Corneal Manifestations of Local and Systemic Therapies

Topical Preservatives

Adverse reactions to topical ophthalmic solutions may result from preservative compounds added to slow biodegradation and provide antimicrobial protection. A range of ocular surface pathologies have been described associated with the use of preservatives, and clinicians must consider these additives a potential culprit. Dry eye patients are at a heightened risk of toxicity due to enhanced baseline epithelial permeability and reduced dilution of preservative concentrations in lower tear volumes.

Benzalkonium chloride (BAK), the most commonly used preservative, is a quaternary ammonium detergent found in concentrations ranging from 0.004% to 0.02%. BAK functions as an antimicrobial via protein denaturation and lysis of cellular plasma membranes. ^, Its effects are not limited to microbes, however, and include host epithelial cell death and destabilization of the precorneal tear film. ^, The surfactant nature of BAK disrupts the tight junctions of the hydrophobic corneal epithelial barrier, a property that has been touted as a method for enhanced drug penetration. Patients may exhibit punctate epitheliopathy, reduced tear break-up time, conjunctival follicles, and hyperemia. Electron microscopy has demonstrated epithelial microvilli loss and desquamation of superficial cells several hours after BAK instillation. Prolonged exposure, particularly to higher concentrations, produces greater toxicity and intraocular penetration in vitro and may rarely be associated with endothelial cell damage in vivo . ^, Intraocular BAK must be avoided, since even dilute concentrations can cause corneal edema and endothelial necrosis.

Toxicity may be addressed by reducing dosing frequency, diluting preservative concentrations, or switching to an alternative formulation. Oxidant preservatives, including stabilized oxychloro complex (SOC or Purite), enter microbial cell walls and disrupt enzymatic function. Human tears rapidly degrade oxidizing compounds, improving ocular surface tolerance but potentially reducing antimicrobial efficacy. Thimerosal, a mercurial formerly found in contact lens solutions, can cause limbal stem cell deficiency with characteristic swirling, vortex keratoconjunctivitis superiorly. Toxic calcific band keratopathy may rarely be seen with prolonged use of phenylmercuric nitrate.

Topical Anesthetics

Topical anesthetics include benoxinate, proparacaine, tetracaine, and cocaine, all of which act by blocking afferent nerve conduction. These agents have significant potential for toxicity, and suspicion of abuse must remain high given that the clinical picture mimics infectious and neurotrophic keratitis and patients often fail to disclose their use. The most common side effect is a punctate epitheliopathy due to toxicity of the anesthetic itself, its preservatives, or the sequelae of corneal numbness, including a diminished blink rate and decreased aqueous tear production. In rabbits, tetracaine produced four times more epithelial cytotoxicity than proparacaine, and patients often find tetracaine more irritating than proparicaine. Topical anesthetics inhibit epithelial cell migration and adhesion and can produce or potentiate nonhealing central epithelial defects that may persist for days to weeks despite stopping the offending drop. Epithelial damage heightens the risk of allowing deeper penetration of anesthetic compounds. Patients may develop dense disciform or secondary infection, including Candida and Streptococcus viridans crystalline keratopathy, and ring-shaped infiltrates, possibly due to stromal deposition of antigen-antibody complexes triggered by epithelial cell breakdown. Epithelial and endothelial edema are reported, as well as severe ulceration and perforation requiring keratoplasty. Treatments for anesthetic abuse keratopathy include amniotic membrane grafting, preservative-free lubricating and anti-inflammatory agents, and prophylactic antibiotic coverage. Although toxicity is more often observed with long-term use of the typical concentrations of 0.4%–0.5%, case reports document severe toxic keratopathies in patients administering frequent dilute oxybuprocaine 0.05% for 2–14 days. ^, Less common topical anesthetic side effects include anterior uveitis and periocular contact dermatitis.

In recent years, the practice of dispensing topical anesthetics to patients who present to the emergency room with corneal abrasions has gained popularity, despite the potential toxic effects of these medications. Proponents argue that, when dispensed appropriately to patients with simple corneal abrasions for short-term use, topical tetracaine is a safe and effective option for pain control ; however, further study is needed to definitively demonstrate safety and efficacy, and to determine straightforward criteria for patient selection.

Topical Antimicrobials

Fluoroquinolones are widely prescribed for anterior segment infections. Both in vitro and in vivo evidence largely demonstrates good ocular surface tolerance. ^, Delayed hypersensitivity may produce mild punctate epitheliopathy, conjunctival hyperemia, and local irritation. Some animal studies suggest delayed corneal wound healing with second-, third-, and fourth-generation fluoroquinolones, particularly at higher concentrations, with potential keratocyte death. The placement of Besivance (besifloxacin) on the stromal bed under a bandage contact lens in the setting of an epithelial defect may delay reepithelization, possibly secondary to the drug’s carbomer-containing polymer vehicle. Increased ulcer perforation with fluoroquinolone therapy has been reported in several clinical studies of microbial keratitis, but not others. ^, White corneal micro and macroprecipitates of ciprofloxacin form clinically in 16% of patients and microscopically in nearly 100%, and may be more common in elderly patients due to higher levels of dry eye and a more alkaline ocular surface ( Figs. 68.1 and 68.2 ). ^, Similar stromal and subepithelial deposits have been reported with other fluoroquinolones in the setting of compromised epithelium, including ofloxacin and gatifloxacin, with variable resolution and effect on visual acuity. Crystallization in human tear film is more likely in formulations with an increased acidic solubility; the pH of ciprofloxacin is 4.5, gatifloxacin 5.5, and ofloxacin 6.4.

