Corneal Ulcer

Etiology

Bacterial: The most common etiology of corneal ulcers is infectious, with bacterial pathogens responsible for a majority of the cases.[5] Ulcers start as keratitis (inflammation of the cornea) after a break in the corneal epithelium allows bacteria to enter. These breaks are most commonly due to contact lens wear, corneal abrasions, and other ocular trauma.[5] Other risk factors include diabetes, prior ocular surgery, chronic ocular disease, use of corticosteroids, contaminated ocular medications, and agricultural work.[6] The most common bacterial pathogens are Staphylococcus aureus, coag negative staphylococcus, and Pseudomonas aeruginosa.[6] Staphylococcus epidermidis and Staphylococcus fusarium species are the most commonly implicated in polymicrobial keratitis with trauma being the most common inciting factor.[2] 

Viral: HSV is a common cause of viral keratitis as well as the most common cause of unilateral infectious corneal blindness in the developed world.[7] Varicella-zoster and cytomegalovirus can also cause viral keratitis although these are much less common.

Fungal: Fungal etiologies account for only 5 to 10% of all corneal infections. They are more common in warmer, humid parts of the country and are most often precipitated by trauma to the cornea with subsequent exposure to plant or vegetable material.[5] The most commonly implicated species organisms include Aspergillus, Fusarium, Scedosporium apiospermum, phaeohyphpmycetes, Candida albicans, and other Candida species.[8] 

Protozoan: Acanthamoeba is a free-living protozoan found in freshwater and in soil that can cause keratitis and corneal ulcers primarily in contact lens wearers.[5]

Autoimmune disease: While most corneal ulcers are infectious it is important to be able to recognize noninfectious causes of corneal ulcers as well. Peripheral ulcerative keratitis (PUK) is a form of noninfectious keratitis found in association with many systemic diseases. After anterior uveitis, PUK is the second most common ocular complication of autoimmune disorders.[9] Collagen vascular diseases account for 50% of all peripheral ulcerative keratitis cases with rheumatoid arthritis most commonly implicated.[10] Peripheral ulcerative keratitis also correlates with Wegener granulomatosis, relapsing polychondritis, polyarteritis nodosa, Churg-Strauss syndrome, and microscopic polyangiitis.[10] 

Epidemiology

Keratitis, the precursor to corneal ulceration, is responsible for approximately one million clinic and emergency department visits a year in the United States.[11] Corneal ulcers affect all groups but are much more common in those who wear contact lenses, especially extended wear lenses. A retrospective chart review from California found the highest rate of bacterial corneal ulcers was in females ages 25 to 34 (incidence of 60.3 per 100000 person-years).[12] Estimates of the incidence of ocular herpes infection run 5 to 20 cases per 10000 per year in developed countries.[13] Of these infections, the causative agent is HSV-1 over 95% of the time.[13] Only 1.3 to 12% of cases are bilateral, and these infections tend to occur in younger patients and be more severe.[13]  Fungal keratitis is rare but more common in young male outdoor workers. Fungal keratitis is also more common in the developing world and incidence varies widely with climate.[8] In the UK a study found the incidence of mycotic keratitis to be 0.32 cases per million person-years. However, in tropical and subtropical environments fungal keratitis may account for up to 50% of all infectious keratitis cases.[8] Peripheral ulcerative keratitis, presenting either as an isolated condition or as part of an underlying autoimmune disorder, has an estimated incidence of 3 per million per year.[14]

History and Physical

The history should include questions about risk factors for corneal ulcers such as contact lens use (the type of lens, storage habits, hygiene, history of prolonged use, swimming or showering in lenses), prior ocular surgery, recent ocular trauma, personal history or exposure to herpes, work exposures, and use of immunosuppressant medications. Other important points in the history include the quality and severity of pain, the rapidity of onset, and the presence or absence of any photophobia or blurry vision. Patient’s past medical history should be explored as diseases such as diabetes and rheumatoid arthritis, and other collagen vascular diseases can predispose patients to develop corneal ulcers.

The physical exam should include testing of visual acuity, intraocular pressures (if no concern for globe rupture or perforated ulcer), and pupillary response. The eyelids and conjunctiva should be examined for any injection, swelling, or discharge as well as for the presence of ciliary flush. A thorough slit lamp examination should be performed to determine the size, location, and shape of the lesion or lesions. Seidel's test can is useful if there is any concern for rupture.

Evaluation

The patient with a bacterial corneal ulcer will often present with rapid onset of pain, photophobia, and conjunctival injection, and a variable degree of vision loss. On slit lamp exam these ulcers appear as clearly defined infiltrates with stromal inflammation and edema.[5] Culture by an Ophthalmologist is often necessary to guide treatment.

