OVERVIEW: What every clinician needs to know
Parasite name and classification
Free-Living Amebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri.
What is the best treatment?
Effective treatment regimens for granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris and for primary amebic meningoencephalitis (PAM) due to Naegleria fowleri have not been established. The mortality rates for diseases caused by all three amebae are high (>90%) and few patients have survived. Although some commonalities in chemotherapeutic regimens exist between survivors, decedents have also received similar drug cocktails. The treatment guidance presented in this chapter is provided by the U.S. Centers for Disease Control and Prevention (CDC) and is based on case reports of survivors, personal experience through clinical consultations with treating physicians, in vivo experimentation (frequently with mice models), and in vitro drug testing. Treatment decisions must be tailored to the clinical situation of each patient. For 24/7 treatment recommendations, diagnostic assistance, specimen collection guidance, and shipping instructions, please contact the CDC Emergency Operations Center at 770-488-7100.
Treatment for Granulomatous Amebic Encephalitis (GAE) and Disseminated Disease Caused by Acanthamoeba spp. Four drugs, given together, have been successfully used to treat a few cases of granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp.: pentamidine (intravenous), sulfadiazine (oral), flucytosine (oral), and fluconazole (intravenous or oral). Although pentamidine has good amebicidal activity in vitro and has been used successfully in the past in combination with the drugs listed above, it is very toxic and does not cross the normal, intact blood-brain barrier well; the decision to use it depends on clinical judgment. Adverse reactions associated with pentamidine include but are not limited to severe hypotension, hypoglycemia, acute pancreatitis, cardiac arrhythmias, impaired renal function, elevated liver function tests, and leukopenia. Other reports of successful therapy have described the use of co-trimoxazole, rifampicin, oral and topical ketoconazole, and skin lesion cleansing with chlorhexidine. Miltefosine (oral) might also be of some value in treating Acanthamoeba GAE and skin lesions. Miltefosine was approved in the United States for the treatment of leishmaniasis in March 2014 and is now commercially available. (NOTE: this review does not cover Acanthamoeba keratitis.)
Treatment for Granulomatous Amebic Encephalitis (GAE) Caused by Balamuthia mandrillaris. A few patients have survived Balamuthia GAE following treatment with multidrug combinations of pentamidine (intravenous), sulfadiazine (oral), flucytosine (oral), fluconazole (intravenous or oral), itraconazole (oral) and either azithromycin (intravenous or oral) or clarithromycin (oral), with or without surgical resection of the CNS lesions. Although pentamidine has good amebicidal activity in vitro and has been used successfully in the past in combination with the drugs listed above, it is very toxic and does not cross the normal, intact blood-brain barrier well; the decision to use it depends on clinical judgment. Miltefosine (oral) might also be of some value in treating Balamuthia infections. Miltefosine was approved in the United States for the treatment of leishmaniasis in March 2014 and is now commercially available.
Treatment for Primary Amebic Meningoencephalitis (PAM) Caused by Naegleria fowleri. Although most cases of PAM have been fatal, there have been five well-documented survivors whose treatment included combinations of amphotericin B (conventional formulation, intravenous, and intrathecal), rifampin (intravenous or oral), fluconazole (intravenous or oral), and azithromycin (intravenous or oral). Two U.S. survivors in 2013 also received miltefosine in addition to the previously listed drugs. Miltefosine was approved in the United States for the treatment of leishmaniasis in March 2014. As of December 2015, it is still not commercially available in the United States and can be obtained through the Centers for Disease Control and Prevention (CDC) for the treatment of free-living ameba infections.
Are there issues of anti-infective resistance?
There are not issues of anti-infective resistance for any of the free-living amebae.
What are the clinical manifestations of infection with these organisms?
