AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Naegleria fowleri is a ubiquitous free-living ameba that is the etiologic agent in primary amebic meningoencephalitis (PAM). Although N fowleri rarely causes disease, it is important because diagnosis can be difficult and PAM is rapidly fatal in more than 95% of cases. In the summer of 2007, 6 fatal cases of N fowleri infection occurred in the United States, all young males.

The earliest known case of N fowleri–associated disease dates back to 1937 and occurred in a patient from Virginia; however, this case was not reported until 1968, when Dos Santos identified the patient during a retrospective review of autopsies. In 1965, Fowler and Carter published the first report of N fowleri–associated CNS disease.¹ In this initial report of 4 patients in Australia, the authors suggested the etiologic amebae probably belonged to the genus Acanthamoeba; however, subsequent investigation shows these cases were most likely due to N fowleri. Acanthamoeba infections tend to progress slower than N fowleri infections, with insidious symptoms that present weeks or months after exposure; these symptoms are more similar to the presentation of a bacterial brain abscess or tumor than to N fowleri infection.

In 1966, Butt reported the first case of N fowleri meningoencephalitis in the United States and coined the term PAM.² The term was chosen to distinguish the disease caused by N fowleri from the secondary meningoencephalitis due to the extension of Entamoeba histolytica from another site.

N fowleri is a member of the subphylum Sarcodina, superclass Rhizopodea. Rhizopodea includes the free-living amebae Entamoeba histolytica and species of Acanthamoeba, Hartmannella, Balamuthia, Naegleria, and others. Although N fowleri is one of several species in the genus Naegleria, to date, it remains the only Naegleria species known to produce human disease.

Most N fowleri infections have occurred in children and young adults who have had recent exposure to swimming or diving in warm freshwater.³ The thermophilic nature of N fowleri allows it to survive in waterways contaminated by thermal discharges from power plants, heated swimming pools, and even hot springs with temperatures up to 45°C (113°F). Most cases of PAM occur during the summer months, when freshwater sources are warm. When water temperatures decrease, N fowleri encyst and enter a dormant stage, which allows them to survive until the next summer.

Pathophysiology

The events that lead to N fowleri–associated PAM usually result from swimming or diving in warm water contaminated with N fowleri. The N fowleri trophozoites enter the nose and invade the olfactory mucosa, penetrate the submucosal nervous plexus, cross the cribriform plate, and gain access to the subarachnoid space. The presence of protein and glucose in the cerebrospinal fluid (CSF) supports the growth of amebae, which then multiply rapidly and invade the parenchyma of the brain. Because N fowleri possess mitochondria, the high oxygen content of the brain and CSF enhance its growth.

The invasive trophozoites are highly phagocytic and ingest RBCs and brain tissue, resulting in severe hemorrhagic necrosis of the involved brain. Brain tissue, unlike RBCs, cannot be ingested whole by the trophozoites; however, N fowleri produces an amebostome, or food cup, into which it secretes lysosomal hydrolases and phospholipases. N fowleri can also use heat-stable hemolytic proteins, heat-labile cytolysin, phospholipase A, and a cysteine protease to kill cells in contact with the trophozoites. In 2000, Chu et al demonstrated that normal human serum is capable of activating protein kinases with subsequent protein phosphorylation, which results in enhanced complement resistance in N fowleri.⁴

N fowleri produces a diffuse hemorrhagic meningoencephalitis associated with purulent meningitis. The cortical gray matter is the most severely involved area. Because of severe edema of the brain, CSF pressures are elevated, and uncal or cerebellar herniation can occur.

Apart from the damage to the CNS, infection with N fowleri is also associated with a neutrophilic myocarditis; however, amebic trophozoites are not present in the myocardium. The clinical significance of this myocarditis is unknown.

The life cycle of N fowleri has 3 stages.

