HOT TOPICS
From Challenges in Cornea and External Disease presented March 3, 2006 by the New England Ophthalmological
Society, Providence, RI
| COMBINATION IMMUNOSUPPRESSION FOR THE MANAGEMENT OF DRY EYE AND OCULAR SURFACE
DISEASE —Eric J. Donnenfeld, MD, Assistant Professor of Ophthalmology, New York University Medical Center, Rockville
Centre, NY
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| Introductory remarks: tear film functions in many ways to provide ocular clarity and surface regularity, to provide
comfort, to protect against infection, to support environment, and to provide growth factors and electrolytes for lubrication;
tear film composed of lipid secretions from meibomian glands, aqueous secretion from lacrimal glands, and mucin
secreted by goblet cells
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| Benefits of ophthalmic cyclosporine A (Restasis): in Food and Drug Administration (FDA) double-masked
clinical trials—3-fold increase in Schirmer score in 15% of patients; 200% increase in goblet cell density; in recent paper
by speaker et al—improves meibomian gland inclusions and lipid secretions; extremely effective for acne rosacea;
less need for artificial tears
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| Dry eye disease after corneal refractive surgery: develops in almost every patient; when evaluating patients for
surgery, must do full dry eye evaluation; need to support patient’s tear film preoperatively; literature shows preoperative
treatment with cyclosporine significantly improves ocular surface disease and improves results of laser-assisted in situ
keratomileusis (LASIK) surgery
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| Comments: overwhelming majority of patients unaware they have dry eye syndrome after surgery because of loss of corneal
sensation; patients complain of fluctuating visual acuity when ocular surface disease develops after surgery; until
proven otherwise, any patient who presents after refractive surgery complaining of visual fluctuation has ocular surface
disease; appearance of eye topography after surgery can be clue to presence of ocular surface disease and dry eye syndrome;
in addition to improving patient comfort and postsurgical visual acuity, several treatment modalities can improve
Hartmann-Shack images for custom ablation
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| Multifocal intraocular lenses (IOLs): revolutionizing treatment of patients with high refractive errors and cataract
surgery patients; however, increase in glare and halo and loss of contrast sensitivity major concern; causes of decreased vision
after multifocal IOL implantation include cystoid macular edema (CME) after cataract surgery (“devastating complication”;
further reduces contrast sensitivity, augmenting initial loss associated with IOL)
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| Complications associated with cyclosporine: burning upon instillation only major complication seen in FDA clinical
trials; combination immunomodulation (cyclosporine plus low-dose corticosteroid) shown to improve signs and
symptoms of dry eye syndrome, improve tear clearance, normalize mucin production, and often has dramatic effect in reducing
complaints of burning and irritation
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| Non-FDA indications for cyclosporine in treatment of ocular surface disease: prevention of steroid-induced
postkeratoplasty glaucoma; in combination immunomodulatory therapy with antifungal agent for treatment of corneal
transplant patient with fungal infection; in combination with antiviral agent in patient with herpetic keratitis to
reduce graft rejection; speaker uses drug routinely in corneal transplant patients who are steroid responders, high-risk
keratoplasty patients, or low-risk patients who want to have sutures removed as early as possible; also effective in treatment
of—meibomian gland disease; patients with combination of dry eye disease, meibomian gland dysfunction, and
aqueous dysfunction; inflammatory corneal ulceration; Thygeson’s keratitis (drug of choice); mild iritis; atopic dermatitis;
severe eczema; vernal conjunctivitis; atopic keratoconjunctivitis; superior limbic keratoconjunctivitis; ocular cicatricial
pemphigoid (T-cell mediated disease)
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| UNUSUAL AND INTERESTING CORNEAL CASES —Dr. Donnenfeld
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| Case #1: woman presented with corneal ulceration in eye; had been self-medicating with topical cocaine every 3 hr to control
pain
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| Case #2: patient claimed to have been struck through keyhole; had foreign material in anterior chamber of eye; eye comfortable
and wide open; on further questioning, determined that patient had been freebasing cocaine when explosion occurred;
piece of crack cocaine had lacerated cornea and entered anterior chamber
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| Case #3: boy 4 yr of age presented with rose branch embedded above left eye; radiologic studies showed branch embedded
in medulla oblongata; removal performed in neurosurgical operating room
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| Case #4: young man presented claiming “something is crawling inside my eye”; upon examination, found to have small
worm in subconjunctival space; patient diagnosed with endemic loiasis, needed systemic therapy; speaker removed worm
after anesthetizing it with q-tip treated with cocaine
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| Case #5: young man presented complaining of foreign body sensation in eye; patient head of arachnid section of Bronx Zoo;
on examination, had small conjunctival granulomas; small foreign bodies could be seen in anterior stroma, surrounded by
inflammatory reaction; over 2 days, bodies moved directly into cornea and embedded themselves in Descemet’s membrane;