Key Symptoms of the Disease – Acanthamoeba spp. and Balamuthia mandrillaris can affect a variety of organ systems, including the skin, sinuses, central nervous system (CNS) and, in the case of Acanthamoeba, the eyes (NOTE: this review does not cover Acanthamoeba keratitis). In the CNS, Acanthamoeba and Balamuthia cause chronic granulomatous amebic encephalitis (GAE). GAE usually has an insidious onset with mild symptoms that progress in severity over weeks to months. Neurologic symptoms can include lethargy, personality changes, confusion, headaches, neck stiffness, photophobia, diplopia, nausea, vomiting, and low-grade fever. GAE may be preceded by skin lesions months before CNS involvement is evident. Amebic sinusitis and osteomyelitis have also been documented. Disseminated acanthamoebiasis and balamuthiasis involving multiple organ systems can occur. Disseminated acanthamoebiasis may or may not include CNS involvement, whereas all documented cases of disseminated balamuthiasis in the United States have involved the CNS. If Naegleria fowleri infects the CNS, it causes primary amebic meningoencephalitis (PAM). PAM has an acute symptom onset with a rapid deterioration and death within 5 days on average (range 1–12 days). Initial PAM symptoms usually include a sudden onset of headaches, high fever, nausea, and vomiting. Irritability, restlessness, lethargy, personality changes, and confusion can also occur as can photophobia, diplopia, and disturbances of smell and taste. PAM symptoms are not distinguishable from those seen in acute meningitis of other causes. PAM is not associated with skin lesions.
Key Physical Findings of the Disease -Signs of granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris may include nuchal rigidity, seizures, altered mental status, and focal neurologic deficits, such as cranial nerve palsies, hemiparesis, impaired speech, and ataxia or other cerebellar signs. Amebic skin lesions may appear as nodules, ulcers, or abscesses. Acanthamoeba lesions tend to be scattered on the trunk and extremities. Balamuthia lesions can be on the face (including oral cavity), torso, or limbs and are more likely than Acanthamoeba lesions to be solitary. (NOTE: this review does not cover Acanthamoeba keratitis) Signs of primary amebic meningoencephalitis (PAM) due to Naegleria fowleri may include nuchal rigidity, Kernig’s and Brudzinski’s signs, altered level of consciousness, and seizures. Third, fourth, and sixth cranial nerve palsies may indicate brain herniation.
Do other diseases mimic its manifestations?
Major Diseases that Can Mimic this Parasitic Disease -The differential diagnosis of granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia
mandrillaris includes brain tumor, lymphoma, stroke, vasculitis, abscess, TB or fungal meningoencephalitis, neurocysticercosis, toxoplasmosis, and acute disseminated encephalomyelitis. The differential diagnosis of primary amebic meningoencephalitis (PAM) due to Naegleria fowleri includes bacterial and viral meningitis.
What laboratory studies should you order and what should you expect to find?
Results consistent with the diagnosis:
Cerebrospinal fluid (CSF) – CSF testing may assist in diagnosis, particularly with primary amebic meningoencephalitis (PAM) due to Naegleria fowleri. With PAM, Naegleria trophozoites are usually present in the CSF. CSF opening pressure is usually elevated (300-600 mm H2O). The CSF typically shows a polymorphonuclear pleocytosis (300-26,000 cells/mm3). CSF protein is usually elevated, and glucose generally ranges from normal to very low. In granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris, amebae are rarely observed in the CSF. With GAE, the CSF usually shows a moderate lymphocytic pleocytosis, typically <500 cells/mm3. There are generally none to a few RBCs. CSF protein is sometimes normal but more often elevated, and glucose is usually normal or low. CSF opening pressure in GAE cases is generally normal or mildly elevated.
Results that confirm the diagnosis
Cerebrospinal Fluid (CSF). In cases of primary amebic meningoencephalitis (PAM) due to Naegleria fowleri, a wet mount of fresh centrifuged CSF sediment (not previously refrigerated or frozen) might demonstrate actively moving trophozoites. A CSF smear stained with Giemsa or Wright stains can show ameboid trophozoites with morphology typical of Naegleria. If Naegleria is identified in the CSF, the diagnosis of PAM should be subsequently confirmed with polymerase chain reaction (PCR) testing of the CSF.