1. Trophozoite (vegetative) stage: The trophozoite is the reproductive stage of the protozoan. The trophozoite measures 10-30 µm in diameter and is characterized by a nucleus with a large centrally placed karyosome with a surrounding halo. Trophozoites are motile and move by extending a blunt lobopodium (pseudopodium) and allowing the cell cytoplasm and contents to flow into the extension. Lobopodia form at different points along the cell surface, allowing the trophozoite to change direction. In their free state, trophozoites feed on bacteria and exhibit aerobic metabolism via their mitochondria. In tissue, trophozoites phagocytize RBCs and WBCs and destroy tissue with which they come into contact. Trophozoites replicate by binary fission, which occurs only in this stage.
2. Flagellate stage: When the N fowleri trophozoites are exposed to a change in ionic concentration, such as placement in distilled water, they transform into pear-shaped biflagellates or multiflagellates.
3. Cyst stage: Trophozoites encyst in response to unfavorable conditions, such as exposure to cold. The spherical cysts have a single nucleus surrounded by a dense cell wall with 1-2 flat pores, which are plugged with mucus. Cysts range from 7-14 µm.

Frequency

United States

Only 23 cases of N fowleri infection were documented in the United States between 1995 and 2004, but an unusual spike of 6 unrelated cases (all fatal) occurred in the summer of 2007. Cases have been reported along the east coast from Virginia to Florida, as well as in California. Several cases were reported annually in Texas throughout the 1990s. Infection can occur in any situation in which exposure to warm freshwater is present, and geographic location should not be used as a means to rule out infection.

International

N fowleri has a worldwide distribution, but more than one half of reported infections have occurred in the United States. This may reflect a reporting bias because of the difficulty in making the diagnosis. Most human infections occur during the summer months, when recreational water use and water temperatures are highest. Around 200 cases of PAM have been reported worldwide.

Breed

Although experimental animals such as rodents, rabbits, and sheep are susceptible to N fowleri infections, only one report has described a naturally acquired infection in an animal, a South American tapir.⁵

Mortality/Morbidity

The mortality rate of N fowleri infections is extremely high. Of more than 200 cases of PAM, only around a dozen people have reportedly survived. The estimated mortality rate is approximately 95%.

Race

N fowleri infection has no known racial predilection.

Sex

The male-to-female ratio is 3:1. This may reflect a greater exposure risk for males rather than a true sexual predisposition to infection.

Age

N fowleri PAM is primarily a disease of children and young adults. The youngest child with PAM described in the literature is a 5-month-old infant.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

N fowleri usually occurs in children or young adults who have a history of exposure to swimming or diving in warm freshwater within the last 7-14 days. Most often, the first symptoms develop 2-5 days after the last exposure to contaminated water. The illness begins suddenly with the abrupt onset of fever, headache, nausea, and vomiting. Occasionally, a prodromal stage of altered taste (ie, ageusia) and smell (ie, parosmia) may occur. Altered mental status occurs in about two thirds of patients and is followed by rapid deterioration to coma and death.

Physical

The physical findings in PAM result from rapid spread of N fowleri from the submucosal olfactory nerves through the cribriform plate and into the olfactory bulb. Virtually all patients have meningismus by the time they reach medical care. Patients do not usually develop focal neurologic defects; however, cranial nerve palsies involving III, IV, and V, as well as cerebellar ataxia and reduced deep tendon reflexes, have been reported. Patients often have papilledema and nystagmus. In the final stage just prior to death, the patient may have decerebrate posturing.

