Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis and Treatments.

Naegleria fowleri is a free-living amoeba (FLA) that is commonly known as the "brain-eating amoeba." This parasite can invade the central nervous system (CNS), causing an acute and fulminating infection known as primary amoebic meningoencephalitis (PAM). Even though PAM is characterized by low morbidity, it has shown a mortality rate of 98%, usually causing death in less than two weeks after the initial exposure. This review summarizes the most recent information about N. fowleri, its pathogenic molecular mechanisms, and the neuropathological processes implicated. Additionally, this review includes the main therapeutic strategies described in case reports and preclinical studies, including the possible use of immunomodulatory agents to decrease neurological damage.

Acanthamoeba and its pathogenic role in granulomatous amebic encephalitis.

Acanthamoeba is a free-living amoeba that is widely distributed in the environment. It is an opportunist protist, which is known to cause rare yet fatal infection of the central nervous system (CNS), granulomatous amebic encephalitis (GAE) in humans. GAE cases are increasingly been reported among immunocompromised patients, with few cases in immunocompetent hosts. Diagnosis of GAE primarily includes neuroimaging, microscopy, cerebrospinal fluid (CSF) culture, histopathology, serology and molecular techniques. Early diagnosis is vital for proper management of infected patients. Combination therapeutic approach has been tried in various GAE cases reported worldwide. We tried to present a comprehensive review, which summarizes on the epidemiology of GAE caused by Acanthamoeba along with the associated clinical symptoms, risk factors, diagnosis and treatment of GAE among infected patients.

Killer amoebas: Primary amoebic meningoencephalitis in a changing climate.

Primary amoebic meningoencephalitis (PAM) caused by Naegleria fowleri is a rare and deadly disease that requires prompt treatment with multiple therapies. Although N. fowleri previously was only found in warmer areas, climate change appears to be contributing to its geographic spread. Clinicians should consider PAM when faced with a patient with meningitis, especially if the patient participates in outdoor water activities or practices nasal rinsing.

The therapeutic strategies against Naegleria fowleri.

Naegleria fowleri is a pathogenic amoeboflagellate most prominently known for its role as the etiological agent of the Primary Amoebic Meningoencephalitis (PAM), a disease that afflicts the central nervous system and is fatal in more than 95% of the reported cases. Although being fatal and with potential risks for an increase in the occurrence of the pathogen in populated areas, the organism receives little public health attention. A great underestimation in the number of PAM cases reported is assumed, taking into account the difficulty in obtaining an accurate diagnosis. In this review, we summarize different techniques and methods used in the identification of the protozoan in clinical and environmental samples. Since it remains unclear whether the protozoan infection can be successfully treated with the currently available drugs, we proceed to discuss the current PAM therapeutic strategies and its effectiveness. Finally, novel compounds for potential treatments are discussed as well as research on vaccine development against PAM.

Primary Amebic Meningoencephalitis in Children: A Report of Two Fatal Cases and Review of the Literature.

BACKGROUND: Primary amebic meningoencephalitis is a rare, almost uniformly fatal disease of cerebral invasion by Naegleria fowleri, occurring most commonly after swimming in warm fresh water in summer months. Treatment using the experimental medication miltefosine demonstrated improved survival and favorable neurocognitive outcome in a 2013 North American patient. There is little information about the electroencephalographic findings of such patients, and our understanding of factors predicting survival is limited. METHODS AND RESULTS: We describe two children, aged four and 14 years, who both presented with seizures and altered mental status after recent fresh water swimming exposures. With evidence of pyogenic meningitis and examination of cerebrospinal fluid demonstrating motile trophozoites on wet mount, N. fowleri meningoencephalitis was diagnosed. Amebicidal antibiotic regimens with miltefosine were administered. Continuous electroencephalography monitoring demonstrated evolution from diffuse slowing to seizures, status epilepticus, and eventually global attenuation and absence of activity. Both patients ultimately died after complications of progressive increasing intracranial pressure and hemodynamic compromise. CONCLUSIONS: Primary amebic meningoencephalitis is a serious, sporadic infection. We describe two fatal pediatric patients, the evolution of their electroencephalography findings, and compare their findings with the 13 reported pediatric survivors.

Surviving Naegleria fowleri infections: A successful case report and novel therapeutic approach.