Biopsy Tissues. The diagnosis of granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris or primary amebic meningoencephalitis (PAM) due to Naegleria fowleri can be made by microscopic examination of tissue sections from relevant biopsy specimens (brain, skin, sinus, etc.) using immunohistochemical staining techniques or polymerase chain reaction (PCR).
Histopathology and Host Defense Responses. In cases of granulomatous amebic encephalitis (GAE), Acanthamoeba trophozoites destroy host nerve cells by cell lysis and phagocytosis. Additionally, Acanthamoeba secretes several enzymes that digest extracellular matrix proteins in connective tissue, which in turn may facilitate the invasion and spread of amebae. Acanthamoeba activates the alternative complement pathway, which stimulates neutrophils to release lysosomal enzymes and reactive oxygen intermediates to destroy the amebae. Macrophages, multinucleated giant cells, and brain microglial cells might also play a role in killing Acanthamoeba, likely contact-dependent. This cell-mediated immunity results in granulomatous reactions within the CNS in many of the GAE cases. Multinucleated giant cells forming granulomas are most often seen in immunocompetent patients but occur less commonly among immunocompromised patients. Generally, multinucleated giant cells are seen in the cerebral hemispheres, cerebellum, brainstem, mid-brain, and basal ganglion. Because amebae are thought to enter the body through the respiratory tract or broken skin and then spread hematogenously to other organs, including the brain, Acanthamoeba trophozoites and cysts are frequently found scattered throughout the CNS but are most commonly seen in the cerebral hemispheres, cerebellum, and brainstem. The amebae are commonly observed cuffing blood vessels along with polymorphonuclear leukocytes (PMNs). Many blood vessels are thrombotic with fibrinoid necrosis. Hemorrhagic infarcts may be present in the cerebral hemispheres, cerebellum, and brainstem. In general, the autopsied brain shows cerebral edema, softening of the cortical and basal ganglia, and multiple necrotic and hemorrhagic areas throughout the CNS tissue. Areas of necrotic tissue with lipid-containing macrophages and neovascularization suggesting tumors are also often observed. Balamuthia GAE produces a histopathologic profile similar to Acanthamoeba GAE, with hematogenous spread from the respiratory tract or skin to the CNS where it causes hemorrhagic necrosis, most frequently in the midbrain, thalamus, brainstem, and cerebellum. In primary amebic meningoencephalitis (PAM) due to Naegleria fowleri, the olfactory lobes are usually badly damaged and are typically hemorrhagic and necrotic with a purulent exudate. The cerebral hemispheres in PAM cases are usually soft and edematous and may show numerous superficial hemorrhages. A fibrino-purulent, leptomeningeal exudate may also be found throughout the cerebral hemispheres, cerebellum, brainstem, and the upper part of the spinal cord. On histologic examination, the hemorrhagic necrosis and destruction of brain tissue is accompanied by an infiltration of inflammatory cells, predominantly PMNs with some macrophages and lymphocytes, which are present in a fibrino-purulent exudate noted previously. Large numbers of N. fowleri trophozoites can be found in groups, without PMNs, within edematous and necrotic areas of tissue and in the Virchow-Robin spaces, usually around blood vessels in the absence of an inflammatory response. Naegleria trophozoites invade the CNS from superficial areas towards deeper tissue, progressing from subarachnoid spaces and along the Virchow-Robin spaces deep into the white matter and basal ganglia. N. fowleri cysts are not found in the CNS.
What imaging studies will be helpful in making or excluding the diagnosis of these infections?
