Corneal Ulcer and Ulcerative Keratitis in Emergency Medicine

A corneal ulcer is a loss of corneal tissue, often associated with inflammation, and ulcerative keratitis is the general term for the group of disease processes leading to corneal ulceration, as well as the term for the inflammation that accompanies ulceration.

Most corneal ulcers are infectious, including bacterial and viral etiologies. Noninfectious ulcers may be due to chemical burns or autoimmune, toxic, neurotrophic, or other causes.

Because of its potential to permanently impair vision or progress to perforation and an open globe, a corneal ulcer is considered an ophthalmologic emergency.

Although corneal ulcers may occasionally be sterile, most are infectious in etiology.

Bacterial keratitis is the most important etiology to exclude in the emergency department (ED). Corneal infections and infectious keratitis are often presumed to be bacterial until proven otherwise.

Bacterial corneal ulcers may follow a break in the corneal epithelium, thereby providing an entry for bacteria. The traumatic episode may be minor, such as a minute abrasion from a small foreign body, or may result from such causes as tear insufficiency, malnutrition, or contact lens use. Increased use of soft contact lenses in recent years has led to a dramatic rise in the occurrence of corneal ulcers, particularly due to Pseudomonas aeruginosa.[1]

Common bacterial isolates cultured from patients with keratitis include P aeruginosa, coagulase-negative staphylococci, Staphylococcus aureus, Streptococcus pneumoniae, and Enterobacteriaceae (including Klebsiella, Enterobacter, Serratia, and Proteus). Klebsiella pneumoniae mucoid phenotype and its ability to form biofilm may be important in producing corneal ulceration. Agents such as N-acetylcysteine, may have a role in treatment because they inhibit biofilm formation.

Ulcers due to viral infection occur on a previously intact corneal epithelium.

Herpes simplex and varicella-zoster viruses can both cause a significant infectious keratitis.[2]

With the introduction of topical corticosteroid drugs in the treatment of eye disease, fungal corneal ulcers have become more common. Fungi (Fusarium and Candida species) and parasitic amoeba (Acanthamoeba) have been found in a small number of patients and frequently present with more severe symptoms.

Peripheral ulcerative keratitis (PUK) is a complication of rheumatoid arthritis (RA) that can lead to rapid corneal destruction (corneal melt) and perforation with loss of vision. An example is shown in the image below.

Peripheral ulcerative keratitis in the right eye of a patient with rheumatoid arthritis. Glue has been placed.

Mooren ulcer is an idiopathic ulceration of the peripheral cornea that may result from an autoimmune reaction or may be associated with hepatitis C virus. It is a rapidly progressive, painful, ulcerative keratitis, which initially affects the peripheral cornea and may spread circumferentially and then centrally. Mooren ulcer can only be diagnosed in the absence of an infectious or systemic cause.

Incidence

United States

Approximately 25,000 Americans develop infectious keratitis annually. The annual incidence of microbial keratitis associated with contact lens use is approximately 2-4 infections per 10,000 users of soft contact lenses and 10-20 infections per 10,000 users of extended-wear contact lenses. Approximately 10% of these infections result in the loss of 2 or more lines of visual acuity.[3]

International

A study from the United Kingdom reported factors associated with an increased risk of a corneal invasive event in the population studied. The factors included use of extended-wear hydrogel lenses, male gender, smoking, and the late winter months.[4]

Morbidity

Corneal scarring and vision loss are possible consequences.

Sex

Studies from the United Kingdom suggest that males who wear extended-wear contact lenses are at increased risk of forming a corneal ulcer.

Other studies suggest that males are at increased risk due to the higher probability of sustaining ocular trauma.

Age

Corneal injury or infection can affect people of all ages. A bimodal distribution is observed. The age groups with a higher prevalence of disease are likely tied to risk factors, those in the first group (< 30 y) who are more likely to be contact lenses wearers and/or sustain ocular trauma, and those in the second group (>50 y) who are more likely to undergo eye surgery.

Contact lenses

Infectious keratitis is significantly more common in contact lens wearers.

Authors from the United Kingdom also report an 8 times higher incidence of corneal invasive event in contact lens wearers who sleep in contact lenses compared with wearers who use lenses only during the waking hours.[5]

Corneal ulcerations should improve daily and should heal with appropriate therapy. If healing does not occur or the ulcer extends, consider an alternate diagnosis and treatment.

