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Infectious Diseases > MEDICAL TOPICS
Naegleria Infection
Article Last Updated: Jun 30, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: 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
Coauthor(s):
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
Editors: Daniel R Lucey, MD, MPH, Chief, Fellowship Program Director, Department of Internal Medicine, Division of Infectious Diseases, Washington Hospital Center; Professor, Department of Internal Medicine, Uniformed Services University of the Health Sciences; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Thomas M Kerkering, MD, Professor of Medicine and Microbiology, Department of Internal Medicine, Division of Infectious Disease, Brody School of Medicine at East Carolina University; Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital; Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Author and Editor Disclosure
Synonyms and related keywords:
Naegleria fowleri, N fowleri, primary amebic meningoencephalitis, PAM, purulent meningoencephalitis
Background
Naegleria fowleri is a free-living thermotolerant amoeba in the phylum Sarcomastigophora that is distributed worldwide, mainly in warm aquatic environments. It has also been isolated in soil and sewage. It cannot tolerate nor has been isolated from seawater.
It exists in trophozoite and cyst forms and in a transient flagellate stage. N fowleri is the etiologic agent of primary amebic meningoencephalitis (PAM), which is a rare and usually fatal disease.
Carter and Fowler, for whom N fowleri is named, reported the first cases of PAM in 1965 in Australia, although these 4 cases were initially mistakenly attributed to Acanthamoeba infections.
Pathophysiology
Most patients with PAM have a history of water exposure that includes swimming or diving through a body of fresh water. In arid climates, cases have arisen from 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 and pass through the cribriform plate to invade brain tissue with resultant purulent meningitis and encephalitis.
The organism produces its pathologic effects by its aggressive phagocytic activity and by the diffusion of phospholipases, neuraminidases, and other cytologic enzymes, which results in diffuse hemorrhage and necrosis of brain tissue.
Focal myocarditis with neutrophilic infiltrates and no visible amoebae has been reported, but its significance is still questionable.
Frequency
United States
Although isolation of N fowleri from the nares of asymptomatic individuals is reported, PAM itself is rare; only 31 cases were reported to the Centers for Disease Control and Prevention (CDC) from 1989-2002.
The risk of infection has been estimated at one case per 2.6 million exposures.
International
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 swam in freshwater pools or lakes.
Mortality/Morbidity
PAM carries a mortality rate of greater than 95%, with death occurring within 4-6 days. As of 2005, only 8 survivors of PAM were known to exist, although N fowleri was not isolated in all of these cases. Rarely, individuals survive only after very early recognition and aggressive therapy. Most survivors have some residual physical or cognitive impairment.
Race
The disease has no predisposition for any racial or ethnic group.
Sex
The disease has no predisposition for either sex, although males make up more of the cases; this is thought to be due to a greater risk of exposure.
Age
Most cases of PAM have been reported in children and young adults. As with the suspected sex predominance, this is thought to be due to a greater risk of exposure because of the activities of this age group. The more porous cribriform plate of children and young adults is thought to place these individuals at a higher risk for disease.
History
Most cases of PAM involve warm water exposure, typically for an extended period. Clusters have been well reported, but this is more the exception than the rule.
The onset incubation is short, the symptoms are acute, and death is almost certain and rapid unless the clinician maintains vigilance in regard to this organism. Treatment must be instituted rapidly.
- 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)
Physical
The physical signs are similar to those of bacterial meningitis, making diagnosis difficult. Alteration of sensorium may help distinguish PAM from strict meningitis.
- Fever
- Positive Kernig and Brudzinski signs
- Mental status changes
- Physical findings associated with encephalitis and eventual herniation (cranial nerve palsies, seizures, coma)
Other Problems to be Considered
Bacterial meningoencephalitis
Viral meningoencephalitis
Lab Studies
- Nonspecific polymorphonuclear (PMN) neutrophil–predominant neutrophilia
- Cerebral spinal fluid
- Increased opening pressure
- PMN pleocytosis
- Elevated RBC count or frank hemorrhagic CSF
- Normal to low CSF glucose level
- Elevated protein level
- CSF Gram stain findings are usually negative.