Imaging Studies. In cases of granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris, a magnetic resonance imaging (MRI) scan of the brain may show single or multiple lesions, even when a computed tomography (CT) scan is initially unremarkable. Lesions typically are of low density, unifocal or multifocal, with peripheral ring enhancement and mass effect. Over time, lesions increase in size and number to involve the cerebral hemispheres, cerebellum, brainstem, and thalamus. Hydrocephalus and/or edema may also be present. Because amebae are frequently found in perivascular areas, cerebral vasculitis is commonly observed. CT and MRI scans may indicate hemorrhages within lesions, and angiography may demonstrate occluded blood vessels corresponding to areas of infarction. In cases of primary amebic meningoencephalitis (PAM) due to Naegleria fowleri, CT scans of the brain without contrast are often unremarkable or show only cerebral edema, but with contrast might show basilar meningeal enhancement. On rare occasions, a MRI scan of the brain might show small enhancing lesions.
What complications can be associated with these infections, and are there additional treatments that can help to alleviate these complications?
In the United States, the mortality rate is approximately 90% from GAE and >97% from PAM. The focus of treatment is survival. Additional treatments to alleviate complications if survival occurs are not well studied.
What is the life cycle of the parasite, and how does the life cycle explain infection in humans?
Parasite Life Cycle – Acanthamoeba, Balamuthia, and Naegleria life cycles
Parasite’s Stages of Development and Intermediate Hosts – Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri are ubiquitous micro-organisms living freely in the environment where they feed on other micro-organisms. They are not dependent on hosts for transmission and spread and are poorly adapted to parasitism because they almost always kill their human hosts. Host-to-host transmission does not occur with the exception of Balamuthia infection spreading from person to person through organ donation/transplantation. Humans and animals become infected when they inadvertently come in contact with these organisms in their environments. In nature, these amebae exist in two forms: trophozoites, which are motile and allow active feeding, and cysts, which are resistant to environmental conditions. Naegleria also has a transitory flagellate stage, believed to play a role in dispersing the amebae within their normal habitats.
Key Vectors for Transmission to Humans – None.
Seasonal Differences in the Incidence of Infection – In the United States, there appears to be no seasonal pattern to granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris. However, primary amebic meningoencephalitis (PAM) due to Naegleria fowleri tends to occur in the warm summer months, most commonly in July and August, when people are more likely to be exposed through swimming and other recreational activities in fresh water bodies, such as ponds and lakes.
Environmental Conditions that Predispose to this Infection – Transmission of free-living amebae occurs when a person comes in contact with the amebae in the micro-organisms’ habitat. Acanthamoeba spp. are found in soil, dust, fresh water (such as lakes, rivers, hot springs), brackish water (such as marshes), and sea water. They can also be found in swimming pools, hot tubs, drinking water systems (in slime layers in pipes and taps), as well as in heating, ventilating, and air conditioning (HVAC) systems and humidifiers. The ecology of Balamuthia mandrillaris is not as well defined as Acanthamoeba but the two types of amebae are thought to share similar habitats and Balamuthia mandrillaris has been isolated from soil. Granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris appears to result from hematogenous spread from the respiratory tract following inhalation of dust or aerosols containing the amebae or following exposure of broken skin to dust, soil, or water containing the amebae. Primary amebic meningoencephalitis (PAM) due to Naegleria fowleri is associated with warm fresh water exposure, such as lakes and ponds in warm months, geothermal water (such as hot springs), warm water discharged from industrial plants, swimming pools that are poorly maintained (minimally-chlorinated or un-chlorinated), and water heaters. N. fowleri has also been found in soil. PAM results when water containing N. fowleri gets up the nose, for example when people submerge their heads during recreational water activities, cleanse their nasal passages during religious practices, or irrigate their sinuses. The amebae then cross the cribriform plate along the olfactory tract and enter the central nervous system (CNS).
