THERAPEUTIC INSIGHTS
Combating Keratitis II
An examination of the parasitic etiology of this condition.
By Larry R. Henry, O.D., Edmond, Okla. 

Acanthamoeba keratitis is a relatively new disease, with the first reported case occurring in 1973. Since then, the incidence of Acanthamoeba keratitis has increased even though the prevalence of the organism hasn't increased in the environment.

Though the first reported case was trauma related, Acanthamoeba keratitis is now usually associated with soft contact lens wear. Other risk factors include poor contact lens hygiene, use of homemade saline and exposure to non-sterile water. Though correct diagnosis is vital, it's also difficult. We'll look at ways to recognize this form of keratitis and treatment options. For part one on fungal keratitis, see September.

The organism at a glance

Acanthamoeba is a free-living parasitic amoeba that has worldwide distribution. It survives in diverse conditions and has been isolated from soil, fresh water, well water, hot tubs, sea water, sewage, vegetative matter and air. It's not naturally parasitic and doesn't require a host. Acanthamoeba can live on its own without invading a host organism; however, if it does enter another organism through an injury, such as a corneal abrasion, then it can be parasitic. Human contact with Acanthamoeba is not uncommon because it's found in water sources and soil, but a disease process, such as Acanthamoeba keratitis, is rare because the organism needs help to enter human tissue to cause an opportunistic infection.

The amoeba is capable of existing in two forms:

1. trophozoites
2. encapsulated cysts.

Trophozoites. This is the active form of amoeba. It feeds on bacteria, fungi, protozoa and blue-green algae and is found in greatest number where other microorganisms are plentiful. When environmental conditions become unfavorable, the trophozoite can transform into encapsulated cysts within 3 days.

Encapsulated cysts. The cyst form is highly resistant to desiccation, temperature extremes and chemicals. Acanthamoeba can remain in cyst form for as long as 1 year but will readily return to the trophozoitic form when favorable conditions return. This unique ability makes eradicating Acanthamoeba keratitis extremely difficult.

Clinical picture

Symptoms of Acanthamoeba keratitis generally begin with redness, foreign-body sensation and photophobia, progressing to often severe frank pain. Pain that's out of proportion to clinical signs has become a hallmark of Acanthamoeba keratitis.

The earliest clinical signs, including fine punctate epithelial erosions, microcystic edema and patchy anterior stromal infiltrates, are usually nonspecific and often wax and wane in their course. Commonly, a dendriform keratitis is mistakenly treated as herpes simplex infection.

In established infections, a pattern of perineural infiltrates appearing in a radial pattern (radial keratoneuritis) is pathog-nomonic for Acanthamoeba keratitis. The infiltrates may progress into an annular central or pericentral ring infiltrate, usually with overlying epithelial defects. An associated iridocyclitis and occasional scleritis are typically present and contiguous with the corneal infiltrate. Disciform stromal infiltrates can develop in advanced cases and lead to necrotizing keratitis with possible corneal perforation.

Testing methodologies

To identify the organism, take samples of the patient's corneal epithelium or stroma, along with cultures of his contact lenses and storage case. Contaminated storage cases are more common among contact lens wearers who use chlorine-based disinfectants or no disinfectants at all.

The most common laboratory method is to inoculate the sample onto non-nutrient agar with an overlay of Gram-negative bacteria such as Escherichia coli. If Acanthamoeba is present, it will migrate across the agar using the bacteria as a food source. You can usually see the migration tracks within 48 hours, but occasionally up to 2 more weeks of incubation are needed. Consider corneal biopsy when your suspicion of Acanthamoeba remains high even after negative culture results.

Stain the corneal epithelium with Gram or Giemsa stains to detect amoebas. You can also use hematox-ylineosin, periodic acid-Schiff, Wright's, trichrome, or acridine orange to identify Acanthamoeba in histopathologic sections; however, you may find it difficult to distinguish amoebas from inflammatory cells.

The most widely used agent to stain the cyst wall of Acanthamoeba is probably calcafluor white, a fluorescent dye which will also stain fungi. Professionals have recently been using confocal microscopy to detect the presence of Acanthamoeba in the cornea in vivo. This method is essentially noninvasive and may be more sensitive than any staining method in detecting Acanthamoeba in early infections.

In advanced cases, confocal microscopy may also help to distinguish between persistent disease or epithelium drug toxicity. Another promising technology, polymerase chain reaction (PCR), uses DNA extracted from corneal tissue to increase the sensitivity for detecting Acanthamoeba.