The patient with HSV keratitis or corneal ulcer will usually present similarly to the patient with bacterial keratitis. They will often have foreign body sensation, photophobia, conjunctival injection, and blurred vision. Slit lamp exam will classically reveal dendritic lesions with fluorescein uptake.[5]

Fungal infections tend to have a more indolent course and often do not have the impressive conjunctival injection seen with bacterial infections. On slit lamp exam fungal lesions appear as gray-white feathery dry appearing lesions with irregular margins. Ulcers due to yeast appear as superficial, white, raised colonies with clearly defined borders.[5]

The patient presenting with Acanthamoeba keratitis will classically present with pain out of proportion to physical exam findings. Severe photophobia is also common. The exam may reveal diffuse punctate epithelial lesions, dendritic-like lesions, or ring-shaped infiltrates.[5] Definitive diagnosis is made with direct scraping, histology, or PCR identification of Acanthamoeba DNA.[15] 

Patients presenting with peripheral ulcerative keratitis (PUK) due to an underlying autoimmune disease may already carry a diagnosis or the corneal ulcer may be the first manifestation of the disease.[10]The damage seen in PUK is usually crescent-shaped and located in the limbal region of the corneal.[9] The patient may have stigmata of their underlying disease, such as swollen and tender joints or rashes. Evaluation in these patients would include a full ophthalmologic examination as well as lab work and imaging to help diagnose or monitor the underlying autoimmune condition. 

Treatment / Management

Treatment of bacterial keratitis and corneal ulcers consists first of topical antibiotics, most commonly with fluoroquinolones such as ciprofloxacin or ofloxacin.[7] Due to growing antibiotic resistance of common ocular pathogens corneal culture and sensitivity testing is recommended for all corneal ulcers, especially those that are large, central, and correlate with significant stromal involvement.  An ophthalmologist should perform a culture of the corneal ulcer. Hospitalization with systemic therapy with ceftriaxone as well as topical therapy is necessary for ulcers caused by gonococcus. Systemic antibiotics may also be necessary for severe infections caused by the more common bacterial pathogens. Hospital admission should also be a consideration for those unable or unwilling to comply with treatment. Adjuvant corticosteroids are controversial but may be beneficial in specific subgroups of patients with culture-positive non-Nocardia bacterial keratitis and low vision or central ulcers covering the central 4mm of the pupil.[16] (Level V) The treating ophthalmologist should decide whether to use adjuvant corticosteroids. (A1)

Treatment for HSV includes topical antivirals and adjuvant topical steroids. In the US the most common topical antiviral is trifluridine while in Europe topical acyclovir is the first line. (Level II) Other options include ganciclovir which also treats VZV and CMV keratitis. Oral acyclovir or valacyclovir are additional options. Oral valganciclovir is the treatment of choice for CMV stromal keratitis, but the patient requires close monitoring while on this medication due to significant side effects such as aplastic anemia.[7]

Fungal ulcers tend to have worse outcomes than bacterial as there are far fewer treatment options. Currently, the primary treatment is natamycin, a topical polyene, first introduced in the 1960s. (Level II) Amphotericin B 0.3% to 0.5% is an alternative, but toxicity limits use. A newer generation triazole called voriconazole recently was found to be inferior to natamycin in the Mycotic Ulcer Treatment Trail (MUTT I).[17] (Level I)(A1)

Treatment of Acanthamoeba keratitis and corneal ulcers generally involves epithelial debridement and 3 to 4 months of antiamoebic therapy.[5] Antiamoebic therapy starts with chlorhexidine and poligexametilen biguanide which, when combined, are effective against trophozoites and cysts.[18] In severe cases, additional agents such as diamidines, fluconazole, itraconazole, neomycin, and iodine-containing medications may be added.[18]  

Treatment of peripheral ulcerative keratitis associated with autoimmune and collagen vascular diseases should be treated with systemic immunosuppressants and cytotoxic agents and requires co-management by both a rheumatologist and ophthalmologist.[10] (Level III). These patients need careful monitoring and frequent bloodwork while on these immunosuppressant medications. (B3)

 An ophthalmologist should see all patients presenting with corneal ulcers within 12 to 24 hours. Emergent ophthalmologic consultation should be considered for a culture of the ulcer to guide antibiotic selection for suspected bacterial ulcers.

Differential Diagnosis

The differential diagnosis for the patient presenting with red, painful eye includes corneal abrasions, nonulcerative keratitis, foreign body, iritis, acute angle-closure glaucoma, chemical burns, episcleritis, scleritis, and anterior uveitis.[6]

Prognosis

Prognosis depends on the etiology, size, and location of the ulcer as well as the response to treatment. 

Complications

Complications of untreated or inadequately treated corneal ulcers include corneal scarring, vascularization, or perforation, glaucoma, irregular astigmatism, cataracts, endophthalmitis, and vision loss.