Introduction
Parasitic infections of the cornea are a significant cause of ocular morbidity. Acanthamoeba keratitis is increasingly recognized in the developed world as a potentially disastrous complication of contact lens wear and requires early, aggressive treatment. Onchocerca infection is still encountered in some parts of the developing world.
Acanthamoeba Keratitis
Epidemiology and Pathogenesis
Acanthamoebae, found ubiquitously in water, soil, and air, are free-living protozoans that exist in an active trophozoite form and a dormant cyst form. The trophozoite feeds on microorganisms and reproduces by binary fission, but if deprived of a food source, it will encyst. Cysts are resistant to desiccation, temperature extremes, and various chemicals and can remain dormant for years. Acanthamoebae are typically speciated according to morphological characteristics, although they can also be classified into one of 15 genotypes. The vast majority of keratitis is caused by the T4 genotype.
Keratitis caused by Acanthamoeba is less common than that caused by bacteria or fungi, although the incidence of Acanthamoeba keratitis increased in the United States for several years in the mid-2000s because of an epidemic related to a contact lens solution. The biggest risk factor for Acanthamoeba keratitis in the developed world is contact lens wear, with approximately 90% of cases occurring in contact lens wearers. Most cases are seen in soft contact lens wearers, although orthokeratology may convey increased risk. Trauma is the other major risk factor and accounts for the vast majority of Acanthamoeba keratitis seen in developing countries. Other risk factors include exposure to water, especially fresh water sources, swimming pools or hot tubs, and homemade contact lens solutions.
Clinical Features
Since a delay in treatment has been shown to adversely affect visual outcome, clinicians must be acutely aware of the sometimes subtle early signs of Acanthamoeba infection. Early infection is confined to the epithelium, which demonstrates irregularity and multifocal infiltration, pseudo-dendrites, or elevated epithelial ridges ( Fig. 4.14.1 ). Stromal radial perineuritis is thought to be very specific for Acanthamoeba keratitis, although it does not appear in many cases ( Fig. 4.14.2 ). Limbitis is common, and may account for significant pain. Later stages of infection are characterized by nonspecific stromal infiltration ( Fig. 4.14.3 ) or a characteristic ring infiltrate ( Fig. 4.14.4 ), and uveitis. When present, fluctuating, nongranulomatous anterior chamber inflammation may contribute to the formation of cataract or elevated intraocular pressure. In the most severe cases, hypopyon, anterior scleritis, or perforation (sometimes associated with optic neuritis) can occur.
It has been reported frequently that patients experience severe pain far out of proportion to clinical findings, but this is an unreliable diagnostic sign, and some patients have reduced or absent corneal sensation.
Diagnosis
Diagnosis is based on characteristic clinical findings and supported by microbiological investigations. Cysts are visible with routine stains, such as Giemsa, Gram, and ink-potassium hydroxide, and with stains that require fluorescent microscopy, such as Calcofluor white and acridine orange. Scrapings should be plated on nonnutrient agar and overlaid with Escherichia coli to assess for growth of trophozoites; plates should be observed for longer than 7 days. If plates are not available, scrapings can be transported to the laboratory in Page’s saline. Culture and smear of samples from contact lens cases and cleaning solutions also can reveal Acanthamoeba .
Polymerase chain reaction (PCR) assays targeting Acanthamoeba 18S ribosomal RNA (rRNA) have been shown to be more sensitive than culture or smear but are not currently available at most laboratories.
In vivo confocal microscopy can be used to visualize Acanthamoeba cysts in the corneal epithelium and stroma. Cysts appear as round, hyperreflective structures measuring 10–25 µµm, often with a “bright spot” or double-walled morphology (see Fig. 4.14.4 ). The technique has been shown to have good sensitivity and specificity.
Corneal biopsy should be considered for cases with only deep stromal involvement or when microbiological tests are negative ( Fig. 4.14.5 ). Biopsies should be stained with hematoxylin and eosin, periodic acid–Schiff, and methenamine silver stains.
Differential Diagnosis
See Box 4.12.1 . The pseudo-dendrites of early disease and the ring infiltrate of more advanced disease are often mistakenly identified as representing herpetic keratitis. In those cases that are refractory to treatment, herpetic keratitis and bacterial superinfection should be considered.
