Naegleria fowleri is a ubiquitous free-living ameba that is the etiologic agent in primary amebic meningoencephalitis (PAM). Although N fowleri rarely causes disease, it is important because diagnosis can be difficult and PAM is rapidly fatal in more than 95% of cases. In the summer of 2007, 6 fatal cases of N fowleri infection occurred in the United States, all young males.
The earliest known case of N fowleri –associated disease dates back to 1937 and occurred in a patient from Virginia; however, this case was not reported until 1968, when Dos Santos identified the patient during a retrospective review of autopsies. In 1965, Fowler and Carter published the first report of N fowleri –associated CNS disease.  In this initial report of 4 patients in Australia, the authors suggested the etiologic amebae probably belonged to the genus Acanthamoeba; however, subsequent investigation shows these cases were most likely due to N fowleri. Acanthamoeba infections tend to progress slower than N fowleri infections, with insidious symptoms that present weeks or months after exposure; these symptoms are more similar to the presentation of a bacterial brain abscess or tumor than to N fowleri infection.
In 1966, Butt reported the first case of N fowleri meningoencephalitis in the United States and coined the term PAM.  The term was chosen to distinguish the disease caused by N fowleri from the secondary meningoencephalitis due to the extension of Entamoeba histolytica from another site.
N fowleri is a member of the subphylum Sarcodina, superclass Rhizopodea. Rhizopodea includes the free-living amebae Entamoeba histolytica and species of Acanthamoeba, Hartmannella, Balamuthia, Naegleria, and others. Although N fowleri is one of several species in the genus Naegleria, to date, it remains the only Naegleria species known to produce human disease.
Most N fowleri infections have occurred in children and young adults who have had recent exposure to swimming or diving in warm freshwater.  The thermophilic nature of N fowleri allows it to survive in waterways contaminated by thermal discharges from power plants, heated swimming pools, and even hot springs with temperatures up to 45°C (113°F). Most cases of PAM occur during the summer months, when freshwater sources are warm. When water temperatures decrease, N fowleri encyst and enter a dormant stage, which allows them to survive until the next summer.
The events that lead to N fowleri –associated PAM usually result from swimming or diving in warm water contaminated with N fowleri. The N fowleri trophozoites enter the nose and invade the olfactory mucosa, penetrate the submucosal nervous plexus, cross the cribriform plate, and gain access to the subarachnoid space. The presence of protein and glucose in the cerebrospinal fluid (CSF) supports the growth of amebae, which then multiply rapidly and invade the parenchyma of the brain. Because N fowleri possess mitochondria, the high oxygen content of the brain and CSF enhance its growth.
The invasive trophozoites are highly phagocytic and ingest RBCs and brain tissue, resulting in severe hemorrhagic necrosis of the involved brain. Brain tissue, unlike RBCs, cannot be ingested whole by the trophozoites; however, N fowleri produces an amebostome, or food cup, into which it secretes lysosomal hydrolases and phospholipases. N fowleri can also use heat-stable hemolytic proteins, heat-labile cytolysin, phospholipase A, and a cysteine protease to kill cells in contact with the trophozoites. In 2000, Chu et al demonstrated that normal human serum is capable of activating protein kinases with subsequent protein phosphorylation, which results in enhanced complement resistance in N fowleri. 
N fowleri produces a diffuse hemorrhagic meningoencephalitis associated with purulent meningitis. The cortical gray matter is the most severely involved area. Because of severe edema of the brain, CSF pressures are elevated, and uncal or cerebellar herniation can occur.
Apart from the damage to the CNS, infection with N fowleri is also associated with a neutrophilic myocarditis; however, amebic trophozoites are not present in the myocardium. The clinical significance of this myocarditis is unknown.
The life cycle of N fowleri has 3 stages.
- Trophozoite (vegetative) stage: The trophozoite is the reproductive stage of the protozoan. The trophozoite measures 10-30 µm in diameter and is characterized by a nucleus with a large centrally placed karyosome with a surrounding halo. Trophozoites are motile and move by extending a blunt lobopodium (pseudopodium) and allowing the cell cytoplasm and contents to flow into the extension. Lobopodia form at different points along the cell surface, allowing the trophozoite to change direction. In their free state, trophozoites feed on bacteria and exhibit aerobic metabolism via their mitochondria. In tissue, trophozoites phagocytize RBCs and WBCs and destroy tissue with which they come into contact. Trophozoites replicate by binary fission, which occurs only in this stage.
- Flagellate stage: When the N fowleri trophozoites are exposed to a change in ionic concentration, such as placement in distilled water, they transform into pear-shaped biflagellates or multiflagellates.
- Cyst stage: Trophozoites encyst in response to unfavorable conditions, such as exposure to cold. The spherical cysts have a single nucleus surrounded by a dense cell wall with 1-2 flat pores, which are plugged with mucus. Cysts range from 7-14 µm.
Only 37 cases of N fowleri infection were documented in the United States between 2006 and 2015, but an unusual spike of 6 unrelated cases (all fatal) occurred in the summer of 2007.  Cases have been reported along the east coast from Virginia to Florida, as well as in California. Several cases were reported annually in Texas throughout the 1990s. Infection can occur in any situation in which exposure to warm freshwater is present, and geographic location should not be used as a means to rule out infection.
N fowleri has a worldwide distribution, but more than one half of reported infections have occurred in the United States. This may reflect a reporting bias because of the difficulty in making the diagnosis. Most human infections occur during the summer months, when recreational water use and water temperatures are highest. Around 200 cases of PAM have been reported worldwide.
The mortality rate of N fowleri infections is extremely high. Of more than 200 cases of PAM, only around a dozen people have reportedly survived. The estimated mortality rate is approximately 95%.
Linam et al presented a survivor of amebic meningoencephalitis in North America. The authors conclude that the patient's survival most likely resulted from a variety of factors, including early identification and treatment, use of a combination of antimicrobial agents that included miltefosine, and management of elevated intracranial pressure based on the principles of traumatic brain injury. This was also the first case reported in which induced hypothermia to 32-34 degrees Celsius was used in the management of PAM. 
N fowleri infection has no known racial predilection.
The male-to-female ratio is 3:1. This may reflect a greater exposure risk for males rather than a true sexual predisposition to infection.
N fowleri PAM is primarily a disease of children and young adults. The youngest child with PAM described in the literature is a 5-month-old infant.
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