eMedicine Specialties > Infectious Diseases > CNS Infections

Naegleria Infection

Author: Subhash Chandra Parija, MBBS, MD, PhD, FRCPath, Director-Professor of Microbiology, Head of Department of Microbiology, Jawaharlal Institute, Postgraduate Medical Education and Research, India
Coauthor(s): Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Barnett Gibbs, MD, Assistant Chief, Department of Clinical Trials, Walter Reed Army Institute of Research, Infectious Disease Service, National Capital Consortium; Assistant Professor of Medicine, Uniformed Services University of the Health Sciences; Diane H Johnson, MD, Assistant Director, Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, Winthrop-University Hospital, State University of New York at Stony Brook School of Medicine
Contributor Information and Disclosures

Updated: Aug 3, 2009

Introduction

Background

Naegleria fowleri, a free-living ameba, is the causal agent of primary amebic meningoencephalitis (PAM), which is an acute, fulminant, and rapidly fatal CNS infection. PAM develops within several days of exposure to the contaminated water source and typically causes death within 1–2 weeks after admittance to the hospital. Few individuals survive the infection, partly because of its rapid onset and partly because of delayed diagnosis.

Bull reported the first case of N fowleri meningoencephalitis in the United States and coined the term primary amebic meningoencephalitis to distinguish it from the secondary meningoencephalitis caused by the intestinal ameba Entamoeba histolytica.

Naegleria species are ameboflagellates that are ubiquitous in soil and fresh or brackish water (lakes, rivers, ponds). In general, they are sensitive to environmental conditions such as aridity and pH extremes and cannot survive in sea water. In humans, they are found in the throat and nasal cavity. N fowleri is heat tolerant and is able to survive temperatures up to 45.8°C, preadapting the species to mammalian body temperature. Indeed, an incubation temperature of 45°C is routinely used to isolate N fowleri from water samples while suppressing growth of other amebae in the samples.

Although some 30 species of Naegleria have been recognized based on sequencing data, N fowleri is the only one that has been isolated in cases of amebic meningoencephalitis. Other Naegleria species (Naegleria australiensis, Naegleria italica, Naegleria philippinensis) have been found to be pathogenic in murine models of PAM but have not been identified in any human cases of the infection.¹ Because it grows best at somewhat elevated temperatures, N fowleri has been isolated from warm-water bodies, including man-made lakes and ponds, hot springs, and thermally polluted streams and rivers. In the United States, most N fowleri infections occur in the summer months.²

Life cycle of N fowleri

The life cycle of the ameba has 3 stages: trophozoite, a temporary flagellar stage known as ameboflagellate, and cyst.

The trophozoite is the vegetative or feeding stage of the ameba. In humans, this form is found in CSF or in tissue. It measures 10-20 μm in diameter and has a granular cytoplasm and a distinct ectoplasm. The trophozoite is characterized by a large central nuclear karyosome surrounded by a halo. Trophozoites are actively motile with the help of a broadly rounded, granule-free projection (ie, lobopodium) that originates from the surface. The projection helps to ingest bacteria, yeast cells, and cellular debris and may serve as an organelle of attachment. In tissue, trophozoites ingest red and white blood cells and cause tissue destruction. The trophozoite stage is the only one in which the ameba multiplies via binary fission.

The flagellate stage, also known as the ameboflagellate stage, is a temporary form of the ameba in which it neither feeds nor divides in culture. The ameba progresses to the ameboflagellate stage when the trophozoites form is exposed to a change in ionic concentration, such as in distilled water. During the ameboflagellate stage, the parasite is pear-shaped with a flagellar apparatus at the broader end. The flagellar apparatus consists of two terminal flagella, two basal bodies, microtubules, and a single striated rootlet, or rhizoplast. During the flagellated stage, the parasite may exhibit a rapid forward movement or a slowly spinning circular movement. It reverts back to the trophozoite stage within 24 hours.

The cystic stage represents the resistant form of the parasite, offering protection from desiccation and food shortage. The cyst is round, measures 7-10 μm in diameter, and is surrounded by a smooth double-layered 1-μm wall. The cyst consists of a single nucleus, contractile vacuoles, and food vacuoles. In stained preparations, only the vacuoles can be demonstrated as fine granules, but not the nucleus. Cysts are usually absent in clinical specimens, as the infection is so rapid and fatal that the patient typically dies before the trophozoites encyst.³

Pathophysiology

N fowleri infections in humans occur while swimming or diving in warm water contaminated with the parasite. Human-to-human transmission has never been reported. This parasite invades its host by penetrating the olfactory mucosa. During the initial stages of infection, the host response is initiated by the secretion of mucus that traps the trophozoites. Despite this response, some trophozoites are able to reach, adhere to, and penetrate the epithelium.

Moreover, it secretes a 37-kDa protein with mucinolytic activity.⁴ The gene nfa1 has been isolated from the free-living pathogenic amoeba. The protein Nfa1, which has cytolytic function, is located in pseudopodia and specifically in food-cups. N fowleri trophozoites are neurotrophic.⁵ They enter the nose and invade the olfactory mucosa and bulbs, penetrate the submucosal nervous plexus, invade the cribriform plate, and reach the subarachnoid space. Glucose and protein in the CSF support the growth and multiplication of the amebae. The high content of oxygen in the CSF and in the brain also facilitates growth of the amebae.

