Naegleriasis

Naegleriasis
Histopathology of primary amebic meningoencephalitis due to Naegleria fowleri. Direct fluorescent antibody stain.
Pronunciation /ˌnɛɡlərˈaɪəsɪs/
Classification and external resources
Specialty Infectious disease
ICD-10 A06.6, B60.2
ICD-9-CM 136.2

Naegleriasis, also known as primary amoebic meningoencephalitis (PAM), amebic encephalitis, and naegleria infection, is an infection of the brain by the free-living protist Naegleria fowleri, also known as the "brain-eating amoeba". The term "brain-eating amoeba" has also been applied to Balamuthia mandrillaris, causing some confusion between the two, however Balamuthia mandrillaris is unrelated to Naegleria fowleri, and causes a different disease called granulomatous amoebic encephalitis, and unlike Naegleriasis, which is usually seen in people with normal immune function, granulomatous amoebic encephalitis is usually seen in people with poor immune function such as those with HIV/AIDS or leukemia.[1]

N. fowleri is typically found in warm bodies of fresh water, such as ponds, lakes, rivers, and hot springs. It is also found in soil, poorly maintained municipal water supplies, water heaters, near warm-water discharges of industrial plants, and in poorly chlorinated, or unchlorinated swimming pools, in an amoeboid or temporary flagellate stage. There is no evidence of it living in salt water.

Although infection occurs rarely,[2] it nearly always results in death,[3] with a case fatality rate greater than 95%.[4]

Signs and symptoms

Onset symptoms of infection can start from one to seven days after exposure. Initial symptoms include changes in taste and smell, headache, fever, nausea, vomiting, and a stiff neck. Secondary symptoms include confusion, hallucinations, lack of attention, ataxia, and seizures. After the start of symptoms, the disease progresses rapidly over three to seven days, with death occurring usually from seven to fourteen days later,[5] although it can take longer. In 2013, a man in Taiwan died twenty-five days after being infected by Naegleria fowleri.[6]

Cause

N. fowleri invades the central nervous system via the nose, specifically through the olfactory mucosa of the nasal tissues. This usually occurs as the result of the introduction of water that has been contaminated with N. fowleri into the nose during activities like swimming, bathing, or nasal irrigation.

The amoeba follows the olfactory nerve fibers through the cribriform plate of the ethmoid bone into the skull. There, it migrates to the olfactory bulbs and subsequently other regions of the brain, where it feeds on the nerve tissue, resulting in significant necrosis and bleeding.[7]

The organism then begins to consume cells of the brain, piecemeal, by means of an amoebostome, a unique actin-rich, sucking apparatus extended from its cell surface.[8] It then becomes pathogenic, causing primary amoebic meningoencephalitis (PAM or PAME). PAM is a disease affecting the central nervous system.[9] PAM usually occurs in healthy children or young adults with no prior history of immune compromise who have recently been exposed to bodies of fresh water.[10]

Pathogenesis

Naegleria fowleri propagates in warm, stagnant bodies of freshwater (typically during the summer months), and enters the central nervous system after insufflation of infected water by attaching itself to the olfactory nerve.[11] It then migrates through the cribriform plate and into the olfactory bulbs of the forebrain,[12] where it multiplies itself greatly by feeding on nerve tissue.

Diagnosis

N. fowleri can be grown in several kinds of liquid axenic media or on non-nutrient agar plates coated with bacteria. Escherichia coli can be used to overlay the non-nutrient agar plate and a drop of cerebrospinal fluid sediment is added to it. Plates are then incubated at 37 °C and checked daily for clearing of the agar in thin tracks, which indicate the trophozoites have fed on the bacteria.[13] Detection in water is performed by centrifuging a water sample with E. coli added, then applying the pellet to a non-nutrient agar plate. After several days, the plate is microscopically inspected and Naegleria cysts are identified by their morphology. Final confirmation of the species' identity can be performed by various molecular or biochemical methods.[14] Confirmation of Naegleria presence can be done by a so-called flagellation test, where the organism is exposed to a hypotonic environment (distilled water). Naegleria, in contrast to other amoebae, differentiates within two hours into the flagellate state. Pathogenicity can be further confirmed by exposure to high temperature (42 °C): Naegleria fowleri is able to grow at this temperature, but the nonpathogenic Naegleria gruberi is not.

