Granulomatous amoebic encephalitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Granulomatous amoebic encephalitis is a central nervous system disease caused by certain species of amoeba, especially Balamuthia mandrillaris.^[1]

Granulomatous amoebic encephalitis is most commonly caused by Acanthamoeba castellanii, A. culbertsoni, A. polyphaga or Balamuthia mandrillaris.^[2] It is rarely due to Entamoeba histolytica.

Balamuthia infection is very rare but often causes fatal disease[1]. Since Balamuthia was first discovered in 1986, about 200 cases of infection have been reported worldwide[2,3,4]. This number includes at least 70 confirmed cases in the United States.

The Balamuthia amoeba is able to infect anyone, including healthy people[1-6]. Those at increased risk for infection[1-4,6,10] include people with HIV/AIDS, cancer, liver disease, or diabetes mellitus, people taking immune system inhibiting drugs, alcoholics, young children or the elderly and pregnant women.^[1].

Balamuthia mandrillaris has only recently been isolated from the environment and has also been isolated from autopsy specimens of infected humans and animals. B. mandrillaris has only two stages, cysts and trophozoites , in its life cycle. No flagellated stage exists as part of the life cycle. The trophozoites replicate by mitosis (nuclear membrane does not remain intact) . The trophozoites are the infective forms, although both cysts and trophozoites gain entry into the body through various means. Entry can occur through the nasal passages to the lower respiratory tract , or ulcerated or broken skin . When B. mandrillaris enters the respiratory system or through the skin, it can invade the central nervous system by hematogenous dissemination causing granulomatous amebic encephalitis (GAE) or disseminated disease , or skin lesions in individuals who are immune competent as well as those with compromised immune systems. B. mandrillaris cysts and trophozoites are found in tissue.

Balamuthia infection is very rare. The Balamuthia amebas can infect the skin, sinuses, brain and other organs of the body. Therefore, Balamuthia infection can cause a wide range of symptoms. Disease can begin with a skin wound on the face, trunk, or limbs and can then progress to the brain where it cause a disease called Granulomatous Amebic Encephalitis

The indirect immunofluorescence assay (IFA) is a test used to detect antibodies attached to Balamuthia amebas in body tissues. In contrast, immunohistochemistry (IHC) uses specific antibodies against Balamuthia to detect the amoebas. Finally, a polymerase chain reaction (PCR) molecular assay can detect Balamuthia DNA.

Magnetic resonance imaging (MRI) scans may show increased signal on T2-weighted images. The lesions may show ring enhancement with intravenous contrast studies. Occasionally, there are neuro-radiographic findings of an expanding intracranial mass that may mimic a cerebral tumor or a brain abscess.

A computerized tomography scan may demonstrate bilateral low-density areas with mild mass effect in the cortex and subcortical white matter.

GAE can, in general, must be treated by killing the pathogenic amoebas which cause it. Even with treatment, the condition is often fatal, and there are very few recorded survivors, almost all of whom suffered permanent neurocognitive deficits. Several drugs have been shown to be effective against GAE-causing organisms in vitro.^[3]

Currently, there are no known ways to prevent infection with Balamuthia since it is unclear how and why some people become infected while others do not. There have been no reports of a Balamuthia infection spreading from one person to another except through organ donation/transplantation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Granulomatous amoebic encephalitis is most commonly caused by Acanthamoeba castellanii, A. culbertsoni, A. polyphaga or Balamuthia mandrillaris.^[1] It is rarely due to Entamoeba histolytica.

E. histolytica rarely infects the central nervous system and when it does, it tends to cause an abscess with a fulminant clinical course culminating in the patient’s death within 12-72 hours (untreated). E. histolytica infection of the brain also tends to occur in patients with a previous diagnosis of E. histolytica infection of the intestines, the liver or the lungs.

Granulomatous amoebic encephalitis is also rarely due to Naegleria fowleri. N. fowleri generally causes acute encephalitis in immunocompetent hosts who go swimming underwater or diving outdoors in fresh water in warm weather.

