CORNEA AND EXTERNAL DISEASE
From Cornea/External Disease—Keratitis: Infectious, Inflammatory, or Indeterminate?
presented by the New England Ophthalmological Society, Boston, MA
| RESTASIS: IT’S NOT JUST FOR DRY EYE ! — Erin S. Fogel, MD, The Eye Center of Concord and Concord Hospital,
Concord, NH
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| Background: topical cyclosporine (1%-2%, mixed with peanut or corn oil) used since 1980s to treat rejection of corneal
transplants; not only inconvenient, but also associated with discomfort and toxicity; cyclosporine ophthalmic emulsion
(0.05%; Restasis)—approved in 2002 for treatment of dry eye; lipid-emulsion vehicle improves comfort, prolongs contact
time, and increases delivery; high penetration into conjunctiva and cornea; low penetration into aqueous humor, vitreous,
and plasma; good safety profile with no systemic adverse effects
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| Pharmacology of cyclosporine: inhibits activation and proliferation of T cells; also inhibits apoptosis; benefits over
corticosteroids—does not affect phagocytosis or viral replication; has antifungal activity; does not increase intraocular
pressure (IOP); does not decrease wound healing or cause cataracts
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| Corneal transplantation: review of literature shows benefit of adding cyclosporine (0.5% in artificial tears or 2% in oil;
higher concentration than found in Restasis) to treatment regimen in difficult cases (eg, patients with history of graft rejection,
corneal neovascularization, nonresponsiveness to steroids, steroid-associated glaucoma, history of fungal keratitis);
prospective study looked at use of Restasis in 52 low-risk patients (included patients with Fuchs’ epithelial corneal dystrophy,
keratoconus, or noninflammatory scars); protocols using Restasis associated with higher rejection rates, compared
to historical controls; conclusions—use of topical cyclosporine (commonly 0.5% in tears) beneficial after corneal
transplantation, but Restasis alone does not appear to prevent rejection
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| Allergic eye disease: seasonal allergic conjunctivitis—adjunctive therapy with Restasis useful for patients with contact
lenses, glaucoma, or dry eye; giant papillary conjunctivitis (GPC)—patients with moderate-to-severe GPC unresponsive
to conventional therapy may benefit from addition of Restasis; atopic and vernal keratoconjunctivitis—
cyclosporine (1%-2%) shown to reduce need for topical corticosteroids; conflicting results seen in prospective studies
using Restasis; Restasis may help relieve symptoms, but higher concentration likely necessary for steroid-sparing effect
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| Herpes simplex virus (HSV) stromal keratitis: small study showed Restasis associated with resolution of inflammation
in 10 of 12 patients with nonnecrotizing HSV stromal keratitis unresponsive to steroid therapy
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| Superior limbic keratoconjunctivitis (SLK): characterized by bilateral inflammation (likely involving T cells) of superior
bulbar and tarsal conjunctiva; report showed benefit of treatment with 0.5% cyclosporine
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| Thygeson’s keratitis: management typically involves long-term use of low-dose topical corticosteroids; 2% cyclosporine
suppresses lesions and may reduce need for steroids
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| BLEPHARITIS AND MEIBOMIAN GLAND DYSFUNCTION — Marian S. Macsai, MD, Professor and Vice Chair, Department
of Ophthalmology, Northwestern University Feinberg School of Medicine, and Chief, Division of Ophthalmology,
Evanston Northwestern Healthcare, Evanston, IL
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| Introduction: blepharitis and meibomian gland dysfunction common conditions that may lead to postoperative infections
and affect surgical outcomes
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| Meibomian gland: dysfunction causes thinning of lipid layer (of tear film), leading to impaired vision and ocular irritation;
symptoms often disproportional to clinical findings; roles of meibomian secretion (meibum)—refracts light (as part of
air-tear interface); provides barrier to cutaneous sebum; retards evaporation of tear film; seals lid margins during sleep;
inflammation—bacteria present on lashes (eg, Staphylococcus) secrete enzymes that break meibum into free fatty acids
which cause inflammation and ocular symptoms; inflammation may affect orifices of meibomian glands and exacerbate
problem
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| Rosacea: persistent erythema and telangiectasias or papulopustules on face, exacerbated by spicy food, sun exposure, and
heat; condition affects 30% of menopausal women; ocular manifestations (common) include tearing, foreign-body sensation,
burning, dry eye, itching, and sensitivity to light
|
 | Ocular rosacea: stage 1—mild; limited to margin of eyelid and meibomian gland; stage 2—moderate; affects conjunctiva,
