PERSPECTIVES ON UVEITIS
From Uveitis for the Other Subspecialist, presented February 4-5, 2005, by Bascom Palmer Eye Institute, Miami
| LOCAL THERAPY FOR UVEITIS: SHOTS AND IMPLANTS —Daniel F. Martin, MD, Thomas M. Aaberg Professor of
Ophthalmology, Emory University School of Medicine, and Director of Retina Services, Emory University Eye Center, Atlanta
|
| Advantages of local therapy: diagnosis of underlying systemic disorder seldom drives choice of therapy in uveitis; concentrates
therapy where needed most; avoids systemic toxicity and problems with patient compliance; blood-ocular barrier
powerful foe in trying to effect change inside eye with systemically administered drugs
|
Periocular Steroids
| Triamcinolone (Kenalog): 40 mg in volume of 1 mL; speaker prefers inferotemporal sub-Tenon injection
|
| Complications of supratemporal sub-Tenon (Nozik-type) injection: primarily, ptosis; once needle passes equator, some
physicians inject directly into levator (steroids around levator weaken it); supratemporal approach (some patients require
ptosis repairs); problem of multiple injections into septum (breach can create prolapsed fat pad requiring cosmetic surgery
or lower lid blepharoplasty); other potential complications—globe penetration; cataract; elevated intraocular pressure
(IOP)
|
| Inferotemporal approach: only critical structure is insertion of inferior oblique muscle; speaker aggressively turns needle
back; consider 40 mg Kenalog via 27-gauge needle; apply topical proparacaine (speaker wets small cotton-tipped applicator
and holds it there 1 min); when entering sub-Tenon space, needle usually 1 to 2 mm anterior to cul-de-sac; speaker
aggressively follows curvature of globe (procedure contraindicated in, eg, 20 D myope); but in most people who have
normal axial length, the greater the curve posteriorly, the less ballooning of conjunctiva and the less anterior displacement
of injection; not ideal as sole therapy for patients with relentless bilateral disease (after, eg, ≥50 periocular steroid injections,
many patients require lower lid procedures)
|
Intravitreal Injection
| Frosted angiitis related to cytomegalovirus (CMV) retinitis (case): patient status post-bone marrow transfusion (BMT)
and HIV negative; most patients have geographic area of CMV in periphery that does not respond as quickly to single injection,
but 1 injection of intravitreal ganciclovir can be effective
|
| Acute retinal necrosis (ARN): historically, intravenous (IV) acyclovir primary treatment; retinal necrosis (RN) caused by
herpesvirus infection—local therapy more effective than systemic therapy in delivering antiviral medication; intravitreal
foscarnet and oral valacyclovir (Valtrex) alternatives to IV acyclovir; valacyclovir—1 g tid has better bioavailability than
oral acyclovir; consider famciclovir (Famvir); from penetrating keratoplasty (PK) studies, 1 g Valtrex equivalent to ≈350
mg of IV acyclovir; plateau effect limits benefit of increased dose; general dose for acyclovir 10 mg/kg (for 70 kg person,
700 mg IV tid); Valtrex cannot replicate IV dose (risk for undertreatment); foscarnet—can be injected safely into vitreous
cavity; studies of CMV retinitis extrapolated to treatment of RN; speaker’s current strategy—foscarnet administered intravitreally
(usually once weekly for 3 wk; additionally, Valtrex); according to recent paper, patients treated with acyclovir
have decreased risk for fellow eye involvement; highest risk period first 14 wk; once patient on Valtrex, speaker continues
for 3 mo
|
| Triamcinolone: not used much for uveitis; target tissue choroid; periocular injection avoids risk for endophthalmitis and
has lower risk for increased IOP; theoretically useful for recalcitrant cystoid macular edema (CME), but not good choice
for long-term therapy
|
| Injection technique: use pledget of 2.0% lidocaine on cotton-tipped applicator for ≈10 min; subconjunctival injection carries
risk for subconjunctival hemorrhage due to piercing of scleral vessel; some put small amount of lidocaine gel in cul-
de-sac; pegaptanib (Macugen)—in recent study, only factor that seems to reduce risk for endophthalmitis with intravitreal
injection was use of lid speculum; speaker not convinced of value of lid speculum (however, medicolegal considerations
may necessitate use); in speaker’s experience, even with no povidone iodine (Betadine) or lid speculum, incidence
of endophthalmitis “zero”; more management tips—physician can inject 0.1 mL safely through 30-gauge needle; for
ganciclovir, usually, 2000 mg in 0.05 solution to avoid IOP spike; speaker does not check IOP routinely afterwards (any
manipulation of eye potentially expresses meibomian gland); typically, topical antibiotics 3 to 4 days
|
| Abdominal non-Hodgkin’s lymphoma (case): 44-yr-old white female patient; 5 mo post-BMT; new hypopyon; anterior