determined to be urticating hairs from back legs of tarantula
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| Case #6: young woman with thermal burn on cornea; caused by inadvertently touching eye with curling iron; “excruciatingly
painful”; thermal damage usually gone after 24 hr
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| Case #7: patient presented with band-saw injury with lashes embedded in anterior chamber and self-sealing cornea laceration;
speaker removed lashes
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| Case #8: patient presented with complaint of foreign body sensation and splinting in right eye; on close examination, determined
that eyebrows growing and striking patient in eye; trimmed eyebrows and resolved symptoms
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| Case #9: patient presented with mass in upper lid; determined to be gas-permeable contact lens that had embedded itself
under conjunctiva and formed granuloma
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| Case #10: corneal transplant patient; wearing gas-permeable contact lens for visual rehabilitation; used suction cup to
help remove lens; applied suction to eye when not wearing lens and pulled off transplanted cornea; speaker sutured cornea
back in
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| Case #11: corneal transplant patient with difficult-to-remove suture; normal procedure in such cases is to use argon laser
to burn suture below level of cornea; patient told to come back next day for procedure; used clamp and tried to pull out
suture, pulled off cornea; speaker sutured cornea back in under operating microscope
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| Case #12: patient presented with black lesion on eye (epinephrine deposit on contact lens); returned after 6 mo with light
perception-only vision; when asked why he waited 6 mo to return, replied that speaker told him to come back after 6 mo;
changed speaker’s practice
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| Case #13: patient presented after gas tank explosion with multiple foreign bodies embedded in cornea; speaker removed bodies
with needle one by one; patient ended up with 20/20 visual acuity
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| Case #14: corneal ulcer diagnosed in patient who wore aphakic contact lenses; led to identification of Streptococcus bovis
and, ultimately, diagnosis of small gastrointestinal (GI) malignancy; take-home message is to not self-diagnose or self-medicate
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| UVEITIS IN CHILDREN —C. Stephen Foster, MD, Clinical Professor of Ophthalmology, Harvard Medical School; President
and CEO, Massachusetts Eye Research and Surgery Institute, Boston
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| Pediatric uveitis: tends to be chronic, recurrent, and often insidious; ocular pathology (eg, vision loss) and complications
frequently occur by time patient seeks medical care; unique risk for amblyopia in patients <7 yr of age who develop
cataract or opacities in vitreous
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| Therapeutic difficulties: cataracts and glaucoma associated with long-term use of topical corticosteroids; growth retardation
substantial problem associated with systemic steroids; use of nonsteroidal immunologic agents has improved
matters; however, “enormous therapeutic dilemma” in timidity of some clinicians to use these medications because of
fear of potential drug toxicity; greater surgical risks associated with pediatric uveitis well known
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| Prevalence of pediatric uveitis: in developed countries, juvenile idiopathic arthritis (JIA) most common identifiable
underlying cause of pediatric uveitis
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| JIA-associated uveitis: often asymptomatic until patient has developed vision loss; typically begins at young age; girl
who is antinuclear antibody (ANA)-positive and has oligoarticular- or pauciarticular-onset arthritis at greatest risk for
JIA; predictors of poor outcome—severity of disease first time patient presents to clinician; male sex; shorter interval
of onset between arthritis and uveitis (or, development of uveitis before joint disease); long-term prognosis guarded, especially
if relying on corticosteroid therapy; significant visual impairment occurs in 15% of children (10% eventually
registered with Commission for the Blind)
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| Pediatric sarcoidosis: other cause of uveitis that can produce significant ocular damage (along with JIA-associated
uveitis, worst form of disease seen in children); therapy same as that for JIA-associated uveitis, ie, corticosteriods followed
by methotrexate
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| Tubulointerstitial nephritis and uveitis (TINU) syndrome: rare but should be kept in mind as potential cause
of pediatric uveitis, especially after consumption of certain medications; might result in need for steroid-sparing immunomodulatory
therapy, but outcome usually good with steroid therapy alone
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| Uveitis with infectious causes: uncommon; however, occasionally see patients with toxicariasis or cat scratch disease;
Lyme disease uncommon cause of uveitis but should be kept in mind, as should “masquerade” syndromes (eg, leukemia,
lymphoma)
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| Conclusions: approach to pediatric uveitis must involve comprehensive medical history, appropriate physical examination,
and laboratory studies; goal of therapy elimination of uveitis by “whatever it takes” (even if that means steroid-sparing
immunomodulatory therapy)
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| UVEITIC CYSTOID MECULAR EDEMA —Robert H. Janigian, Jr., Clinical Assistant Professor of Surgery, Brown University
