RETINAL SYMPOSIUM
From the 2006 Ophthalmology Symposium, presented by Kaiser Permanente, Pasadena, CA
| DIABETIC RETINOPATHY: OPTIMAL LASER TECHNIQUES —David J. Browning, MD, Charlotte Eye, Ear, Nose
and Throat Associates, Charlotte, NC
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Diabetic Macular Edema (DME)
| Focal laser (historical approach): based on first report of Early Treatment of Diabetic Retinopathy Study (ETDRS;
1985); threshold for treatment (clinically significant macular edema)—foveal thickening; thickening within 500 µm
or one third disc diameter of fovea; macular thickening of at least disc area, any part of which disc diameter from fovea;
focal laser applied to microaneurysms and dilated capillaries; results—some cases of DME do not resolve with focal laser;
at 1 yr, 35% of patients did not have clearing of edema, despite multiple treatments
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| Current concepts: white burns discontinued; fluorescein angiography not necessary to guide treatment; optical coherence
tomography (OCT) useful to locate areas of subretinal fluid to avoid breaking through Bruch’s membrane; vitrectomy
for DME and taut hyaloid (study by Lewis)—posterior vitreous cortex adherent to macula; sometimes dramatic
efficacy in thinning macula and improving vision; focal laser compared to intravitreal triamcinolone (Diabetic Retinopathy
Clinical Research Network [DRCR.net])—800 eyes; study ongoing (results to be published in 2009); anti-
vascular endothelial growth factor (VEGF) drugs—in preliminary data, pegaptanib (Macugen) effective in reducing
DME, at least temporarily; more recently, bevacizumab (Avastin), ranibizumab (Lucentis), and VEGF Trap show promise
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| Choice of therapy: historical approach—start with focal laser (if not effective and posterior hyaloid membrane attached,
consider vitrectomy; if hyaloid not attached, consider intravitreal injection of triamcinolone); if all else fails, consider
intravitreal Macugen; alternative approaches—consider invasiveness, efficacy, cost, safety, and clinical
characteristics (eg, findings on OCT); speaker’s approach—issues whether therapy alters state of eye; state-changing
therapies (focal laser and vitrectomy increase oxygen concentration in vitreous)
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| Effect size vs time: focal laser—change in central subfield mean thickness; up to one quarter of eyes thicker after treatment;
wide response (from marked thinning to thickening); average response modest (25-50 µm of thinning); intravitreal
triamcinolone—4% of eyes thicken after treatment; on average, response quick (within 2 wk to 1 mo, ≈100 µm of
thinning); waning effect dose-dependent; with 4 mg, effect gone by about 4 mo (20 to 25 mg, effect persists 1 yr; 10 mg,
3 to 4 mo or more); vitrectomy—less data; effect more significant than with laser; more paradoxical responses than with
triamcinolone (fewer than with focal laser); data highly variable; thinning does not wane
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| Baseline thickening: calculation—thickness of central subfield minus average seen in normal eyes; focal laser—
linear response (thicker at baseline, greater response to single focal laser treatment); much variability, but on average
≈45% reduction in thickening; intravitreal triamcinolone—≈70% of thickening eliminated; vitrectomy—119% reduction;
typically, eyes selected for procedure ≥500 µm (toxic level of edema); with treatment, result atrophic macula
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| Proposed changes in management
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 | Mild or focal DME: proposal to treat with focal laser only
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| More severe DME: 2-pronged approach—jump-starting eye with intravitreal triamcinolone or anti-VEGF drug, then
focal laser for sustainability; recent paper showed promising results; if eye phakic or glaucomatous, consider bevacizumab;
if pseudophakic, consider triamcinolone (may be more effective than anti-VEGF drug); threshold for treatment
depends on patient, compliance, and follow-up; consider it for eyes with thickness >300 µm and vision worse than 20/
30; 3-pronged approach—considered in eyes with worst DME; primary vitrectomy (with or without posterior hyaloids
attached), with intravitreal anti-VEGF or triamcinolone, and focal laser; threshold (eyes with ≥500 µm thickening,
or vision 20/60 or worse)
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Proliferative Diabetic Retinopathy (PDR)
| Current concepts: severe non-PDR or non-high-risk PDR—scatter laser; frequency of induced DME (single- vs
multiple-session treatment)—small sessions may reduce rate of DME exacerbation (but with more modern, lighter intensity
panretinal laser, difference may not matter); DRCR.net trial ongoing; DME or subclinical DME with PDR—
consider intravitreal triamcinolone or Avastin as initial therapy; wait 1 wk to apply scatter laser (proliferations less luxuriant;
anecdotally effective); focal laser vs focal laser plus Avastin (DRCR phase 2; ongoing)
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| CONTROVERSY: INTRAVITREAL TRIAMCINOLONE SHOULD PLAY A VITAL ROLE IN THE TREATMENT OF
DIABETIC MACULAR EDEMA —J. Michael Lahey, MD, Permanente Medical Group, Hayward, CA; Associate Clinical
Professor, University of California, San Francisco, School of Medicine
