and severity; good evidence that AMD is
form of focal ocular atherosclerosis
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| Role of genetics: AMD is polygenic disorder (congenital genetic factors predispose patients to this disease); unique opportunity
for gene-gene interactions that increase or diminish risk for AMD, and gene-environment interaction; nonmodifiable
factors—age; race; heredity (may become modifiable); modifiable factors—cigarette smoking; coronary artery
disease (CAD); hypertension; elevated cholesterol, body mass index (BMI), and body weight; dietary and nutritional factors;
sunlight exposure; all linked to oxidative stress and chronic low-grade inflammation; possibility of interplay among
themselves and with carotenoid homeostasis
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| Role of inflammation in pathogenesis of AMD
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 | Histopathologic evidence of involvement of leukocytes, macrophages, and giant cells in AMD; some evidence that antiretinal
antibodies in serum of patients with AMD; current focus on AMD as genetically modulated inflammatory disease
(rather than autoimmune disease); studies by Hageman—series of donor eyes affected by AMD; shared
immunoactivity patterns between atherosclerosis, Alzheimer’s disease, glomerulonephritis, and AMD; other
evidence—vitronectin essential constituent of drusen (also present in atherosclerosis, Alzheimer’s disease, and glomerulonephritis
deposits); some molecules associated with drusen formation also associated with inflammatory and immune
process (especially IgG and complement); dendritic inflammatory cells of choroidal origin infiltrate drusen;
retinal pigment epithelium (RPE) cells may become target of antibody-mediated complement attack; accumulating immune
complexes degenerate and contribute to drusen formation in cells
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| Laboratory evidence: direct link to human disease not yet established; mice deficient in MCP1 (aka CCL2) or its receptor
(CCR2) develop cardinal features of AMD; mice do not have maculas but do develop deposits clinically and histopathologically
resembling human drusen, and neovascular events (thickening of Bruch membrane; endothelial fenestrations);
genes and proteins involved in modulation of inflammatory phenomena
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| Epidemiologic evidence: association with C-reactive protein (CRP); some evidence of association with positive IgG serology
for Chlamydia pneumoniae (among inciting factors in atherogenesis); AMD not infectious disease, but C
pneumoniae may be trigger for chronic poorly controlled inflammatory response (especially in predisposed individuals);
risk factors for AMD include smoking, hypertension, and CAD (all linked to atherosclerosis); atherosclerosis
chronic low-grade inflammatory disease linked to abnormality in oxidation-mediated signals in endothelial cells of
blood vessels; chronic inflammatory state leads to upregulation of oxidative reactions (oxidative stress); self-reinforcing
cycle can lead to accumulation of reactive O2 species within target cells (in endothelial cells, atherosclerosis); presumably
contributes to formation of AMD lesions and disease
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| Role of carotenoids: conflicting results in literature may be due to confounding inflammation; carotenoids studied negatively
correlated with amount of inflammatory markers (higher markers of inflammation, lower carotenoids; correlation
not 1 to 1); determinants of lutein and zeaxanthin serum levels—carotenoids that form macular pigments tested with
omega-3 fatty acids in Age-Related Eye Disease Study (AREDS) II; smoking, fat mass, BMI, and waist-hip ratio independent
determinants of lutein and zeaxanthin serum levels (supports hypothesis linking inflammation and carotenoid
bioavailability); however, best model accounted for only 24% of variability; smoking, history of cardiovascular disease,
physical activity, and elevated BMI significant predictors of nonresponse to high dietary intake of lutein and zeaxanthin
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| Single nucleotide polymorphisms (SNPs): play role in inflammation associated with increased risk for AMD; most
important—1) complement factor H (CFH); 2) pleckstrin homology domain-containing protein, family A, member 1
(PLEKHA1); toll-like receptor 4 (TLR4)—also involved
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| Complement factor H: part of regulator of complement activation (RCA) gene cluster; serum protein needed to “quench”
