Toxic Keratoconjunctivitis : Introduction, Symptoms, Causes, Diagnosis, Management and Prevention - www.genericdrugscan.com

Toxic Keratoconjunctivitis : Information

Toxic keratoconjunctivitis or Toxic conjunctivitis may result from topical preparations for the treatment of ophthalmic conditions. Topical ophthalmic preparations can confuse the diagnosis of toxic keratoconjunctivitis. Medications often alleviate the symptoms initially and only at a later time, sometimes years after initiating therapy, will the patient develop discomfort. Common toxic agents are glaucoma medications, preservatives, antibiotics and antivirals. Patients with keratoconjunctivitis sicca (dry eye syndrome) are particularly at risk.

Ebers papyrus from ancient Egypt mentions eye remedies including red lead, antimony, lead, sea salt, iron and sulphur (Magnus H. Ophthalmology of the ancients. In: Wayenborgh J, editor. Hirschberg history of ophthalmology, vol. 4. Ist ed. Oostende: Wayenborgh; 1998: 4-12). In 1864, Albrecht von Graefe reported a case of toxic keratoconjunctivitis following administration of topical atropine (Wilson 2nd FM. Adverse external ocular effects of topical ophthalmic therapy: an epidemiologic, laboratory, and clinical study. Trans Am Ophthalmol Soc 1983; 81: 854-965). Treatment for Glaucoma is of particular importance, since topical therapy may last for decades.

Main ocular allergic diseases under chronic allergic conjunctivitis (CAC) are viz. seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis and, to a certain extent, giant papillary conjunctivitis (GPC). Contact dermatitis is due to exogenous factors and it may be produced by irritant or is allergic in nature. Irritant contact dermatitis, such as toxic reaction to eye-drops, is caused by direct damage. Toxic keratoconjunctivitis may be produced due to damage of ocular tissues by an agent, usually an ocular drug or a preservative. Allergic contact dermatitis is a delayed type IV hypersensitivity reaction to a particular allergen.

References:

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Boyd Samuel, Gutierrez Angela Maria, McCulley James P. Atlas and Text of Corneal Pathology and Surgery. Jaypee-Highlights Medical Publishers, Inc. An Editorial Branch of Jaypee Brothers Medical Publishers (P) Ltd. 2011. P. 306-308.

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Sihota Ramanjit, Tandon Radhika. Parson's Diseases of the Eye. Reed Elsevier India Private Limited. 22nd Edition. 2015. P.183.

Magnus H. Ophthalmology of the ancients. In: Wayenborgh J, editor. Hirschberg history of ophthalmology, vol. 4. Ist ed. Oostende: Wayenborgh; 1998: 4-12.

Wilson 2nd FM. Adverse external ocular effects of topical ophthalmic therapy: an epidemiologic, laboratory, and clinical study. Trans Am Ophthalmol Soc 1983; 81: 854-965.

Spector S & Raizman M (1994): Conjunctivitis medicamentosa. J Allergy Clin Immunol 94: 134136.

Toxic keratoconjunctivitis may produce symptoms such as:

Eyelids and Periorbital skin:

• Oedema.
• Itching (pruritus).
• Urticaria.
• Dermatitis.

Conjunctiva:

• Redness.
• Mucoid discharge.
• Chemosis.
• Itching.

Cornea:

• Photophobia (sensitivity to light).
• Corneal lesions, such as ulcers.]

There is no single mechanism responsible for drug intolerance or toxicity, but a combination of these occurs simultaneously, or in sequence and cause symptoms.

Direct toxic effects: Medications can be directly toxic to the conjunctival and corneal epithelium, damaging its structure and altering its function with or without an inflammatory response. Some preparations are directly toxic due to change in pH, osmolarity of solution, or due to photosensitisation. Direct toxic effects usually occur after the first contact and appear after a threshold is reached.

The cellular reaction may reflect the direct effect due to

• Active compound.
• Accompanying preservative.
• Breakdown products.

Immunological mechanisms: Topical preparations can also induce damage through immunological mechanisms. These reactions are classified into following categories:

• Type I hypersensitivity: Allergic reactions due to type I hypersensitivity are triggered by the union of allergen and initiation of Immunoglobulin E (IgE) - mast cell axis, leading to de-granulation and release of inflammatory mediators.
• Type II-III hypersensitivity: Type II-III hypersensitivity is triggered by antibody-specific and immune-complex-mediated effects.
• Type IV or delayed hypersensitivity: Type IV or delayed hypersensitivity is associated with marked epithelial and sub-epithelial oedema and infiltration by CD4+ lymphocytes and Langerhans cells (Langerhans cells are potent antigen-presenting cells of the conjunctival epithelium).