- Wright-Giemsa–stained CSF may show trophozoites with large karyosome and may show a contractile vacuole.
- Direct wet-mount microscopy may show trophozoites with lobopodia extension and retraction. Close observation is important because PAM can be diagnosed based on the observation of trophozoites; however, these have been confused with WBCs in reported cases.
- Indirect immunofluorescence is available in some laboratories.
- Polymerase chain reaction (PCR) is available at some research sites using a number of different primers.
- Serologic testing has no role in the diagnosis of acute PAM because little time is available from onset to death to mount an antibody response. In one survivor, detectable antibody persisted past 4 years.
Imaging Studies
- CT scan of the head findings are nonspecific.
Procedures
- Lumbar puncture: Wet-mount examination of CSF is the main diagnostic tool.
Medical Care
Early diagnosis, treatment, and aggressive supportive care hold the only chance for patient survival. Few people have survived PAM, and no standard treatment regimen has been developed. However, of the confirmed survivors, amphotericin B appears to be the cornerstone of therapy. The best-described case was treated with intravenous and intrathecal amphotericin B and miconazole, as well as oral rifampin.
- Numerous other drugs have been used clinically with variable success and most often in conjunction with amphotericin B.
- Lipid formulations of amphotericin B are reported to be less effective than amphotericin B deoxycholate, but the case numbers are too low to demonstrate any clinical significance.
- Various drugs used in vitro have also been studied with variable success. MIC50 was usually determined with serial dilutions of drugs in an axenic culture and compared with drug-free solutions. Mouse models have also been used for drug testing.
- The drugs showing some degree of in vitro efficacy include ketoconazole, allopurinol, cyclophosphamide, tetracycline, azithromycin, fluconazole, clotrimazole, miconazole, miltefosine, and voriconazole.
- Less activity has been demonstrated in vitro with itraconazole, metronidazole, sulfamethoxazole, trimethoprim (both alone and in combination), polymyxin B sulfate, pentamidine, paromomycin sulfate, 5-fluorocytosine, and clindamycin hydrochloride.
Surgical Care
In cases with evidence of increased intracranial pressure and possible herniation, an emergent neurosurgical consult is warranted for ventriculostomy.
Consultations
Consult with an infectious disease specialist early in the course of illness.
The goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications.
Amphotericin B has the only clear evidence for survival benefit.
Drug Category: Antifungals
Mechanism of action usually involves inhibiting pathways (enzymes, substrates, transport) necessary for sterol/cell membrane synthesis or altering the permeability of the cell membrane (polyenes) of the fungal cell.
| Drug Name | Amphotericin B (Amphocin, Fungizone) |
|---|
| Description | Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. |
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| Adult Dose | 25-300 mcg IT q48-72h and increase to 500 mcg as tolerated; alternatively, 0.25-1.5 mg/kg/d IV |
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| Pediatric Dose | 25-100 mcg IT q48-72h and increase to 500 mcg as tolerated; alternatively, 0.5-0.7 mg/kg/d IV |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC, and hemoglobin concentrations; resume the therapy at the lowest level (eg, 0.25 mg/kg) when the therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock |
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Drug Category: Antibiotics
Further Inpatient Care
- Monitor patients with PAM in the ICU.
Deterrence/Prevention
- Since N fowleri trophozoites and cysts are susceptible to chlorine, swimming pools should be adequately chlorinated. Case clusters have been reported in associated with poorly chlorinated pools.
- Strongly consider closure of a site if a case of PAM occurs.
Prognosis
- PAM has a very poor prognosis, with a mortality rate of greater than 95%.
Medical/Legal Pitfalls
- Consider PAM in all patients with meningoencephalitis, especially with an appropriate exposure history.
- Anderson K, Jamieson A, Jadin JB. Primary amoebic meningoencephalitis. Lancet. Mar 24 1973;1(7804):672. [Medline].
- Brown RL. Successful treatment of primary amebic meningoencephalitis [see comments]. Arch Intern Med. Jun 1991;151(6):1201-2. [Medline].
- Centers for Disease Control (CDC). Primary amebic meningoencephalitis--North Carolina, 1991. MMWR Morb Mortal Wkly Rep. Jun 26 1992;41(25):437-40.