The trophozoites enter the ventricular system through the foramen of Luschka and Magendie and reach the choroid plexus. These then destroy the ependymal layer of the third, fourth, and lateral ventricles and produce acute ependymitis. They multiply by a process known as promitosis, during which an intact nuclear membrane (demonstrable on electron microscopy) is present. Only trophozoites are found in pathologic lesions in humans.

Most patients with PAM have a history of swimming or diving in a body of fresh water. In arid climates, some cases of PAM have been attributable to the inhalation of cysts. Trophozoites or cysts, which give rise to trophozoites after they excyst, penetrate the nasal mucosa and ascend along the olfactory nerves after phagocytosis by sustentacular cells of the neuroepithelium. Subsequently, they pass through the cribriform plate to invade brain tissue, with resultant purulent meningitis and encephalitis.

Host immunity

The course of N fowleri infection is fulminant and rapid, and patients with PAM die usually within a short period (5-10 d). Therefore, detectable levels of specific antibodies are not produced in the serum during the disease. The role of the cell-mediated immunity (CMI) in resistance to N fowleri infection is not fully understood.

Frequency

United States

Although isolation of N fowleri from the nares of asymptomatic individuals has been reported, PAM itself is rare in the United States. Only 31 cases were reported to the Centers for Disease Control and Prevention (CDC) from 1989-2002. In 2007, 6 cases of PAM were reported in the United States, and all were fatal.² From 1998-2007, 33 infections were reported in the United States. Thirty-one of the infected individuals had come into contact with recreational water, and two had come into contact with water from a geothermal (naturally hot) water supply.⁶

In a survey of 16 sites from Lake Anna in Virginia, a lake that is used to cool reactors at a nuclear power plant and for recreational activities, sampled during the summer of 2007, 9 were found to be positive for N fowleri by a nested polymerase chain reaction (PCR) assay. However, total ameba counts, inclusive of N fowleri, never exceeded 12/50 mL of lake water at any site. The presence of N fowleri was not found to correlate with the conductivity, dissolved oxygen, temperature, or pH of water. To date, no cases of PAM have been reported from this thermally enriched lake.⁷

In August 2005, two Oklahoma boys, aged 7 and 9 years, died of N fowleri infection after swimming in hot stagnant water in lakes in the Tulsa area. In August 2008, a 9-year-old boy died after acquiring N fowleri infection while swimming several times in Lake Elsinore in California. It was the first-ever confirmed case of N fowleri infection in Riverside County, California.⁸

International

The risk of infection has been estimated at one case per 2.6 million exposures to N fowleri. Approximately 200 cases of PAM have been reported worldwide, with some well-publicized outbreaks related to a single source. Most cases occur during the warm summer months in individuals who swim in freshwater pools or lakes.

Most worldwide cases have been reported in the United States. Other cases of N fowleri infection have been reported in Czechoslovakia, Australia, Mexico, New Zealand, Nigeria, Great Britain, and India. A total of 17 cases have been reported so far from different parts of India.⁹

Mortality/Morbidity

PAM carries a mortality rate of greater than 95%, with death occurring within 4-6 days. PAM was the reported cause of death in 23 people in the United States from 1995 to 2004 and in 6 in 2007. As of 2005, only 8 survivors of PAM had been reported, although N fowleri was not isolated in all of these cases. In the rare cases of survival, PAM was recognized very early, allowing for early institution of aggressive therapy. Most survivors have some residual physical or cognitive impairment. One recent survivor was an 8-month-old male infant from India who was treated vigorously and avoided any neurological deficit.¹⁰

Race

PAM has no racial predilection.

Sex

PAM has a male-to-female ratio of 3:1. Although PAM has no natural sexual predilection, the predominance in males is thought to be secondary to a greater risk of exposure due to behavioral factors.

Age

Most cases of PAM have been reported in children and young adults, presumably because of a greater exposure risk in these populations due to behavioral factors. In addition, the more porous cribriform plate in children and young adults is thought to place these individuals at a higher risk for disease.

Clinical

History

Most cases of primary amebic meningoencephalitis (PAM) involve a history of exposure to fresh warm water. Patients with PAM generally present with a history of bathing in a pond or lake 2-6 days prior to the onset of symptoms of meningeal irritation.

The index of suspicion should be increased in children and young adults who have a history of recently swimming in freshwater lakes, ponds, and pools. Isolated cases of PAM have followed bathing in tap and hot water.

Clusters of cases of PAM have been documented during the summer months when freshwater sources are warm. The higher temperature during the hot summer months facilitates the growth of N fowleri.

Physical

The physical signs of PAM are similar to those of bacterial meningitis, as follows:

• Fever
• Alteration in taste (ageusia) or smell (parosmia)
• Sudden-onset headache (usually frontal or bitemporal)
• High temperature (up to 40°C)
• Nausea, vomiting, or both
• Stiff neck
• Photophobia (later in the course of illness)
• Positive Kernig and Brudzinski signs
• Mental status changes
• Physical findings associated with encephalitis and eventual herniation (cranial nerve palsies, seizures, coma)
• Rapid onset of coma and death (within 2 wk)

Causes

PAM is caused by infection with the ameba N fowleri.

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