Pathology
Trophozoites bind to the corneal epithelium and establish infection. This is followed by thinning and necrosis of the epithelium, which allow the organism to enter the stroma, where it may enter progressively deeper layers of the stroma. The organism can become encysted in the corneal stroma and can cause inflammatory sequelae for months after successful antimicrobial treatment.
Treatment
Treatment of Acanthamoeba keratitis is based on eradication of cysts from the cornea. Although trophozoites are susceptible to many antimicrobial agents, the cysts are largely resistant. The most effective medications are the biguanide antiseptic agents chlorhexidine and polyhexamethylene biguanide (PHMB), which act by inhibiting membrane function and are consistently cysticidal ( Table 4.14.1 ). Second-line agents include the diamidines (hexamidine, pentamidine, and propamidine), which inhibit DNA synthesis. Diamidines also generally are cysticidal, though their activity is more variable. Azole medications have activity against trophozoites but are generally not cysticidal. There are reports of effective treatment with oral and topical voriconazole, although the in vitro susceptibility patterns for this agent have not been well characterized. Aminoglycosides such as neomycin and paromomycin were used in the past, but these agents are not cysticidal and cause significant corneal toxicity, so there is little rationale to support their use.
| Agent | Trade Name | Manufacturer | Dosage Form | Concentration for Ocular Use | Availability | Comment |
|---|---|---|---|---|---|---|
| Cationic Antiseptics | ||||||
| Chlorhexidine | Solution | 0.02% | As 20% concentrate | Used as disinfectant | ||
| Polyhexamethylene biguanide (PHMB) | Baquacil | Zeneca | Solution | 0.02% | As 20% pool disinfectant | Used also as a preservative, contact lens solutions |
| Aromatic Diamidines | ||||||
| Propamidine isethionate | Brolene | Mays & Baker | Solution | 0.1% w/v 10 mL | Over-the-counter in UK | |
| Hexamidine | Désomédine | Chauvin | Solution | 0.1% | Available in Europe | |
| Azoles | ||||||
| Clotrimazole | Lotrimin | Schering | Suspension | 1% | As powder from manufacturer | Poor suspension; difficult to make |
| Fluconazole | Diflucan | Roerig | Solution | 0.2% | As 2 mg/mL solution | Withdraw from vial with filter needle |
| Ketoconazole | Nizoral | Janssen | Oil solution | 5% | As 200 mg tablet | In mortar, dissolve 2.5 200 mg tablets in 10 mL of peanut oil |
| Miconazole | Monistat | Janssen | Solution | 1% | As 10 mg/mL solution | Simple 1 : 1 solution or directly from vial via filter |
| Voriconazole | Vfend | Pfizer | Oral | 200 mg twice daily 1% | As 200 mg tablet As 200 mg vial | Monitor liver function |
There is little consensus on the best way to treat Acanthamoeba keratitis. A clinical trial compared chlorhexidine monotherapy and PHMB monotherapy and found no significant differences, with high success rates in both groups (78% and 86%, respectively). Because cysts can be difficult to eradicate, many clinicians treat with multiple agents, usually with one of the biguanide agents and one of the diamidines. As with other types of infectious keratitis, topical therapy initially should be applied frequently (every 30–60 minutes), and then the frequency can be reduced based on the clinical response. Topical medications generally are continued for many months. Pain should be addressed with cycloplegics and oral nonsteroidal anti-inflammatory drugs.
The role of corticosteroids in the treatment of Acanthamoeba infection has not been established. Corticosteroids promote excystment and proliferation of trophozoites and lead to worse visual outcomes when used before starting anti-amebic treatment. However, corticosteroids also reduce pain and inflammation and may reduce the likelihood of corneal vascularization. A large retrospective study found that initiation of corticosteroids after a median of 2 weeks of antiamebic therapy was not associated with worse outcomes in eyes with Acanthamoeba keratitis and persistent inflammation, providing some reassurance for patients requiring anti-inflammatory therapy. Antiamebic agents should be started before and continued during corticosteroid therapy.
The role of therapeutic keratoplasty for active Acanthamoeba keratitis is controversial. Recurrence of Acanthamoeba infection has been reported to occur in more than half the grafts, leading to poor postoperative visual outcomes. Others have found much lower rates of recurrence, and good visual outcomes. Antiacanthamebic medications should be continued after keratoplasty.
