PATHOGENESIS

Acanthamoeba is a genus of free-living ubiquitous protozoa found in fresh-water and soil. These organisms are resistant to killing by freezing; desiccation; and the levels of chlorine routinely used in municipal water supplies, swimming pools, and hot tubs. They may exist as motile trophozoites or dormant cysts. Initial corneal epithelial adherence is thought to be mediated by a mannose-binding protein, with subsequent stromal invasion promoted by the expression of a mannose-induced protein (MIP-133) and various collagenases. In Western countries, the majority (≈90%) of reported cases of amebic keratitis have been associated with contact lens use, with the remainder associated with various other risk factors. Historically, episodic outbreaks of disease have been associated with water contamination, as for example, homemade saline contact lens solutions that were inappropriately made, groundwater contaminated because of river flooding (United States), or contaminated rooftop cisterns (United Kingdom).

Since 2003, an increased number of Acanthamoeba cases have occurred in the United States, particularly on the East Coast and in the Midwest. Two initial case-control studies found an association between Acanthamoeba keratitis and the use of Complete MoisturePlus multipurpose cleaning solution (Advanced Medical Optics, Santa Ana, CA) for soft contact lens care, resulting in the voluntary recall of the product from the market in May 2007. Unfortunately, the outbreak has persisted, prompting a second multistate case-control study in 2011, led by the Centers for Disease Control and Prevention, which, to date, has not identified a definitive source for the outbreak.

Joslin CE, Tu EY, McMahon TT, Passaro DJ, Stayner LT, Sugar J. Epidemiological characteristics of a Chicago-area Acanthamoeba keratitis outbreak. Am J Ophthalmol. 2006;142(2): 212–217.

Joslin CE, Tu EY, Shoff ME, et al. The association of contact lens solution use and Acanthamoeba keratitis. Am J Ophthalmol. 2007;144(2):169–180.

CLINICAL PRESENTATION

Patients with amebic keratitis are classically described as having severe ocular pain; photophobia; and a protracted, progressive course. The disease is bilateral in 7%–11% of patients. Frequently, they have shown no therapeutic response to a variety of topical antimicrobial agents. In early cases, however, Acanthamoeba infection is localized to the corneal epithelium and may manifest as a mildly symptomatic, diffuse punctate epitheliopathy or dendritic epithelial lesion. Epithelial pseudodendrites are often misdiagnosed as herpetic keratitis and treated with antiviral agents and/or corticosteroids. Stromal infection typically manifests in the central cornea, and early cases have a gray-white superficial, nonsuppurative infiltrate. As the disease progresses, a centered, partial or complete ring infiltrate in the central cornea is frequently observed (Fig 10-19). When noted, inflamed corneal nerves, called radial perineuritis or radial keratoneuritis, are nearly pathognomonic of amebic keratitis; limbitis, scleritis (focal, nodular, or diffuse), or even dacryoadenitis may be seen as well. Although intraocular extension may occur, consecutive encephalitis has not been reported.

LABORATORY EVALUATION

Diagnosis of Acanthamoeba keratitis is made by visualizing amebae in stained smears or by culturing organisms obtained from corneal scrapings. However, culture yield is laboratory dependent, with larger studies reporting only 35%–50% positivity for Acanthamoeba; a significant number of cases are treated based on clinical presentation and/or confocal microscopy findings. Lamellar corneal biopsy may be required to establish the diagnosis in some cases. Contact lenses and related paraphernalia can be examined, but amebic contamination is not uncommon, even in patients without disease.

Amebae are seen in smears stained with Giemsa or with periodic acid–Schiff (PAS), calcofluor white, or acridine orange stains. Nonnutrient agar with E coli or Enterobacter aerogenes overlay is the preferred medium for culturing amebae, but the organisms also grow well on buffered charcoal–yeast extract agar. Characteristic trails form as the motile trophozoites travel across the surface of the culture plate. In vivo confocal microscopy can also be used to show organisms, particularly the cyst forms (Fig 10-20).