Medical School, Providence, RI
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| Introductory remarks: cystoid macular edema (CME) one of most common causes of visual loss in uveitis (responsible
for 40% of patients with visual impairment and 30% of those legally blind); 50% of patients with uveitis develop
CME
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| Pathogenesis of CME: while exact pathogenesis not immediately clear, disruption of blood-retinal barrier involved;
Muller cells also play role in dehydration of retina; pathogenesis involves leukocyte adhesion followed by cytokine release
and subsequent increased vascular permeability, resulting in intracellular and extracellular fluid accumulation in
central macula
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| Optical coherence tomography (OCT): provides high-resolution images of retina; high reproducibility; noninvasive;
comfortable and safe; clearly superior to split lamp biomicroscopy and at least as good as fluorescein angiography
in detecting CME
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| Comments: although OCT studies of CME show poor correlation between thickness and vision, vision does seem to correlate
inversely with patient age, presence of subretinal fluid, duration of CME, and presence of capillary closure
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| Treatment: must be started quickly and administered aggressively to eradicate CME and prevent permanent cell degeneration;
corticosteroids most commonly used; help to stabilize blood-retinal barrier and have rapid onset of action; topical
steroids have limited use in patients whose uveitis primarily posterior, but play important role in treatment of patients
with anterior uveitis (need to be given aggressively, qhr); consider adding topical nonsteroidal agent when anterior uveitis
present; prednisone can be used at dose of 1.0 to 1.5 mg/kg (do not combine with oral nonsteroidal agents because of
potential GI side effects); oral nonsteroidal agents have shown therapeutic effect (but require several months of use before
benefit seen); can also administer steroids periocularly (speaker primarily administers by sub-Tenon’s injection);
when administering retrobulbar or periocular steroid, watch for steroid response
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| Pars plana vitrectomy: shown in several case series to modulate inflammation by removal of antigenic load and reduction
of T-helper cells and cytokines; may also offer better penetration of medications into retina; recent review of literature
concluded that, although not good evidence vitrectomy beneficial for CME, has scientific basis and should be
considered in some patients
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| Intravitreal steroids: “new kid on the block” in treatment of uveitic CME; triamcinolone used (longer acting than
water-soluble steroids); currently, should be reserved for eyes with chronic refractory edema; repeated injections necessary
as steroid has relatively short half-life; most effective in eyes that have had CME <12 mo; other benefit possible
reduction of immunosuppressive regimen in patients on immunomodulatory therapy; risks—steroid response in up to
40% to 50% of patients; cataract more common in older eyes; endophthalmitis in 1 in 1000 injections; retinal detachment
“always a possibility”
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| Other treatments: carbonic anhydrase inhibitors; octreotide; laser grid photocoagulation
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| Treatment algorithm: most essential aspect eradication of underlying inflammation; keep in mind that visual improvement
may lag behind improvement on OCT; first step should be aggressive topical steroid regimen (with or without topical
or oral nonsteroidal agent); if thickening on OCT not improved in 3 to 4 wk, move to sub-Tenon’s or retrobulbar
injection of steroid (2-3 injections at intervals of 3-4 wk); trial of acetazolamide reasonable; if CME persistent, consider
laser cryopexy or pars plana vitrectomy (if not pars planitis, consider short course of oral steroids); at this point, if still
good visual potential but vision <20/40, consider intravitreal steroid; if CME rapidly recurs or recalcitrant, consider vitrectomy
with peeling of posterior hyaloid (if still attached); while role in treatment of CME not clear, consider Retisert
implant in patients who are not steroid responders
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Educational Objectives
| The goal of this activity is to review some of the challenges in corneal and external disease, including the management of
dry eye syndrome and ocular surface disease, pediatric uveitis, and uveitic cystoid macular edema (CME). After hearing
and assimilating this program, the clinician will be better able to:
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 | 1. Discuss the evidence supporting the use of ophthalmic cyclosporine A in the management of dry eye and ocular surface
disease, and describe the benefits and complications associated with the use of this drug.
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| 2. Prescribe and apply combination immunomodulatory therapy (with cyclosporine and low-dose topical steroids) in
the treatment of patients with dry eye syndrome.
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| 3. Cite the characteristics and prevalence of pediatric uveitis, identify the forms of disease responsible for significant
vision loss in children, and describe the recommended course of treatment (as well as its potential complications).
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| 4. Describe the pathogenesis of uveitic CME and recognize and identify the pathologic and clinical signs that lead to
the diagnosis of this disease.