Topical aminoglycosides gentamicin, tobramycin, and neomycin can produce a superficial punctate keratitis, conjunctival hyperemia, chemosis, allergic contact dermatitis, and transient symptoms of burning, stinging, and irritation. Rarely, a pseudomembranous conjunctivitis has been reported in association with topical gentamicin that resolved after drop cessation. Higher doses of these drugs may inhibit corneal reepithelization.

Fortified antimicrobial preparations offer the advantage of increased potency, but the high concentrations and frequent dosing in the setting of compromised corneal epithelium can result in morbidity. Epithelial toxicity is seen with topical vancomycin, particularly at higher concentrations (such as 50 mg/mL) due to its acidic pH. ^, Cefazolin has shown minimal effect on wound healing in animal and clinical studies. ^, Severe canalicular stenosis has been reported in a patient using fortified gentamicin (14 mg/mL) and vancomycin (50 mg/mL), presumably secondary to apposition of damaged epithelial surfaces.

Early topical antiherpetic agents included the nonselective nucleoside analogs idoxuridine (IDU), adenine arabinoside (vidarabine or Ara-A), and trifluridine (Viroptic). These agents inhibit DNA replication in both healthy and virally infected cells, and have been frequently reported to cause ocular toxicity, limiting patient compliance and clinical utility. IDU was abandoned for other antivirals due to poor bioavailability and significantly adverse drug events, including allergic contact dermatoblepharitis, epitheliopathy, papillary and follicular conjunctivitis, and punctal obstruction. Dose-dependent epithelial toxicity is also found with trifluridine use and may range from punctate keratitis to ulceration, edema, dysplastic lesions, and delayed cornea wound healing. Rarely, extended trifluridine use may cause anterior segment ischemia, cicatrization, punctal and canalicular stenosis, and corneal neovascularization. Acyclovir, a selective nucleoside analog, is available as a 3% ointment in Europe. Ganciclovir 0.15% gel is available in the United States and abroad. Both are well-tolerated with mild surface toxicity reported, although the gel and ointment formulations result in blurred vision disliked by some patients.

Amphotericin B has been repeatedly shown in vitro to retard epithelial wound healing, decrease cell viability, and increase epithelial permeability as compared to voriconazole and natamycin. ^{, ,} Toxicity may be reduced by decreasing the concentration. Natamycin produces less toxicity, but achieves poor corneal penetration in the setting of an intact epithelial barrier. Voriconazole appears well-tolerated by both the corneal epithelium and endothelium with topical and intraocular use. ^,

Topical Antiinflammatories

Topical nonsteroidal antiinflammatories have a range of indications, including cystoid macular edema, ocular inflammation, and pain. The literature includes multiple reports of corneal toxicity, ranging from punctate epitheliopathy and persistent epithelial defects to subepithelial and stromal infiltrates, immune rings, and corneal melting with perforation ( Fig. 68.3 ). Melts have been described with the use of ketorolac, diclofenac, nepafenac, and bromfenac in patients on b.i.d. to q.i.d. dosing for less than 2 weeks following ocular surgery, surface ablation, and laser trabeculoplasty. Ulceration occurred inferiorly, paracentrally, and near prior corneal wounds, and a concomitant anterior chamber reaction was frequently present. Presentation may be delayed as ketorolac and diclofenac can cause reversible corneal hypesthesia. Patients with underlying ocular surface disease, such as dry eye or Stevens-Johnson syndrome, are at increased risk of ulceration. Potential mechanisms include the aberrant expression of matrix metalloproteinases promoting keratolysis. However, simultaneous administration of topical steroids and antibiotics in most cases clouds the clinical picture. Adhering to recommended dosing regimens, avoiding unconventional indications such as infectious keratitis, and using caution in patients with bandage contact lenses is advised to minimize toxicity.

Serious and well-known adverse effects of topical corticosteroids prednisolone acetate 1%, dexamethasone 0.1%, and difluprednate 0.05% include cataract formation, elevated intraocular pressure, and microbial susceptibility. These medications can also delay epithelialization and wound healing in vivo and in vitro. Preservative free methylprednisolone 1% demonstrated less epithelial toxicity compared to prednisolone 1% in the treatment of anterior uveitis, highlighting the effects of the preservative BAK. ^, Rare reports describe corneal calcium deposition in patients using topical steroid phosphate preparations in the presence of a preexisting epithelial defect with concurrent use of timolol maleate or other drops.