Indirect mechanisms: Ophthalmic treatments may also be toxic through more indirect mechanisms.

• Bacterial colonisation: Antimicrobials modify the ocular surface microbes and may favour bacterial colonisation by selecting resistant strains.
• Decreased local immune mechanisms: Corticosteroids may decrease local immune mechanisms.
• Decrease in tear production: Parasympatholytics and antihistamines may decrease tear production.
• Toxicity to goblet cells: Preservatives may cause direct cytotoxicity to goblet cells.
• Detergent effect: Preservative like benzalkonium chloride may have a detergent like effect on lipid layer of tear film leading to evaporation of tears.]

For the diagnosis of Toxic keratoconjunctivitis, a detailed clinical history is important. A common history is that the eye disease improved upon initial treatment, but the symptoms in eye worsened with continued use. Clinical manifestations resolve when the topical medication is discontinued. Patients often do not communicate the routine use of over-the-counter (OTC) eye preparations, such as artificial tears or vasoconstrictors. Hypersensitivity reactions to topical ocular medications usually take place early in the course of treatment, but toxic reactions usually occur after prolonged use of drugs.

One should be aware of topical anaesthetic abuse or indiscriminate use of topical antibiotics. It is important to obtain information on medication storage habits and to confirm expiry dates, since patients often keep previously used medicines and use it, if symptoms return.

Diagnosis requires examination under slit-lamp (bio-microscopy) by an eye specialist. Staining of cornea and conjunctiva with fluorescein sodium and rose Bengal dye may be required to identify the lesions.

Clinical ocular (eye) features:

Most common toxic reaction is toxic papillary keratoconjunctivitis, which occurs due to repeated use of irritating medicine. The effect usually develops two weeks after exposure to the drug and may lead to a decreased compliance by patient.

Periorbital Skin and Eyelids (ocular adnexa):

• Oedema.
• Pruritus (itching).
• Urticaria:

Oedema, pruritus (itching) and urticaria of the eyelids are characteristic of type I hypersensitivity.

• Dermatitis: Dermatitis involving periorbital skin is characteristic of type IV hypersensitivity, specifically if it appears a few days after the initiation of a new drug. Dermatitis may rarely simulate seborrhoeic blepharitis.
• Lacrimal punctum: There may be fibrosis and obliteration of lacrimal punctum, thereby compromising its patency.

Conjunctival features may be:

• Up-down sign of drug toxicity: When patient looks up, the lower bulbar and forniceal conjunctiva show intense congestion. Inferior bulbar conjunctiva may also show epithelial defects when stained with fluorescein sodium dye. When patient looks down, the upper bulbar and forniceal conjunctiva are white and non-congested.
• Papillary reaction.
• Follicular reaction.
• Mucoid discharge.
• Pruritus.
• Conjunctival scarring.
• Conjunctival erosions.
• Chemosis.
• Hyperaemia.

Hyperaemia and chemosis are more subtle and difficult to assess.

Cornea:

• Punctate epitheliopathy: Punctate epitheliopathy predominates in the inferior-nasal quadrant, where there is maximal contact time between the drug and ocular surface.
• Persistent epithelial corneal defects.
• Hurricane keratopathy: Hurricane keratopathy is the whorl pattern, seen with exaggerated corneal epithelial cell turnover. The corneal epithelium may be opaque and oedematous.
• Corneal ulcers: Inferior-nasal quadrant is also the usual location of corneal ulcers (with rolled edges) due to anaesthetic abuse, which resembles neurotrophic keratitis. There may be papillary response and intense ciliary flush.
• Filamentary keratopathy.
• Corneal necrosis.
• Pseudo-dendrites.

Tear film:

• Tear film break-up time (BUT) may be reduced.

Histopathology:

Topical ophthalmic preparations can confuse the diagnosis of Toxic conjunctivitis. Medications may damage structure and alter function of conjunctiva and cornea with or without an inflammatory response. Toxic effect of these substances may lead to infiltration of substantia propria, by inflammatory cells and fibroblasts, which eventually lead to fibrosis.

Immunological mechanisms may lead to:

• Type I hypersensitivity: There is release of inflammatory mediators triggered by the union of the allergen with IgE-mast cell axis.
• Type II-III hypersensitivity: Leads to antibody-specific and immune-complex-mediated effects.
• Type IV or delayed hypersensitivity: There is marked epithelial and sub-epithelial oedema and infiltration by CD4+ lymphocytes and cells of Langerhans.

Diagnostic tests:

Most tests are not practical or not widely available and are difficult to perform in the clinical set up.

