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Balamuthia mandrillaris (True Pathogen – Granulomatous Amebic Encephalitis/GAE)

Organism:
The free-living ameba, Balamuthia mandrillaris, is relatively uncommon and was originally thought to be another harmless soil organism, unlikely or unable to infect mammals. However, since B. mandrillaris was first discovered in a pregnant mandrill at the San Diego Wild Animal Park that died of meningoencephalitis, a number of primates including gorillas, gibbons, baboons, orangutans, and monkeys, as well as a sheep and a horse, have died of CNS infection caused by this organism.  Over 400 cases of human amebic encephalitis worldwide (Acanthamoeba, Balamuthia) have been identified, with about half of the cases of Balamuthia diagnosed within the United States. Death can occur from a week to several months after the onset of stroke‑like symptoms, which can mimic other conditions, including brain stem glioma.  Patients eventually die with a massive CNS infection. 

http://www.cdc.gov/parasites/images/balamuthia/cysts.jpg
Balamuthia trophozoite and cysts in tissue

 

http://radiographics.rsna.org/content/31/1/31/F6.large.jpg http://www.dpd.cdc.gov/dpdx/images/ParasiteImages/A-F/FreeLivingAmebic/Balamuthia_IIF_Vish1.jpg
Lesion in brain Balamuthia IFA

 

Figure 2
   

Life Cycle:
The life cycle is similar to that seen with Acanthamoeba spp.; like Acanthamoeba spp., Balamuthia does not have a flagellated stage in its life cycle as do organisms classified as N. fowleri.

Acquired:
The amebae may enter through the lower respiratory tract or through ulcerated or broken skin, causing GAE, particularly those who are immunocompromised. 

Epidemiology:
Although attempts to isolate B. mandrillaris from soil samples related to previous encephalitis cases were unsuccessful, there was always some question regarding the designation “free-living” amebae.  However, following the death of a 3-year-old northern California resident from amebic encephalitis caused by Balamuthia, environmental samples were collected around the child’s home and outdoor play areas.  An ameba, consistent with Balamuthia, was isolated from the soil found in a potted plant in the home.  Thus, the isolation of Balamuthia organisms from soil affirms its status as a free-living ameba; like Acanthamoeba and Naegleria, Balamuthia is also an opportunistic pathogen.

Clinical Features:
GAE.  The disease is very similar to GAE caused by Acanthamoeba spp. and has an unknown incubation period. The clinical course tends to be subacute or chronic and is usually not associated with swimming in freshwater. No characteristic clinical symptoms, laboratory findings, or radiologic indicators have been found to be diagnostic for GAE. The neuroimaging findings show heterogeneous, hyperdense, nonenhancing, space‑occupying lesions. Whether single or multiple, they involve mainly the cerebral cortex and subcortical white matter. These findings suggest a CNS neoplasm, tuberculoma, or septic infarcts. Patients complain of headaches, nausea, vomiting, fever, visual disturbances, dysphagias, seizures, and hemiparesis. There may also be a wide range in terms of the clinical course, from a few days to several months.
In Immunocompetent hosts, an inflammatory response is mounted, and amebae are surrounded by macrophages, lymphocytes, and neutrophils.  However, with rare exceptions, these patients also tend to die with severe CNS disease.
Both trophozoites and cysts of B. mandrillaris are found in many of the same CNS tissues as are Acanthamoeba spp. Although differentiation of these two organisms in tissue by light microscopy is difficult, B. mandrillaris appears to have more than one nucleolus in the nucleus in some tissue sections.  Generally, electron microscopy and histochemical methods are required for definitive identification of B. mandrillaris.  An immunofluorescence test using species-specific sera is the most reliable means of distinguishing between Acanthamoeba spp. and Balamuthia sp.

Clinical Specimen:
Tissue or Scans:  In the differential diagnosis, other space‑occupying lesions of the CNS (tumor, abscess, fungal infection, etc.) must also be considered.
PCR:  Genotyping studies indicate that lethal infections caused by B. mandrillaris are due to a single species with a global distribution.  Apparently, there is no correlation between a particular mitochondrial sequence and the genus of infected vertebrate.  Also, the mitochondrial sequence from the mandrill isolate is identical to that obtained from a human.

Laboratory Diagnosis:  THIS REQUEST IS ALWAYS A STAT!
Specimens should never be refrigerated prior to examination. When centrifuging the CSF, low speeds (250 ´ g) should be used so that the trophozoites are not damaged. Although bright‑field microscopy with reduced light is acceptable, phase microscopy, if available, is recommended. Use of smears stained with Giemsa or Wright's stain or a Giemsa‑Wright's stain combination can also be helpful. If N. fowleri is the causative agent, trophozoites only are normally seen. If the infecting organism is Acanthamoeba spp. or Balamuthia mandrillaris, cysts may also be seen in specimens from CNS infection. Unfortunately, most cases are diagnosed at autopsy; confirmation of these tissue findings must include culture and/or special staining with monoclonal reagents in indirect fluorescent antibody procedures.
B. mandrillaris has been shown not to grow well on E. coli‑seeded nonnutrient agar plates. The amebae can be identified in histologic preparations by indirect immunofluorescence and immunoperoxidase techniques. The organism in tissue sections looks very much like an Iodamoeba bütschlii trophozoite, with a very large karyosome and no peripheral nuclear chromatin; the organisms can also be seen with routine histologic stains.
Serum antibodies to B. mandrillaris have been found in both adults and children; however, testing is not currently available for routine use.

Organism Description:
Trophozoite:  The trophozoites are characterized by extensive branching and a single nucleus (occasionally binucleate forms are seen) with a central karyosome. Occasionally, a few elongated forms with several contractile vacuoles are seen.
Cyst:  The cysts have a single nucleus (occasionally, binucleate forms are seen) and have the typical double wall with the outer wall being thick and irregular.
Culture:   In the diagnostic laboratory, these organisms can be cultured in mammalian cell cultures; some success has been obtained with monkey kidney cells and with MRC, HEp‑2, and diploid macrophage cell lines. Using human brain microvascular endothelial cells, B. mandrillaris has been cultured post-mortem from brain and CSF from a case of granulomatous amebic meningoencephalitis.  A cell-free growth medium is also now available

Laboratory Report:
Balamuthia confirmed (confirmation to genus/species is available through CDC).

Treatment:
In vitro studies indicate that B. mandrillaris is susceptible to pentamidine isethiocyanate and that patients with this infection may benefit from this treatment. Other studies indicate that ketoconazole, propamidine isethionate, clotrimazole, and certain biguanides have amebicidal activity
Garcia, L.S. 2007.  Diagnostic Medical Parasitology, 5th ed., ASM Press, Washington, D.C.

Control:
General preventive measures are similar to those for N. fowleri and Acanthamoeba.