chamber tap (lesion genetically identical to original tumor); recurrent hypopyon while on 60 mg of prednisone with IOP
60 mm Hg and visual acuity 20/60; ascites and abdominal recurrence; survived only 3 mo; palliative therapy intravitreal
methotrexate (400 µg once weekly for 4 wk, then once monthly thereafter); role in treatment of intraocular lymphoma remains
to be studied
|
Sustained-Release Drug Delivery Devices
| Ganciclovir implant: studies can be extrapolated to other diseases and sustained-release drug delivery devices (eg, fluocinolone
implant)
|
 | Efficacy: study—implant ≈3 times more effective to 21 days vs 71 days; later study—CMV retinitis; patients treated
with systemic ganciclovir IV (probably can substitute valganciclovir now); reimplantation possible with reasonable
safety; study population profoundly immunocompromised
|
| Vitreous hemorrhage: study 1—>5000 cases (risk ≈0.5%); many individuals had thrombocytopenia or other blood dyscrasias
(risk for vitreous hemorrhage 1.1%); speaker’s series—620 implant procedures performed; several patients who
had vitreous hemorrhage had visual acuity worse than 20/200 1 mo after procedure; study 2—if devices exchanged,
slight increased risk for vitreous hemorrhage with repeat procedures; persistent hypotony more an issue in fluocinolone
implant (some eyes with severe uveitis do not make aqueous); in CMV retinitis, eyes otherwise healthy; transient decrease
in vision only significant problem; 5.5-mm incision vs 3.0- to 3.5-mm incision used for fluocinolone implant
(smaller device permits smaller incision)
|
| Retinal detachment (study): with fluocinolone implant, no significant increase in risk over baseline; probably small increased
risk for detachment early on (not long-term because of better control of CMV)
|
| Long-term fixation: nylon not adequate; fluocinolone implant sewn in with proline; some risk for proline eroding through thin
conjunctiva; group of immune-recovered patients with dislocated implants beginning about third year postoperatively
|
| Protocol 2304 (study): if CMV retinitis treated locally with implant, CMV viremia still needs treatment; consider valganciclovir
at maintenance dose and implant for patients who have severe sight-threatening disease
|
| Cyclosporine implant: primarily inhibits T-cell activation and proliferation (occurs in node); paper—intravitreal injections
of cyclosporine; seemed to decrease risk for full expression of experimental autoimmune uveoretinitis; some toxicity
issues; small trial—not as effective as would like; trying to avoid steroid implant
|
| Dexamethasone implant: 10-mo device; with cyclosporine implant, 10-yr device possible; with fluocinolone implant, ≥3
yr
|
| Fluocinolone implant (study): dosage 2.0 mg or 0.5 mg; potential complications of long-term steroid use (diabetes, hypertension,
osteoporosis, and weight gain)
|
| Inclusion criteria: 278 patients with severe, intermediate, or posterior uveitis who required oral steroids for at least last 3
mo; many patients had been on immunosuppressive therapy or oral steroids for years, or multiple periocular steroid injections
over 6 mo; implant placed in 1 eye; systemic immunosuppressive therapy withdrawn (goal to discontinue by 7 to
8 wk; achieved in most); primary outcome measure recurrence of uveitis; 2-step increase in anterior chamber cell, 2-step
increase in vitreous opacity, or 15-letter decrease in visual acuity (presumably due to CME); secondary outcome measures
visual acuity, adjunctive treatment, and safety
|
| Results: steroids work very well; recurrence rate during first year 4.3% in study eye (56% in fellow eye); visual acuity
(not much change in study eye; continued decrease in fellow eye); 26% of patients had 3-line increase in vision (at 2 yr,
greater increase expected); all patients develop cataracts (by 1 yr, many not treated); amount of systemic therapy significantly
decreased after implantation; number of periocular injections decreased in involved eye (number increased in
fellow eye); IOP—at 1 yr, 30% of patients required topical therapy; risk for trabeculectomy 12%; almost every patient
who has had implant requires glaucoma filtering procedure; cataracts—≈25% of patients have had cataract extraction
by 1 yr; over time, speaker expects risk to approach 100%
|
| Summary: significant reduction in recurrence in implanted eye, compared to fellow eye; significant decrease in adjunctive
therapy postimplantation; on average, visual acuity stable, with 3-line improvement in 26%; adverse events managed
by conventional means
|
| MASQUERADE SYNDROMES —David G. Callanan, MD, Assistant Clinical Professor of Ophthalmology, University of
Texas, Southwestern Medical Center, Dallas
|
| Infectious uveitis: fluorescent treponemal antibody (FTA) test and rapid plasma reagin (RPR) indicated to rule out syphilis;
