Primary Amoebic Meningoencephalitis (PAM)

There is no escaping the fact that our world is teeming with microorganisms. They share our world and are all around us. They live on, as well as inside, everyone. Some are beneficial. In industry, they are used to help break down hazardous waste in the development of food, biofuels, biotechnologies, and pharmaceuticals. Human flora and fauna contribute greatly to an individual’s overall heath. They help boost our immune system and are key players in the production of biotin and vitamin K. It has even been suggested that mitochondria, our cellular powerhouse, are derived from a symbiotic relationship between eukaryotic cells (cells with a nucleus) and ancient bacteria that could produce energy through aerobic respiration. However, for every benefit bestowed upon microorganisms, their pathogenic nature is highly disconcerting. There is a continuing effort to develop more effective vaccines, antibiotics, and sanitation methods to protect against diseases they cause.

One such waterborne disease is primary amoebic meningoencephalitis (PAM), a rapidly progressing, fatal infection of the brain and meninges caused by Naegleria fowler. N fowleri is a heat-loving (thermophilic), free-living amoeboflagellate. It has been found in nearly every region of every continent. It has been identified from samples taken from freshwater lakes, ponds, poorly chlorinated swimming pools, spas, water heaters, hot tubs, soil, dust, and even air conditioners. It does not require a host to survive, and in its natural environment, it primarily ingests bacteria, yeast, and algae. Thriving in warmer climates, particularly southern regions, it multiplies most rapidly in temperatures around 105^oF to 115^oF. However, it can survive in cyst form at nearly freezing temperatures, and for a short while in temperatures that exceed 122^oF and up to 149^oF. There is a growing fear that rising global temperatures might spur N fowler to move to traditionally cooler regions, with reports of new infections reaching as far north as Minnesota. PAM is a rare diagnosis and experts are perplexed as to why some individuals contract the disease while millions of exposed individuals do not. In 1977, a survey of Florida lakes found that 46% were infested with the N fowler amoebae, yet only 18 cases of PAM were reported from 1962 to 2000.

These resilient protozoa have 3 distinct morphological stages:

• The trophozoite: This is its active feeding and reproductive stage, effectively the classic amoeba. They have a characteristic “food cup,” or a suction cup–like appendage that allows them to break down (lyse) and ingest bacteria, yeast, and cells. These protozoa reproduce asexually in a process called binary fission, which is essentially mitosis. A classical lobopodia, it moves rapidly by expanding and contracting bulges that push its cytoplasm through its ectoplasm over and over (sinusoidal/limacine locomotion).
• The cyst: In this stage, the amoeba encapsulates itself typically in response to some environmental stressor (eg, frigid temperatures, deficient nutrients, overcrowding). The outer cyst wall has 1 or 2 flat mucus-plugged pores in which the trophozoite will emerge when conditions are optimal.
• The flagellate: In this stage, the trophozoite transforms into a flagellate with usually 2 flagella (whip-like protrusions) that can propel it more rapidly through water. This is done in response to potential lethal changes in its environment. Typically either a change in ion concentration or sub-optimal pH levels will cause this transformation, which can be seen in minutes.

Death from parasitic infections is unusual, with a few exceptions. Ultimately the parasite’s life is tied to its host: when the host dies, so does the parasite. This is not the case with N fowleri. PAM infections are nearly uniformly fatal, with a staggering mortality rate in healthy, non-immunocompromised individuals of over 99%. Studies suggest that the innate immune repose may be the strongest defense against this pathogen. It has also been suggested that through evolution, N fowler has developed mechanisms to evade the host’s immune system. In vitro, it has demonstrated a resistance to lysis (being destroyed/dissolved) by a host’s cytolytic molecules, such as tumor necrosis factor. The major issue with this disease is its rapid progression, which allows little time for an immune response and even less time to make a correct diagnosis.

PAM is not a communicable disease and is most often acquired from swimming in contaminated fresh water; N fowleri cannot survive in salt water. However, last year in Louisiana, 2 reports surfaced in which the victims acquired the disease from contaminated tap water used in a “neti pot.” To date, officials do not know how their tap water became contaminated, especially because the incidences were separated by a period of months. The rout of infection is through the nose; the pathogen has to be inhaled, either as a cyst or as a trophozoite. Once inside, it penetrates the nasal mucosa, making its way through the cribriform plate and into the subarachnoid space, eventually reaching the CNS. Only trophozoites have been identified within the brain, CSF, and surrounding areas. In the brain, it destroys nerve cells as well as other cells through a process called trogocytosis (piecemeal ingestion). The modes in which it destroys cells have been examined in vitro and differ depending on the strain. Weaker strains utilize their sucker-like appendages, which nibble away at tissue directly, while more virulent strains lyse nerve cells on contact and ingest the debris. Either way, they cause extensive damage, including inflammation, necrosis, and hemorrhaging within the CNS.

