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Naegleria fowleri: Diagnosis, Pathophysiology of Brain Inflammation, and Antimicrobial Treatments J. Jeffrey Pugh† and Rebecca A. Levy*,‡ †
Department of Pharmacy, and ‡Department of Pathology, Arkansas Children’s Hospital, Little Rock, Arkansas 72202, United States ABSTRACT: Primary amoebic meningoencephalitis (PAM) is a very rare disease with a high mortality rate. PAM is caused by Naegleria fowleri, an amoeba which resides in freshwater lakes and ponds and can survive in inadequately chlorinated pools (Lopez, C.; Budge, P.; Chen, J., et al. Primary amebic meningoencephalitis: a case report and literature review. Pediatr. Emerg. Care 2012, 28, 272−276). In the past 50 years, there have been over 130 cases of Naegleria induced PAM in the United States with only three known survivors; one survivor was diagnosed and treated at Arkansas Children’s Hospital. Successful treatment of PAM started with a rapid diagnosis, extensive antimicrobial therapy including an investigational medication miltefosine, supportive care, an intraventricular shunt, and hypothermia. These treatments address different aspects of the disease process. Increased understanding of the diagnosis and treatment of PAM is important especially for patients who present with meningitislike findings during the summer months. KEYWORDS: Primary amoebic meningoencephalitis, Naegleria fowleri, miltefosine treatment, brain eating amoeba cerebrospinal fluid (CSF) where Naegleria trophozoites were rapidly identified by their large, round- to pear-shaped cells with a prominent, dark nucleus, and scattered vacuoles (see Figure 1).4 The results were reported to the Emergency
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nfections of Naegleria fowleri are most commonly seen in Southern states; however, fatal cases of primary amoebic meningoencephalitis (PAM) have been reported in Minnesota and Ohio, which highlights the importance of clinical suspicion and history regardless of geography. N. fowleri infection begins with the amoebae entering the nasal cavity, usually through introduction of water via submersion, diving, or splashing. Naegleria enters the body through the nares and travels through the nasal mucosa along the olfactory nerves, across the cribriform plate, and enters the brain.2 Patients commonly present with symptoms similar to meningitis including fever, headache, nausea, and stiff neck. Occasionally, patients may present with seizures. N. fowleri is known as a “brain eating amoeba” because the microorganism can destroy neurons. The presence of microorganisms in the central nervous system causes an inflammatory reaction and has an associated release of cytotoxic molecules which results in extensive tissue damage and necrosis. There are several pathogenic mechanisms which allow for the amoeba to harm its host, including secretion of pore-forming proteins, proteases, and phospholipases that likely contribute to demyelination.3 This destruction leads to the lysis of erythrocytes and surrounding nerve cells. The amoeba also has immune evasion mechanisms such as removal of the membrane attack complex and resistance to cytokines.2 The immune response by the patient’s humoral and complement systems is not entirely understood, but they include the response of neutrophils and macrophages which produce cytotoxic effects through their oxidative burst mechanism.2 Acute necrotizing meningoencephalitis leads to mortality in most cases; death results from increased intracranial pressure and edema with lethal herniation.1 Arkansas Children’s Hospital had a case of PAM with successful treatment in 2013. The patient presented to ACH with a 3 day history of headache, tiredness, and fever (up to 103 °F); on the day of admission to the hospital she had developed nausea and vomiting. Her workup including examination of © XXXX American Chemical Society
Figure 1. Images of Naegleria fowleri on Wright−Giemsa stained CSF cytospin slides (1000×, oil immersion). Black arrows point to Naegleria trophozoites with a background of neutrophils.
