Toxic conjunctivitis

INTRODUCTION — Toxic conjunctivitis (also called toxic keratoconjunctivitis) implies direct damage to ocular tissues from an offending agent, usually a preservative or medication. The toxic agent can cause a papillary or follicular response in the conjunctiva with chronic use, and the conjunctiva can become chemotic, edematous, and hyperemic. These features also occur in allergic conjunctivitis, with which toxic conjunctivitis is often confused.

The most common form of toxic conjunctivitis is ocular surface medicamentosa (OSM). OSM is a chemical toxicity and/or a delayed, cell-mediated hypersensitivity response of the ocular surface and adnexa to active drugs and/or preservatives. Topical preserved eye drops are increasingly used to treat glaucoma and ocular surface disorders, such as dry eye disease (DED). OSM is usually associated with protracted use of topical drops. If not diagnosed and treated in a timely manner, OSM can result in significant ocular surface symptoms and visual dysfunction, affecting quality of life, daily activities, and workplace productivity. Thus, proper diagnosis, differentiation from DED, and correct management are important.

Toxic conjunctivitis is reviewed here. The various forms of ocular allergy are reviewed separately. (See "Allergic conjunctivitis: Clinical manifestations and diagnosis" and "Vernal keratoconjunctivitis" and "Atopic keratoconjunctivitis" and "Giant papillary conjunctivitis".)

EPIDEMIOLOGY — Toxic conjunctivitis may take days to years to develop but typically occurs with protracted use of topical ocular medications (usually longer than three months but can vary with the type of medication) [1]. There also appears to be a dose-response effect with regard to the preservative concentration and total amount of preservative-containing medications used [2]. Thus, toxic ocular reactions are most frequently reported in patients with glaucoma, who are on lifelong therapy with multiple medications [3].

ETIOLOGY — Certain topical medications and the preservatives in those medications, contact lens solutions, and artificial tears are the most common causes of toxic ocular reactions [4]. Cosmetics used on the eyelids are also implicated.

Topical eye medications are commercially available in two forms: single and multidose bottles or vials. Multidose bottles are convenient, cheap, and easy to use for patients, but they contain antimicrobial preservatives in order to prevent microorganism contamination and to ensure long-term stability as mandated by the US Food and Drug Administration (FDA) [5]. These preservatives can induce toxicity and hypersensitivity, resulting in ocular surface medicamentosa (OSM), particularly in patients who have chronic ocular disease, such as dry eye disease (DED) and glaucoma, in which multiple drops are used for long periods.

The most common commercially available preservatives used for topical eye drops are benzalkonium chloride (BAK or BAC), thimerosal, chlorobutanol, sodium perborate, stabilized oxychloro complex (SOC), polyquaternium-1, and an ionic buffer containing borate, sorbitol, propylene glycol, and zinc. They can cause toxic, irritant, or hypersensitivity reactions [6], although data from rabbit models suggest that the newer-generation SOC is less cytotoxic than the other preservatives [1,3]. In a randomized trial, patients who received newer-generation ionic buffer-preserved topical eye drops showed higher tear breakup time and lower superficial punctate keratopathy scores compared with those who received BAK-preserved drops [7].

BAK, a detergent, was first used as a preservative in hard contact lens solutions and has a broad range of antimicrobial activity. Since then, BAK has evolved as the most frequently used preservative in most classes of ophthalmic solutions, including antiglaucoma eye drops, due to its ability to break down corneal epithelial tight junctions and facilitate drug penetration [8]. It may damage the ocular surface, sensory nerves, and tear film. As a quaternary ammonium compound, BAK has been shown to cause apoptosis of corneal and conjunctival epithelial cells, subclinical inflammation of the conjunctival epithelium, loss of conjunctival goblet cells, conjunctival squamous metaplasia, and subepithelial fibrosis in both clinical and preclinical studies [9]. In one clinical study of BAK-containing drops, corneal permeability increased threefold in patients with DED compared with normal subjects [10].

Toxicity is especially common in the following topically applied eye medications [11-17]:

●Aminoglycoside antibiotics, including gentamicin and tobramycin

●Antiviral agents, including trifluorothymidine (Viroptic) and idoxuridine (Herplex)

●Glaucoma medications, including brimonidine (Alphagan), timolol maleate (Timoptic), and pilocarpine

●Topical anesthetics

Among the cosmetics, mascara, creams, and hair spray are commonly implicated in toxic reactions [18,19]. Typical cosmetics are known to contain >100 chemical compounds, but the specific triggers in cosmetics are not known.