Chronically ill, debilitated, immunosuppressed or immunodeficient patients tend not to engage in such activities.

The amoebae producing granulomatous encephalitis characteristically produce cysts in the infected tissue whereas E. histolytica and N. fowleri do not.

Multifocal encephalomalacia, edema, necrosis, hemorrhage and sometimes abscess formation are observed. The meninges may be cloudy. Uncal or cerebellar tonsillar herniation may be present. Lesions occur in the cerebral hemispheres, the basal ganglia, the brainstem and the cerebellum. A necrotizing subacute or chronic granulomatous encephalitis with lymphocytes, macrophages and multinucleated giant cells, and variable numbers of organisms are observed microscopically. There may be thrombosis of small blood vessels associated with necrosis and hemorrhage. In AIDS patients, the inflammatory reaction is minimal and composed mainly of CD-68 positive macrophages.

A brain biopsy will reveal the presence of infection by pathogenic amoebas. In GAE, these present as general inflammation and sparse granules. On microscopic examination, infiltrates of amoebic cysts and/or trophozoites will be visible.

The CSF demonstrates a lymphocytic pleocytosis, with mildly elevated protein and normal glucose, but diagnostic organisms are not readily identified. Lumbar puncture is contraindicated if there are signs and symptoms of an increase in intracranial pressure.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Balamuthia mandrillaris has only recently been isolated from the environment and has also been isolated from autopsy specimens of infected humans and animals. B. mandrillaris has only two stages, cysts and trophozoites , in its life cycle. No flagellated stage exists as part of the life cycle. The trophozoites replicate by mitosis (nuclear membrane does not remain intact) . The trophozoites are the infective forms, although both cysts and trophozoites gain entry into the body through various means. Entry can occur through the nasal passages to the lower respiratory tract , or ulcerated or broken skin . When B. mandrillaris enters the respiratory system or through the skin, it can invade the central nervous system by hematogenous dissemination causing granulomatous amebic encephalitis (GAE) or disseminated disease , or skin lesions in individuals who are immune competent as well as those with compromised immune systems. B. mandrillaris cysts and trophozoites are found in tissue.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

An open wound, such as a cut or scrape, may be a potential entry point for Balamuthia.

Balamuthia infection is very rare but often causes fatal disease[1]. Since Balamuthia was first discovered in 1986, about 200 cases of infection have been reported worldwide[2,3,4]. This number includes at least 70 confirmed cases in the United States. Because disease caused by Balamuthia is so uncommon, it is possible that there have been additional cases that were misdiagnosed [2,4].

Balamuthia amoebas (single-celled living organisms) are thought to enter the body when soil containing Balamuthia comes in contact with skin wounds and cuts, or when dust containing Balamuthia is breathed in or gets in the mouth[1]. Once inside the body, the amebas can then travel to the brain and cause Granulomatous Amebic Encephalitis (GAE)[1]. GAE is a severe disease of the brain that is fatal in over 95% of cases[2]. It can take weeks to months to develop the first symptoms of Balamuthia GAE after initial exposure to the amebas[2,3].

Balamuthia amoebas live freely in soil around the world[1-13]. Gardening, playing with dirt, or breathing in soil carried by the wind might increase the risk for infection[1,2,5]. Balamuthia might also be present in fresh water[1]. There have been reports of Balamuthia GAE infection in dogs that swam in ponds. However, there have been no reported human cases where the only potential exposure was swimming.

In the United States, Balamuthia infection might be more common among Hispanic Americans[6,13]. However, the cause of this trend is unknown and might be due to differences in exposure, biology, data collection, or other reasons[1,13-17]. More research is needed to understand what factors might be associated with increased reporting among persons of Hispanic ethnicity.

There have been no reports of a Balamuthia infection spreading from one person to another except through organ donation/transplantation.

