OPHTHALMOLOGY: INFLAMMATORY DISEASE
Educational Objectives
| The goal of this program is to improve diagnosis and management of ocular inflammatory diseases, especially those
associated with potentially life-threatening or vision-threatening disorders. After hearing and assimilating this program,
the clinician will be better able to:
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 | 1. Identify the distinguishing features of episcleritis and scleritis.
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| 2. Differentiate between categories of scleritis and discuss their clinical manifestations.
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| 3. Explain the most common underlying causes of scleritis and their implications for ocular prognosis.
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| 4. Review the most effective short- and long-term treatments for seasonal and perennial allergic conjunctivitis.
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| 5. Recognize clinical signs and symptoms of atopic and vernal keratoconjunctivitis.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee 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 and planning committee reported
nothing to disclose.
Acknowledgements
Drs. Foster and Trocme were recorded at Update for the Comprehensive Ophthalmologist 2008, held May 16, 2008,
in Cleveland, OH, and presented by University Hospitals Case Medical Center, Case Western Reserve University
School of Medicine, Cleveland, OH. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation
in the production of this program.
| SCLERITIS UPDATE —C. Stephen Foster, MD, Clinical Professor of Ophthalmology, Harvard Medical School, and
Founder and President, Massachusetts Eye Research and Surgery Institution, Cambridge, MA
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| Pain: episcleritis never causes pain, even upon palpation of globe; patients may complain of discomfort or burning sensation;
scleritis invariably causes pain, and globe tender when touched
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| Redness type: sometimes difficult to distinguish; purplish or bluish tinge to redness may indicate scleritis; bright, purer
red, more likely episcleritis
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| Edema: often difficult to determine which vascular plexus most engorged and whether edema in episclera or sclera; superficial
episcleral plexus congested in episcleritis; deep and superficial episcleral plexi congested in scleritis; deep
episcleral and superficial episcleral plexi maintain relationship with each other in scleritis, but separated from each
other in episcleritis because of edema in episcleral tissue
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| Diagnosis: review of systems (richest source of diagnostic leads); no predetermined tests; clinical observations should extend
beyond ocular, including skin, face, eyelids, and fingernails; observations during ocular examination can classify
patient into specific disease category; eg, necrotizing scleritis or peripheral ulcerative keratitis (PUK) always originate
from ocular, if not also systemic, vasculitis
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| Categories of episcleritis and scleritis
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| Episcleritis: painless; mild redness with no blue hue; radial vascular pattern preserved; nodules mobile and painless
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| Scleritis: more impressive in appearance; blue hue to redness; painful; vessels no longer perfectly radial
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| Nodular scleritis: characterized by immobile, tender nodules
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| Necrotizing scleritis: always associated with vasculitis; often associated with potentially lethal and often occult systemic
vasculitis
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| Scleromalacia perforans: vasculitic, but occurs only in patients with rheumatoid arthritis
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| Posterior scleritis: pain radiating to brow, frequently awakening patient during night, and accentuated on binocular rotations;
no observable features of ocular inflammation upon examination; often seen in association with anterior scleritis; funduscopic
examination may reveal fine striae (accentuated on fluorescein angiography); possible decrease in vision due to induced
hyperopia; B-scan ultrasonography—easiest way to make diagnosis; thickening of retinal choroid layer; edema
in Tenon’s space; at level of optic nerve, “T sign” present
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| Ocular prognosis: depends on underlying cause of scleritis; patients with classic connective tissue or vasculitic disorders
may have relatively benign prognosis; patients with lupus typically respond well to low-dose corticosteroids or systemic
hydroxychloroquine (Plaquenil), as do those with spondyloarthropathies; patients with rheumatoid disease or
relapsing polychondritis have slightly worse ocular prognosis; may require more aggressive use of systemic drugs, eg,
steroids, immunomodulators (scleritis never responds to topical therapy); patients with polyarteritis nodosa or Wegener’s
granulomatosis have most guarded prognosis for ocular outcome, involving loss of vision or even loss of eye; delayed diagnosis
