cue THE CONJUNCTIVA Section 2 Meare Prypodtiginn | Exholiophte Disopepiteorphoaphate Neosignine Foret fii Aveiro donate Poractnisie Bomonkine Evropene pwn botlrophte Nsom sulci Sullamethenke Sutonazae Amphoteren & Diatieoate Mogiunine Fig. 51.1 Toxic ulcerative keratopathy secondary to preservatives in lal ear solutions. Note the oval epthokal defect with coare surtounding keratts, resembling a *comet’s impact” crater. The ‘epithelia defect has 3 wel-defned,rolec margin. Marked inferior anc inforonasal conjunctival injpcticn is present, as well as infense cilary‘Ack on Von ML A Sikes Ms Feller cont ‘ssacined with aprslonne, Am J Opbinaina 19 1):105-108, (89% Wats F, Hasksworm N. Dasyes Pyprsensivy fo rene fate 0.2% ‘associ with high inocu esau, Eye TO) 122-135, 2002: ard Cal tute a, anne Ma irene: pases we Gols ac sap to eck epee anibociog atl oa redtod nvm Ct Fy fe 7881-5), 1988 hyperemia. Papillary 1 Junctivitis also, but in addition, a follicular componeat may bbe present. Follicles are generally not seen in allergy alone, and may be a key sign suggesting toxicity. raple 51.1 Lists medications associated with follicular conjunctivitis.”” In addition, the hyperemia and chemosis that may occur with toxicity may not be as diffusely distributed on the bulbar conjunctiva as in the allergic reaction, but may spare the superior aspect relatively. It is often more prominent in the inferonasal comes and conjunctiva from the natural ell’ phenomena and the locus of the direct placement of topical drops (Figs 51.1, 51.2 and 51.2), Allergic conjunctivitis is often associated with a mucous discharge that is typically thin and cleat, A more purulent ‘or mucopurulent discharge may De associated with toxicity. The cornea in allergic conjunctivitis is often unattected or may show punciate staining with fluorescein, more promi nent inferiorly, The cornea in toxic reactions, on the other hand, may demonstrate a broad range of involvement, from mild punctate keratitis to severe ulcerative keratopa thy, As described by Wilson, the most common manifes- tations ate coarse and punctate epithelial lesions. Heaps and swiels of opaque epithelium may occur as well, which may lead to large erosions. Pscudodendiites may develop, resembling herpetic dendrites.” Schwab and Abbott empha- sized the Importance of the laigely unrecognized. probl (9-512 Towle keratccorjuncthiis sacondery to topical gentarich, he epithellim i cfuely regula, but more so infeticey. The nicreased onjancival injection inferiorly anc! inferonasally is characteristic: (Courtesy of Wan P. Schwab) of toxic ulcerative Keratopathy.* They described a. series of patients with similar findings secondary to. inappropri- ate use of topical medications, including anesthetic abuse. All of these patients had oval epithelial defects located primarily in the inferonasal quadrants, with coarse sur- rounding keratitis, resembling @ “comet's impact” craterFig. 81.3 Toxic keraoconuncivils secondary to topbal ituorothymicine (Vioplig. Once again, seen here isthe characteristic ‘comedl epithelial iregularty and c jection more prominent in the infor agpect ofthe aye. (Courtesy of han B. Schwab} (see fig. S1-1). Mucous threads, intense ciliary flush, papillary tarsal resporise, chemosls, and marked inferior or interonasal injection werealso common (see Figs 1.1, 51.2 and 51.3).The epithelialdefects typically demonstraterrolled, butnotheaped, margins. These findings were observed in patients with iatro. genic toxic keratopathy as well as in factitious, self-induced Keratoconjunctivitis. Diagnostic testing CHAPTER 51 Toxic Conjunctivitis active chemical or from degradation products and preserva. tives, Topical drugs produce higher concentrations in the comea and conjunctiva than in the other ocular tissues and may more easily affect the function and structure of the epithelial cells adversely.” Methods of assessing toxi ity Many techniques have been devised to measure the adverse effects of topical agents to the extemal eye quantitatively or qualitatively. Animal testing has long been a standard method of evaluating the acceptability of drugs for safe human use. A modified Draize test uses rabbits, whose eyes are more sensitive than those of monkeys or humans to many chemicals. In this ocular irritation test, the rabbit eye is treated with topical agents for three weeks, evaluated for one week, and then sacrificed for histological study. As pointed out by Burstein, however, this method cannot reli- ably detect surface defects, because epithelial defects are able to heal in less than three days.” Other tests include wound healing models to evaluate the adverse or beneficial effects of drugs on re-epithelialization and comeal permeability measurements with fuorometry, electrophysiologic meni: toring, and isotope localization. Morphologic evaluation is possible