vascularization in the host bed is associated with a much higher risk of rejection in these keratoplasty cases. Keratoprosthesis surgery is another option for these patients and, again, the prognosis is best when the inflammation has been brought under control.

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Rao SK, Rajagopal R, Sitalakshmi G, Padmanabhan P. Limbal autografting: comparison of results in the acute and chronic phases of ocular surface burns. Cornea. 1999;18(2):164–171.

Tejwani S, Kolari RS, Sangwan VS, Rao GN. Role of amniotic membrane graft for ocular chemical and thermal injuries. Cornea. 2007;26(1):21–26.

Toxic Keratoconjunctivitis From Medications

A commonly encountered and frequently unrecognized clinical problem is that of epithelial keratopathy secondary to topically applied ocular medications. One of the most toxic ingredients in these preparations is the preservative, usually benzalkonium chloride. The corneal and conjunctival epithelia absorb and retain preservatives. Residual amounts of preservatives are detectable in the epithelium days after a single topical application. Toxic effects on the epithelium include loss of microvillae, plasma membrane disruption, and subsequent cell death.

Topical anesthetics can be toxic if used for prolonged periods. Prolonged use can lead to frank epithelial loss, stromal edema, ring infiltrate, focal infiltrate, and corneal opacities. However, sometimes even a single application of a topical anesthetic may cause transient epithelial irregularity. Medical personnel with easy access to anesthetics are especially susceptible to this factitious disorder (see Chapter 3, Fig 3-25).

Pathogenesis

Toxic conjunctivitis or keratoconjunctivitis may occur as a complication of exposure to various substances (Table 13-2). Topically applied ophthalmic medications can result in a dose-dependent cytotoxic effect on the ocular surface. The epithelium of the conjunctiva and cornea may show punctate staining or erosive changes indicative of direct toxicity. A conjunctival reaction may be observed in the form of either a papillary reaction (vascular dilation) or a follicular response. An immune response can also produce subepithelial corneal infiltrates.

Table 13-2

Clinical Presentation

Although these reactions generally occur after long-term use (weeks to months) of a drug, they may take place sooner in individuals with delayed tear clearance from aqueous tear deficiency or tear drainage obstruction. A generalized injection of the tarsal and bulbar conjunctiva may be associated

with a mild to severe papillary reaction of the tarsal conjunctiva, mucopurulent discharge, and punctate keratopathy. Occasionally, the discharge may be severe and mimic bacterial conjunctivitis. Infrequently, the reaction occurs in only 1 eye even though the medication has been applied to both.

In its mildest form, toxic keratitis consists of punctate epithelial erosions of the inferior cornea. A diffuse punctate epitheliopathy, occasionally in a whorl pattern, may be observed in more severe cases. This pattern is sometimes called vortex or hurricane keratopathy. The most severe cases may involve a corneal epithelial defect of the inferior or central cornea, stromal opacification, and neovascularization. This severe type of corneal disease is seen with extensive damage to the limbal stem cells. A sign of limbal stem cell deficiency is effacement of the palisades of Vogt. Prolonged use of preservative-containing medications or administration of antifibrotic agents (eg, topical mitomycin C drops, which have a radiomimetic effect on surrounding cells) may be the cause. Even when used in correct dosages for brief periods, mitomycin has been associated with prolonged, irreversible stem cell damage with resultant chronic keratopathy. Localized application of mitomycin using a cellulose surgical sponge to the surgical field (as in trabeculectomy or pterygium excision) is believed to incur a lower risk than more widespread topical administration and is the preferred method of antifibrotic therapy.

A different type of toxic keratitis manifests as peripheral corneal infiltrates located in the epithelium and anterior stroma, leaving a clear zone between them and the limbus. Conjunctival and/or corneal toxic reactions are typically seen following use of aminoglycoside antibiotics, antiviral agents, or medications preserved with benzalkonium chloride or thimerosal.

Chronic follicular conjunctivitis is another manifestation of external ocular toxicity. Generally, the follicular reaction involves both the upper and lower palpebral conjunctivae, but the follicles are usually most prominent on the inferior tarsus and fornix. Bulbar follicles are uncommon but highly suggestive of a toxic etiology when present (Fig 13-5). The medications most commonly associated with toxic follicular conjunctivitis include atropine, antiviral agents, miotics, sulfonamides, epinephrine (including dipivefrin), apraclonidine, α2-adrenergic agonists (eg, brimonidine), and vasoconstrictors. Inferior punctate epithelial erosions may occasionally accompany toxic follicular conjunctivitis.

Figure 13-5 Drug-induced chronic follicular conjunctivitis induced by topical dipivefrin. (Courtesy of James J. Reidy, MD.)

With ongoing use of topical medications, the conjunctiva shows an increased number of chronic inflammatory cells and fibroblasts. Although any medication may potentially cause this low-grade inflammatory response, it is most common with the long-term use of miotics for treatment of glaucoma. Asymptomatic subconjunctival fibrosis is not uncommon with long-term topical drug use, but a small minority of affected patients will develop an insidiously progressive and more severe type of subconjunctival scarring that can lead to contraction of the conjunctival fornix, symblepharon formation, and corneal pannus formation. This entity is called drug-induced cicatricial pemphigoid.

Management

Treatment of toxicity requires discontinuation of the offending topical medications. Severe cases may take months to resolve completely; thus, the failure of symptoms and signs to resolve within a period of days to a few weeks is not inconsistent with a toxic etiology. Patients who are experiencing significant ocular irritation may find relief with nonpreserved topical lubricant drops or ointment. It is important to stress that toxic reactions to ocular medications can lead to irreversible changes, as may occur in rare instances with use of cholinergic (pilocarpine-like) and other medications.

Drug-induced pemphigoid should be confirmed with a conjunctival biopsy, which often (but not always) demonstrates the characteristic diffuse, nonlinear immunofluorescent staining indicative of antibody deposition. Withdrawal of the medication is generally followed by a lag of weeks to months before progressive scarring can be stabilized. If clinical observation and photographic documentation