RETINAL CONSULT
From the 2008 Annual Meeting, Current Trends and Advances in Ophthalmology, presented by the Washington Academy of
Eye Physicians and Surgeons, Seattle, WA
David S. Boyer, MD, Clinical Professor of Ophthalmology, Keck School of Medicine, University of Southern California,
Doheny Eye Institute, and Partner, Retina-Vitreous Associates Medical Group, Los Angeles, CA
Educational Objectives
| The goal of this program is to improve the management of diabetic retinopathy, dry age-related macular degeneration (AMD),
and blurred vision after cataract surgery. After hearing and assimilating this program, the participant will be better able to:
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 | 1. Recognize the causes of vision loss in patients with diabetes and review the data on the new treatment options.
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| 2. Evaluate the strengths and limitations of medical and surgical methods for the treatment of diabetic retinopathy.
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| 3. Describe the roles of diagnostic methods such as fluorescein angiography and optical coherence tomography in detecting
dry AMD, and choose among vitamin and pharmacologic therapies for treatment.
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| 4. Assess patients for potential retinal conditions that could complicate cataract surgery.
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| 5. Identify and treat the causes of blurred vision after cataract surgery.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, Dr. Boyer reported relationships as a consultant and investigator
with Alcon, Pfizer, iCo, Novartis, QLT Inc, and Genentech. The planning committee reported nothing to disclose.
Acknowledgements
Dr. Boyer’s lectures were recorded at the 2008 Annual Meeting, Current Trends and Advances in Ophthalmology, held
March 27-28, 2008, in Seattle, WA, and sponsored by the Washington Academy of Eye Physicians and Surgeons. The
Audio-Digest Foundation thanks Dr. Boyer and the Washington Academy of Eye Physicians and Surgeons for their
cooperation in the production of this program.
| CLINICAL TRIALS IN DIABETIC RETINOPATHY
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Current Treatments
| Medical management: control of glycemia and blood pressure (BP)—medical management first-line treatment because
of higher hemoglobin A1C (Hb A1C ; glycosylated), poorer control of diabetes, and higher incidence of diabetic retinopathy
(DR) over time; confirmed by the Diabetes Control and Complications Trial [DCCT], Kumamoto Study, and
United Kingdom Prospective Diabetes Study [UKPDS], which showed 10% decrease in Hb A1C produced 23% to 46%
reduction in retinopathy; not necessary to reduce Hb A1C levels to <7%; patients under poor control had increased incidence
and rates of progression of DR, compared to those with Hb A1C ≤7%; UKPDS showed strong effect of lowering
BP (ideally, 130/80 mm Hg) in reducing vision loss in patients with retinopathy (greater effect than that with lowering Hb
A1C ); angiotensin-converting enzyme (ACE) inhibitors—EUrodiab Controlled trial of Lisinopril in Insulin-dependent
Diabetes (Euclid) and substudy of Heart Outcomes Prevention Evaluation (Micro-hope) showed using ACE inhibitors
may help reduce DR, but effects may be from lowered BP rather than from drug; ongoing prospective trial (Diabetic
Retinopathy Candesartan Trials) evaluating direct effects of angiotensin-receptor blockers (ARBs) on DR; cholesterol
and triglycerides—elevated levels double risk for retinal hard exudates at baseline; increase risk for retinal hard exudates
during follow-up by 50%; increase incidence of moderate vision loss by 50% at 5 yr; Fenofibrate Intervention and Event
Lowering in Diabetes trial (FIELD study)—compared treatment with fenofibrate (200 mg/day) to placebo in patients
with type 2 diabetes; showed significant reduction in need for first laser treatment (3.4% incidence) vs placebo (4.9%);
treatment significantly reduced 2-step progression rate (3.1%) in patients with preexisting retinopathy vs placebo (15%);
limitations of medical management—only ≈7% of patients respond adequately; many diabetic patients suffer from retinopathy
at diagnosis, although reversal of some early changes possible by controlling BP and glycemia
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| Laser photocoagulation: primary treatment for proliferative and nonproliferative forms; Early Treatment Diabetic Retinopathy
Study (ETDRS)—showed lower incidence of moderate vision loss (ie, 3-line decrease) in treated vs untreated patients
after 3 yr (13% vs 33%); treatment given as grid (for wide diffuse ill-defined areas of leakage) or focally (for small
microaneurysms); early laser treatment produced 1 line of vision improvement in 40% to 45% of patients (vs 20%-25% of