• Conjunctival Scraping: The presence of eosinophils and basophils on conjunctival scrapings points to an allergic reaction but it is relatively non-specific, since these cells can also be found in toxic keratoconjunctivitis. In clinical setting, this test is most often used to rule out infectious disease and allergy.
• Conjunctival Biopsy: Conjunctival biopsies are reserved for confirmation or exclusion of autoimmune diseases and are usually reserved for the diagnosis of cicatrising conjunctivitis (e.g. pemphigoid). Patients, after long-term glaucoma treatment, may show squamous metaplasia of the conjunctival epithelium and sub-conjunctival inflammation and fibrosis.
• Impression Cytology: Impression Cytology provides a homogeneous cell layer for histological studies. Epithelial cells, goblet cells and inflammatory cells can be differentiated with immune-staining and can even be used for flow cytometry analysis, which allows measurement of membrane and cytoplasmic inflammatory markers.
• Tear analysis: Tear samples can be used to measure levels of IgE or inflammatory cytokines, though they are rarely used except for research purposes.

When tear samples are positive, skin tests and conjunctival allergen challenge may be of clinical value, but negative findings do not rule out allergy.

Toxicity of common ophthalmic preparations:

Glaucoma medications:

Patients with glaucoma frequently require topical treatment for many years to control intraocular pressure. Like all ophthalmic medications, any anti-glaucoma drop may initiate sudden allergic response. However, patients may develop a late onset reaction, appearing months or even decades after treatment. Patients present with foreign body sensation, conjunctival hyperaemia, and staining of the conjunctiva with fluorescein sodium and rose Bengal. Topical anti-glaucoma medications have been shown to reduce density of superficial epithelial cells and increase tear film break-up time (BUT). Severe cases may induce sub-conjunctival fibrosis and a pseudo-pemphigoid syndrome. Long term therapy may induce subclinical inflammation and increased postoperative fibrosis; hence, the long-term use of topical anti-glaucoma drugs may be an important risk factor for the failure of filtration surgery. Care of ocular surface and reduction of inflammation before surgery may be achieved, whenever possible.

Specific glaucoma medications can be associated with certain clinical manifestations. Pilocarpine and beta-blockers have been associated with follicular conjunctivitis and drug-induced pemphigoid. Beta-blockers have also been found to produce pseudo-dendrites and corneal hypo-aesthesia. Both epinephrine and dipivefrin may also induce a follicular reaction. Epinephrine is associated with pigmented adenochrome deposits in the conjunctiva. Alfa-2-adrenergic agonists may produce an acute allergic blepharoconjunctivitis.

Preservatives:

Preservatives are antiseptic substances formulated with the principal compound of eye-drops to prevent microbial contamination.

Multi-dose eye drops contain antimicrobial preservatives. Many substances have been used for this purpose, including benzalkonium chloride, chlorhexidine, chlorbutanol, thiomersal, paraben esters, and mercuric salts. Preservatives are probably the most common cause of toxic keratoconjunctivitis. Repeated application of multiple medications may lead to significant accumulation of preservative in ocular (eye) tissue and thus, increased risk of ocular damage. Toxicity is more common in patients taking preserved medications as compared to those taking preservative-free eye drops.

Benzalkonium chloride can disrupt tear film by detergent action, cause epithelial toxicity and irreversible corneal oedema. Thiomersal is a common cause of hypersensitivity reaction and follicular conjunctivitis. Chlorobutanol is an alcohol that increases lipid solubility and is normally well tolerated and has been found to be less toxic than benzalkonium chloride or thiomersal.

Anaesthetics:

Anaesthetics are inappropriately used by patients to relieve pain, but the action is short-lived and the drug may be easily abused. The indiscriminate use of topical anaesthetics is a well known cause of toxic keratoconjunctivitis. Proparacaine, tetracaine, lidocaine, cornecaine, and benoxinate, all have been associated with toxicity. Patient may have clinical features such as pain, swelling of lids, conjunctival hyperaemia or mucopurulent discharge. The most frequent manifestation is superficial keratopathy, which can be detected even after instillation of a single drop. More severe cases can have corneal ulceration and stromal necrosis. Toxic lesions are due to decreased blinking reflexes, tear film instability with loss of epithelial microvilli, and corneal desiccation. Anaesthetics interfere with cell metabolism, cell membrane permeability, alter function of cytoskeletal proteins, and decrease the rate of epithelial wound healing.

Topical Antibiotics:

Topical antibiotics are the mainstay of treatment for bacterial conjunctivitis and keratitis. The most used antibiotics are topical amino-glycosides and fluoroquinolones, followed by sulphonamides, macrolides, and chloramphenicol.