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| Drug profile: intravitreal triamcinolone potent anti-inflammatory steroid; onset within hours or days; reliably reduces
clinically significant macular edema, unless traction present; effects reversible; no evidence of damage to retinal tissue;
blocks multiple inflammatory pathways (probably blocks some isoforms of VEGF); problem of side effects and waning
benefit
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| Complications: cataract and glaucoma; floaters (usually die down at 1 to 2 wk); sterile and bacterial endophthalmitis
(incidence decreased by removing supernatant); does not change state of eye (disease can recur)
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| Disadvantages of laser: 35% of diffuse DME not responsive to laser; problem of thermal damage to retina; frequently,
laser added after triamcinolone injections; inflammation tends to exacerbate DME; DME difficult to treat with laser
alone; triamcinolone and panretinal photocoagulation (PRP)—often, vision improved
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| Vitrectomy: performed on almost every patient with significant diabetic retinopathy (exception those with severe glaucoma
or at high risk for glaucoma); postoperative triamcinolone—decreased problems with intraocular pressure (IOP;
probably due to decreased half-life); indicated in many patients with epiretinal membranes or thickened posterior hyaloid
(normalization on OCT may take months after peeling alone); added steroid usually prevents IOP spike and achieves
good result
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| Diabetic macular traction syndrome: OCT indicated in most patients with diabetes (not many have classic thickened
hyaloid at optic nerve and classic vitreomacular traction [VMT] on clinical examination); most patients with severe
DME treated with intravitreal triamcinolone first (laser added 1-4 wk later)
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| Summary: best candidates for intravitreal triamcinolone have diffuse DME not responsive to laser, or severe DME; in
most cases, drug administered at end of vitrectomy; can be combined with focal laser therapy; induced cataract especially
common in older patients (glaucoma can develop 3 or 4 mo after treatment, especially if high doses used); phakic patients
and those with glaucoma risk factors less likely good candidates; intravitreal triamcinolone helps significant percentage
of patients regain vision
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| CONTROVERSY: INTRAVITREAL TRIAMCINOLONE SHOULD BE USED SPARINGLY FOR TREATMENT OF
DIABETIC MACULAR EDEMA —Jennifer I. Lim, MD, Associate Professor of Ophthalmology, Doheny Eye Institute,
Keck School of Medicine, University of Southern California
|
| Focal laser: ETDRS—treating focal microaneurysms, or using grid to treat areas of leakage or nonperfusion results in
reduction in thickening of DME in ≈50% of eyes; disadvantages—focal inflammation and retinal damage; induction of
cytokines (may exacerbate DME); scotomas; if burn too hot, rupture of Bruch’s membrane and choroidal neovascularization;
advantages—ability to prevent moderate vision loss (in small percentage of patients, improvement); decreased risk
for loss of color vision; visual field loss minor
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| Intravitreal Steroid Therapy (overview): advantages—fast response; improved visual acuity; consider it in eyes
with poorer visual acuity (eyes with diffuse DME or chronic diffuse DME may respond); disadvantages—risk for cataract
with multiple injections; 20% to 50% increase in IOP; endophthalmitis (incidence 1 in 500 to 1 in 1000); vitreous
hemorrhage (1 in 200); edema recurs (usually within 24 wk or 6 mo); triamcinolone (Kenalog 40; decanting supernatant
may be necessary); rate of sterile endophthalmitis or hypopyon 1% to 5% (benzyl alcohol and polysorbate 80 toxic to retina)
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| Intravitreal Steroid Injection Study (ISIS): parameters—Kenalog 40 (2- or 4-mg dose); findings—greater efficacy
and duration of 4-mg dose at 3 and 6 mo; if foveal cystoid macular edema (CME) present, 62% of eyes improved ≥3
lines (for noncystoid, rate 9%); side effects—IOP increased ≥10 mm Hg in 31% (IOP >30 mm Hg in 28%)
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| Intravitreal fluocinolone implant (Retisert; study): device able to deliver drug up to 3 yr; parameters—
comparison of 0.5-mg dose, 0.3 mg, and standard care; 24-mo data—resolution of edema centrally in 53.7% of treated
patients (if untreated, rate 28%); average loss of letters (untreated, 9 letters; treated, <2); adverse events—0.3-mg dose
(cataract progression in 77% of treated eyes (without treatment, rate 13%); IOP increased in 31.7% of treated eyes (0% of
untreated eyes); cataract surgery needed in 74% of treated eyes (13% of untreated eyes)
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| Intravitreal dexamethasone implant (Posurdex; study): device injected into eye (degrades in 6-8 wk); capable
of delivering drug 35 days (effect may last up to 180 days); parameters—patients received 350- or 700-µg dose, or observation;
6-mo results—for 700 µg, 19.4% gained ≥3 lines of vision (8% in observation group); IOP increased >10 mm
Hg in ≈17% (3% in observation group); phase 3 studies—22-gauge injector that can be given in office