patients in control group); signs of poor prognosis—hard exudates in center of fovea; capillary dropout and nonperfusion;
severe cystoid macular edema (CME); visual acuity <20/200; complications—transient decrease in central visual acuity;
due to increased macular edema, altered color perception, blind spots outside fovea, development of choroidal neovascularization
if Bruch’s membrane broken, and development of laser scar expansion; patients with proliferative DR—Diabetic
Retinopathy Study (DRS) showed laser treatment in high-risk patients reduced severe (ie, 6 lines) vision loss by 50%
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| Vitrectomy: patients who undergo vitrectomy (posterior vitreous detachment) have lower incidence of progression to proliferative
DR and possible reduction in proliferative and nonproliferative retinopathy; eyes with spontaneous release of vitreomacular
traction may have improvement in DME; investigational drugs—2 drugs currently in trials (hyaluronidase
[Vitrase] and microplasmin); evaluating early treatment to avoid risk for vitreous hemorrhages and tractional detachments
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| Limitations of current treatments: patients may develop DR even when diabetes well controlled; fear of hypoglycemia
may limit Hb A1C reduction
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New Treatments
| Diabetic Retinopathy Clinical Research (DRCR) network: conducting small pilot and larger studies to evaluate
various treatments (eg, triamcinolone compared to laser, combination of triamcinolone and laser to reduce macular
edema, benefits of diabetic vitrectomy)
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| New pharmacologic targets: growth factors—vascular endothelial growth factor (VEGF); pigment epithelium-derived
factor (PEDF); insulinlike growth factor (IGF)-1; inhibitors of protein kinase C (PKC) and mitogen-activated protein kinase
(MAPK); inhibitors of integrins, metalloproteases, and inflammation
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| Corticosteroid treatment: can address many of changes contributing to DME (eg, tight junctions, antioxidant capacity
of retinal pigment epithelium [RPE], chronic inflammation, leukostasis); steroids also target many contributing factors
and cytokines (eg, intercellular adhesion molecule [ICAM-1], VEGF, stromal-derivative factor); triamcinolone—
randomized prospective and retrospective trials under way with variable results; overall, 75% of patients had some improvement
and reduction in macular thickness, as determined by optical coherence tomography (OCT); 55% of patients
in one study had vision gain of ≈1 line; recurrence rates high, and injection lasted only 3 to 8 mo before reinjection necessary;
triamcinolone complications—increased intraocular pressure (IOP) in 30% to 50% of patients; noninfectious and
infectious endophthalmitis; cataracts likely over time (1-2 yr) and after repeated (2-3) injections; sustained-release
fluocinolone—implantable device, approved by Food and Drug Administration (FDA) for noninfectious uveitis; not approved
(but has important role) for treatment of diabetic patients; significant improvement in visual acuity (3 lines) at 3
yr; resolution of edema at center of macula at 1 yr; 2-step improvement in retinal thickness sustained after 1 yr; improved
DR scores; safety—cataract rate 95%; 60% of patients had IOP >30 mm Hg; 33% required glaucoma filtration surgery
(greater incidence than seen with triamcinolone); procedure—small incision, 3.5 to 4 mm from limbus, 4 to 4.5 mm in
width; trial results—patients with diffuse macular edema (poor prognosis) improved after 6 wk, with good visualization
of retinal vessels; treated patients more likely to have 3 lines of improvement in visual acuity; several patients required
cataract surgery; 55% of patients receiving treatment had 2 grades of improvement in edema at center of macula, compared
to 31% of patients receiving standard of care (including laser)
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| Implanted devices: Medidur implant—currently in trial; injected in office, releases drug for 18 mo; nonabsorbable
(small cylinder remains in inferior vitreous); doses of 0.5 and 0.2 µg/day; Posurdex—combination of dexamethasone
(strong, short-acting steroid) and polyglycolic acid; in-office; releases drug for 3 mo; breaks down to H2 O and CO2 ; trial
of 350-µg and 700-µg doses showed 33% of patients found 10 letters and 18% found 15; significant difference over conventional
laser treatment; I-Vation—implant coated with steroid (or other drug), similar to heart stent; easily removed;
adjustable dilution rates; implanted via 25-gauge needle, through incision 3.5 mm back in conjunctiva; larger phase 2 and
phase 3 trials expected
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| Intravitreal VEGF inhibitors: pegaptanib (Macugen)—first FDA-approved VEGF inhibitor; modest improvement
