Primary amoebic meningoencephalitis
Template:Short description Template:Use dmy dates Template:Infobox medical condition
Primary amoebic meningoencephalitis (PAM), also known as naegleriasis, is an almost invariably fatal infection of the brain by the free-living protozoan Naegleria fowleri. Symptoms include headache, fever, nausea, vomiting, a stiff neck, confusion, hallucinations and seizures.<ref name="cdc.gov-2019" /> Symptoms progress rapidly over around five days with characteristics of both meningitis and encephalitis, making it a type of meningoencephalitis. Death usually results within one to two weeks of symptom onset.<ref name="cdc.gov-2019" /><ref name="mw" />
N. fowleri is typically found in warm bodies of fresh water, such as ponds, lakes, rivers and hot springs. It is found in an amoeboid, temporary flagellate stage or microbial cyst in soil, poorly maintained municipal water supplies, water heaters, near warm-water discharges of industrial plants and in poorly chlorinated or unchlorinated swimming pools. There is no evidence of it living in salt water. As the disease is rare, it is often not considered during diagnosis.<ref name="Pathology">Template:Cite journal</ref>
Although infection occurs very rarely,<ref name="mw">Template:Cite web</ref> it almost inevitably results in death, with a mortality rate of 95-98%.<ref>Template:Cite news</ref><ref>One death in September 2018 was the first confirmed case of the infection in the United States since 2016. Template:Cite news)l</ref><ref name="Mortality rate">Template:Cite journal</ref><ref name="History">Template:Cite journal</ref>
Signs and symptoms
The onset of symptoms begins one to twelve days following exposure (with a median of five).<ref name="cdc.gov-2019">Template:Cite web</ref> Initial symptoms include changes in taste and smell, headache, fever, nausea, vomiting, back pain,<ref name="Talaro 2015 p. ">Template:Cite book</ref> and a stiff neck. Secondary symptoms are also meningitis-like including confusion, hallucinations, lack of attention, ataxia, cramp and seizures. After the start of symptoms, the disease progresses rapidly, with death usually occurring anywhere from one to eighteen days later (with a median of five),<ref>Template:Cite web</ref> although it can take longer. In 2013, a man in Taiwan died 25 days after being infected by Naegleria fowleri.<ref>Template:Cite journal</ref>
It affects healthy children or young adults who have recently been exposed to bodies of fresh water.<ref name="MMWR2008">Template:Cite journal</ref> Scientists speculate that lower age groups are at a higher risk of contracting the disease because adolescents have a more underdeveloped and porous cribriform plate, through which the amoeba travels to reach the brain.<ref name="Adolescent infection">Template:Cite journal</ref>
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 such as swimming, bathing or nasal irrigation.<ref name="Safe Ritual Nasal Rinsing">Template:Cite web</ref>
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. The organism then begins to consume cells of the brain, piecemeal through trogocytosis,<ref>Template:Cite journal</ref> by means of an amoebostome, a unique actin-rich sucking apparatus extended from its cell surface.<ref name="Cytopathogenicity">Template:Cite journal</ref> It then becomes pathogenic, causing primary amoebic meningoencephalitis (PAM or PAME).<ref name="Pathology" />
Primary amoebic meningoencephalitis presents symptoms similar to those of relatively common bacterial and viral meningitis. Upon abrupt disease onset, a plethora of symptoms arise. Endogenous cytokines, released in response to the pathogens, affect the thermoregulatory neurons of the hypothalamus, causing a rise in body temperature.<ref name="Montgomery">Template:Cite web</ref> Additionally, the cytokines may act on the vascular organ of the lamina terminalis, leading to upregulation of Prostaglandin E2 contributing to hyperthermia.<ref>Template:Cite journal</ref> Further, the release of cytokines, exotoxins released by the pathogens, and an increase in intracranial pressure stimulate the nociceptors in the meninges<ref name="Montgomery" /> resulting in pain sensations.
The release of cytotoxic molecules in the central nervous system leads to extensive tissue damage and necrosis, such as damage to the olfactory nerve through lysis of nerve cells and demyelination.<ref name="Pugh">Template:Cite journal.</ref> Specifically, the olfactory nerve and bulbs become necrotic and hemorrhagic.<ref name="Fero">Template:Cite web</ref> Spinal flexion leads to nuchal rigidity, or stiff neck, due to the stretching of the inflamed meninges.<ref name="Montgomery" /> The increase in intracranial pressure stimulates the area postrema to create nausea sensations which may lead to brain herniation and damage to the reticular formation.<ref name="Montgomery" /> Ultimately, the increase in cerebrospinal fluid from inflammation of the meninges increases intracranial pressure to an extent that leads to the destruction of the central nervous system. Although the exact pathophysiology behind the seizures caused by PAM is unknown, it is speculated that the seizures arise from altered meningeal permeability<ref name="Montgomery" /> caused by increased intracranial pressure.