activation of alternative complement pathway (restricted to microbial infections) and protect host tissues from complement-
induced collateral damage; CRP activates classical pathway, but binds to CFH to promote quenching function; recent papers
confirm role of CFH (and role of Y402H variant in CFH); changing 1 copy of gene increases risk for macular degeneration
2.25 to 4.6 times (if variant homozygous, risk increased 3.3-7.4-fold); 45% to 68% of AMD explained by single gene; mutations
in gene cause hereditary form of glomerulonephritis (affected patients develop macular drusen); clear connection between
dysfunction of complement regulation and drusen
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| Toll-like receptor 4: variant associated with susceptibility to AMD; associated with 2-fold increase in risk for AMD
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| Apolipoprotein E (ApoE) gene: implicated in increased risk for AMD; carriage of AMD-predisposing variants of ApoE
and ATP-binding cassette transporter A1 (ABCA1) increases risk for AMD 4-fold; TLR4 mediates proinflammatory signal
pathways and regulates cholesterol efflux and photoreceptor outer segment phagocytosis
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| MEDICAL RETINAL UPDATE —Steve Charles, MD, Clinical Professor of Ophthalmology, University of Tennessee
Health Science Center College of Medicine, Memphis
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| AMD prevention strategies (overview): smoking associated with 350% to 500% increase in progression rate; high-dose
β-carotene combined with smoking increases lung cancer rates by 25%; diet for AMD same diet for longevity (protective
against atherosclerosis and stroke)
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| Failed strategies: laser-based surgical methods; direct photocoagulation of macula (in Macular Photocoagulation Study
[MPS], difference 1.5 lines at 18 mo); unacceptable to turn relative scotoma into absolute scotoma; mechanical strategies
not successful
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| Minimally effective therapies: pegaptanib (Macugen); photodynamic therapy (PDT; in some patients, severe complications);
administration into tissue may require skin grafts
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| Anecortave: did not meet primary end point of noninferiority in recent comparison with PDT; problem of drug reflux; recent
pharmacokinetic study (effect lasts up to 6 mo; many patients reinjected outside window); advantages—does not
enter eye; not systemic (no systemic or ocular adverse events reported); Anecortave Acetate Risk Reduction Trial
(AART)—wet AMD in one eye (in other eye, hyperpigmentation and intermediate drusen); treat other eye q6 mo as prevention
(safe); bevacizumab (Avastin) combined with anecortave (Retaane)—may suppress activity long-term (not
proven)
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| Systemic Avastin: first approved for colon and rectal cancer; ovarian, lung, and breast cancer treated with Avastin;
study—patients followed for systemic events; thromboembolic events (excessive clotting) commonplace in patients with
cancer (so, events not necessarily attributable to Avastin); terrific results but average intraocular pressure (IOP) increased
9 mm Hg; systolic hypertension associated with squalamine (another systemic antivascular endothelial growth factor
[VEGF] strategy); ranibizumab (Lucentis) much smaller molecule (49 kD), Avastin molecule larger (2 receptors instead
of 1; lasts longer)
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| Following patients: difficult to distinguish leakage from staining on fluorescein angiography, unless case straightforward;
goal to avoid retinal edema and subretinal fluid; do not treat patients every 4 to 6 wk (follow with optical coherence tomography
[OCT] and treat as needed)
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| Anti-VEGF therapy: squalamine—systemic therapy; some concerns about data; intravenous Avastin—problem of systemic
hypertension; Macugen—specific to 165 isoform of VEGF-A; relatively minimal effect (Avastin and Lucentis suppress
all isoforms of VEGF-A; loss of normal vasculature has not occurred)
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| Pharmacokinetics: Macugen, Avastin, and Lucentis work at same site; Retaane—slightly different; molecule resembles
steroid, except devoid of glucocorticoid activity; molecule goes through sclera and affects process at different levels
