Primary amoebic meningoencephalitis

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. Symptoms progress rapidly over around five days with characteristics of both meningitis and encephalitis; becoming a type of meningoencephalitis. Death usually results within one to two weeks of symptom onset. 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. Although infection occurs very rarely, it almost inevitably results in death, with a mortality rate of 95-98%.

Signs and symptoms The onset of symptoms begins one to twelve days following exposure (with a median of five). Initial symptoms include changes in taste and smell, headache, fever, nausea, vomiting, back pain, 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), although it can take longer. In 2013, a man in Taiwan died 25 days after being infected by Naegleria fowleri. It affects healthy children or young adults who have recently been exposed to bodies of fresh water. 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.

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. 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, by means of an amoebostome, a unique actin-rich sucking apparatus extended from its cell surface. It then becomes pathogenic, causing primary amoebic meningoencephalitis (PAM or PAME). 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. Additionally, the cytokines may act on the vascular organ of the lamina terminalis, leading to upregulation of prostaglandin E2 contributing to hyperthermia. Further, the release of cytokines, exotoxins released by the pathogens, and an increase in intracranial pressure stimulate the nociceptors in the meninges 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. Specifically, the olfactory nerve and bulbs become necrotic and hemorrhagic. Spinal flexion leads to nuchal rigidity, or stiff neck, due to the stretching of the inflamed meninges. 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. 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 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. It then migrates through the cribriform plate and into the olfactory bulbs of the forebrain, 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. 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. 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.

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