with specular and confocal microscopy, transmis- sion election microscopy, and scanning electron. mierns- copy. Pfister and Burstein have looked at the effects of many drugs, vehicles, and preservatives on the corneal epithelium with the scanning electron microscope, demonstrating effects ranging from changes in the cellular microvilli posi tion to frank loss of superficial layers of epithelial cells.” In vivo tandem scanning confocal microscopy has been usedVarious clinical tests are available, although not often per- formed, which may help to distinguish allergy from toxi The standard clinical test for the diagnosis of type I hyper. sensitivity is the intradermal skin test, in which injection of the agent intradermally elicits a wheal and flare reaction within seconds or minutes. The ocular equivalent of this ~ application of the substance into the conjunctival fornix ~ may yield a positive result with immediate chemosis, hyperemia, itching, and eyelid swelling.’ ‘The standard test for type IV hypersensitivity, or contact dermatitis, is the patch test. Here, the substance is applied to the skin and covered. Examination of the skin 24 to 48 hours later may reveal a contact dermatitis if positive. However, false nega- tives and false positives may both occur, and a careful history is often more helpful in making this diagnosis. Conjunctival scrapings may show eosinophils in. allergic conjunctivitis and not in toxic reactions. In addition, large toxic granules may be present in the cytoplasm of epithetial, mononuclear, and polymorphonuctear cells. These are large basophilic granules that differ from the usual smaller neutrophilic gran- tles. However, they are not specific for toxicity, and may be found in allergic responses as well.” Toxic Keratoconjunctivitis Related to Topical Medications Topical medications of all therapeutic categories may cause external ocular irritation, either from the direct effect of an to detect desquamation of superficial epithelial cells second- ary to benzalkonium chloride in rabbits.® Cell culture tech- niques allow in vitro assessment of cytologic effects of drugs but are not an accurate depiction of the in vive environ- ment, Efforts are being made to avoid testing of damaging chemicals and drugs on animals, a potentially advantageous but difficult proposition; many recent publications are con- cerned with ceveloping altematives to testing on animal yes, Investigators are now using cultured rabbit and human conjunctival cell lines in vitro to collect data conceming toxicity of topical ophthalmic preparations, Toxicity of specific agents The specific effects of all topical medications have been cata- logued in other comprehensive sources.’ The following is a review of some of the more common medications associated with toxic keratoconjunctivitis. Anti ‘Topical antiviral preparations, IDU (Stoxil, Hexplex, Dendrid), vidarabine (Vira-A), trifluorothymidine (Viroptic) and Gan: ciclovit (Zirgan), ate associated with toxic keratoconjuncti- vitis. IDU may cause more severe irritation than the others and is no longer in common use. In the treatment of herpes simplex keratitis, IU not uncommonly produces a punctate keratitis, epithelial edema, and corneal erosions with heaped opaque epithelium and_pseudodendrites. Overtreatment with IDU may produce the clinical appearance of continued als:aa ‘THE CONJUNCTIVA ESSE! Corjunetivitis ‘or worsened herpetic disease because of its ability to perpetu- ate postherpetic defects or indolent ulcers. IDU is also one ‘of several medications known to elicit a follicular response ‘on the palpebral conjunctiva with occasional conjunctival scarring and punctal occlusion (pseudotrachoma or pet: dopemphigcid syndrome). Although IDU probably does not retard epithelial healing, wounds involving the corneal stroma exhibit abnormally slow healing.” Trifluorothymidine and vidarabine also may produce punctate keratitis and corneal erosions, but toa lesser degree. ‘These medications are generally not associated with a pseu. dopemphigold syndrome. Corneal epithelial dysplasia may develop with trflucrothymidine use.” Although not avai able in the US, topical acyclovir is also an effective antiviral agent with low toxieity that has been very well tolerated.""