Contributed by Qing Li, Xiao-He Yang, Jiang Qian
DIAGNOSIS: GRANULOMATOUS AMEBIC MENINGOENCEPHALITIS CAUSED BY BALAMUTHIA MANDRILLARIS.
DISCUSSION:
Balamuthia mandrillars is a relatively newly described pathogen related to the free-living ameba superfamily (4), which also includes Naegleria fowleri and Acanthamoeba species. These free-living amebas, except for B. mandrillaris, have been isolated from the soil, fresh water of swimming pool, and air conditioning unit (4, 6). They can cause infections of skin, respiratory tract and brain in both human and animals. The first few cases of human CNS infection due to free-living amebas were described in 1965 (1). Since then nearly four hundred cases have been reported worldwide (3, 4). Although the route of invasion into the brain is still unclear, hematogenous spread of amebas through a skin lesion or the respiratory tract has been postulated. Individuals infected by amebas, especially N. fowleri, are usually with a recent history of fresh water-related activities. The patient in our report did have a history of swimming in a fresh water pound in her backyard during summer time. N. fowleri causes primary amebic meningoencephalitis (PAM), which has an abrupt onset and a fulminate, rapid progression to coma and death (5). Both Acanthamoeba species and B. mandrillaris cause granulomatous amebic encephalitis (GAE), which has a subacute to chronic course with an almost invariably fatal outcome (1, 4). Since its first isolation from the brain of a mandrill baboon at the San Diego Wild Animal Park in 1990 (8), B. mandrillaris has caused human CNS infection in more than 85 cases worldwide, including 40 cases in USA (4).
No characteristic clinical symptoms, laboratory or neuroimaging findings have been found to be diagnostic of B. mandrillaris GAE. The infected patient may present with headache, stiff neck, low-grade fever, personality and mental status changes, and cranial nerve palsies mainly affecting the third and sixth cranial nerves. Cerebellar ataxia and diplopia have also been reported in some cases. The infection may mimic space-occupying lesions in CNS, and the infected patient may present with hemiparesis, aphasia or seizures. In such instances, head CT and MRI may reveal ring-enhancing lesion suggestive of a brain abscess or tumor. The CSF analysis may show lymphocytes, normal or slightly low glucose level, and normal or mild elevation of proteins. In most cases, the CSF study resembles that of aseptic meningitis. Clinically, the symptoms and laboratory data closely mimic and are often mistaken for a bacterial or viral encephalitis/ leptomeningitis or tuberculous meningitis. The direct cause of death is usually acute bronchopneumonia, hepatic or renal failure, septicemia and brain edema leading to uncal and cerebellar tonsillar herniation (4, 8). Histopathologically, the CNS infection is characterized by brain edema, hemorrhage and a subacute necrotizing meningoencephalitis with associated vasculitis and/or thrombosis. A modest inflammatory infiltration composed of lymphocytes, plasma cells and macrophages is often present. The lymphocytes may be the predominant inflammatory cells depending on the immunological status of the patient. Giant cells may also be present, but well-formed granulomas may not be a prominent feature. Like Acanthamoeba species, B. mandrillaris has a vegetative trophic stage and a dormant cyst stage in its life cycle, both of which can be seen in tissue section. The trophozoites measure 15-60 mm in diameter and have a round nucleus with a large nucleolus. The nuclei containing more than one nucleolus can be seen, which distinguishes B. mandrillaris from Acanthamoeba. The cysts of B. mandrillaris are usually spherical and measure 6-30 m in diameter, with a mean of 15 m. They consist of an outer wrinkled wall (ectocyst) and an inner thin wall (endocyst). There is also a refractile granule layer beneath the inner cyst wall. Ultrastructurally, an additional thick, amorphous, fibrillar middle layer (mesocyst) can also be seen (4). Amebic trophozoites and cysts are usually present within perivascular spaces and within the necrotic CNS parenchyma.
The identification of the organism in tissue section is the key to make the diagnosis of amebic meningoencephalitis. The presence or absence of a cyst wall of trophozoites can be used to distinguish Balamuthia and Acanthamoeba from N. fowleri since the latter does not produce cyst forms in tissue. Although bi- and multi-nucleolus trophozoites are indicative of Balamuthia, the distinction between the Balamuthia and Acanthamoeba usually requires special techniques such as immunofluorescence antibody stain as in our case. In infected brain specimen, marked necrosis due to tissue destruction either directly by ameba or indirectly by infarct secondary to vascular thrombosis can often mask the trophozoites, and the degenerated parasites can mimic macrophages, making detection challenging. Therefore, a high index of suspicion is needed in any brain infection with granulomatous feature. Retrospective review of the first biopsy identified several degenerated structures within necrotic background that were thought to be macrophages, but were in fact the degenerated trophozoites.
There is no specific treatment for B. mandrillaris infections (4, 8). Some in vitro studies demonstrated that B. mandrillaris is sensitive to pentamidine methionate, azithromycin and clarithromycin, but none are amebicidal at nontoxic concentrations (2, 7). In fact, the treatment for CNS amebic infection is in general non-specific and late, mainly due to difficulty of diagnosis.
Although Balamuthia encephalitis is rare, human infection resulting from B. mandrillaris has increased significantly (4). It should be considered in the differential diagnosis in a patient with subacute or chronic granulomatous meningoencephalitis, even if CSF glucose or protein concentration suggests a bacterial or viral pathogen, or when the patient has poor response to the antibiotic therapy.
REFERENCES:
Contributed by Qing Li, Xiao-He Yang, Jiang Qian
International Society of Neuropathology