PATHOGENESIS — Preservatives commonly damage the corneal epithelium. Preexisting damage to the cornea due to dry eyes or other causes is a risk factor for toxic conjunctivitis but is not required for its development.

Results from a monkey model and human corneal epithelial cell culture suggest that preservatives in ophthalmic solutions are unlikely to cause significant direct toxicity to epithelium of normal cornea [20]. However, studies in rabbit models consistently demonstrate ocular surface toxicity with topical preservative-containing medications [3,21]. In one study, patients with dry eyes were at greater risk for the development of toxic papillary reactions than those without dry eyes [22].

A number of findings are seen in patients treated with preserved medications compared with those using preservative-free therapies:

●Decreased goblet cell density [23] and reduced tear film breakup time [3]. Disruption of the tear lipid layer by preservatives in multidose eye drops results in increased tear film evaporation, which subsequently leads to increased tear hyperosmolarity and ocular surface desiccation. Tear hyperosmolarity causes osmotic stress on the ocular surface epithelium.

●Subclinical inflammation of conjunctival epithelium [3]. Biopsies show an increase in surface expression of inflammatory markers and mediators, including human leukocyte antigen (HLA)-DR, intercellular adhesion molecule 1 (ICAM-1), and chemokine (C-C motif) receptors CCR4 and CCR5 [3,23,24].

●Epithelial keratinization, squamous metaplasia, subconjunctival fibrosis, and increased apoptosis in the ocular epithelium [3,24].

CLINICAL MANIFESTATIONS — Patients typically present with noticeable burning of the eyes. Conjunctival hyperemia, chemosis, mucus discharge, papillary reaction of the palpebral conjunctiva, and itching are common (picture 1). The eyelids can become swollen, thickened, and excoriated. Involvement is usually bilateral, unless the offending agent was used in only one eye.

In mild cases of toxic conjunctivitis, the cornea will show punctate epithelial staining with fluorescein dye application. In more severe cases, large epithelial erosions and corneal ulceration may develop. Degenerated epithelium can roll up and form pseudodendrites that are sometimes confused with herpetic dendrites.

DIAGNOSIS — The diagnosis should be suspected in any patient with conjunctival injection who is using topical ocular products, particularly those containing preservatives.

The clinician should take account of all topical ocular medications that the patient is using and their duration of usage. The patient should be questioned about all systemic/topical medications and contact lens solutions used, with special attention to preservative-containing eye drops, their dosing, frequency, and duration of use. A common history is that the original eye condition improved upon initial treatment, but the eye symptoms worsened with continued use. A complete clinical evaluation of the ocular surface should be performed, which includes the Schirmer test, tear breakup time, corneal staining with fluorescein staining, and conjunctival staining with lissamine green. The diagnosis is typically confirmed when the eyedrops are discontinued and the clinical manifestations resolve. (See "Diagnosis and classification of Sjögren’s disease", section on 'Tests for dry eye'.)

Patch testing is rarely helpful for identification of the offending agent since toxic conjunctivitis is a local reaction. However, in vivo confocal microscopy is a promising diagnostic tool to assess and monitor the level of cellular inflammation and neurotoxicity in toxic conjunctivitis [25-29].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes the various forms of ocular allergy (seasonal and perennial allergic conjunctivitis [SAC and PAC], vernal and atopic keratoconjunctivitis [VKC and AKC], and giant papillary conjunctivitis [GPC]), hypersensitivity (allergic) reactions to ophthalmic medications, conjunctivitis medicamentosa, dry eye disease (DED), and early-stage ocular cicatricial pemphigoid (OCP). Toxic conjunctivitis can occur in addition to one of these conditions since most of these patients are treated with topical ophthalmic medications.

●Ocular allergy – The eyelids can become swollen, thickened, and excoriated in toxic conjunctivitis. By contrast, these eyelid findings are unusual in the various forms of ocular allergy (the exception being AKC). In addition, ocular allergy more commonly presents with itching. While itching can present in both, it is more common with allergy. Many times, the symptoms of toxic conjunctivitis coincide with the use of eyedrops. (See "Allergic conjunctivitis: Clinical manifestations and diagnosis" and "Vernal keratoconjunctivitis" and "Atopic keratoconjunctivitis" and "Giant papillary conjunctivitis".)

●Hypersensitivity reactions – Hypersensitivity reactions to topical ocular medications typically occur early in the course of treatment, whereas toxic reactions usually occur after prolonged use.