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| Macugen (phase 2 trial): parameters—0.3, 1.0, or 3.0 mg administered every 6 wk, for 12 wk; at 16 wk, repeat injection
or laser at discretion of investigator; outcomes at 36 wk—more eyes in 3.0-mg group improved ≥5 lines, ≥10 lines, or
stabilized, compared to sham; at 0.3-mg dose, average outcome 68 µ decrease in central thickness (3.7 µ or no change in
sham group); >100 µ decrease in central thickness (with treatment, rate 42%; in sham group, 16%); safety—rate of endophthalmitis
0.15%; retinal detachment (1 case in sham group); no increase in IOP or incidence of cataract; bottom line—anti-
VEGF therapies may be reasonable in patients with glaucoma, glaucoma suspects, and ocular hypertensives not able to withstand
IOP increase associated with triamcinolone or fluocinolone implants
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| RATIONAL WORK-UP AND PROPHYLAXIS OF VEIN OCCLUSION —Dr. Lahey
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| Etiologic factors in thrombosis (Virchow’s triad): changes in blood vessel wall, blood flow, or coagulability
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| Patient history: small percentage of patients treated with intra-vitreal thrombolytics; onset of vision loss (arterial occlusion
acute; vein occlusion more insidious); in some patients, vision 20/20 and vein occlusion discovered incidentally;
thrombolytic must be used early to be effective; in study by Blumenkranz, 17% of patients have occlusion in fellow eye
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| Ocular examination: afferent pupillary defect (APD) testing least expensive way to distinguish ischemic from nonischemic
problem (quick and fairly reliable); gonioscopy indicated especially in first-time patient with no risk factors and
angle that looks questionable, and on follow-up to detect neovascularization; bilateral dilated examination best way to detect
thrombophilia (if bilateral central retinal vein occlusion [CRVO] present, thrombophilia likely); hyperviscosity
(more rare than congenital tortuosity of veins; associated with hemorrhages, decreased vision, and thickening of macula
[unlike congenital tortuosity of veins])
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| Diagnostic tools: OCT mainstay for documenting severity of thickening; helpful for monitoring effect of treatment (tissue
plasminogen activator [tPA], steroid, Macugen, or Avastin); nerve fiber layer test to detect subtle changes associated
with glaucoma; Fast Macular Thickness Scan quick and easy; angiography and color photography to document off-label
use of medications (eg, tPA) or to show patients severity of CRVO
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| Study 1: control group much less obese; rate of diabetes and glaucoma significantly different in control group, compared
to study group; no familial thrombophilias found; ≈8% had collagen vascular diseases (not new diagnosis); more common
clues to retinal vein occlusion include hypertension, diabetes, hyperlipidemia, and glaucoma
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| Study 2: findings—27% of patients had positive laboratory test; homocysteine, antiphospholipid antibodies, and anticardiolipin
antibody levels significantly different from control group; some believe antiphospholipid antibodies marker
for previous thrombosis
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| Work-up: for 60-yr-old patient with normal blood pressure, mildly elevated cholesterol, and vein occlusion, speaker usually
does not perform work-up (elevated cholesterol sufficient); if patient 30 yr of age, approach different; disease that
causes clotting usually occurs at younger age; take history (ask whether family member has history of clotting at <50 yr
of age); look for bilateral CRVOs; battery of tests available (eg, platelet tests); group most likely to have true positive
tests young people who have clotting in absence of other risk factors; bread-and-butter tests for RVO—hemoglobin
A1C standard; fasting or random glucose; complete blood count (CBC) with differential and platelets to detect hypercoagulable
states and hyperviscosity syndrome; lipid profile (cholesterol and tri-glycerides); blood pressure; measure IOP at
every visit
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| Prophylaxis: warfarin (Coumadin) not safe (old studies reported positive treatment effect; no randomized study); low-
molecular-weight heparin slightly safer; blood tests used to identify patients with impending CRVOs (helpful anecdotally;
no randomized studies); intravitreal tPA (safe; effective in only 38% of eyes); 2% of patients treated with thrombolytics;
best prophylaxis control of major risk factors—fighting and treating obesity difficult; no definite evidence
that aspirin helpful; obesity, longer lifespan, and diabetes increasing; (decreased percentage of thrombophilias); focus on
hypertension, diabetes, and hyperlipidemias
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Educational Objectives
| The goal of this program is to educate the listener about strategies for managing diabetic macular edema and retinal vein occlusion
(RVO). After hearing and assimilating this program, the clinician will be better able to:
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| 1. Describe strategies of laser photocoagulation that may optimize outcome in patients with treatable diabetic macular
edema (DME).
