POSTERIOR SEGMENT DISORDERS
From What’s New in Posterior Segment Disorders, presented by the Ocular Immunology and Uveitis Foundation,
Cambridge, MA, and jointly sponsored by the Massachusetts Eye Research and Surgery Institute, Cambridge, and
the Dulaney Foundation, Southeastern, PA
| RETINAL VASCULITIS: LOCAL OR SYSTEMIC THERAPY ?—C. Stephen Foster, MD, Clinical Professor of Ophthalmology,
Harvard Medical School, and President and CEO, Massachusetts Eye Research and Surgery Institute, Boston, MA
|
| Causes: infection, autoimmune disease, malignancy, trauma; some vasculitides isolated to eye; others associated with systemic
vascular diseases, especially autoimmune disorders of connective tissue
|
| Location of vascular inflammation: arterial—associated systemic diseases include systemic lupus erythematosus
(SLE), polyarteritis nodosa, and Churg-Strauss syndrome; infections (eg, syphilis) may have extraocular manifestations
(rare); venous—sarcoidosis most common etiology; other causes include localized ocular disorders (eg, Eales disease,
birdshot chorioretinopathy), paraviral syndromes, toxoplasmosis, and HIV infection; both—may occur in patients with
Behcet’s syndrome, multiple sclerosis, and Wegener’s granulomatosis
|
| Cases secondary to SLE: if no organs threatened, treat patient with nonsteroidal anti-inflammatory drugs (NSAIDs)
then antimalarial agent; if organs threatened, use high-dose systemic corticosteroids; lupus retinal vascular disease—
marker for renal and central nervous system involvement (often fatal); plasmapheresis recommended, followed by induction
therapy with intravenous (IV) cyclophosphamide then transition to, eg, methotrexate and taper corticosteroids; damage
to disc—caused by ischemia and optic neuropathy
|
| Behçet’s syndrome: case—patient, 24 yr of age, with history of recurrent bilateral panuveitis and retinal vasculitis (partially
responsive to high-dose corticosteroids) and retinal and choroidal infarcts; high-dose oral and IV steroids administered;
cyclophosphamide (eg, Cytoxan) also prescribed immediately; visual acuity restored to 20/20 (bilaterally); systemic
inflammation resolved; prednisone tapered; cyclophosphamide stopped after 9 mo to preserve patient’s fertility; “explosive
recurrence” affected brain and eyes; patient hospitalized and treated IV; remission achieved, but maculae and optic nerves
permanently damaged; visual acuity decreased to 20/200 and 20/70; take-home message—retinal vasculitis may profoundly
threaten sight; sometimes associated with life-threatening systemic vasculitis; prolonged aggressive systemic therapy
required for patients with associated Behçet’s syndrome, Wegener’s granulomatosis, polyarteritis nodosa, or SLE
|
| NEW THERAPIES FOR UVEITIS: FROM IMPLANTS TO BIOLOGICS —Dr. Foster
|
| Approach to therapy: stepladder approach recommended, with goal of abolishing active inflammation; specific therapy
to address underlying infection (eg, acyclovir for herpes; penicillin for syphilis); inflammation—steroids used as
first step, followed by NSAIDs; immunomodulators for recurrent cases
|
| Immunosuppressive chemotherapy (immunomodulatory therapy [IMT]): International Uveitis Study
Group (IUSG) published guidelines for use; absolute indications—sympathetic ophthalmia; Vogt-Koyanagi-Harada
syndrome; rheumatoid sclerouveitis; Behçet’s syndrome; steroid monotherapy for these conditions deemed “essentially
negligent” due to high risk for adverse effects with long-term use; initial management should include IMT plus
steroid, with gradual steroid withdrawal; relative indications—intermediate uveitis; retinal vasculitis; juvenile rheumatoid
arthritis; other forms of severe chronic uveitis
|
 | American Uveitis Society Consensus Panel on Immunosuppression for Ocular Inflammatory Disorders: evidence-based
review included recommendations similar to those of IUSG, with addition of ocular cicatricial pemphigoid as indication
|
| Conclusions: IMT should be prescribed more often for patients with ocular inflammatory disease (OID); good evidence
scarce, but IMT effective and well tolerated; absolute indications include Wegener’s granulomatosis and polyarteritis
nodosa; most patients prefer IMT over steroids
|
| Myths associated with IMT: increases risk for cancer; produces adverse effects similar to those seen with cancer chemotherapy
(false if used appropriately for patients with autoimmune diseases); causes infertility (only if alkylating drugs