For excellent patient education resources, visit eMedicineHealth's Eye and Vision Center. Also, see eMedicineHealth's patient education articles Anatomy of the Eye, Corneal Ulcer, and Iritis.

The history may suggest an etiology and may reveal clues concerning the likelihood of an infectious etiology.

Important questions include the following:

• Symptoms
• Contact lens use; sleeping in contacts
• Trauma
• Medications
• Medical history
• Surgical history

Symptoms

Symptoms may include any of the following:

• Erythema of eyelid and conjunctiva
• Mucopurulent discharge from eye
• Foreign body sensation (suggests an epithelial defect, which is suggestive of a bacterial etiology)
• Decreased vision
• Light sensitivity
• Pain

Contact lens use

Contact lens use, including the following:[6]

• Type of contact lens (soft, hard, daily, extended wear)
• Type of contact lens solution
• Contact lens hygiene

Medication use

Current medications, including systemic and especially ocular medications, particularly steroids

Past medical history

See the list below:

• History of ocular disease or eye surgery
• Diabetes mellitus
• History of HIV or other immunodeficiency disorder
• Exposure to sulphur mustard ^[7]
• Tear-film deficiencies
• Collagen vascular diseases (eg, Wegener granulomatosis rheumatoid arthritis [RA])

Social history

Smoking is an important risk factor.

The physical examination findings may suggest an etiology, including the likelihood of an infectious etiology.

In addition, a careful physical examination is necessary to assess severity, ie, the risk of perforation and the risk of vision loss.

The physical examination should include measurement of visual acuity, external ex­amination, and slit-lamp examination.[8]

Visual acuity

Visual acuity should be tested at triage, and, if in doubt, the physician should repeat the measurement personally. Visual function is variably affected, depending on the location of the ulcer and whether associated corneal and uveal inflammation is present. Obtain visual acuities on all patients with ocular complaints.

Gross examination

Gross examination should include the eyelids, surface of the eye, pupils, extraocular muscles, and fundi. Examination of the lids and the conjunctiva may reveal associated inflammation in these locations. The eye is often erythematous, and ciliary injection is often present. Pupillary constriction may be present secondary to ciliary spasm and iritis. Purulent exudate may be seen in the conjunctival sac or on the surface of the ulcer, and infiltration of the stroma may result in a whitish opacity of the cornea.

Slit lamp examination

Slit lamp examination should follow gross examination in all suspected cases.

Clinical features suggestive of bacterial keratitis include suppurative stromal infiltrate (particularly >1 mm) with indistinct edges, edema, and white cell infiltration in surrounding stroma. An epithelial defect is typically present. An anterior chamber reaction is often seen.[8] The ulcer often is round or oval, and the border is generally demarcated sharply, with the base appearing ragged and gray. Slit lamp examination may reveal findings of iritis, and hypopyon may be present. Hypopyon is an accumulation of inflammatory cells in the anterior chamber that produces a layered meniscus in the inferior anterior chamber.

Slit-lamp examination should include assessment of the following:[8]

• Corneal epithelium, including defects and punctate keratopathy, edema
• Corneal stroma, including ulceration, thinning, perforation, and infiltrate (location [central, peripheral, perineural, surgical, or traumatic wound], density, size, shape [ring], number [satellite], depth, character of infiltrate margin [suppuration, necrosis, feathery, soft, crystalline], color), edema
• Corneal endothelium
• Corneal (or scleral) foreign bodies
• Signs of corneal dystrophies (eg, epithelial basement membrane dystrophy)
• Previous corneal inflammation (thinning, scarring, or neovascularization)
• Signs of previous corneal or refractive surgery
• Anterior chamber for depth and the presence of inflammation, including cell and flare, hypopyon, hyphema

Fluorescein staining of the cornea

Fluorescein staining of the cornea is usually performed and may provide additional information about other factors, such as the presence of dendrites, pseudodendrites, loose or exposed sutures, foreign body, and any epithelial defect.[8] Fluorescein staining may reveal characteristic findings, such as the dendritic ulcer of herpes simplex virus infection.

Additional tips

Always examine the contralateral eye.

In a patient who cannot sit up in a slit lamp, and a portable slit lamp is not available, a Wood lamp may be the only available tool for fluorescein examination.

Although some corneal ulcers are sterile, most are infectious in etiology. Risk factors for corneal ulcer include contact lens use, HIV infection, trauma, ocular surface disease, and ocular surgery.[1] Overnight contact lens wear has been shown to be associated with an increased risk. Other identified risk factors include older age, male gender, smoking, low socioeconomic class, and inadequate contact lens hygiene.