Naegleria fowleri is a deadly human pathogen recognized as the causative agent of Primary Amoebic Meningitis (PAM). N. fowleri is commonly found in warm freshwater environments such as natural or man-made lakes, hot springs, and resort spas frequented by tourists. PAM infections have a mortality rate between 95 and 99% with minimal progress being made toward a successful treatment therapy. We report the case of a 12-year old American female who survived a PAM infection and propose a new drug therapy which includes the antimicrobial drug Miltefosine.

Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri.

Naegleria fowleri causes one of the most devastating necrotic meningoencephalitis in humans. The infection caused by this free-living amoeba is universally fatal within a week of onset of the signs and symptoms of the disease called primary amoebic meningoencephalitis (PAM). In all the affected patients, there is always a history of entry of water into the nose. Even though the diagnostic and treatment protocols have been revised and improved, the obstinate nature of the disease can be gauged by the fact that the mortality rate has persisted around ∼95% over the past 60 years. Some of the unanswered questions regarding PAM are is there a neurochemical basis of the chemotaxis of N. fowleri to the brain? What immune evasion means occurs preceding the neurotropic invasion? What is the contribution of the acute inflammatory response in the fatal cases? Can a combination of anti-amoebic drugs with antagonism of the acute inflammation help save the patient's life? As prevention remains the most valuable safeguard against N. fowleri, a quicker diagnosis, better understanding of the pathogenesis of PAM coupled with testing of newer and safer drugs could improve the chances of survival in patients affected with PAM.

Naegleria fowleri That Induces Primary Amoebic Meningoencephalitis: Rapid Diagnosis and Rare Case of Survival in a 12-Year-Old Caucasian Girl.

Primary amoebic meningoencephalitis (PAM) is a rare and almost always fatal disease that is caused by Naegleria fowleri, a freshwater thermophilic amoeba. Our case involves an adolescent female who presented with fever of unknown origin. A lumbar puncture was performed, and the Wright-Giemsa and Gram stained cerebrospinal fluid (CSF) cytospin slides showed numerous organisms. Experienced medical technologists in the microbiology and hematology laboratories identified the organisms as morphologically consistent with Naegleria species. The laboratory made a rapid diagnosis and alerted emergency department care providers within 75 minutes. The patient was treated for PAM with amphotericin, rifampin, azithromycin, fluconazole and aggressive supportive therapy including dexamethasone. The Centers for Disease Control and Prevention (CDC) was contacted, and miltefosine, an investigational medication, was started. Additional treatment included an intraventricular shunt and controlled hypothermia in order to mitigate potential cerebral edema. Our patient is a rare success story, as she was diagnosed swiftly, successfully treated, and survived PAM.

Diagnosis, Clinical Course, and Treatment of Primary Amoebic Meningoencephalitis in the United States, 1937-2013.

BACKGROUND: Primary amoebic meningoencephalitis (PAM) is a rapidly progressing waterborne illness that predominately affects children and is nearly always fatal. PAM is caused by Naegleria fowleri, a free-living amoeba found in bodies of warm freshwater worldwide. METHODS: We reviewed exposure location, clinical signs and symptoms, diagnostic modalities, and treatment from confirmed cases of PAM diagnosed in the United States during 1937-2013. Patients were categorized into the early (ie, flu-like symptoms) or late (ie, central nervous system signs) group on the basis of presenting clinical characteristics. Here, we describe characteristics of the survivors and decedents. RESULT: The median age of the patients was 12 years (83% aged ≤18 years); males (76%) were predominately affected (N = 142). Most infections occurred in southern-tier states; however, 4 recent infections were acquired in northern states: Minnesota (2), Kansas (1), and Indiana (1). Most (72%) of the patients presented with central nervous system involvement. Cerebrospinal fluid analysis resembled bacterial meningitis with high opening pressures, elevated white blood cell counts with predominantly neutrophils (median, 2400 cells/µL [range, 5-26 000 cells/µL]), low glucose levels (median, 23 mg/dL [range, 1-92 mg/dL]), and elevated protein levels (median, 365 mg/dL [range, 24-1210 mg/dL]). Amoebas found in the cerebrospinal fluid were diagnostic, but PAM was diagnosed for only 27% of the patients before death. Imaging results were abnormal in approximately three-fourths of the patients but were not diagnostic for amoebic infection. Three patients in the United States survived. CONCLUSIONS: To our knowledge, this is the first comprehensive clinical case series of PAM presented in the United States. PAM is a fatal illness with limited treatment success and is expanding into more northern regions. Clinicians who suspect that they have a patient with PAM should contact the US Centers for Disease Control and Prevention at 770-488-7100 (available 24 hours/day, 7 days/week) to discuss diagnostic testing and treatment options (see cdc.gov/naegleria).