can affect ocular prognosis; eye often first manifestation of systemic disease and may progress significantly before
diagnosis made; manifestations may begin as diffuse scleritis and progress to PUK, indicating vasculitis
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| Complications of scleritis: enucleation considerably less frequent today; ophthalmologists willing to utilize systemic
therapies that do not involve corticosteroids
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| Underlying causes: frequently found for scleritis; rarely found for episcleritis
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| Scleritis: usually connective tissue vasculitic disorders; infection also potential cause
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| Episcleritis: diagnostic possibilities same as for scleritis, but much less likely; frequently idiopathic (one study revealed
70% of patients had no known cause); recurrent and aggravating, but never vision-threatening; treatment—begins
with benign neglect; oral nonsteroidal anti-inflammatory drugs (NSAIDs) and iced artificial tears alleviate symptoms
for patients requiring treatment; steroid therapy ill-advised and prolongs duration
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| Diagnostic evaluation: driven by review of systems; possibilities include Type III Gell and Coombs hypersensitivity
reactions, with circulating immune complexes (CICs); C1q binding assay and Raji cell assay available for detecting
CICs; cryoglobulinemia uncommon; production of autoantibodies and consumption of complement (reduced C3 and C4
typical); antineutrophil cytoplasmic autoantibody (ANCA)—critical for detecting Wegener’s granulomatosis; scleritis
patients require ANCA testing; enzyme-linked immunosorbent assay (ELISA) testing for anti-proteinase 3 (PR3) and antimyeloperoxidase
critically important
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| Tissue biopsy: final step in evaluating patients; processed with light microscopy; immunoprobing, electron microscopy;
homogenization with DNA extraction and polymerase chain reaction (PCR) studies for detecting microbial causes
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| Immunosuppression study: examined death rates among patients with rheumatoid disease and “burnt out” arthritis
who developed necrotizing scleritis or PUK; deaths higher among those treated with steroids; no deaths reported among
those receiving immunosuppressive chemotherapy
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| Treatment of scleritis: in patients without underlying systemic disease, begin with NSAID, eg, celecoxib (Celebrex) at 200
mg bid; if unresponsive, treat with systemic prednisone at 1 mg/kg per day; after treatment takes effect, slowly taper to
avoid relapse and eventually switch to every other day; can use subconjunctival steroid injections adjunctively in nodular
scleritis
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| Classes of medications: antimetabolites, cytotoxic agents, signal transduction inhibitors (eg, cyclosporine), biologic response
modifiers; stepwise approach to medications contraindicated in patients with Behcets disease and retinal vasculitis,
Wegener’s granulomatosis, or polyarteritis nodosa
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| Diagnostic pearls: repeat biopsies indicated as evaluation progresses; repeat previously negative tests; 60% of patients with
Wegener’s develop eye inflammation, and of these, 25% have ocular before nonocular manifestations; delayed diagnosis common;
only 67% of Wegener’s patients ANCA-positive; in necrotizing polychondritis with eye involvement, cyclophosphamide
(eg, Cytoxan) indicated to prevent life-altering complications
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| Biologic therapy: biologic response modifiers offer selective, rather than global immunosuppression, with potentially
fewer side effects; successful treatment of joint inflammation promised success in treating ocular inflammation; instituted
off-label use of intravenous immunoglobulin (IVIG), daclizumab (Zenapax), and infliximab (Remicade), followed
by others; study of 51 patients, 12 with scleritis, found 71% improved on daclizumab; well tolerated, administered IV
every 2 wk, then gradually less often
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| Other biologic therapies: among tumor necrosis factor (TNF)-α inhibitors, adalimumab (Humira) and infliximab effective
in eyes; dosage 5 to 10 mg/kg every month; eyes may require more medication than joints; 83% of ocular inflammation
cases improved, with no adverse side effects; other studies revealed serious side effects, including pulmonary
embolism and congestive heart failure; IVIG—well tolerated when patient not IgA-deficient; requires 3 infusions each
month; most recent—rituximab therapy combined with IVIG for ocular inflammation with antibody participation
(eg, immune complex diseases); biologic therapies expensive and not curative
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| OCULAR ALLERGY UPDATE— Stefan D. Trocme, MD, Assistant Professor, Department of Ophthalmology and Visual
Science, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH
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| Conjunctivitis: types—include seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC); vernal
keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) low in prevalence but severe and potentially blinding;
