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

The free-living amebae Naegleria fowleri,¹ Acanthamoeba species, and Balamuthia mandrillaris² cause extremely rare and sporadic CNS infections, which were first described in 1965. Typically, N fowleri produces primary amebic meningoencephalitis (PAM), which is clinically indistinguishable from acute bacterial meningitis. The other amebae cause granulomatous amebic encephalitis (GAE), which is a more subacute or chronic infection. The presentation of GAE can mimic a brain abscess, aseptic or chronic meningitis, or CNS malignancy.

Pathophysiology

Although it is ubiquitous in most soils and environments, N fowleri can also be found in warm, particularly stagnant, freshwater.³ PAM is an exceptionally uncommon result of CNS invasion of the typically healthy host by N fowleri, following the very common exposure to the amebae. Especially in warmer months and climates, children younger than 2 years frequently carry the organism asymptomatically in their noses and throats. During a period of a few days to 2 weeks after swimming, diving, bathing, or playing in warm, usually stagnant, freshwater, the N fowleri amebae migrate through the cribriform plate, along the fila olfactoria and blood vessels, and into the anterior cerebral fossae, where they cause extensive inflammation, necrosis, and hemorrhage.

In contrast, GAE apparently results from either acanthamebic keratoconjunctivitis, which is the uncommon spread of the amebae from the cornea into the CNS, or from hematogenous spread of all of these ubiquitous organisms (eg, Acanthamoeba species, Balamuthia species) from primary inoculation sites in the lungs or skin into the CNS, where abscesses and focal granulomatous infections result. These infections often occur in hosts who are debilitated or otherwise immunocompromised; however, GAE may also affect previously healthy hosts.

Frequency

United States

PAM and GAE are both extremely rare but continue to be reported. PAM is more common in warmer regions and in the warmer months of spring and summer.

International

More than 440 cases have been reported; although rare, cases of PAM and GAE have been reported worldwide, reflecting the ubiquity of the organisms. Most reports come from the United States, Australia, and Europe; this frequency is likely because of identification and reporting bias. In addition, a predominance of cases occurs in warmer climes and during warmer seasons of the year.

Mortality/Morbidity

These infections are nearly uniformly fatal. Only 5 survivors of PAM have been reported;⁴ this represents approximately 3% of reported cases. The high mortality rate is likely because of the difficulty of diagnosis and poor-to-marginal response to therapy. In most individuals with PAM or GAE, diagnosis is made after their deaths.

Race

PAM and GAE demonstrate no particular ethnic or racial predilection.

Sex

• The male-to-female ratio of PAM is 2:1.
• The male-to-female ratio of GAE is 5:1.

Age

• PAM has been reported in infants as young as 4 months and is most commonly observed in the first 3 decades of life.
• Although persons of all ages are affected by GAE, this infection appears to occur more commonly in individuals at the extremes of age.

CLINICAL

Section 3 of 10  

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

History

The history seldom helps to differentiate these infections from other CNS diseases.

• Primary amebic meningoencephalitis (PAM)
• • PAM commonly affects children and young adults who have previously been healthy.
  • This disease occurs more often during the warmer months of the year and in warmer climates.
  • Patients with PAM may have a history of swimming, diving, bathing, or playing in warm, generally stagnant, freshwater during the previous few days to 2 weeks.
  • Rarely, patients with PAM may experience disordered smell or taste.
  • Most often, the symptoms of PAM are indistinguishable from acute bacterial meningitis.
  • Acute onset of PAM occurs over hours to 1-2 days.
  • Symptoms of PAM include high fever, headache, photophobia, stiff neck, nausea, and vomiting.
  • Additional symptoms include confusion, somnolence, seizures, and coma.
  • Infection may rapidly progress.
• Granulomatous amebic encephalitis (GAE)
• • GAE affects individuals of all ages, although very young or very old persons may be more susceptible.
  • Persons with debility or immunocompromise may be more susceptible to GAE.
  • GAE occurs throughout the year because the causative organisms are ubiquitous.
  • Individuals with GAE may have keratoconjunctivitis or a skin ulcer or lesion.
  • A subacute or chronic presentation of GAE lasting days or weeks is most common.
  • GAE must be differentiated from brain abscess or tumor and aseptic or chronic meningitis.
  • Typical symptoms include low-grade fever and focal neurologic signs, including cranial nerve palsies, hemiplegia, ataxia, aphasia, diplopia, and seizures.
  • Patients with GAE may exhibit behavioral changes, stiff neck, signs of increasing intracranial pressure (ICP), stupor, or coma.
  • Progression varies; occasionally, patients survive for weeks or months.