Pathogenesis
Naegleria fowleri propagates in warm, stagnant bodies of fresh water (typically during the summer months), and enters the central nervous system after insufflation of infected water by attaching itself to the olfactory nerve.<ref name="MMWR2008"/> It then migrates through the cribriform plate and into the olfactory bulbs of the forebrain,<ref name="pmid18374627">Template:Cite journal</ref> where it rapidly multiplies 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 indicates the trophozoites have fed on the bacteria.<ref>Template:Cite bookTemplate:Page needed</ref>
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.<ref>Template:Cite journal</ref>
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 can grow at this temperature, but the nonpathogenic Naegleria gruberi can not.<ref name="Temperature tolerance">Template:Cite journal</ref><ref name="N. fowleri">Template:Cite journal</ref><ref name="Growth Temps">Template:Cite journal</ref>
Prevention
Michael Beach, a recreational waterborne illness specialist for the Centers for Disease Control and Prevention, stated in remarks to the Associated Press that wearing of nose clips to prevent insufflation of contaminated water would be effective protection against contracting PAM, noting that "You'd have to have water going way up in your nose to begin with".<ref>"6 die from brain-eating amoeba in lakes", Chris Kahn/Associated Press, 9/28/07</ref>
Advice stated in the press release from Taiwan's Centers for Disease Control recommended that people prevent fresh water from entering the nostrils and avoid putting their heads down into fresh water or stirring mud in the water with their feet. When starting to suffer from fever, headache, nausea, or vomiting after any exposure to fresh water, even in the belief that no fresh water has traveled through the nostrils, people with such conditions should be carried to hospital quickly and make sure doctors are well-informed about the history of exposure to fresh water.<ref name="衛生福利部疾病管制署 2013">Template:Cite webTemplate:PD-notice</ref>
Treatment
Based on laboratory evidence and case reports, heroic doses<ref>Template:Cite book</ref> of amphotericin B have been the traditional mainstay of PAM treatment since the first reported survivor in the United States in 1982.<ref name="Treatment" />
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.<ref>Template:Cite book</ref>
While the use of rifampicin has been common, including in all four North American cases of survival, its continued use has been questioned.<ref name="Treatment" /> It has variable activity only in vitro, and it has strong effects on the therapeutic levels of other antimicrobials used by inducing cytochrome p450 pathways.<ref name="CYP450">Template:Cite journal</ref><ref name="Treatment" /> Fluconazole is commonly used as it has been shown to have synergistic effects against Naegleria when used with amphotericin in vitro.<ref name="Treatment" />
In 2013–2016, three successfully treated cases in the United States utilized the medication miltefosine.<ref name="Treatment" /> In one of the cases, a 12-year-old female was given miltefosine and targeted temperature management to manage cerebral edema, which is secondary to the infection. She survived with no neurological damage. The targeted temperature management, coupled with early diagnosis and medication, has been attributed to her survival.<ref name="12 y.o. survivor">Template:Cite journal</ref> In 2016, a 16-year-old male also survived PAM. He was treated with the same protocols as the 12-year-old female in 2013. He recovered with a near-complete neurological recovery; however, the patient has mentioned difficulties with learning post-recovery.<ref name="CDC">Template:Cite web</ref><ref>Template:Cite web</ref> Template:As of the U.S. CDC offered miltefosine to doctors for the treatment of diseases caused by free-living amoebas, including Naegleria,<ref name="CDC" /> despite a lack of any data on how well the drug reaches the central nervous system.<ref name="Treatment" /> In 2022, another 13-year-old male survived the infection, although the CDC did not confirm it.<ref>Template:Cite web</ref>
In 2018, a 10-year-old girl in the Spanish city of Toledo became the first person to contract the disease in Spain, and was successfully treated using intravenous and intrathecal amphotericin B.<ref>Template:Cite news</ref>
A 2023 study on mice has shown that treatment that included a derivative of the drug acoziborole known as AN3057 significantly prolonged survival and showed a 28% recovery rate without relapse.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref>
Prognosis
Since its first description in the 1960s, only seven people worldwide have been reported to have survived PAM out of 450 cases diagnosed, implying a fatality rate of about 98.5%.<ref name="Survivors">Template:Cite journal</ref><ref>Template:Cite web</ref><ref name="MMWR2008" /> The survivors include four in the United States, one in Mexico, and one in Spain. One of the US survivors had likely permanent brain damage, but two documented surviving cases in the United States made a full recovery with no neurological damage; they were both treated with the same protocols.