Tackling infection owing to brain-eating amoeba.

In view of the devastating nature of primary amoebic meningoencephalitis caused by Naegleria fowleri and the problems associated with diagnostic delays and chemotherapeutic failures, here we propose a noninvasive diagnostic method using the 'reverse transcribrial route device', a novel strategy in the management of this life-threatening infection with a case fatality rate of more than 90%. The proposed rationale should stimulate interest in this emerging infection that almost always proves fatal.

Primary amoebic meningoencephalitis caused by Naegleria fowleri: an old enemy presenting new challenges.

First discovered in 1899, Naegleria fowleri is a protist pathogen, known to infect the central nervous system and produce primary amoebic meningoencephalitis. The most distressing aspect is that the fatality rate has remained more than 95%, despite our advances in antimicrobial chemotherapy and supportive care. Although rare worldwide, most cases have been reported in the United States, Australia, and Europe (France). A large number of cases in developing countries go unnoticed. In particular, religious, recreational, and cultural practices such as ritual ablution and/or purifications, Ayurveda, and the use of neti pots for nasal irrigation can contribute to this devastating infection. With increasing water scarcity and public reliance on water storage, here we debate the need for increased awareness of primary amoebic meningoencephalitis and the associated risk factors, particularly in developing countries.

Rickettsiae, protozoa, and opisthokonta/metazoa.

Rhizobiales (formerly named Rickettsiales) cause in rare instances meningitis and meningovasculitis, respectively. In case of history of exposure, infection by Rhizobiales needs to be considered since both diagnosis and therapy may be extremely difficult and pathogen-specific. The same applies to protozoa; in this chapter, Babesia species, free-living amoebae and Entamoeba histolytica infection, including severe meningitis and brain abscess, infection by Trypanosoma species (South American and African trypanosomiasis) are discussed with respect to history, epidemiology, clinical signs, and symptoms as well as differential diagnosis and therapy. Parasitic flatworms and roundworms, potentially able to invade the central nervous system, trematodes (flukes), cestodes (in particular, Cysticercus cellulosae), but also nematodes (in particular, Strongyloides spp. in the immunocompromised) are of worldwide importance. In contrast, filarial worms, Toxocara spp., Trichinella spp., Gnathostoma and Angiostrongylus spp. are seen only in certain geographically confined areas. Even more regionally confined are infestations of the central nervous system by metazoa, in particular, tongue worms (=arthropods) or larvae of flies (=maggots). The aim of this chapter is (1) to alert the neurologist to these infections, and (2) to enable the attending emergency neurologist to take a knowledgeable history, with an emphasis on epidemiology, clinical signs, and symptoms as well as therapeutic management possibilities.

Infections with free-living amebae.

Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri are mitochondria-bearing, free-living eukaryotic amebae that have been known to cause infections of the central nervous system (CNS) of humans and other animals. Several species of Acanthamoeba belonging to several different genotypes cause an insidious and chronic disease, granulomatous amebic encephalitis (GAE), principally in immunocompromised hosts including persons infected with HIV/AIDS. Acanthamoeba spp., belonging to mostly group 2, also cause infection of the human cornea, Acanthamoeba keratitis. Balamuthia mandrillaris causes GAE in both immunocompromised and immunocompetent hosts mostly in the very young or very old individuals. Both Acanthamoeba spp. and B. mandrillaris also cause a disseminated disease including the lungs, skin, kidneys, and uterus. Naegleria fowleri, on the other hand, causes an acute and fulminating, necrotizing infection of the CNS called primary amebic meningoencephalitis (PAM) in children and young adults with a history of recent exposure to warm fresh water. Additionally, another free-living ameba Sappinia pedata, previously described as S. diploidea, also has caused a single case of amebic meningoencephalitis. In this review the biology of these amebae, clinical manifestations, molecular and immunological diagnosis, and epidemiological features associated with GAE and PAM are discussed.

Emerging trends in free-living amebic infections of the brain: implications for organ transplantation.

