Continuing Education Activity

Amebic encephalitis is a rare but lethal central nervous system infection caused by free-living amoebae found in freshwater, lakes, and rivers. There are two types of amebic encephalitis, namely primary meningoencephalitis (PAM) and granulomatous amebic encephalitis (GAE). The initial symptoms of PAM are indistinguishable from bacterial meningitis, while the symptoms of GAE can mimic a brain abscess, encephalitis, or meningitis. These infections are almost uniformly fatal. The mortality rate is above 90%, despite antimicrobial therapy. This activity discusses the role of the interprofessional team, describes the causative agent of amebic meningoencephalitis, its pathophysiology, the clinical presentation, and highlights measures of prevention.

Objectives:

• Review the causative agents of amebic encephalitis.
• Describe the clinical presentation of amebic encephalitis and plan the diagnostic evaluation and treatment.
• Summarize the treatment and management options available for amebic encephalitis.
• Outline the measures to prevent the disease and the treatment by the interprofessional team that will decrease the number of cases and improve outcomes.

Introduction

Free-living amebas are protozoan environmental parasites, mainly in freshwater, lakes, and rivers, without needing a definitive host.[1] In humans, there are four main genera of amebas that can cause disease, namely Naegleria (only Naegleria fowleri), Acanthamoeba (several species), Sappinia (only S. pedata), and Balamuthia (only Balamuthia mandrillaris).[2] The amebas have a propensity to cause central nervous system infections, but Acanthamoeba is well-known to cause keratitis and disseminated infections as well.[1][3]

These free-living amebas can cause two distinct clinical syndromes, primary amebic meningoencephalitis (PAM) and granulomatous amebic encephalitis (GAE). The initial symptoms of PAM are indistinguishable from bacterial meningitis, while the symptoms of GAE can mimic a brain abscess, encephalitis, or meningitis. These infections are almost uniformly fatal. The mortality rate is above 90%, despite antimicrobial therapy.[4]

Etiology

Primary amebic meningoencephalitis (PAM) is caused by Naegleria fowleri, a thermophilic, free-living ameba that lives in temperatures above 30 C and can tolerate temperatures up to 45 C. This protozoan parasite is found in the soil and freshwaters, such as ponds, lakes, rivers, streams, hot springs, and unchlorinated swimming pools. Risk factors for infection include swimming, diving, waterskiing, surfing, and exposure to hot springs. The use of tap water for nasal irrigation has also been reported as a risk factor for the disease.[1][3]

Granulomatous amebic encephalitis (GAE) is a subacute to chronic infection of the CNS caused by Acanthamoeba species such as A.culbertsoni, A. polyphagia, A.castellani, A.astronyxis, A.hatchetti, A.rhysodes, A. divionensis, A.lugdunensis, A. lenticulata, and A. haely, and B. mandrillaris. Acanthamoeba is found in soil as well as brackish water, sewage, and humidifiers.[1][3]

Epidemiology

PAM and GAE are very rare disease processes, with only 3.7 cases reported per year worldwide. PAM is more common in warmer regions, such as the southern part of the United States, and generally occurs in the warmer months of spring and summer, possibly due to the increased likelihood of participation in waterborne activities. The mean age of patients affected by PAM was 12 years (range from eight months to 66 years); 79% were males.[5][6][7][8]

Pathophysiology

PAM occurs in healthy young individuals exposed to warm freshwater. Naegleria fowleri infects susceptible individuals when contaminated water enters the body through the nose. Trophozoites penetrate the olfactory mucosa, cross the cribriform plates, and ultimately reach the olfactory bulb and cause the inflammatory reaction and the parenchymal damage associated with PAM.[7] 

GAE occurs when the infective form of Acanthamoeba, the trophozoites, enters the body through the eyes, nasal passages, and respiratory tract or ulcerated skin. Once it gains entry, the parasite invades the central nervous system by hematogenous dissemination resulting in GAE. Once in the central nervous system, the parasite stimulates abscess and focal granuloma formation. Disseminated disease, skin disease, and keratitis can also occur.[9]

Histopathology

Naegleria fowleri has a 3 stage life cycle: amoeboid trophozoites, flagellate, and cysts. Hostile environmental changes can cause the trophozoites to change to the flagellated form, and the parasite will revert when conditions improve. Naegleria fowleri trophozoites are found in cerebrospinal fluid (CSF) and tissue, and occasionally, flagellated forms may be noted in the CSF. Cysts are not seen in brain tissue.[1][3]