giant papillary conjunctivitis associated with contact lenses
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| SAC and PAC: majority of ocular allergies; both mast-cell mediated, Type I hypersensitivity reactions; differ according
to allergen; perennial allergy—determine which allergen causes symptoms
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| Mechanism of acute allergic conjunctivitis: begins when allergen first taken up by antigen presenting cell; plasma
cells produce IgE specific to allergen; no allergic reaction on first encounter; on second encounter, allergen may interact
with IgE bound to mast cell; proinflammatory mediators released; mast cells degranulate; products of degranulation enter
surrounding tissue, resulting in incompetent vasculature and extravasation of fluid; edema and itching follow
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| Mechanism of chronic keratoconjunctivitis and allergic conjunctivitis: similar to that of acute, but followed
by repeated or chronic allergen challenge; or by recruitment of other inflammatory cells, eg, eosinophils, that degranulate
and cause further inflammation; activation of subset of lymphocytes that release proinflammatory mediators and cause
chronic condition; repetition in predisposed patients results in severe and debilitating forms of ocular allergy, ie, AKC and
VKC
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| Presentation of allergic conjunctivitis: ranges from mild to intermittent disease; possibly florid and inflammatory; may
include hyperemia; appropriate and timely treatment enhances function and vision
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| Multiple pathologies: conjunctivitis can occur concurrently with, aggravate, and worsen other conditions, eg, blepharitis
or dry eye; concurrent treatment required
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| Allergic rhinoconjunctivitis: >50% of patients affected by both ocular and nasal symptoms; treatment regimen should address
both; in >70% of patients, oral antihistamines alone do not sufficiently control conjunctivitis; supplemental medication
for eyes needed
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| Other measures: determine specific allergen; in addition to oral and topical medications, allergy shots available; consider allergen
filters for air-conditioning systems; special rug shampoos can address perennial allergens, such as dust and mites
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| Treatment: has moved to addressing >1 component of inflammatory cascade; to encourage patient compliance, pursue
user-friendly medications with multiple mechanisms of action; include topical treatment that provides quick relief of
symptoms; establish long-term control in patients at risk of developing chronic allergy; to foster compliance, choose
once- or twice-daily medications over those taken 4 times/day; avoid one-dimensional drugs; plug as many inflammatory
mediators as possible
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| Ocular allergy pharmacopoeia
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| Olopatadine (Patanol): combines instant relief of symptoms with long-term control; provides antihistaminic activity
along with mast-cell stabilization; user-friendly double-dose formulation available for once-daily use; nasal spray (Patanase)
under development; current formulation of Patanol already helps stabilize nasal allergy component
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| Nedocromil (Alocril): controls most mechanisms of allergy; sometimes difficult to obtain; solution’s yellow color and metallic
taste unappealing to some users, but highly effective
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| Pemirolast (Alamast): more effective than cromolyn; taken 4 times/day; when taken as prescribed, reasonably effective at
controlling symptoms
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| Ketotifen (Zaditor): bid multimodal medication; available over-the-counter
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| Epinastine (Elestat): bid multimodal medication
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| Loteprednol (eg, Alrex): “soft” steroid; deactivated by corneal esterases, so less likely to cause cataract or secondary
glaucoma; but speaker uses as adjunctive treatment
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| Treatment goals for chronic conjunctivitis: provide instant relief to avoid losing patient to noncompliance; break
inflammatory cycle with short-term (1-2 wk) site-directed steroid (eg, Alrex) combined with multimodal allergy drug; once
control accomplished, provide long-term control with multimodal drug
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| Treatment of acute allergic conjunctivitis: steroids often unnecessary; in mild cases, artificial tears suffice to dilute
allergen in tear film and rinse out inflammatory mediators; can use antihistamine vasoconstrictors for very mild
cases; ketorolac (Acular) approved (controls itching only); may also use single-modal antihistamines, eg, levocabastine
(Livostin); however, these medications address only that portion of allergic reactions responsive to antihistamines
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| Laser in situ keratomileusis (LASIK): determine history of atopic conditions; active allergy requires treatment before