inner lid, tear secretion, and ocular surface; stage 3—advanced; associated with ulcers, iritis, keratitis, episcleritis,
and risk for vision loss; incidence—present in 58% to 100% of patients with facial rosacea (more commonly recognized
by ophthalmologists than by dermatologists); 20% of patients who initially present with lid margin disease later
develop rosacea; signs and symptoms—keratoconjunctivitis sicca (evaporative or aqueous-deficient); burning; irritation;
redness; decreased or fluctuating vision; thick white meibum (expressed by pushing on lid margin with cotton
swab); filigree telangiectasias; orifices of meibomian glands may become displaced, misshapen, or blocked
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| Topical therapy: educating patients improves compliance (key for successful treatment); eyelash shampoo—patients
wash eyelashes (using preferred product and washcloth) daily in shower; tarsal massage—for patients with meibomian
gland involvement; topical ointments—antibiotic (alone or in combination with corticosteroid) applied at bedtime, prevents
overgrowth of bacteria, decreases inflammation, and increases compliance by encouraging daily cleansing; topical
metronidazole gel—used off-label; applied twice daily; may cause stinging; leaves crust on lashes; Restasis—long-
term use beneficial; tacrolimus—commonly used for atopic blepharitis and dermatitis, but not approved for use on eye;
excessive use increases risk for burning
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| Systemic therapy: doxycycline—tolerated better than tetracycline; standard dose 100 mg bid; adverse effects include
photosensitivity, pseudotumor, interference with efficacy of oral contraceptives (OCs), and teratogenic effects; formulations
include doxycycline hyclate (eg, Vibramycin; low pH associated with esophageal irritation and gastrointestinal upset),
doxycycline monohydrate (eg, Oracea; neutral pH, but not commonly available in United States [Oracea approved
by Food and Drug Administration in summer 2006 for use in rosacea; not studied in blepharitis but prospective study imminent]),
and enteric-coated doxycycline hyclate (eg, Doryx); minocycline—less photosensitizing; not associated with
pseudotumor; adverse effects include vertigo, blue staining of skin and conjunctiva, and interference with efficacy of
OCs
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| Dietary therapy: omega-3 fatty acids (FA) have anti-inflammatory properties; omega-6 FA have pro-inflammatory properties;
insulin favors conversion of omega-3 FA to omega-6 FA; dietary sources—omega-3 FA found in flax seed and
cold-water oily fish (eg, salmon); unhealthy omega-6 FA found in vegetable oil (some herbal supplements have healthy
form of omega-6 FA); flax seed oil—contains α-linoleic acid; may reduce inflammation; useful in patients with
Sjögren’s syndrome (improves consistency of lipid layer of tear film); fish oil supplements—microfilter processing removes
mercury and other toxins; patients who ingest large quantities may develop fishy odor; dietary intake—2:1 ratio
of omega-6 FA to omega-3 FA ideal, but most Americans ingest 12 times more omega-6 FA than omega-3 FA; “noninflammatory
diet” involves reducing red meat, fried foods, and carbohydrates (affects ratio by lowering production of insulin);
adverse effects—omega-3 FA increase bleeding; dosage—1000 to 2000 mg, up to 3 times daily; prospective
randomized trial to evaluate dosing regimens underway
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| Management strategies: stage 1—daily eyelash shampoo; artificial tears, prn; topical antibiotic ointment at bedtime;
dietary supplementation; stage 2—hygiene and dietary strategies, as described for stage 1; antibiotic-corticosteroid
combination ointment at bedtime (on limited basis); topical cyclosporine; oral antibiotics; stage 3—topical corticosteroids;
tacrolimus ointment; surgical intervention; corticosteroids, antibiotics, and cycloplegia, as necessary to treat episcleritis,
marginal ulcers, and iritis; facial therapy—manage facial rosacea with topical metronidazole; reserve
tacrolimus for severe cases (refer to dermatologist); advise patients to avoid irritating cosmetics and thoroughly remove
make-up; oral doxycycline—various regimens reported; speaker usually begins with twice-daily dosing for 6 wk, then
tapers to once-daily dosing for 6 wk, and then every other day for 3 mo
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| GLAUCOMA MEDICATIONS AND THE OCULAR SURFACE — Cynthia Mattox, MD, Assistant Professor, Department
of Ophthalmology, Tufts University School of Medicine, and Director, Glaucoma Department, New England Eye
Center, Boston, MA
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| Glaucoma medications: all may cause toxicity or allergic reaction (especially in patients with preexisting surface disease
or history of allergy); drugs, vehicle, and preservatives associated with adverse effects; compliance—affected by complexity
of dosing regimen, cost, efficacy, communication (eg, treatment goals), comfort, and adverse effects; improved
by using smallest effective dose; adverse effects—burning; stinging; foreign-body sensation; tearing; hyperemia; dry