used for >1 yr); however, significant risks do exist; appropriate use requires experience
|
| Biologic response modifiers (BRMs): designed for selective immunosuppression; originally developed to treat autoimmune
diseases (eg, rheumatoid arthritis) and to prevent rejection of solid-organ allografts; use in patients with
OID—may be associated with better outcomes and less risk; BRMs used off-label for patients with steroid-dependent
vision-robbing disease; preliminary anecdotal reports good
|
| IV immunoglobulin (IVIG): very safe, but difficult to administer due to high protein content (must infuse 1-mo supply
over 3 successive days); potential adverse effects include aseptic meningitis and cardiac overload; patients must be
screened for cardiac reserve and selective IgA deficiency; indications—strong evidence supports use for patients with
autoimmune diseases (eg, idiopathic thrombocytopenic purpura); off-label use for patients with OID (eg, Behçet’s syndrome,
pemphigoid, birdshot chorioretinopathy, and other uveitides)
|
| Daclizumab (Zenapax): monoclonal antibody directed against CD25 glycoprotein on surface of activated T cells (only
activated T cells killed); typically given 1 mg/kg every 2 wk; approved for reversal of solid-organ allograft rejection;
generally well tolerated; speaker’s experience—51 patients with treatment-resistant OID; inflammation diminished
in 71% of cases; vision improved in 60%; adverse events uncommon
|
| Infliximab (Remicade): effective against selected forms of OID (eg, scleritis, uveitis); adverse effects—generally well
tolerated, but may induce lupus-like syndrome, infusion reaction, nausea, fatigue, fever, or shortness of breath; should
be administered only by experienced clinicians; clinical studies—off-label treatment of patients with OID resistant to
conventional immunosuppressive therapy showed improved inflammation in 83% of cases and stable visual acuity in
80%; study treating patients with treatment-resistant uveitis had high rate of serious adverse effects (eg, pulmonary
embolism, congestive heart failure, lupus reaction, and vitreous hemorrhage); concurrent administration of methotrexate
prevents development of autoantibodies; small studies show good initial results among patients with Behçet’s syndrome,
but recurrence typical
|
| Drawbacks: cost; insurance coverage; logistics of administration; potential for serious adverse effects; “dose creep” (patient
needs increasing doses to remain in remission; especially problematic with infliximab); inability to produce durable
drug free remission
|
| MM-093: genetically engineered form of α-fetoprotein (AFP) shows promise in treating patients with rheumatoid arthritis
and psoriasis; speaker and colleagues now performing manufacturer-sponsored studies on patients with uveitis; observations
during pregnancy (ie, improvement in inflammatory disorders) led to investigation of AFP as
immunomodulatory agent
|
| Devices and implants: Posurdex (by Allergan)—biodegra-dable dexamethasone implant injected into vitreous cavity;
drug released over 1 yr as polymer matrix dissolves; safety and efficacy studies completed in patients with diabetic
macular edema; speaker’s group testing it in patients with uveitis; good results reported among patients with macular
edema; adverse events—most occur within 1 wk of injection and include anterior chamber cells and flares, vitreous
hemorrhage, pain, elevated intraocular pressure (IOP), floaters, and eye redness; phase 2 studies confirmed safety and efficacy
(including improved visual acuity) of 700-µg dose for patients with uveitis; phase 3 study under way
|
| WHAT’S NEW IN POSTERIOR SEGMENT TUMORS? —Jay S. Duker, MD, Professor of Ophthalmology, Tufts University
School of Medicine and Tufts-New England Medical Center, and Director, New England Eye Center, Boston, MA
|
| Chemotherapy for bilateral retinoblastoma: currently considered state-of-the-art therapy; can spare at least one
eye
|
| Photodynamic therapy: effective low-risk treatment for vascular tumors of choroid and retina
|
Choroidal Melanoma
| Incidence: cumulative incidence 1 in 2000; average age at diagnosis, 60 yr, but may occur at any age; dysplastic nevus
syndrome only genetic predisposition; local predispositions include light-colored irides, ocular melanocytosis, and extreme
exposure to sunlight
|
| Clinical features: abrupt elevation of lesion; pigmentation varies, but orange surface indicates presence of lipofuscin, suggesting
