Chapter 348. Free-Living Amebic Infections

Amebiasis and infections due to Entamoeba species are discussed in Chapter 341. The ubiquitous, free-living amoebae of the genera Naegleria, Balamuthia,Acanthamoeba, and Sappinia are the etiologic agents of rare infections of the central nervous system and eyes.1Naegleria fowleri is the agent of primary amebic meningoencephalitis; Acanthamoeba and Balamuthia cause granulomatous amebic meningoencephalitis; and Acanthamoeba also can infect the eye, resulting in amebic keratitis.2-4 Recently, Sappinia diploidea, another free-living amoeba that is normally found in soil contaminated with herbivore feces, has been identified as causing encephalitis in a healthy young man.5Naegleria, Balamuthia,Acanthamoeba, and Sappinia have trophozoite and cyst stages; in addition, Naegleria has a flagellate stage. For Naegleria, only trophozoites are found in tissues. Naegleria trophozoites are 10 to 30 μm in diameter and have a clear nucleus with a prominent central dense nucleolus and cytoplasmic pseudopodia. Acanthamoeba and Balamuthia trophozoites are of similar size and appearance to Naegleria, but the cyst form of these parasites may also be observed in tissue.1,6Sappinia trophozoites are 40 to 80 μm in diameter and have an ovoid or oblong shape. They appear to be flattened with occasional wrinkles on the surface, and food vacuoles are seen in cytoplasm. The mature cysts are 15 to 30 μm in diameter and are round. They have two adjoining nuclei.1 Unequivocal identification of these amoebae is not routine, and specimens should be referred to a qualified protozoologist for confirmation.

Almost every example of acute primary amebic meningoencephalitis reveals a recent patient history of swimming in fresh or brackish water. The organisms probably gain access to neural tissue via the nasal mucosa and the cribriform plate. There have been several epidemics in which the same swimming facility was the focus of infection. This disease has been reported in England, the Czech Republic, Australia, Virginia, Texas, and Florida. Naegleria fowleri has been isolated from soil and the bottom sediment of lakes and pools from all parts of the world. It also has been reported in thermally polluted water, where it can reproduce at temperatures up to 46°C (114.8°F). Seroepidemiologic studies demonstrate that most young adults in the southern United States have agglutinating antibodies against Naegleria.7,8

Granulomatous amebic encephalitis caused by Acanthamoeba affects those who are immunocompromised and debilitated, whereas Balamuthia causes a subacute to chronic infection in both immunocompetent and immunocompromised individuals. These infections have incubation periods that exceed 1 week, and the clinical course, which usually is fatal, can last for weeks to months. The one known case of granulomatous amebic encephalitis caused by Sappinia diploidea occurred in a 38-year-old healthy white male. The patient’s prior medical history showed a recent frontal sinus infection.5

Keratitis caused by Acanthamoeba is most common in individuals who wear contact lenses. It is also seen as a complication of other corneal injuries. Corneal infection is associated with wearing the lenses while swimming in freshwater lakes and rivers and with using homemade saline solutions to store the lenses.3

Clinical Manifestations

Primary amebic meningoencephalitis has occurred in young, previously healthy individuals between the ages of 2 and 27 years. Most patients had swum in warm fresh water 2 to 5 days prior to the onset of symptoms. Very early in the infection, the patient may notice changes in taste or smell, followed by the abrupt onset of fever, headache, meningismus, nausea, vomiting, and a rapidly deepening coma. Death follows the onset of symptoms in approximately 1 week in most patients. Cerebrospinal fluid usually reveals large numbers of polymorphonuclear leukocytes, blood, hypoglycorrhachia, and elevated protein levels. Motile amoebae can be found if the fluid is examined under high magnification on a warm stage. Most histopathologic studies show severe lytic necrosis and hemorrhage along the base of the brain in the regions of the olfactory bulbs and cerebellum.2