* ‘Topical ganciclovir is now in wide use arid is well tolerated. Ganciclovir can cause a punctate keratitis but overall tolerability was better than topical acyclovir in. several clinical tials. Glaucoma medications ‘The miotic alkaloids, such as pilocarpine and carbachol, ate fairly common causes of nonspecific irritative conjunc tivitis, most likely related to the fact that these drugs form toxic degradation products.” Pilocarpine is also one of the topical medications known to cause conjunctival follicles” and also be a cause of drugeinduced mucous membrane pemphigoid." occurs in up to 20-30% of patients.” The discontinuation rate of lopidine 0.5% has been reported at 15%. tt has also been reported to cause follicular conjunctivitis.” Brimoni- dine has undergone a change in its preservative from ben- zalkonium chloride (BAK) to Purite in an attempt to tiny toxic side effects of the medication. A study by Katz. demon- strated a 41% lower incidence of allergic conjunctivitis in the brimonidine with Purite group versus the brimonidine with BAK group. The prostaglandin gioup of antiglaucoma medications has become a major class of medications with known toxic- ty to conjunctiva, Latanoprost, travoprost, bimatoprost, unoprostone isopropyl, and tafluprost are included in this class of medication. common side effect is conjunctival hyperemia, but true toxicity has been reported with latano- prost (Nalatan).”” Antibiotics and antifungals Of the aminoglycoside antibioties, tobramycin may be the least irritating, with generally less ocular toxicity than gen- tamicin.”” Localized ocular toxicity and hypersensitivity, eyelid itching, eyelid swelling, and conjunctival hyperemia have occurred occasionally with tobramycin, as well as gentamicin, Fortified cefazolin (54%) is commonly used in the empiric treatment of infectious keratitis, offen in conjunction with fortified gentamicin or tobramycin. It is relatively nontoxic and affects corneal epithelial wound healing less than tobra-Epinephrine, not commonly in current use, is associated with contact sensitivity as well as an actual toxic effect on the epithelium. Follicular conjunctivitis and occasionally mucous membrane pemphigoid are also associated. with long-tem use. Adrenomelanin (adrenochrome) deposits, tiny black or brown specks in the conjunctiva, are com: monly produced by chronic use of epinephrine eye drops, and are not associated with discomfort or intlammation.' ‘Thesedeposits represent material produced by oxidation and polymerization of epinephrine. A blaek cornea. in which the cornea appears coated with a black plaque of amorphous material, may occur as a result of the same adrenomelanin ‘accumulating in the anterior comes; this usually occurs ‘ases in which the corneal epithelium is already abnor from edema or trauma, Dipiveftin (Propine), an ophthalmic adrenergic designed to minimize some of the adverse effects of epinephrine, 1s also associated with a follicular conjunctivitis that resolves with discontinuation of the drag. Topical beta-adrenergic blockers such as timolol are gener- ally associated with little external ocular irritation, although systemic and cardiovascular effects are well documented, ‘Timolol has been associated with corneal hypesthesia, pun tate epithelial keratopathy, and pseudodentrites.”” Corneal epithelial erosions have been reported with timolol use and concomitant contact fens wear.” Dorzolamide has been associated with the development ‘of a mucopurulent sterile conjanctivitis as a toxic side effect ‘of this class of antigiaucoma medication.” Apracionidine hydrochloride (opidine) and brimonidine (Aiphagan), alpha-2-adrenergic agonists, have as their most common adverse effect allergic blepharoconjunctivitis that 576 mycin, gentamici sulfacetamide, and neomycin.” Topical bacitracin, in a dose of $00 units/g, is not irritat- ing to the conjunctiva or comea and does net interfere with epithelial healing. Contaet sensitivity, however, is frequently associated with bacitracin.” Neomycin commonly causes an allergic reaction of the ee with prolonged use, as well a8 a toxte conjunctivitis, with cutaneous and conjunctival sensitization reported to occur in 5-15% of patients.” Topical penicillin is rarely used because of its well-known allergenic tendency and it may cause anaphylaxis in 2 sen- sitized person. Allergic blepharitis is noted in as many as 16% of patients.” Chloramphenicol is another rarely used topical antibiotic. Although it is generally very well tolerated, with very little effect on epithelial integrity and wound healing, it nas been associated with bone marrow suppression and aplastic anemia, and for this reason is used uncommonly." Polymyxin B is generally nonirritating to the eye, but repeated applications can lead to irritation and low-grade conjunctivitis; allergic reactions are rare.” Topical sulfonamides may produce an allergic reaction, and the more serious may rarely induce StevensJohnson syndrome or toxic epidermal necrolysis."~"* Circumscribed sunburn of the lid margin has occurred trom local photosen- sitization after topical sulfisoxazole ointment application." The fluoroquinolones, currently the most commonly employed topical antimicrobial agents, are generally. less toxic than aminoglycosides. A study’ by Sosa, Epstein, and Asbell demonstrated toxicity to both corneal and con: junctival epithelial cells by commercially available topical . chloramphenico)