Bacterial keratitis

Bacterial infection is the most important etiology to exclude in the ED. Corneal infections and infectious keratitis are often presumed to be bacterial until proven otherwise.

Bacterial corneal ulcer

Bacterial corneal ulcers may follow a break in the corneal epithelium, thereby providing an entry for bacteria. The traumatic episode may be minor, such as a minute abrasion from a small foreign body, or may result from such causes as tear insufficiency, malnutrition, or contact lens use. Increased use of soft contact lenses in recent years has led to a dramatic rise in the occurrence of corneal ulcers, particularly due to Pseudomonas aeruginosa.[1]

Bacteria that can penetrate through intact corneal epithelium include Corynebacterium diphtheriae, Haemophilus influenzae, Neisseria gonorrhoea, Neisseria meningitidis, and Listeria species.

Common bacterial isolates cultured from patients with keratitis include P aeruginosa, coagulase-negative staphylococci, S aureus, S pneumoniae, and Enterobacteriaceae (including Klebsiella, Enterobacter, Serratia, and Proteus). K pneumoniae mucoid phenotype and its ability to form biofilm may be important in producing a corneal ulceration. Agents such as N-acetylcysteine may have a role in treatment because they inhibit biofilm formation.

Viral corneal ulcer

Corneal ulcers due to viral infection often occur on a previously intact corneal epithelium.

Herpes simplex and varicella-zoster viruses can both cause significant infectious keratitis.[2]

Fungal and parasitic corneal ulcer

With the introduction of topical corticosteroid drugs in the treatment of eye disease, fungal corneal ulcers have become more common. Fungi (Fusarium and Candida species) and parasitic amoeba (Acanthamoeba) have been found in a small number of patients and frequently present with more severe symptoms.

The complications of corneal ulcer can be devastating. Corneal perforation, although rare, can occur. Corneal scarring may develop, resulting in partial or complete loss of vision. Anterior and posterior synechiae, glaucoma, and cataracts also can develop.

Culture

Most community-acquired cases of bacterial keratitis resolve with empiric therapy and are managed without cultures. However, cultures are indicated in cases that involve a corneal infiltrate that is central and large and extends to the middle to deep stroma, cases that are unresponsive to antibiotic therapy, and cases that have atypical clinical features suggestive of fungal, amoebic, or mycobacterial keratitis.[8] Consult with an ophthalmologist.

Appropriate care of a corneal ulcer depends on an assessment of risk of visual loss and perforation.

Consulting with an ophthalmologist from the ED is the best practice whenever a corneal ulcer is identified. Because of its potential to permanently impair vision or progress to perforation and an open globe, a corneal ulcer is considered an ophthalmologic emergency.

Although most community-acquired cases of bacterial keratitis resolve with empiric therapy and are managed without cultures, cultures are indicated in cases that involve a corneal infiltrate that is central, large, and extends to the middle to deep stroma, cases that are unresponsive to antibiotic therapy, and cases that have atypical clinical features suggestive of fungal, amoebic, or mycobacterial keratitis.[8]

Antibiotic therapy

Low risk of vision loss

Small (< 1 mm), peripheral, nonstaining infiltrate. No epithelial defect. Shallow, minimal anterior chamber reaction, no discharge

Fluoroquinolone eyedrops every 1-2 hours[9]

In contact lens wearers, add tobramycin ointment or ciprofloxacin ointment every bedtime

Medium risk of vision loss

Medium (1-1.5 mm) peripheral infiltrate or any epithelial defect, discharge, or anterior chamber reaction regardless of ulcer size (including small [< 1 mm])

Fluoroquinolone eyedrops every 5 minutes in the ED for 5 doses, then every 1 hour.[9]

Vision threatening

Large (>1.5 mm) and/or central infiltrate, deep anterior chamber inflammation, and/or any scleral involvement

Consult with ophthalmologist immediately, and consider emergent ophthalmology consult in the ED; transfer may be appropriate in order to effect this evaluation.