Department clinicians who consulted the Infectious Disease service who began to treat the patient for PAM with amphotericin B, rifampin, azithromycin, fluconazole, and miltefosine, an investigational medication. The patient also received aggressive supportive therapy, including dexamethasone, to control for cerebral edema. Overall, the patient received 27 days of treatment with antifungals and antibiotics, in addition to placement of an external ventricular drain, hyperosmolar treatment with mannitol, and induced hypothermia to lower intracranial pressure.5 Received: August 2, 2016 Accepted: August 3, 2016
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DOI: 10.1021/acschemneuro.6b00232 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience Notes
As PAM is a rare diagnosis, the literature supporting any particular antimicrobial therapy is sparse; comprehensive treatment with a variety of antibiotic agents is typically employed, based on case reports and in vitro studies. In many cases, the exact mechanism of action against N. fowleri is not clear. Amphotericin B, a polyene antifungal, is considered to be the foundation of treatment. It acts by binding to ergosterol in the cell membrane, forming pores which alter membrane permeability and lead to cell death. Fluconazole, a triazole antifungal, exhibits synergistic activity with amphotericin B by inhibiting ergosterol synthesis through inhibition of the cytochrome P450 enzyme 14α-demethylase. Azithromycin, a macrolide antibiotic, inhibits RNA-dependent protein synthesis by binding to ribosomal subunits and blocking transpeptidation. Rifampin, a rifamycin-class antibiotic, inhibits RNA polymerase activity. Miltefosine is available through the CDC as an investigation drug for treatment of PAM. Miltefosine is an alkylphosphocholine initially investigated as an antineoplastic agent, and is currently used in the treatment of the protozoal disease leishmaniasis.6 While its exact mechanism of action against N. fowleri is uncertain, it is believed to interact with steroids and phospholipids in the cellular membrane, as well as through inhibitory action against protein kinase B.3 A key factor to effective treatment is the speed of diagnosis. PAM is a rare occurrence and is not often considered as a likely diagnosis; therefore, the clinical laboratory’s identification of the microorganism may be the first time an amoebic etiology is considered. The rapid identification can help to avoid delays in diagnosis and therapy. Amoeba cultures and real-time PCR studies for N. fowleri are diagnostic of PAM, however, they are not readily available at most institutions and would require being performed at a reference laboratory. The time of presentation of the patient can also affect the identification of the microorganism as PAM has a variable incubation time, ranging from 1 to 7 days.3 The clinical signs of PAM are similar to bacterial and viral meningitis, including fever, neck stiffness, and severe headaches. Symptoms can progress to prolonged nausea, vomiting, and even seizures. The disease can progress to acute hemorrhagic necrotizing meningoencephalitis, which can lead to death in as soon as 7−10 days.2 A variable delay in treatment can be secondary to time intervals in multiple stages of care, including exposure to exhibition of symptoms; arrival for treatment at a health care facility; workup of the diagnosis (initial diagnosis of likely bacterial meningitis); and finally, from diagnosis to initiation of recommended therapy.4 Successful treatment of PAM is a rare occurrence and can only be attempted after correct diagnosis, which relies on rapid recognition of the microorganism by medical technologists and pathologists.4 It is critical that medical technologists consistently provide timely CSF evaluation, explore the diagnosis of PAM, and look for amoebae in the setting of meningitis, especially in the summertime.4 Then, clinicians can treat with a multidrug combination and contact the Centers for Disease Control and Prevention for miltefosine treatment.6
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The authors declare no competing financial interest.
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REFERENCES
(1) Lopez, C., Budge, P., Chen, J., et al. (2012) Primary amebic meningoencephalitis: a case report and literature review. Pediatr. Emerg. Care 28 (3), 272−276. (2) Marciano-Cabral, F., and Cabral, G. A. (2007) The immune response to Naegleria fowleri amebae and pathogenesis of infection. FEMS Immunol. Med. Microbiol. 51, 243−259. (3) Grace, E., Asbill, S., and Virga, K. (2015) Naegleria fowleri: pathogenesis, diagnosis, and treatment options. Antimicrob. Agents Chemother. 59 (11), 6677−6681. (4) Dunn, A. L., Reed, T., Stewart, C., and Levy, R. A. (2016) Naegleria fowleri That Induces Primary Amoebic Meningoencephalitis: Rapid Diagnosis and Rare Case of Survival in a 12-Year-Old Caucasian Girl. Lab. Med. 47 (2), 149−154. (5) Linam, W. M., Ahmed, M., Cope, J. R., Chu, C., Visvesvara, G. S., da Silva, A. J., Qvarnstrom, Y., and Green, J. (2015) Successful treatment of an adolescent with Naegleria fowleri primary amebic meningoencephalitis. Pediatrics 135 (3), e744−e748. (6) Cope, J. R., Conrad, D. A., Cohen, N., Cotilla, M., DaSilva, A., Jackson, J., and Visvesvara, G. S. (2016) Use of Novel Therapeutic Agent Miltefosine for the Treatment of Primary Amebic Meningoencephalitis: Report of 1 Fatal and 1 Surviving Case. Clin. Infect. Dis. 62 (6), 774−776.
AUTHOR INFORMATION
Corresponding Author
*Mailing address: University of Arkansas for Medical Sciences/ Arkansas Children’s Hospital, Department of Pathology, 1 Children’s Way, Slot #820, Little Rock, AR 72202-3066. Ph: 501-364-1970. Fax: 501-364-3155. E-mail:
[email protected]. B
DOI: 10.1021/acschemneuro.6b00232 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