On the contrary, Acanthamoeba exists in only two forms, cysts and trophozoites. The trophozoites are the infective forms. Both Acanthamoeba spp. cysts and trophozoites are found in tissue.[3]

History and Physical

Patients with PAM typically present acutely with fever, severe headache, photophobia, nausea, vomiting, behavioral abnormalities, seizures, and altered mental status. A history of olfactory and taste abnormalities is frequently associated with PAM. Patients with PAM typically have a history of swimming, diving, bathing, or playing in warm, generally stagnant freshwater during the previous 1 through 9 days. On physical examination, meningismus and cranial nerve palsies can be seen.[10] The disease progresses rapidly with increased intracranial pressure leading to uncal herniation and death.[8]

The clinical presentation of GAE differs from that of PAM considerably. GAE presents as a subacute to chronic disease process with weeks to months of progressive headache, low-grade fevers, visual disturbances, behavioral abnormalities, and focal neurologic deficits. Ultimately, the patient develops increased intracranial pressure, seizures, coma, and death.[8] Among patients with HIV, focal neurologic lesions mimicking toxoplasma encephalitis have also been reported.[11]

Evaluation

Lumbar puncture for cerebral spinal fluid (CSF) analysis is the primary diagnostic tool for PAM, whereas tissue diagnosis is essential for GAE. Unfortunately, amebic meningoencephalitis is very rarely diagnosed before autopsy. Laboratory findings suggestive of PAM include leukocytosis with a left shift. The CSF opening pressure is very high. The cerebrospinal fluid (CSF) white cell count ranges from 300 to 26,000 cells/mm with polymorphonuclear predominance. CSF red blood cells are usually seen, and hemorrhagic fluid is seen as the disease progresses. Hypoglycorrhachia and elevated protein are characteristic.

A definitive diagnosis is made by observation of motile trophozoites on centrifuged CSF wet mount preparation. Giemsa or trichrome stains help in identifying morphologic features of the trophozoites. The diagnosis can also be made by using laboratory testing for Naegleria fowleri nucleic acid in CSF, biopsy, or tissue specimens or Naegleria fowleri antigen in CSF, biopsy, or tissue specimens.

To establish the diagnosis of GAE, brain tissue demonstrating trophozoites and cysts is needed. Moderate granulomatous inflammation with prominent vascular involvement is typically present on brain biopsy. CSF parameters show mild pleocytosis with lymphocytic predominance, high protein concentration, and low or normal glucose concentration. Rarely, Acanthamoeba trophozoites may be seen on the Giemsa stain of the CSF sediment. Head computed tomography (CT) scanning or magnetic resonance imaging (MRI) should precede lumbar puncture if clinical signs of focal CNS involvement or elevated intracranial pressure (ICP) are present.

Magnetic resonance imaging of the brain shows the presence of single or multiple space-occupying lesions with ring enhancement. Computed tomography may show progressive hydrocephalus, meningeal thickening, pseudotumoral lesions, largely isolated lesions, or multifocal ring-enhancing lesions. On post-mortem examination, significant edema and hemorrhage of the brain are seen.[12][13][14]

Treatment / Management

Due to the rarity of the disease and lack of clinical trials, the definitive treatment for GAE is not clear at this time. A combination of drugs is used. The Centers for Disease Control and Prevention recommend combination treatment with pentamidine, sulfadiazine, flucytosine, and either fluconazole or itraconazole. Multiple other regimens are also recommended. Chronic Acanthamoeba meningitis was successfully treated in 2 children with a combination of oral trimethoprim/ sulfamethoxazole, rifampin, and ketoconazole. Resection of brain lesions may help as well.[12][13][14]

Similarly, the optimal treatment of PAM is unknown; reports range from 9 to 30 days. For the treatment of PAM amphotericin B, both intravenously and intrathecally is recommended, but considering the fulminant course of the disease and high mortality rates, a combination of drugs is generally used. Reports include the use of amphotericin in addition to rifampin, fluconazole, miltefosine, and azithromycin. Posaconazole has also been shown to be effective in mouse models of disease. It may replace fluconazole as the azole of choice, although further studies are warranted to confirm this choice.[12][13][14]

Only one case of GAE due to Sappinia has been reported in humans (attributed to S. diploidea).[15] The patient was a previously healthy male farmer who engaged in handling livestock. The disease manifested as headache, vomiting, blurry vision, and loss of consciousness following a sinus infection. Histopathology of a single 2 cm focal lesion in the posterior left temporal lobe demonstrated trophozoites (40 to 60 microns in diameter) with two nuclei. The infection was likely acquired by inhalation. He was treated with a combination of flucytosine (2.75 g four times a day for 25 weeks), itraconazole (200 mg/day), intravenous pentamidine isethionate (300 mg/day for six weeks), and azithromycin (250 mg/day for 31 weeks). The treatment resulted in complete recovery.