Two fortified eyedrops every 5 minutes in the ED for 5 doses, tobramycin 15 mg/mL every 1 hour, alternating every 30 minutes with fortified vancomycin 25-50 mg/mL every 1 hour (alternative, cefazolin 50 mg/mL every 1 hour in place of vancomycin)[9]

Consider adding oral or intravenous ciprofloxacin

Cycloplegics

Cycloplegic drops (atropine 1% or cyclopentolate 1% [most common agent]) are applied to provide comfort and to prevent synechiae formation (adhesions between the iris and the lens capsule or cornea, posterior or anterior).

Avoidance of contact lens wear

Contact lens wear should be discontinued until cleared by an ophthalmologist.

Oral pain medications

Pain medication should be given as needed.

Viral infection

If tests results confirm viral infection, begin therapy with mechanical debridement of the infected rim along with a rim of the normal epithelium, followed by topical instillation of antiviral medications.

Fungal infection

A broad-spectrum antifungal drug usually is chosen for fungal infections. Common medications include natamycin, voriconazole, and amphotericin B. Other options include fluconazole, miconazole, and ketoconazole. Natamycin is the first-line treatment in fungal infections of the cornea.[10] Consult with an ophthalmologist.

Consulting with an ophthalmologist from the ED is the best practice whenever corneal ulcer is identified. Because of its potential to permanently impair vision or progress to perforation and an open globe, a corneal ulcer is considered an ophthalmologic emergency.

Most corneal ulcers are managed on an outpatient basis. Consultation with an ophthalmologist from the ED is the best practice whenever a corneal ulcer is identified. 

Inpatient care is occasionally required, most commonly when the ulcer is vision threatening. Inpatient care may also be required where there are significant issues of compliance with medications or follow-up.

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

Anesthetics are indicated for pain relief and for conjunctival and corneal scrapings. Local anesthetics stabilize the neuronal membrane and prevent the initiation and transmission of nerve impulses, thereby producing the local anesthetic action.

Proparacaine

Has a rapid onset of anesthesia that begins within 13-30 sec after instillation. Short duration of action (about 15-20 min). Since prolonged eye anesthesia can eliminate the patient's awareness of mechanical damage to the cornea, do not use outside of the ED. Frequent use of anesthetics may retard healing.

Class Summary

Therapy must cover all likely pathogens in the context of the clinical setting.

Cefazolin

First-generation cephalosporin antibiotic for gram-positive bacterial coverage. Commonly used in combination with an aminoglycoside to achieve broad-spectrum coverage.

This 50-133 mg/mL solution must be compounded.

Gentamicin (Gentak)

Aminoglycoside antibiotic used for gram-negative bacterial coverage. Commonly used in combination with a first-generation cephalosporin.

Erythromycin (PCE, Ery-Tab, Erythrocin Lactobionate, E.E.S.)

Indicated for treatment of infections caused by susceptible strains of microorganisms and for prevention of corneal and conjunctival infections.

Ciprofloxacin ophthalmic (Ciloxan)

Bactericidal antibiotic that inhibits bacterial DNA synthesis, and consequently growth, by inhibiting DNA gyrase in susceptible organisms.

Indicated for pseudomonal infections and those due to multidrug-resistant gram-negative organisms.

Class Summary

These agents are used in the treatment of rheumatoid arthritis associated corneal ulcer.

Infliximab (Remicade, Inflectra, Renflexis)

Chimeric anti-tumor necrosis factor alpha monoclonal antibody. Neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Mix in 250-mL normal saline for infusion over 2 h. Must use with low-protein-binding filter (1.2 micron or less). Indicated to reduce signs and symptoms of active ankylosing spondylitis.

Class Summary

Instillation of a long-acting cycloplegic agent can relax any ciliary muscle spasm that can cause a deep aching pain and photophobia.

Cyclopentolate (Cyclogyl)

Blocks the action of acetylcholine at parasympathetic sites in the smooth muscle, producing pupillary dilation (mydriasis) and paralysis of accommodation (cycloplegia).

Atropine ophthalmic

Blocks the action of acetylcholine at parasympathetic sites in the smooth muscle, producing pupillary dilation (mydriasis) and paralysis of accommodation (cycloplegia).

Class Summary

Broad-spectrum antifungal agents that cause minimal pain and corneal irritation are recommended. Natamycin is the first-line treatment in fungal infections of the cornea. Candidal infections refractory to natamycin may respond to voriconazole, amphotericin B, miconazole, fluconazole, and ketoconazole. Topical application of these drugs, however, is somewhat limited because most of them must be compounded.