Causes

PAM is the term applied to the severe hemorrhagic meningoencephalitis caused by pathogenic strains of N fowleri. N fowleri is the only member of genus Naegleria known to be pathogenic to humans.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Viral encephalitis must also be differentiated from N fowleri infection. Naegleria infection is best differentiated based on the patient's history and examination of the CSF, including wet-mount preparation of spun CSF.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• For practical purposes, N fowleri meningoencephalitis must be rapidly diagnosed. Patients who present with a clinical picture of meningitis (ie, fever, headache, meningismus, nausea and vomiting) should undergo a spinal tap as soon as they present.
• In patients with PAM, the CSF pressure is often elevated, and the CSF is hemorrhagic. The WBC count can be within the reference range in early infections but rapidly increases to range from 400-26,000 cells/µL with a neutrophilic predominance. The CSF glucose level may be low or within the reference range, but the CSF protein is usually elevated. Results on a Gram stain of the CSF sediment are negative for bacteria. A wet mount must be made because the trophozoites of N fowleri lyse during the heat fixation that precedes the Gram stain. On the wet preparation, motile trophozoites are evident. Care must be taken to avoid confusing N fowleri trophozoites with WBCs and vice versa. In examining CSF for N fowleri, a regular glass slide for a wet mount is preferred to a WBC counting chamber. The regular glass slide allows for better definition of internal structures.
• The CSF is centrifuged at 150g for 5 minutes. The supernatant is carefully aspirated, and the sediment is gently suspended in the remaining fluid. A drop of this suspension is placed on a slide and covered with a No. 1 coverslip. The slide is observed under a compound microscope using 10 and 40 objectives. Phase contrast optics is preferable. The slide may be warmed to 35°C (to promote amebic movement). The amebae are detected based on their active directional movements. CSF indices in N fowleri include the following:
• • CSF protein levels are elevated.
  • CSF glucose levels are within the reference range or reduced.
  • CSF WBC count is elevated (400-26,000 cells/µL).
  • CSF RBC count is high, and the CSF is often hemorrhagic.
  • CSF Gram stain results are negative for bacteria.
  • CSF wet mount is positive for motile trophozoites and is of paramount importance for the diagnosis.
• Additional methods of diagnosing N fowleri infection include polymerase chain reaction (PCR), monoclonal antibodies, DNA probes, and isoenzyme profile analysis. However, these methods are more time consuming and labor intensive than routine CSF studies. They are useful in postmortem diagnoses and for research purposes.
• Other nonspecific laboratory findings in peripheral blood include the following:
• • The WBC count is elevated with a neutrophilic predominance.
  • Complete metabolic panel (CMP) may show abnormalities, including hyponatremia associated with acquired diabetes insipidus, hyperglycemia, or both.

Imaging Studies

• Limited data are available on imaging studies. One patient has been reported who had a CT scan of the head that demonstrated diffuse enhancement of the gray matter and obliteration of the interpeduncular and quadrigeminal cisterns.

Other Tests

• EEG may show signs of reduced cerebral blood flow, including slow and disorganized fundamental rates.

Procedures

• The main diagnostic procedure for PAM is to obtain CSF for wet-mount examination for N fowleri, along with standard laboratory examination of the CSF (eg, WBC, RBC, glucose, protein, bacterial and fungal cultures). N fowleri can be cultured on nonnutrient agar plates, which have a lawn of gram-negative bacteria, such as Escherichia coli, covering its surface. "Trails" in the lawn of bacteria that are left by migrating amebae can be visualized following incubation.

Histologic Findings

• Amebic trophozoites in perivascular spaces and paraventricular areas
• Fibrinoid necrosis in some blood vessels
• Hemorrhage and necrosis
• Meningeal exudate composed of neutrophils, chronic inflammatory cells, and degenerating amebae
• Focal demyelination in the white matter of the brain and spinal cord
• Acute inflammatory reaction in nasal mucous membranes
• Trophozoites demonstrated on hematoxylin- and eosin-stained slides in involved tissues

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The medical care in patients with PAM is complicated by the rarity of the disease, the difficulty in diagnosing N fowleri infection early, and the fact that N fowleri is so rapidly lethal. Once clinical symptoms begin, the patient has a very short time during which therapy might be effective. The exceedingly high mortality rate of PAM suggests that many, if not most, patients have already entered into a stage that is not responsive to currently available therapy by the time they present for medical care.

The drug of choice (DOC) is amphotericin B. Lipid preparations of amphotericin B are not superior to conventional amphotericin B, and the lipid preparations have been shown to have higher minimal inhibitory concentrations. Other drugs that have been used include miconazole IV, which is not available in the United States, as well as rifampin, sulfonamides, chloramphenicol, and tetracycline. Miconazole may be useful and even synergistic with amphotericin B, but the other drugs are of questionable value.

Surgical Care

In patients who develop life-threatening elevations in intracranial pressure, ventriculostomy and drainage of CSF may be necessary to relieve intracranial pressure. In one survivor, surgical drainage of a brain abscess was performed in addition to treatment with a 6-week course of amphotericin B, rifampicin, and chloramphenicol.

Consultations

When the diagnosis of PAM is considered, appropriate considerations for consultations include an infectious disease specialist and a neurosurgeon.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

To date, the most effective proven therapy remains amphotericin B. Eight patients have survived PAM, and nearly all of them received amphotericin B with or without additional agents. One survivor was treated with intravenous and intrathecal miconazole plus rifampin and sulfisoxazole.