Prevention

Michael Beach, a recreational waterborne illness specialist for the Centers for Disease Control and Prevention, stated in remarks to the Associated Press that the wearing of nose-clips to prevent insufflation of contaminated water would be an effective protection against contracting PAM, noting that "You'd have to have water going way up in your nose to begin with".[15]

Treatment

Since its first description in the 1960s, only seven people worldwide have been reported to have survived PAM as of 2015, with three in the United States and one in Mexico.[16][17] The prognosis remains poor for those who contract PAM, and survival remains less than 1%.[10]

On the basis of the laboratory evidence and case reports, amphotericin B has been the traditional mainstay of PAM treatment since the first reported survivor in the US in 1982.[17][18]

Treatment has often also used combination therapy with multiple other antimicrobials in addition to amphotericin such as fluconazole, miconazole, rifampicin and azithromycin. They have shown limited success only when administered early in the course of an infection.[19] Fluconazole is commonly used as it has been shown to have synergistic effects against naegleria when used with amphotericin in-vitro.[17]

While the use of rifampicin has been common, including in all four North American cases of survival, its continued use has been questioned.[17] It only has variable activity in-vitro and it has strong effects on the therapeutic levels of other antimicrobials used by inducing cytochrome p450 pathways.[17]

Steroids such as dexamethasone have also been used to try to reduce inflammation of the brain.[20]

In 2013, the two most recent successfully treated cases in the US utilized drug combinations that included the medication miltefosine as well as targeted temperature management.[16] There is currently no data on how well miltefosine is able to reach the central nervous system.[17] The US CDC is currently offering miltefosine to doctors for the treatment of free-living ameobas including naegleria.[16]

Chlorpromazine has shown promise in in-vitro as well as animal models of Naegleria meningoencephalitis.[21]

Untimely diagnoses remain a very significant impediment to the successful treatment of infection, as most cases have only been discovered post mortem. Infection killed 121 people in the United States from 1937 through 2007.

Epidemiology

The disease is rare and highly lethal: there have only been 300 cases as of 2008.[22] Drug treatment research at Aga Khan University in Pakistan has shown that in-vitro drug susceptibility tests with some FDA approved drugs used for non-infectious diseases have proved to kill Naegleria fowleri with an amoebicidal rate greater than 95%.[23] The same source has also proposed a device for drug delivery via the transcranial route to the brain.[24]

This form of nervous system infection by amoeba was first documented in Australia in 1965.[25][26] In 1966, four cases were reported in the USA. By 1968 the causative organism, previously thought to be a species of Acanthamoeba or Hartmannella, was identified as Naegleria. This same year, occurrence of 16 cases over a period of two years (1963–1965) was reported in Ústí nad Labem, Czechoslovakia.[27] In 1970, the species of amoeba was named N. fowleri.[28]

The number of cases of infection could increase due to climate change.[29] In 2016 an infection was contracted in Maryland, four miles south of the Pennsylvania border;[30] this was the northernmost [31] North American case other than the three or four Minnesota cases from 2008 to 2015.[32] Also, the numbers of reported cases are expected to show an increase, simply because of better informed diagnoses being made both in living patients and also in autopsy findings.[33][34]

Naegleriasis cases by country
Country Cases
China 1 in 2016 [35]
Costa Rica 1 in 2014 [36]
Czechoslovakia 16 from 1962-1965 [37]
India 3 from 2001 to 2009 (two infants and one adult) and 1 in 2016 [38][39][40][41]
Iran 1 infant in 2012 [42]
New Zealand 8 from 1968 to 1979 in geothermal water [43]
Pakistan 69 from 2012 to 2014 [44][45][46]
Taiwan 1 in 2013 from a thermal spring [47]
United Kingdom 2 in 1969 and 1 in 1979, with 2 historic cases suspected retrospectively [48]
United States 133 between 1962 and 2015[49][50][51] with most cases in the Southeast U.S.[52]
Venezuela 1 in 1998 and 2 in 2006 [53][54]
Australia 1 infant in 2015[55]

History

Physicians M. Fowler and R. F. Carter first described human disease caused by amebo-flagellates in Australia in 1965.[56] Their work on amebo-flagellates has provided an example of how a protozoan can effectively live both freely in the environment, and in a human host. Since 1965, more than 144 cases have been confirmed in different countries. In 1966, Fowler termed the infection resulting from N. fowleri, primary amoebic meningoencephalitis (PAM) to distinguish this central nervous system (CNS) invasion from other secondary invasions made by other amoebae such as Entamoeba histolytica.[57] A retrospective study determined the first documented case of PAM possibly occurred in Britain in 1909.[58]

Research

Diagnostics

Current diagnostic research is focused on development of real time PCR methods. One method being developed involves monitoring the amplification process in real time with fluorescent-labeled hybridization probes targeting the MpC15 sequence – which is unique to N. fowleri.[59] Another group has multiplexed three real-time PCR reactions as a diagnostic for N. fowleri, as well as Acanthamoeba spp. and Balamuthia mandrillaris.[60] This could prove to be an efficient diagnostic test.