Natamycin (Natacyn)

Predominantly fungicidal tetraene polyene antibiotic, derived from Streptomyces natalensis that possesses in vitro activity against a variety of yeast and filamentous fungi, including Candida, Aspergillus, Cephalosporium, Fusarium, and Penicillium species. Binds fungal cell membrane forming a polyene sterol complex that alters membrane permeability and depleting essential cellular constituents. Activity against fungi is dose related, but it is not effective in vitro against gram-negative or gram-positive bacteria. Generally, therapy should be continued for 14-21 d or until the fungal keratitis has resolved. In many cases, reducing the dosage gradually at 4-7 d intervals may help ensure that the organism has been eliminated.

Class Summary

Mechanism of action is believed to be through inhibition of the cyclooxygenase enzyme that is essential in the biosynthesis of prostaglandins. Inhibition of prostaglandin synthesis results in vasoconstriction and decreases in vascular permeability, leukocytosis, and intraocular pressure (IOP). These agents, however, have no significant effect on IOP.

Ibuprofen (Addaprin, Caldolor, Genpril, Dyspel, Motrin, Advil)

Usually the DOC for treatment of mild to moderate pain, if no contraindications exist.

Inhibits inflammatory reactions and pain, probably by decreasing the activity of the enzyme cyclooxygenase, which results in prostaglandin synthesis.

Naproxen (Aleve, Naprosyn, Naprelan, Flanax Pain Relief, Anaprox DS)

Used for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing activity of the enzyme cyclooxygenase, resulting in prostaglandin synthesis.

Ketoprofen

Used for the relief of mild-to-moderate pain and inflammation. Small doses are initially indicated in small and elderly patients and in those with renal or liver disease. Doses >75 mg do not increase therapeutic effects. Administer high doses with caution, and closely observe patient for response.

Diclofenac (Cambia, Dyloject, Zipsor, Zorvolex)

Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclo-oxygenase, which in turn decreases formation of prostaglandin precursors. Has anti-inflammatory, antipyretic, and analgesic properties.

Class Summary

Pain control is essential to quality patient care, ensuring patient comfort, promoting pulmonary toilet, and containing sedating properties that benefit patients who experience mild or severe pain.

Oxycodone and acetaminophen (Percocet, Endocet, Primlev, Xartemis XR)

Drug combination indicated for the relief of moderate to severe pain. Oxycodone inhibits ascending pain pathways by binding to the opiate receptor. Alters the response and perception of pain and produces generalized CNS depression. Acetaminophen inhibits prostaglandin synthesis in the CNS and blocks pain impulse generation peripherally.

Oxycodone and aspirin (Percodan)

This drug combination is indicated for the relief of moderate to severe pain. Oxycodone binds to opiate receptors in the central nervous system (CNS), inhibiting the ascending pain pathways, altering pain response and perception. Aspirin inhibits platelet aggregation; has analgesic and ant-inflammatory properties.

Morphine (Arymo ER, Duramorph, Kadian, MS Contin)

An opioid analgesic, morphine interacts with endorphin receptors in the CNS, inhibiting the pain pathways, altering pain response and perception.

Codeine and acetaminophen (Tylenol with Codeine #3, Tylenol with Codeine #4)

Acetaminophen and codeine combination is used for the treatment of mild to moderate pain.

Hydrocodone and acetaminophen (Hycet, Lorcet, Norco, Vicodin, Zamicet)

This combination is used for the relief of moderate to severe pain. Analgesics alter the perception of and response to pain.

Class Summary

Therapy of viral infections begins with mechanical debridement of the involved rim along with a rim of normal epithelium. This is followed by the topical instillation of antiviral medications.

Trifluridine ophthalmic (Viroptic)

A structural analogue of thymidine, this agent inhibits viral DNA polymerase. Viroptic has better penetration through the cornea and greater efficacy (95% heal rate) than other topical agents.

Ganciclovir ophthalmic (Zirgan)

Acyclic nucleoside analogue of 2'deoxyguanasine. Phosphorylates first to monophosphate form by viral-encoded protein kinase homologue, then to diphosphate and triphosphate forms by cellular kinases, allowing for greater concentration of ganciclovir in virus-infected cells, possibly due to preferential phosphorylation of ganciclovir in virus-infected cells. Thought to inhibit HSV replication by competitive inhibition of viral DNA polymerases and by incorporating itself into viral DNA, causing termination of viral DNA elongation. Like acyclovir, ganciclovir is virostatic and exerts its effect only on replicating virus.