One report has described highly effective and selective in vitro activity of voriconazole (Vfend) against N fowleri.⁶ It showed lasting inhibition from concentrations of more than 1 µg/mL. The anticancer drug miltefosine (Miltex; not available in the United States) was also tested and found to be amebicidal in serum concentrations of more than 55 µmol. Neither drug is currently recommended in the treatment of PAM, but these preliminary data may lead to in vivo studies or case reports of empirical use.

Drug Category: Polyene antibiotics

Amphotericin B is the most effective drug against N fowleri.

Drug Category: Antibiotic agents

Antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Survival after PAM has been uncommon, and death occurs in 95% or more of patients. In patients who do survive, careful attention to the prevention of seizures and control of intracranial pressure is critical. Other measures include prevention of secondary bacterial infections (especially intravenous catheter–related infections and urinary tract infections in patients with Foley catheters), prevention of decubitus ulcers, and prevention of aspiration in patients with coma or seizures.

Further Outpatient Care

• In survivors, outpatient care should include assessment of neurologic function and control of seizures, if present.

In/Out Patient Meds

• Therapy for PAM requires hospitalization. Survivors may need seizure medications.

Transfer

• The rapidity of progression in PAM usually precludes transferring the patient long distances; however, treating patients in a medical facility with an intensive care unit and neurosurgical and infectious disease support is best whenever possible.

Deterrence/Prevention

• N fowleri is ubiquitous and is present in warm freshwater and soil. The widespread presence of anti–N fowleri antibodies in the population indicates that exposure to this ameba is common and usually not associated with disease. Thus, general prevention of exposure to N fowleri is difficult if not impossible; however, most cases of clinical disease (ie, PAM) follow swimming or diving in warm freshwater. In swimming pools, proper chlorination is effective in significantly reducing risk; in open waterways, eradication of N fowleri is not a reasonable expectation.

Complications

• Most survivors have improved and fared well. A risk of persistent seizures is observed.

Prognosis

• The overall prognosis of PAM is very poor. Many reported cases have been diagnosed only postmortem. The overall mortality rate exceeds 95%.

Patient Education

• As part of general public health information, people should be aware that swimming or diving in warm freshwater (ie, not saltwater) poses risks of bacterial, parasitic, and protozoal infections. Patients' families should be aware that they should provide complete histories to physicians trying to care for critically ill patients.
• Physicians, especially in emergency departments, should be aware of the possibility that a child or young adult who presents with what appears to be acute pyogenic meningitis could have PAM.⁷ A history of recent swimming or diving in warm freshwater should suggest the diagnostic possibility of N fowleri infection.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Clinical infection with N fowleri is rare, but it has one of the highest mortality rates of any infectious disease. Because patients with PAM present in a manner similar to patients with acute pyogenic meningitis and because PAM is much less common than pyogenic meningitis, physicians may miss the diagnosis. Furthermore, few physicians ever see a case of this rare disease, and most never even know other physicians who have seen a case. However, virtually all physicians have had direct experience with patients who have had pyogenic meningitis; therefore, most physicians are at a decided disadvantage in making this diagnosis premortem.
• The history of recent exposure to swimming or diving in warm freshwater is one of the few clues that may alert physicians so that they can inform the clinical laboratory of the possible presence of N fowleri. These difficulties in the diagnosis of this rare disease may lead to inappropriate claims of failure to diagnose. In fact, many, if not most, cases of PAM have been diagnosed postmortem; at least one case was diagnosed more than 2 decades after the patient died.
• Routine CSF examination does not include wet-mount preparation of spun specimens. Therefore, in patients in whom bacterial meningitis is suspected because of the severity and rapid progression of symptoms that are not clearly due to a more likely pathogen (eg, purpuric lesions that suggest meningococcal infection), questioning about recent exposure to contaminated warm freshwater or obtaining the test on an empirical basis may be prudent.
• The lack of amebic organisms upon initial examination of the CSF does not preclude the diagnosis, especially in the presence of other compatible CSF markers (as discussed in Lab Studies), and repeated samples may need to be taken, depending on the clinical progression of the patient.
• If N fowleri infection is suspected based on history and physical examination findings, treatment should not be withheld while awaiting confirmatory testing because of the rapid fulminant nature of the infection.

Special Concerns

• Report all cases of N fowleri infection to local public health authorities. Information regarding the source of the infection, especially if it is a swimming pool, can reduce the likelihood of other cases.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Mar 7, 2008