MANAGEMENT

Early diagnosis of Acanthamoeba keratitis is the most important prognostic indicator of a successful treatment outcome. Diagnostic delay is common, however, because of the nonspecific presentation of the disease and the need for special microbiological diagnostic methods. Clinical features that suggest a diagnosis of Acanthamoeba keratitis rather than herpes simplex virus (HSV) keratitis include

• noncontiguous or multifocal pattern of granular epitheliopathy and subepithelial opacities (unlike the contiguous, dendritic pattern in HSV keratitis)

• disproportionately severe ocular pain (unlike disproportionately mild pain secondary to trigeminal nerve involvement in HSV)

• presence of epidemiologic risk factors such as contact lens use or exposure to possibly contaminated freshwater

• failure to respond to initial antiviral therapy

Cases identified early, defined as epithelial or anterior stromal, have an excellent visual prognosis and generally respond well to epithelial debridement, followed by an extended (3–4-month) course of antiamebic therapy. The presence of deep stromal inflammation, a ring infiltrate, or extracorneal manifestations significantly worsens the prognosis because of the development of stromal scarring and often necessitates longer treatment (up to a year or more), other adjunctive therapy, or therapeutic keratoplasty.

A number of antimicrobial agents have been recommended for medical treatment of Acanthamoeba keratitis based on their in vitro amebicidal effects as well as their clinical effectiveness. Agents used for topical administration include

• diamidines: propamidine, hexamidine

• biguanides: polyhexamethylene biguanide (polyhexanide), chlorhexidine

• aminoglycosides: neomycin, paromomycin

• imidazoles/triazoles: voriconazole,miconazole,clotrimazole,ketoconazole,itraconazole

Of these, only the biguanides have been shown to have consistent in vitro and clinical efficacy against both cysts and trophozoites; the others are effective primarily against trophozoites. Therefore, the mainstay of pharmacologic treatment is a biguanide, with a diamidine sometimes used early in the course of therapy, although successful resolution can be achieved with a biguanide alone. A comparison of biguanides did not detect a difference between chlorhexidine 0.02% and polyhexamethylene biguanide (PHMB) 0.02%. Single-agent systemic treatment with voriconazole has been shown to be efficacious in some recalcitrant cases.

Corticosteroid exposure incites acanthamoebal excystment in vitro and may worsen clinical outcomes when used prior to effective antiacanthamoebal therapy. Much of the morbidity of Acanthamoeba keratitis is from the exuberant host response, however, which causes noninfectious corneal and extracorneal complications, including scleritis, glaucoma, and cataracts. The judicious use of topical and systemic immunosuppressants in selected cases is valuable after the patient has been treated for a period of at least 2 weeks.

Traditionally, keratoplasty has been reserved for vision rehabilitation after completion of treatment or for cases that are progressing despite maximal medical therapy and leading to possible perforation. However, recent reports find that with effective antiacanthamoebal agents used as adjunctive therapy, lamellar and penetrating keratoplasty may now have a lower rate of recurrent infection, have a successful visual outcome, and avoid the primary risk factor for graft failure, late inflammatory sequelae, including glaucoma. Medical treatment is preferred, however, in the vast majority of cases. Because late recurrences can occur when medical therapy is stopped before completion, it is advisable to perform any optical keratoplasties only after a full course of amebicidal therapy. Collagen crosslinking is increasingly described as an adjunctive therapy for Acanthamoeba keratitis; its mechanism of action is unclear, however, and this treatment is unlikely to be beneficial in advanced disease.

Dart JK, Saw VP, Kilvington S. Acanthamoeba keratitis: diagnosis and treatment update 2009. Am J Ophthalmol. 2009;148(4):487–499.e2.

Robaei D, Carnt N, Minassian DC, Dart JK. The impact of topical corticosteroid use before diagnosis on the outcome of Acanthamoeba keratitis. Ophthalmology. 2014;121(7):1383–1388.

Robaei D, Carnt N, Minassian DC, Dart JK. Therapeutic and optical keratoplasty in the management of Acanthamoeba keratitis: risk factors, outcomes, and summary of the literature. Ophthalmology. 2015;122(1):17–24.

Tu EY. Acanthamoeba and other parasitic corneal infections. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Philadelphia: Elsevier; 2017:976–985.

Tu EY, Joslin CE, Sugar J, Shoff ME, Booton GC. Prognostic factors affecting visual outcome in Acanthamoeba keratitis. Ophthalmology. 2008;115(11):1998–2003.

Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.