- Centers for Disease Control and Prevention (CDC). Primary amebic meningoencephalitis--Georgia, 2002. MMWR Morb Mortal Wkly Rep. Oct 10 2003;52(40):962-4. [Medline].
- Cogo PE, Scagli M, Gatti S. Fatal Naegleria fowleri meningoencephalitis, Italy. Emerg Infect Dis. Oct 2004;10(10):1835-7. [Medline].
- De Jonckheere JF, Brown S. Primary amebic meningoencephalitis in a patient with AIDS: unusual protozoological findings. Clin Infect Dis. Oct 1997;25(4):943-4. [Medline].
- Duma RJ, Finley R. In vitro susceptibility of pathogenic Naegleria and Acanthamoeba speicies to a variety of therapeutic agents. Antimicrob Agents Chemother. Aug 1976;10(2):370-6.
- Gustavo dos Santos Neto. Fatal primary amebic meningoencephalitis. A retrospective study in Richmond, Virginia. Am J Clin Pathol. Nov 1970;54(5):737-42. [Medline].
- Hara T, Fukuma T. Diagnosis of the primary amoebic meningoencephalitis due to Naegleria fowleri. Parasitol Int. Dec 2005;54(4):219-21.
- John DT. Primary amebic meningoencephalitis and the biology of Naegleria fowleri. Annu Rev Microbiol. 1982;ID - AI 18788/AI/NIAID:101-23. [Medline].
- Ledbetter BR, Corson KP, Mader JT. Amoebic meningoencephalitis. J Undersea Hyperbaric Med Soc. 1995;22:118.
- Ma P, Visvesvara GS, Martinez AJ. Naegleria and Acanthamoeba infections: review. Rev Infect Dis. May-Jun 1990;12(3):490-513. [Medline].
- Oh YH, Jeong SR, Kim JH. Cytopathic changes and pro-inflammatory cytokines induced by Naegleria fowleri trophozoites in rat microglial cells and protective effects of an anti-Nfa1 antibody. Parasite Immunol. Dec 2005;27(12):453-9.
- Patterson TF, Patterson JE, Barry M. Parasitic infections of the central nervous system. In: Infections of the Central Nervous System. New York, NY:. Springer-Verlag;1990:234-261.
- Schuster FL, Guglielmo BJ, Visvesvara GS. In-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. J Eukaryot Microbiol. Mar-Apr 2006;53(2):121-6.
- Schuster FL. Cultivation of pathogenic and opportunistic free-living amebas. Clin Microbiol Rev. Jul 2002;15(3):342-54. [Medline].
- Schuster FL, Visvesvara GS. Free-living amoebae as opportunistic and non-opportunistic pathogens of humans and animals. Int J Parasitol. Aug 2004;34(9):1001-27.
- Seidel JS, Harmatz P, Visvesvara GS. Successful treatment of primary amebic meningoencephalitis. N Engl J Med. Feb 11 1982;306(6):346-8. [Medline].
- Singh U, Petri WA. Free living amebas. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and Practice of Infectious Diseases. Vol 2. New York, NY:. Churchill Livingstone;2000:2811-2817.
- Tiewcharoen S, Junnu V, Chinabut P. In vitro effect of antifungal drugs on pathogenic Naegleria spp. Southeast Asian J Trop Med Public Health. Mar 2002;33(1):38-41.
- Vargas-Zepeda J, Gómez-Alcalá AV, Vásquez-Morales JA. Successful treatment of Naegleria fowleri meningoencephalitis by using intravenous amphotericin B, fluconazole and rifampicin. Arch Med Res. Jan-Feb 2005;36(1):83-6. [Medline].
- Visvesvara GS, Martinez AJ. Protozoa: Free living amebae.In: Infectious Diseases. Vol 2. Philadelphia, Pa:. Mosby;1999:33.1-33.6.
- Yoder JS, Blackburn BG, Craun GF. Surveillance for waterborne-disease outbreaks associated with recreational water--United States, 2001-2002. MMWR Surveill Summ. Oct 22 2004;53(8):1-22. [Medline].
Naegleria Infection excerpt Article Last Updated: Jun 30, 2006
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