Treatment

Although several antimicrobial medications are effective against the trophozoite stage, the cyst form can prove highly resistant to treatment. The early cases of Acanthamoeba keratitis typically resulted in severe vision loss or enucleation because of the disease's persistent nature. Today's improved drug therapies and earlier diagnoses have improved the disease's prognosis.

The earliest successful treatment of Acanthamoeba keratitis employed the aromatic diamidines, propamidine isethionate 0.1% (Brolen) alone or with dibromopropamidine 0.15% ointment. Aromatic diamidines act by inhibiting DNA synthesis. Aminoglycosides such as neomycin were used as adjunctive treatment because of their ability to disrupt the organism's cell wall and increase penetration of the aromatic diamidines. The prolonged use of these medications, typically for more than 1 year, was complicated by the development of toxic keratopathy or hypersensitivity reactions.

Although not well established, today's standard of care uses cationic antiseptics that inhibit membrane function. Cationic antiseptics appear to have the best amoebicidal and cysticidal activity of drug classes studied to date. Chlorhexidine 0.02% and polyhexamethyl biguanide 0.02% (PHMB) are the most often used medications in this class and over all other classes of drugs because of their efficacy and minimal epithelial toxicity.

An additive effect is seen between chlorhexidine and propamidine and between PHMB and neomycin. Treatment begins with hourly doses for the first 72 hours, and is then tapered according to improvement. This regimen continues at q.i.d. dosing for 3 to 6 months after resolution of ocular inflammation to maintain cysticidal action.

Corticosteriod usage isn't advised because of the possibility of increasing stromal infiltrates and enhancing corneal necrosis. Treat inflammation associated with Acanthamoeba keratitis with topical nonsteroidal agents and cycloplegic medications.

In cases of apparent medical failure, consider including the imidazoles, clotrimazole 1% cream or oral ketoconazole 200 mg to 600 mg daily as adjunctive therapy. Their amoebicidal activity is improved by their superior corneal penetration.

Surgical options

In early cases, surgical intervention of Acanthamoeba keratitis was common because of medical failure or pending corneal perforation. Penetrating keratoplasty early in the course of the disease was soon contraindicated because of recurrence of Acanthamoeba infection in the graft tissue.

The success of the newer therapy regimens has decreased the need for therapeutic penetrating keratoplasties. Currently, the most common indication for keratoplasty is to improve vision in an eye in which the infection has resolved on medical therapy but has left the cornea scarred. Visual prognosis is excellent in this situation. Penetrating keratoplasty is usually unnecessary if Acanthamoeba keratitis is diagnosed and treated within 4 to 6 weeks of onset.

General keratitis tips

Keratitis, when unresponsive to treatment, can be visually threatening to the patient. Proper diagnosis in the early stage of the disease is the key to successful treatment. Any keratitis that's lingering or progressive despite aggressive therapy should raise the suspicion of atypical etiologies, such as fungal or parasitic.

Pay specific attention to the patient's case history. Clues such as contact lens wear, water or vegetative matter exposure, improper contact lens hygiene and tropical travels can point early to the underlying cause. It's not uncommon for the eye to be occasionally exposed to both fungi and Acanthamoeba.

However, both fungi and Acanthamoeba have difficulty penetrating intact epithelium. Corneal trauma, both accidental and surgical, is what typically gives these organisms the opportunity to infect. Immunocompromised patients are also at higher risk for atypical keratitis.

The road that lies ahead

Advances in laboratory testing have made the confirmation of Acanthamoeba keratitis much easier. Stained corneal scrapings may give an immediate identification of the offending organism, but cultures are usually the definitive way to identify the cause of a corneal infection.

Proper culturing technique is critical. Take cultures as soon as you suspect Acanthamoeba keratitis because the culture results typically take a while.

Confocal microscopy and PCR are promising technologies that should increase our ability to detect Acanthamoeba early in the course of the disease. When laboratory testing doesn't identify the affecting organism, consider a corneal biopsy.

If you identify Acanthamoeba keratitis early, you can initiate the appropriate treatment aggressively to preserve the vision and integrity of the eye. When medical therapy fails or corneal scarring affects the patient's vision, surgical intervention is typically both warranted and successful.

Dr. Henry is clinical director for BVA Advanced Surgical Eyecare in Edmond, Okla. He serves as adjunct professor and residency supervisor for Northeastern State University College of Optometry.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.