Lyme disease
|
Primary Central Nervous System (CNS) or Ocular Lymphoma
| Presentation: varies from obvious subretinal infiltrate to large, serous subretinal area and hemorrhage; primary CNS
lymphoma—primary intraocular lymphoma (PIOL); bilateral or unilateral; mild or moderate vitreitis with no focal lesions
or typical subretinal infiltrates; in middle-aged to older individual, lymphoma in differential diagnosis; subretinal
infiltrates steer diagnosis towards primary CNS or intraocular lymphoma; lymphoma cells invade subretinal space; significant
vitreitis and no CME in middle-to-older aged individual sometimes clue to lymphoma; if no pars plana exudate,
birdshot lesions, or evidence of vasculitis, and laboratory studies negative, speaker performs diagnostic vitrectomy; if primary
CNS or intraocular lymphoma suspected, order magnetic resonance imaging (MRI) with contrast; if signs more
subtle, order MRI with contrast and flare (fat suppression); specify need to rule out CNS lymphoma; not lumbar puncture
(yield low)
|
| Vitreous biopsy: consider 25-gauge vitrectomy; specimen must be taken immediately for processing (send to National Eye
Institute or refer case to tertiary center); average time to diagnosis in PIOL as long as 18 mo; tertiary referral centers offer
more sophisticated evaluation of vitreous specimen and cerebrospinal fluid (CSF); additional tests—cytokine evaluation
for interleukin-10 to -6 ratio (using enzyme-linked immunosorbent assay [ELISA]) helpful in confirming diagnosis (ratio
>1 suggests lymphoma); flow cytometry; immunohistochemistry, looking for chemokine receptor expression; molecular
analysis (microdissection followed by polymerase chain reaction [PCR] test to detect immunoglobulin gene rearrangements)
|
| Treatment: when patient presents with primary CNS lymphoma or PIOL, speaker involves neuro-oncologist quickly to follow
up MRI and CSF analysis (often, serial testing used to detect disease); if primary CNS lymphoma patients given
methotrexate and other chemotherapeutic agents, then brain irradiated, many develop dementia; ocular-only involvement
controversial; in past, radiation standard in patient diagnosed with intraocular lymphoma; patients appeared cured, but
later developed radiation retinopathy; use of intraocular methotrexate increasing
|
Metastatic Lymphoma
| Introduction: any systemic lymphoma (Hodgkin’s, non-Hodgkin’s, or cutaneous) can present in eye; case—patient treated
until lymphoma in remission; not treated for 18 mo, but problem in eye; first suspicion recurrence of lymphoma; on angiography,
evidence of infiltrates; retreatment with chemotherapy; no response initially, so patient received radiation therapy;
after treatment, lesions resolved; in uveitis, remember systemic history; PIOL tends to enter subretinal space (most
metastatic lymphomas in choroid)
|
| Hodgkin’s lymphoma (case): history of chronic uveitis almost 1 yr; work-up normal (abdominal computed tomography
[CT]; MRI; blood tests); patient followed 1 yr, then presented with small bump above clavicle; speaker recognized node;
once treated, vision returned to 20/20
|
| Cutaneous T-cell lymphoma (case): patient presented with cutaneous T-cell lymphoma; followed by oncologist; started to
lose vision in right eye; treatment started for suspected CMV retinitis, then vitreous biopsy; not common, but once eye involved,
life expectancy ≈6 mo
|
Other Masquerade Syndromes
| Ocular ischemic syndrome: most cases referred for chronic uveitis; rubeosis raises suspicion; perform carotid duplex scan
or ultrasonography; perfusion to eye; almost always unilateral in older patients
|
| Chronic peripheral rhegmatogenous retinal detachment (case): patient had history of iritis; followed for serous retinal
detachment for ≈6 mo; tiny tear in inferotemporal periphery; once repaired, vision returned to 20/20; did not look like
typical serous detachment (small corrugations seen in rhegmatogenous retinal detachment)
|
| Bilateral diffuse uveal melanocytic proliferation (BDUMP): unusual; rapid vision loss; patients frequently develop cataracts;
most commonly associated with systemic malignancy, often, retroperitoneal tumors; obtain abdominal CT scan;
case—significant pigmentation next to nerve in right eye; almost fibrous infiltrate under retina; leopard-spot lesions—
in patient, eg, 69 yr of age, raises suspicion of renal adenocarcinoma, but also suggestive of lymphoma, leukemia, or
BDUMP
|
Educational Objectives
| The goal of this program is to educate the listener about local therapy for uveitis and diagnosis of masquerade syndromes in
uveitis. After hearing and assimilating this program, the clinician will be better able to:
|
| 1. Describe advantages of local therapy, compared to systemic therapy for managing uveitis.