1) Visvesvara GS, Moura H, Schuster FL. Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp. , Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol Med Microbiol. Jun 2007;50(1):1-26.

2) Siddiqui R, Khan NA. Balamuthia amoebic encephalitis: an emerging disease with fatal consequences. Microb Pathog. Feb 2008;44(2):89-97.

3) Perez MT, Bush LM. Balamuthia mandrillaris amebic encephalitis. Curr Infect Dis Rep. Jul 2007;9(4):323-328.

4) Perez MT, Bush LM. Fatal amebic encephalitis caused by Balamuthia mandrillaris in an immunocompetent host: a clinicopathological review of pathogenic free-living amebae in human hosts. Ann Diagn Pathol. Dec 2007;11(6):440-447.

5) Huang ZH, Ferrante A, Carter RF. Serum antibodies to Balamuthia mandrillaris, a free-living amoeba recently demonstrated to cause granulomatous amoebic encephalitis. J Infect Dis. May 1999;179(5):1305-1308.

6) Maciver SK. The threat from Balamuthia mandrillaris. J Med Microbiol. Jan 2007;56(Pt 1):1-3.

7) Balamuthia amebic encephalitis–California, 1999-2007. MMWR Morb Mortal Wkly Rep. Jul 18 2008;57(28):768-771.

8) Schuster FL, Visvesvara GS. Free-living amoebae as opportunistic and non-opportunistic pathogens of humans and animals. Int J Parasitol. Aug 2004;34(9):1001-1027.

9) Schuster FL, Visvesvara GS. Opportunistic amoebae: challenges in prophylaxis and treatment. Drug Resist Updat. Feb 2004;7(1):41-51.

10) Martinez AJ, Visvesvara GS. Free-living, amphizoic and opportunistic amebas. Brain Pathol. Jan 1997;7(1):583-598.

11) Bravo F, Sanchez MR. New and re-emerging cutaneous infectious diseases in Latin America and other geographic areas. Dermatol Clin. Oct 2003;21(4):655-668, viii.

12) Dunnebacke TH, Schuster FL, Yagi S, Booton GC. Isolation of Balamuthia amebas from the environment. J Eukaryot Microbiol. 2003;50 Suppl:510-511.

13) Schuster FL, Glaser C, Honarmand S, Maguire JH, Visvesvara GS. Balamuthia amebic encephalitis risk, Hispanic Americans. Emerg Infect Dis. Aug 2004;10(8):1510-1512.

14) Schuster FL, Yagi S, Gavali S, et al. Under the Radar: Balamuthia Amebic Encephalitis. Clin Infect Dis. Apr 1 2009;48(7):879-887.

Schuster FL, Visvesvara GS. Balamuthia mandrillaris. In: Khan N, ed. Emerging Protozoan Pathogens. London: Taylor & Francis; 2008.

Schuster FL, Honarmand S, Visvesvara GS, Glaser CA. Detection of antibodies against free-living amoebae Balamuthia mandrillaris and Acanthamoeba species in a population of patients with encephalitis. Clin Infect Dis. May 1 2006;42(9):1260-1265.

15) Schuster FL, Yagi S, Wilkins PP, Gavali S, Visvesvara GS, Glaser CA. Balamuthia mandrillaris, agent of amebic encephalitis: detection of serum antibodies and antigenic similarity of isolates by enzyme immunoassay. J Eukaryot Microbiol. Jul-Aug 2008;55(4):313-320.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The Balamuthia amoeba is able to infect anyone, including healthy people. Those at increased risk for infection include people with HIV/AIDS, cancer, liver disease, or diabetes mellitus, people taking immune system inhibiting drugs, alcoholics, young children or the elderly and pregnant women.^[1].

The Balamuthia ameba is able to infect anyone, including healthy people. Those at increased risk for infection include:

• People with HIV/AIDS, cancer, liver disease, or diabetes mellitus
• People taking immune system inhibiting drugs
• Alcoholics
• Young children or the elderly
• Pregnant women

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