This epidemiological review analyzed cases of Naegleria fowleri primary amebic meningoencephalitis (PAM) and Balamuthia mandrillaris granulomatous amebic encephalitis (GAE) for behavioral and demographic risk factors for pathogen exposures and potential transmission by organ transplantation. The Centers for Disease Control and Prevention (CDC) Naegleria Workgroup Registry provided 121 cases of laboratory-confirmed PAM over the period, 1937-2007. The CDC and the California Encephalitis Project provided 28 cases of GAE over the period, 1994-2010. There was a statistically significant increase in clusters of PAM cases between the periods, 1937-1996 and 1997-2007. Risk factors for PAM included male gender, freshwater exposures, summer exposures, and exposures in southern-tier US (United States) states. Risk factors for GAE included male gender, exposures in southern-tier US states, Hispanic ethnicity in California, occupational or recreational contacts with soil, and recent organ transplantation. Fatal free-living amebic infections of the brain are increasing today due to more frequent environmental, recreational, and occupational exposures; organ transplantation; and unanticipated clusters of PAM due to N. fowleri inoculations following nasal sinus irrigation using neti pots filled with municipal tap water. Potential organ donors dying from meningoencephalitis of unexplained causes should be screened for free-living amebic infections of the brain capable of hematogenous dissemination in organ recipients.

Primary amebic meningoencephalitis: a case report and literature review.

Primary amebic meningoencephalitis (PAM) is a rare but nearly always fatal disease caused by infection with Naegleria fowleri, a thermophilic, free-living ameba found in freshwater environments. Cases of N. fowleri infection have been reported from many of the southern-tier states in the United States, with Florida and Texas disproportionately represented among them. Primary amebic meningoencephalitis presents clinically in a fashion that may be indistinguishable from bacterial and viral meningitis. Unfortunately, because the disease is so rare, PAM is often excluded from the differential diagnosis of children with meningitis resulting in delayed diagnostic and therapeutic efforts.Pediatric acute care practitioners in emergency departments, general pediatric wards, and critical care units, especially those practicing in the southern United States, should be familiar with the risk factors for acquisition of PAM, its clinical presentation, and the fact that common empiric treatment of bacterial meningitis will not treat N. fowleri. Herein, we present the case of an adolescent who died of PAM and review the (a) epidemiology, (b) pathophysiology, (c) available diagnostic modalities, (d) treatment options, and (e) outcomes of patients treated for N. fowleri infection of the central nervous system.

Acute granulomatous acanthamoeba encephalitis in an immunocompetent patient.

BACKGROUND: Acanthamoeba sp. are known to cause fatal granulomatous Acanthamoeba encephalitis (GAE) in immunocompromised patients. METHODS: The case of a 17 year old immunocompetent patient with acute purulent meningoencephalitis is reported. RESULTS: After substantial improvement of cerebrospinal fluid under conventional antimicrobial treatment the patient was suffering several relapses. The causative agent was identified as Acanthamoeba lenticulata T5 which entered the CNS through a bone dehiscence of ethmoidal cells. Due to severe vasospasm the patient developed multiple strokes, which led to marked neurologic sequels. CONCLUSIONS: This case report demonstrates successful treatment of usually lethal GAE in an immunocompetent patient with high dose meropenem, linezolid, moxifloxacin and fluconazole followed by a partially adapted antimicrobial combination therapy.

Plasmodium vivax malaria presenting with severe thrombocytopenia, cerebral complications and hydrocephalus.

Two cases of a one and 4 year old child of plasmodium vivax malaria are reported in association with CNS complications. Both presented with encephalopathy and seizures. One had severe thrombocytopenia, massive intracranial bleed and hydrocephalus requiring shunt surgery while the other had gastrointestinal manifestations, encephalopathy and hydrocephalus. Both responded to quinine but are left with sequelae.

Animal models of human African trypanosomiasis--very useful or too far removed?

Animal models of human African trypanosomiasis, also known as sleeping sickness, have been used for many years both to investigate disease pathogenesis and to test novel drug therapies. Model systems used have included mice, rats and non-human primates such as monkeys. Whilst such animal models have some definite but unavoidable limitations, it is argued that these are outweighed by their advantages. The latter include the ability to investigate disease pathogenesis mechanistically and the mechanisms of trypanosome traversal of the blood-brain barrier, as well as the identification of new potential drug targets and staging biomarkers, new drug therapies and combinations, and potential drug toxicity.