eye; allergic dermatitis; others
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| β-blockers: some newer agents (eg, timolol gel-forming solution [eg, Timoptic XE]) contain benzododecinium bromide
instead of benzalkonium chloride; thicker vehicle increases contact time, reducing dosing to once daily (but more aggravating
for some patients); corneal penetration—some agents (eg, timolol maleate 0.5% [Istalol]) use potassium sorbate
to increase penetration (associated with more discomfort); timolol hemihydrate—eg, Betimol, associated with less
punctate staining, compared to timolol maleate
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| α2 -adrenergic agonists: majority of patients develop allergic conjunctivitis or severe dermatitis with long-term use of
apraclonidine (eg, Iopidine); brimonidine 0.2% formulation (generic); Alphagan P (brand-name brimonidine, 0.15% and
0.1%) has higher pH than generic formulation, achieving same efficacy with lower concentration and reducing risk for allergic
reaction because of purite preservative (nonbenzalkonium chloride) and artificial tear-like formulation
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| Carbonic anhydrase inhibitors (CAIs): low pH of dorzolamide (Trusopt) and dorzolamide plus timolol (Cosopt) causes
more discomfort than brinzolamide (Azopt), but brinzolamide thicker and stickier; adverse effects include superficial punctate
keratopathy; allergy—although agents contain sulfonamide moieties, some patients with sulfonamide allergies tolerate
use
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| Prostaglandins: most commonly used class of glaucoma medications; include latanoprost (Xalatan), travoprost (Travatan,
Travatan Z), and bimatoprost (Lumigan); efficacy—some patients respond better to bimatoprost (achieve target IOP
with lower dose); preservatives—only Travatan Z available without benzalkonium chloride; adverse effects—all
cause hyperemia initially (taking medication earlier in evening reduces morning redness); activation or reactivation of
HSV keratitis may occur; cosmetic effects include hypertrichiasis of eyelashes or nearby skin, deepening of orbital sulcus,
and darkening of periorbital skin
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| Preservatives: benzalkonium chloride damages corneal epithelium (increasing penetration); study shows increased number of
inflammatory cells in conjunctiva of eyes treated \>1 yr with glaucoma medications; concentration—similar among CAIs;
among prostaglandins, bimatoprost has least amount of benzalkonium chloride (Travatan Z has none) and latanoprost has
most
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| Ocular effects: for patients on \>1 medication, important to identify responsible agent; brimonidine allergy usually manifests
as bulbar erythema, follicular symptoms, inflammation, and elevated IOP (result of allergy, not uncontrolled glaucoma);
eyelid manifestations (eg, scaling, excoriation) common with CAI allergies; follicular symptoms less common;
prostaglandins associated with many reactions, including itching (common); suggestions for management—avoid topical
corticosteroids or nonsteroidal anti-inflammatory agents (dependence-producing); discontinue suspected agent; follow
up (reaction should resolve steadily over 10-14 days); consider other allergies (eg, environmental) if reaction does
not resolve
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| FOURTH-GENERATION FLUOROQUINOLONES vs FORTIFIED ANTIBIOTICS — Vincent P. de Luise, MD, Assistant
Clinical Professor, Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven,
CT, and Waterbury Hospital, Waterbury, CT
|
| Background: potency of aminoglycosides (eg, gentamicin) and fluoroquinolones (eg, moxifloxacin) increases with concentration,
whereas potency of cephalosporins and penicillins increases with contact time; postoperative
endophthalmitis—occurs in ≈1 in 1000 patients who undergo cataract surgery (lower rate associated with pars plana vitrectomy);
gram-positive pathogens responsible for ≈94% of cases
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| Fortified antibiotics: topical aminoglycosides have relatively low bioavailability; standard concentrations insufficient to
kill organisms at target site; increasing concentration increases potency; attempt to supersede increased incidence of bacterial
resistance to second- and third-generation fluoroquinolones
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| Fourth-generation fluoroquinolones: high activity against gram-positive bacteria; adequate coverage of gram-negative
bacteria; bioavailability and potency of gatifloxacin (Zymar) and moxifloxacin (eg, Vigamox) higher than those of other
topical antibiotics (ie, “already fortified”); near-neutral pH enhances solubility relative to older agents; concentrations at
target site (eg, corneal stroma) exceed minimum inhibitory concentrations (MICs) of atypical mycobacteria
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| Advantages and disadvantages: fourth-generation fluoroquinolones—available in most formularies; potent; safe;