Amino-glycosides, such as gentamicin and tobramycin can produce conjunctival and corneal hypersensitivity, pruritus and hyperaemia. Toxic effects of topical fluoroquinolones, even of the first generations, are less common than those produced by amino-glycosides. The most common corneal finding is a white crystalline precipitate after the use of ciprofloxacin. However, epithelial toxicity, due to the preservative benzalkonium chloride present in topical gatifloxacin, can occur. Suphonamides may produce mild allergic reaction. The most devastating complication of sulphonamides is the induction of Stevens-Johnson syndrome or toxic epidermal necrolysis. Photosensitisation after topical sulfisoxazole ointment use may cause sunburn of the lid margin.

Topical antivirals:

All antiviral medicines may cause toxic keratoconjunctivitis to some extent. Idoxuridine may produce punctate epitheliopathy, erosions and epithelial oedema on cornea. In conjunctiva, it causes follicular response, subconjunctival scarring and may occlude punctum. Similar effects, but to a lesser degree, may be caused by trifluorothymidine and vidarabine.

Topical antifungals:

Antifungals used in topical preparations may impair epithelial healing. Natamycin, the most commonly used anti-fungal agent, is generally non-irritating.

Miscellaneous toxic agents:

Almost all topical treatment, given enough time and frequency of use, may be associated with toxicity. One must be aware that substances other than approved medications may be in contact with the ocular surface. Substances such as mascara, eyeliner, hair gel, hair sprays, skin preparations, and virtually any substance with direct or indirect contact with the body may produce toxicity. Many a times, patients use home-prepared remedies for common eye complaints, and are often reluctant to disclose these.

Toxic keratoconjunctivitis should be differentiated from conditions such as:

• Allergic conjunctivitis.
• Ocular cicatricial pemphigoid: Ocular cicatricial pemphigoid is characterised by auto-antibodies directed against adhesion molecules in epithelial membrane complex. It leads to chronic ocular cicatricial conjunctivitis, besides affecting skin and other mucous membranes. There may be subconjunctival fibrosis, symblepharon formation, fornix foreshortening or punctal occlusion.
• Pseudo-pemphigoid: Pseudo-pemphigoid is a severe toxic scarring reaction of the ocular surface, similar to ocular ciactricial pemphigoid. Unlike ocular cicatricial pemphigoid, investigations fail to show any auto-antibodies in the conjunctiva.
• Factitious disease: Factitious disease is an intentional disease produced by patient.
• Conjunctivitis medicamentosa: Conjunctivitis medicamentosa (medicamentosa is a potentially prolonged inflammatory state that can last for several weeks or months of rebound mucosal congestion) is caused by overuse of topical vasoconstrictors. It presents with increase in conjunctival congestion and rebound hyperaemia on discontinuation of medicine. ( conjunctivitis medicamentosa ) (Spector S & Raizman M (1994): Conjunctivitis medicamentosa. J Allergy Clin Immunol 94: 134 136.).]

Management should be carried out under medical supervision.

Ocular surface toxicity is related to concentration, frequency and duration of administration of drug, while allergy does not have such relationship.

Management of Toxic keratoconjunctivitis depends on the time of exposure and severity of the ocular surface disease.

General measures:

• Discontinuation of the offending toxic agent: Primary therapeutic strategy is the discontinuation of the offending toxic agent. Attempts should be made to stop medications or to substitute them with less toxic or preservative-free formulations. Contact lens wear, if required, should be used cautiously, since they can act as a toxic reservoir.
• Cold compresses: Cold compresses may be soothing and may help in ocular irritation.

Medical therapy:

• Preservative free artificial tears: For mild disease, a preservative free artificial tear may be used for symptomatic relief.
• Topical corticosteroids: Topical corticosteroids may be needed for more symptomatic patients.

Surgical therapy:

Patients may require surgical measures, for complications and sequlae, such as:

• Tarsorrhaphy: Tarsorrhaphy may be required for persistent corneal epithelial defects.
• Conjunctival flap: Conjunctival flap is an alternative for persistent epithelial defects of cornea.
• Amniotic membrane grafting: Amniotic membrane grafting may be beneficial in covering epithelial defects, thereby promoting corneal healing.
• Keratoplasty: Keratoplasty may be required for impending corneal perforation or necrosis.

Prognosis:

Toxic keratoconjunctivitis is usually non sight-threatening. Overall time taken for resolution of drug reactions and clinical improvement may be prolonged.

For prevention:

• Patients should avoid routine use of over-the-counter (OTC) eye preparations, such as artificial tears or vasoconstrictors. If necessary, these should be used less frequently and for shorter duration.
• Topical preservative-free formulations for the eye should be used, whenever possible, to prevent preservative related toxic keratoconjunctivitis.
• Contact lens wear, if required, should be used cautiously, since they can act as a toxic reservoir.]