Granulomatous amebic encephalitis predominantly affects those who are immunocompromised, although Balamuthia can cause disease in the absence of identifiable immune defects. Onset is insidious, and presentation with focal neurological deficits is common. Presenting signs and symptoms include mental status abnormalities and seizures in approximately 66% of patients; fever, headache, and meningismus in 50% of patients; and ataxia or visual disturbances in 20% of patients. Skin ulcerations or nodules can be observed for months before the onset of central nervous system disease. In both subacute and chronic disease, single or multiple foci of granulomatous inflammation have been reported that involve the cerebellum, midbrain, and brain stem. Examination of the spinal fluid usually reveals many mononuclear cells and is nondiagnostic. Amoebae can be demonstrated in brain biopsies and in skin nodules or ulcers.2

Nongranulomatous amebic encephalitis caused by Sappinia diploidea occurred only in a 38-year-old previously healthy man. Presenting signs and symptoms included loss of consciousness for 45 minutes, bifrontal headache, photophobia, and visual disturbance for 2 to 3 days. Magnetic resonance imaging showed a solitary 2-cm tumorlike cerebral mass in the left temporal-parietal region of the brain. It contained centrally located necrotic and hemorrhagic inflammation with acute and chronic inflammatory cells but without granulomas or eosinophils. Trophozoites with distinctive double nucleus were visible in the mass, but no cysts were seen. Trophozoites often contained engulfed host blood cells.1

Acanthamoeba keratitis is frequently misdiagnosed as a herpes simplex virus or bacterial keratitis. Symptoms begin with a foreign-body sensation in the eye followed by severe pain, tearing, photophobia, and blurred vision. The disease progresses over days to months, with periods of temporary remission common. Signs include iritis, a distinctive corneal ring infiltrate in most patients, and an early dendriform epithelial pattern of inflammation in some patients. There may be marked inflammatory changes in the anterior and posterior chambers, and uveitis also occurs. Organisms often can be found in corneal scrapings or biopsy material.6

Diagnosis and Therapy

Consider the diagnosis in a child with meningoencephalitis, a recent history of freshwater exposure, and cerebrospinal fluid (CSF) with a neutrophilic pleiocytosis and no bacteria demonstrated by CSF cultures or Gram stain. The disease can be diagnosed by finding motile amoebae in the unfixed purulent cerebrospinal fluid. Therapy for Naegleria infection is not satisfactory. There is a single well-documented report in which early diagnosis of primary amebic meningoencephalitis was successfully treated with amphotericin B by both the systemic and intracisternal routes. It may be necessary to rapidly achieve therapeutic levels. Many other patients who were treated with this drug were not helped. Although a 9-year-old girl was treated successfully with a combination of IV and intrathecal amphotericin B and miconazole plus oral rifampin, recent use of this regimen in several other patients was unsatisfactory. In experimental Naegleria meningoencephalitis, tetracycline markedly potentiated the efficacy of amphotericin B. There is also little information to guide the treatment of granulomatous amebic encephalitis. There are interspecies and interstrain differences in drug susceptibility, but in general, the diamidine derivatives (propamidine, pentamidine, dibromopropamidine), ketoconazole, paromomycin, neomycin, 5-flucytosine, and, to a lesser extent, amphotericin B are active against many isolates.3

Sappinia diploidea encephalitis can be diagnosed by hematoxylin and eosin stains in the formalin-fixed, paraffin-embedded brain specimens taken from a tumorlike mass. This should identify trophozoites containing characteristic closely apposed “diploid” nuclei (in which both nuclei may contain a dark nucleolus) and possibly engulfed erythrocytes. Trophozoites stain brightly with Giemsa and periodic acid Schiff (PAS). The sole patient with S diploidea infection was successfully treated with antimicrobial therapy consisting of azithromycin, pentamidine, itraconazole, and flucytosine.1

In contrast, Acanthamoeba keratitis has been successfully treated with aggressive surgical debridement combined with the frequent (up to nine times per day) application of topical 0.1% propamidine isethionate plus neosporin or oral itraconazole and topical miconazole. Topical polyhexamethylene biguanide also has been an effective treatment for this condition in a limited number of patients.3,4