(ie, 3-line gain) seen in patients given 0.3-mg dose; ranibizumab (Lucentis)—small study found improvement in OCT
continued for 6 mo after treatment; varying results seen in different trials (OCT best at 0.5 mg, but best visual improvement
at lower dose); bevacizumab (Avastin)—similar mechanism as ranibizumab; equivocal trial results; some studies
showed 2-line improvement in visual acuity, but not sustained; vitreous hemorrhages may clear more rapidly (used preoperatively
to reduce vascularity and increase safety of vitrectomy); one study of patients with diffuse macular edema
showed improved OCT at 12 wk, but no improvement in vision; comparison study of bevacizumab plus triamcinolone vs
bevacizumab vs sham showed no difference after 3 injections
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| VEGF Trap: soluble recombinant decoy receptor; binds VEGF more tightly than monoclonal antibodies or aptamers;
long half-life
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| siRNA: Cand5—under investigation; iCo-007—second-generation antisense molecule (more stable, potent, and less inflammatory);
stops inflammatory cycle by targeting expression of c-Raf protein kinase and blocking mitogen-activated
protein (MAP) kinase signaling
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| DRY AGE-RELATED MACULAR DEGENERATION (AMD): TREATMENTS IN THE PIPELINE
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Management
| Lifestyle modifications: smoking cessation; exercise; maintaining healthy weight; normal BP; good nutrition
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| Vitamin therapy: Age-Related Eye Disease Study (AREDS) showed therapy with vitamin C (500 mg), vitamin E (400
IU), beta carotene (15 mg), zinc (80 mg), and copper (2 mg) associated with 28% reduction in progression and 20% reduction
in vision loss after 5 yr; AREDS II enrolling patients to study effects of replacing beta carotene with 10 mg lutein, adding
2 mg zeaxanthin, 1 g omega-3 fish oils, and reducing levels of zinc
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| Anecortave (Retaane): Anecortave Acetate Risk Reduction Trial (AART) ongoing in patients who had dry AMD in
one eye and wet AMD in other eye; anecortave given as juxtascleral injection in eye with dry AMD to test prevention of
progression to neovascularization
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| Clinical end points in therapy for geographic atrophy: morphologic—area and rate of enlargement measured
from digital photographs or autofluorescence; functional—visual acuity, visual field, contrast sensitivity, color vision;
autofluorescence—measures changes in A2E of lipofuscin; patterns include patchy, focal, and diffuse; may be strong predictor
of damage to RPE and patients likely to benefit from treatment
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Therapeutic Options
| Neuronal survival agents: not curative, but stabilizing; ciliary neurotrophic growth factor—device implanted under
local anesthesia (contains modified RPE cells that release ciliary neurotrophic factor without eliciting immune response)
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| OT-551: topical eye drop; placebo-controlled trial in 100 patients; drug penetrates cornea and transformed by esterases to
tetramethylpiperidine hydrochloride (TPH); multiple mechanisms of action lead to antioxidant, anti-inflammatory, and
antiangiogenic activities; antiangiogenic activity appears synergistic with anti-VEGF agent (eg, Lucentis)
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| Fenretinide: with dry AMD, accumulation of autofluorescent debris before death of ocular tissue; fenretinide binds to retinol-
binding-protein and competes with retinol to reduce toxic effects; phase 2 study under way; most patients do not notice night
vision problems, despite changes detected by electroretinography (ERG)
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| Glatiramer (Copaxone): FDA-approved for multiple sclerosis; to treat drusen, 20 mg injected subcutaneously once
per week
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| MANAGING RETINAL PROBLEMS IN CATARACT PATIENTS
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| Preoperative assessment: standard questions address level of problem (eg, driving, reading, watching television); additional
questions assess specific retinal conditions (ie, presence of distortion, central visual scotoma, problems with peripheral
vision, acquired changes in color vision suggesting problem with macular optic nerve, night blindness, sudden
onset of vision loss); medication history—patients with cystoid edema may take latanoprost (Xalatan), bimatoprost (Lumigan),
or travoprost (Travatan); niacin and ginkgo may contribute to bleeding; diabetic patients—must control DR before
surgery; fluorescein angiography (FA) helpful to detect exudates in macula, capillary dropout, and nonperfusion; in