actively growing tumor; subretinal fluid also suggests tumor activity, but biopsy showing malignant cells only diagnostic
test; most melanocytic lesions >3 mm thick melanomas; mushroom-shaped growth breaking through Bruch’s
membrane in pigmented tumor signals melanoma; growth pattern may be diffuse (may cover 50% of globe); ring melanoma
suggests choroidal detachment; mnemonic—“To Find Small Ocular Melano-mas”; Thickness >2mm; Fluid; Symptoms;
Orange pigment; Margin touching disc; prognosis—when present together, features suggest melanoma; lacking all
these, lesion has 4% chance of growth within 5 yr (observation appropriate course of action); likelihood of growth increases
to ≈33% for lesions with one feature, and to >50% for lesions with >2 features
|
| Systemic issues: work-up should include complete history, physical examination, chest radiography, liver function tests,
and computed tomography of liver; 98% of patients have no detectable metastases at time of diagnosis; mortality—
thick-ness main clinical determinant; 5-yr mortality <5% for patients with lesions <3 mm, 16% for those with lesions 3
to 4 mm, 32% for those with lesions 4 to 8 mm, and ≈50% for those with lesions >8 mm
|
| Collaborative Ocular Melanoma Study (COMS): patients with small tumors observed; those with medium-sized
tumors randomized to enucleation or I125 irradiation (iodine plaque); all patients with large tumors underwent enucleation;
50% of these received presurgical radiation; results—pre-enucleation irradiation “of no benefit”; 35% of tumors
metastasized within 5 yr; main risk factors for mortality include size, thickness, disc proximity, and cell type; <5% of
small tumors metastasized; major finding—irradiation and enucleation associated with similar risks for metastasis
|
| Metastasis: risk factors include larger size, ciliary body involvement, and extraocular extension; pathologic features—
epithe-lioid cell types; closed, periodic acid-Schiff (PAS)-positive vascular loops; increased mitotic rate (>4 mitoses in
40x field)
|
| Cytogenetic analysis: stratifies patients according to risk by analyzing tumor DNA; techniques—fluorescein in situ
hybridization (earlier technique; still used but requires specialty laboratory); polymerase chain reaction (PCR; available
at most hospitals); tissue sampling—enucleated specimens; fine needle aspiration biopsy (transvitreal approach may increase
risk for conjunctival and orbital metastasis [seeding]; transscleral approach may be used immediately before radiation
plaque therapy); small-gauge vitrectomy (may reduce risk for metastasis from seeding); findings—monosomy of
chromosome 3 associated with poor prognosis (mortality 50% at 3 yr and 80% at 5 yr); disomy of chromosome 3 associated
with negligible risk for metastasis; trisomy of chromosome 8 or 8q also may increase risk
|
| Treatment: radiation therapy—used for tumors <8 mm thick and 16 mm in diameter (doses required by larger tumors
often destroy eye); local control achieved in >90% of cases; usually delivered via brachytherapy (eg, radiation plaque;
proton beam irradiation also used); commonly associated with radiation retinopathy
|
| Gamma knife: linear accelerator that directs gamma rays at tumor (201 beams produce cumulative effect); widely available;
primarily used for intracranial tumors; requires extensive treatment planning to minimize adverse effects; patient’s
head and globe fixed during procedure (only invasive portion of procedure is retrobulbar block used to fix
globe); tumor localized using high-resolution magnetic resonance imaging; computer-assisted treatment planning
helps spare optical structures; dose—speaker’s group uses 21 to 25 Gy; use of 20 to 80 Gy reported; higher doses increase
risk for adverse effects; advantages—does not require particle accelerator or surgery; requires only one treatment
session; disadvantages—no randomized trials; Tufts experience—used for patients with no treatment option
other than enucleation (including patients with optic disc tumors); local control achieved in 92% of patients; 15% mortality
(associated with metastasis); visual acuity spared in some patients
|
| MANAGEMENT OF RETINAL VENOUS OBSTRUCTIONS —Dr. Duker
|
| Chorioretinal anastomosis: creates “retinal bypass” by focusing laser on distal vein; decreases IV pressure, allowing
venous outflow; results—when anastomosis achieved, visual acuity improves significantly in 83% of patients; status—