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| 2. Describe strategies for managing proliferative diabetic retinopathy.
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| 3. Decide whether to treat DME with intravitreal triamcinolone.
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| 4. Investigate the etiology of RVO.
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| 5. Appraise the efficacy of prophylaxis against RVO.
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Discussed on This Program
Bevacizumab [Avastin]
Heparin sodium injection Heparin sodium lock flush solution [Heparin Lock Flush, Hep-Lock, Hep-Lock U/P]
Pegaptanib sodium [Macugen]
Ranibizumab (RhuFab V2) [Lucentis] (investigational)
Reteplase, recombinant (recombinant tissue plasminogen activator) [Retavase]
Triamcinolone acetonide (several formulations and trade names)
Warfarin sodium [Coumadin]
Suggested Reading
[No authors listed]: Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report
number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 103:1796, 1985; Browning
DJ: Potential pitfalls from variable optical coherence tomograph displays in managing diabetic macular edema. Am J
Ophthalmol 136:555, 2003; Holekamp NM et al: Vitrectomy surgery increases oxygen exposure to the lens: a possible
mechanism for nuclear cataract formation. Am J Ophthamol 139:302, 2005; Jonas JB et al: Duration of the effect of intravitreal
triamcinolone acetonide as treatment for diffuse diabetic macular edema. Am J Ophthalmol 138:158, 2004; Lahey
JM et al: Combining phacoemulsification and vitrectomy in patients with proliferative diabetic retinopathy. Curr
Opin Ophthalmol 15:192, 2004; Lahey JM et al: Hypercoagulable states and central retinal vein occlusion. Curr Opin
Pulm Med 9:385, 2003; Lahey JM et al: Laboratory evaluation of hypercoagulable states in patients with central retinal
vein occlusion who are less than 56 years of age. Ophthalmology 109:126, 2002; Lahey JM et al: Sequential treatment
of central retinal vein occlusion with intravitreal tissue plasminogen activator and intravitreal triamcinolone. Br J Ophthalmol
88:1100, 2004; Lim JI: Macular disease. Introduction. Ophthalmol Clin North Am 15:xi, 2002; Pelzek C, Lim
JI: Diabetic macular edema: review and update. Ophthalmol Clin North Am 15:555, 2002; Rosenblatt BJ et al: Pars
plana vitrectomy with internal limiting membranectomy for refractory diabetic macular edema without a taut posterior hyaloid.
Graefes Arch Clin Exp Ophthalmol 243:20, 2005; Spandau UH et al: Dosage dependency of intravitreal triamcinolone
acetonide as treatment for diabetic macular edema. Br J Ophthalmol 89:999, 2005; Stolba U et al: Vitrectomy
for persistent diffuse diabetic macular edema. Am J Ophthalmol 140:295, 2005; Yanyali A et al: Modified grid laser
photocoagulation versus pars plana vitrectomy with internal limiting membrane removal in diabetic macular edema. Am J
Ophthalmol 139:795, 2005.
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, Dr. Lim disclosed
that she has served on the Advisory Boards of Genentech, EyeTech/OSI, Allergan, and Novartis; she has received
educational or research grants from Genentech, EyeTech, and Norvartis.
Drs. Browning, Lahey, and Lim were recorded at the 2006 Ophthalmology Symposium, presented June 3, 2006, in Long
Beach, CA, by Kaiser Permanente. The Audio-Digest Foundation thanks the speakers and Kaiser Permanente for their cooperation
in the production of this program.
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