|
| 2. Evaluate the efficacy of steroid injections for managing uveitis.
|
| 3. Evaluate the efficacy of sustained-release implant devices for managing uveitis.
|
| 4. Recognize masquerade syndromes in uveitis.
|
| 5. Describe management strategies for selected systemic diseases that present with uveitis.
|
Discussed on This Program
Acyclovir (acycloguanosine) [Zovirax]
Cyclosporine (cyclosporin A) [Neoral, Sandimmune, SangCya]
Cyclosporine, ophthalmic [Optimmune, Restasis]
Dexamethasone (several formulations and trade names)
Dexamethasone intravitreous pellets (investigational) [Posurdex, Surodex]
Famciclovir [Famvir]
Fluocinolone acetonide (several formulations and trade names)
Fluocinolone acetonide intravitreal implant [Retisert]
Foscarnet sodium (phosphonoformic acid; PFA) [Foscavir]
Ganciclovir intravitreal implant [Vitrasert Implant]
Ganciclovir sodium (DHPG) [Cytovene]
Lidocaine HCl (several formulations and trade names)
Methotrexate (amethopterin; MTX) [Methotrexate LPF, Rheumatrex Dose Pack, Trexall]
Pegaptanib sodium [Macugen]
Povidone iodine (several formulations and trade names)
Prednisone (several formulations and trade names)
Prilocaine HCl [Citanest HCl]
Proparacaine hydrochloride [Alcaine, Opthaine, Opthetic]
Triamcinolone (oral) [Aristocort, Atolone, Kenacort]
Valacyclovir HCl [Valtrex]
Valganciclovir [Valcyte]
Suggested Reading
Becker MD et al: Management of sight-threatening uveitis: new therapeutic options. Drugs 65:497, 2005; BenEzra D et
al: Uveitis in children and adolescents. Br J Ophthalmol 89:444, 2005; Dunn JP et al: Complications of ganciclovir implant
surgery in patients with cytomegalovirus retinitis: the Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial. Retina
24:41, 2004; Imai Y et al: Emergence of drug-resistant cytomegalovirus retinitis in the contralateral eyes of patients with
AIDS treated with ganciclovir. J Infect Dis 189:611, 2004; Jaffe GJ et al: Long-term follow-up results of a pilot trial of a
fluocinolone acetonide implant to treat posterior uveitis. Ophthalmology 112:1192, 2005; Lim WK et al: Bilateral uveitis
in a patient with autoimmune lymphoproliferative syndrome. Am J Ophthalmol 139:562, 2005; Menezo V, Lightman S:
The development of complications in patients with chronic anterior uveitis. Am J Ophthalmol 139:988, 2005; Murphy CC
et al: Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis. Arch Ophthalmol 123:634, 2005; Srivastava
SK et al: Pathologic findings in eyes with the ganciclovir implant. Ophthalmology 112:780, 2005; Zaldivar RA et
al: Primary intraocular lymphoma: clinical, cytologic, and flow cytometric analysis. Ophthalmology 111:1762, 2004;
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. Dr. Martin has been a consultant
for Bausch & Lomb; Dr. Callanan has been a member of the advisory board for Bausch & Lomb.
Drs. Martin and Callanan were recorded at Uveitis for the Other Subspecialist, presented February 4-5, 2005, in Miami by
Bascom Palmer Eye Institute, Miami. The Audio-Digest Foundation thanks Drs. Martin and Callanan, and the Institute, for
their cooperation in the production of this program.
|