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| 5. Review the various treatment modalities available, and follow a treatment algorithm for the management of uveitic
CME.
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Discussed on This Program
Acetazolamide [Dazamide, Diamox, Diamox Sequels]
Ciprofloxacin [Ciloxan, Cipro, Cipro I.V., Cipro XR, Proquin XR]
Cocaine [Cocaine HCl, Cocaine Viscous]
Cyclosporine, ophthalmic [Restasis]
Doxycycline (several trade names)]
Fluocinolone acetonide intravitreal implant [Retisert]
Fluorescein sodium (several trade names)
Methotrexate (amethopterin; MTX) [Methotrexate LPF, Rheumatrex Dose Pack, Trexall]
Octreotide acetate [Sandostatin, Sandostatin LAR, Sandostatin LAR Depot]
Prednisolone (several trade names)
Prednisolone acetate ophthalmic (several trade names)
Prednisone (several trade names)
Rifampin (rifampicin) [Rifadin, Rimactane]
Triamcinolone acetonide (several trade names)
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) (several trade names)
Tumor necrosis factor (TNF) [Endrel]
Suggested Reading
Androudi S et al: Safety and efficacy of intravitreal triamcinolone acetonide for uveitic macular edema. Ocul Immunol
Inflamm 13:205, 2005; Becker M, Davis J: Vitrectomy in the treatment of uveitis. Am J Ophthalmol 140:1096, 2005;
de Boer J et al: Visual loss in uveitis of childhood. Br J Ophthalmol 87:879, 2003; Donnenfeld ED et al: Effect of
hinge width on corneal sensation and dry eye after laser in situ keratomileusis. J Cataract Refract Surg 30:790, 2004;
Foster CS: Diagnosis and treatment of juvenile idiopathic arthritis-associated uveitis. Curr Opin Ophthalmol 14:395,
2003; Kafkala C et al: Ahmed valve implantation for uncontrolled pediatric uveitic glaucoma. J AAPOS 9:336, 2005;
Kump LI et al: Analysis of pediatric uveitis cases at a tertiary referral center. Ophthalmology 112:1287, 2005; Marsh
P, Pflugfelder SC: Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome.
Ophthalmology 106:811, 1999; Okhravi N, Lightman S: Cystoid macular edema in uveitis. Ocul Immunol
Inflamm 11:29, 2003; Papadaki T et al: Somatostatin for Uveitic Cystoid Macular Edema (CME). Ocul Immunol Inflamm
13:469, 2005; Perry HD et al: Efficacy of commercially available topical cyclosporine A 0.05% in the treatment
of meibomian gland dysfunction. Cornea 25:171, 2006; Perry HD et al: Topical cyclosporine A 0.5% as a possible new
treatment for superior limbic keratoconjunctivitis. Ophthalmology 110:1578, 2003; Perry HD, Donnenfeld ED, et
al: Topical cyclosporin A in the management of postkeratoplasty glaucoma. Cornea 16:284, 1997; Perry HD, Donnenfeld
ED: Dry eye diagnosis and management in 2004. Curr Opin Ophthalmol 15:299, 2004; Perry HD, Donnenfeld
ED: Topical 0.05% cyclosporin in the treatment of dry eye. Expert Opin Pharmacother 5:2099, 2004; Rojas B et
al: Medical treatment of macular edema in patients with uveitis. Doc Ophthalmol 97:399, 1999; Rothova A: Medical
treatment of cystoid macular edema. Ocul Immunol Inflamm 10:239, 2002; Samson CM, Ekong A, Foster CS:
Uveitis in children: diagnosis and management. Int Ophthalmol Clin 41:199, 2001; Tranos PG et al: Macular edema.
Surv Ophthalmol 49:470, 2004; van Kooij B et al: The pros and cons of intravitreal triamcinolone injections for uveitis
and inflammatory cystoid macular edema. Ocul Immunol Inflamm 14:73, 2006; Waheed NK, Miserocchi E, Foster
CS: Ocular concerns in juvenile rheumatoid arthritis. Int Ophthalmol Clin 41:223, 2001.
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. The following has been disclosed:
Dr. Donnenfeld has a financial interest in Allergan, Inc., Advanced Medical Optics, Inc., Alcon Laboratories,
Bausch & Lomb, Ista Pharmaceuticals, Inc., and TLC Vision Corporation.
Drs. Donnenfeld, Foster, and Janigian were recorded at Challenges in Cornea and External Disease, held March 3, 2006,
in Boston, MA, and sponsored by the New England Opththalmological Society. The Audio-Digest Foundation thanks Drs.
Donnenfeld, Foster, and Janigian and the New England Ophthalmological Society for their cooperation in the production of
this program.
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