Outcome
With timely diagnosis, Acanthamoeba organisms can be eradicated from the cornea by medical therapy. A minority of patients develop rapidly progressive cataract and glaucoma, presumably from prolonged exposure to topical medications or to the host inflammatory response. Severe corneal inflammation and necrosis can result in substantial scarring, necessitating penetrating keratoplasty for visual rehabilitation. Optical keratoplasty performed well after eradication of Acanthamoeba infection carries a good prognosis, but results of therapeutic keratoplasty performed during active infection are much more variable.
Epidemiology and Pathogenesis
Acanthamoebae, found ubiquitously in water, soil, and air, are free-living protozoans that exist in an active trophozoite form and a dormant cyst form. The trophozoite feeds on microorganisms and reproduces by binary fission, but if deprived of a food source, it will encyst. Cysts are resistant to desiccation, temperature extremes, and various chemicals and can remain dormant for years. Acanthamoebae are typically speciated according to morphological characteristics, although they can also be classified into one of 15 genotypes. The vast majority of keratitis is caused by the T4 genotype.
Keratitis caused by Acanthamoeba is less common than that caused by bacteria or fungi, although the incidence of Acanthamoeba keratitis increased in the United States for several years in the mid-2000s because of an epidemic related to a contact lens solution. The biggest risk factor for Acanthamoeba keratitis in the developed world is contact lens wear, with approximately 90% of cases occurring in contact lens wearers. Most cases are seen in soft contact lens wearers, although orthokeratology may convey increased risk. Trauma is the other major risk factor and accounts for the vast majority of Acanthamoeba keratitis seen in developing countries. Other risk factors include exposure to water, especially fresh water sources, swimming pools or hot tubs, and homemade contact lens solutions.
Clinical Features
Since a delay in treatment has been shown to adversely affect visual outcome, clinicians must be acutely aware of the sometimes subtle early signs of Acanthamoeba infection. Early infection is confined to the epithelium, which demonstrates irregularity and multifocal infiltration, pseudo-dendrites, or elevated epithelial ridges ( Fig. 4.14.1 ). Stromal radial perineuritis is thought to be very specific for Acanthamoeba keratitis, although it does not appear in many cases ( Fig. 4.14.2 ). Limbitis is common, and may account for significant pain. Later stages of infection are characterized by nonspecific stromal infiltration ( Fig. 4.14.3 ) or a characteristic ring infiltrate ( Fig. 4.14.4 ), and uveitis. When present, fluctuating, nongranulomatous anterior chamber inflammation may contribute to the formation of cataract or elevated intraocular pressure. In the most severe cases, hypopyon, anterior scleritis, or perforation (sometimes associated with optic neuritis) can occur.
It has been reported frequently that patients experience severe pain far out of proportion to clinical findings, but this is an unreliable diagnostic sign, and some patients have reduced or absent corneal sensation.
Diagnosis
Diagnosis is based on characteristic clinical findings and supported by microbiological investigations. Cysts are visible with routine stains, such as Giemsa, Gram, and ink-potassium hydroxide, and with stains that require fluorescent microscopy, such as Calcofluor white and acridine orange. Scrapings should be plated on nonnutrient agar and overlaid with Escherichia coli to assess for growth of trophozoites; plates should be observed for longer than 7 days. If plates are not available, scrapings can be transported to the laboratory in Page’s saline. Culture and smear of samples from contact lens cases and cleaning solutions also can reveal Acanthamoeba .
Polymerase chain reaction (PCR) assays targeting Acanthamoeba 18S ribosomal RNA (rRNA) have been shown to be more sensitive than culture or smear but are not currently available at most laboratories.
In vivo confocal microscopy can be used to visualize Acanthamoeba cysts in the corneal epithelium and stroma. Cysts appear as round, hyperreflective structures measuring 10–25 µµm, often with a “bright spot” or double-walled morphology (see Fig. 4.14.4 ). The technique has been shown to have good sensitivity and specificity.
Corneal biopsy should be considered for cases with only deep stromal involvement or when microbiological tests are negative ( Fig. 4.14.5 ). Biopsies should be stained with hematoxylin and eosin, periodic acid–Schiff, and methenamine silver stains.