enthusiasm for procedure has waned in United States due to difficulty of achieving anastomosis and advent of medication
(anti-vascular endothelial growth factor [anti-VEGF])
|
| Retinal vein cannulation: involves puncturing retinal vein and injecting tissue plasminogen activator; never widely
accepted, due to lack of instrumentation, absence of confirmatory data, and introduction of medication
|
| Radial optic neurotomy: involves pars plana vitrectomy and incision of optic nerve sheath with microvitreoretinal
blade; popularity waned due to paucity of confirmatory data and availability of medication
|
| Anti-VEGF agents: intravitreal triamcinolone (eg, Kenalog)—good anatomic results (visual results less impressive)
in several small retrospective studies with short follow-up; no well-controlled prospective trials; IOP increases in
≈50% of patients; good short-term therapy for central retinal vein obstruction (CRVO); intravitreal bevacizumab
(Avastin)—anti-VEGF antibody; ophthalmic use off-label; usual dose 1.25 mg; associated with modest improvements
in vision and anatomy; ranibizumab (Lucentis) and pegaptanib (Macugen)—approved for age-related macular
degeneration; limited off-label use in CRVO; in manufacturer-sponsored trials using Lucentis, macular edema
resolved in all patients with ischemic CRVO, but no significant improvement in vision
|
| Summary: no anti-VEGF agents proven effective; corticosteroids riskier but more effective; anatomic vs visual
results—anatomic improvement seen in 70% to 80% of patients treated with triamcinolone; visual results much more
limited; “macular edema is not the only reason why these eyes do not see”
|
Suggested Reading
Damato B: Legacy of the collaborative ocular melanoma study. Arch Ophthalmol 125:966, 2007; Gilger BC et al: A
novel bioerodible deep scleral lamellar cyclosporine implant for uveitis. Inves Ophthalmol Vis Sci 47:2596, 2006; Gul A:
Standard and novel therapeutic approaches to Behcet’s disease. Drugs 67:2013, 2007; Hsu J: Drug delivery methods for
posterior segment disease. Curr Opin Ophthalmol 18:235, 2007; Kupperman BD et al: Randomized controlled study of
an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol 125:309,
2007; Margo CE: The Collaborative Ocular Melanoma Study: an overview. Cancer Control 11:304, 2004; Margolis R
et al: Intravitreal bevacizumab for macular edema due to occlusive vasculitis. Semin Ophthalmol 22:1025, 2007; Scott IU,
Ip MS: It’s time for a clinical trial to investigate intravitreal triamcinolone for macular edema due to retinal vein occlusion:
the SCORE study. Arch Ophthalmol 123:581, 2005; Smith JR, Rosenbaum JT: Management of immune-mediated
uveitis. BioDrugs 13:9, 2000; Sobrin L et al: Infliximab therapy for the treatment of refractory ocular inflammatory disease.
Arch Ophthalmol 125:895, 2007.
Educational Objectives
| The goal of this program is to improve the management of posterior segment disorders associated with malignant, inflammatory,
and autoimmune diseases. After hearing and assimilating this program, the clinician will be better able to:
|
| 1. Name the most common causes of retinal vascular inflammation.
|
| 2. Manage retinal vasculitis secondary to lupus and Behçet’s syndrome.
|
| 3. Explain why the International Uveitis Study Group considers it negligent to treat ocular inflammatory disease
with steroid monotherapy.
|
| 4. Develop treatment plans for patients with choroidal melanoma.
|
| 5. Describe the role of triamcinolone in treating patients with retinal venous obstructions.
|
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
members 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, the following has been disclosed:
Dr. Foster is on the Speakers’ Bureaus of Ista Pharmaceuticals, Bausch & Lomb, Alcon, and Allergan, and receives
grant support from Allergan and Ista Pharmaceuticals; Dr. Duker receives research support from Optivue and Carl
Zeiss Meditech, is a consultant for Alcon and Genentech, and is on the scientific advisory board of Paloma Pharmaceuticals.
The planning committee reported nothing to disclose.
Acknowledgments
Drs. Foster and Duker were recorded at What’s New in Posterior Segment Disorders, presented by the Ocular Immunology
and Uveitis Foundation, and jointly sponsored by the Massachusetts Eye Research and Surgery Institute and
the Dulaney Foundation, and held October 20, 2007, in Cambridge, MA. The Audio-Digest Foundation thanks the
speakers and the sponsors for their cooperation in the production of this program.
|