Prevalence of this Infection and Regions of the World Where It Is Most Prevalent – Granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris is rare but infections occur worldwide and there is no geographic pattern associated with GAE cases. In the United States, 144 cases of disease caused by Acanthamoeba spp. (excluding Acanthamoeba keratitis) were documented from 1955–2009 and 94 cases of GAE caused by Balamuthia mandrillaris were documented from 1974–2014. Like GAE, primary amebic meningoencephalitis (PAM) due to Naegleria fowleri is also rare and occurs worldwide. Unlike GAE, PAM does have a geographic pattern in the United States, occurring most commonly in southern-tier states. However, PAM was diagnosed for the first time in Minnesota in 2010, suggesting the geographic range might be changing. From 1962–2014, 133 cases of PAM were documented in the United States.
Human Populations Most Susceptible to this Infection – Granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. occurs at any age, most commonly among males and most commonly among immunocompromised individuals. Balamuthia GAE also occurs at any age, most commonly among males. However, patients can be either immunocompromised or immunocompetent. Hispanic ethnicity appears to be a risk factor for Balamuthia GAE but the reason for this is unclear. Primary amebic meningoencephalitis (PAM) due to Naegleria fowleri can occur at any age but is more common among young immunocompetent males with a median age of 12 years.
Incidence of this Infection -In the United States, diseases caused by the free-living amebae are not nationally notifiable and surveillance for granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris and for primary amebic meningoencephalitis (PAM) due to Naegleria fowleri is limited. Each year, 0–12 cases of non-keratitis Acanthamoeba disease, 0–8 cases of Balamuthia GAE, and 0–8 cases of PAM have been documented.
Infection Control Issues – Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri infection control issues – None
Recommended Anti-Infective Prophylaxis -None.
Recommended vaccine – None.
Strategies for Avoiding Exposure to the Vector -Diseases caused by free-living amebae are not vector-borne. It is unclear what steps an individual can take to prevent granulomatous amebic encephalitis (GAE) due to Acanthamoeba spp. or Balamuthia mandrillaris. The transplant community should be aware that transmission of B. mandrillaris infection has occurred via organ transplantation from an infected donor. Transplant transmission of Acanthamoeba spp. has not been confirmed but cases of acanthamoebiasis have been documented among organ and bone marrow transplant recipients. There is no treatment regimen for Balamuthia GAE that has been consistently successful, no prophylactic chemotherapy for this disease that has been defined, and no screening test for donated organs. Therefore, the risks of transplantation with one or more organs possibly harboring B. mandrillaris from donors with diagnosed Balamuthia GAE or central nervous system (CNS) pathology of unknown etiology should be carefully weighed for each individual organ recipient against the risks of delaying transplantation while waiting for other suitable organs. For primary amebic meningoencephalitis (PAM) due to Naegleria fowleri, recreational water users should assume that there is always a low level of risk whenever they enter warm freshwater lakes, rivers, and hot springs (for example, when swimming, diving, or waterskiing), particularly in southern-tier states. The only certain way to prevent PAM due to recreational water use is to refrain from water-related activities in warm freshwater. Personal actions to reduce the risk of PAM should focus on limiting the amount of water going up the nose and lowering the chances that N. fowleri might be in the water. These include holding the nose shut, using nose clips, keeping the head above water, avoiding freshwater during periods of high water temperatures or low water levels, and avoiding stirring up sediment in warm shallow freshwater areas. PAM has also been associated with nasal irrigation using drinking water. Persons cleansing their noses during religious practices or irrigating their sinuses should use water that has been previously boiled for 1 minute (at elevations above 6,500 feet, boiled for 3 minutes) and left to cool, filtered with an absolute pore size of 1 micron or smaller, or purchased with a label specifying that it is distilled or sterile.
Ways to Eliminate the Vector or Interrupt Its Life Cycle – Diseases caused by free-living amebae are not vector-borne. Free-living amebae are naturally occurring in the environment. Therefore, there are no ways to eliminate the vector or interrupt its life cycle.
How do these organisms cause disease?