Differential Diagnosis

The clinical presentation of PAM is very similar to acute bacterial meningitis, and CSF parameters are also alike. Therefore, obtaining an epidemiological history in patients with suspected bacterial meningitis but negative cultures and failure to improve cannot be emphasized enough.[8]

The differential diagnosis of GAE includes bacterial brain abscesses, tuberculosis, Nocardia, CNS aspergillosis, cryptococcosis, and Histoplasma. Toxoplasmosis and cysticercosis, as well as CNS lymphoma, should be considered.[8]

Treatment Planning

Table 1. Drugs for primary amebic meningoencephalitis

Prognosis

PAM is associated with an extremely high mortality rate. Studies have reported a case-fatality rate of as high as 99%. The mean time from onset of symptoms to death was 5.3 days (range from 1 to 12 days), and the mean time from exposure to death was 9.9 days (range from 6 to 17 days).

Complications

• Hallucinations
• Seizures
• Comma
• Death

Consultations

The patient is managed by emergency physicians, internists, and infectious disease consultants.

Deterrence and Patient Education

Measures to prevent primary amebic meningoencephalitis due to Naegleria include the following:

• Avoidance of diving and jumping into stagnant freshwater.
• Consider using nose plugs for unavoidable exposures or pinching your nose shut when diving or swimming in freshwater.
• Keep your head above water when swimming in freshwater, hot springs, and other untreated thermal bodies of water.
• When participating in water-related activities, avoid digging, or stirring up, the sediment.
• Use boiled, filtered, or sterile water for nasal or sinus irrigation, not tap water. 

Measures to prevent GAE and keratitis due to Acanthamoeba include:

• Replace contacts as prescribed.
• Remove lenses before activity involving contact with water.
• Wash hands with soap before handling contact lenses and clean lenses as instructed by the manufacturer.

Pearls and Other Issues

• Patients with PAM typically have a history of swimming, diving, bathing, or playing in warm, generally stagnant freshwater during the previous 1 to 9 days.
• GAE presents as a subacute to chronic disease process with weeks to months of progressive headache, low-grade fevers, visual disturbances, behavioral abnormalities, and focal neurologic deficits.
• Two patterns of clinical presentation have been described with Balamuthia mandrillaris. While some patients present with an initial skin lesion followed by neurologic manifestations in weeks or months, others present with CNS involvement. The skin lesion consists of an asymptomatic nonulcerated plaque, most commonly on the central face or the knee area. Wide resection of the skin may prove to be therapeutic.
• A definitive diagnosis of PAM is made by observation of motile trophozoites on centrifuged CSF wet mount preparation.
• Approximately 11 survivors of PAM have been reported in the literature.[16][17]

Enhancing Healthcare Team Outcomes

Amebic encephalitis is an exceptionally rare and highly lethal central nervous system infection caused by free-living amoebae found in freshwater, lakes, and rivers. There are two types of amebic encephalitis: primary amebic meningoencephalitis and granulomatous amebic encephalitis. The initial symptoms of PAM are indistinguishable from bacterial meningitis, while the symptoms of GAM can mimic a brain abscess or meningitis.

These infections are almost always fatal. The high mortality rate is due to a lack of optimal treatment, the rarity of the disease, and delays in diagnosis. 

Clinicians working in communities with potential exposure to large stagnant bodies of freshwater should play a role in educating patients about the risk and providing information about how to mitigate the risk. If the disease is being considered in the differential diagnosis of a patient, early laboratory evaluation and emergent consultations with infectious disease specialists, neurologists, and neurosurgeons are recommended to facilitate prompt diagnosis and treatment. 

Patients with amebic meningoencephalitis may require monitoring in the intensive care unit. A hypothermia protocol may be considered as this has been shown to increase survival. An interprofessional healthcare team, including intensivists, infectious disease specialists, nurses, social workers, and pharmacists (specialized in infectious disease), may help facilitate family support and provide updates regarding the condition and prognosis of the patient. Intensive care nurses monitor patients and notify the team of status changes. The few reported survivors have been left with severe neurological disabilities and sequelae of encephalitis. Infectious disease pharmacists review treatment protocols, assess microbial susceptibility to the regimen chosen, and check for drug-drug interactions, reporting their findings to the prescribing/ordering clinician. This interprofessional model will increase the odds of improved patient outcomes, despite the bleak prognosis. [Level 5]