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| Safety: off-label use in AMD; in Lucentis trial, inflammation noted in significant number of patients (on further study,
these patients had PDT within 1 mo; adjunctive PDT contraindicated); intravitreal Avastin first-line monotherapy (not
in combination with triamcinolone [Kenalog] or PDT); intravitreal dose ≈1/50 of systemic dose; intraocular studies
(Cooperman)—Avastin safe (no effects in tissue culture); pilot study (Rosenfeld)—results equivalent or better than Lucentis
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| Indications for laser therapy: for well-defined extrafoveal lesion, laser therapy effective; if lesion juxtafoveal (within
1000 µ), recurrence rate 50% (likely subfoveal); document lesion with angiography (monitor with OCT)
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| Sterile technique: in Macugen study, 14 or 16 cases of endophthalmitis due to lack of sterile technique; use sterile speculum
and gloves and povidone iodine (Betadine) preparation (preparation of lid margins); if using, eg, Kenalog, do not
reuse vial
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| Follow-up: 6-wk intervals with OCT; if no response, repeat intravitreal injection once (repeat at second or third 6-wk interval);
recurrence of subretinal fluid or edema resolved after initial therapy; fluorescein angiography follow-up no
longer necessary; one third of patients have improved vision (unlike Macugen or PDT)
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| Diabetic retinopathy: clinically significant macular edema; fundus contact lens best diagnostic aid (consider 90D lens); if
macula-threatened, Early Treatment Diabetic Retinopathy Study (ETDRS)-style focal laser indicated; but, if central macular
edema and microaneurysms present, perform focal and grid laser; OCT essential to document extent of edema and to
determine whether vitreomacular traction present; if taut posterior vitreous cortex pulling on macula and causing subretinal
fluid, unreasonable to assume that traction on internal limiting membrane (ILM) making macula edematous (hypothesis
that macula edematous because macula pulled away from pigment epithelial pump); these patients can be treated
with vitrectomy and membrane peeling (speaker performs focal laser in conjunction with those procedures); if central
macular edema due to microaneurysms, use standard ETDRS-style focal laser (if not effective, consider Avastin; if Avastin
therapy fails, Kenalog); incidence of steroid glaucoma 30% (with implants as high at 100%; high incidence of cataract)
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| Proliferative diabetic retinopathy with neovascularization: panretinal photocoagulation (PRP) standard of care; follow-up
at 90 days inadequate; speaker’s second PRP often at 1 mo (as needed [prn]); patients potentially blind from
neovascular glaucoma or retrolenticular neovascularization at 90 days (see patients at 1 mo); if confluent PRP and no regression
of neovascularization, consider Avastin (some stunning results)
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| Branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO): macular edema with intraretinal
blood—cannot perform focal or sector photocoagulation (aka grid); use OCT to rule out traction and document thickness;
some good responses to Avastin; macular edema without intraretinal blood—in BRVO, perform sector PRP as
needed for edema (not prophylactically; in CRVO, posterior grid or scatter)
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| Surgical interventions: for BRVO—complete failure; radial optic neurotomy (RON) does not work; most successful cases
20/400 in 6 mo (may be natural history); need randomized trial; cannulation of CRV with tissue plasminogen activator
(tPA)—anecdotal reports of significant complications (vitreous hemorrhage; retinal detachment; no light perception
[NLP]); need randomized trial; BRV decompression—abandoned by speaker (did not cause capillary reperfusion; did
not help vision); no randomized trial; translocation—contraindicated (complication rate too high; ≥25% of patients
blind after procedure); no randomized trial; treatment of BRVO with intravitreal Kenalog (IVK)—restoration of
foveal architecture; CRVO—visual recovery not as impressive as with BRVO or macular edema; patient treated with
Avastin (at 1 wk, tremendous edema gone)
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| Submacular hemorrhage: if present within 2 wk and vitrectomy performed, inject tPA with 41-gauge canula into submacular