Physical

Physical examination seldom helps to differentiate these infections from other CNS diseases. Findings outside the neurologic examination are exceptional.

• PAM
• • Patients may experience abnormal smell or taste.
  • Other signs of PAM include high fever, photophobia, stiff neck, mental status changes, and seizures.
  • PAM infection may progress rapidly to evidence of increased ICP and cerebral herniation.
  • Rarely, myocarditis may occur, although amebae are not present in the myocardium.
• GAE
• • Individuals with GAE may have low-grade fever, photophobia, or stiff neck. Focal neurologic findings, such as cranial nerve palsies, hemiplegias, aphasias, ataxias, or diplopia, may be observed in addition to seizures, which may be focal.
  • Individuals with GAE may demonstrate signs of elevated ICP and cerebral herniation.
  • Keratoconjunctivitis, primarily in people who wear contact lenses, or skin lesions may rarely occur.

Causes

• PAM
• • Exposure to and carriage of free-living amebae appears to be common.
  • Although the cause is unclear, CNS invasion is exceptionally rare.
  • The protozoologic basis for CNS tropism remains to be fully elucidated.
  • Individuals with frequent exposure to warm, often stagnant, freshwater (eg, persons swimming in freshwater lakes, ponds, and pools during the summer months) are most at risk of infection with PAM.
• GAE
• • Exposure to and carriage of free-living amebae appears to be common.
  • Although the cause is unclear, hematogenous spread of GAE to the CNS from eye, skin, or lung portals of entry is exceptionally rare.
  • The protozoologic basis for CNS tropism remains to be fully elucidated.
  • The basis for the observed male preponderance in CNS infection is uncertain.
  • Hosts who are debilitated and immunocompromised appear to be most at risk, although hosts who are healthy can become infected as well.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Angiostrongylus cantonensis
Baylisascaris procyonis
Brain abscess
Cryptococcosis
Cysticercus cellulosae
Encephalitis
Intracranial hemorrhage
Sappinia diploidea

WORKUP

Section 5 of 10  

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

Lab Studies

• Primary amebic meningoencephalitis (PAM): Lumbar puncture for cerebrospinal fluid (CSF) analysis is the primary diagnostic tool.
• • CSF analysis is indistinguishable from that in acute bacterial meningitis, except that Gram stain is always negative.
  • A predominance of neutrophils is observed, with elevated protein levels, decreased glucose levels, and RBCs present.
  • If PAM is suspected, light microscopy with phase contrast on fresh, still-warm CSF may reveal motile trophozoites.
  • Recently, a triplex real-time polymerase chain reaction (PCR) assay for Naegleria, Acanthamoeba, and Balamuthia has been developed by the Centers for Disease Control and Prevention (CDC).⁵
• Granulomatous amebic encephalitis (GAE): Lumbar puncture for CSF analysis is the primary diagnostic tool.
• • CSF analysis typically demonstrates less inflammation than that observed in individuals with PAM.
  • Opening pressure is elevated.
  • CSF analysis mimics that of aseptic meningitis, with low-to-moderate, primarily mononuclear WBCs; elevated protein levels; and, often, near-normal or slightly decreased glucose levels.
  • No trophozoites appear in the CSF.
  • Recently, a triplex real-time PCR assay for Naegleria, Acanthamoeba, and Balamuthia has been developed by the CDC.⁵

Imaging Studies

• CT or MRI
• • Head CT scanning or MRI should precede lumbar puncture if evidence of focal CNS involvement or elevated ICP is present.
  • CT and MRI frequently reveal meningeal hyperemia and cerebral edema.
  • Imaging studies may reveal evidence of increased ICP or cerebral herniation.
  • In an individual with PAM, the olfactory bulbs, temporal lobes, and frontal lobes are involved; however, disease may be diffuse.
• In individuals with GAE, focal lesions are very common and may be found throughout the CNS.

Procedures

• A biopsy of focal granulomatous lesions in persons with GAE may assist in making the diagnosis.