presence of mild macular edema, treat with steroidal or nonsteroidal agent 2 wk before and 4 wk after surgery; if edema
present and patient already receiving treatment, discuss possible use of bevacizumab or triamcinolone with retinal surgeon;
patients with AMD—AREDS data show no increased risk for choroidal neovascularization associated with cataract
surgery; necessary to rule out occult disease with OCT or FA; if distortion present, perform FA or OCT; potential or
retinal acuity meters (PAM or RAM) may overestimate vision (especially with geographic atrophy or macular disease, in
which patients may have islands of good vision)
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| Blurred vision after cataract surgery: causes—CME; vitreomacular traction; occult AMD; progression of diabetic
maculopathy; phototoxicity; epiretinal membrane; REP or choroidal folds; small vein occlusions; uveitis; vitreous or anterior
chamber hemorrhage; retinal or choroidal detachment; subclinical central serous retinopathy; idiopathic parafoveal
telangiectasis; optic nerve disease; hypotony—may occur in patients with combined procedures (look for choroidal
folds); can significantly decrease vision; easily detected on FA; often seen in posttrauma patients
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| Cystoid macular edema: common cause of blurred vision (now rare); could be Irvine-Gass syndrome, vascular occlusion,
idiopathic perifoveal telangiectasis, epiretinal membrane with vitreoretinal traction, niacin toxicity, birdshot choroidopathy,
or effect of drugs
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| Epiretinal membranes and vitreoretinal traction: severely underdiagnosed before OCT; appear similar to cystoid
edema (macula wet, and small yellow reflex present); epiretinal membranes common before and after surgery; advise patient
of possible temporary or permanent decrease in vision after surgery
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| Idiopathic perifoveal telangiectasis: may appear similar to branch vein occlusion, diabetes, x-ray irradiation, carotid
artery obstruction, or old vein occlusion; more common than previously thought; manifests usually in sixth decade; incidence
equal in men and women; abnormal glucose metabolism seen in 25% of patients; type 1—unilateral with much exudation;
type 2—more common; bilateral and can be subtle with slight asymmetry, pigment alteration, or crystals in
foveal area; type 3—very rare; signs and symptoms—slight decrease in vision (between 20/25 and 20/40); metamorphopsia;
positive scotoma; crystalline deposits; patients at risk for choroidal neovascularization
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| Macular hole: difficult to diagnose in early form; carefully evaluate patients with positive scotoma on Amsler grid; after
surgery, appears similar to cystoid edema until hole progresses from stage 2 to stage 3
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Suggested Reading
Almeida DR et al: Effect of prophylactic nonsteroidal anti-inflammatory drugs on cystoids macular edema assessed using
optical coherence tomography quantification of total macular volume after cataract surgery. J Cataract Refract Surg
34:64, 2008; Bryan RG: The quest to conquer age-related macular degeneration. Med Health RI 91:51, 2008; Cook HL
et al: Age-related macular degeneration: diagnosis and management. Br Med Bull 85:127, 2008; Cunningham MA et
al: Intravitreal steroids for macular edema: the past, the present, and the future. Surv Ophthalmol 53:139, 2008; Fraser-
Bell et al: Update on treatments for diabetic macular edema. Curr Opin Ophthalmol 19:185, 2008; Grover D et al: Intravitreal
steroids for macular edema in diabetes. Cochrane Database Syst Rev Jan 23:CD005656, 2008; Helbig H: Surgery
for diabetic retinopathy. Ophthalmologica 221:103, 2007; Jonas B: Intravitreal triamcinolone acetonide for diabetic
retinopathy. Dev Ophthalmol 39:96, 2007; Kem TS: Contributions of inflammatory processes to the development of the
early stages of diabetic retinopathy. Exp Diabetes Res 2007:95103, 2007; Khan ZA, Chakrabarti S: Cellular signaling
and potential new treatment targets in diabetic retinopathy. Exp Diabetes Res 2007:31864. 2007; Moutray T et al:
Relationships between clinical measures of visual function, fluorescein angiographic and optical coherence tomography
features in patients with subfoveal choroidal neovascularization. Br J Ophthalmol 92:361, 2008; Patel JI: Is cataract surgery
a risk factor for progression of macular degeneration? Curr Opin Ophthalmol 18:9, 2007; Smiddy WE: The cost of
vision for vitreoretinal interventions. Curr Opin Ophthalmol 19:195, 2008; Vasconcelos-Santos DV et al: Secondary
Ocular Hypertension after Intravitreal Injection of 4 mg of Triamcinolone Acetonide: Incidence and Risk Factors. Retina
28:573, 2008.
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