An updated report from the Centers for Disease Control and Prevention shows a total of 167 reported cases of PAM between 1962-2024 in the United States, as with their last report there are still only four known survivors of PAM in the United States.<ref name="Survivors update">Template:Cite web</ref> An updated study of cases of PAM caused by N. fowleri, published in 2021, identified a total of 381 cases worldwide as of 2018, with only seven cases of recovery being confirmed.<ref name="Worldwide cases">Template:Cite journal</ref>
Epidemiology
The disease is rare and highly lethal: there had been only 381 cases Template:As of<ref name="pmid18820207">Template:Cite journal</ref> 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 (digoxin and procyclidine were shown to be most effective of the drugs studied) have proved to kill Naegleria fowleri with an amoebicidal rate greater than 95%.<ref>Template:Cite journal</ref> The same source has also proposed a device for drug delivery via the transcranial route to the brain.<ref>Template:Cite journal</ref>
In the US, the most common states with cases reported of PAM from N. fowleri are the southern states, with Texas and Florida having the highest prevalence. The most commonly affected age group is 5–14-year-olds (those who play in water).<ref>"Number of Case-Reports of Primary Amebic Meningoencephalitis Caused by Naegleria Fowleri (N=133) by State of Exposure*— United States, 1962–2014". CDC.gov, CDC, www.cdc.gov/parasites/naegleria/pdf/naegleria-state-map-2014.pdf.</ref> The number of cases of infection could increase due to climate change, which was posited as the reason for three cases in Minnesota in 2010, 2012, and 2015.<ref name="ReferenceA">Template:Cite journal</ref><ref>Template:Cite web</ref>
Template:As of the numbers of reported cases were expected to increase simply because of better-informed diagnoses being made both in ongoing cases and in autopsy findings.<ref>Template:Cite journal</ref>
History
In 1899, Franz Schardinger first discovered and documented an amoeba he called Amoeba gruberi that could transform into a flagellate.<ref>Template:Cite journal</ref> The genus Naegleria was established by Alexis Alexeieff in 1912, who grouped the flagellate amoeba. He coined the term Naegleria after Kurt Nägler, who researched amoebae.<ref>Template:Cite journal</ref> It was not until 1965 that doctors Malcolm Fowler and Rodney F. Carter in Adelaide, Australia reported the first four human cases of amoebic meningoencephalitis. These cases involved four Australian children, one in 1961 and the rest in 1965, all of whom had succumbed to the illness.<ref name="pmid5825411">Template:Cite journal</ref><ref name="pmid5354833">Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name=NEJM1966/>
In 1966, Butt 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.<ref name=NEJM1966>Template:Cite journal</ref> A retrospective study determined the first documented case of PAM possibly occurred in Britain in 1909.<ref name="pmid5354833"/> In 1966, four cases were reported in the US. By 1968, the causative organism, previously thought to be a species of Hartmannella, was identified as a novel species of Naegleria. This same year, the occurrence of sixteen cases over three years (1962–1965) was reported in Ústí nad Labem, Czechoslovakia.<ref>Template:Cite journal</ref> In 1970, Carter named the species of amoeba N. fowleri, after Malcolm Fowler.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref>
Society and culture
Naegleria fowleri is also known as the "brain-eating amoeba". This common name has also been applied to Balamuthia mandrillaris, causing some confusion between the two; Balamuthia mandrillaris is unrelated to Naegleria fowleri, and causes a different disease called granulomatous amoebic encephalitis. 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.<ref>Template:Cite journal</ref>
Naegleriasis was the topic in Season 2 of the medical mystery drama House, M.D. in the two-part episode titled "Euphoria".<ref>Template:Cite web</ref><ref>Template:Cite web</ref> It is also the topic of the episode "39 Differences" of season 6 of The Good Doctor after a patient is diagnosed with N. Fowleri infection.<ref>Template:Cite web</ref>
Research
The U.S. National Institutes of Health budgeted $800,000 for research on the disease in 2016.<ref>Template:Cite news</ref> Phenothiazines have been tested in vitro and in animal models of PAM.<ref>Template:Cite journal</ref> Improving case detection through increased awareness, reporting, and information about cases might enable earlier detection of infections, provide insight into the human or environmental determinants of infection, and allow improved assessment of treatment effectiveness.<ref name="MMWR2008"/>
See also
- Balamuthia mandrillaris – unrelated pathogenic organism that shares the same common name as N. fowleri