Histologic Findings

• Biopsies or postmortem specimens from persons with PAM reveal the intense inflammation with invasion of polymorphonuclear leukocytes, hemorrhage, and necrosis typical of acute meningitis.
• Fluorescent antibodies may help to identify the numerous trophozoites present.
• In individuals with GAE, moderate granulomatous inflammation with prominent vascular involvement is typically present.
• Both trophozoites and cysts, which are less numerous, can be identified through the use of fluorescent antibodies.
• Recently, tissue-based PCR has been proposed as a diagnostic aid.⁵

TREATMENT

Section 6 of 10  

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

Medical Care

• Primary amebic meningoencephalitis (PAM)
• • Amebic meningitis is seldom diagnosed before an individual's death. Difficulties in diagnosis and rapid progression make this condition extremely difficult to treat. For this reason, aggressively pursue the diagnosis in the patient with CSF findings consistent with bacterial meningitis, with a history of water exposure, and in whom the CSF Gram stain is negative.
  • Typically, PAM infection proceeds as an overwhelming acute bacterial meningitis that is unresponsive to routine antibacterials.
  • The treatment of choice is amphotericin B, at maximally tolerated doses, with adjunctive rifampin and doxycycline. Successful treatment may also require intrathecal amphotericin B. Sulfisoxazole, phenothiazine, and qinghaosu may have some benefit. Studies have suggested some role for azithromycin as an adjunct to amphotericin B.^{6, 7} The effectiveness of these treatments remains unproven.
• Granulomatous amebic encephalitis (GAE): Ketoconazole and amphotericin B (alone or in combination) as well as sulfadiazine may be indicated.

Surgical Care

• PAM
• • PAM may require the placement of a reservoir for intrathecal amphotericin B or miconazole.
  • Hydrocephalus may necessitate shunting.
• GAE
• • Biopsy findings may permit diagnosis.
  • Excision of solitary or isolated lesions may benefit the individual with GAE.
  • Hydrocephalus may necessitate shunting.

Consultations

• Emergent consultations with infectious disease specialists, neurologists, and neurosurgeons are recommended if PAM or GAE is suspected.

MEDICATION

Section 7 of 10  

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

The goals of pharmacotherapy are to eradicate the infection, prevent complications, and reduce morbidity.

Drug Category: Amebicidal agents

Various amebicidal antibiotics and antifungals are used in combination and at maximal doses and, often, both parenterally and intrathecally. Manage elevated ICP and seizures as necessary. A recent case report suggests that oral combination therapy for Acanthamoeba meningitis may be successful, but this has not been reproduced.

Drug Name	Amphotericin B, lipid-based (Abelcet, AmBisome, Amphotec) [#Amphotericin B]
Description	Among the 3 lipid formulations, no data regarding therapeutic efficacy, safety, and dosing for these infections are available. No basis for choosing among them is recognized. Despite lack of data supporting use of these preparations for amebic meningoencephalitis, they are recommended because of dismal outcomes.
Adult Dose	Abelcet or AmBisome: 5 mg/kg/d or more (as tolerated) IV qd infused over at least 2 h Amphotec: 5-7.5 mg/kg/d IV, not to exceed infusion rate of 1 mg/kg/h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antineoplastic agents may enhance potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Closely monitor renal, hepatic, electrolyte, and hematologic status; hypercalciuria, hypokalemia, hypomagnesemia, renal tubular acidosis, renal failure, acute hepatic failure, hypotension, and phlebitis; common infusion-related reactions include fever, chills, headache, hypotension, nausea, and vomiting; may premedicate with acetaminophen and diphenhydramine 30 min before and 4 h after infusion