convenient; good coverage (moxifloxacin even has activity against Chlamydia trachomatis), but expensive; less potent
against gram-negative bacteria than older fluoroquinolones and aminoglycosides; intermediate efficacy against methicillin-resistant
Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and
Pseudomonas; fortified antibiotics—good coverage against gram-positive and gram-negative bacteria; but, not available
in formularies; more expensive than fourth-generation fluoroquinolones; less convenient (require compounding
pharmacy; have shorter shelf-life); associated with ocular surface irritation (ie, epithelial toxicity) and delayed wound
healing
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| Culturing corneal ulcers: important to culture central and deep liquefactive ulcers; chocolate agar grows most organisms;
additional tests—Gram stain; potassium hydroxide if fungal etiology suspected
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| Antibiotic efficacy: microbial keratitis—studies comparing fourth-generation fluoroquinolones with fortified aminoglycosides
have not shown significant differences in clinical outcomes; adverse effects—some reports of corneal perforation
with fluoroquinolones; sensitivity—susceptibility break points based on systemic disease; break points for
ophthalmic disease needed; sensitivity data useful for redirecting treatment of ulcer if not responding to initial therapy
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Suggested Reading
Asbell PA, Potapova N: Effects of topical antiglaucoma medications on the ocular surface. Ocul Surf 3:27, 2005;
Donaldson KE et al: Evaluation and treatment of children with ocular rosacea. Cornea 26:42, 2007; Fiscella RG,
Jensen MK: Evaluation of the penetration of fluoroquinolones in human conjunctival tissue. Arch Ophthalmol 124:1796,
2006; Kaufman S et al: Comparison of the biocompatibility of gatifloxacin 0.3% and moxifloxacin 0.5%. Cornea 25(9
Suppl 2):S31, 2006; Lewis RA et al: Travoprost 0.004% with and without benzalkonium chloride: a comparison of safety
and efficacy. J Glaucoma 16:98, 2007; McLeod SD: Integrating Iquix, Vigamox, and Zymar in the management of ocular
infectious disease. Int Ophthalmol Clin 46:41, 2006; Perry H et al: Efficacy of commercially available topical cyclosporine
A 0.05% in the treatment of meibomian gland dysfunction. Cornea 25:171, 2006; Pinna A et al: Effect of oral linoleic
and gamma-linoleic acid on meibomian gland dysfunction. Cornea 26:260, 2007; Rao SN: Treatment of herpes
simplex virus stromal keratitis unresponsive to topical prednisolone 1% with topical cyclosporine 0.05%. Am J Ophthalmol
141:771, 2006; Rao SN, Rao RD: Efficacy of topical cyclosporine 0.05% in the treatment of dry eye associated with
graft versus host disease. Cornea 25:674, 2006; Rhee SS, Mah FS: Comparison of tobramycin 0.3%/dexamethasone
0.1% and tobramycin 0.3%/ loteprednol 0.5% in the management of blepharo-keratoconjunctivitis. Adv Ther 24:60, 2007;
Rubin M et al: Efficacy of topical cyclosporin 0.05% in the treatment of posterior blepharitis. J Ocul Pharmacol Ther
22:47, 2006; Stern ME et al: Effects of fourth-generation fluoroquinolones on the ocular surface, epithelium, and wound
healing. Cornea 25 (9 Suppl 2):S12, 2006; Wilson SE, Perry HD: Long-term resolution of chronic dry eye symptoms
and signs after topical cyclosporine treatment. Ophthalmology 114:76, 2007; Yee RW: The effect of drop vehicle on the
efficacy and side effects of topical glaucoma therapy: a review. Curr Opin Ophthalmol 18:134, 2007.
Educational Objectives
| The goal of this program is to improve the management of inflammatory and infectious ocular diseases. After hearing and
assimilating this program, the clinician will be better able to:
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| 1. Incorporate topical cyclosporine into the management of inflammatory eye diseases.
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| 2. Describe, classify, and manage ocular rosacea.
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| 3. Recognize allergic reactions to glaucoma medications.
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| 4. Improve compliance with glaucoma management strategies by educating patients about ocular effects associated
with glaucoma medications.
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| 5. Compare fourth-generation fluoroquinolones to fortified antibiotics for the management of ocular infectious disease.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty 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 faculty reported the following: Dr. Mattox is on the Speakers’ Bureaus of, and
receives research support from, Alcon and Allergan; Dr. de Luise is on the Speakers’ Bureaus for Alcon and Allergan.
Acknowledgements
Drs. Fogel, Macsai, Mattox, and de Luise were recorded at Cornea/External Disease—Keratitis: Infectious, Inflammatory,
or Indeterminate? presented by New England Ophthalmological Society, and held April 20, 2007, in Boston, MA. The
Audio-Digest Foundation thanks the speakers and New England Ophthalmological Society for their cooperation in the production
of this program.
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