Diagnosing PAM has proven difficult because it is not widely understood and is relatively unheard of by many physicians. It presents in a similar fashion to acute bacterial meningitis and has been mistaken for a cytomegalovirus infection, toxoplasmosis, viral or fungal meningitis, as well as other opportunistic pathogens. The initial onset of symptoms can be seen in 3 to 7 days (incubation period) and has been reported in as few as 24 hours. Death occurs within 7 to 12 days of initial exposure. Differences in the rate of progression may be attributed to the virulence of that specific strain as well as the concentration during initial exposure. It is typically seen in young adults and children, disproportionally affecting males at a 3:1 ratio. The difference in male/female infection rates is most likely attributed to how the disease is contracted rather than any real gender differences. There exists, within the general population, a widespread prevalence of anti–N fowleri antibodies, which suggests prior exposure without becoming clinically significant. However, it still remains unclear if an antibody presence may provide protection from future infections.

Worldwide PAM reports are sporadic at best. This condition is often underdiagnosed or misdiagnosed, which makes it difficult to glean insight into its true prevalence rates. Most diagnoses are made after death using a wet preparation of CSF, and even under high magnification, the amoeba may not be identified. In the United States, since 1962, there have been 123 verified PAM infections with only 1 survivor (California, 1979). One report has estimates as high as 10 survivors worldwide, but a more conservative estimate is roughly 3 to 5 worldwide. It has also been estimated that chances of contracting PAM once exposed is about 1 in 100 million. One French study reports slightly higher infection risks. Swimming once in contaminated water with a concentration of 10 amoebas per liter has an associated infection risk of approximately 1 in 85 million. There is some dispute over infection rates. According to the CDC, infection levels have not changed since 1962, with 2 to 4 infections per year. Others assert worldwide infection rates are on the rise, and the reported numbers represent a mere fraction of actual infections. 

With an incubation period between 3 and 7 days, PAM symptoms progress as follows:

• Sore throat (1-7 days)
• Severe frontal headache (1-7 days)
• Fever (1-7 days)
• Nausea (1-7 days)
• Vomiting (1-7 days)
• Stiff neck (1-12 days)
• Irritability (1-12 days)
• Altered mental status, confusion (1-12 days)
• Cerebral ataxia, with demonstrable Kernig’s and Brudzinski’s signs (7-12 days)
• Hallucinations (7-12 days)
• Seizures (7-12 days), leading to coma, with death occurring 4 to 6 days later
• Coma (7-12 days)
• Death (7-12 days)

Research suggests that N fowleri demonstrates a more rapid rate of locomotion and growth in the presence of nerve cells and nerve cell products. Other research suggests an increased virulence of N fowleri after it passes through CNS tissue. Computerized brain tomography from infected individuals shows a complete destruction of the cisternae surrounding the midbrain and the subarachnoid space over the cerebral hemispheres. A microscopic examination of fresh CSF is the best diagnostic method to determine the presence of motile trophozoites. A culture may also be conclusive but the window for initiating treatment is short and this method takes time. CSF will appear hazy to the naked eye. CSF tests indicate elevated levels of RBCs, WBCs, neutrophils, and lymphocytes, as well as high protein levels and decreased glucose levels.

Currently, amphotericin B is the first-line treatment for PAM, but an argument can be made about its efficacy. Of the known US patients, all were treated intravenously with amphotericin B and all but 1 died. The California survivor received a cocktail that included amphotericin B (IV and intrathecal), oral rafampicin, miconazole (IV and intrathecal), dexamethasone, sulfisoxazole (IV), and phenytoin. Miconazole is longer available in the US, and sulfisoxazole was discontinued after N fowleri wasdiagnosed. Laboratory tests from the California survivor determined the strain she was infected with was less virulent, was slower acting, and did not damage cells as rapidly, which allowed for a small serological response. Miltefosine, an antiprotozoal agent, is being investigated as an alternative/additional treatment for PAM, but is not approved by the FDA for this condition. For PAM, preventative measures may be the best option. If you use a “neti pot,” fill it with sterile water, and wear nose plugs when swimming in lakes, ponds, poorly chlorinated pools, or other bodies of water where an infestation may occur.

Death comes to us all; it is an inevitability of life. However, even with death we have certain expectations. We often expect death to occur around a particular age and/or because of a particular disease, but only after the “good long fight.” Losing someone is never easy but losing someone young can be particularly devastating, with an abrupt loss even more so. A slow disease progression can be horrific but may also assist in preparing us for the eventual outcome. This is not the case with PAM. The victim starts with a headache and rapidly becomes ill, followed by death. Traditional platitudes of an end to suffering, or going to a better place, seem especially hollow in these cases. From a distance, one might marvel at the simple nature of these protozoa. For the people who are close, PAM kills quickly and randomly, leaving a wake of devastation and confusion.

Reference

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