Drug Name	Rifampin (Rifadin IV)
Description	Amebicidal activity in vitro and synergistic with amphotericin B when administered IV. Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription.
Adult Dose	600 mg IV qd
Pediatric Dose	10-20 mg/kg/d IV divided q12-24h; not to exceed 600 mg/d
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; BP may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Obtain CBC counts and baseline clinical chemistries before and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Drug Name	Doxycycline (Vibramycin, Doxy)
Description	Amebicidal activity in vitro and is synergistic with amphotericin B when administered IV. Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Adult Dose	200 mg/d IV divided q12h
Pediatric Dose	5 mg/kg/d IV divided q12h; not to exceed 200 mg/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Sulfisoxazole (Gantrisin)
Description	Amebicidal activity in vitro and synergistic with amphotericin B. Sulfonamide derivative that exerts bacteriostatic action by antagonizing PABA, an essential component in folic acid synthesis.
Adult Dose	2 g/d PO divided q12h
Pediatric Dose	1 g/d PO divided q12h
Contraindications	Documented hypersensitivity
Interactions	May enhance warfarin effects and hemorrhage can occur; thiopental anesthetic effects may be enhanced; risk of nephrotoxicity may increase when administered concurrently with cyclosporine; serum hydantoin levels may increase when administered concurrently with sulfisoxazole; methotrexate-induced bone marrow suppression may be enhanced when administered concurrently with sulfisoxazole Coadministration with diuretics may increase incidence of thrombocytopenia with purpura; sulfonamides' free-drug concentration may be increased when administered concurrently with indomethacin; when used concomitantly with methenamine mandelate, sulfonamides may form precipitate in acidic urine; probenecid and salicylates may displace sulfonamides from plasma albumin resulting in increased free-drug concentrations potentiating its toxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Pregnancy category D near term (may cause kernicterus in the newborn); caution in hepatic or renal dysfunction; maintain hydration; fever, rash, hepatitis, systemic lupus erythematosus like syndrome, vasculitis, bone marrow suppression, hemolysis in G-6-PD deficiency, and Stevens-Johnson syndrome

Drug Name	Ketoconazole (Nizoral)
Description	Amebicidal imidazole is DOC for GAE, in combination with amphotericin B. Inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.
Adult Dose	800 mg/d PO divided q12h
Pediatric Dose	3.3-6.6 mg/kg/d PO divided q12h; not to exceed 800 mg/24h
Contraindications	Documented hypersensitivity; cisapride, terfenadine recalled from US market, or astemizole recalled from US market use
Interactions	Potent inhibitor of CYP450 3A4; cardiac arrhythmia may occur with cisapride, terfenadine, or astemizole; isoniazid may decrease bioavailability of ketoconazole; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Monitor LFTs in long-term use; may cause nausea, vomiting, rash, headache, pruritus, or fever

Drug Name	Sulfadiazine (Microsulfon)
Description	Amebicidal activity in vitro and is synergistic with ketoconazole, amphotericin B, or both. Exerts bacteriostatic action by competitive antagonism of PABA.
Adult Dose	4-6 g/d PO divided q6h
Pediatric Dose	100-200 mg/kg/d PO divided q6h
Contraindications	Documented hypersensitivity
Interactions	Increases effect of oral anticoagulants and oral hypoglycemic agents; effects are decreased when administered concurrently with PABA or PABA metabolites of drugs (eg, proparacaine, tetracaine, sunscreens, procaine)
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Pregnancy category D near term (may cause kernicterus in the newborn); caution in hepatic or renal dysfunction; maintain hydration; fever, rash, hepatitis, systemic lupus erythematosus like syndrome, vasculitis, bone marrow suppression, hemolysis in G-6-PD deficiency, and Stevens-Johnson syndrome

Drug Name	Azithromycin (Zithromax)
Description	Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Treats mild-to-moderate microbial infections. May have an adjunctive role with amphotericin B to treat GAE/PAM.
Adult Dose	Not established; typical adult dose is 500 mg PO on day 1, then 250 mg/d for days 2-5
Pediatric Dose	Not established; typical pediatric dose is 10-12 mg/kg/d PO
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized, geriatric, or debilitated patients

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Admit to the ICU for intensive monitoring and therapy.

Transfer

• Arrange transfer if appropriate specialists and resources are otherwise unavailable.

Complications

• Depending on the extent of CNS injury, complications vary among the rare survivors of these infections.

Prognosis

• Prognosis is abysmal, even with timely therapy.

Patient Education

• Routinely discuss the risks of exposure to free-living amebae in warm, typically stagnant, freshwater.
• Some have advocated the avoidance of diving and jumping into these waters.
• Advise individuals to consider the use of nose plugs for unavoidable exposures.
• Advise individuals to verify adequate chlorination of swimming pools.
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Brain Infection.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Failure to make the diagnosis of CNS infection
• Failure to consider the diagnosis of amebic meningoencephalitis when no response occurs to routine antibacterials for acute bacterial meningitis
• Failure to obtain a thorough history that would suggest the diagnosis of amebic meningoencephalitis

Special Concerns

• See the Gorgas Courses in Clinical Tropical Medicine for an interesting case.

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: Feb 7, 2008