surgery; determine whether patient on oral antihistamines (can cause dry eye, worsening common complication of
LASIK); discontinue oral antihistamine and control symptoms with topical treatment; delay LASIK if necessary; oral antihistamines
also delay postsurgical healing of epithelial defects
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| Photorefractive keratectomy: allergic conjunctivitis shown to cause complications, eg, haze regression
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| Atopic keratoconjunctivitis: critical to identify early; affects subset of patients with active or past history of atopic
dermatitis; definitive diagnosis requires this history
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| Presentation: severe staphylococcal blepharitis often seen; examine arms for active atopic dermatitis; conjunctivitis
sometimes severe enough to cause cicatrization; edematous eye lids; superficial punctate keratitis and ulcers; superficial
corneal infiltrates; keratoconus; anterior polar cataracts possible but rare; presentation often clouded by frequent
steroid use (can cause cataract in its own right, interrupting natural progression of true atopic cataract); ocular signs—
include blepharitis, meibomianitis, staphylococcal conjunctival injection, and endofibrosis; cicatricial component evident
as white lipid deposit around cornea
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| Treatment: control blepharitis with eyelid scrubs and lid hygiene; systemic treatments include antibiotics, antihistamines,
and doxycycline; severe cases may benefit from short course of prednisone; patients prone to corneal melting; corneal
transplant (poor prognosis; may retain intact structure of eye, but not conducive to good vision); improve prognosis early
on by remaining alert for history of atopic dermatitis
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| Vernal keratoconjunctivitis: pediatric variety of AKC; median age at onset 3 yr; male predominance; present with intense
itching; ptosis; severe conjunctival injection; large, nonuniform cobblestone papillae; limbal bumps; Trantas’
dots; corneal shield ulcers in extreme cases; 4% to 10% of patients develop permanent vision deficit; some patients
have less palpebral component and more limbal component; more common in blacks and American Indian children;
corneal transplant may be required
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| Treatment: aggressive use of topical steroids; also topical cyclosporine A; concentration required for control often mixed
with castor oil (created by compounding pharmacy); systemic antihistamines help control severe itch; steroids typically
mainstay in control
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Suggested Reading
Ahmed M et al: Diagnosis of limited ophthalmic Wegener granulomatosis: distinctive pathologic features with ANCA test
confirmation. Int Ophthalmol 28:35, 2008; Bellini LP et al: Topical cyclosporin A in severe allergic conjunctivitis. Cornea
27:625, 2008; Bielory L, Friedlaender MH: Allergic conjunctivitis. Immunol Allergy Clin North Am 28:43, 2008;
Bielory L: Intranasal corticosteroids and the eye: from negative ocular effects to clinical efficacy as a class effect. Ann Allergy
Asthma Immunol 100:506, 2008; Borazan M et al: Efficacy of olopatadine HCI 0.1%, ketotifen fumarate 0.025%, epinastine
HCI 0.05%, emedastine 0.05% and fluorometholone acetate 0.1% ophthalmic solutions for seasonal allergic conjunctivitis: a
placebo-controlled environmental trial [published online ahead of print July 8, 2008]. Acta Ophthalmol: Calonge M, Herreras
JM: Clinical grading of atopic keratoconjunctivitis. Curr Opin Allergy Clin Immunol 7:442, 2007; Galor A,
Thorne JE: Scleritis and peripheral ulcerative keratitis. Rheum Dis Clin North Am 33:835, 2007; Hoang LT et al: Antineutrophil
cytoplasmic antibody-associated active scleritis. Arch Ophthalmol 126:651, 2008; Jain V et al: Microbial scleritis:
experience from a developing country [published online ahead of print January 25, 2008]. Eye. doi:10.1038/sj.eye.6703099.
Jun J et al: Vernal conjunctivitis. Immunol Allergy Clin North Am 28:59, 2008; Kim EC, Foster CS: Immunomodulatory
therapy for the treatment of ocular inflammatory disease: evidence-based medicine recommendations for use. Int Ophthalmol
Clin 46:141, 2006; Lim L et al: Biologic therapies for inflammatory eye disease. Clin Experiment Ophthalmol 34:365,
2006; Michalova K, Lim L: Biologic agents in the management of inflammatory eye diseases. Curr Allergy Asthma Rep
8:339, 2008; Rich RM et al: Infectious scleritis after retinal surgery. Am J Ophthalmol 145:695, 2008; Torkildsen GL
et al: Bioequivalence of two formulations of ketotifen fumarate ophthalmic solution: a single-center, randomized, double-
masked conjunctival allergen challenge investigation in allergic conjunctivitis. Clin Ther 30:1272, 2008; Torkildsen GL et
al: Ocular comfort and drying effects of three topical antihistamine/mast cell stabilizers in adults with allergic conjunctivitis: a
randomized, double-masked crossover study. Clin Ther 30:1264, 2008; van der Maesen K et al: Posterior scleritis in a 7-
month old infant. J Pediatr Ophthalmol Strabismus 44:377, 2007; Wagner RS, Aquino M: Pediatric ocular inflammation.
Immunol Allergy Clin North Am 28:169, 2008; Wu CC et al: Rare extra-articular manifestation of rheumatoid arthritis:
scleromalacia perforans. Kaohsiung J Med Sci 21:233, 2005.
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