●Conjunctivitis medicamentosa – Conjunctivitis medicamentosa is caused by overuse of vasoconstricting eyedrops [30]. It presents with increased conjunctival injection and rebound hyperemia that occurs when the medication is discontinued. It is thought to be similar to rhinitis medicamentosa that occurs with topical nasal decongestants. (See "Chronic nonallergic rhinitis", section on 'Management of rhinitis medicamentosa'.)

●Dry eye disease – The signs and symptoms of DED can closely mimic those of toxic conjunctivitis. Differentiating the two conditions can be challenging because overuse of preserved artificial tears may result in the development of toxic conjunctivitis in underlying DED. Referral to a corneal specialist is recommended to try to determine whether the patient has DED, toxic conjunctivitis, or both. (See "Dry eye disease".)

●Ocular cicatricial pemphigoid – In its early phase, this disease may present only with signs of a chronic or relapsing conjunctivitis, with symptoms such as tearing, irritation, burning, or mucus drainage (picture 2). Eye involvement is usually unilateral initially. Extraocular involvement is seen in some patients. (See "Ocular cicatricial pemphigoid".)

TREATMENT — Recognition of the diagnosis of toxic conjunctivitis and removal of the offending agent(s) are imperative to the success of treating this condition. Stopping as many topical medications as feasible is a good first step. The patient should be monitored closely by an ophthalmologist after the suspected agent is discontinued in case the actual cause was infectious.

A preservative-free preparation should be used if a specific medication is required and preservative toxicity is suspected. An oral medication may be offered in situations in which a topical medication is causing toxicity, if that option is available.

Cold compresses and preservative-free artificial tears or ointments may help with ocular irritation.

●Topical corticosteroids – We use a short course (typically two to six weeks) of topical corticosteroid agents one to four times daily to aid in suppressing chronic ocular surface inflammation and alleviating symptoms in moderate to severe cases [31]. In mild cases, treatment one to two times a day is sufficient [31]. Topical corticosteroid treatment should be carried out only by an ophthalmologist.

Treatment options include loteprednol etabonate 0.5% gel (0.003% benzalkonium chloride [BAK]), loteprednol 0.38% (0.003% BAK), loteprednol etabonate ointment (BAK-free), prednisolone sodium phosphate 0.5% (BAK-free), or other preservative-free topical corticosteroids.

In cases of concurrent glaucoma and where toxicity is induced by glaucoma drops, loteprednol etabonate drops or gel are preferred as they carry a lower risk for increased intraocular pressure. Further, in these cases, loteprednol etabonate 0.5% gel or 0.38% are preferred over loteprednol etabonate suspension (0.01% BAK), which has a higher concentration of BAK.

All patients should have intraocular pressure monitored during treatment as topical corticosteroids can increase intraocular pressure. This is particularly true in patients with a personal or family history of glaucoma or intraocular hypertension.

Non-benzalkonium chloride (BAK)-containing formulations of topical medications are increasingly available, and use of these formulations may prevent many cases of toxic conjunctivitis. Further development of preservative-free or novel preservative preparations for ocular surface disease therapy may provide a promising approach in the prevention of ocular surface disease.

SUMMARY AND RECOMMENDATIONS

●Definition – Toxic conjunctivitis implies direct damage to ocular tissues from a topically applied agent, either a medication or its preservative. Its clinical manifestations resemble those caused by allergens; therefore, it is frequently confused with allergic ocular disease. (See 'Introduction' above and 'Etiology' above and 'Pathogenesis' above.)

●Epidemiology – Toxic conjunctivitis most commonly occurs in patients on long-term therapy with multiple preservative-containing topical ocular medications, such as those used to treat glaucoma. (See 'Epidemiology' above and 'Etiology' above.)

●Clinical manifestations – Conjunctival hyperemia is the most common manifestation (picture 1). The eyelids may swell and the corneal epithelium become eroded. (See 'Clinical manifestations' above.)

●Diagnosis – A common history is that the original eye condition improved upon initial treatment but that the eye symptoms worsened with continued use of the offending agent. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis includes the various forms of ocular allergy, hypersensitivity reactions to ophthalmic medications, conjunctivitis medicamentosa, dry eye disease (DED), and early-stage ocular cicatricial pemphigoid (OCP). (See 'Differential diagnosis' above and "Allergic conjunctivitis: Clinical manifestations and diagnosis" and "Vernal keratoconjunctivitis" and "Atopic keratoconjunctivitis" and "Giant papillary conjunctivitis".)

●Management - Treatment involves discontinuing the suspected offending agent(s) and switching to preservative-free topical therapies or oral medications. (See 'Treatment' above.)