Primary amoebic meningoencephalitis

Primary amoebic meningoencephalitis (PAM, or PAME) is a rare disease of the central nervous system caused by infection from the amoeboid excavate Naegleria fowleri.

Signs and symptoms

During the stage occurring approximately 3â€"7 days post-infection, the typical symptoms are distortion of the sense of smell, rapidly progressing to inability to smell (with resultant inability to taste) as the nerve cells of the olfactory bulbs are consumed and replaced with lesions made up of dead cells.

After the organisms have multiplied and largely consumed the olfactory bulbs, the infection rapidly spreads through the mitral cell axons to the rest of the cerebrum, resulting in onset of frank encephalitic symptoms, including headache, nausea, and rigidity of the neck muscles, progressing to vomiting, delirium, seizures, and eventually irreversible coma. Death usually occurs within 14 days of exposure as a result of respiratory failure when the infection spreads to the brain stem, destroying the autonomic nerve cells of the medulla oblongata.

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. It then migrates through the cribriform plate and into the olfactory bulbs of the forebrain, where it multiplies itself greatly by feeding on nerve tissue.

Cause

Naegleria fowleri is a parasite commonly referred to as an amoeba, but is more precisely an excavate that is ubiquitous in soils and warm waters. Infection typically occurs during the summer months and patients typically have a history of exposure to a natural body of water. The organism specifically prefers temperatures above 32 °C (89.6 F) as might be found in a tropical climate or in water heated by geothermal activity. The organism is extremely sensitive to chlorine (<0.5 ppm). Exposure to the organism is extremely common due to its wide distribution in nature, but thus far lacks the ability to infect the body through any method other than direct contact with the olfactory nerve, which is exposed only at the extreme vertical terminus of the paranasal sinuses; the contaminated water must be deeply insufflated into the sinus cavities for transmission to occur.

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".

Epidemiology

The disease is rare and highly lethal: there had been fewer than 200 confirmed cases in recorded medical history as of 2004, 300 cases as of 2008.

This form of nervous system infection by amoeba was first documented in Australia in 1965. 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 (1963â€"1965) was reported in Ústí nad Labem. In 1970, the species of amoeba was named N. fowleri.

In October 1978, a young girl swimming with the Bath Dolphins, a local swimming club, in the restored Roman bath in Bath, Somerset, contracted meningitis and died, leading to the closure of the bath for several years. Tests showed that N. fowleri was in the water.

There were 31 reported occurrences between 2003 and 2012 in the United States, which is very low compared to the millions of recreational water exposures each year. Though most cases have occurred in large lakes and rivers, in December 2011, two individuals in Louisiana died after inhaling infected tap water while using a neti pot.

Despite being rare and usually occurring in isolated cases, 8 people died from N. fowleri infections within a week in the southern part of Pakistan in July 2012.

Treatment

The current standard treatment is prompt intravenous administration of heroic doses of amphotericin B, a systemic antifungal that is one of the few effective treatments for systemic infections of protozoan parasitic diseases (such as leishmaniasis and toxoplasmosis). The success rate in treating PAM is usually quite poor, since by the time of definitive diagnosis most patients have already manifested signs of end-stage brain cell death. Even if definitive diagnosis is effected early enough to allow for a course of medication, amphotericin B also causes significant and permanent kidney toxicity in the doses necessary to quickly halt the progress of the amoebae through the brain.

The high mortality rate of this disease is largely blamed on the unusually non-suggestive symptomology of the early-stage disease compounded by the necessity of microbial culture of the cerebrospinal fluid to effect a positive diagnosis. The parasite also demonstrates a particularly rapid late-stage propagation through the nerves of the olfactory system to many parts of the brain simultaneously (including the vulnerable medulla). For those reasons, it has been suggested that physicians should give an array of antimicrobial drugs, including the drugs used to treat amoebic encephalitis, before the disease is actually confirmed in order to increase the number of survivors. However, administering several of those drugs at once (or even some of them known to treat the condition) is often very dangerous and unpleasant for the patient.

Rifampicin has also been used with amphotericin B in successful treatment. However, there is some evidence that it does not effectively inhibit Naegleria growth.

Two cases of similar amoebic infections (caused by Balamuthia mandrillaris) were successfully treated for amoebic encephalitis and recovered, including a 5-year-old girl and a 64-year-old man. The successful use of a combination regimen that includes one amebicidal drug (miltefosine) along with two amebistatic drugs capable of crossing the brain-blood barrier (fluconazole and albendazole) provides hope for attaining clinical cure for an otherwise lethal condition.

There is preclinical evidence that the relatively safe, inexpensive, and widely available phenothiazine antipsychotic chlorpromazine is a highly efficacious amebicide against N. fowleri, with laboratory animal survival rates nearly double those receiving treatment with amphotericin B. The mechanism of action is possibly the inhibition of the nfa1 and Mp2CL5 genes, found only in pathogenic strains of N. fowleri, which are involved in amoebic phagocytosis and regulation of cellular growth, respectively.