space, leave patient on back for 1 hr postoperatively, then have them sit up (because of gravity, liquified clot
sinks down to bottom half of eye, and macula clear; some failures, but speaker has not encountered complications; effective
in selected cases
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| Central serous retinopathy: no evidence that condition VEGF-related (Avastin not helpful); treatment—observation;
no evidence that laser changes long-term visual results (but focal laser option in single extrafoveal leak); PDT works well
for subfoveal, juxtafoveal, diffuse, or multiple leaks; if patient steroid-responder or has history of glaucoma or cupping,
add IVK (PDT proinflammatory and upregulates VEGF)
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| Idiopathic perifoveal telangiectasia: if macular edema present and lesion outside macula, treat with focal light laser; if
within focal avascular zone, PDT effective (not VEGF-related)
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| Postoperative cystoid macular edema (CME): aka Irvine-Gass syndrome; in speaker’s opinion, anterior segment inflammation
causes all macular edema (not treating macula; goal to eliminate anterior segment inflammation); postoperative
iritis caused by iris damage with Weck sponges during anterior vitrectomy (cellular debris left); if total posterior
vitrectomy performed, no cells and flare postoperatively; vitrectomy does not cause CME; causes of CME—mechanical
traumatic surgical iritis; vitreous in wound; residual lens material; viscoelastics; implant; medical therapy treats inflammatory
process in front of eye (do not worry about getting to macula); treatment of diabetic macular edema with topical
steroids or nonsteroidal anti-inflammatory drugs (NSAIDs) makes no sense (consider, eg, subTenon’s Kenalog and topical
nepafenac (Nevanac)
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Educational Objectives
| The goal of this program is to educate the listener about recent scientific and clinical advances in retinal disease. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. Recognize risk factors for the development of age-related macular degeneration (AMD).
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| 2. Describe the role of inflammation in the pathogenesis of AMD.
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| 3. Describe newer therapies for managing AMD.
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| 4. Implement appropriate follow-up after panretinal laser photocoagulation in patients with proliferative diabetic retinopathy.
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| 5. Identify potential causes of cystoid macular edema after vitrectomy.
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Discussed on This Program
Anecortave acetate [Retaane] (investigational)
Beta carotene
Bevacizumab [Avastin]
Nepafenac ophthalmic suspension 0.1% [Nevanac]
Pegaptanib sodium [Macugen]
Povidone iodine (several trade names)
Ranibizumab (RhuFab V2) [Lucentis] (investigational)
Squalamine lactate (orphan drug)
Triamcinolone acetonide (several formulations and trade names)
Suggested Reading
Birchall W et al: Cyclical central serous chorioretinopathy associated with cystoid macular oedema. Br J Ophthalmol
85:756, 2001; Charles S: An engineering approach to vitreoretinal surgery. Retina 24:435, 2004; Edwards AO: Genetic
testing for age-related macular degeneration. Ophthalmology 113:509, 2006; Gruber M et al: Correlates of serum lutein
+ zeaxanthin: findings from the Third National Health and Nutrition Examination Survey. J Nutr 134:2387, 2004; Iannaccone
A: Genotype-phenotype correlations and differential diagnosis in autosomal dominant macular disease. Doc Ophthalmol
102:197, 2001; Seddon JM et al: The US twin study of age-related macular degeneration: relative roles of
genetic and environmental influences. Arch Ophthalmol 123:321, 2005; Tuo J et al: Genetic factors of age-related macular
degeneration. Prog Retin Eye Res 23:229, 2004; Yates JR, Moore AT: Genetic susceptibility to age related macular
degeneration. J Med Genet 37:83, 2000.
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 following
has been disclosed: Dr. Charles has been a consultant to Alcon.
Drs. Iannaccone and Charles were recorded at the Ninth Annual Clinical Update for the Comprehensive Ophthalmologist
, presented December 3, 2005, in Memphis, TN, by the University of Tennessee Health Science Center, Department
of Ophthalmology. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in
the production of this program.
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