Treatment

The U.S. National Institutes of Health approved only $800,000 for research on the disease in 2016, due to its rarity.[61]

One line of research (as of 2006) into a potential treatment is searching for factors specific to N. fowleri that make it pathogenic; virulence factors may be targeted by drugs. One potential factor in motility of the "amoeba" is the protein coded by Nfa1. When the Nfa1 gene is expressed in non-pathogenic Naegleria gruberi and the amoebae are co-cultivated with target tissue cells, the protein is found to be located on the food cup which is responsible for ingestion of cells during feeding.[62] Following up that research, Nfa1 gene expression knockdown experiments were performed using RNA interference. In these experiments (reported in 2008), double-stranded RNA targeting the Nfa1 sequence was introduced and subsequently expression levels of the gene product dramatically decreased.[63] This method could potentially be a technique applicable for knockdown of expression of pathogenicity factors in N. fowleri trophozoites.

In 2016, it was reported that two teams were working together to find a workable treatment.[61] One was using a high-throughput screening to test tens of thousands of already-approved drugs as well as natural compounds to identify any that kill the amoeba. The other was using X-ray crystallography to study proteins in the organism that might make good drug targets. The X-ray team is hoping to use what it learns to tweak compounds identified by assay to make them more effective.

Prevention

A vaccine, using adjuvant Cry1Ac, has undergone initial research (reported in 2004).[64]