Key Virulence Factors that Allow the Pathogen to Colonize, Spread from Person to Person, Invade Tissue, and Cause Tissue Destruction – The mechanisms of pathogenicity of the free-living amebae remain poorly defined. Some possible virulence factors are listed here. Acanthamoeba virulence factors include amoebostomes, cysteine and serine proteases, metalloproteinases, phospholipase, induction of programmed cell death (apoptosis) in target cells, and the presence of a 136-kDa mannose-binding protein on the surface of the ameba. Since immunosuppressed individuals may lack T-lymphocytes and macrophages and have impaired cell-mediated immunity, Acanthamoeba is able to proliferate and damage the central nervous system (CNS) and other tissues. Possible Balamuthia virulence factors are not as well defined but perhaps include amoebostomes, metalloproteinases, contact-dependent lysis of host cells, and destruction of the extracellular matrix thus facilitating the penetration of Balamuthia into the brain parenchyma. Balamuthia stimulates IL-6 production and release in the host, which alters the blood-brain barrier facilitating movement of leukocytes (and perhaps Balamuthia) across this barrier. Naegleria fowleri virulence factors include amoebostomes, pore-forming protein, phospholipase A, lysophospholipase, neuraminidase, elastase, cysteine proteases, induction of programmed cell death (apoptosis) in target cells, and resistance to complement-mediated lysis.
How Virulence Factors Explain the Clinical Manifestations – Various possible virulence factors have been reported for Acanthamoeba. Several species of Acanthamoeba produce food cups (amoebostomes) on their surface that engulf cell fragments and aid in phagocytosis. Secreted cysteine and serine proteases and metalloproteinases digest extracellular matrix proteins like collagen, fibronectin, and laminin in connective tissue and may facilitate the invasion of the CNS. The 136 kDa mannose-binding protein adheres to mannose glycoproteins on the surface of the epithelial cells, facilitating the invasion and destruction of the tissue. Serine protease might also destroy immunoglobulins attacking the amebae. Phospholipase might also be secreted to act on cell membranes and facilitate lysis. Additionally, Acanthamoeba trophozoite secretions appear to mediate lysis of target cells by inducing programmed cell death (apoptosis), as indicated by membrane blebbing and by DNA fragmentation and “laddering” (DNA molecules of different length). Little information is available about possible Balamuthia mandrillaris virulence factors. Recent studies have indicated that B. mandrillaris, like Acanthamoeba, might degrade extracellular matrix proteins and secrete metalloproteinases. Balamuthia might also produce amoebostomes. Naegleria fowleri seems to lyse cells on contact and then ingest cell debris using amoebostomes. A variety of secreted proteins appear to play a role in cell lysis, including a pore-forming protein that creates a hole in the target cell membrane, depolarizing the membrane potential and facilitating cell lysis. N. fowleri also secretes phospholipase A, lysophospholipase, and neuraminidase, which contribute to glycolipid and phospholipid alterations in target cell membranes. Other potentially destructive secreted enzymes include elastase and cysteine proteases that can degrade a variety of connective tissue and extracellular matrix proteins. Like Acanthamoeba, N. fowleri can also trigger apoptosis in target cells. The N. fowleri trophozoite also appears to have surface proteins that resist complement-mediated lysis of the ameba and can form and release surface membrane vesicles to remove any membrane attack complex (MAC) of complement that attaches to the surface of the ameba.
WHAT’S THE EVIDENCE for specific management and treatment recommendations?
Visvesvara, GS, Moura, H, Schuster, FL. “Pathogenic and opportunistic free-living amoebae: spp., , , and “. FEMS Immunol Med Microbiol. vol. 50. 2007. pp. 1-26.
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- OVERVIEW: What every clinician needs to know
- Parasite name and classification
- What is the best treatment?
- Are there issues of anti-infective resistance?
- What are the clinical manifestations of infection with these organisms?
- Do other diseases mimic its manifestations?
- What laboratory studies should you order and what should you expect to find?
- What imaging studies will be helpful in making or excluding the diagnosis of these infections?
- What complications can be associated with these infections, and are there additional treatments that can help to alleviate these complications?
- What is the life cycle of the parasite, and how does the life cycle explain infection in humans?
- How do these organisms cause disease?