See also

References

  1. ↑ Shadrach, WS; Rydzewski, K; Laube, U; Holland, G; Ozel, M; Kiderlen, AF; Flieger, A (May 2005). "Balamuthia mandrillaris, free-living ameba and opportunistic agent of encephalitis, is a potential host for Legionella pneumophila bacteria.". Applied and Environmental Microbiology. 71 (5): 2244–9. doi:10.1128/AEM.71.5.2244-2249.2005. PMC 1087515Freely accessible. PMID 15870307.
  2. ↑ "The Centers for Disease Control and Prevention, Division of Parasitic Diseases – Naegleria fowleri - Primary Amoebic Meningoencephalitis (PAM) - General Information". Retrieved 2014-05-26.
  3. ↑ "6 die from brain-eating amoeba after swimming". MSNBC. Associated Press. 28 September 2007.
  4. ↑ Cetin N, Blackall D (Apr 2012). "Naegleria fowleri meningoencephalitis". Blood. 119 (16): 3658. doi:10.1182/blood-2011-06-353136. PMID 22645743.
  5. ↑ "CDC - 01 This Page Has Moved: CDC Parasites Naegleria". Retrieved 27 July 2015.
  6. ↑ Su MY, Lee MS; et al. (Apr 2013). "A fatal case of Naegleria fowleri meningoencephalitis in Taiwan". Korean J Parasitol. 51 (2): 203–6. doi:10.3347/kjp.2013.51.2.203. PMID 23710088.
  7. ↑ Gautam PL, Sharma S; et al. (Jan 2012). "A rare case of survival from primary amebic meningoencephalitis". Indian Crit Care med. 16 (1): 34–6. doi:10.4103/0972-5229.94432. PMID 22557831.
  8. ↑ Marciano-Cabral, F; John, DT (1983). "Cytopathogenicity of Naegleria fowleri for rat neuroblastoma cell cultures: scanning electron microscopy study". Infection and immunity. 40 (3): 1214–7. PMC 348179Freely accessible. PMID 6852919.
  9. ↑ Monsters Inside Me (2010-12-22). "Monsters Inside Me: The Brain-Eating Amoeba : Video : Animal Planet". Animal.discovery.com. Retrieved 2012-09-04.
  10. 1 2 Centers for Disease Control and Prevention (CDC) (2008). "Primary amebic meningoencephalitis – Arizona, Florida, and Texas, 2007". MMWR. Morbidity and mortality weekly report. 57 (21): 573–7. PMID 18509301.
  11. ↑ Centers for Disease Control and Prevention (CDC) (May 2008). "Primary amebic meningoencephalitis—Arizona, Florida, and Texas, 2007". MMWR Morb. Mortal. Wkly. Rep. 57 (21): 573–7. PMID 18509301.
  12. ↑ Cervantes-Sandoval I, Serrano-Luna Jde J, García-Latorre E, Tsutsumi V, Shibayama M (September 2008). "Characterization of brain inflammation during primary amoebic meningoencephalitis". Parasitol. Int. 57 (3): 307–13. doi:10.1016/j.parint.2008.01.006. PMID 18374627.
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  15. ↑ "6 die from brain-eating amoeba in lakes", Chris Kahn/Associated Press, 9/28/07
  16. 1 2 3 "Naegleria fowleri — Primary Amebic Meningoencephalitis (PAM) — Amebic Encephalitis". April 23, 2015. Retrieved 17 January 2016.
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  21. ↑ Kim, J.-H.; Jung, S.-Y.; Lee, Y.-J.; Song, K.-J.; Kwon, D.; Kim, K.; Park, S.; Im, K.-I.; Shin, H.-J. (2008). "Effect of Therapeutic Chemical Agents In Vitro and on Experimental Meningoencephalitis Due to Naegleria fowleri". Antimicrobial Agents and Chemotherapy. 52 (11): 4010–6. doi:10.1128/AAC.00197-08. PMC 2573150Freely accessible. PMID 18765686.
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  37. ↑ Ccaronerva, L.; Novak, K. (1968). "Amoebic Meningoencephalitis: Sixteen Fatalities". Science. 160 (3823): 92–92. doi:10.1126/science.160.3823.92. PMID 5642317.
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  39. ↑ Hebbar S, Bairy I; et al. (Sep 2005). "Fatal case of Naegleria fowleri meningo-encephalitis in an infant: case report". Ann Trop Paediatr. 25 (3): 223–6. doi:10.1179/146532805X58166. PMID 16156990.
  40. ↑ Gupta N, Bhaskar H; et al. (Jun 2009). "Primary amoebic meningoencephalitis: first reported case from Rohtak, North India". Braz J Infect Dis. 13: 236–7. doi:10.1590/s1413-86702009000300016. PMID 20191204.
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  47. ↑ Reference10
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  52. ↑ "Naegleria – Frequently Asked Questions (FAQs)". Centers for Disease Control and Prevention. 5 July 2011. Retrieved 2011-08-17.
  53. ↑ Rodríguez R, Méndez O; et al. (Jun 1998). "Central nervous system infection by free-living amebas: report of 3 Venezuelan cases". Rev Neurol. 26 (154): 1005–8. PMID 9658480.
  54. ↑ Petit F, Vilchez V; et al. (Dec 2006). "Primary amebic meningoencephalitis: two new cases report from Venezuela". Arq Neuropsiquiatr. 64 (4): 1043–6. PMID 17221024.
  55. ↑ Online, ABC News. "Australian Story". Retrieved 2016-12-01.
  56. ↑ Fowler, M; Carter, RF (1965). "Acute pyogenic meningitis probably due to Acanthamoeba sp.: a preliminary report". British Medical Journal. 2 (5464): 740–2. doi:10.1136/bmj.2.5464.734-a. PMC 1846173Freely accessible. PMID 5825411.
  57. ↑ Butt, Cecil G. (1966). "Primary Amebic Meningoencephalitis". New England Journal of Medicine. 274 (26): 1473–6. doi:10.1056/NEJM196606302742605. PMID 5939846.
  58. ↑ Symmers, WC (1969). "Primary amoebic meningoencephalitis in Britain". British Medical Journal. 4 (5681): 449–54. doi:10.1136/bmj.4.5681.449. PMC 1630535Freely accessible. PMID 5354833.
  59. ↑ Maďarová, Lucia; Trnková, Katarína; Feiková, Soňa; Klement, Cyril; Obernauerová, Margita (2010). "A real-time PCR diagnostic method for detection of Naegleria fowleri". Experimental Parasitology. 126 (1): 37–41. doi:10.1016/j.exppara.2009.11.001. PMID 19919836.
  60. ↑ Qvarnstrom, Y.; Visvesvara, G. S.; Sriram, R.; Da Silva, A. J. (2006). "Multiplex Real-Time PCR Assay for Simultaneous Detection of Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri". Journal of Clinical Microbiology. 44 (10): 3589–95. doi:10.1128/JCM.00875-06. PMC 1594764Freely accessible. PMID 17021087.
  61. 1 2 https://www.statnews.com/2016/07/22/brain-eating-amoeba/
  62. ↑ Song, K; Jeong, S; Park, S; Kim, K; Kwon, M; Im, K; Pak, J; Shin, H (2006). "Naegleria fowleri: Functional expression of the Nfa1 protein in transfected Naegleria gruberi by promoter modification". Experimental Parasitology. 112 (2): 115–20. doi:10.1016/j.exppara.2005.10.004. PMID 16321386.
  63. ↑ Jung, S; Kim, J; Lee, Y; Song, K; Kim, K; Park, S; Im, K; Shin, H (2008). "Naegleria fowleri: nfa1 gene knock-down by double-stranded RNAs". Experimental Parasitology. 118 (2): 208–13. doi:10.1016/j.exppara.2007.08.008. PMID 17904122.
  64. ↑ Rojas-Hernández S, Rodríguez-Monroy MA, López-Revilla R, Reséndiz-Albor AA, Moreno-Fierros L (2004). "Intranasal coadministration of the Cry1Ac protoxin with amoebal lysates increases protection against Naegleria fowleri meningoencephalitis". Infect. Immun. 72 (8): 4368–75. doi:10.1128/IAI.72.8.4368-4375.2004. PMC 470623Freely accessible. PMID 15271892.
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